Patent Application
20110105544
The invention relates to compounds of general formula (I), or pharmaceutically acceptable salts, which possess anti-proliferative activity and are therefore useful in methods of treatment of cancer.
Cancer is a class of diseases or disorders characterized by uncontrolled division of cells and the ability of these cells to invade other tissues, either by direct growth into adjacent tissue through invasion or by implantation into distant sites by metastasis (in which cancer cells are transported through the blood or lymphatic system).
There are a series of types of cancer and the severity of symptoms depends on the site and character of the malignancy and the presence or absence of metastasis. Most cancers can be treated and some cured, depending on the specific type, location, and stage. The current therapies include surgery, chemotherapy, immunotherapy, hormone therapy, radiation therapy, and other treatment methods such as e.g. bone marrow transplantation, photodynamic therapy, and gene therapy.
The unregulated growth that characterizes cancer is caused primarily by damage to DNA, resulting in mutations of genes that encode proteins controlling cell division, apoptosis, and angiogenesis. Mutations are in general caused upon chemical or physical agents termed carcinogens, by close exposure to radioactive materials, or by certain viruses such as Human Papilloma Virus (HPV) or Epstein-Barr Virus (EBV), amongst others. Mutations occur spontaneously, or are hereditary and passed down generations as a result of germ line mutations.
Many forms of cancer are associated with exposure to environmental factors such as tobacco smoke, radiation, alcohol, and tumour-associated viruses. While some of these can be avoided, there is no known way to entirely avoid the disease.
Hence, cancer is still one of the leading causes of death in developed countries. In some Western countries, cancer is overtaking cardiovascular disease as the leading cause of death in spite of improved surgery and radiochemotherapy. In the last decades great efforts have been made to understand the molecular basis of cancer and to develop new therapies. As cancer has often a great impact on life quality of the patients and may lead to life threatening, there is still a need for developing new therapeutic agents with improved properties.
The present inventors have found that the compounds of formula (I) has anti-proliferative activity. Owing to this anti-proliferative activity the compounds of the present invention are useful in the treatment of cancer.
Surprisingly, the inventors have found that the compounds of general formula (I) show a good anti-proliferative activity, being efficient in the treatment of cancer.
Thus, in a first aspect the present invention relates to a compound of general formula (I), or a pharmaceutical acceptable salt thereof, or a solvate thereof including a hydrate, or any stereoisomer or mixture of stereoisomers:
wherein:
R1 is a radical derived from one of the known ring systems selected from the group consisting of:
It is remarkable that the aromatic nature of both R1 and R2 enhances the activity of the compounds of the present invention as it is shown below. For this reason, it is important that R1 has aromatic nature (in addition to R2 which is phenyl optionally substituted), specially when R1 is a 2-fused ring system: it is necessary that at least one of the rings forming the system is aromatic in order to achieve the therapeutic effect. In fact, the inventors of the present invention believe that from the activity data obtained with the compounds of the present invention other useful compounds could be obtained which differed from those provided in the present application in that R2 is an aromatic ring having 5-6 carbon atoms (other than phenyl), being optionally one of said carbon atoms replaced by one N, O, or S atom; or a two fused ring system, wherein one of the rings is aromatic and the other is aromatic or partially insaturated, each ring has 5-6 carbon atoms, and being optionally 1-3 of said carbon atoms replaced by N, O, or S.
In a second aspect the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I) as defined in the first aspect of the invention, together with the appropriate amounts of pharmaceutical excipients or carriers.
In a third aspect the present invention relates to a compound of general formula (I) as defined in the first aspect of the invention, or a compound selected from the group consisting of:
In a fourth aspect the present invention relates to a compound of general formula (I) as defined in the first aspect of the invention, or a compound selected from the group consisting of:
In a further aspect, the present invention provides a compound as defined according to the first aspect of the invention for use as a medicine.
In a still further aspect, the present invention provides a compound as defined according to the first aspect of the invention, for use in the treatment of cancer. This aspect can be also formulated as the use of a compound as defined in the first aspect of the invention for the manufacture of a medicament for the treatment of cancer.
Another aspect of the present invention is to provide a method for the treatment of cancer which comprises administering to a mammal, preferably a human, a therapeutically effective amount of the compound, as defined in the first or fourth aspect of the invention, together with one or more pharmaceutically acceptable carriers, excipients, diluents or adjuvants.
Throughout the description and claims the word “comprise” and variations of the word, such as “comprising”, is not intended to exclude other technical features, additives, components, or steps. Additional objects, advantages and features of the invention will become apparent to those skilled in the art upon examination of the description or may be learned by practice of the invention. The following examples are provided by way of illustration, and are not intended to be limiting of the present invention.
In the present invention, the term “fluoralkyl” means a hydrocarbon chain wherein one or more hydrogen atoms are replaced by one or more fluorine atoms.
In the same way, the term “fluoroalkoxy” means an alcoxy wherein one or more hydrogen atoms are replaced by one or more fluorine atoms.
Illustrative non-limitative examples of known ring systems consisting of one ring are those derived from: cyclopropenyl, cyclobutenyl, cyclopentenyl, phenyl, aziridinyl, oxirenyl, thiiranyl, azetidinyl, oxetanyl, pyrrolyl, furanyl, and thiophenyl.
Illustrative non-limitative examples of known ring systems consisting of two rings totally fused, are those derived from benzofuran, isobenzofuran, indole, isoindole, indolizine, indoline, isoindoline, benzofurazan, benzothiofuran, heterocyclic chromene, isochromene, chroman, isochroman, quinoline, isoquinoline, and quinolizine.
As used herein, the symbols —C(O)—, —S(O)— and —S(O2)— means, respectively:
In one embodiment of the first aspect of the invention, the compound of formula (I) according to the first aspect of the invention is one wherein:
R1 is a radical derived from one of the known ring systems selected from the group consisting of:
In another embodiment of the first aspect of the invention, the compound of general formula (I) is one wherein:
R1 is a radical derived from naphtyl; phenyl and thiophene,
In a more preferred embodiment of the first of the invention,
R1 is a radical derived from naphtyl; phenyl and thiophene,
In still another preferred embodiment of the first aspect of the invention,
R1 is selected from the group consisting:
wherein the symbol # indicates the position at which R1 is attached to Xn;
wherein R9 is —CH3, —Rx or —CH2—Rx;
wherein
In another embodiment of the first aspect of the invention, the compound of general formula (I) is one where:
R1 is selected from the group consisting of:
wherein the symbol indicates the position at which R1 is attached to Xn;
R2 is selected from the group consisting of:
wherein R′2 and R″2 are selected from the group consisting of: hydrogen, —NH2, —OH, —OCH3, —Cl, —Br, —CONH2, and phenyl; and the symbol indicates the position at which R2 is attached to Yn.
Xn is selected from the group consisting of: —(CH2)—, —(CH2)2—, —(CH2)3—,
wherein the symbol indicates the position at which Xn is attached to R1;
Yn is selected from the group consisting of:
wherein the symbol indicates the position at which Yn is attached to R2; and
R3 is hydroxyl, methoxy, ethoxy —O—CH2—O—C(O)—CH3, or
wherein the symbol indicates the position wherein the group C═O is attached to R3.
In another embodiment of the first aspect of the invention,
R1 is phenyl;
R2 is a phenyl radical substituted by at least one radical selected from the group consisting of: (C1-C4)alkoxy, (C1-C4)alkyl, —NHC(O)CH3, halogen, —O—CH2—R8, —OH, —NH2, —OR11, —R8, —NHR11, and —NH—CH2-phenyl;
R8 is a aromatic known ring having 5-6 members independently selected from N, O, S, CH, and NH;
R11 is a phenyl ring optionally substituted with —F, —CF3, —OCH3 and —CN;
R3 is selected from the group consisting of: —OH, (C1-C4)alkoxy and —O—CH2—O—C(O)—CH3;
Xn is selected from the group consisting of: —(CH2)3—; and
Yn is selected from the group consisting of: —(CH2)2.
In another embodiment of the first aspect of the invention,
R1 is phenyl substituted by at least one radical selected from —S(O2)NR4R5, —NR4S(O2)R5 and —NR4C(O)R5,
R2 is phenyl optionally substituted by one (C1-C4)alkyl radical;
R3 is selected from the group consisting of: —OH, methoxy, and —O—CH2—O—C(O)—CH3;
R4 is hydrogen; and
R5 is -Ln-R7, where
wherein the symbol # indicates the position at which Xn is attached to R1; and
In another embodiment of the first aspect of the invention,
R1 is naphtyl;
R2 is phenyl optionally substituted by one radical selected from the group consisting of: (C1-C4)alkyl radical, thiophene and pyridine;
In another embodiment of the first aspect of the invention,
R1 is thiophene substituted by one —S(O2)NR4R5 radical;
R2 is phenyl;
R4 is hydrogen;
R5 is a (C1-C4)alkyl radical;
Preferably the compound of general formula (I) according to the first aspect of the invention is selected from the group consisting of:
The compounds of the present invention are obtained carrying out the steps summarized in the following scheme 1:
Step (a) corresponds to the alkylation of a compound of general formula (II) with a compound of general formula (III), wherein Z represents halogen. This reaction is carried out in the presence of a suitable base, for instance LDA, although other bases can be used as it is well-known for those skilled in the art.
When it is used as electrophile of formula (III) an alkenyl or alkenyl halide, the resulting product of the previous step can be subjected to hydrogenation.
Step (b) corresponds to the hydrolysis of the product resulting from the alkylation of step (a) or from the hydrogenation. This step is carried out in a basic medium, such as an alkaline or alkaline earth metal hydroxide.
When the compound of general formula (I) is one wherein R3 is different from —OH (for instance an alkoxy or an amine), an additional step, (c), is carried out. This step consists of:
Suitable bases and coupling agents are well-known in the state of the art.
When the compound of formula (I) is one wherein R2 is phenyl substituted by R10 (i.e. a known ring system as defined above), it can be obtained following the routes summarizes in the following Scheme 2:
wherein:
Ar1=corresponds to R1;
Ar2=is an aromatic known ring having 5-6 members independently selected from N, O, S, CH, and NH
Ar2B(OR)2=boronic acid based reagent for the introduction of Ar2; and
LG=is a leaving group such as halogen
and being Xn and Yn as defined above.
The active compound or pharmaceutical composition comprising the active compound may be administered to a subject by any convenient route of administration, whether systemically/peripherally or at the site of desired action, including but not limited to, oral (e.g. by ingestion); topical (including e.g. transdermal, intranasal, ocular, buccal, and sublingual); pulmonary (e.g. by inhalation or insufflation therapy using, e.g. an aerosol, e.g. through mouth or nose); rectal; vaginal; parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal by implant of a depot, for example, subcutaneously or intramuscularly. The active compound of the present invention can be administered in the form of an acid or in the form of a pharmaceutically acceptable prodrug. “A pharmaceutically acceptable prodrug” is a compound that may be converted under physiological conditions or by solvolysis to the specified compound or to a pharmaceutically acceptable salt of such compound.
The compounds according to the present invention have the ability of binding to the histone deacetylase (HDAC), inhibiting its activity. Histone deacetylases are a family of enzymes that can deacetylate acetyl lysines. HDACs are primarily involved in regulation of chromatin structure and gene expression via their ability to modulate histone acetylation, although they also play roles in other important cellular functions like microtubule deacetylation. As it is well-known in the state of the art, HDAC inhibitors have shown activity in numerous disease models including, but not limited to, many cancers such as colon cancer, lymphoma, leukemias, lung cancer, breast cancer, prostate cancer; neurogenerative disease like Spinal Muscular Atrophy, Huntington Disease, Alzheimer's disease, immune disorder including graft vs. host disorders, Multiple Sclerosis, renal disease, Nervous system conditions, diabetes, malaria, HIV, and stimulation of stem cells/reprogramming of somatic cells to induce pluripotent stem cells. Therefore, the compounds of the present invention not only are useful for the treatment of cancer but also for the treatment of a pathology associated with an increase of HDAC activity and/or HDAC protein levels.
In one embodiment of the present invention, it is provided a compound of formula (I) as defined in the first aspect of the invention for the treatment of neurodegenerative diseases. This aspect can be formulated as the use of a compound of formula (I) for the manufacture of a medicament for the treatment of a neurodegenerative disease. Preferably, the neurodegenerative disease is selected from Alzheimer's disease, Parkinson's disease, Huntington disease, Lewy Body dementia, and Spinal Muscular Atrophy.
The invention further provides a method for the treatment of a neurodegenerative disease which comprises administering to a mammal, preferably a human, a therapeutically effective amount of the compound, as defined in the first or fourth aspect of the invention, together with one or more pharmaceutically acceptable carriers, excipients, diluents or adjuvants.
The pharmaceutical composition (e.g. formulation) may comprise a therapeutically effective amount of the compound of formula (I), as defined above, together with one or more pharmaceutically acceptable excipients or carriers such as adjuvants, diluents, fillers, buffers, stabilizers, preservatives, lubricants.
The term “pharmaceutically acceptable” as used herein pertains to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject (e.g. human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. Each carrier, excipient, etc. must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation.
Suitable carriers, excipients, etc. can be found in standard pharmaceutical texts, for example, Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton, Pa., 1990.
The term “therapeutically-effective amount,” as used herein, pertains to that amount of an active compound, or a material, composition or dosage form comprising an active compound, which is effective for producing some desired therapeutic effect.
In one embodiment of the third aspect of the invention, the compounds can be used as an anti-cancer agent.
The term “anti-cancer agent” as used herein, pertains to a compound which treats a cancer (i.e., a compound which is useful in the treatment of a cancer). The anti-cancer effect may arise through one or more mechanisms, including but not limited to, the regulation of cell proliferation, the inhibition of cell cycle progression, the inhibition of angiogenesis (the formation of new blood vessels), the inhibition of metastasis (the spread of a turnout from its origin), the inhibition of invasion (the spread of turnout cells into neighboring normal structures), or the promotion of apoptosis (programmed cell death).
In one embodiment of the fourth aspect of the invention, the cancer is selected from breast cancer and colon cancer.
The subject may be a eukaryote, an animal, a vertebrate animal, a mammal, a rodent (e.g. a guinea pig, a hamster, a rat, a mouse), murine (e.g. a mouse), canine (e.g. a dog), feline (e.g. a cat), equine (e.g. a horse), a primate, simian (e.g. a monkey or ape), a monkey (e.g. marmoset, baboon), an ape (e.g. gorilla, chimpanzee, orangutang, gibbon), or a human.
Molecule names were generated using IsisDraw version 2.4. For molecules larger than 50 atoms, the molecule was fragmented to generate the name. In the case of a conflict between a name and a drawing of the structure, the drawing is controlling.
R1=Phenyl. Methyl 2-{2-(4-{[(trifluoromethyl)sulfonyl]oxy}phenyl)ethyl}-5-phenylpentanoate (Intermediate A).
A suspension of 4-(4-methoxyphenyl)butanoic acid (2.0 g, 9.603 mmol) in HBr (20 mL, 48% aqueous solution) was refluxed for 2 h. The reaction mixture was allowed to reach room temperature (hereinafter abbreviated as “r.t.”), poured into H2O (150 mL) and extracted with EtOAc (200 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated, to give 1.81 g of 4-(4-hydroxyphenyl)butanoic acid (white solid). The crude residue was submitted to next step without purification.
H2SO4 (2 mL, 37.32 mmol) was added to a solution of 4-(4-hydroxyphenyl)butanoic acid (9.603 mmol) in MeOH (40 mL). The reaction mixture was refluxed for 1 h, allowed to reach r.t., and poured into H2O (150 mL). It was extracted with CH2Cl2 (200 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated, to give 1.59 g of crude methyl 4-(4-hydroxyphenyl)butanoate (colourless oil, yield: 85%). The compound was submitted to next step without further purification.
1H NMR (CDCl3, 250 MHz) δ ppm: 7.02 (d, J=7.9 Hz, 2H), 6.75 (d, J=7.9 Hz, 2H), 5.47 (bs, 1H), 3.67 (s, 3H), 2.57 (t, J=7.7 Hz, 2H), 2.32 (t, J=7.7 Hz, 2H), 1.92 (m, 2H).
BnBr (2.5 mL, 21.018 mmol) was added to a suspension of K2CO3 (3.0 g, 21.706 mmol) and methyl 4-(4-hydroxyphenyl)butanoate (2.10 g, 10.812 mmol) in CH3CN (100 mL). The reaction mixture was stirred at r.t. overnight (18 h). It was poured into H2O (200 mL) and extracted with EtOAc (150 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (0→5% EtOAc/hexanes), to afford 3.05 g of methyl 4-[4-(benzyloxy)phenyl]butanoate (colourless oil, yield: 99%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.38 (m, 5H), 7.10 (d, J=8.5 Hz, 2H), 6.90 (d, J=8.5 Hz, 2H), 5.05 (s, 2H), 3.66 (s, 3H), 2.59 (m, 2H), 2.31 (m, 2H), 1.92 (m, 2H).
A solution of methyl 4-[4-(benzyloxy)phenyl]butanoate (3.0 g, 10.550 mmol) in THF (5 mL) was added to a −78° C. cooled solution of LDA (13 mL, 1 M THF solution, 13 mmol) in THF (30 mL). The reaction mixture was stirred at low temperature for 2 min, and a solution of [(1E)-3-bromoprop-1-enyl]benzene (3.30 g, 16.744 mmol) in THF (5 mL) was added. The reaction was allowed to reach r.t. overnight (18 h). It was poured into H2O (150 mL), taken up to pH=2 with HCl and extracted with EtOAc (150 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (2→4% EtOAc/hexanes), to give 3.51 g of methyl (4E)-2-[2-(4-benzyloxyphenyl)ethyl]-5-phenylpent-4-enoate (colourless oil, yield: 83%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.43-7.11 (m, 11H), 7.04 (d, J=8.5 Hz, 2H), 6.83 (d, J=8.5 Hz, 2H), 4.99 (s, 2H), 3.63 (s, 3H), 2.56-2.23 (m, 5H), 1.89 (m, 1H), 1.75 (m, 1H).
Methyl (4E)-2-[2-(4-benzyloxyphenyl)ethyl]-5-phenylpent-4-enoate (3.45 g, 8.613 mmol) was added to a suspension of Pd/C (900 mg, 10% Pd/C, 0.845 mmol) in MeOH (60 mL). The reaction mixture was stirred under H2 atmosphere (balloon) for 8 h. It was filtered through Celite (eluted with EtOAc) and solvent was concentrated off. The crude residue was flash chromatographed on SiO2 (20% EtOAc/hexanes), to furnish 2.34 g of methyl 2-[2-(4-hydroxyphenyl)ethyl]-5-phenylpentanoate (white solid, yield: 87%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.28-7.07 (m, 5H), 6.96 (d, J=8.5 Hz, 2H), 6.70 (d, J=8.5 Hz, 2H), 5.00 (bs, 2H), 3.64 (s, 3H), 2.59-2.32 (m, 5H), 1.88 (m, 1H), 1.75-1.43 (m, 5H).
Trifluoromethanesulfonic anhydride (2.60 g, 9.21 mmol) was added to a −18° C. cooled solution of methyl 2-[2-(4-hydroxyphenyl)ethyl]-5-phenylpentanoate (2.30 g, 7.361 mmol) and DIPEA (2.6 mL, 15.187 mmol) in CH2Cl2 (45 mL). The reaction mixture was allowed to react at low temperature for 10 min, poured into H2O (150 mL), taken up to pH=3 with HCl and extracted with CH2Cl2 (120 mL).
The crude residue was purified by flash chromatography on SiO2 (2 6% EtOAc/hexanes), to give 3.04 g of methyl 2-{2-(4-{[(trifluoromethyl)sulfonyl]oxy}phenyl)ethyl}-5-phenylpentanoate (colourless oil, yield: 93%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.37-7.17 (m, 9H), 3.73 (s, 3H), 2.63 (m, 4H), 2.45 (m, 1H), 1.99 (m, 1H), 1.86-1.48 (m, 5H).
R1=Naphthyl. Methyl 2-[2-(4-{[(trifluoromethyl)sulfonyl]oxy}phenyl)ethyl]-5-(1-naphthyl)pentanoate (Intermediate B).
A solution of methyl 4-[4-(benzyloxy)phenyl]butanoate (1.5 g, 5.27 mmol) in THF (5 mL) was added to a −78° C. cooled solution of LDA (6 mL, 1 M THF solution, 6 mmol) in THF (30 mL). The reaction mixture was stirred at low temperature for 3 min, and a solution of 1-(3-bromoprop-1-ynyl)naphthalene (1.68 g, 6.86 mmol) in THF (5 mL) was added. The reaction was allowed to reach r.t. and stirred for 6 h. It was poured into H2O (100 mL), taken up to pH=2 with HCl and extracted with EtOAc (2×100 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (5→10% EtOAc/hexanes), to furnish 950 mg of methyl 2-[2-(4-benzyloxyphenyl)ethyl]-5-(1-naphthyl)pent-4-ynoate (colourless oil, yield: 40%).
1H NMR (CDCl3, 250 MHz) δ ppm: 8.29 (m, 1H), 7.80 (m, 3H), 7.62-7.48 (m, 3H), 7.47-7.32 (m, 5H), 7.14 (d, J=8.8 Hz, 2H), 6.91 (d, J=8.8 Hz, 2H), 5.04 (s, 2H), 3.75 (s, 3H), 2.82 (m, 3H), 2.67 (m, 2H), 2.13 (m, 2H).
