Patent Application
20100048898
The field of the invention is synthetic organic chemistry, more particularly, pharmaceutical chemistry and quinazoline derivatives.
HER2, ErbB3, and ErbB4 belong to the ErbB family and form a heterocomplex that interacts in intracellular signal transduction. Co-expression of the EGF receptor and HER2 accelerates tumorigenesis, is associated with poor prognoses in breast cancer, oral cancer, and lung cancer, and is associated with resistance to endocrine therapy in breast cancer.
Certain 4-aminoquinazolines inhibit EGF receptor tyrosine kinase and HER2 tyrosine kinase and may prove useful in the treatment of a wide variety of cancers. United States Patent Publication No. 2004/0116422 (the complete disclosure of which is hereby incorporated by reference) discloses syntheses of 7-alkynyl-4-aminoquinaozolines which are useful inhibitors of EGF receptor tyrosine kinase and HER2 tyrosine kinase. PCT WO2005/051924 also describes syntheses of 7-alkynylaminoquinaozolines.
Useful anticancer agents disclosed in United States Patent Publication No. 2004/0116422 include 4-[N-3-chloro-4-fluorophenyl)]-7-[3-methyl-3-(4-methyl-1-piperazinyl)-1-butynyl]-6-[N-methyl acrylamide]quinazoline, which has the following structure:
The syntheses described in United States Patent Publication No. 2004/0116422 substitute the 7-position of a 4-aminoquinazoline with an acetylinic moiety. These syntheses would be simplified—and process efficiencies enhanced—if the acetylenic moiety could be introduced prior to formation of the 4-aminoquinazoline pharmacore, thereby reducing the requisite number of process steps.
Accordingly, the need exists for new and improved processes for making 7-alkynyl-4-aminoquinaozoline anti cancer agents.
The invention provides improved and readily-scalable processes for synthesizing 7-alkynyl-4-aminoquinaozolines in high yields. Processes of the invention minimize the number of process steps needed to make 7-alkynyl-4-aminoquinaozolines and achieve high yields of purified products.
In one embodiment, the invention provides a process for synthesizing 7-alkynyl-4-aminoquinazoline compounds having the formula (1):
Processes of the invention are conducted at approximately atmospheric pressure and can be done one-pot or in steps using reactant amounts and reaction media which are either described herein or which can be determined by those of ordinary skill in the art.
In one embodiment, the invention provides a process for synthesizing 4-[N-3-chloro-4-fluorophenyl)]-7-[3-methyl-3-(4methyl-1-piperazinyl)-1-butynyl]-6-[N-methyl acrylamide]quinazoline by:
In a preferred embodiment, the invention provides a process for synthesizing a pharmaceutically acceptable salt (e.g., a tosic acid salt) of 4-[N-3-chloro-4-fluorophenyl)]-7-[3-methyl-3-(4-methyl-1-piperazinyl)-1-butynyl]-6-[N-methyl acrylamide]quinazoline by:
An example of the aforementioned preferred embodiment is illustrated by the following reaction schemes:
Step (a) of the preferred embodiment described above can use CFA derivatives in which the CFA amine group of is protected by a variety of protecting groups, including acid-removable (acid-labile) protecting groups, such as a t-butyloxycarbonyl group, n-butyloxycarbonyl group other substituted oxycarbonyl (e.g., N-alphafluorenyloxycarbonyl, hexadienyloxycarbonyl) group, various carbamate groups such as methyl or ethyl carbamate (deprotection under a variety of conditions), 2,2,2-trichloroethylcarbamate or Troc group (deprotection with a reducing agent such as Zn, in water at a pH of about 4.2), or a trityl group such as a methyltrityl group or methoxytrityl group, among others. An exhaustive listing of alternative protecting groups which may be used in the present invention may be found in the text “Protecting Groups in Organic Synthesis, 3rd Edition”, by Philip J. Kocienski or “Greene's Protective Groups in Organic Synthesis, 4th Edition” by Peter G. M. Wuts and Theodora W. Greene. Steps (b)-(d) of the preferred embodiment described above proceed in the same manner irrespective of which protecting group is used, the only difference being the modification of conditions during the removal of the protecting group, which must be effective to remove the protecting group without appreciably impacting other groups within the molecule.
