Patent Application
20170166586
The present invention is directed to a process for preparing Tetracyclic Heterocycle Compounds which are useful as intermediates for the synthesis of HCV NS5A inhibitors. The present invention is also directed to compounds that are useful as synthetic intermediates in the process of the invention.
Various substituted multicyclic heterocyclic compounds are useful as pharmaceutical drugs, including inhibitors of the HCV NS5A enzyme. Included in these heterocycles is the tetracyclic heterocyclic core of dimethyl ((2S,2′S)-((2S,2′S)-2,2′-(5,5′((S)-6-phenyl-6H-benzo[5,6][1,3]oxazino[3,4-a]indole-3,10-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl))dicarbamate, as defined and described below. These compounds and pharmaceutically acceptable salts thereof are useful in the treatment or prophylaxis of infection by HCV and in the treatment, prophylaxis, or delay in the onset or progression of HCV infection. Representative tetracyclic heterocyclic compounds that are useful for treating HCV infection are described, for example, in US Patent Publication No. US20120083483.
US Patent Publication No. US20120083483 discloses methodology that can be employed to prepare such tetracyclic HCV NS5A inhibitors. This general methodology is illustrated immediately below:
The methods described in US Patent Publication No. US20120083483 are practical routes for the preparation of tetracyclic heterocyclic compounds useful as HCV NS5A inhibitors. Nonetheless, there is always a need for alternative preparative routes which, for example, use reagents that are less expensive and/or easier to handle, consume smaller amounts of reagents, provide a higher yield of product, involve fewer steps, have smaller and/or more eco-friendly waste products, and/or provide a product of higher purity or higher enantiomeric excess.
The present invention is directed to a process (alternatively referred to herein as Process P) for preparing Compounds of Formula (I) (the “Tetracyclic Heterocycle Compounds”)
and pharmaceutically acceptable salts thereof,
(A) contacting a compound of Formula (II):
with a compound of formula (IIIa):
R3—CHO (IIIa)
and/or a compound of formula (IIIb):
R3—CH═NR5 (IIIb)
in the presence of an acid and optionally, a dehydrating agent, in an organic solvent A, for a time and at a temperature sufficient to form a compound of formula (IV):
and
(B) contacting the compound of formula (IV) with a transition metal catalyst in the presence of a base, in an organic solvent B, for a time and at a temperature sufficient to form a compound of formula (I),
wherein:
X1 and X2 are each independently selected from Cl, Br, I, OTf, OTs, OMs, OBs and
R1 represents up to 3 optional ring substituent groups, which can be the same or different and are selected from —C1-C6 alkyl, halo, —OR5, —C(O)R5, —C(O)2R5, —NHC(O)R5, —C(O)N(R5)2, —SR5, —C1-C6 hydroxyalkyl, —C1-C6 haloalkyl, —N(R5)2, —S(O)R5, —S(O)2R5, —CN and —NO2;
R2 represents up to 3 optional ring substituent groups, which can be the same or different and are selected from —C1-C6 alkyl, halo, —OR5, —C(O)R5, —C(O)2R5, —NHC(O)R5, —C(O)N(R5)2, —SR5, —C1-C6 hydroxyalkyl, —C1-C6 haloalkyl, —N(R5)2, —S(O)R5, —S(O)2R5, —CN and —NO2;
R3 is C1-C6 alkyl , C6-C10 aryl, 5 or 6-membered monocyclic heteroaryl or 9 or 10-membered bicyclic heteroaryl, wherein said C6-C10 aryl group, said 5 or 6-membered monocyclic heteroaryl group and said 9 or 10-membered bicyclic heteroaryl group can each be optionally and independently substituted with up to 3 groups, each independently selected from C1-C6 alkyl, C3-C7 cycloalkyl, halo, —OR5, —C(O)R5, —C(O)2R5, —NHC(O)R5, —C(O)N(R5)2, —SR5, —C1-C6 hydroxyalkyl, —C1-C6 haloalkyl, —N(R5)2, —S(O)R5, —S(O)2R5, —CN and —NO2;
R4 is selected from Br, Cl, I, —OTf, —OMs, —OTs, —OBs, and —OS(O)2R5; and
each occurrence of R5 is independently selected from H, —C1-C6 alkyl, C3-C7 cycloalkyl, C6-C10 aryl, 5 or 6-membered monocyclic heteroaryl and 9 or 10-membered bicyclic heteroaryl;
each occurrence of RY is independently selected from H, —C1-C6 alkyl, C3-C7 cycloalkyl, C6-C10 aryl, 5 or 6-membered monocyclic heteroaryl and 9 or 10-membered bicyclic heteroaryl; and
each occurrence of RZ is independently C1-C6 alkyl.
Other embodiments, aspects and features of the present invention are either further described in or will be apparent from the ensuing description, examples, and appended claims.
The present invention is directed to a process for preparing Tetracyclic Heterocycle Compounds of Formula (I) which are useful as intermediates for making HCV NSSA inhibitors. One aspect of the present invention is the process comprising Steps A and B as set forth above in the Summary of the Invention (i.e., Process P).
The term “C1-C6 alkyl” as used herein, refers to an aliphatic hydrocarbon group, having from 1 to 6 carbon atoms wherein one of its hydrogen atoms is replaced with a bond. A C1-C6 alkyl group may be straight or branched and contain. Non-limiting examples of C1-C6 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, isopentyl, n-hexyl, isohexyl and neohexyl. A C1-C6 alkyl group may be unsubstituted or substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkenyl, alkynyl, aryl, cycloalkyl, cyano, hydroxy, —O-alkyl, —O-aryl, -alkylene-O-alkyl, alkylthio, —NH2, —NH(alkyl), —N(alkyl)2, —NH(cycloalkyl), —O—C(O)-alkyl, —O—C(O)-aryl, —O—C(O)-cycloalkyl, —C(O)OH and —C(O)O-alkyl. In one embodiment, a C1-C6 alkyl group is linear. In another embodiment, a C1-C6 alkyl group is branched. Unless otherwise indicated, a C1-C6 alkyl group is unsubstituted.