Methyl 2-[2-(4-benzyloxyphenyl)ethyl]-5-(1-naphthyl)pent-4-ynoate (940 mg, 2.095 mmol) was added to a suspension of Pd/C (220 mg, 10% Pd/C, 0.210 mmol) in MeOH (20 mL). The reaction mixture was stirred under H2 atmosphere (balloon) for 2 h. It was filtered through Celite (eluted with EtOAc) and solvent was concentrated off. The crude residue was flash chromatographed on SiO2 (20→30% EtOAc/hexanes), to furnish 579 mg of methyl 2-[2-(4-hydroxyphenyl)ethyl]-5-(1-naphthyl)pentanoate (colourless oil, yield: 76%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.99 (m, 1H), 7.84 (m, 1H), 7.71 (d, J=7.7 Hz, 1H), 7.48 (m, 2H), 7.39 (m, 1H), 7.27 (m, 1H), 7.01 (d, J=7.4 Hz, 2H), 6.74 (d, J=7.4 Hz, 2H), 5.10 (bs, 1H), 3.67 (s, 3H), 3.04 (m, 2H), 2.49 (m, 3H), 1.93 (m, 1H), 1.73 (m, 5H).
Trifluoromethanesulfonic anhydride (530 mg, 1.89 mmol) was added to a −18° C. cooled solution of methyl 2-[2-(4-hydroxyphenyl)ethyl]-5-(1-naphthyl) pentanoate (570 mg, 1.57 mmol) and DIPEA (430 mg, 3.37 mmol) in CH2Cl2 (30 mL). The reaction mixture was allowed to react at low temperature for 15 min, poured into H2O (150 mL), taken up to pH=3 with HCl and extracted with CH2Cl2 (100 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was purified by flash chromatography on SiO2 (2→10% EtOAc/hexanes), to give 645 mg of methyl 2-[2-(4-{[(trifluoromethyl)sulfonyl]oxy}phenyl)ethyl]-5-(1-naphthyl)pentanoate (colourless oil, yield: 83%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.99 (m, 1H), 7.85 (m, 1H), 7.71 (d, J=7.7 Hz, 1H), 7.48 (m, 2H), 7.38 (t, J=7.8 Hz, 1H), 7.28 (m, 1H), 7.18 (m, 4H), 3.66 (s, 3H), 3.05 (m, 2H), 2.59 (m, 2H), 2.44 (m, 1H), 1.96 (m, 1H), 1.74 (m, 5H).
H2SO4 (7.16 ml, 73.08 mmol) was added to a solution of 4-phenylbutanoic acid (40.0 g, 243.60 mmol) in MeOH (300 ml). The reaction mixture was stirred at room temperature for 1 h, poured into H2O (500 ml) and extracted with CH2Cl2 (2×400 ml). The organic layer was washed with NaHCO3 (300 ml, saturated aqueous solution), dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (10→20% EtOAc/hexanes), to furnish methyl 4-phenylbutanoate (41.95 g, colourless oil, yield: 96%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.28 (m, 2H), 7.20 (m, 3H), 3.68 (s, 3H), 2.67 (t, J=7.4 Hz, 2H), 2.35 (t, J=7.4 Hz, 2H), 1.99 (m, 2H).
A solution of methyl 4-phenylbutanoate (500 mg, 2.80 mmol) in THF (5 ml) was dropwise added to a −78° C. cooled solution of freshly prepared LDA (1 M in THF, 3.08 ml, 3.08 mmol) in THF (10 ml). The reaction mixture was stirred at low temperature for 10 min, and MeI (0.23 ml, 3.64 mmol) was added. The reaction was allowed to stir at low temperature until full conversion was achieved (30 min, checked by TLC analysis).
The mixture was poured into H2O (50 ml) and extracted with EtOAc (100 ml). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (10% EtOAc/hexanes), to afford methyl 2-methyl-4-phenylbutanoate (440 mg, colourless oil, yield: 82%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.28 (m, 2H), 7.18 (m, 3H), 3.69 (2, 3H), 2.61 (t, J=8.2 Hz, 2H), 2.49 (m, 1H), 2.10-1.94 (m, 2H), 1.81-1.62 (m, 2H), 1.20 (d, J=7.1 Hz, 3H).
LiOH (5.72 ml, 2M solution in H2O, 11.44 mmol) was added to a solution of methyl-4-phenylbutanoate (440 mg, 2.28 mmol) in a mixture of THF (10 ml) and MeOH (10 ml). The reaction mixture was warmed up to reflux, and stirred until no unreacted ester was detected by TLC analysis (30 min). The reaction mixture was allowed to reach room temperature and poured into H2O (100 ml). It was acidified with HCl (10% aqueous solution) until pH 2-3, and extracted with EtOAc (100 ml). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was purified by flash chromatography on SiO2 (10° 50% EtOAc/hexanes) to furnish 2-methyl-4-phenylbutanoic acid (225 mg, colourless oil, yield: 55%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.29 (m, 2H), 7.21 (m, 3H), 2.68 (t, J=8.2 Hz, 2H), 2.52 (m, 1H), 2.15-1.98 (m, 1H), 1.83-1.68 (m, 1H), 1.26 (d, J=6.8 Hz, 3H).
This compound was prepared following the same procedure than the one followed in Example 2, using EH as alkylating reagent instead of MeI. Flash chromatography purification afforded the title compound as a colourless oil (yield: 49%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.23 (m, 5H), 3.69 (2, 3H), 2.60 (m, 2H), 2.32 (m, 1H), 1.92 (m, 1H), 1.84-1.47 (m, 4H), 0.89 (t, J=7.4 Hz, 3H).
This compound was prepared following the same procedure than the one followed in Example 3, using as starting ester the methyl 2-ethyl-4-phenylbutanoate, to furnish the title compound as a colourless oil after flash chromatography purification (yield: 37%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.19 (m, 2H), 7.11 (m, 3H), 2.68-2.48 (m, 2H), 2.30 (m, 1H), 1.90 (m, 1H), 1.79-1.45 (m, 2H), 1.19 (m, 1H), 0.89 (t, J=7.4 Hz, 3H).
This compound was prepared following the same procedure than the one followed in Example 2, using PrI as alkylating reagent instead of MeI. Flash chromatography purification afforded the title compound as a colourless oil (yield: 45%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.35 (m, 2H), 7.25 (m, 3H), 3.76 (s, 3H), 2.67 (m, 2H), 2.49 (m, 1H), 2.03 (m, 1H), 1.92-1.61 (m, 2H), 1.56 (m, 1H), 1.36 (m, 2H), 0.96 (t, J=7.1 Hz, 3H).
This compound was prepared following the same procedure than the one followed in Example 3, using as starting ester the methyl 2-(2-phenylethyl)pentanoate, to furnish the compound as a colourless oil after flash chromatography purification (yield: 43%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.31-7.15 (m, 5H), 2.65 (m, 2H), 2.43 (m, 1H), 1.97 (m, 1H), 1.86-1.58 (m, 2H), 1.55-1.23 (m, 3H), 0.91 (t, J=7.1 Hz, 3H).
This compound was prepared following the same procedure than the one followed in Example 2, using BnBr as alkylating reagent instead of MeI. Flash chromatography purification afforded the compound as a colourless oil (yield: 82%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.32-7.07 (m, 10H), 3.61 (s, 3H), 2.97 (m, 1H), 2.82-2.53 (m, 4H), 1.98 (m, 1H), 1.81 (m, 1H).
This compound was prepared following the same procedure than the one described in Example 3, using as starting ester the methyl 2-benzyl-4-phenylbutanoate to furnish the compound as a colourless oil after flash chromatography purification (yield: 56%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.61-7.36 (m, 10H), 3.30 (m, 1H), 3.13-2.79 (m, 4H), 2.27 (m, 1H), 2.09 (m, 1H).
This compound was prepared following the same procedure than the one followed in Example 2, using PhCH2CH2CH2Br as alkylating reagent instead of MeI. Flash chromatography purification afforded the compound as a colourless oil (yield: 20%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.35-7.10 (m, 10H), 3.67 (s, 3H), 2.57 (m, 3H), 2.24 (m, 2H), 1.93-1.81 (m, 4H), 1.19 (m, 2H).
This compound was prepared following the same procedure than the one followed in Example 3, using as starting ester the methyl 5-phenyl-2-(2-phenylethyl)pentanoate, to furnish the compound as a colourless oil after flash chromatography purification (yield: 13%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.52-7.27 (m, 10H), 2.78 (m, 4H), 2.60 (m, 1H), 2.15 (m, 1H), 2.04-1.66 (m, 5H).
MeNH2 (8 ml, 8 M solution in EtOH, 64 mmol) was added to a solution of 4-methylbenzenesulfonyl chloride (4.72 g, 24.757 mmol) in THF (100 ml). The reaction mixture was stirred at room temperature for 5 min, poured into H2O (400 ml) and extracted with CH2Cl2 (500 ml). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated, to furnish N,4-dimethylbenzenesulfon-amide, that was submitted to next step without further purification (4.27 g, white solid, yield: 93%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.74 (d, J=8.2 Hz, 2H), 7.31 (d, J=8.2 Hz, 2H), 4.66 (c, J=5.5 Hz, 1H), 2.63 (d, J=5.5. Hz, 3H), 2.42 (s, 3H).
Boc2O (2.82 g, 12.955 mmol) was added to a solution of N,4-dimethyl benzenesulfonamide (2.0 g, 10.796 mmol), DMAP (197 mg, 1.619 mmol) and DIPEA (5.5 ml, 32.38 mmol) in CH3CN (80 ml). The reaction mixture was stirred at room temperature for 30 min, poured into H2O (200 ml) and extracted with EtOAc (200 ml). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (10→20% EtOAc/hexanes), to afford tert-butyl methyl[(4-methylphenyl)sulfonyl]carbamate (3.07 g, white solid, yield: 99%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.77 (d, J=8.3 Hz, 2H), 7.30 (d, J=8.3 Hz, 2H), 3.34 (s, 3H), 2.44 (s, 3H), 1.34 (s, 9H).
NBS (1.03 g, 5.786 mmol) was added to a solution of tert-butyl[4-(bromomethyl)phenyl]sulfonyl(methyl)carbamate (1.50 g, 5.256 mmol) in CCl4 (40 ml). The reaction mixture was warmed up to reflux, and allowed to react for 6 h. Solvent was concentrated off, and the crude residue was flash chromatographed on SiO2 (10→30% EtOAc/hexanes), to afford tert-butyl[4-(bromomethyl)phenyl]sulfonyl(methyl)carbamate (2.0 g, pale yellow-coloured oil, yield: 100%. Purity: 60%). Mixture of starting material and product, which was submitted to next step without further purification.
1H NMR (CDCl3, 250 MHz) δ ppm: 7.86 (d, J=8.5 Hz, 2H), 7.53 (d, J=8.5 Hz, 2H), 4.50 (s, 2H), 3.35 (s, 3H), 1.35 (s, 9H).
The compound was prepared following the same procedure than the one of Example 2, using tert-butyl[4-(bromomethyl)phenyl]sulfonyl(methyl) carbamate as alkylating reagent instead of MeI. Flash chromatography purification afforded the compound as a colourless oil (yield: 36%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.78 (d, J=8.5 Hz, 2H), 7.30-7.10 (m, 7H), 3.60 (s, 3H), 3.34 (s, 3H), 3.04 (m, 1H), 2.91-2.83 (m, 4H), 1.98 (m, 1H), 1.82 (m, 1H), 1.32 (s, 9H).
Starting from the product resulting from step (d), it was followed the same process than the one followed in Example 3, to furnish the compound as a white solid after flash chromatography purification (yield: 62%).
1H NMR (CDCl3, 250 MHz) ppm: 7.74 (d, J=8.2 Hz, 2H), 7.34-7.10 (m, 7H), 5.14 (bs, 1H), 3.09-2.83 (m, 2H), 2.74-2.48 (m, 6H), 2.03 (m, 1H), 1.82 (m, 1H).
MeNH2 (7.5 ml, 8 M solution in EtOH, 60 mmol) was added to a solution of 4-bromobenzenesulfonyl chloride (5.0 g, 19.568 mmol) in THF (120 ml). The reaction mixture was stirred at room temperature for 5 min, poured into NH4Cl (saturated aqueous solution, 300 ml) and extracted with EtOAc (500 ml). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated, to furnish 4-bromo-N-methylbenzenesulfonamide, which was submitted to next step without further purification (4.60 g, white solid, yield: 94%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.70 (m, 4H), 4.49 (bs, 1H), 2.67 (d, J=5.2 Hz, 3H).
Boc2O (4.711 g, 21.589 mmol) was added to a solution of 4-bromo-N-methylbenzenesulfonamide (4.5 g, 17.99 mmol), DMAP (329 mg, 2.698 mmol) and DIPEA (9.25 ml, 53.97 mmol) in CH3CN (100 ml). The reaction mixture was stirred at room temperature for 30 min, poured into H2O (200 ml) and extracted with EtOAc (200 ml). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (10→20% EtOAc/hexanes), to afford tert-butyl (4-bromophenyl)sulfonyl(methyl)carbamate (6.18 g, white solid, yield: 98%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.77 (d, J=9.0 Hz, 2H), 7.66 (d, J=9.0 Hz, 2H), 3.34 (s, 3H), 1.37 (s, 9H).
A solution of prop-2-yn-1-ol (949 mg, 16.939 mmol) in THF (6 ml) was dropwise added to a refluxing suspension of tert-butyl (4-bromophenyl) sulfonyl(methyl)carbamate (6.18 g, 17.645 mmol), CuI (152 mg, 0.794 mmol) and PdCl2(PPh3)2 (557 mg, 0.794 mmol) in a mixture of Et3N (49 ml) and THF (100 ml). The reaction mixture was refluxed for 3 h, and then allowed to reach room temperature Solvent was concentrated off, and the crude residue was flash chromatographed on SiO2 (0→10% EtOAc/hexanes), to afford tert-butyl [4-(3-hydroxyprop-1-ynyl)phenyl]sulfonyl(methyl)carbamate (4.48 g, pale yellow-coloured oil, yield: 78%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.82 (d, J=8.8 Hz, 2H), 7.53 (d, J=8.8 Hz, 2H), 4.53 (s, 2H), 3.35 (s, 3H), 1.99 (bs, 1H), 1.35 (s, 9H).
CBr4 (1.172 g, 3.534 mmol) was added to a −18° C. cooled solution of tert-butyl [4-(3-hydroxyprop-1-ynyl)phenyl]sulfonyl(methyl)carbamate (1.0 g, 3.073 mmol) and PPh3 (967 mg, 3.687 mmol) in CH2Cl2 (40 ml). The reaction mixture was allowed to react at low temperature for 30 min, poured into H2O (200 ml), and extracted with CH2Cl2 (200 ml). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (50% EtOAc/hexanes), to afford tert-butyl[4-(3-bromoprop-1-ynyl)phenyl]sulfonyl(methyl)carbamate (1.03 g, pale coloured solid, yield: 86%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.85 (d, J=8.5 Hz), 7.55 (d, J=8.5 Hz), 4.16 (s, 2H), 3.34 (s, 3H), 1.33 (s, 9H).
The resulting product of step (d) was submitted to the procedure described in Example 2, using tert-butyl[4-(3-bromoprop-1-ynyl)phenyl]sulfonyl(methyl)carbamate as alkylating reagent instead of MeI. Flash chromatography purification afforded the compound as a pale yellow-coloured solid (yield: 26%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.79 (d, J=8.5 Hz, 2H), 7.47 (d, J=8.5 Hz, 2H), 7.34-7.16 (m, 5H), 3.75 (s, 3H), 3.35 (s, 3H), 2.70 (m, 5H), 2.08 (m, 2H), 1.36 (s, 9H).
A suspension of methyl 5-{4-[tert-butyl(methylamino)sulfonyl]phenyl}-2-(2-phenylethyl)pent-4-ynoate (211 mg, 0.434 mmol) and Pd/C (69 mg, 10% palladium on activated carbon, 0.065 mmol) in MeOH (15 ml) was stirred under H2 atmosphere (balloon) for 1 h. It was filtered through Celite, washed with MeOH, and concentrated, to furnish methyl 5-{4-[tert-butyl(methylamino) sulfonyl]phenyl}-2-(2-phenylethyl)pent-4-ynoate (195 mg, pale yellow-coloured oil, yield: 91%). The crude residue was submitted to next step without purification.
1H NMR (CDCl3, 250 MHz) δ ppm: 7.63 (d, J=8.6 Hz, 2H), 7.14 (m, 5H), 7.00 (d, J=8.6 Hz, 2H), 3.53 (s, 3H), 3.19 (s, 3H), 2.58-2.11 (m, 5H), 2.02-1.65 (m, 2H), 1.60-1.35 (m, 4H), 1.20 (s, 9H).
Starting from the product resulting in step (f), it was followed the same procedure than the one described in Example 3, to furnish the compound as a colourless oil after flash chromatography purification (yield: 37%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.70 (d, J=8.2 Hz, 2H), 7.22 (m, 4H), 7.12 (m, 3H), 4.71/bs, 1H), 2.58 (s, 3H), 2.68-2.49 (m, 4H), 2.36 (m, 1H), 1.93 (m, 1H), 1.78-1.41 (m, 5H).
The compound was synthesized from methyl-4-phenylbutanoate and (4-iodobutyl)benzene following the experimental procedure detailed in Method A. It was purified by flash chromatography on SiO2 (0→4% EtOAc/hexanes) to furnish a colourless oil (yield: 88%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.36-7.09 (m, 10H), 3.67 (s, 3H), 2.58 (m, 4H), 2.39 (m, 1H), 2.00-1.43 (m, 6H), 1.39 (m, 2H).
The compound was synthesized from methyl 6-phenyl-2-(2-phenylethyl)hexanoate following the experimental procedure detailed in Method B. The crude residue was purified by flash chromatography on SiO2 (5→25% EtOAc/hexanes) to furnish a colourless oil (yield: 70%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.29-7.08 (m, 10H), 2.58 (m, 4H), 2.41 (m, 1H), 1.96 (m, 1H), 1.83-1.46 (m, 5H), 1.35 (m, 2H). EI MS: m/z=295 (M−1).
Bromomethyl acetate (0.125 mL, 1.274 mmol) was added to a solution of 2-benzyl-4-phenylbutanoic acid (Example 9) (300 mg, 1.179 mmol) and DIPEA (0.25 mL, 1.46 mmol) in CH3CN (15 mL). The reaction mixture was stirred at r.t. for 30 min, poured into H2O (100 mL) and extracted with EtOAc (100 mL). The organic layer was washed with HCl (100 mL, 1% aqueous solution), NaHCO3 (100 mL, saturated aqueous solution), dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (5→20% EtOAc/hexanes), to afford 200 mg of (acetyloxy)methyl 2-benzyl-4-phenylbutanoate (colourless oil, yield: 52%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.29 (m, 6H), 7.20 (m, 4H), 5.49 (m, 2H), 3.02 (m, 1H), 2.83 (m, 2H), 2.66 (m, 2H), 1.86 (s, 3H), 1.84-1.56 (m, 2H).
EI MS: m/z=327 (M+1), 344 (M+18).
Bromomethyl acetate (0.2 mL, 2.039 mmol) was added to a solution of 5-phenyl-2-(2-phenylethyl)pentanoic acid (Example 11) (514 mg, 1.82 mmol) and DIPEA (0.39 mL, 2.275 mmol) in CH3CN (25 mL). The reaction mixture was stirred at r.t. for 1 h and then it was poured into H2O (40 mL) and extracted with EtOAc (2×50 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (5→10% EtOAc/hexanes), to afford 224 mg of (acetyloxy)methyl 5-phenyl-2-(2-phenylethyl)pentanoate (yellow coloured oil, yield: 35%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.32-7.24 (m, 4H), 7.23-7.11 (m, 6H), 5.77 (s, 2H), 2.68-2.47 (m, 6H), 2.07 (s, 3H), 1.85-1.52 (m, 5H).
EI MS: m/z=355 (M+1).
Bromomethyl acetate (0.1 mL, 1.019 mmol) was added to a solution of 5-(3-{[(3,4-dimethoxyphenyl)amino]sulfonyl}phenyl)-2-(2-phenylethyl)pentanoic acid (Example 43) (370 mg, 0.743 mmol) and DIPEA (0.2 mL, 1.168 mmol) in CH3CN (25 mL). The reaction mixture was stirred at r.t. for 4 h and solvent was concentrated off. The crude residue was flash chromatographed on SiO2 (10 40% EtOAc/hexanes), to afford 374 mg of (acetyloxy)methyl 5-(3-{[(3,4-dimethoxyphenyl)amino]sulfonyl}phenyl)-2-(2-phenylethyl)pentanoate (colourless oil, yield: 88%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.59 (m, 2H), 7.32 (m, 5H), 7.21 (m, 3H), 6.82-6.58 (m, 3H), 5.81 (m, 2H), 3.83 (s, 3H), 3.79 (s, 3H), 2.63 (m, 4H), 2.45 (m, 1H), 2.15 (s, 3H), 2.00 (m, 1H), 1.84-1.46 (m, 5H).
EI MS: m/z=570 (M+1), 587 (M+18).
Bromomethyl acetate (116 mg, 0.758 mmol) was added to a solution of 5-(3-[(4-methylanilinosulfonyl]phenyl)-2-(2-phenylethyl)pentanoic acid (Example 36) (250 mg, 0.554 mmol) and DIPEA (0.15 mL, 0.869 mmol) in CH3CN (20 mL). The reaction mixture was stirred at r.t. for 4 h and solvent was concentrated off. The crude residue was flash chromatographed on SiO2 (5→20% EtOAc/hexanes), to afford 122 mg of (acetyloxy)methyl 5-(3-[(4-methylanilino sulfonyl]phenyl)-2-(2-phenylethyl)pentanoate (colourless oil, yield: 42%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.57-7.47 (m, 2H), 7.34-7.24 (m, 5H), 7.16 (t, J=7.1 Hz, 2H), 6.98 (m, 4H), 6.68 (s, 1H), 5.77 (dd, J=7.9 Hz, 5.5 Hz, 2H), 2.67-2.30 (m, 5H), 2.25 (s, 3H), 2.11 (s, 3H), 1.63-1.47 (m, 6H).
EI MS: m/z=524 (M+1), 541 (M+18).