As illustrated in the reaction scheme below, 7-[3-methyl-3-(4methyl-piperazin-1-yl)-but-1-ynyl]-6-nitro-quinazolin-4-ol (A) can be formed by derivatizing 7-chloro-6-nitro-3H-quinazolin-4-one (3) at the 7-position with 3-methyl-3-(4-methyl-piperazin-1-yl)-but-1-ynyl (PBN). In an exemplary reaction, this occurs using approximately equimolar amounts of 1-(1,1-dimethyl-prop-2-ynyl)-4-methyl-piperazine and 7-chloro-6-nitro-3H-quinazolin-4-one at a temperature of between about 20° C. to about 100° C. and in a reaction medium comprising an amine acid scavenger such as triethyl amine, a polar aprotic solvent (e.g., dimethylacetamide (DMA), dimethylformamide (DMF), acetonitrile, or dimethyl sulfoxide, most preferably dimethyl sulfoxide) and a palladium catalyst (most preferably, a palladium chloride catalyst).
Alternatively, as shown in the following reaction, 7-[3-methyl-3-(4-methyl-piperazin-1-yl)-but-1-ynyl]-6-nitro-quinazolin-4-ol (A) can be formed by derivatizing 7-chloro-6-nitro-3H-quinazolin-4-one (3) at the 7-position with 3-methyl-3-(4-methyl-piperazin-1-yl)-but-1-ynyl (PBN) by reaction of approximately equimolar amounts of 1-(1,1-dimethyl-prop-2-ynyl)-4-methyl-piperazine and 7-chloro-6-nitro-3H-quinazolin-4-one at a temperature of between about 20° C. to about 100° C. or above and in a reaction medium comprising a solvent, preferably a polar aprotic solvent such as DMA, DMF, DMSO, acetonitrile, etc.
In another embodiment, the invention provides the compound 7-[3-methyl-3-(4-methyl-piperazin-1-yl)-but-1-ynyl]-6-nitro-quinazolin-4-ol (A):
which, as described above, is useful as an intermediate in the synthesis of 7-alkynyl-4-aminoquinazolines.
In still another embodiment, the invention provides a process comprising derivatizing 7-chloro-6-nitro-3H-quinazolin-4-one (3)
at the 7-position with a moiety of formula (IA) by reacting—through Sonogashira coupling or other reaction mechanism which favors substitution of the 7-position chlorine of 7-chloro-6-nitro-3H-quinazolin-4-one with an acetylenic moiety—approximately equimolar amounts of 7-chloro-6-nitro-3H-quinazolin-4-one and a compound of formula (IA) at a temperature of between about 20° C. to abut 100° C.
In still another embodiment the invention provides a process for synthesizing 7-[3-methyl-3-(4-methyl-piperazin-1-yl)-but-1-ynyl]-6-nitro-quinazolin-4-ol (A) by reacting 7-chloro-6-nitro-3H-quinazolin-4-one (3) and 1-(1,1-dimethyl-prop-2-ynyl)-4-methyl-piperazine (PBN) under reaction conditions which favor substitution of the 7-position chlorine of 7-chloro-6-nitro-3H-quinazolin-4-one. For example, 7-chloro-6-nitro-3H-quinazolin-4-one (3) and 1-(1,1-dimethyl-prop-2-ynyl)-4-methyl-piperazine (PBN) are reacted in a reaction medium comprising triethyl amine or other amine acid scavenger, a polar aprotic solvent (e.g., dimethylacetamide (DMA), dimethylformamide (DMF), acetonitrile, or dimethyl sulfoxide, most preferably dimethyl sulfoxide), and a palladium catalyst (preferably a palladium chloride catalyst) in accordance with the following reaction scheme:
These and other aspects of the invention are described further in the following detailed description.
The following definitions apply unless indicated otherwise.
The term “compound”, as used herein, unless otherwise indicated within context, refers to any specific chemical compound(s) disclosed herein. The compounds of the present invention include all stereoisomers (i.e, cis and trans isomers), tautomers, and all optical isomers of the present compound and related analogs within context (eg., R and S enantiomers), as well as racemic, diastereomeric and other mixtures of such isomers, as well as all polymorphs and salts of the compounds, where relevant.
The term “protecting group” refers to a group which renders a functional group in a molecule such as an amine group inert to further reaction conditions and can be readily removed under conditions which do not appreciably impact the rest of the molecule. “Acid-removable protecting groups” are protecting groups as defined above which are removed under acidic conditions.
The term “alkyl” as used herein, unless otherwise indicated, includes saturated and monovalent C1 to C7 hydrocarbon radicals having straight, branched, or cyclic moieties or combinations thereof. C1 to C5 alkyls are preferred.