The term “C6-C10 aryl” refers to phenyl and naphthyl. In one embodiment, an aryl group is phenyl.
The term “3 to 7-membered cycloalkyl” refers to a non-aromatic mono- or ring system comprising from about 3 to about 7 ring carbon atoms. Examples of “3 to 7-membered cycloalkyl” groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. A 3 to 7-membered cycloalkyl group can be optionally substituted with one or more “ring system substituents” which may be the same or different, and are as defined herein below. In one embodiment, a 3 to 7-membered cycloalkyl group is unsubstituted. A ring carbon atom of a 3 to 7-membered cycloalkyl may be functionalized as a carbonyl group. An illustrative example of such a 3 to 7-membered cycloalkyl (also referred to herein as a “cycloalkanoyl” group) includes, but is not limited to, cyclobutanoyl:
The term “halo” as used herein, refers to fluorine, chlorine, bromine and iodine (alternatively referred to as fluoro, chloro, bromo, and iodo).
The term “5 or 6-membered monocyclic heteroaryl,” as used herein, refers to an aromatic monocyclic ring system comprising about 5 to about 6 ring atoms, wherein from 1 to 4 of the ring atoms is independently O, N or S and the remaining ring atoms are carbon atoms. A 5 or 6-membered monocyclic heteroaryl group can be optionally substituted by one or more “ring system substituents” which may be the same or different, and are as defined herein below. A 5 or 6-membered monocyclic heteroaryl group is joined via a ring carbon atom, and any nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. The term “5 or 6-membered monocyclic heteroaryl” also encompasses a 5 or 6-membered monocyclic heteroaryl group, as defined above, which is fused to a benzene ring. Non-limiting examples of 5 or 6-membered monocyclic heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, imidazolyl, benzimidazolyl, thienopyridyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, 1,2,4-triazinyl, benzothiazolyl and the like, and all isomeric forms thereof. Unless otherwise indicated, a 5 or 6-membered monocyclic heteroaryl group is unsubstituted.
The term “9 or 10-membered bicyclic heteroaryl,” as used herein, refers to an aromatic bicyclic ring system comprising about 9 to about 10 ring atoms, wherein from 1 to 4 of the ring atoms is independently 0, N or S and the remaining ring atoms are carbon atoms. A 9 or 10-membered bicyclic heteroaryl group can be optionally substituted by one or more “ring system substituents” which may be the same or different, and are as defined herein below. A 9 or 10-membered bicyclic heteroaryl group is joined via a ring carbon atom, and any nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. Non-limiting examples of 9 or 10-membered bicyclic heteroaryls include and the like, and all isomeric forms thereof. Unless otherwise indicated, a 9 or 10-membered bicyclic heteroaryl group is unsubstituted.
The term “transition metal catalyst,” as used herein, refers to a complex comprising a transition metal and one or more ligands, which are independently selected from any organic and/or any inorganic ligands.
The term “phenol protecting group,” as used herein, refers to a group that can be used to protect the hydroxyl group of a phenol moiety from reacting during any chemical reactions that take place in the presence of said phenol protecting group. Non-limiting examples of phenol protecting groups include organosilyl groups, such as trimethylsilyl (TMS) and t-butyldimethylsilyl (TBDMS); alkyl groups; benzyl; allyl; and those recognized by those with ordinary skill in the art as well as those disclosed in standard textbooks such as, for example, T. W. Greene et al, Protective Groups in Organic Synthesis (1991), Wiley, N.Y.
Unless expressly stated to the contrary in a particular context, any of the various cyclic rings and ring systems described herein may be attached to the rest of the compound of which they are a part at any ring atom (i.e., any carbon atom or any heteroatom) provided that a stable compound results.
Unless expressly stated to the contrary, all ranges cited above are inclusive; i.e., the range includes the values for the upper and lower limits of the range as well as all values in between. When any variable occurs more than one time in a compound involved in the process of the invention (e.g., R1 or R2), its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in a stable compound.
Unless expressly stated to the contrary, substitution by a named substituent is permitted on any atom in a ring (e.g., cycloalkyl, aryl, or heteroaryl) provided such ring substitution is chemically allowed and results in a stable compound.
In reference to the compounds employed as reactants or reagents in the process of the invention (e.g., Compounds II, III, and IV), a “stable” compound is one whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow its use in the process of the invention so as to achieve the preparation of Compound of Formula (I). In reference to Compound of Formula (I), a “stable” compound is a compound which can be prepared in accordance with the process of the present invention and then isolated and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow use of the compound for its intended purpose; e.g., for use as a synthetic intermediate to make medicinally useful compounds, such as compounds useful for treating HCV infection in a subject.
When a functional group in a compound is termed “protected”, this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al, Protective Groups in Organic Synthesis (1991), Wiley, N.Y.
The Tetracyclic Heterocycle Compounds can form salts which are also within the scope of this invention. Reference to a Tetracyclic Heterocycle Compound herein is understood to include reference to salts thereof, unless otherwise indicated. The term “salt(s)”, as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a Tetracyclic Heterocycle Compound contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions (“inner salts”) may be formed and are included within the term “salt(s)” as used herein. In one embodiment, the salt is a pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salt. In another embodiment, the salt is other than a pharmaceutically acceptable salt. Salts of the Compounds of Formula (I) may be formed, for example, by reacting a Tetracyclic Heterocycle Compound with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates) and the like. Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference thereto.
Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamine, t-butyl amine, choline, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g., decyl, lauryl, and stearyl chlorides, bromides and iodides), arylalkyl halides (e.g., benzyl and phenethyl bromides), and others.
All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.
Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well-known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Sterochemically pure compounds may also be prepared by using chiral starting materials or by employing salt resolution techniques. Also, some of the Tetracyclic Heterocycle Compounds may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be directly separated using chiral chromatographic techniques.
It is also possible that the Tetracyclic Heterocycle Compounds may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. For example, all keto-enol and imine-enamine forms of the compounds are included in the invention.
All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, hydrates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention. If a Tetracyclic Heterocycle Compound incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention.
Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms “salt”, “solvate”, “ester”, “prodrug” and the like, is intended to apply equally to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, racemates or prodrugs of the inventive compounds.
The following abbreviations are used below and have the following meanings: Ac is acetate, Boc or BOC is t-butoxy carbonyl, Bs is besyl (benzenesulfonyl), t-Bu is tertiary butyl, n-Bu is n-butyl, dba is dibenzylideneacetone, DCM is dichloromethane, DMA is N,N-dimethylacetamide, DME is dimethoxyethane, EtOAc is ethyl acetate, HPLC is high performance liquid chromatography, Me is methyl, Ms is mesyl (methanesulfonyl), MS is molecular sieves, MS4A is 4 angstrom molecular sieves, Tf is triflate (trifluoromethanesulfonyl), TFA is trifluoroacetic acid, TLC is thin-layer chromatography, and Ts is tosyl (p-toluenesulfonyl).
The present invention is directed to a process for preparing Tetracyclic Heterocycle Compounds of Formula (I) which are useful as synthetic intermediates for the synthesis of HCV NS5A inhibitors. One aspect of the present invention is the process comprising Steps A and B as set forth above in the Summary of the Invention (i.e., Process P).
In another aspect, the present invention provides each individual step of Process P as a separate and individual embodiment (e.g. in one embodiment the present invention provides the process illustrated in Step A of Process P; in another embodiment the present invention provides the process illustrated in Step B of Process P)
In one embodiment, for Process P, step A, the compound of formula (II) is reacted with a compound of formula (IIIa).
In another embodiment, for Process P, step A, the compound of formula (II) is reacted with a compound of formula (IIIb).
In another embodiment, for Process P, step A, the compound of formula (II) is reacted with a mixture of a compound of formula (IIIa) and a compound of formula (IIIb).
In one embodiment, for Process P, each occurrence of R1 and R2 is independently H or halo.
In another embodiment, for Process P, each occurrence of R1 and R2 is independently H or F.
In another embodiment, for Process P, each occurrence of R1 is H and each occurrence of R2 is independently H or F.
In one embodiment, for Process P, R3 is 5 or 6-membered heteroaryl or C6-C10 aryl, wherein R3 can be optionally substituted with a group selected from C1-C6 alkyl and C3-C7 cycloalkyl.
In another embodiment, for Process P, R3 is phenyl.
In another embodiment, for Process P, R3 is 5-membered heteroaryl, which can be optionally substituted with a group selected from C1-C6 alkyl and C3-C7 cycloalkyl.
In another embodiment, for Process P, R3 is thiophenyl or thiazolyl, either of which can be optionally substituted with a C1-C6 alkyl group or a C3-C7 cycloalkyl group.
In still another embodiment, for Process P, R3 is thiophenyl or thiazolyl, either of which can be optionally substituted with a C3-C7 cycloalkyl group.
In another embodiment, for Process P, R3 is thiophenyl or thiazolyl, either of which can be optionally substituted with a C3-C7 cyclopropyl group.
In one embodiment, for Process P, X1 and X2 are each —Cl.
In another embodiment, for Process P, R4 is —Br.
In one embodiment, for Process P, each occurrence of R1 and R2 is independently H or halo and R3 is 5 or 6-membered heteroaryl or C6-C10 aryl, wherein R3 can be optionally substituted with a group selected from C1-C6 alkyl and C3-C7 cycloalkyl.
In another embodiment, for Process P, each occurrence of R1 and R2 is independently H or halo; R3 is 5 or 6-membered heteroaryl or C6-C10 aryl, wherein R3 can be optionally substituted with a group selected from C1-C6 alkyl and C3-C7 cycloalkyl; R4 is Br; and X1 and X2 are each —Cl.
In another embodiment, for Process P, each occurrence of R1 is H; each occurrence of R2 is independently H or halo; R3 is phenyl, thiophenyl or thiazolyl, any of which can be optionally substituted with a C1-C6 alkyl group or a C3-C7 cycloalkyl group; R4 is Br; and X1 and X2 are each —Cl.
In one embodiment, for Process P:
the organic solvent A is selected from toluene, dichloromethane, dichloroethane, benzene, tetrahydrofuran, 2-methyl tetrahydrofuran, ethyl acetate and acetonitrile;
the acid employed in Step A is an organic acid;
Step A is conducted at a temperature in a range of from about 0° C. to about 100° C.;
the organic solvent B is selected from toluene, dimethylacetamide, dioxane, acetonitrile, tetrahydrofuran, 2-methyl tetrahydrofuran, t-amyl alcohol, benzene, xylenes, N,N-dimethylformamide, dichloromethane, dichloroethane and dimethoxyethane;
the transition metal catalyst employed in Step B, is selected from an organopalladium, organocopper, organonickel or organoiron compound that is bound to a chiral ligand;
the base employed in step B is selected from a carbonate base, a phosphate base, a fluoride base, an acetate base, a bicarbonate base and a hydroxide base; and
Step B is conducted at a temperature in a range of from about 0° C. to about 120° C.