Bromomethyl acetate (0.09 mL, 0.917 mmol) was added to a solution of 5-(3-[(methylamino)sulfonyl]phenyl)-2-(2-phenylethyl)pentanoic acid (Example 41) (300 mg, 0.789 mmol) and DIPEA (0.2 mL, 1.168 mmol) in CH3CN (20 mL). The reaction mixture was stirred at r.t. for 30 min, it was poured into H2O (100 mL) and extracted with EtOAc (100 mL). The organic layer was washed with HCl (60 mL, 2% aqueous solution), NaHCO3 (60 mL, saturated aqueous solution), dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (20→100% EtOAc/hexanes), to afford 120 mg of (acetyloxy)methyl 5-(3-[(methylamino)sulfonyl]phenyl)-2-(2-phenylethyl)pentanoate (colourless oil, yield: 34%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.70 (m, 2H), 7.52-7.26 (m, 4H), 7.25-7.16 (m, 3H), 5.85 (dd, J=5.5 Hz, 2.5 Hz, 2H), 4.78 (m, 1H), 2.90 (d, J=5.5 Hz, 3H), 2.67-2.41 (m, 5H), 2.19 (s, 3H), 2.01 (m, 1H), 1.89-1.55 (m, 5H).
EI MS: m/z=448 (M+1), 465 (M+18).
NaH (25 mg, 60% mineral oil suspension, 0.64 mmol) was added to a solution of 5-phenyl-2-(2-phenylethyl)pentanoic acid (Example 11) (200 mg, 0.708 mmol) in THF (10 mL). The reaction mixture was stirred at r.t. for 15 min, and solvent was concentrated off. The crude residue was slurred with Et2O (2×5 mL) and hexanes (5 mL), to give 95 mg of sodium 5-phenyl-2-(2-phenylethyl) pentanoate (white solid, yield: 45%).
1H NMR (MeOD, 250 MHz) δ ppm: 7.38-7.17 (m, 10H), 2.70 (m, 4H), 2.42 (m, 1H), 1.95 (m, 1H), 1.74 (m, 4H), 1.55 (m, 1H).
EI MS: m/z=281 (M−18).
The compound was prepared from methyl 4-phenylbutanoate following the general procedure A, by using [(1E)-3-bromoprop-1-enyl]benzene as alkylating reagent. The crude residue was flash chromatographed on SiO2 (0→2% EtOAc/hexanes), to afford the compound as a yellow-coloured oil (yield: 41%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.36-7.14 (m, 10H), 6.41 (d, J=15.6 Hz, 1H), 6.11 (m, 1H), 3.69 (s, 3H), 2.74-2.28 (m, 5H), 2.11-1.75 (m, 2H).
The compound was synthesized from methyl (4E)-5-phenyl-2-(2-phenylethyl)pent-4-enoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO2 (5 10% EtOAc/hexanes) to furnish a white solid (yield: 79%).
1H NMR (CDCl3, 250 MHz) ppm: 7.39-7.12 (m, 10H), 6.44 (d, J=15.6 Hz, 1H), 6.14 (m, 1H), 2.80-2.29 (m, 5H), 2.10-1.78 (m, 2H).
The compound was synthesized from 2-bromonaphthalene following the experimental procedure detailed in Method C. It was purified by flash chromatography on SiO2 (10→40% EtOAc/hexanes) to furnish a brown coloured solid (yield: 98%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.97 (s, 1H), 7.80 (m, 3H), 7.50 (m, 3H), 4.56 (s, 2H), 2.15 (bs, 1H).
The compound was synthesized from 3-(2-naphthyl)prop-2-yn-1-ol following the experimental procedure detailed in Method D. It was purified by flash chromatography on SiO2 (0→10% EtOAc/hexanes) to furnish a brown coloured solid (yield: 96%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.99 (s, 1H), 7.80 (m, 3H), 7.50 (m, 3H), 4.23 (s, 2H).
The compound was synthesized from 2-(3-bromoprop-1-ynyl)naphthalene and methyl 4-phenylbutanoate following the experimental procedure detailed in Method A. It was purified by flash chromatography on SiO2 (10→15% EtOAc/hexanes) to furnish an orange coloured solid (yield: 76%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.91 (s, 1H), 7.79 (m, 3H), 7.47 (m, 3H), 7.37-7.17 (m, 5H), 3.77 (s, 3H), 2.88-2.61 (m, 5H), 2.14 (m, 2H).
The compound was synthesized from methyl 5-(2-naphthyl)-2-(2-phenylethyl)pent-4-ynoate following the experimental procedure detailed in Method E. It was purified by flash chromatography on SiO2 (10→15% EtOAc/hexanes) to furnish a colourless oil (yield: 80%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.80 (m, 3H), 7.61 (s, 1H), 7.45 (m, 2H), 7.30 (m, 3H), 7.19 (m, 3H), 3.71 (s, 3H), 2.79 (t, J=7.4 Hz, 2H), 2.66-2.34 (m, 3H), 1.97 (m, 1H), 1.86-1.53 (m, 5H).
The compound was synthesized from methyl 2-(2-phenylethyl)-5-(2-naphthyl)pentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO2 (10→15% EtOAc/hexanes) to furnish a white solid (yield: 35%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.78 (m, 3H), 7.60 (s, 1H), 7.44 (m, 2H), 7.28 (m, 3H), 7.19 (m, 3H), 2.84-2.39 (m, 5H), 2.01 (m, 1H), 1.87-1.54 (m, 5H).
EI MS: m/z=350 (M+18).
The compound was synthesized from 1-bromonaphthalene following the experimental procedure detailed in Method C. It was purified by flash chromatography on SiO2 (10→30% EtOAc/hexanes) to furnish a yellow coloured oil (yield: 55%).
1H NMR (CDCl3, 250 MHz) δ ppm: 8.33 (d, J=6.8 Hz, 1H), 7.85 (m, 3H), 7.68 (d, J=6.8 Hz, 1H), 7.54 (m, 3H), 7.42 (m, 1H), 4.66 (s, 2H), 2.04 (bs, 1H).
The compound was synthesized from 3-(1-naphthyl)prop-2-yn-1-ol following the experimental procedure detailed in Method D. It was purified by flash chromatography on SiO2 (0→10% EtOAc/hexanes) to furnish a yellow coloured oil (yield: 82%).
1H NMR (CDCl3, 250 MHz) δ ppm: 8.31 (dd, J=1.1 Hz, 8.2 Hz, 1H), 7.85 (dd, J=0.8 Hz, 7.1 Hz, 2H), 7.68 (dd, J=1.1 Hz, 7.1 Hz, 1H), 7.63-7.49 (m, 2H), 7.43 (dd, J=7.1 Hz, 8.2 Hz, 1H), 4.34 (s, 2H).
The compound was synthesized from 1-(3-bromoprop-1-ynyl)naphthalene and methyl 4-phenylbutanoate following the experimental procedure detailed in Method A. It was purified by flash chromatography on SiO2 (5→10% EtOAc/hexanes) to furnish a yellow coloured oil (yield: 60%).
1H NMR (CDCl3, 250 MHz) δ ppm: 8.34 (m, 1H), 7.87 (m, 2H), 7.69-7.53 (m, 3H), 7.45 (t, J=7.1 Hz, 1H), 7.37-7.21 (m, 5H), 3.81 (s, 3H), 2.94-2.54 (m, 5H), 2.21 (m, 2H).
The compound was synthesized from methyl 5-(1-naphthyl)-2-(2-phenylethyl)pent-4-ynoate following the experimental procedure detailed in Method E. It was purified by flash chromatography on SiO2 (5→10% EtOAc/hexanes) to furnish a yellow coloured oil (yield: 79%).
1H NMR (CDCl3, 250 MHz) δ ppm: 8.05 (m, 1H), 7.89 (m, 1H), 7.75 (m, 1H), 7.53 (m, 2H), 7.45 (m, 1H), 7.36-7.14 (m, 6H), 3.72 (s, 3H), 3.10 (t, J=6.8 Hz, 2H), 2.70-2.46 (m, 3H), 2.10-1.68 (m, 6H).
The compound was synthesized from methyl 5-(1-naphthyl)-2-(2-phenylethyl)pentanoate, following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO2 (10 15% EtOAc/hexanes) to yield a white solid (yield: 35%).
1H NMR (CDCl3, 250 MHz) δ ppm: 8.05 (m, 1H), 7.90 (m, 1H), 7.76 (m, 1H), 7.59-7.38 (m, 3H), 7.36-7.15 (m, 6H), 3.12 (t, J=7.4 Hz, 2H), 2.81-2.45 (m, 3H), 2.12-1.64 (m, 6H).
EI MS: m/z=331 (M−1).
BnBr (7 mL, 58.524 mmol) was added to a suspension of K2CO3 (7 g, 50.647 mmol) and 3-bromoaniline (3.0 g, 17.438 mmol) in CH3CN (100 mL). The reaction mixture was warmed up to reflux and stirred for 4 h. It was allowed to reach r.t. poured into H2O (300 mL) and extracted with EtOAc (300 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated.
The crude residue was flash chromatographed on SiO2 (0→5% EtOAc/hexanes) to furnish 6.0 g of N,N-Dibenzyl-N-(3-bromophenyl)amine (colourless oil, yield: 97%).
EI MS: m/z=353 (M+1).
The compound was synthesized from N,N-Dibenzyl-N-(3-bromophenyl)amine following the experimental procedure detailed in Method C. It was purified by flash chromatography on SiO2 (10→20% EtOAc/hexanes) to yield a colourless oil (yield: 67%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.88-7.65 (m, 11H), 7.58 (m, 1H), 7.30 (m, 2H), 7.18 (dd, J=8.2 Hz, 2.4 Hz, 1H), 5.13 (s, 4H), 4.92 (s, 2H).
The compound was synthesized from 3-[3-(dibenzylamino)phenyl]prop-2-yn-1-ol following the experimental procedure detailed in Method D. It was purified by flash chromatography on SiO2 (10→20% EtOAc/hexanes) to yield a yellow-coloured oil (yield: 87%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.86-7.65 (m, 11H), 7.58 (t, J=7.9 Hz, 1H), 7.33-7.18 (m, 3H), 5.11 (s, 4H), 4.60 (s, 2H).
The compound was synthesized from methyl 4-phenylbutanoate and N,N-dibenzyl-N-[3-(3-bromoprop-1-ynyl)phenyl]amine following the experimental procedure detailed in Method A. It was purified by flash chromatography on SiO2 (5% EtOAc/hexanes) to yield a yellow-coloured oil (yield: 65%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.41-7.12 (m, 15H), 7.06 (t, J=8.2 Hz, 1H), 6.79-6.61 (m, 3H), 4.62 (s, 4H), 3.64 (s, 3H), 2.64 (m, 5H), 1.89 (m, 1H).
The compound was synthesized from methyl 5-(3-N,N-dibenzylaminophenyl)-2-(2-phenylethyl)pent-4-ynoate following the experimental procedure detailed in Method E. It was purified by flash chromatography on SiO2 (20→60% EtOAc/hexanes) to yield an orange-coloured oil (yield: 40%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.32-7.12 (m, 7H), 7.06 (t, J=7.6 Hz, 1H), 6.53 (m, 3H), 3.68 (s, 3H), 2.63-2.35 (m, 5H), 2.03-1.43 (m, 6H).
4-(Dimethylamino)benzoyl chloride (320 mg, 1.742 mmol) was added to a solution of methyl 5-(3-aminophenyl)-2-(2-phenylethyl)pentanoate (450 mg, 1.444 mmol), DIPEA (0.8 mL, 4.673 mmol) and DMAP (30 mg, 0.246 mmol) in CH2Cl2 (30 mL). The reaction mixture was stirred at r.t. for 1 h, poured into H2O (200 mL), and extracted with CH2Cl2 (100 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (10→40% EtOAc/hexanes) to furnish 642 mg of methyl 5-[3-{[4-(dimethylamino)benzoyl]amino}phenyl]-2-(2-phenylethyl)pentanoate (orange-coloured oil, yield: 97%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.78 (d, J=9.0 Hz, 2H), 7.67 (bs, 1H), 7.44 (m, 2H), 7.31-7.12 (m, 5H), 6.89 (m, 1H), 6.71 (d, J=9.0 Hz, 2H), 3.68 (s, 3H), 3.05 (s, 6H), 2.64-2.35 (m, 5H), 2.02-1.46 (m, 6H).
The compound was synthesized from methyl 5-[3-{[4-(dimethylamino)benzoyl]amino}phenyl]-2-(2-phenylethyl)pentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO2 (10→50% EtOAc/hexanes) to yield a colourless oil (yield: 95%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.78 (m, 3H), 7.44 (m, 2H), 7.30-7.12 (m, 5H), 6.89 (m, 1H), 6.69 (d, J=9.0 Hz, 2H), 3.03 (s, 6H), 2.70-2.35 (m, 5H), 2.02-1.59 (m, 6H).
EI MS: m/z=445 (M+1).
A suspension of 5-[3-{[4-(Dimethylamino)benzoyl]amino}phenyl]-2-(2-phenylethyl)pentanoic acid (1.373 mmol) in HCl.Et2O (2 mL, 2 M solution, 4 mmol) was stirred at r.t. for 18 h. Solvent was concentrated off, and the crude residue was slurred with Et2O (2×15 mL), to give 5-[3-{[4-(dimethylamino)benzoyl]amino}phenyl]-2-(2-phenylethyl)pentanoic acid hydrochloride (white solid, yield: 48%).
1H NMR (MeOD, 250 MHz) δ ppm: 8.14 (d, J=9.0 Hz, 2H), 7.69 (d, J=9.0 Hz, 2H), 7.28 (m, 3H), 7.18 (m, 3H), 7.01 (d, J=7.6 Hz, 1H), 2.63 (m, 4H), 2.41 (m, 1H), 1.93 (m, 1H), 1.83-1.50 (m, 5H).
EI MS: m/z=445 (M+1-C1-).
p-TsCl (223 mg, 1.168 mmol) was added to a solution of methyl 5-(3-aminophenyl)-2-(2-phenylethyl)pentanoate (280 mg, 0.899 mmol), DMAP (27 mg, 0.22 mmol) and Et3N (0.25 mL, 1.79 mmol) in THF (30 mL). The reaction was stirred at r.t. overnight. It was poured into H2O (80 mL) and extracted with EtOAc (100 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (0→5% EtOAc/hexanes) to furnish 270 mg of methyl 5-(3′-{[(4-methylphenyl)sulfonyl]amino}phenyl)-2-(2-phenylethyl)pentanoate (yellow-coloured oil, yield: 65%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.80 (d, J=7.7 Hz, 2H), 7.35-7.12 (m, 11H), 6.84 (m, 1H), 6.76 (bs, 1H), 3.68 (s, 3H), 2.50 (m, 4H), 2.45 (s, 3H), 2.37 (m, 1H), 1.95 (m, 1H), 1.80-1.39 (m, 5H).
The compound was synthesized from methyl 5-(3′-{[(4-methylphenyl)sulfonyl]amino}phenyl)-2-(2-phenylethyl)pentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO2 (10→40% EtOAc/hexanes) to yield a colourless oil (yield: 18%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.64 (d, J=8.5 Hz, 2H), 7.33-7.04 (m, 8H), 6.85 (m, 3H), 6.75 (bs, 1H), 2.69-2.37 (m, 5H), 2.35 (s, 3H), 1.98 (m, 1H), 1.81-1.40 (m, 5H).
EI MS: m/z=452 (M+1), 469 (M+18).
MeNH2 (10.3 mL, 8 M solution in EtOH, 82.12 mmol) was added to a solution of 2-thiophenesulfonyl chloride (5.0 g, 27.37 mmol) in THF (70 mL). The reaction mixture was stirred at r.t. for 2 h, poured into H2O (100 mL) and extracted with CH2Cl2 (2×100 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated, to give 5.05 g of N-methylthiophene-2-sulfonamide, that were submitted to next step without purification (brown-coloured solid, yield: quantitative).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.60 (m, 2H), 7.09 (dd, J=3.7 Hz, 4.0 Hz, 1H), 4.88 (bs, 1H), 2.71 (s, 3H).
Br2 (3 mL, 51.46 mmol) was added to a solution of N-methylthiophene-2-sulfonamide (4.56 g, 25.73 mmol) in CHCl3 (70 mL). The reaction mixture was refluxed for 7 h, allowed to reach r.t., poured into H2O (100 mL) and extracted with CH2Cl2 (100 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (15→30% EtOAc/hexanes) to furnish 1.23 g of 5-bromo-N-methylthiophene-2-sulfonamide (off-white solid, yield: 19%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.61 (m, 1H), 7.10 (dd, J=3.8 Hz, 4.5 Hz, 1H), 4.79 (bs, 1H), 2.73 (d, J=5.2 Hz, 3H).
Boc2O (1.17 g, 5.36 mmol) was added to a solution of 5-bromo-N-methylthiophene-2-sulfonamide (1.23 g, 4.78 mmol), DMAP (55 mg, 0.45 mmol) and DIPEA (2.3 mL, 13.67 mmol) in CH3CN (50 mL). The reaction mixture was stirred at r.t. for 1 h, poured into H2O (50 mL) and extracted with CH2Cl2 (100 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (15% EtOAc/hexanes) to furnish 1.61 g of tert-butyl (5-bromothien-2-yl)sulfonyl(methyl)carbamate (orange-coloured solid, yield: 95%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.49 (d, J=3.9 Hz, 1H), 7.07 (d, J=3.9 Hz, 1H), 3.28 (s, 3H), 1.48 (s, 9H).
The compound was prepared from tert-butyl (5-bromothien-2-yl)sulfonyl(methyl)carbamate following the general procedure C. Flash chromatography purification on SiO2 (20→30% EtOAc/hexanes) afforded the desired product as a yellow-coloured solid (yield: 86%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.57 (d, J=3.8 Hz, 1H), 7.11 (d, J=3.8 Hz, 1H), 4.52 (s, 2H), 3.29 (s, 3H), 1.83 (bs, 1H), 1.47 (s, 9H).
The compound was prepared from tert-Butyl[5-(3-hydroxyprop-1-ynyl)thien-2-yl]sulfonyl(methyl)carbamate following the general procedure D. Flash chromatography purification on SiO2 (15→20% EtOAc/hexanes) afforded the desired product as a white solid (yield: 92%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.58 (d, J=3.9 Hz, 1H), 7.16 (d, J=3.9 Hz, 1H), 4.16 (s, 2H), 3.29 (s, 3H), 1.47 (s, 9H).
The compound was prepared from methyl 4-phenylbutanoate and tert-butyl [5-(3-bromoprop-1-ynyl)thien-2-yl]sulfonyl(methyl)carbamate following the general procedure A. Flash chromatography purification on SiO2 (10→20% EtOAc/hexanes) afforded the desired product as a yellow-coloured oil (yield: 45%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.55 (d, J=3.8 Hz, 1H), 7.37-7.12 (m, 5H), 7.02 (d, J=3.8 Hz, 1H), 3.73 (s, 3H), 3.29 (s, 3H), 2.72 (m, 5H), 1.99 (m, 2H), 1.46 (s, 9H).
The compound was prepared from methyl 5-{5-[tertbutoxycarbonylmethyl amino)sulfonyl]thien-2-yl}-2-(2-phenylethyl)pent-4-ynoate following the general procedure E. The crude residue was submitted to next step without purification (colourless oil, yield: 96%).
EI MS: m/z=496 (M+1).
The compound was synthesized from methyl 5-{5-[tertbutoxycarbonylmethyl amino)sulfonyl]thien-2-yl}-2-(2-phenylethyl)pentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO2 (5→10% MeOH/CH2Cl2) to give a yellow-coloured solid (yield: 37%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.42 (d, J=3.6 Hz, 1H), 7.29 (m, 2H), 7.18 (m, 3H), 6.75 (d, J=3.6 Hz, 1H), 4.75 (bs, 1H), 2.83 (m, 2H), 2.70 (bs, 3H), 2.63 (m, 1H), 2.42 (m, 2H), 1.99 (m, 1H), 1.85-1.54 (m, 5H).
EI MS: m/z=382 (M+1), 380 (M−1).
Benzylamine (2.6 mL, 23.48 mmol) was added to a solution of 3-bromobenzenesulfonyl chloride (2.0 g, 7.83 mmol) in THF (30 mL). The reaction mixture was stirred at r.t. for 3 h, poured into H2O (50 mL) and extracted with CH2Cl2 (120 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (10→50% EtOAc/hexanes) to furnish 2.31 g of N-benzyl-3-bromobenzenesulfonamide (white solid, yield: 90%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.76 (m, 1H), 7.60-7.46 (m, 2H), 7.22-6.94 (m, 6H), 4.82 (t, J=5.5. Hz, 1H), 3.97 (d, J=6.0 Hz, 2H).
Boc2O (2.00 g, 9.20 mmol) was added to a solution of N-benzyl-3-bromobenzenesulfonamide (2.31 g, 7.08 mmol), DMAP (87 mg, 0.71 mmol) and DIPEA (3.6 mL, 21.24 mmol) in CH3CN (30 mL). The reaction mixture was stirred at r.t. for 40 min, poured into H2O (80 mL) and extracted with EtOAc (100 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (20→30% EtOAc/hexanes) to furnish 2.93 g of tert-butylbenzyl[(3-bromophenyl)sulfonyl]carbamate (off-white solid, yield: 97%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.83 (m, 1H), 7.77 (m, 1H), 7.66 (m, 1H), 7.58-7.34 (m, 6H), 5.15 (s, 2H), 1.46 (s, 9H).
The compound was synthesized from tert-butylbenzyl[(3-bromophenyl)sulfonyl]carbamate following the experimental procedure detailed in Method C. It was purified by flash chromatography on SiO2 (10→50% EtOAc/hexanes) to furnish a yellow coloured oil (yield: 72%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.71 (m, 1H), 7.58 (m, 2H), 7.37 (m, 6H), 5.05 (s, 2H), 4.50 (s, 2H), 1.92 (bs, 1H), 1.33 (s, 9H).
The compound was synthesized from tert-butylbenzyl[3-(3-hydroxyprop-1-ynyl)phenyl]sulfonylcarbamate following the experimental procedure detailed in Method D. It was purified by flash chromatography on SiO2 (10→20% EtOAc/hexanes) to furnish a colourless oil (yield: 85%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.65 (m, 1H), 7.59 (m, 2H), 7.37 (m, 6H), 5.05 (s, 2H), 4.13 (s, 2H), 1.35 (s, 9H).