“Alkenyl” means a branched or unbranched hydrocarbon group containing 2 to about 7 carbon atoms and at least one double bond, such as ethenyl, n-propenyl, isopropenyl, n-butenyl and isobutenyl. C1 to C5 alkenyls are preferred.
“Alkynyl” means a branched or unbranched hydrocarbon group containing 2 to about 7 carbon atoms and at least one triple bond, such as ethynyl, n-propynyl, isopropynyl, n-butynyl, and isobutynyl. C1 to C5 alkynyls are preferred.
“Alkoxy groups” include but are not limited to an alkyl group bound through an ether linkage; that is, an “alkoxy” group may be represented as —O-alkyl where alkyl is as defined above. C1 to C5 alkoxy groups are preferred.
“Alkanoyl groups” means an acyl group derived from an alkanecarboxylic acid such as acetyl, propionyl, and butyryl, among others.
“4-C1-C5 alkylpiperazin-1-yl” means a piperazin-1-yl group substituted at the 4-position with alkyl as defined herein. 4methyl-piperazin-1-yl is preferred.
“Halogenating agents” are agents which introduce a halogen atom into a compound and include, but are not limited, to thionyl halides (preferably thionyl chloride) or phosphorous oxychloride, as well as a phosphorus halide (e.g., phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride), and hydrochloric acid.
“Reducing agents” and “base” include but are not limited to hydrazine, as well as hydrogen gas (generally with a metal catalyst such as Pt or Pd), phenylhydrazine, Sn/HCl, SnCl2/HCl, Zn/H2O, NaBH4/CuCl, NaBH4/TiCl4, Fe, Na2S, NaH, LiH, and KH, as well as other examples of same as are otherwise set forth herein.
“Lewis acids” include but are not limited to FeCl3, aluminum chloride, boron trifluoride, niobium pentachloride, and ytterbium (III) triflate.
“Bases”, especially including “strong bases” are those described above. These generally facilitate reactions by abstracting protons from a weak acid, thus producing strongly nucleophilic species which can participate in reactions.
The term “N-protected”, when used in chemical names such as “4-[N-protected 3-chloro-4-fluorophenyl)]-7-[3-methyl-3-(4-methyl-1-piperazinyl)-1-butynyl]-6-[nitro]quinazoline”, means that the nitrogen atom substituent, for example, at the quinazoline 4-position, is protected by a removable, preferably an acid-removable protecting group as defined herein.
“Reacting the second reaction product with a reducing agent and a Lewis acid” entails reducing the nitro group of the second reaction product, thereby forming a third reaction product under reaction conditions that are compatible with the acetylenic and haloaromatic functionalities in the second and third reaction products, i.e., reacting the second reaction product with a reducing agent and a Lewis acid (e.g. FeCl3, BF3) or an appropriate heterogeneous or homogeneous catalyst (e.g., Pd, Ni, Pt, Ru, or Rh-based catalysts) under reaction conditions which favor the selective reduction of aromatic nitro compounds to aromatic amines. Preferably, hydrazine is the reducing agent and FeCl3 is the Lewis acid. A number of other approaches may be used as well to reduce the aromatic nitro group without affecting other functional groups in the molecule.
“Acylating agents” include an acylating agent derived by the combination of acrylic acid or, more generally, a carboxylic acid, with an activating agent such as acryloyl chloride (ACC), carbodiimide reagents (e.g. dicyclohexylcarbodiimide, diisopropylcarbodimide), EDC, HOBt, HATU, BOP, pyBOP, or any of the other known activating agents. Alternatively, carboxylic acid derivatives such as acid halides (esp. acid chlorides), thioesters, anhydrides, or esters can be used as acylating agents either in the absence or presence of (i.e., optionally combined with) an activator such as a tertiary or aromatic amine (e.g. dimethylaminopyridine, triethylamine, diisopropylethylamine, pyridine, and lutidine).
“Palladium catalysts” include, but are not limited to Pd(OAc)2, Pd(dba)2 (palladium dibenzylideneacetone), PdCl2, (CH3CN)2PdCl2, among others.
“Polar aprotic solvents” include but are not limited to dimethylacetamide (DMA), dimethylformamide (DMF), acetonitrile, or dimethyl sulfoxide (DMSO), preferably dimethyl sulfoxide.
“Approximately equimolar amounts” shall be used in the context of a reaction to describe amounts or quantities of reactants in the various reaction steps of the present invention wherein the ratio of reactants is approximately one to one. Such amounts in context may vary from about 2:1 to about 1:2, about 1.5:1 to about 1:1.5 or about 1.25:1 to about 1:1.25, or about 1:1.