In another embodiment, for Process P:
the organic solvent A is toluene, 2-methyl THF, dichloroethane or dichloromethane;
the acid employed in Step A is trifluoroacetic acid, trifluoromethylsulfonic acid, or camphorsulfonic acid;
Step A is conducted at a temperature in a range of from about 25° C. to about 65° C.;
the organic solvent B is toluene or dimethoxyethane;
the transition metal catalyst employed in Step B, is an organopalladium compound that is bound to a chiral ligand;
the base employed in step B is a phosphate base; and
Step B is conducted at a temperature in a range of from about 30° C. to about 70° C.
In another embodiment, for Process P:
the organic solvent A is toluene, 2-methyl THF, dichloroethane or dichloromethane;
the acid employed in Step A is trifluoroacetic acid, trifluoromethylsulfonic acid, TMSOTf, or camphorsulfonic acid;
Step A is conducted at a temperature in a range of from about 0° C. to about 65° C.;
the organic solvent B is N,N-dimethylacetamide, toluene, or acetonitrile;
the transition metal catalyst employed in Step B, is an organocopper compound;
the base employed in step B is a carbonate base or a phosphate base; and
Step B is conducted at a temperature in a range of from about 25° C. to about 100° C.
In another embodiment, the present invention provides a process (“Process A”) for preparing a compound of Formula (Ia):
wherein said process comprises the steps:
(A) contacting a compound of Formula (II):
with a compound of formula (IIIa):
R3—CHO (IIIa)
in the presence of an acid in an organic solvent , and optionally, a dehydrating agent, for a time and at a temperature sufficient to form a compound of formula (IV):
and
(B) contacting the compound of formula (IV) with a transition metal catalyst in the presence of a base, in an organic solvent B, for a time and at a temperature sufficient to form a compound of formula (I),
wherein:
R1 represents up to 3 optional ring substituent groups, which can be the same or different and are selected from —C1-C6 alkyl and halo;
R2 represents up to 3 optional ring substituent groups, which can be the same or different and are selected from —C1-C6 alkyl and halo;
R3 is C1-C6 alkyl , C6-C10 aryl or 5 or 6-membered monocyclic heteroaryl, wherein said C6-C10 aryl group, and said 5 or 6-membered monocyclic heteroaryl group can each be optionally and independently substituted with up to 2 groups, each independently selected from C1-C6 alkyl and C3-C7 cycloalkyl;
each occurrence of RY is independently selected from H, —C1-C6 alkyl, C3-C7 cycloalkyl, C6-C10 aryl, 5 or 6-membered monocyclic heteroaryl and 9 or 10-membered bicyclic heteroaryl; and
each occurrence of RZ is independently C1-C6 alkyl.
In one embodiment, for Process A:
the organic solvent A is 2-methyl THF, toluene or dichloromethane;
the acid employed in Step A is trifluoromethanesulfonic acid, camphorsulfonic acid or TFA;
Step A is conducted at a temperature in a range of from about 20° C. to about 70° C.;
the organic solvent B is toluene;
the transition metal catalyst employed in Step B, is an organopalladium compound that is bound to a chiral ligand;
the base employed in step B is a phosphate base;
Step B is conducted at a temperature in a range of from about 30° C. to about 70° C.
In another embodiment, for Process A:
the organic solvent A is 2-methyl THF, toluene or dichloromethane;
the acid employed in Step A is trifluoromethanesulfonic acid, camphorsulfonic acid or TFA;
Step A is conducted at a temperature in a range of from about 40° C. to about 65° C.;
the organic solvent B is toluene;
the transition metal catalyst employed in Step B, is an organopalladium compound that is bound to a chiral ligand, wherein said chiral ligand has the formula:
the base employed in step B is K3PO4;
Step B is conducted at a temperature in a range of from about 40° C. to about 60° C.
In another embodiment, the present invention provides a process (“Process B”) for preparing a compound of Formula (Ia):
wherein said process comprises the steps:
(A) contacting a compound of Formula (IIa):
with a compound of formula (IIIb):
R3—CH═NR5 (IIIb)
in the presence of an acid in an organic solvent A, and optionally, a dehydrating agent, for a time and at a temperature sufficient to form a compound of formula (IV):
and
(B) contacting the compound of formula (IV) with a transition metal catalyst in the presence of a base, in an organic solvent B, for a time and at a temperature sufficient to form a compound of formula (I),
wherein:
R1 represents up to 3 optional ring substituent groups, which can be the same or different and are selected from —C1-C6 alkyl and halo;
R2 represents up to 3 optional ring substituent groups, which can be the same or different and are selected from —C1-C6 alkyl and halo;
R3 is C1-C6 alkyl , C6-C10 aryl or 5 or 6-membered monocyclic heteroaryl, wherein said C6-C10 aryl group, and said 5 or 6-membered monocyclic heteroaryl group can each be optionally and independently substituted with up to 2 groups, each independently selected from C1-C6 alkyl and C3-C7 cycloalkyl; and
R5 is C1-C6 alkyl or phenyl.
In one embodiment, for Process B:
the organic solvent A is toluene or 2-methyl THF;
the acid employed in Step A is trifluoromethanesulfonic acid or TFA;
Step A is conducted at a temperature in a range of from about 10° C. to about 40° C.;
the organic solvent B is toluene;
the transition metal catalyst employed in Step B, is an organopalladium compound that is bound to a chiral ligand;
the base employed in step B is a phosphate base; and
Step B is conducted at a temperature in a range of from about 30° C. to about 70° C.
In another embodiment, for Process B:
the organic solvent A is toluene;
the acid employed in Step A is TFA;
Step A is conducted at a temperature in a range of from about 20° C. to about 30° C.;
the organic solvent B is toluene;
the transition metal catalyst employed in Step B, is an organopalladium compound that is bound to a chiral ligand, wherein said chiral ligand has the formula:
the base employed in step B is K3PO4; and
Step B is conducted at a temperature in a range of from about 40° C. to about 60° C.