The compound was synthesized from tert-butylbenzyl{[3-(3-bromoprop-1-ynyl)phenyl]sulfonyl}carbamate and methyl 4-phenylbutanoate following the experimental procedure detailed in Method A. It was purified by flash chromatography on SiO2 (5→20% EtOAc/hexanes) to furnish a colourless oil (yield: 60%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.68 (m, 1H), 7.51 (m, 2H), 7.41-7.23 (m, 8H), 7.19 (m, 3H), 5.03 (s, 2H), 3.74 (s, 3H), 2.66 (m, 5H), 2.62 (m, 2H), 1.31 (s, 9H).
The compound was synthesized from methyl 5-(3-{[(tert-butyl benzyl)sulfonyl]carbamate}phenyl)-2-(2-phenylethyl)pent-4-ynoate following the experimental procedure detailed in Method E. It was submitted to next step without purification (colourless oil, 88%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.58 (m, 1H), 7.47 (m, 2H), 7.45-7.29 (m, 8H), 7.22 (m, 3H), 5.11 (s, 2H), 3.74/s, 3H), 2.74-2.36 (m, 5H), 2.00 (m, 1H), 1.85-1.44 (m, 5H), 1.33 (s, 9H).
The compound was synthesized from methyl 5-(3-{[(tert-butyl benzyl)sulfonyl]carbamate}phenyl)-2-(2-phenylethyl)pentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO2 (25→35% EtOAc/hexanes) to yield a colourless oil (yield: 62%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.71 (m, 2H), 7.49-7.35 (m, 2H), 7.34-7.17 (m, 10H), 4.97 (t, J=6.0 Hz, 1H), 4.17 (d, J=6.0 Hz, 2H), 2.69 (m, 4H), 2.47 (m, 1H), 2.02 (m, 1H), 1.88-1.55 (m, 5H).
EI MS: m/z=452 (M+1).
4-Ethoxy-4-oxobutylzinc bromide (3.3 mL, 0.5M solution in THF, 1.65 mmol) was added to a solution of 2-bromopyridine (200 mg, 1.265 mmol) and (Ph3P)4Pd (105 mg, 0.09 mmol) in THF (15 mL). The reaction mixture was stirred at r.t. for 3 h and poured into H2O (50 mL). It was taken up to pH=2 with HCl (10% aqueous solution) and extracted with EtOAc (100 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (10→40% EtOAc/hexanes) to furnish 180 mg of ethyl 4-pyridin-2-ylbutanoate (yellow oil, yield: 74%).
1H NMR (CDCl3, 250 MHz) δ ppm: 8.50 (d, J=4.1 Hz, 1H), 7.57 (dt, J=7.6 Hz, 2.3 Hz, 1H), 7.10 (m, 2H), 4.10 (q, J=7.0 Hz, 2H), 2.81 (t, J=8.2 Hz, 2H), 2.34 (t, J=7.6 Hz, 2H), 2.06 (m, 2H), 1.23 (t, J=7.0 Hz, 3H).
The compound was synthesized from ethyl 4-pyridin-2-ylbutanoate and PhCH2CH2CH2I as alkylating agent, following the experimental procedure detailed in Method A. It was purified by flash chromatography on SiO2 (10→20% EtOAc/hexanes) to furnish a yellow coloured oil (yield: 40%).
1H NMR (CDCl3, 250 MHz) δ ppm: 8.52 (d, J=4.1 Hz, 1H), 7.58 (dt, J=7.6 Hz, 2.3 Hz, 1H), 7.1 (m, 3H), 7.16 (m, 4H), 4.14 (q, J=7.0 Hz, 2H), 2.76 (m, 2H), 2.59 (t, J=7.6 Hz, 2H), 2.41 (m, 1H), 2.02 (m, 2H), 1.68 (m, 4H), 1.26 (t, J=7.0 Hz, 3H).
The compound was synthesized from ethyl 5-phenyl-2-(2-pyridin-2-ylethyl)pentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO2 (10→70% EtOAc/hexanes), and slurred with Et2O to furnish a white solid (yield: 31%).
1H NMR (CDCl3, 250 MHz) δ ppm: 8.54 (d, J=4.1 Hz, 1H), 7.74 (t, J=7.6 Hz, 1H), 7.37-7.07 (m, 7H), 2.96 (t, J=8.2 Hz, 2H), 2.59 (q, J=8.2 Hz, 2H), 2.41 (m, 1H), 2.05 (m, 1H), 1.94-1.49 (m, 4H), 1.41 (m, 1H).
EI MS: m/z=284 (M+1).
4-Ethoxy-4-oxobutylzinc bromide (13 mL, 0.5M solution in THF, 6.5 mmol) was added to a solution of 1-bromo-3-methoxybenzene (1.0 g, 5.35 mmol) and (Ph3P)4Pd (742 mg, 0.642 mmol) in THF (25 mL). The reaction mixture was refluxed for 2 h, allowed to reach r.t. and poured into H2O (80 mL). It was taken up to pH=2 with HCl (10% aqueous solution) and extracted with EtOAc (90 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (0→4% EtOAc/hexanes) to furnish 677 mg of ethyl 4-(3-methoxyphenyl)butanoate (coloureless oil, yield: 57%).
EI MS: m/z=223 (M+1).
The compound was synthesized from ethyl 4-(3-methoxyphenyl)butanoate and PhCH2CH2CH2I, following the experimental procedure detailed in Method A. It was purified by flash chromatography on SiO2 (0→5% EtOAc/hexanes) to furnish a yellow coloured oil (yield: 64%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.30 (m, 2H), 7.16 (m, 4H), 6.72 (m, 3H), 4.16 (c, J=7.1 Hz, 2H), 3.81 (s, 3H), 2.57 (m, 4H), 2.37 (m, 1H), 1.91 (m, 1H), 1.85-1.43 (m, 6H), 1.27 (t, J=7.1 Hz, 3H).
The compound was synthesized from ethyl 2-[2-(3-methoxyphenyl)ethyl]-5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO2 (15→20% EtOAc/hexanes) to furnish a colourless oil (yield: 57%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.29-7.12 (m, 6H), 6.74 (m, 3H), 3.79 (s, 3H), 2.61 (m, 4H), 2.44 (m, 1H), 1.94 (m, 1H), 1.88-1.53 (m, 5H).
EI MS: m/z=311 (M−1).
BBr3 (2.5 mL, 1 M solution in CH2Cl2, 2.5 mmol) was added to a −78° C. cooled solution of 2-[2-(3-hydroxyphenyl)ethyl]-5-phenylpentanoic acid (261 mg, 0.83 mmol) in CH2Cl2 (15 mL). The reaction mixture was stirred at low temperature for 30 min, and allowed to reach r.t. It was stirred overnight (18 h), poured into H2O (15 mL) and extracted with CH2Cl2 (50 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (15→30% EtOAc/hexanes) to furnish 85 mg of 2-[2-(3-hydroxyphenyl)ethyl]-5-phenylpentanoic acid (off-white solid, yield: 34%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.96 (d, J=8.5 Hz, 1H), 7.31-7.10 (m, 5H), 6.77 (m, 1H), 6.67 (m, 1H), 6.56 (bs, 1H), 2.90 (m, 2H), 2.63 (m, 2H), 2.45 (m, 1H), 2.17 (m, 1H), 2.03-1.49 (m, 5H).
EI MS: m/z=281 (M−17).
H2SO4 (0.16 mL, 2.868 mmol) was added to a solution of 4-(4-nitrophenyl)butanoic acid (2.0 g, 9.56 mmol) in MeOH (20 mL). The reaction mixture was stirred at r.t. for 16 h, poured into H2O (50 mL) and extracted with CH2Cl2 (2×50 mL). The organic layer was washed with NaHCO3 (300 mL, saturated aqueous solution), dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (10 EtOAc/hexanes), to furnish methyl 4-(4-nitrophenyl)butanoate (2.00 g, colourless oil, yield: 94%).
1H NMR (CDCl3, 250 MHz) δ ppm: 8.14 (d, J=8.8 Hz, 2H), 7.33 (d, J=8.8 Hz, 2H), 3.67 (s, 3H), 2.76 (t, J=7.9 Hz, 2H), 2.33 (t, J=7.6 Hz, 2H), 1.98 (q, J=7.7 Hz, 2H).
A suspension of methyl 4-(4-nitrophenyl)butanoate (3.05 g, 13.67 mmol) and Pd/C (1.0 g, 10% Pd on activated C, 1.09 mmol) in MeOH (40 mL) was stirred under H2 atmosphere (balloon) for 3 h. The reaction mixture was filtered through Celite (washing with EtOAc). Solvent was concentrated off, to furnish 2.33 g of methyl 4-(4-aminophenyl)butanoate (brown solid, yield: 88%). It was submitted to next step without purification.
1H NMR (CDCl3, 250 MHz) δ ppm: 6.96 (d, J=8.5 Hz, 2H), 6.63 (d, J=8.2 Hz, 2H), 3.66 (s, 3H), 2.55 (t, J=7.6 Hz, 2H), 2.31 (t, J=7.7 Hz, 2H), 1.90 (q, J=7.6 Hz, 2H).
BnBr (4.33 mL, 36.17 mmol) was added to a suspension of K2CO3 (5.0 g, 36.18 mmol) and methyl 4-(4-aminophenyl)butanoate (2.33 g, 12.056 mmol) in CH3CN (60 mL). The reaction mixture was warmed up to reflux and allowed to react for 12 h. It was poured into H2O (100 mL) and extracted with EtOAc (2×100 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (5 10% EtOAc/hexanes) to furnish 3.61 g of methyl 4-[4-(N,N-dibenzylamino)phenyl]butanoate (brown solid, yield: 80%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.25 (m, 10H), 6.94 (d, J=8.5 Hz, 2H), 6.62 (d, J=8.5 Hz, 2H), 4.59 (2, 4H), 3.61 (s, 3H), 2.49 (t, J=7.4 Hz, 2H), 2.28 (t, J=7.4 Hz, 2H), 1.86 (q, J=7.6 Hz, 2H).
The compound was synthesized from methyl 4-[4-(N,N-dibenzylamino)phenyl]butanoate and PhCH2CH2CH2I as alkylating agent, following the experimental procedure detailed in Method A. It was purified by flash chromatography on SiO2 (5% EtOAc/hexanes) to furnish a yellow coloured oil (yield: 34%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.07 (m, 15H), 6.83 (d, J=8.5 Hz, 2H), 6.53 (d, J=8.5 Hz, 2H), 4.50 (s, 4H), 3.54 (s, 3H), 2.52-2.20 (m, 5H), 1.61-1.39 (m, 6H).
A suspension of methyl 2-{2-[4-(N,N-dibenzylamino)phenyl]ethyl}-5-phenylpentanoate (1.60 g, 3.254 mmol) and Pd/C (380 mg, 10% Pd on activated C, 0.36 mmol) in MeOH (30 mL) was stirred under H2 atmosphere (balloon) for 4 h. The reaction mixture was filtered through Celite (washing with EtOAc). Solvent was concentrated off, to furnish 0.927 g of methyl 2-[2-(4-aminophenyl)ethyl]-5-phenylpentanoate (red oil, yield: 92%). It was submitted to next step without purification.
1H NMR (CDCl3, 250 MHz) δ ppm: 7.12 (m, 2H), 6.95 (m, 3H), 6.75 (d, J=8.3 Hz, 2H), 6.43 (d, J=8.3 Hz, 2H), 3.47 (s, 3H), 2.43-2.12 (m, 5H), 1.79-1.25 (m, 6H).
Ac2O (0.37 mL, 3.86 mmol) was added to a solution of methyl 2-[2-(4-aminophenyl)ethyl]-5-phenylpentanoate (926 mg, 2.97 mmol) and Et3N (1.25 mL, 8.95 mmol) in CH2Cl2 (30 mL). The reaction mixture was stirred at r.t. for 4 h, poured into H2O (100 mL), taken up to pH=2 and extracted with EtOAc (2×150 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (10→40% EtOAc/hexanes) to furnish 925 mg of methyl 2-[2-(4-(acetylamino)phenyl)ethyl]-5-phenylpentanoate (red coloured oil, yield: 88%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.32 (m, 2H), 7.24-6.98 (m, 7H), 3.61 (s, 3H), 2.58-2.17 (m, 5H), 2.09 (s, 3H), 1.93-1.34 (m, 6H).
The compound was synthesized from methyl 2-[2-(4-(acetylamino)phenyl)ethyl]-5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO2 (10→50% EtOAc/hexanes) to furnish a yellow coloured oil (yield: 35%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.25 (m, 2H), 7.13 (m, 2H), 7.00 (m, 6H), 2.59 (m, 4H), 2.40 (m, 1H), 2.16 (s, 3H), 1.80 (m, 1H), 1.52 (m, 5H).
EI MS: m/z=340 (M+1), 357 (M+18).
The compound was synthesized from methyl 2-[2-(4-aminophenyl)ethyl]-5-phenylpentanoate following the experimental procedure detailed in Method B. The crude residue was slurred with hexanes to furnish a white solid (yield: 63%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.33-7.09 (m, 5H), 6.92 (d, J=8.2, 2H). 6.70 (d, J=8.2, 2H), 2.64-2.19 (m, 5H), 1.83 (m, 1H), 1.90-1.45 (m, 5H).
EI MS: m/z=298 (M+1).
PhCHO (390 mg, 3.71 mmol) was added to a solution of methyl 2-[2-(4-aminophenyl)ethyl]-5-phenylpentanoate (1.10 g, 3.532 mmol) in ClCH2CH2Cl (50 mL). The reaction mixture was stirred at r.t. for 15 min, and NaBH(OAc)3 (1.50 g, 7.06 mmol) was added in portions. The mixture was allowed to react for 45 min, and poured into H2O (100 mL). It was extracted with CH2Cl2, and the organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (0→10% EtOAc/hexanes) to furnish 833 mg of methyl 2-[2-(4-(benzylamino)phenyl)ethyl]-5-phenylpentanoate (colourless oil, yield: 59%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.41-7.10 (m, 10H), 6.95 (d, J=8.0 Hz, 2H), 6.56 (d, J=8.0 Hz, 2H), 4.30 (s, 2H), 3.94 (bs, 1H), 3.67 (s, 3H), 2.58 (m, 2H), 2.42 (m, 3H), 1.86 (m, 1H), 1.59 (m, 6H).
The compound was synthesized from methyl 2-[2-(4-(benzylamino)phenyl)ethyl]-5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO2 (5 20% EtOAc/hexanes) to furnish a yellow-coloured oil (yield: 72%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.51-7.19 (m, 10H), 7.06 (d, J=8.2 Hz, 2H), 6.66 (d, J=8.2 Hz, 2H), 4.37 (s, 2H), 2.75-2.43 (m, 5H), 2.05 (m, 1H), 1.88-1.58 (m, 5H).
EI MS: m/z=388 (M+1).
H2SO4 (1.7 mL, 31.89 mmol) was added to a solution of 5-phenylpentanoic acid (15.0 g, 84.161 mmol) in MeOH (80 mL). The reaction mixture was stirred at r.t. for 3 h, poured into H2O (400 mL) and extracted with CH2Cl2 (2×300 mL). The organic layer was washed with NaHCO3 (300 mL, saturated aqueous solution), dried over Na2SO4 (anhydrous), filtered and concentrated, to furnish methyl 5-phenylpentanoate (16.30 g, colourless oil, yield: 100%). The crude residue was submitted to next step without further purification.
1H NMR (CDCl3, 250 MHz) δ ppm: 7.45 (m, 2H), 7.35 (m, 3H), 3.84 (s, 3H), 2.81 (t, J=7.2 Hz, 2H), 2.52 (t, J=7.2 Hz, 2H), 1.84 (m, 4H).
The compound was prepared from methyl 5-phenylpentanoate following the general procedure A, by using PhCH2CH2CH2I as alkylating reagent. Flash chromatography purification afforded the compound as a colourless oil (yield: 16%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.25 (m, 10H), 7.17 (m, 5H), 3.67 (s, 3H), 2.60 (m, 3H), 2.32 (m, 2H), 1.71-1.51 (m, 8H).
It was prepared from methyl 5-phenyl-2-(3-phenylpropyl)pentanoate following the general procedure B, to furnish the compound as a colourless oil after flash chromatography purification (yield: 15%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.31 (m, 5H), 7.22 (m, 5H), 2.65 (m, 3H), 2.45 (m, 1H), 1.80-1.51 (m, 9H).
EI MS: m/z=295 (M−1).
The compound was prepared from methyl 5-phenylpentanoate following the general procedure A, by using Prl as alkylating reagent. Flash chromatography purification afforded the compound as a yellow coloured oil (yield: 55%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.31 (m, 2H), 7.20 (m, 3H), 3.72 (s, 3H), 2.65 (t, J=7.4 Hz, 2H), 2.42 (m, 1H), 1.73-1.55 (m, 4H), 1.50-1.26 (m, 4H), 0.94 (t, J=7.4 Hz, 3H).
It was prepared from methyl 5-phenyl-2-propylpentanoate following the general procedure B, to furnish the compound as a colourless oil after flash chromatography purification (yield: 62%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.29 (m, 2H), 7.20 (m, 3H), 2.66 (t, J=7.4 Hz, 2H), 2.42 (m, 1H), 1.77-1.55 (m, 4H), 1.52-1.27 (m, 4H), 0.93 (t, J=7.4 Hz, 3H).
EI MS: m/z=219 (M−1).
p-Toluidine (1.68 g, 15.655 mmol) was added to a solution of 3-bromobenzenesulfonyl chloride (2.0 g, 7.827 mmol) and Et3N (2.19 mL, 15.655 mmol) in THF (60 mL). The reaction mixture was allowed to react for 1 h and poured into H2O (120 mL). It was taken up to pH=1 with HCl (15% aqueous solution) and extracted with EtOAc (2×100 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated, to furnish the product as a waxy solid. The crude residue was submitted to next step without purification.
1H NMR (CDCl3, 250 MHz) δ ppm: 7.91 (t, J=1.9 Hz, 1H), 7.65 (dd, J=6.3 Hz, 1.6 Hz, 2H), 7.30 (t, J=7.9 Hz, 1H), 7.02 (m, 4H), 6.83 (bs, 1H), 2.28 (s, 3H).
Boc2O (2.22 g, 10.175 mmol) was added to a solution of 3-bromo-N-(4-methylphenyl)benzenesulfonamide (7.827 mmol), DMAP (95 mg, 0.782 mmol) and DIPEA (4.0 mL, 23.48 mmol) in CH3CN (60 mL). The reaction mixture was stirred at r.t. for 2 h, poured into H2O (200 mL) and extracted with EtOAc (200 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (5 10% EtOAc/hexanes), to afford 2.90 g of tert-butyl (3-bromophenyl)sulfonyl(4-methylphenyl)carbamate (white solid, yield: 87%).
1H NMR (CDCl3, 250 MHz) δ ppm: 8.15 (t, J=1.9 Hz, 1H), 7.90 (m, 1H), 7.78 (m, 1H), 7.43 (t, J=7.9 Hz, 1H), 7.24 (d, J=7.4 Hz, 2H), 7.13 (d, J=8.5 Hz, 2H), 2.40 (s, 3H), 1.37 (s, 9H).
The compound was synthesized from tert-butyl (3-bromophenyl)sulfonyl(4-methylphenyl)carbamate following the experimental procedure detailed in Method C. It was purified by flash chromatography on SiO2 (10→40% EtOAc/hexanes) to furnish an orange coloured solid (yield: 89%).
1H NMR (CDCl3, 250 MHz) δ ppm: 8.05 (s, 1H), 7.92 (d, J=7.9 Hz, 1H), 7.66 (d, J=7.6 Hz, 1H), 7.48 (t, J=7.9 Hz, 1H), 7.24 (d, J=8.2 Hz, 2H), 7.15 (d, J=8.2 Hz, 2H), 4.47 (s, 2H), 2.91 (bs, 1H), 2.38 (s, 3H), 1.34 (s, 9H).
The compound was synthesized from tert-butyl[3-(3-hydroxyprop-1-ynyl)phenyl]sulfonyl(phenyl)carbamate following the experimental procedure detailed in Method D. It was purified by flash chromatography on SiO2 (5→20% EtOAc/hexanes) to furnish a white solid (yield: 85%).
1H NMR (CDCl3, 250 MHz) δ ppm: 8.07 (t, J=1.3 Hz, 1H), 7.93 (m, 1H), 7.69 (m, 1H), 7.51 (t, J=7.9 Hz, 1H), 7.25 (d, J=7.4 Hz, 2H), 7.13 (d, J=8.5 Hz, 2H), 4.15 (s, 2H), 2.40 (s, 3H), 1.36 (s, 9H).
The compound was synthesized from tert-butyl[3-(3-bromoprop-1-ynyl)phenyl]sulfonyl(phenyl)carbamate and methyl 4-phenylbutanoate following the experimental procedure detailed in Method A. It was purified by flash chromatography on SiO2 (5-30% EtOAc/hexanes) to furnish a white solid (yield: 72%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.99 (m, 1H), 7.88 (m, 1H), 7.61 (m, 1H), 7.46 (t, J=7.4 Hz, 1H), 7.35-7.09 (m, 9H), 3.74 (s, 3H), 2.83-2.57 (m, 5H), 2.39 (s, 3H), 2.25-1.94 (m, 2H), 1.34 (s, 9H).
The compound was synthesized from methyl 5-[3-(tert-butoxycarbonyl anilinosulfonyl)phenyl]-2-(2-phenylethyl)pent-4-ynoate following the experimental procedure detailed in Method E to furnish a waxy solid (yield: 94%). The crude residue was submitted to next step without purification.