The compounds identified herein can be named and numbered by using CS ChemDrawUltra 6.0® structure=name algorithm, or through conventions (e.g., CAS, IUPAC) which are accepted by those of ordinary skill in the art. The structures identified herein take precedence insofar as the identification of any compound is concerned.
The invention is illustrated firer in the following non-limiting examples.
PBN (199.5 g, 1.2 mol, 1.2 equiv) (1,1-dimethyl-prop-2-ynyl)-4-methyl-piperazine) is dissolved in isopropyl acetate to a volume of 1 L. Compound 3 (226 g, 1 mol) (7-chloro-6-nitro-3H-quinazolin-4-one) and PdCl2 (5.32 g, 0.03 mol, 3 mol %) are added to the solution, followed by Et3N (2,024 g, 20 mol, 20 equiv) and dimethylsulfoxide (DMSO, 156.3 g, 2 mol). The resulting solution is heated to 85° C. for 6 h and then allowed to cool to ambient temperature. Water (5 L) is added, the mixture is agitated and then the phases separated. The organic phase is extracted twice with water (3 L) and the combined aqueous phases are extracted with isopropyl acetate (2 L) two times. Activated charcoal (25 g) is added to the combined organic phases, and the mixture is stirred 30 min and then filtered. The resulting solution is concentrated to dryness by rotary evaporation, and the residue is recrystallized from methanol/ethyl acetate to afford product A (249-284 g, 70-80% yield) (7-[3-methyl-3-(4-methyl-piperazin-1-yl)-but-1-ynyl]-6-nitro-quinazolin-4-ol) in >99% purity.
PBN (199.5 g, 1.2 mol, 1.2 equiv) is dissolved in isopropyl acetate to a volume of 1 L. Compound 3 (226 g, 1 mol), Pd(OAc)2 (3.37 g, 0.015 mol, 1.5 mol %), and PPh3 (7.87 g, 0.03 mol, 3 mol %) are added to the solution, followed by Et3N (2,024 g, 3 mol, 3 equiv) and dimethylsulfoxide (DMSO, 2 L). The resulting solution is stirred at 25° C. for 4 h and then poured into an aqueous solution of N,N,N′,N′-tetramethylethylene diamine (TMEDA, 5% v/v). The mixture is extracted with isopropyl acetate (2 L) two times, and the combined organic phases are shed with another portion of aqueous TMEDA. The organic phase is separated and activated charcoal (25 g) is added. The mixture is stirred 30 min and filtered, and the resulting solution is concentrated to dryness by rotary evaporation, and the residue is recrystallized from methanol/ethyl acetate to afford product A (302-320 g, 85-90% yield) in >99% purity.
Compound A (355 g, 1 mol) is dissolved in toluene (2 L). Thionyl chloride (SOCl2, 595 g, 5 mol, 5 equiv) and DMF (3.65 g, 0.05 mol, 0.05 equiv) are added, and the mixture is heated to reflux for 4 h. The resulting solution is cooled to 0° C., and 3-chloro fluoroaniline (CFA, 174.7 g, 1.2 mol. 1.2 equiv) is added as a 1 M solution in 2-methoxyethanol. The resulting mixture is stirred at 0° C. for 2 h, and then product B is purified by extraction with water (2 L), treatment of the organic phase with charcoal (20 g), filtration, and concentration to dryness. The residue is recrystallized from methanol/ethyl acetate to afford product B (386-410 g, 80-85% yield) (4-[N-3-chloro-4-fluorophenyl)]-7-[3-methyl-3-(4methyl-1-piperazinyl)-1-butynyl]-6-[nitro]quinazoline) in >99% purity.
Compound A (355 g, 1 mol) is dissolved in toluene (2 L). Phosphoryl chloride (POCl3, 230 g, 1.5 mol 1.5 equiv) and diisopropylethylamine (258.5 g, 2 mol, 2 equiv) are added, and the mixture is heated to 70° C. for 8 h. The resulting solution is cooled to 0° C., and 3-chloro-4-fluoroaniline (CFA, 174.7 g, 1.2 mol, 1.2 equiv) is added as a 1 M solution in isopropanol. The resulting mixture is stirred at 0° C. for 2 h, and then product B is purified by extraction with water (2 L), treatment of the organic phase with charcoal (20 g), filtration, and concentration to dryness. The residue is recrystallized from methanol/ethyl acetate to afford product B (362-381 g, 75-79% yield) in >99% purity.