In one embodiment, for Processes A, B and P, the base employed in Step B is selected from KHCO3, Na2CO3, Cs2CO3, K2CO3, Na3PO4, K3PO4, Na2PO4 and K2PO4.
In another embodiment, for Processes A, B and P, the base employed in Step B is K3PO4.
In one embodiment, for Processes A, B and P, the ligands used in the transition metal catalyst employed in Step B are selected from one or more of: dba, chalcone, (R,R)-QuinoxP, (R,S)-QuinoxP, (S,R)-QuinoxP, (S,S)-QuinoxP, halo, —OAc, (S)-BINAPINE , (R)-Quinap, (R)—N-PINAP85, SL-J210-1, (R)-(S)-xyl2P-Fc-PtBu2, —(S)-tBu-PHOX, (S)-tBuO-Tol-PHOX, (S)—(S)-Ph2P-Fc-tBu-oxazoline, SL-N004, (Sa,S)-DTB-Bn-SIPHOX, ChenPhos SL-356-1, (S)-f-Binaphane, SL-J001-1, SL-J204-1, SL-J304-1, (R)-BINAP, (R)-SEGPHOS, (R)-P-Phos, (R)-DTBM-SEGPHOS, (S)-DTBM-Garphos, (S)-DTBM-MeO-BIPHEP, (R)-3,5-tBuPh-MeO-BIPHEP, (R)-3,5-iPr-4-Me2NPh-MeO-BIPHEP, SL-J001-1, SL-J204-1, SegPhos, MeO-BIPHEP, GarPhos, SL-J304-1 and 3,5-di-t-butyl-4-methoxybenzene.
In another embodiment, for Processes A, B and P, the ligand used in the transition metal catalyst employed in Step B is (R,R)-QuinoxP.
In still another embodiment, for Processes A, B and P, a ligand used in the transition metal catalyst employed in Step B is (R,S)-QuinoxP.
In another embodiment, for Processes A, B and P, the ligand used in the transition metal catalyst employed in Step B is (S,R)-QuinoxP.
In yet another embodiment, for Processes A, B and P, a ligand used in the transition metal catalyst employed in Step B is (S,S)-QuinoxP.
In another embodiment, for Processes A, B and P, the ligand used in the transition metal catalyst employed in Step B is selected from:
In still another embodiment, for Processes A, B and P, the ligand used in the transition metal catalyst employed in Step B is:
In one embodiment, for Processes A, B and P, in step A, the optional dehydrating agent is absent.
In another embodiment, for Processes A, B and P, in step A, the optional dehydrating agent is present.
In another embodiment, for Processes A, B and P, in step A, the optional dehydrating agent is present and is selected from molecular sieves, trimethylsilyl chloride and magnesium sulfate.
In still another embodiment, for Processes A, B and P, in step A, the optional dehydrating agent is present and is molecular sieves.
In one embodiment, for Processes A, B and P, the compound of formula (I) being made is:
wherein each occurrence of X1 is independently selected from Br, Cl and I and each occurrence of X2 is independently selected from Br, Cl and I.
In another embodiment, for Processes A, B and P, the compound of formula (I) being made is:
In another embodiment, for Processes A, B and P, the compound of formula (I) being made is:
In another embodiment, for Processes A, B and P, the compound of formula (I) being made is:
In one embodiment, the present invention provides a compound of formula (IV):
or a pharmaceutically acceptable salt thereof,
wherein:
X1 and X2 are each independently selected from Cl, Br, I, OTf, OTs, OMs, OBs and
R1 represents up to 3 optional ring substituent groups, which can be the same or different and are selected from —C1-C6 alkyl, halo, —OR6, —C(O)R6, —C(O)2R6, —NHC(O)R6, —C(O)N(R6)2, —SR6, —C1-C6 hydroxyalkyl, —C1-C6 haloalkyl, —N(R6)2, —S(O)R6, —S(O)2R6, —CN and —NO2;
R2 represents up to 3 optional ring substituent groups, which can be the same or different and are selected from —C1-C6 alkyl, halo, —OR6, —C(O)R6, —C(O)2R6, —NHC(O)R6, —C(O)N(R6)2, —SR6, —C1-C6 hydroxyalkyl, —C1-C6 haloalkyl, —N(R6)2, —S(O)R6, —S(O)2R6, —CN and —NO2;
R3 is C1-C6 alkyl , C6-C10 aryl, 5 or 6-membered monocyclic heteroaryl or 9 or 10-membered bicyclic heteroaryl, wherein said C6-C10 aryl group, said 5 or 6-membered monocyclic heteroaryl group and said 9 or 10-membered bicyclic heteroaryl group can each be optionally and independently substituted with one or more R5 groups; and
R4 is selected from Br, Cl, I, —OTf, —OMs, —OTs, —OBs, and —OS(O)2R6;
each occurrence of R5 is independently selected from C1-C6 alkyl, C3-C7 cycloalkyl, halo, —OR6, —C(O)R6, —C(O)2R6, —NHC(O)R6, —C(O)N(R6)2, —SR6, —C1-C6 hydroxyalkyl, —C1-C6 haloalkyl, —N(R6)2, —S(O)R6, —S(O)2R6, —CN and —NO2;
each occurrence of R6 is independently selected from H, —C1-C6 alkyl, C3-C7 cycloalkyl, C6-C10 aryl, 5 or 6-membered monocyclic heteroaryl and 9 or 10-membered bicyclic heteroaryl; and
each occurrence of RY is independently selected from H, —C1-C6 alkyl, C3-C7 cycloalkyl, C6-C10 aryl, 5 or 6-membered monocyclic heteroaryl and 9 or 10-membered bicyclic heteroaryl; and
each occurrence of RZ is independently C1-C6 alkyl.