1H NMR (CDCl3, 250 MHz) δ ppm: 7.77 (m, 2H), 7.43 (m, 2H), 7.34-7.19 (m, 5H), 7.14 (t, J=7.6 Hz, 4H), 3.69 (s, 3H), 2.74-2.51 (m, 4H), 2.39 (s, 3H), 2.07-1.87 (m, 1H), 1.83-1.46 (m, 6H), 1.33 (s, 9H).
The compound was synthesized from methyl 5-[3-(tert-butoxycarbonyl anilinosulfonyl)phenyl]-2-(2-phenylethyl)pentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO2 (10 30% EtOAc/hexanes) to yield a white solid (yield: 56%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.59-7.47 (m, 2H), 7.27 (m, 5H), 7.18 (t, J=8.2 Hz, 2H), 7.01 (d, J=8.5 Hz, 2H), 6.93 (d, J=8.5 Hz, 2H), 6.76 (bs, 1H), 2.79-2.52 (m, 4H), 2.51-2.34 (m, 1H), 2.24 (s, 3H), 2.11-1.87 (m, 1H), 1.85-1.42 (m, 5H).
EI MS: m/z=452 (M+1).
NaH (16 mg, 60% mineral oil suspension, 0.40 mmol) was added to a solution of 5-(3-[(4-methylanilinosulfonyl]phenyl)-2-(2-phenylethyl)pentanoic acid (Example 36) (180 mg, 0.398 mmol) in THF (10 mL). The reaction mixture was stirred at r.t. for 15 min, and solvent was concentrated off. The crude residue was slurred with Et2O (5 mL) and hexanes (5 mL), to give 120 mg of sodium 5-(3-[(4-methylanilinosulfonyl]phenyl)-2-(2-phenylethyl)pentanoate (white solid, yield: 64%).
1H NMR (MeOD, 250 MHz) δ ppm: 7.50 (m, 2H), 7.34 (m, 2H), 7.17 (m, 5H), 6.93 (m, 4H), 2.66 (m, 4H), 2.27 (m, 1H), 2.20 (s, 3H), 1.81 (m, 1H), 1.59 (m, 4H).
EI MS: m/z=452 (M−Na+1).
The compound was synthesized from methyl 5-[3-(tert-butoxycarbonyl-4-methylanilinosulfonyl)phenyl]-2-(2-phenylethyl)pent-4-ynoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO2 (10→50% EtOAc/hexanes) to yield a colourless oil (yield: 40%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.82 (s, 1H), 7.58 (d, J=7.9, 1H), 7.48 (d, J=6.7 Hz, 1H), 7.35-7.15 (m, 6H), 7.04-6.88 (m, 5H), 2.78-2.69 (m, 5H), 2.26 (m, 3H), 2.17-2.01 (m, 2H).
EI MS: m/z=448 (M+1), 465 (M+18).
Aniline (1.42 g, 15.655 mmol) was added to a solution of 3-bromobenzenesulfonyl chloride (2.0 g, 7.827 mmol) and Et3N (2.19 mL, 15.655 mmol) in THF (60 mL). The reaction mixture was allowed to react for 1 h and poured into H2O (120 mL). It was taken up to pH=1 with HCl (15% aqueous solution) and extracted with EtOAc (2×100 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated, to furnish the product as a waxy solid. The crude residue was submitted to next step without purification.
Boc2O (2.22 g, 10.175 mmol) was added to a solution of 3-bromo-N-phenylbenzenesulfonamide (7.827 mmol), DMAP (95 mg, 0.782 mmol) and DIPEA (4.0 mL, 23.48 mmol) in CH3CN (60 mL). The reaction mixture was stirred at r.t. for 2 h, poured into H2O (200 mL) and extracted with EtOAc (200 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (5→10% EtOAc/hexanes), to afford 2.55 g of tert-butyl (3-bromophenyl)sulfonyl(phenyl)carbamate (white solid, yield: 79%).
1H NMR (CDCl3, 250 MHz) δ ppm: 8.21 (t, J=1.6 Hz, 1H), 7.96 (m, 1H), 7.84 (m, 1H), 7.49 (m, 4H), 7.30 (m, 2H), 1.43 (s, 9H).
The compound was synthesized from tert-butyl (3-bromophenyl)sulfonyl(phenyl)carbamate following the experimental procedure detailed in Method C. It was purified by flash chromatography on SiO2 (10→50% EtOAc/hexanes) to furnish a yellow coloured oil (yield: 75%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.90 (m, 1H), 7.79 (m, 1H), 7.53 (m, 1H), 7.41-7.24 (m, 4H), 7.10 (m, 2H), 4.38 (s, 2H), 1.43 (bs, 1H), 1.19 (s, 9H).
The compound was synthesized from tert-butyl[3-(3-hydroxyprop-1-ynyl)phenyl]sulfonyl(phenyl)carbamate following the experimental procedure detailed in Method D. It was purified by flash chromatography on SiO2 (0→5% EtOAc/hexanes) to furnish a waxy solid (yield: 88%).
1H NMR (CDCl3, 250 MHz) δ ppm: 8.13 (s, 1H), 8.00 (m, 1H), 7.76 (m, 1H), 7.67-7.44 (m, 4H), 7.32 (m, 2H), 4.23 (s, 2H), 1.41 (s, 9H).
The compound was synthesized from tert-butyl[3-(3-bromoprop-1-ynyl)phenyl]sulfonyl(phenyl)carbamate and methyl 4-phenylbutanoate following the experimental procedure detailed in Method A. It was purified by flash chromatography on SiO2 (10→20% EtOAc/hexanes) to furnish a colourless oil (yield: 57%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.98 (m, 1H), 7.88 (m, 1H), 7.62 (m, 1H), 7.51-7.40 (m, 3H), 7.33-7.15 (m, 6H), 3.73 (s, 3H), 2.70 (m, 5H), 2.11 (m, 2H), 1.34 (s, 9H).
The compound was synthesized from methyl 5-[3-(tert-butoxycarbonylanilinosulfonyl)phenyl]-2-(2-phenylethyl)pent-4-ynoate following the experimental procedure detailed in Method E to furnish a yellow oil (yield: 92%). The crude residue was submitted to next step without purification.
1H NMR (CDCl3, 250 MHz) δ ppm: 7.79 (m, 2H), 7.42 (m, 5H), 7.30-7.12 (m, 7H), 3.68 (s, 3H), 2.73-2.50 (m, 4H), 2.42 (m, 1H), 1.95 (m, 1H), 1.79-1.49 (m, 5H), 1.32 (s, 9H).
The compound was synthesized from methyl 5-[3-(tert-butoxycarbonylanilinosulfonyl)phenyl]-2-(2-phenylethyl)pentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO2 (5→20% EtOAc/hexanes) to yield a yellow coloured oil (yield: 45%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.51 (m, 2H), 7.31-7.22 (m, 5H), 7.17 (m, 4H), 7.04 (m, 3H), 6.75 (bs, 1H), 2.58 (m, 4H), 2.37 (m, 1H), 1.96 (m, 1H), 1.81-1.41 (m, 5H).
EI MS: m/z=438 (M+1), 455 (M+18).
Aniline (1.837 g, 19.725 mmol) was added to a solution of 4-bromobenzenesulfonyl chloride (2.5 g, 9.784 mmol) and DIPEA (3 mL, 17.524 mmol) in THF (50 mL). The reaction mixture was allowed to react for 30 min and poured into H2O (120 mL). It was taken up to pH=1 with HCl (15% aqueous solution) and extracted with EtOAc (2×100 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated, to furnish the product as a yellow coloured oil. The crude residue was submitted to next step without purification.
Boc2O (2.80 g, 12.829 mmol) was added to a solution of 4-bromo-N-phenylbenzenesulfonamide (9.784 mmol), DMAP (150 mg, 1.227 mmol) and DIPEA (5.0 mL, 29.207 mmol) in CH3CN (80 mL). The reaction mixture was stirred at r.t. for 2 h, poured into H2O (200 mL) and extracted with EtOAc (200 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (5→10% EtOAc/hexanes), to afford 3.86 g of tert-butyl (4-bromophenyl)sulfonyl(phenyl)carbamate (white solid, yield: 79%).
EI MS: m/z=413 (M+1).
The compound was synthesized from tert-butyl (4-bromophenyl)sulfonyl(phenyl)carbamate following the experimental procedure detailed in Method C. It was purified by flash chromatography on SiO2 (20→80% EtOAc/hexanes) to furnish an orange coloured solid (yield: 73%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.99 (d, J=8.6 Hz, 2H), 7.64 (d, J=8.6 Hz, 2H), 7.48 (m, 3H), 7.30 (m, 2H), 4.58 (s, 2H), 1.39 (s, 9H).
The compound was synthesized from tert-butyl[4-(3-hydroxyprop-1-ynyl)phenyl]sulfonyl(phenyl)carbamate following the experimental procedure detailed in Method D. It was purified by flash chromatography on SiO2 (10→40% EtOAc/hexanes) to furnish a yellow coloured solid (yield: 99%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.81 (d, J=8.6 Hz, 2H), 7.47 (d, J=8.6 Hz, 2H), 7.28 (m, 3H), 7.09 (m, 2H), 4.04 (s, 2H), 1.21 (s, 9H).
The compound was synthesized from tert-butyl[4-(3-bromoprop-1-ynyl)phenyl]sulfonyl(phenyl)carbamate and methyl 4-phenylbutanoate following the experimental procedure detailed in Method A. It was purified by flash chromatography on SiO2 (5→15% EtOAc/hexanes) to furnish a yellow coloured oil (yield: 80%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.73 (d, J=8.3 Hz, 2H), 7.34 (d, J=8.3 Hz, 2H), 7.24 (m, 3H), 7.15-6.95 (m, 7H), 3.58 (s, 3H), 2.52 (m, 5H), 1.94 (m, 2H), 1.18 (s, 9H).
The compound was synthesized from methyl 5-[4-(tert-butoxycarbonyl anilinosulfonyl)phenyl]-2-(2-phenylethyl)pent-4-ynoate following the experimental procedure detailed in Method E. It was purified by flash chromatography on SiO2 (4→12% EtOAc/hexanes) to furnish a colourless oil (yield: 73%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.87 (d, J=8.3 Hz, 2H), 7.42 (m, 3H), 7.37-7.11 (m, 9H), 3.70 (s, 3H), 2.69 (m, 2H), 2.57 (m, 2H), 2.41 (m, 1H), 1.92 (m, 1H), 1.81-1.48 (m, 5H), 1.35 (s, 9H).
The compound was synthesized from methyl 5-[4-(tert-butoxycarbonyl anilinosulfonyl)phenyl]-2-(2-phenylethyl)pentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO2 (10→50% EtOAc/hexanes) to yield a white solid (yield: 53%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.93 (d, J=8.5 Hz, 2H), 7.68 (bs, 1H), 7.56-7.24 (m, 12H), 2.83 (m, 4H), 2.65 (m, 1H), 2.24 (m, 1H), 2.09-1.69 (m, 5H).
EI MS: m/z=438 (M+1), 455 (M+18).
MeNH2 (6 mL, 8 M solution in EtOH, 48 mmol) was added to a solution of 3-bromobenzenesulfonyl chloride (3.50 g, 13.698 mmol) in THF (60 mL). The reaction mixture was allowed to react for 5 min and poured into H2O (200 mL) and extracted with CH2Cl2 (2×100 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated, to furnish the product as a yellow coloured solid. The crude residue was submitted to next step without purification.
1H NMR (CDCl3, 250 MHz) δ ppm: 8.01 (t, J=1.6 Hz, 1H), 7.82-7.68 (m, 2H), 7.41 (t, J=8.0 Hz, 1H), 4.70 (bs, 1H), 2.68 (d, J=4.9 Hz, 3H).
Boc2O (3.41 g, 15.624 mmol) was added to a solution of 3-bromo-N-methylbenzenesulfonamide (13.698 mmol), DMAP (166 mg, 1.358 mmol) and DIPEA (7.0 mL, 40.89 mmol) in CH3CN (70 mL). The reaction mixture was stirred at r.t. for 15 min, poured into H2O (200 mL) and extracted with EtOAc (200 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (2→10% EtOAc/hexanes), to afford 4.72 g of tert-butyl (3-bromophenyl)sulfonyl(methyl)carbamate (white solid, yield: 89%).
1H NMR (CDCl3, 250 MHz) δ ppm: 8.04 (t, J=1.9 Hz, 1H), 7.89-7.71 (m, 2H), 7.40 (t, J=8.0 Hz, 1H), 3.35 (s, 3H), 1.37 (s, 9H).
The compound was synthesized from tert-butyl (3-bromophenyl)sulfonyl (methyl)carbamate following the experimental procedure detailed in Method C. It was purified by flash chromatography on SiO2 (20 40% EtOAc/hexanes) to furnish a yellow coloured oil (yield: 40%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.93 (t, J=1.1 Hz, 1H), 7.83 (m, 1H), 7.64 (m, 1H), 7.46 (t, J=7.6 Hz, 1H), 4.50 (s, 2H), 3.37 (s, 3H), 1.36 (s, 9H).
The compound was synthesized from tert-butyl[3-(3-hydroxyprop-1-ynyl)phenyl]sulfonyl(methyl)carbamate following the experimental procedure detailed in Method D. It was purified by flash chromatography on SiO2 (5→20% EtOAc/hexanes) to furnish a colourless oil (yield: 86%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.95 (t, J=1.7 Hz, 1H), 7.85 (m, 1H), 7.65 (m, 1H), 7.48 (t, J=7.6 Hz, 1H), 4.14 (s, 2H), 3.36 (s, 3H), 1.36 (s, 9H).
The compound was synthesized from tert-butyl[3-(3-bromoprop-1-ynyl)phenyl]sulfonyl(methyl)carbamate and methyl 4-phenylbutanoate following the experimental procedure detailed in Method A. It was purified by flash chromatography on SiO2 (2→15% EtOAc/hexanes) to furnish a colourless oil (yield: 75%).
EI MS: m/z=486 (M+1).
The compound was synthesized from methyl 5-[3-(tert-butoxycarbonyl methylaminosulfonyl)phenyl]-2-(2-phenylethyl)pent-4-ynoate following the experimental procedure detailed in Method E to furnish a colourless oil (yield: 96%). The crude residue was submitted to next step without purification.
1H NMR (CDCl3, 250 MHz) δ ppm: 7.61 (m, 2H), 7.36 (m, 2H), 7.20 (m, 2H), 7.11 (m, 3H), 3.64 (s, 3H), 3.31 (s, 3H), 2.67-2.42 (m, 4H), 2.35 (m, 1H), 1.88 (m, 1H), 1.72-1.39 (m, 5H), 1.26 (s, 9H).
The compound was synthesized from methyl 5-[3-(tert-butoxycarbonylmethylaminosulfonyl)phenyl]-2-(2-phenylethyl)pentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO2 (10→50% EtOAc/hexanes) to yield a colourless oil (yield: 87%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.70 (m, 2H), 7.41 (m, 2H), 7.30 (m, 2H), 7.20 (m, 3H), 4.69 (c, J=2.7 Hz, 1H), 2.76-2.57 (m, 7H), 2.44 (m, 1H), 1.99 (m, 1H), 1.84-1.50 (m, 5H).
EI MS: m/z=376 (M+1), 393 (M+18).
H2SO4 (0.05 mL) was added to a solution of 5-(3-[(methylamino)sulfonyl]phenyl)-2-(2-phenylethyl)pentanoic acid (Example 41) (350 mg, 0.932 mmol) in MeOH (25 mL). The reaction mixture was warmed up to reflux and allowed to react for 3 h. It was poured into H2O (150 mL) and extracted with CH2Cl2 (150 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (10→40% EtOAc/hexanes), to afford 264 mg of methyl 5-(3-[(methylamino)sulfonyl]phenyl)-2-(2-phenylethyl)pentanoate (colourless oil, yield: 73%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.67 (m, 2H), 7.39 (m, 2H), 7.26 (m, 2H), 7.18 (m, 3H), 4.42 (c, J=5.4 Hz, 1H), 3.70 (s, 3H), 2.65 (d, J=5.4 Hz, 3H), 2.58 (m, 4H), 2.41 (m, 1H), 1.92 (m, 1H), 1.78-1.44 (m, 5H).
EI MS: m/z=390 (M+1), 407 (M+18).
3,4-Dimethoxyaniline (2.0 g, 13.056 mmol) was added to a solution of 3-bromobenzenesulfonyl chloride (1.75 g, 6.849 mmol) and Et3N (2 mL, 14.349 mmol) in THF (40 mL). The reaction mixture was allowed to react for 30 min, poured into H2O (200 mL) and taken to pH=2. It was extracted with EtOAc (200 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated, to furnish the product as a brown coloured oil. The crude residue was submitted to next step without purification.
Boc2O (1.85 g, 8.476 mmol) was added to a solution of 3-bromo-N-(3,4-dimethoxyphenyl)benzenesulfonamide (6.849 mmol), DMAP (100 mg, 0.818 mmol) and DIPEA (3.0 mL, 17.524 mmol) in CH3CN (100 mL). The reaction mixture was stirred at r.t. for 45 min, poured into H2O (200 mL) and extracted with EtOAc (2×120 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (10→30% EtOAc/hexanes), to afford 3.12 g of tert-butyl (3-bromophenyl)sulfonyl(3,4-dimethoxyphenyl)carbamate (white solid, yield: 96%).
1H NMR (CDCl3, 250 MHz) δ ppm: 8.14 (t, J=1.9 Hz, 1H), 7.92 (m, 1H), 7.79 (m, 1H), 7.44 (t, J=8.2 Hz, 1H), 6.92-6.71 (m, 3H), 3.91 (s, 3H), 3.88 (s, 3H), 1.39 (s, 9H).
The compound was synthesized from tert-butyl (3-bromophenyl)sulfonyl(3,4-dimethoxyphenyl)carbamate following the experimental procedure detailed in Method C. It was purified by flash chromatography on SiO2 (10→60% EtOAc/hexanes) to furnish a red coloured solid (yield: 89%).
1H NMR (CDCl3, 250 MHz) δ ppm: 8.05 (t, J=1.6 Hz, 1H), 7.94 (m, 1H), 7.69 (m, 1H), 7.51 (t, J=7.7 Hz, 1H), 6.90-6.72 (m, 3H), 4.51 (d, J=6.2 Hz, 2H), 3.91 (s, 3H), 3.88 (s, 3H), 1.88 (t, J=6.2 Hz, 1H), 1.36 (s, 9H).
The compound was synthesized from tert-butyl[3-(3-hydroxyprop-1-ynyl)phenyl]sulfonyl(3,4-dimethoxyphenyl)carbamate following the experimental procedure detailed in Method D. It was purified by flash chromatography on SiO2 (20→30% EtOAc/hexanes) to furnish a colourless oil (yield: 97%).
1H NMR (CDCl3, 250 MHz) δ ppm: 8.03 (bs, 1H), 7.92 (m, 1H), 7.66 (m, 1H), 7.49 (t, J=7.9 Hz, 1H), 6.89-6.69 (m, 3H), 4.11 (s, 2H), 3.88 (s, 3H), 3.84 (s, 3H), 1.35 (s, 9H).
The compound was synthesized from tert-butyl[3-(3-bromoprop-1-ynyl)phenyl]sulfonyl(3,4-dimethoxyphenyl)carbamate and methyl 4-phenyl butanoate following the experimental procedure detailed in Method A. It was purified by flash chromatography on SiO2 (10→40% EtOAc/hexanes) to furnish a colourless oil (yield: 89%).
EI MS: m/z=608 (M+1).
The compound was synthesized from methyl 5-[3-(tert-butoxycarbonyl(3,4-dimethoxyanilino)sulfonyl)phenyl]-2-(2-phenylethyl)pent-4-ynoate following the experimental procedure detailed in Method E. It was purified by flash chromatography on SiO2 (10→40% EtOAc/hexanes) to furnish a colourless oil (yield: 85%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.79 (m, 2H), 7.44 (m, 2H), 7.32-7.11 (m, 5H), 6.94-6.72 (m, 3H), 3.91 (s, 3H), 3.86 (s, 3H), 2.73-2.49 (m, 4H), 2.40 (m, 1H), 1.96 (m, 1H), 1.78-1.54 (m, 5H), 1.35 (s, 9H).
The compound was synthesized from methyl 5-[3-(tert-butoxycarbonyl(3,4-dimethoxyanilino)sulfonyl)phenyl]-2-(2-phenylethyl)pentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO2 (10→60% EtOAc/hexanes) to yield a white solid (yield: 87%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.64 (bs, 1H), 7.57 (m, 1H), 7.42-7.31 (m, 4H), 7.29-7.17 (m, 3H), 7.10 (s, 1H), 6.77 (m, 2H), 6.61 (m, 1H), 3.86 (s, 3H), 3.82 (s, 3H), 2.69 (m, 4H), 2.50 (m, 1H), 2.06 (m, 1H), 1.90-1.49 (m, 5H).
EI MS: m/z=498 (M+1), 515 (M+18).
The compound was synthesized from methyl 5-phenylpentanoate and tert-butyl [3-(3-bromoprop-1-ynyl)phenyl]sulfonyl(4-methylphenyl)carbamate following the experimental procedure detailed in Method A. It was purified by flash chromatography on SiO2 (10→15% EtOAc/hexanes) to furnish a yellow-coloured oil (yield: 72%).
1H NMR (CDCl3, 250 MHz) δ ppm: 8.09 (m, 1H), 7.97 (m, 1H), 7.67 (m, 1H), 7.55 (t, J=7.7 Hz, 1H), 7.38-7.21 (m, 9H), 3.81 (s, 3H), 2.74 (m, 5H), 2.47 (s, 3H), 1.79 (m, 4H), 1.44 (s, 9H).
The compound was synthesized from methyl 5-[3-(tert-butoxycarbonyl-4-methylanilinosulfonyl)phenyl]-2-(3-phenylpropyl)pent-4-ynoate following the experimental procedure detailed in Method E. The crude residue was submitted to next step without purification.
1H NMR (CDCl3, 250 MHz) δ ppm: 7.82 (m, 2H), 7.48 (m, 2H), 7.36-7.14 (m, 9H), 3.70 (s, 3H), 2.71 (m, 2H), 2.62 (m, 2H), 2.43 (s, 3H), 1.76-1.48 (m, 9H), 1.38 (s, 9H).