Compound B (482.2 g, 1 mol) is dissolved in methanol (3 L). Hydrazine (80%, 64.1 g, 2 mol, 2 equiv), FeCl3 (1.62 g, 0.01 mol, 1 mol %) and activated charcoal (40 g) are added and the mixture is heated to reflux for 4 h. After the mixture is allowed to cool to ambient temperature, dichloromethane (1 L) is added the mixture is filtered and concentrated to dryness. The residue is purified by reslurrying with methanol and isolation by filtration. Product C (394-417 g, 87-92% yield) (4-[N-3-chloro-4-fluorophenyl)]-7-[3-methyl-3-(4-methyl-1-piperazinyl)-1-butynyl]-6-[amino]quinoline) is thus isolated in >99% purity.
Compound C (453 g, 1 mol) is dissolved in THF (2 L) and the solution is cooled to 0° C. Acrylic acid (93.7 g, 1.3 mol, 1.3 equiv) and acryloyl chloride (108.6 g, 1.2 mol, 1.2 equiv) and triethylamine (253 g, 2.5 mol, 2.5 equiv) are added, and the resulting solution is stirred at 0° C. for 6 h and then allowed to warm to ambient temperature. Isolation and purification is carried out by solvent removal, trituration with isopropanol/water, and reslurrying acetonitrile. Compound D (324-350 g, 64-69% yield) (4-[N-3-chloro-4-fluorophenyl)]-7-[3-methyl-3-(4-methyl-1-piperazinyl)-1-butynyl]-6-[N-methyl acrylamide]quinoline is thus isolated in >99% purity.
Compound A (355 g, 1 mol) is dissolved in toluene (2 L). Thionyl chloride (SOCl2, 230 g, 1.5 mol, 1.5 equiv) and diisopropylethylamine (258.5 g, 2 mol, 2 equiv) are added, and the mixture is heated to 70° C. for 8 h. The resulting solution is cooled to 0° C., and Boc-3-chloro-4-fluoroaniline (Boc-CFA, 174.7 g, 1.2 mol, 1.2 equiv) is added as a 1 M solution in sodium hydroxide. The resulting mixture is stirred at 0° C. for 2 h, and than product B1 is purified by extraction with water (2 L), treatment of the organic phase with charcoal (20 g), filtration, and concentration to dryness. The residue is recrystallized from methanol/ethyl acetate to afford product B1 (362-381 g, 75-79% yield) in >99% purity.
Compound B1 (482.2 g, 1 mol) is dissolved in methanol (3 L). Hydrazine (80%, 64.1 g, 2 mol, 2 equiv), FeCl3 (1.62 g, 0.01 mol, 1 mol %) and activated charcoal (40 g) are added and mixture is heated to reflux for 4 h. After the mixture is allowed to cool to ambient temperature, dichloromethane (1 L) is added the mixture is filtered and concentrated to dryness. The residue is purified by reslurrying with methanol and isolation by filtration. Product C1 (394-417 g, 87-92% yield) (4-[N-Boc-3-chloro-4-fluorophenyl)]-7-[3-methyl-3-(4-methyl-1-piperazinyl)-1-butynyl]-6-[amino]quinazoline) is tis isolated in >99% purity.
Compound C1 (453 g, 1 mol) is dissolved in THF (2 L) and the solution is cooled to 0° C. Acrylic acid (93.7 g, 1.3 mol. 1.3 equiv) and acryloyl chloride (108.6 g, 1.2 mol. 1.2 equiv) and triethylamine (253 g, 2.5 mol, 2.5 equiv) are added, and the resulting solution is stirred at 0° C. for 6 h and hen allowed to warm to ambient temperature. Isolation and purification is carried out by solvent removal, trituration with, and reslurrying acetonitrile. Compound D1 (324-350 g, 64-69% yield) (4-[N-Boc-3-chloro-4-fluorophenyl)]-7-[3-methyl-3-(4-methyl-1-piperazinyl)-1-butynyl]-6-[N-methyl acrylamide]quinazoline is thus isolated in >99% purity. The acid-labile protecting group BOC is removed in near quantitative yield using an organic acid such as toluenesulfonic acid (TsOH) or methanesulfonic acid in methanol to provide compound D (see example 6).
This application claims the benefit of priority of provisional application U.S. 60/778,805 of identical title, filed Mar. 3, 2006.
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/US2007/005468 | 3/2/2007 | WO | 00 | 11/17/2008 |
| Number | Date | Country | |
|---|---|---|---|
| 60778805 | Mar 2006 | US |