In another embodiment, the present invention provides a compound of formula (IVa):
or a pharmaceutically acceptable salt thereof,
wherein:
R2 represents an optional ring substituent group, which is —C1-C6 alkyl or halo; and
R3 is C6-C10 aryl or 5 or 6-membered monocyclic heteroaryl wherein said C6-C10 aryl group and said 5 or 6-membered monocyclic heteroaryl can each be optionally and independently substituted with C1-C6 alkyl, halo or C3-C7 cycloalkyl.
In one embodiment, the present invention provides a compound having the structure:
or a pharmaceutically acceptable salt thereof.
In another embodiment, the present invention provides a compound having the structure:
or a pharmaceutically acceptable salt thereof.
In another embodiment, the present invention provides a compound having the structure:
In another embodiment, the present invention provides a compound having the formula (V):
or a pharmaceutically acceptable salt thereof,
wherein:
X1 and X2 are each independently selected from Cl, Br, I, OTf, OTs, OMs, OBs and
Ra is selected from H, acyl, —C(O)O—(C1-C6 alkyl), allyl, benzyl, a metal cation and a phenol protecting group;
R1 represents up to 3 optional ring substituent groups, which can be the same or different and are selected from —C1-C6 alkyl, halo, —OR6, —C(O)R6, —C(O)2R6, —NHC(O)R6, —C(O)N(R6)2, —SR6, —C1-C6 hydroxyalkyl, —C1-C6 haloalkyl, —N(R6)2, —S(O)R6, —S(O)2R6, —CN and —NO2;
R2 represents up to 3 optional ring substituent groups, which can be the same or different and are selected from —C1-C6 alkyl, halo, —OR6, —C(O)R6, —C(O)2R6, —NHC(O)R6, —C(O)N(R6)2, —SR6, —C1-C6 hydroxyalkyl, —C1-C6 haloalkyl, —N(R6)2, —S(O)R6, —S(O)2R6, —CN and —NO2;
R3 is C1-C6 alkyl , C6-C10 aryl, 5 or 6-membered monocyclic heteroaryl or 9 or 10-membered bicyclic heteroaryl, wherein said C6-C10 aryl group, said 5 or 6-membered monocyclic heteroaryl group and said 9 or 10-membered bicyclic heteroaryl group can each be optionally and independently substituted with one or more R5 groups; and
R4 is selected from Br, Cl, I, —OTf, —OMs, —OTs, —OBs, and —OS(O)2R6;
each occurrence of R5 is independently selected from C1-C6 alkyl, C3-C7 cycloalkyl, halo, —OR6, —C(O)R6, —C(O)2R6, —NHC(O)R6, —C(O)N(R6)2, —SR6, —C1-C6 hydroxyalkyl, —C1-C6 haloalkyl, —N(R6)2, —S(O)R6, —S(O)2R6, —CN and —NO2;
each occurrence of R6 is independently selected from H, —C1-C6 alkyl, C3-C7 cycloalkyl, C6-C10 aryl, 5 or 6-membered monocyclic heteroaryl and 9 or 10-membered bicyclic heteroaryl; and
each occurrence of RY is independently selected from H, —C1-C6 alkyl, C3-C7 cycloalkyl, C6-C10 aryl, 5 or 6-membered monocyclic heteroaryl and 9 or 10-membered bicyclic heteroaryl; and
each occurrence of RZ is independently C1-C6 alkyl.
In one embodiment, the present invention provides a compound having the structure:
In another embodiment, the present invention provides a compound having the structure:
In one embodiment, any step of any of the processes described herein can be conducted in any organic solvent.
Solvents, reagents, and intermediates that are commercially available were used as received. Reagents and intermediates that are not commercially available were prepared in the manner as described below. 1H NMR spectra were obtained on a Bruker Ultrashield 400 (400 MHz) and are reported as ppm downfield from Me4Si with number of protons, multiplicities, and coupling constants in Hertz indicated parenthetically. Where LC/MS data are presented, analyses was performed using an Agilent 1100 LCMS system with LC column: Ascentis Express C18, 2.7 micron, 150 mm×3 mm ID; gradient flow: 0 minutes—10% CH3CN/2 mM aqueous NH4COOH/HCOOH, 6 minutes—95% CH3CN, 6-12 minutes—95% CH3CN, 14 minutes—stop. The observed parent ion is given. Flash column chromatography was performed using pre-packed normal phase silica from Biotage, Inc. or bulk silica from Fisher Scientific. Unless otherwise indicated, column chromatography was performed using a gradient elution of hexanes/ethyl acetate, from 100% hexanes to 100% ethyl acetate.
3-chloro-5-fluorophenol (1, 98 wt %, 10.0 g, 66.9 mmol) and 2-(2-bromo-5-chlorophenyl)acetic acid (2, 20.02 g, 80.0 mmol) were mixed with TfOH (91 mL) and heated to 60° C. under an nitrogen atmosphere. After stirring at this temperature for 16 hours, the mixture was cooled to room temperature and poured over a 20 minute period into isopropanol (500 mL) that had been cooled in an ice/water bath. The resulting slurry was diluted with water (125 mL), which was added over 10 minutes. After aging for 30 minutes in the ice/water bath, the mixture was filtered, and the collected solid was washed with 4:1 isopropanol/water (50 mL). The solid was dried under vacuum to provide compound 4 (20.14 g, 53.3 mmol, 80% yield).
Compound 4 (2.03 g, 5.37 mmol) was taken up in 2-methyltetrahydrofuran (20.3 mL, 10 volumes), and to this solution was added ammonia in methanol (11.51 mL of 7N, 81 mmol, 15 eq.). The resulting solution was aged at room temperature for 16 hours, then concentrated by the removal of 25 mL of solvent and the slurry was treated with toluene (70 mL). The resulting solution was then redistilled to remove a further 35 mL of solvent and achieve a final solution of the imine in 20 volumes of toluene. This solution was used without further purification. A sample of this solution was analyzed and found to contain a 97.5:2.5 ratio of compound 5:compound 4.