The compound was prepared from methyl 5-[3-(tert-butoxycarbonyl-4-methylanilinosulfonyl)phenyl]-2-(3-phenylpropyl)pentanoate following the general procedure B. Flash chromatography purification on SiO2 (20→50% EtOAc/hexanes), afforded the desired product as a yellow-coloured oil (yield: 73%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.66 (m, 2H), 7.41-7.17 (m, 8H), 7.09 (m, 4H), 2.70 (m, 4H), 2.48 (m, 1H), 2.34 (s, 3H), 1.92-1.36 (m, 8H).
EI MS: m/z=466 (M+1), 483 (M+18).
Ethyl propiolate (470 mg, 4.85 mmol) was added to a −78° C. cooled solution of LiHMDS (5.2 mL, 1 M solution in THF, 5.22 mmol) in THF (15 mL). The reaction mixture was stirred at low temperature for 5 min, and 4-ethylbenzaldehyde (500 mg, 3.73 mmol) was added. It was allowed to reach r.t. and poured into H2O (90 mL). It was taken up to pH=2 with HCl (10% aqueous solution), and the product was extracted with EtOAc (2×100 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated, to furnish a red oil, that was submitted to next step without purification.
The compound was prepared from ethyl 4-(4-ethylphenyl)-4-hydroxybut-2-ynoate following the general procedure E. Flash chromatography purification on SiO2 (0→10% EtOAc/hexanes) afforded ethyl 4-(4-ethylphenyl)butanoate as a colourless oil (yield: 75%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.12 (m, 4H), 4.12 (c, J=7.1 Hz, 2H), 2.60 (m, 4H), 2.34 (t, J=7.4 Hz, 2H), 1.96 (c, J=8.2 Hz, 2H), 1-32.1.20 (m, 6H).
The compound was prepared from ethyl 4-(4-ethylphenyl)butanoate following the general procedure A, by using PhCH2CH2CH2I as alkylating reagent Flash chromatography purification on SiO2 (5→10% EtOAc/hexanes) afforded ethyl 2-[2-(4-ethylphenyl)ethyl]-5-phenylpentanoate as a colourless oil (yield: 53%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.27 (m, 2H), 7.09 (m, 7H), 4.16 (c, J=7.1 Hz, 2H), 2.59 (m, 6H), 2.37 (m, 1H), 1.95 (m, 1H), 1.69-1.48 (m, 5H), 1.25 (m, 6H).
The compound was prepared from ethyl 2-[2-(4-ethylphenyl)ethyl]-5-phenylpentanoate following the general procedure B. Flash chromatography purification on SiO2 (5→20% EtOAc/hexanes), afforded 2-[2-(4-ethylphenyl)ethyl]-5-phenylpentanoic acid as a colourless oil (yield: 25%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.47-7.34 (m, 9H), 2.88 (m, 7H), 2.22 (m, 1H), 2.07-1.73 (m, 5H), 1.47 (t, J=7.7 Hz, 3H).
EI MS: m/z=309 (M−1).
The compound was prepared from methyl 4-(4-ethylphenyl)butanoate following the general procedure A, by using tert-butyl[4-(3-bromoprop-1-ynyl)phenyl]sulfonyl(phenyl)carbamate as alkylating reagent. Flash chromatography purification on SiO2 (5→15% EtOAc/hexanes) afforded the desired product as a yellow coloured oil (yield: 55%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.90 (d, J=7.4 Hz, 2H), 7.53 (d, J=7.4 Hz, 2H), 7.42 (m, 3H), 7.24 (m, 2H), 7.13 (m, 4H), 3.75 (s, 3H), 2.80-2.56 (m, 7H), 2.04 (m, 2H), 1.34 (s, 9H), 1.25 (c, J=7.1 Hz, 3H).
The compound was prepared from methyl 5-[4-(tert-butoxycarbonyl anilinosulfonyl)phenyl]-2-[2-(4-ethylphenyl)ethyl]pent-4-ynoate following the general procedure E. Flash chromatography purification on SiO2 (20% EtOAc/hexanes) afforded the desired product as a colourless oil (yield: 88%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.88 (d, J=8.2 Hz, 2H), 7.42 (m, 3H), 7.34-7.22 (m, 4H), 7.09 (m, 4H), 3.68 (s, 3H), 2.73-2.35 (m, 7H), 1.94 (m, 1H), 1.81-1.48 (m, 5H), 1.33 (s, 9H), 1.21 (t, J=7.4 Hz).
The compound was prepared from methyl 5-[4-(tert-butoxycarbonylanilino sulfonyl)phenyl]-2-[2-(4-ethylphenyl)ethyl]pentanoate following the general procedure E. Flash chromatography purification on SiO2 (15→70% EtOAc/hexanes) afforded 5-[4-(Anilinosulfonyl)phenyl]-2-[2-(4-ethylphenyl)ethyl]pentanoic acid as a colourless oil (yield: 62%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.62 (d, J=8.1 Hz, 2H), 7.36 (bs, 1H), 7.18-6.93 (m, 11H), 2.52 (m, 6H), 2.34 (m, 1H), 1.87 (m, 1H), 1.71-1.38 (m, 5H), 1.13 (t, J=7.6 Hz, 3H).
EI MS: m/z=466 (M+1), 483 (M+18).
H2SO4 (360 mg, 0.373 mmol) was added to a solution of 5-[4-(anilinosulfonyl)phenyl]-2-[2-(4-ethylphenyl)ethyl]pentanoic acid (200 mg, 0.429 mmol) in MeOH (20 mL). The reaction mixture was allowed to react at r.t. for 10 h, poured into H2O (150 mL) and extracted with CH2Cl2 (2×70 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (10→20% EtOAc/hexanes) to furnish 177 mg of methyl 5-[4-(anilinosulfonyl)phenyl]-2-[2-(4-ethylphenyl)ethyl]pentanoate (colourless oil, yield: 86%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.60 (d, J=8.5 Hz, 2H), 7.45 (bs, 1H), 7.13-6.88 (m, 11H), 3.55 (s, 3H), 2.44 (m, 6H), 2.28 (m, 1H), 1.81 (m, 1H), 1.65-1.29 (m, 5H), 1.10 (t, J=7.6 Hz, 3H).
EI MS: m/z=480 (M+1), 497 (M+18).
The compound was synthesized from methyl 4-(4-ethylphenyl)butanoate and (4-iodobutyl)benzene following the experimental procedure detailed in Method A. It was purified by flash chromatography on SiO2 (0→2% EtOAc/hexanes) to furnish a colourless oil (yield: 73%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.19 (m, 2H), 7.13-6.91 (m, 7H), 3.60 (s, 3H), 2.51 (m, 6H), 2.32 (m, 1H), 1.85 (m, 1H), 1.67-1.39 (m, 5H), 1.15 (m, 5H).
The compound was synthesized from methyl 2-[2-(4-ethylphenyl)ethyl]-6-phenylhexanoate following the experimental procedure detailed in Method B. The crude residue was purified by flash chromatography on SiO2 (10→30% EtOAc/hexanes) to furnish a colourless oil (yield: 63%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.25 (m, 2H), 7.20-7.05 (m, 7H), 2.59 (m, 6H), 2.40 (m, 1H), 1.94 (m, 1H), 1.82-1.48 (m, 4H), 1.37 (m, 2H), 1.20 (m, 4H).
EI MS: m/z=342 (M+18).
The compound was synthesized from methyl 4-(4-ethylphenyl)butanoate and N,N-dibenzyl-N-[3-(3-bromoprop-1-ynyl)phenyl]amine following the experimental procedure detailed in Method A. It was purified by flash chromatography on SiO2 (0→5% EtOAc/hexanes) to yield a yellow-coloured oil (yield: 67%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.42 (m, 11H), 7.22 (m, 4H), 6.91 (m, 3H), 4.79 (s, 4H), 3.81 (s, 3H), 2.79 (m, 8H), 2.15 (m, 1H), 1.40 (t, J=7.6 Hz, 3H).
The compound was synthesized from methyl 5-[3-N,N-dibenzylaminophenyl]-2-[2-(4-ethylphenyl)ethyl]pent-4-ynoate following the experimental procedure detailed in Method E. It was purified by flash chromatography on SiO2 (10→30% EtOAc/hexanes) to yield a yellow-coloured oil (yield: 64%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.09 (m, 5H), 6.53 (m, 3H), 3.71 (s, 3H), 3.60 (bs, 2H), 2.51 (m, 6H), 1.94 (m, 1H), 1.78-1.43 (m, 6H), 1.20 (t, J=7.6 Hz, 3H).
4-(Dimethylamino)benzoyl chloride (350 mg, 1.89 mmol) was added to a solution of methyl 5-(3-aminophenyl)-2-[2-(4-ethylphenyl)ethyl]pentanoate (630 mg, 1.58 mmol), DIPEA (0.87 mL, 5.06 mmol) and DMAP (30 mg, 0.246 mmol) in CH2Cl2 (40 mL). The reaction mixture was stirred at r.t. for 12 h, poured into H2O (100 mL), and extracted with CH2Cl2 (100 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (10→30% EtOAc/hexanes) to furnish 615 mg of methyl 5-(3-{[4-(dimethylamino)benzoyl]amino}phenyl)-2-[2-(4-ethylphenyl)ethyl]pentanoate (yellow-coloured oil, yield: 80%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.79 (m, 2H), 7.70 (s, 1H), 7.46 (m, 2H), 7.23 (m, 1H), 7.09 (m, 4H), 6.87 (m, 1H), 6.70 (m, 2H), 3.68 (s, 3H), 3.06 (s, 6H), 2.70-2.35 (m, 7H), 1.91 (m, 1H), 1.80-1.49 (m, 5H), 1.22 (m, 3H).
The compound was synthesized from methyl 5-(3-{[4-(dimethylamino)benzoyl]amino}phenyl)-2-[2-(4-ethylphenyl)ethyl]pentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO2 (10→40% EtOAc/hexanes) to yield a white solid (yield: 43%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.63 (m, 4H), 7.28 (m, 2H), 7.04 (m, 1H), 6.92 (m, 4H), 6.70 (m, 1H), 6.49 (d, J=8.8 Hz, 2H), 2.84 (s, 6H), 2.42 (m, 6H), 2.24 (m, 1H), 1.78 (m, 1H), 1.63-1.34 (m, 5H), 1.03 (t, J=7.4 Hz, 3H).
EI MS: m/z=473 (M+1).
The compound was synthesized from methyl 4-(4-ethylphenyl)butanoate and 1-(3-bromoprop-1-ynyl)naphthalene following the experimental procedure detailed in Method A. It was purified by flash chromatography on SiO2 (0→10% EtOAc/hexanes) to yield a yellow-coloured oil (yield: 42%).
EI MS: m/z=371 (M+1).
The compound was synthesized from methyl 5-(1-naphthyl)-2-[2-(4-ethylphenyl)ethyl]-pent-4-ynoate following the experimental procedure detailed in Method E. It was purified by flash chromatography on SiO2 (2→4% EtOAc/hexanes) to yield a colourless oil (yield: 78%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.87 (m, 1H), 7.70 (m, 1H), 7.57 (m, 1H), 7.44-7.12 (m, 3H), 6.97 (m, 5H), 3.56 (s, 3H), 2.93 (m, 1H), 2.68-2.28 (m, 6H), 1.97-1.36 (m, 6H), 1.11 (t, J=7.6 Hz, 3H).
The compound was synthesized from methyl 5-(1-naphthyl)-2-[2-(4-ethylphenyl)ethyl]-pentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO2 (5→20% EtOAc/hexanes) to yield a colourless oil (yield: 14%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.90 (m, 1H), 7.75 (m, 1H), 7.61 (m, 1H), 7.43-7.15 (m, 4H), 6.99 (m, 4H), 2.96 (m, 2H), 2.59-2.28 (m, 5H), 1.90 (m, 1H), 1.81-1.45 (m, 5H), 1.14 (t, J=7.6 Hz, 3H).
EI MS: m/z=361 (M+1), 378 (M+18).
NaH (760 mg, 60% mineral oil suspension, 19.0 mmol) was added to a solution of dimethyl malonate (1.0 g, 7.568 mmol) in DMF (40 mL). The mixture was stirred at r.t. for 15 min, and (2-bromoethyl)benzene (4.3 mL, 31.78 mmol) was added. The reaction mixture was warmed up to 50° C. and stirred for 4 h. It was allowed to reach r.t., diluted with NaCl (saturated aqueous solution, 200 mL) and extracted with Et2O (200 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (2→10% EtOAc/hexanes) to furnish 1.023 g of dimethyl bis(2-phenylethyl)malonate (colourless oil, yield: 39%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.34 (m, 4H), 7.23 (m, 6H), 3.79 (s, 6H), 2.59 (m, 4H), 2.34 (m, 4H).
The compound was synthesized from dimethyl bis(2-phenylethyl)malonate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO2 (5 MeOH/CH2Cl2) to yield a white solid (yield: 25%). The compound was directly submitted to next step.
H2O (1 mL, 35.12 mmol) was added to a solution of bis(2-phenylethyl)malonic acid (300 mg, 0.878 mmol) in DMSO (25 mL), and the mixture was refluxed for 2 h. It was allowed to reach r.t., poured into H2O (20 mL), taken up to pH=1 and extracted with EtOAc (20 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (10→20% EtOAc/hexanes) to furnish 70 mg of 4-phenyl-2-(2-phenylethyl)butanoic acid (yellow-coloured oil, yield: 30%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.35-7.08 (m, 10H), 2.67 (m, 5H), 2.46 (m, 1H), 2.01 (m, 2H), 1.80 (m, 2H).
EI MS: m/z=267 (M−1).
H2SO4 (0.35 mL, 6.49 mmol) was added to a solution of 4-(4-bromophenyl)butanoic acid (5.26 g, 21.64 mmol) in MeOH (100 mL). The reaction mixture was stirred at r.t. for 16 h, and poured into H2O (120 mL). It was extracted with CH2Cl2 (150 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated, to give 5.50 g of methyl 4-(4-bromophenyl)butanoate (colourless oil, yield: 98%). The compound was submitted to next step without further purification.
The compound was synthesized from methyl 4-(4-bromophenyl)butanoate and (3-iodopropyl)benzene following the experimental procedure detailed in Method A. It was purified by flash chromatography on SiO2 (0→5% EtOAc/hexanes) to give a colourless oil (yield: 76%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.40 (m, 2H), 7.28 (m, 2H), 7.16 (m, 3H), 7.05 (m, 2H), 3.68 (s, 3H), 2.71-2.48 (m, 4H), 2.39 (m, 1H), 1.94 (m, 1H), 1.76-1.50 (m, 5H).
The compound was synthesized from methyl 2-[2-(4-bromophenyl)ethyl]-5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO2 (10→30% EtOAc/hexanes) to give a colourless oil (yield: 46%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.39 (m, 2H), 7.26 (m, 2H), 7.16 (m, 3H), 7.04 (m, 2H), 2.72-2.49 (m, 4H), 2.41 (m, 1H), 1.95 (m, 1H), 1.82-1.51 (m, 5H).
EI MS: m/z=359, 361 (M−1).
H2SO4 (3.5 mL, 64.92 mmol) was added to a solution of indole-3-butyric acid (4.0 g, 19.68 mmol) in MeOH (100 mL). The reaction mixture was stirred at r.t. for 5 h, and poured into H2O (150 mL). It was extracted with CH2Cl2 (2×100 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated, to give 4.22 g of methyl 4-(1H-indol-3-yl)butanoate (white solid, yield: 98%). The compound was submitted to next step without further purification.
1H NMR (CDCl3, 250 MHz) ppm: 7.97 (bs, 1H), 7.61 (d, J=7.7 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.24-7.07 (m, 2H), 7.23 (bs, 1H), 3.66 (s, 3H), 2.81 (t, J=7.4 Hz, 2H), 2.40 (t, J=7.4 Hz, 2H), 2.06 (q, J=7.4 Hz, 2H).
Cs2CO3 (9.0 g, 27.62 mmol) was added to a solution of methyl 4-(1H-indol-3-yl)butanoate (4.0 g, 18.41 mmol) and BnBr (4.4 mL, 36.83 mmol) in CH3CN (100 mL). The reaction mixture was refluxed for 14 h, allowed to reach r.t. and poured into H2O (150 mL). It was extracted with EtOAc (180 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (20→25% EtOAc/hexanes) to furnish 2.94 g of methyl 4-(1-benzyl-1H-indol-3-yl)butanoate (colourless oil, yield: 53%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.56 (d, J=8.0 Hz, 1H), 7.31-6.98 (m, 8H), 6.85 (s, 1H), 5.18 (s, 2H), 3.60 (bs, 3H), 2.76 (t, J=7.4 Hz, 2H), 2.40 (t, J=7.4 Hz, 2H), 2.05-1.97 (m, 2H).
The compound was synthesized from methyl 4-(1-benzyl-1H-indol-3-yl)butanoate and [(1E)-3-bromoprop-1-enyl]benzene following the experimental procedure detailed in Method A. It was purified by flash chromatography on SiO2 (0→5% EtOAc/hexanes) to give a colourless oil (yield: 46%).
The compound was synthesized from (E)-methyl 2-(2-(1-benzyl-1H-indol-3-yl)ethyl)-5-phenylpent-4-enoate following the experimental procedure detailed in Method E. It was purified by flash chromatography on SiO2 (10→50% EtOAc/hexanes) to give a colourless oil (mixture of isomers, yield: 8%).
1H NMR (CDCl3, 250 MHz, signals of the major isomer) δ ppm: 7.41-7.11 (m, 8H), 6.76-6.59 (m, 1H), 3.67 (s, 3H), 3.29 (m, 1H), 3.27-3.11 (m, 2H), 2.65-2.53 (m, 2H), 2.46-2.26 (m, 3H), 1.79-1.36 (m, 7H).
The compound was synthesized from methyl 2-(2-(indolin-3-yl)ethyl)-5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO2 (5% MeOH/CH2Cl2) to give a colourless oil (mixture of isomers, yield: 33%).
1H NMR (CDCl3, 250 MHz, signals of the major isomer) δ ppm: 7.26-7.03 (m, 5H), 7.03-6.89 (m, 2H), 6.72-6.52 (m, 3H), 3.73 (t, J=7.7 Hz, 1H), 3.38-3.17 (m, 2H), 2.69 (t, J=7.0 Hz, 2H), 2.47 (bs, 1H), 1.85-1.35 (m, 8H).
EI MS: m/z=324 (M+1).
The compound was synthesized from methyl 2-[2-(4-hydroxyphenyl)ethyl]-5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO2 (5→20% MeOH/CH2Cl2) to furnish, to afford a white solid (yield: 36%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.33 (m, 5H), 7.03 (d, J=8.2 Hz, 2H), 6.74 (d, J=8.2 Hz, 2H), 2.60 (m, 4H), 2.43 (m, 1H), 1.93 (m, 1H), 1.80-1.48 (m, 5H).
EI MS: m/z=297 (M−1), 316 (M+18).
K2CO3 (1.40 mmol) was added to a solution of methyl 2-[2-(4-hydroxyphenyl)ethyl]-5-phenylpentanoate (1.60 g, 5.121 mmol) and BnBr (1 mL, 8.407 mmol) in CH3CN (30 mL). The reaction mixture was stirred at r.t. for 6 h, poured into H2O (120 mL) and extracted with EtOAc (150 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was purified by flash chromatography on SiO2 (10→20% EtOAc/hexanes), to give 1.73 g of methyl 2-[2-(4-benzyloxyphenyl)ethyl]-5-phenylpentanoate (colourless oil, yield: 84%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.44-7.19 (m, 7H), 7.18-7.08 (m, 3H), 7.03 (d, J=8.6 Hz, 2H), 6.86 (d, J=8.6 Hz, 2H), 5.01 (s, 2H), 3.64 (s, 3H), 2.60-2.32 (m, 5H), 1.90 (m, 1H), 1.76-1.44 (m, 5H).
The compound was synthesized from methyl 2-[2-(4-benzyloxyphenyl)ethyl]-5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO2 (15→30% EtOAc/hexanes) to furnish a white solid (yield: 58%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.32-7.04 (m, 7H), 7.03-6.88 (m, 5H), 6.72 (m, 2H), 4.86 (s, 2H), 2.42 (m, 4H), 2.24 (m, 1H), 1.78 (m, 1H), 1.50 (m, 5H).
EI MS: m/z=389 (M+1), 406 (M+18).
Bromomethyl acetate (0.055 mL, 0.564 mmol) was added to a solution of 2-[2-(4-benzyloxyphenyl)ethyl]-5-phenylpentanoic acid (Example 55) (160 mg, 0.412 mmol) and DIPEA (0.11 mL, 0.646 mmol) in CH3CN (20 mL). The reaction mixture was stirred at r.t. for 3 h and solvent was concentrated off. The crude residue was flash chromatographed on SiO2 (10→20% EtOAc/hexanes), to afford 134 mg of (acetyloxy)methyl 2-[2-(4-benzyloxyphenyl)ethyl]-5-phenylpentanoate (colourless oil, yield: 71%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.47-7.13 (m, 7H), 7.22-7.10 (m, 3H), 7.06 (d, J=8.8 Hz, 2H), 6.89 (d, J=8.8 Hz, 2H), 5.75 (s, 2H), 5.04 (s, 2H), 2.63-2.37 (m, 5H), 2.07 (s, 3H), 1.82-1.47 (m, 6H).
EI MS: m/z=478 (M+18).