Compound 6 (0.58 g, 3.79 mmol, 1.1 eq.) was taken up in toluene (20 mL), (±)-camphorsulphonic acid (0.16 g, 0.69 mmol, 0.2 eq.) was added and the resulting solution was heated to 60° C. To this solution was added compound 5 (1.30 g, 3.45 mmol) as a solution in toluene (26 mL, 20 volumes) over a 1 hour period while distilling the reaction mixture at an equal rate to remove toluene (26 mL). The final solution was aged for an additional 2 hours then cooled to room temperature and treated with triethylamine (0.087 g, 0.862 mmol, 0.25 eq.). The resulting solution was then washed sequentially with citric acid solution(17 mL of 15% aqueous solution), sodium bicarbonate solution (17 mL of saturated aqueous solution) and water (17 mL). The resulting solution was solvent switched to 2-propanol (17 mL) seeded and water (1.7 mL) was added. The solid was filtered and dried in vacuo to provide compound 7 (1.33 g, 75%).
To a dry 1000 mL flask was charged activated 4A molecular sieves (55 g) followed by compound 5 (25 g, 66.3 mmol), 2-cyclopropylthiazole-5-carbaldehyde (20.32 g, 133 mmol) and DCM (275 mL). The resulting slurry was cooled using an ice-water bath then 2,2,2-trifluoroacetic acid (15.33 mL, 199 mmol) was added over 10 minutes, (T batch <10° C.). The resulting reaction was allowed to stir at room temperature for about 20 hours, then was cooled using an ice-water bath, and triethylamine (28.8 mL, 206 mmol) was added to the cooled solution using a syringe pump (T batch <15° C.). The reaction mixture was then filtered to remove molecular sieves, and washed with DCM. The organic layer was washed sequentially with water (60 mL), citric acid (5% aq. 60 mL), brine (5% wt 100 mL), NaHCO3 (2 wt %, 70 mL), brine (2 wt %, 70 mL), dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was taken up into 270 mL ethyl acetate at 45° C., then the solution was seeded and concentrated at 200 psi to about 3-4 volumes. Heptane (200 mL) was added over 2 hours and the resulting solution was cooled to 25° C. The solid formed was filtered and washed with ethyl acetate/Heptene=⅓ (2×40 mL) to provide a crude product that was recrystallized from ethyl acetate/heptane (½) to provide compound 7 (26 g) as a light yellow solid.
1H NMR (CDCl3):δ 7.54 (s, 1H), 7.51 (d; J=8.5 Hz, 1H), 7.21 (d, J=2.5 Hz, 1H), 7.13 (dd, J=8.5, 2.5 Hz, 1H), 6.80 (d; J=1.8 Hz, 1H); 6.78 (dd, J=10.4, 1.8 Hz), 6.61 (s, 1H), 4.23 (d, J=8.4 Hz, 1H), 4.21 (d, J=8.2 Hz, 1H); 2.28-2.23 (m, 1H), 1.13-1.09 (m, 2H), 1.08-1.04 (m ,2H); 1H NMR (CDCl3):175.6, 160.6, 160.2 (d, J=6.1 Hz), 158.5, 156.2 (J=7.0 Hz), 141.8, 139.9 (d, J=13.9 Hz), 138.2 (d, J=2.0 Hz),133.9, 133.3 (d, J=21.6 Hz), 131.3, 128.8, 123.5, 114.0 (d, J=6.3 Hz), 111.0 (d, J=7.3 Hz), 106.5 (d, J=16.4 Hz), 84.1, 43.9 (d, J=8.7 Hz), 14.8, 11.4 (d, J=4.1 Hz); [M+1]:512.8.
A solution of methylamine in ethanol (33 wt %, 3.7 g, 39.2 mmol) was added to a solution of 2-cyclopropylthiazole-5-carbaldehyde (6, 2.0 g, 13.1 mmol) in toluene (15 mL) at room temperature. The resulting solution was allowed to stir at room temperature for 1.5 h, then concentrated by removing 10 mL of solvent on rotary evaporator in vacuo. The resulting solution was diluted with PhCH3, and concentrated in vacuo to a final volume of 12 mL on a rotary evaporator to provide a toluene solution of compound 6A (2.17 g, 13.1 mmol, 100% yield). 1H NMR (DMSO-d6, 400 MHZ): δ 8.42 (d, J=1.5 Hz, 1H), 7.88 (s, 1H), 3.36 (d, J=1.3 Hz, 3H), 2.41 (m, 1H), 1.14 (m, 2H), 1.00 (m, 2H)
The resulting solution of 6A obtained above was combined with a slurry of 2-(2-(2-bromo-5-chlorophenyl)-1-iminoethyl)-5-chloro-3-fluorophenol (5, 4.52 g, 12.0 mmol) in PhCH3 (90 mL). The resulting slurry was concentrated by removing 60 mL of solvent on a rotary evaporator, and the flask was then placed in an room temperature water bath. TFA (2.77 mL, 36.0 mmol) was added to The resulting solution over 5 min, and The resulting solution aged at room temperature for 18 hours. The resulting slurry was filtered, the flask and pad washed with PhCH3 (45 mL), and the PhCH3 filtrates combined. The resulting solution was washed sequentially with 4% wt/wt aq. NaHCO3 (80 mL) and water (25 mL), then concentrated on a rotary evaporator. The resulting oil was concentrated twice from ethyl acetate (45 mL), leaving a residual solution of approximately 12 mL from which a solid precipitated. This slurry was warmed to a bath temperature of 50° C., then heptane (45 mL) was added over 1 hour. The resulting slurry was cooled to room temperature, aged for 15 hours, and cooled in an ice/water bath for 1 hour. The mixture was filtered, the flask and pad were washed with heptane (20 mL), and the solid was dried in vacuo at 50° C. to provide compound 7 (3.43 g, 56% yield).