K2CO3 (1.40 mmol) was added to a solution of methyl 2-[2-(4-hydroxyphenyl)ethyl]-5-phenylpentanoate (1.60 g, 5.121 mmol) and MeI (1.20 g, 8.407 mmol) in CH3CN (30 mL). The reaction mixture was stirred at r.t. for 6 h, poured into H2O (120 mL) and extracted with EtOAc (150 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was purified by flash chromatography on SiO2 (10% EtOAc/hexanes), to give 1.55 g of methyl 2-[2-(4-methoxyphenyl)ethyl]-5-phenylpentanoate (white solid, yield: 93%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.32-7.11 (m, 5H), 7.07 (d, J=8.6 Hz, 2H), 6.82 (d, J=8.6 Hz, 2H), 3.79 (s, 3H), 3.69 (s, 3H), 2.65-2.34 (m, 5H), 1.91 (m, 1H), 1.78-1.40 (m, 5H).
The compound was synthesized from methyl 2-[2-(4-methoxyphenyl)ethyl]-5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO2 (0→5% EtOAc/hexanes) to furnish a yellow-coloured oil (yield: 58%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.31-7.12 (m, 5H), 7.09 (d, J=8.6 Hz, 2H), 6.81 (d, J=8.6 Hz, 2H), 3.78 (s, 3H), 2.62 (m, 4H), 2.42 (m, 1H), 1.96 (m, 1H), 1.83-1.50 (m, 5H).
EI MS: m/z=313 (M+1), 330 (M+18).
2-(Bromomethyl)pyridine hydrobromide (425 mg, 1.68 mmol) was added to a suspension of methyl 2-[2-(4-hydroxyphenyl)ethyl]-5-phenylpentanoate (400 mg, 1.28 mmol) and Cs2CO3 (1.30 g, 3.99 mmol) in DMF (25 mL). The reaction mixture was warmed up to 60° C. and stirred for 3 h. It was allowed to reach r.t. and poured into H2O (150 mL), taken up to pH=3 with HCl and extracted with Et2O (100 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was purified by flash chromatography on SiO2 (10→30% EtOAc/hexanes), to give 452 mg of methyl 2-{2-[4-(pyridin-2-ylmethoxy)phenyl]ethyl}-5-phenylpentanoate (colourless oil, yield: 88%).
1H NMR (CDCl3, 250 MHz) δ ppm: 8.69 (d, J=4.9 Hz, 1H), 7.80 (m, 1H), 7.62 (m, 1H), 7.42-7.21 (m, 6H), 7.17 (m, 2H), 7.00 (m, 2H), 5.29 (s, 2H), 3.77 (s, 3H), 2.72-2.42 (m, 5H), 2.00 (m, 1H), 1.88-1.53 (m, 5H).
The compound was synthesized from methyl 2-{2-[4-(pyridin-2-ylmethoxy)phenyl]ethyl}-5-phenylpentanoate following the experimental procedure detailed in Method B. The crude residue was slurred with Et2O, to afford a white solid (yield: 76%).
1H NMR (CDCl3, 250 MHz) δ ppm: 8.62 (d, J=6.0 Hz, 1H), 7.75 (m, 1H), 7.57 (m, 1H), 7.28-7.00 (m, 8H), 6.89 (d, J=8.5 Hz, 2H), 5.21 (s, 2H), 2.57 (m, 4H), 2.41 (m, 1H), 1.91 (m, 1H), 1.80-1.44 (m, 5H).
EI MS: m/z=390 (M+1).
3-(Bromomethyl)pyridine hydrobromide (260 mg, 1.027 mmol) was added to a suspension of methyl 2-[2-(4-hydroxyphenyl)ethyl]-5-phenylpentanoate (250 mg, 0.800 mmol) and Cs2CO3 (820 mg, 2.516 mmol) in DMF (20 mL). The reaction mixture was warmed up to 60° C. and stirred for 6 h. It was allowed to reach r.t. and poured into H2O (150 mL), taken up to pH=3 with HCl and extracted with Et2O (120 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was purified by flash chromatography on SiO2 (10→80% EtOAc/hexanes), to give 85 mg of methyl 2-{2-[4-(pyridin-3-ylmethoxy)phenyl]ethyl}-5-phenylpentanoate (colourless oil, yield: 26%).
1H NMR (CDCl3, 250 MHz) δ ppm: 8.66 (bs, 1H), 8.57 (bs, 1H), 7.75 (d, J=7.9 Hz, 1H), 7.25 (m, 3H), 7.20-7.03 (m, 5H), 6.87 (m, 2H), 5.03 (s, 2H), 3.66 (s, 3H), 2.55 (m, 4H), 2.38 (m, 1H), 1.90 (m, 1H), 1.78-1.45 (m, 5H).
The compound was synthesized from methyl 2-{2-[4-(pyridin-3-ylmethoxy)phenyl]ethyl}-5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO2 (30→50% MeOH/CH2Cl2) to afford a white solid (yield: 22%).
1H NMR (MeOD, 250 MHz) δ ppm: 8.63 (bs, 1H), 8.51 (bs, 1H), 7.94 (d, J=7.7 Hz, 1H), 7.45 (m, 1H), 7.28-7.02 (m, 7H), 6.95 (m, 2H), 5.12 (s, 2H), 2.56 (m, 4H), 2.31 (m, 1H), 1.87 (m, 1H), 1.72-1.42 (m, 5H).
EI MS: m/z=390 (M+1).
4-(Bromomethyl)pyridine hydrobromide (500 mg, 1.976 mmol) was added to a suspension of methyl 2-[2-(4-hydroxyphenyl)ethyl]-5-phenylpentanoate (400 mg, 1.28 mmol) and Cs2CO3 (1.30 g, 3.98 mmol) in DMF (20 mL). The reaction mixture was warmed up to 60° C. and stirred for 3 h. It was allowed to reach r.t. and poured into H2O (150 mL), taken up to pH=3 with HCl and extracted with Et2O (100 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was purified by flash chromatography on SiO2 (10→80% EtOAc/hexanes), to give 245 mg of methyl 2-{2-[4-(pyridin-4-ylmethoxy)phenyl]ethyl}-5-phenylpentanoate (colourless oil, yield: 49%).
1H NMR (CDCl3, 250 MHz) δ ppm: 8.60 (m, 2H), 7.34 (m, 2H), 7.26 (m, 2H), 7.21-7.03 (m, 5H), 6.85 (m, 2H), 5.07 (s, 2H), 3.67 (s, 3H), 2.61-2.33 (m, 5H), 1.90 (m, 1H), 1.75-1.46 (m, 5H).
The compound was synthesized from methyl 2-{2-[4-(pyridin-4-ylmethoxy)phenyl]ethyl}-5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO2 (5→20% MeOH/CH2Cl2) to afford a white solid (yield: 36%).
1H NMR (CDCl3, 250 MHz) δ ppm: 11.23 (m, 2H), 8.85 (m, 2H), 7.67 (m, 2H), 7.57-7.15 (m, 7H), 7.05 (d, J=8.2 Hz, 2H), 5.27 (s, 2H), 2.81 (m, 4H), 2.63 (m, 1H), 2.15 (m, 1H), 2.07-1.63 (m, 5H).
EI MS: m/z=390 (M+1).
K2CO3 (200 mg, 1.447 mmol) was added to a solution of methyl 2-[2-(4-hydroxyphenyl)ethyl]-5-phenylpentanoate (200 mg, 0.640 mmol) and 2-fluorobenzonitrile (200 mg, 1.651 mmol) in DMF (20 mL). The reaction mixture was warmed up to 130° C., and allowed to react for 30 min. It was poured into H2O (120 mL) and extracted with Et2O (100 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was purified by flash chromatography on SiO2 (4→16% EtOAc/hexanes), to give 232 mg of methyl 2-{2-[4-(2-cyanophenoxy)phenyl]ethyl}-5-phenylpentanoate (colourless oil, yield: 88%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.69 (dd, J=7.9 Hz, 1.9 Hz, 1H), 7.50 (m, 1H), 7.36-7.11 (m, 8H), 7.04 (m, 2H), 6.87 (d, J=7.9 Hz, 1H), 3.74 (s, 3H), 2.64 (m, 4H), 2.45 (m, 1H), 2.00 (m, 1H), 1.85-1.54 (m, 5H).
The compound was synthesized from methyl 2-{2-[4-(2-cyanophenoxy)phenyl]ethyl}-5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO2 (10→40% EtOAc/hexanes) to furnish a colourless oil (yield: 72%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.72 (m, 1H), 7.51 (m, 1H), 7.38-7.12 (m, 8H), 7.07 (d, J=8.5 Hz, 2H), 6.90 (d, J=8.5 Hz, 1H), 2.71 (m, 4H), 2.51 (m, 1H), 2.08 (m, 1H), 1.95-1.58 (m, 5H).
EI MS: m/z=398 (M−1), 400 (M+1).
K2CO3 (250 mg, 1.808 mmol) was added to a solution of methyl 2-[2-(4-hydroxyphenyl)ethyl]-5-phenylpentanoate (250 mg, 0.800 mmol) and 3-fluorobenzonitrile (250 mg, 2.064 mmol) in DMF (25 mL). The reaction mixture was warmed up to 130° C., and allowed to react for 6 h. It was poured into H2O (120 mL) and extracted with Et2O (100 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was purified by flash chromatography on SiO2 (5→15% EtOAc/hexanes), to give 142 mg of methyl 2-{2-[4-(3-cyanophenoxy)phenyl]ethyl}-5-phenylpentanoate (colourless oil, yield: 43%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.28-6.91 (m, 11H), 6.78 (dd, J=8.2 Hz, 1.3 Hz, 2H), 3.54 (s, 3H), 2.40 (m, 4H), 2.28 (m, 1H), 1.78 (m, 1H), 1.69-1.28 (m, 5H).
The compound was synthesized from methyl 2-{2-[4-(3-cyanophenoxy)phenyl]ethyl}-5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO2 (30→40% EtOAc/hexanes) to furnish a colourless oil (yield: 50%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.59 (m, 1H), 7.48-6.97 (m, 10H), 6.86 (d, J=8.5 Hz, 2H), 2.53 (m, 4H), 2.37 (m, 1H), 1.91 (m, 1H), 1.78-1.41 (m, 5H).
EI MS: m/z=398 (M−1), 400 (M+1).
K2CO3 (100 mg, 0.723 mmol) was added to a solution of methyl 2-[2-(4-hydroxyphenyl)ethyl]-5-phenylpentanoate (100 mg, 0.320 mmol) and 4-fluorobenzonitrile (100 mg, 0.825 mmol) in DMF (15 mL). The reaction mixture was warmed up to 130° C., and allowed to react for 2 h. It was poured into H2O (120 mL) and extracted with Et2O (100 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was purified by flash chromatography on SiO2 (5→15% EtOAc/hexanes), to give 133 mg of methyl 2-{2-[4-(4-cyanophenoxy)phenyl]ethyl}-5-phenylpentanoate (colourless oil, yield: 99%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.66 (m, 2H), 7.41-7.20 (m, 7H), 7.06 (m, 4H), 3.79 (s, 3H), 2.67 (m, 4H), 2.50 (m, 1H), 2.05 (m, 1H), 1.97-1.60 (m, 5H).
The compound was synthesized from methyl 2-{2-[4-(4-cyanophenoxy)phenyl]ethyl}-5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO2 (5→40% EtOAc/hexanes) to furnish a colourless oil (yield: 54%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.48 (m, 2H), 7.23-6.99 (m, 7H), 6.88 (m, 4H), 2.55 (m, 4H), 2.36 (m, 1H), 1.91 (m, 1H), 1.77-1.43 (m, 5H).
EI MS: m/z=398 (M−1), 400 (M+1).
Cu(OAc)2 (150 mg, 0.825 mmol) was added to a solution of methyl 2-[2-(4-hydroxyphenyl)ethyl]-5-phenylpentanoate (100 mg, 0.320 mmol), pyridine (0.15 mL, 1.854 mmol) and 4-fluorophenylboronic acid (90 mg, 0.643 mmol) in CH2Cl2 (25 mL). The reaction mixture was stirred at r.t. for 20 h. It was poured into H2O (150 mL), taken up to pH=2 and extracted with CH2Cl2 (100 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was purified by flash chromatography on SiO2 (2→8% EtOAc/hexanes), to give 122 mg of methyl 2-{2-[4-(4-fluoro phenoxy)phenyl]ethyl}-5-phenylpentanoate (colourless oil, yield: 94%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.39 (m, 2H), 7.34-7.20 (m, 5H), 7.18-6.95 (m, 6H), 3.82 (s, 3H), 2.69 (m, 4H), 2.55 (m, 1H), 2.08 (m, 1H), 1.94-1.58 (m, 5H).
The compound was synthesized from methyl 2-{2-[4-(4-fluorophenoxy)phenyl]ethyl}-5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO2 (10→80% EtOAc/hexanes) to furnish a colourless oil (yield: 62%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.25 (m, 2H), 7.21-7.07 (m, 5H), 7.01-6.83 (m, 6H), 2.60 (m, 4H), 2.40 (m, 1H), 1.96 (m, 1H), 1.84-1.47 (m, 5H).
EI MS: m/z=391 (M−1).
Cu(OAc)2 (232 mg, 1.28 mmol) was added to a solution of methyl 2-[2-(4-hydroxyphenyl)ethyl]-5-phenylpentanoate (160 mg, 0.512 mmol), pyridine (0.21 mL, 2.56 mmol) and phenylboronic acid (123 mg, 1.02 mmol) in CH2Cl2 (25 mL). The reaction mixture was stirred at r.t. for 20 h. It was poured into H2O (150 mL), taken up to pH=2 and extracted with CH2Cl2 (2×20 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was purified by flash chromatography on SiO2 (0→8% EtOAc/hexanes), to give 119 mg of methyl 2-{2-[4-phenoxyphenyl]ethyl}-5-phenylpentanoate (colourless oil, yield: 60%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.30 (m, 5H), 7.15 (m, 5H), 6.98 (m, 4H), 3.70 (s, 3H), 2.57 (m, 4H), 2.46 (m, 1H), 1.96 (m, 1H), 1.83-1.48 (m, 5H).
The compound was synthesized from methyl 2-{2-[4-phenoxyphenyl]ethyl}-5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO2 (10→80% EtOAc/hexanes) to furnish a colourless oil (yield: 12%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.40-6.90 (m, 14H), 2.63 (m, 4H), 2.48 (m, 1H), 2.01 (m, 1H), 1.87-1.50 (m, 5H).
EI MS: m/z=373 (M−1).
Cu(OAc)2 (232 mg, 1.28 mmol) was added to a solution of methyl 2-[2-(4-hydroxyphenyl)ethyl]-5-phenylpentanoate (160 mg, 0.512 mmol), pyridine (0.21 mL, 2.56 mmol) and 4-(trifluoromethyl)phenylboronic acid (193 mg, 1.02 mmol) in CH2Cl2 (25 mL). The reaction mixture was stirred at r.t. for 20 h. It was poured into H2O (150 mL), taken up to pH=2 and extracted with CH2Cl2 (2×20 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was purified by flash chromatography on SiO2 (0→8% EtOAc/hexanes), to give 200 mg of methyl 2-{2-[4-(4-trifluoromethylphenoxy)phenyl]ethyl}-5-phenylpentanoate (colourless oil, yield: 60%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.56 (m, 2H), 7.37-6.84 (m, 11H), 3.71 (s, 3H), 2.66-2.35 (m, 5H), 1.95 (m, 1H), 1.83-1.42 (m, 5H).
The compound was synthesized from methyl 2-{2-[4-(4-trifluoromethyl phenoxy)phenyl]ethyl}-5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO2 (10→80% EtOAc/hexanes) to furnish a colourless oil (yield: 36%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.56 (d, J=9.0 Hz, 2H), 7.37-7.13 (m, 8H), 7.00 (m, 3H), 2.67 (m, 4H), 2.47 (m, 1H), 2.00 (m, 1H), 1.86-1.53 (m, 5H).
EI MS: m/z=441 (M−1).
Cu(OAc)2 (232 mg, 1.28 mmol) was added to a solution of methyl 2-[2-(4-hydroxyphenyl)ethyl]-5-phenylpentanoate (160 mg, 0.512 mmol), pyridine (0.21 mL, 2.56 mmol) and 4-(methoxy)phenylboronic acid (155 mg, 1.02 mmol) in CH2Cl2 (25 mL). The reaction mixture was stirred at r.t. for 20 h. It was poured into H2O (150 mL), taken up to pH=2 and extracted with CH2Cl2 (2×20 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was purified by flash chromatography on SiO2 (0→8% EtOAc/hexanes), to give 110 mg of methyl 2-{2-[4-(4-methoxyphenoxy)phenyl]ethyl}-5-phenylpentanoate (colourless oil, yield: 52%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.30-6.99 (m, 9H), 6.98-6.75 (m, 4H), 3.77 (s, 3H), 3.66 (s, 3H), 2.57 (m, 4H), 2.38 (m, 1H), 1.76-1.47 (m, 5H).
The compound was synthesized from methyl 2-{2-[4-(4-methoxyphenoxy)phenyl]ethyl}-5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO2 (0→5% EtOAc/hexanes) to furnish a colourless oil (yield: 69%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.40.7.14 (m, 8H), 7.09-6.90 (m, 5H), 3.88 (s, 3H), 2.70 (m, 4H), 2.52 (m, 1H), 2.03 (m, 1H), 1.91-1.56 (m, 5H).
EI MS: m/z=403 (M−1).
NaBH4 (625 mg, 16.521 mmol) was added to a −18° C. cooled solution of ethyl 2-oxo-4-phenylbutyrate in EtOH (70 mL). The reaction mixture was stirred at low temperature for 5 min, poured into H2O (120 mL), taken up to pH=2 with HCl and extracted with CH2Cl2 (200 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was purified by flash chromatography on SiO2 (5→15% EtOAc/hexanes), to give 2.85 g of ethyl 2-hydroxy-4-phenylbutanoate (colourless oil, yield: 83%).
Trifluoromethanesulfonic anhydride (1.70 g, 6.025 mmol) was added to a −78° C. cooled solution of ethyl 2-hydroxy-4-phenylbutanoate (1.0 g, 4.801 mmol) and 2,6-luitidine (1.7 mL, 14.642 mmol) in CH2Cl2 (40 mL). The reaction mixture was allowed to react at low temperature for 5 min, poured into H2O (150 mL), taken up to pH=3 with HCl and extracted with CH2Cl2 (150 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was purified by flash chromatography on SiO2 (4→10% EtOAc/hexanes), to give 1.41 g of ethyl 4-phenyl-2-{[(trifluoromethyl)sulfonyl]oxy}butanoate (colourless oil, yield: 86%).
EI MS: m/z=341 (M+1).
Benzeneethanethiol (0.45 mL, 3.33 mmol) was added to a solution of ethyl 4-phenyl-2-{[(trifluoromethyl)sulfonyl]oxy}butanoate (750 mg, 2.20 mmol) and DIPEA (1.5 mL, 8.76 mmol) in CH2Cl2 (50 mL). The reaction mixture stirred at r.t. for 2 h, poured into H2O (200 mL) and extracted with Et2O (100 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was purified by flash chromatography on SiO2 (0 4% EtOAc/hexanes), to give 635 mg of ethyl 4-phenyl-2-[(2-phenylethyl)thio]butanoate (colourless oil, yield: 88%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.62-7.34 (m, 10H), 4.46 (c, J=7.1 Hz, 2H), 3.50 (t, J=7.1 Hz, 1H), 3.27-2.93 (m, 6H), 2.48 (m, 1H), 2.24 (m, 1H), 1.55 (t, J=7.1 Hz, 3H).
The compound was synthesized from ethyl 4-phenyl-2-[(2-phenylethyl)thio]butanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO2 (5→40% EtOAc/hexanes) to afford a colourless oil (yield: 56%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.36-7.09 (m, 10H), 3.22 (t, J=7.4 Hz, 1H), 2.90 (m, 4H), 3.22 (t, J=7.6 Hz, 2H), 2.21 (m, 1H), 1.99 (m, 1H).
EI MS: m/z=299 (M−1).
A solution of (3-bromopropyl)benzene (2.0 g, 10.045 mmol) in Et2O (10 mL) was dropwise was added to a refluxing suspension of Mg (powder, 240 mg, 9.872 mmol) and 1,2-dibromoethane (drops) in Et2O (20 mL). After 30 min, the mixture was allowed to reach r.t. and transferred to flask containing a 0° C. cooled a solution of diethyl oxalate (1.185 g, 8.114 mmol) in Et2O (30 mL). The reaction mixture was stirred at r.t. overnight. It was poured into H2O (100 mL) and taken up to pH=2 with HCl (10% aqueous solution). The product was extracted with EtOAc (100 mL), and the organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (5→10% EtOAc/hexanes) to furnish 1.6 g of ethyl 2-oxo-5-phenylpentanoate (colourless oil, yield: 89%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.14 (m, 2H), 7.06 (m, 3H), 4.41-4.24 (m, 2H), 2.85 (t, J=7.4 Hz, 2H), 2.66 (t, J=7.4 Hz, 2H), 1.97 (t, J=7.1 Hz, 2H), 1.36 (t, J=7.1 Hz, 3H).
NaBH4 (300 mg, 7.932 mmol) was added to 0° C. cooled a solution of ethyl 2-oxo-5-phenylpentanoate (1.52 g, 6.90 mmol) in EtOH (40 mL). After 5 min, the reaction mixture was poured into H2O (150 mL) and taken up to pH=1 with HCl (10% aqueous solution). The product was extracted with CH2Cl2 (2×120 mL), and the organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (5→20% EtOAc/hexanes) to furnish 843 mg of ethyl 2-hydroxy-5-phenylpentanoate (colourless oil, yield: 55%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.21 (m, 2H), 7.12 (m, 3H), 4.31-4.14 (m, 3H), 2.80-2.56 (m, 3H), 1.92-1.59 (m, 4H), 1.29 (t, J=7.1 Hz, 3H).
BnBr (1.1 mL) was added to a suspension of ethyl 2-hydroxy-5-phenyl pentanoate (830 mg, 3.733 mmol) and Ag2O (1.20 g, 5.178 mmol) in DMF (30 mL). The reaction mixture was warmed up to 70° C. and stirred at that temperature for 7 h. It was allowed to reach r.t., filtered through Celite (washing with EtOAc) and washed with H2O (100 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (5→15% EtOAc/hexanes) to furnish 680 mg of ethyl 2-(benzyloxy)-5-phenylpentanoate (yellow coloured oil, yield: 58%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.38 (m, 10H), 5.20 (m, 2H), 4.71 (d, J=11.5 Hz, 1H), 4.59-4.08 (m, 2H), 2.59 (m, 2H), 1.84-1.6 (m, 4H), 1.28 (m, 3H).
The compound was prepared from ethyl 2-(benzyloxy)-5-phenylpentanoate following the general procedure B, to furnish the compound as a yellow coloured oil after flash chromatography purification (yield: 10%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.39-7.05 (m, 10H), 4.69 (d, J=11.5 Hz, 1H), 4.35 (d, J=11.5 Hz, 1H), 3.80 (m, 1H), 2.56 (m, 2H), 1.36 (m, 4H).
EI MS: m/z=283 (M−1).
BnBr (3.5 mL, 29.425 mmol) was added to a suspension of K2CO3 (5.10 g, 36.90 mmol) and methyl mercaptoacetate (2 mL, 22.366 mmol) in CH3CN (50 mL). The reaction mixture was stirred at r.t. for 10 min, poured into H2O (150 mL), and extracted with EtOAc (100 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated, and the crude residue was flash chromatographed on SiO2 (0→4% EtOAc/hexanes) to furnish 4.14 g of methyl(benzylthio)acetate (colourless oil, yield: 94%).
The compound was prepared from methyl(benzylthio)acetate following the general procedure A, by using PhCH2CH2CH2I as alkylating reagent. Flash chromatography purification afforded the compound as a colourless oil (yield: 77%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.06 (m, 10H), 3.64 (s, 2H), 3.54 (s, 3H), 2.36 (t, J=7.1 Hz, 2H), 1.70 (m, 1H), 1.48 (m, 4H).
The compound was prepared from methyl 2-(benzylthio)-5-phenylpentanoate following the general procedure B, to furnish the compound as a colourless oil after flash chromatography purification (yield: 11%).
EI MS: m/z=299 (M−1).
NaH (16 mg, 60% mineral oil suspension, 0.40 mmol) was added to a solution of 2-(benzylthio)-5-phenylpentanoic acid (123 mg, 0.409 mmol) in THF (10 mL). The reaction mixture was stirred at r.t. for 15 min, and solvent was concentrated off. The crude residue was slurred with Et2O (5 mL) and hexanes (5 mL), to give 84 mg of sodium 2-(benzylthio)-5-phenylpentanoate (white solid, yield: 64%).
1H NMR (MeOD, 250 MHz) δ ppm: 7.33 (m, 3H), 7.22 (m, 4H), 7.14 (m, 3H), 3.76 (m, 2H), 3.20 (m, 1H), 2.55 (t, J=7.4 Hz, 2H), 1.86-1.55 (m, 4H).
EI MS: m/z=299 (M−Na−1).
The compound was prepared from methyl(benzylthio)acetate following the general procedure A, by using BnBr as alkylating reagent. Flash chromatography purification on SiO2 (0→10% EtOAc/hexanes) afforded methyl 2-(benzylthio)-3-phenylpropanoate as a colourless oil (yield: 95%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.28 (m, 10H), 3.77 (s, 2H), 3.61 (s, 3H), 3.41 (m, 1H), 3.14 (m, 1H), 2.86 (m, 1H).
The compound was prepared from methyl 2-(benzylthio)-3-phenylpropanoate following the general procedure B. Flash chromatography purification on SiO2 (5→20% EtOAc/hexanes), followed by slurries with hexanes, afforded 2-(benzylthio)-3-phenylpropanoic acid as a white solid (yield: 5%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.23 (m, 8H), 7.05 (m, 2H), 3.82 (m, 2H), 3.37 (t, J=8.5 Hz, 1H), 3.16 (m, 1H), 2.85 (m, 1H).
EI MS: m/z=271 (M−1).
Pd(PPh3)4 (65 mg, 0.056 mmol) was added to a suspension of methyl 2-{2-(4-{[(trifluoromethyl)sulfonyl]oxy}phenyl)ethyl}-5-phenyl pentanoate (Intermediate A) (210 mg, 0.559 mmol), Cs2CO3 (375 mg, 1.150 mmol) and phenylboronic acid (110 mg, 0.902 mmol) in DMF (14 mL). The reaction mixture was stirred at 90° C. until no unreacted Intermediate A was detected by TLC analysis (5 h). It was allowed to reach r.t., poured into H2O (100 mL) and extracted with Et2O (100 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was purified by flash chromatography on SiO2 (0→4% EtOAc/hexanes), to afford 54 mg of methyl 2-[2-(1,1′-biphenyl-4-yl)ethyl]-5-phenylpentanoate (colourless oil, yield: 26%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.56 (m, 3H), 7.43 (m, 2H), 7.36-7.12 (m, 9H), 3.71 (s, 3H), 2.60 (m, 4H), 2.45 (m, 1H), 2.00 (m, 1H), 1.88-1.46 (m, 5H).
The compound was synthesized from methyl 2-[2-(1,1′-biphenyl-4-yl)ethyl]-5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO2 (10→30% EtOAc/hexanes) to furnish a white solid (yield: 44%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.54-7.01 (m, 14H), 2.55 (m, 4H), 2.38 (m, 1H), 1.91 (m, 1H), 1.78-1.38 (m, 5H).
EI MS: m/z=357 (M−1).
The compound was synthesized from Intermediate A and furan-2-boronic acid, following the experimental procedure detailed in Method F. It was purified by flash chromatography on SiO2 (5→10% EtOAc/hexanes) to give a colourless oil (yield: 47%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.69 (d, J=7.9 Hz, 2H), 7.56 (m, 1H), 7.37 (m, 2H), 7.27 (m, 5H), 6.71 (d, J=3.2 Hz, 1H), 6.56 (m, 1H), 3.83-3.76 (m, 3H), 2.76-2.62 (m, 4H), 2.53 (m, 1H), 2.07 (m, 1H), 1.92-1.60 (m, 5H).
The compound was synthesized from methyl 2-{2-[4′-(2-furyl)phenyl]ethyl}-5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO2 (20→100% EtOAc/hexanes) to give a white solid (yield: 75%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.68 (d, J=7.9 Hz, 2H), 7.53 (m, 1H), 7.44-7.20 (m, 7H), 6.69 (d, J=3.2 Hz, 1H), 6.55 (m, 1H), 2.71 (m, 4H), 2.53 (m, 1H), 2.09 (m, 1H), 1.98-1.58 (m, 5H).
EI MS: m/z=347 (M−1).
The compound was synthesized from Intermediate A and furan-3-boronic acid, following the experimental procedure detailed in Method F. It was purified by flash chromatography on SiO2 (5% EtOAc/hexanes) to give a colourless oil (yield: 27%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.79 (s, 1H), 7.51 (m, 2H), 7.31 (m, 8H), 6.77 (s, 1H), 3.78 (s, 3H), 2.67 (m, 4H), 2.52 (m, 1H), 2.05 (m, 1H), 1.88-1.60 (m, 5H).
The compound was synthesized from methyl 2-{2-[4′-(3-furyl)phenyl]ethyl}-5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO2 (20→100% EtOAc/hexanes) to furnish an off-white solid (yield: 75%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.51 (d, J=8.2 Hz, 2H), 7.39 (d, J=6.8 Hz, 2H), 7.32-7.11 (m, 8H), 2.61 (m, 4H), 2.45 (m, 1H), 1.99 (m, 1H), 1.86-1.50 (m, 5H).
EI MS: m/z=349 (M+1).
The compound was synthesized from Intermediate A and 3-thiopheneboronic acid, following the experimental procedure detailed in Method F. It was purified by flash chromatography on SiO2 (5→10% EtOAc/hexanes) to afford a colourless oil (yield: 43%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.40 (d, J=8.2 Hz, 2H), 7.31-7.21 (m, 2H), 7.18-6.99 (m, 8H), 3.57 (s, 3H), 2.54-2.41 (m, 4H), 2.32 (m, 1H), 1.83 (m, 1H), 1.64-1.42 (m, 5H).
The compound was synthesized from methyl 2-{2-[4′-(3-thienyl)phenyl]ethyl}-5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO2 (15→50% EtOAc/hexanes) to give an off-white solid (yield: 80%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.51 (d, J=8.2 Hz, 2H), 7.44-7.35 (m, 2H), 7.31-7.12 (m, 8H), 2.62 (m, 4H), 2.46 (m, 1H), 2.00 (m, 1H), 1.86-1.53 (m, 5H).
EI MS: m/z=363 (M−1).
The compound was synthesized from Intermediate A and 4-pyridineboronic acid, following the experimental procedure detailed in Method F. It was purified by flash chromatography on SiO2 (20→40% EtOAc/hexanes) to give a yellow-coloured oil (yield: 52%).
1H NMR (CDCl3, 250 MHz) δ ppm: 8.64 (m, 2H), 7.52 (m, 5H), 7.28 (m, 4H), 7.16 (m, 2H), 3.70 (s, 3H), 2.59 (m, 4H), 2.45 (m, 1H), 1.97-1.45 (m, 6H).
The compound was synthesized from methyl 2-{2-[(4′-pyridinyl)phenyl-4-yl]ethyl}-5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO2 (0→10% MeOH/CH2Cl2) to give a colourless oil (yield: 98%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.99 (bs, 1H), 7.83 (bs, 1H), 7.70 (d, J=7.9 Hz, 1H), 7.54-7.42 (m, 3H), 7.39-7.21 (m, 4H), 7.14 (d, J=7.9 Hz, 2H), 7.08-7.01 (m, 1H), 2.93-2.54 (m, 4H), 2.50 (m, 1H), 2.00 (m, 1H), 1.87-1.62 (m, 5H).
A suspension of 2-{2-[(4′-Pyridinyl)phenyl-4-yl]ethyl}-5-phenylpentanoic acid (0.267 mmol) in HCl.MeOH (0.5 mL, 1 M solution, 0.5 mmol) was stirred at r.t. for 1 h. Solvent was concentrated off, and the crude residue was precipitated from a mixture of MeOH (2 mL) and Et2O (15 mL), to give 40 mg of a white solid (yield: 38%).
1H NMR (MeOD, 250 MHz) δ ppm: 8.71 (m, 2H), 8.74 (bs, 2H), 7.83 (m, 2H), 7.36 (bs, 2H), 7.11 (m, 2H), 7.05 (m, 3H), 2.60 (m, 2H), 2.49 (m, 2H), 2.27 (m, 1H), 1.85 (m, 1H), 1.69 (m, 1H), 1.50 (m, 4H).
EI MS: m/z=360 (M−Cl−).
The compound was synthesized from Intermediate A and 3-pyridineboronic acid following the experimental procedure detailed in Method F. It was purified by flash chromatography on SiO2 (10→40% EtOAc/hexanes) to give a yellow-coloured oil (yield: 49%).
1H NMR (CDCl3, 250 MHz) δ ppm: 8.83 (m, 1H), 8.57 (m, 1H), 7.50 (d, J=7.9 Hz, 2H), 7.35 (m, 1H), 7.31-7.23 (m, 4H), 7.16 (m, 3H), 3.69 (s, 3H), 2.60 (m, 4H), 2.45 (m, 1H), 1.99 (m, 1H), 1.84-1.52 (m, 5H).
The compound was synthesized from methyl 2-[2-(4-pyridin-3′-ylphenyl)ethyl]-5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO2 (10→60% EtOAc/hexanes) to give a colourless oil (yield: 38%).
1H NMR (CDCl3, 250 MHz) δ ppm: 8.86 (bs, 1H), 8.58 (m, 1H), 7.89 (d, J=10.1 Hz, 1H), 7.56-7.07 (m, 10H), 2.65 (m, 4H), 2.47 (m, 1H), 2.03 (m, 1H), 1.90-1.47 (m, 5H).
EI MS: m/z=360 (M+1).
The compound was synthesized from Intermediate A and 2-thiopheneboronic acid, following the experimental procedure detailed in Method F. It was purified by flash chromatography on SiO2 (2→4% EtOAc/hexanes) to give a colourless oil (yield: 56%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.53 (d, J=7.4 Hz, 2H), 7.32-7.22 (m, 4H), 7.21-7.04 (m, 6H), 3.68 (s, 3H), 2.58 (m, 4H), 2.41 (m, 1H), 1.95 (m, 1H), 1.83-1.46 (m, 5H).
The compound was synthesized from methyl 2-{2-[4′-(2-thienyl)phenyl]ethyl}-5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO2 (10→60% EtOAc/hexanes) to afford a white solid (yield: 38%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.54 (d, J=8.2 Hz, 2H), 7.33-7.13 (m, 9H), 7.06 (m, 1H), 2.63 (m, 4H), 2.45 (m, 1H), 2.00 (m, 1H), 1.86-1.49 (m, 5H).
EI MS: m/z=363 (M−1).
The compound was synthesized from Intermediate B and 2-thiopheneboronic acid, following the experimental procedure detailed in Method F. It was purified by flash chromatography on SiO2 (10→20% EtOAc/hexanes) to afford a yellow-coloured oil (yield: 78%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.99 (m, 1H), 7.83 (m, 1H), 7.70 (d, J=7.9 Hz, 1H), 7.54-7.42 (m, 3H), 7.39-7.21 (m, 5H), 7.14 (d, J=7.9 Hz, 2H), 7.08-7.01 (m, 1H), 3.67 (s, 3H), 3.07 (m, 2H), 2.60 (m, 2H), 2.40 (m, 1H), 1.95 (m, 1H), 1.86-1.62 (m, 5H).
The compound was synthesized from methyl 5-(1-naphthyl)-2-[2-(4′-thien-2-ylphenyl)ethyl]-pentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO2 (10→30% EtOAc/hexanes) to give a white solid (yield: 20%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.99 (m, 1H), 7.83 (m, 1H), 7.70 (d, J=7.9 Hz, 1H), 7.54-7.42 (m, 3H), 7.39-7.21 (m, 5H), 7.14 (d, J=7.9 Hz, 2H), 7.08-7.01 (m, 1H), 3.07 (m, 2H), 2.63 (m, 2H), 2.47 (m, 1H), 1.95 (m, 1H), 1.87-1.62 (m, 5H).
The compound was synthesized from Intermediate B and 3-pyridineboronic acid, following the experimental procedure detailed in Method F. It was purified by flash chromatography on SiO2 (20→50% EtOAc/hexanes) to give a colourless oil (yield: 79%).
1H NMR (CDCl3, 250 MHz) δ ppm: 8.83 (m, 1H), 8.57 (m, 1H), 7.99 (m, 1H), 7.84 (m, 3H), 7.54-7.23 (m, 9H), 3.68 (s, 3H), 3.07 (m, 2H), 2.80-2.20 (m, 4H), 2.00-1.67 (m, 5H).
The compound was synthesized from methyl 5-(1-naphthyl)-2-[2-(4′-pyridin-3-ylphenyl)ethyl]-pentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO2 (0→30% MeOH/EtOAc) to give a colourless oil (yield: 48%).
1H NMR (CDCl3, 250 MHz) δ ppm: 8.66 (s, 1H), 8.38 (d, J=4.9 Hz, 1H), 7.94 (m, 2H), 7.74 (d, J=7.1 Hz, 1H), 7.60 (d, J=7.9 Hz, 1H), 7.48-7.32 (m, 5H), 7.28-7.13 (m, 4H), 2.97 (m, 2H), 2.54 (m, 2H), 2.33 (m, 1H), 1.86 (m, 1H), 1.72-1.56 (m, 5H).
EI MS: m/z=410 (M+1).
Cu(OAc)2 (150 mg, 0.825 mmol) was added to a solution of methyl 2-[2-(4-aminophenyl)ethyl]-5-phenylpentanoate (100 mg, 0.320 mmol), pyridine (0.13 mL, 1.60 mmol) and phenylboronic acid (58 mg, 0.475 mmol) in CH2Cl2 (20 mL). The reaction mixture was stirred at r.t. for 14 h. It was poured into H2O (150 mL), taken up to pH=6 and extracted with CH2Cl2 (2×100 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was purified by flash chromatography on SiO2 (0→8% EtOAc/hexanes), to give 60 mg of methyl 2-[2-(4-anilinophenyl)ethyl]-5-phenylpentanoate (colourless oil, yield: 48%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.36-7.12 (m, 8H), 7.10-6.87 (m, 6H), 5.65 (bs, 1H), 3.70 (s, 3H), 2.67-2.35 (m, 5H), 1.96 (m, 1H), 1.82-1.48 (m, 5H).
The compound was synthesized from methyl 2-[2-(4-anilinophenyl)ethyl]-5-phenylpentanoate following the experimental procedure detailed in Method B. It was purified by flash chromatography on SiO2 (20→50% EtOAc/hexanes) to furnish a colourless oil (yield: 17%).
1H NMR (CDCl3, 250 MHz) δ ppm: 7.33-7.13 (m, 8H), 7.12-6.85 (m, 6H), 2.61 (m, 4H), 2.44 (m, 1H), 1.93 (m, 1H), 1.88-1.48 (m, 5H).
EI MS: m/z=372 (M−1), 374 (M+1).
The human colon cancer cell line HCT116 and the human breast cancer cell line MCF-7 were from the American Type Culture Collection (ATCC; CCL-247 and HTB-22, respectively).
Additionally, the following cancer cell lines were used:
The NP-9 cell line from pancreas, was provided by Dr. R. Alemany from Translational Research Laboratory (Institut Catala d'Oncologia). (cf., Cascallò, M. et al., “Ras-dependent Oncolysis with an Adenovirus VAI mutant”, Cancer Research, 2003, 63, 5544-5550). This cells was maintained in DMEM:F12 (Invitrogen) supplemented with 10% fetal calf serum (Invitrogen), L-glutamine 10M (Invitrogen), pyruvate 5M (Invitrogen).
The HCT116 cell line was maintained in DMEM GlutaMAX (Invitrogen) supplemented with 10% fetal calf serum and the MCF7 cell line was maintained in RPMI1640 GlutaMAX (Invitrogen) containing 1 mM sodium piruvate and 10% fetal calf serum.
Cells were grown in a humidified incubator at 37° C. in 5% CO2.
Cells were plated in 96-well plates at a density of 6000 cells/well in 100 μl medium 24 h before addition of drugs. They were then added in concentrations from 100 μM to 0.45 nM (each concentration in triplicate). To do so, a drugs-dilution plate at twice the screening concentrations was prepared. 72 hours later, alamarBlue (Biosource, Invitrogen) viability assay was performed following manufacturer's protocol. In brief, alamarBlue diluted in media was added to cells to have a 5% solution. Cells were incubated at 37° C., 3 hours and at room temperature, 30 min. Cells with no drug and, cells with no drug and lysed with triton X-100 were used as controls. Fluorescence was monitored at 530 nm excitation and 590 nm emission wavelengths. Results were quantified using Infinite F200 Microplate Reader (Tecan Group, Ltd.). EC50 were calculated as the dose of drugs required to inhibit cell growth by 50%, with Origin 7.0 computer program.
The EC50 values (μM) obtained for the compounds of the present invention on HCT-116 and MCF-7 cell lines are summarized in Table 1.
Carboxylate-based compounds have a great solubility which allows administration at the doses required for achiving an effect in-vivo). Carboxylates such as valproic acid showed similar activities in cell-based assays but are progressing in clinical phases for cancer treatments. Moreover, example 12 showed clear inhibition of the target of these compounds (i.e. HDACs).
Panel of cell lines (EC50's) (Table 2)
HDAC inhibition was determined indirectly by measuring the fluorescence generated by deacetylated fluorogenic substrate (KI-104 fluor de Lys™ Biomol®, used at 125 μM) product reacting with a developer solution (KI-105 Fluor de Lys™ Biomol®). All assays were carried out in the assay buffer: 50 mM Tris/Cl, pH 8.0, 137 mM NaCl, 2.7 mM KCl, 1 mM MgCl2).
Reactions were carried out in a 96-wells microplate (Corning 96 well Flat Bottom Non-binding surface (black) ref. 3651).
Potential inhibitors were added after five fold serial dilutions in DMSO. Final DMSO concentration in the assay microplate was kept at 2%.
Afterwards, human recombinant HDAC1, HDAC 2 or HDAC 8 were added up to 125 nM, 33.3 nM, 25 nM and 1850 nM respectively in assay buffer. When necessary, the mixture was incubated at room temperature prior the addition of substrate.
Finally, substrate was added at 125 nM. Total reaction volume of 50 μl. Human recombinant HDACs could be acquired from commercial sources (HDAC1: ref. #50001, BPS Bioscience™; HDAC 2: ref. #50002, BPS Bioscience™; HDAC 8: ref. #50008, BPS Bioscience™).
Inhibitor-protein incubation, reaction time and reaction temperature are reported in the following Table 3:
Reactions were stopped with 50 μl Developer (KI-105 Fluor de Lys™, BIOMOL®) with 2 μmol/L trichostatin A (TSA, final concentration 1 μmol/L). After 20 minutes at 37° C., fluorescence (excitation 360 nm, emission 460 nm) was measured using an Infinite F200 fluorimeter (Tecan). Background was determined in reactions using substrate in the absence of enzyme.
IC50 values are defined as the compound concentration at which the deacetylase activity is 50% inhibited. In these assays the following grading was used (I: IC50≦10 μM; II: 10 μM<IC50≦100 μM; III: 100 μM<IC50≦1 mM) The results obtained are summarized in Table 4.
Compounds where R3 is —OR4 or —OCR4R4—O—C(O)—R4 instead of —OH do not show inhibition of HDACs in inhibition assays because the —OH is required for the binding with the protein. In in-vivo or cell-based conditions the —OR4 and —OCR4R4—O—C(O)—R4 groups are biotransformed to —OH, thus these groups acts as prodrugs of the carboxylate form.
| Number | Date | Country | Kind |
|---|---|---|---|
| 07150330.4 | Dec 2007 | EP | regional |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP2008/067952 | 12/18/2008 | WO | 00 | 1/3/2011 |