A 1 L round-bottom flask equipped with an air condenser was charged with compound 6 (25 g, 163 mmol), 4-methoxyaniline (22.1 g, 180 mmol), and isopropanol (250 mL). The resulting slurry was warmed to 50° C. and stirred for 3.5 h, during which time a precipitate formed. The resulting slurry was cooled to 0° C., aged for 1 h, and filtered. The flask and pad were rinsed twice with 0° C. isopropanol (84 mL), and the solid was dried to a constant weight in a vacuum oven at 50° C. to provide compound 6B (39.0 g, 93% yield). 1H NMR (DMSO-d6, 400 MHZ): δ 8.77 (s, 1H), 8.06 (s, 1H), 7.26 (d, J=8.8 Hz, 2H), 6.96 (d, J=8.8 Hz, 2H), 3.77 (s, 3H), 2.45 (m, 1H), 1.19 (m, 2H), 1.05 (m, 2H)—imine geometry not determined, drawn as (E) for convenience.
A 3-neck roundbottom flask equipped with a magnetic stirbar, a temperature probe, and a nitrogen inlet was charged with compound 6B (7.54 g, 29.2 mmol) and a solution of compound 5 in toluene (5.72 wt %, 174.8 g, 26.5 mmol) was added. The resulting suspension was allowed to stir at room temperature until the solid dissolved, and the resulting solution was cooled using an ice/water bath. TFA (2.45 mL, 31.8 mmol) was added while the internal temperature was maintained below 5° C. The resulting solution was stirred in the ice/water bath for 16 hours as it warmed to room temperature. The resulting slurry was filtered, the flask and pad were washed with toluene (27 mL), and the organic solution was washed with aqueous NaHCO3 (4 wt %, 54 mL) and water (54 mL). The organic layer was concentrated in vacuo to ˜25 mL, diluted with isopropanol (110 mL), and concentrated in vacuo to ˜50 mL total volume. The resulting slurry was warmed to 40° C., diluted with water (10 mL, added over 30 min), aged at 0° C. for 1 hour, and filtered. The flask and pad were washed with 4:1 isopropanol/water (25 mL), and the solid dried to a constant weight in a vacuum oven at 50° C. to provide compound 7 (10.1 g, 74% yield).
To a solution of Pd(OAc)2 (219 mg, 0.98 mmol) and (R)-QuinoxP* (7e) (343 mg, 1.03 mmol) in a 100 mL round bottom flask was added degassed toluene (45 mL). The solution was subjected to three cycles of evacuation with vacuum and backfill with nitrogen and then purged with nitrogen above surface for 5 minutes. The catalyst solution was then allowed to age at 20° C. for 2 hours. A 1 L, 3-neck round bottom flask fitted with an overhead stirrer was then charged with compound 7 (25 g, 48.8 mmol) and K3PO4 (41.4 g, 195 mmol) and toluene (700 mL). The mixture was subjected to three cycles of vacuum evacuation and nitrogen backfill and then purged with nitrogen above surface for 5 minutes. Degassed water (0.88 mL, 48.8 mmol) was then added dropwise, after which the premade catalyst solution was added and the resulting reaction was heated to 50-55° C. and allowed to stir at this temperature for 11 hours. During the first 6 hours of the reaction time, additional water (5.28 mL, 293 mmol) was added in six equal portions, each hour. After a total of 11 hours at 50-55° C., the reaction mixture was cooled to 20° C. and charged with 75 mL of water and 5 mL 50% w/v KOH (˜9N). The aqueous layer was cut away and the organic layer was washed with 100 mL of water. The organic layer was then filtered and concentrated in vacuo and the resulting residue was purified using flash column chromatography to provide compound 8. The ee was determined using SFC under the following conditions:
For purified compound 8: (23 mg, 90% yield, in 91% ee). 1H NMR (CDCl3, 500 MHz): δ 7.663 (d, J=2.0 Hz, 1H), 7.407 (d, J=0.4 Hz, 1H), 7.200 (dd, J=2.0, 8.8 Hz, 1H), 7.092 (d, J=0.4 8.4 Hz, 1H), 7.048-7.039 (m, 2H), 6.958-6.910 (m, 2H), 2.194-2.153 (m, 1H), 1.275-1.075 (m, 2H), 1.018-0.991 (m, 2H).
Into a 1000 mL flask were charged 2-(2-bromo-5-chlorophenyl) acetic acid (7a, 60 g, 242 mmol) and trifluoromethanesulfonic acid (1.1 kg). The mixture was allowed to stir for 10 minutes, then 3-chlorophenol (27 g, 211 mmol) was added. The reaction was heated to 55 degrees and allowed to stir at this temperature for about 15 hours. The reaction mixture was then cooled to room temperature and poured into 3 kg of ice-water. The suspension formed was allowed to stir for 30 minutes and then filtered. The solid was collected and washed with water (300 mL x 3). The solid was dissolved in ethyl acetate (1000 mL was discard) and the collected organic layer was dried with Na2SO4, filtered and concentrated in vacuo to provide compound 7b (82 g, crude) as a solid. It was used directly to the next step. 1H NMR (500 MHz, CDCl3): δ (ppm) 12.10 (s, 1H), 7.81 (d, 1H, J=8.5 Hz), 7.55 (d, 1H, J=8.5 Hz), 7.26 (d, 1H, J=3.5 Hz), 7.20 (dd, 1H, J=8.5 Hz, 2.5 Hz), 7.05 (d, 1H, J=2.5 Hz), 6.95 (dd, 1H, J=8.5 Hz, 2.0 Hz), 4.42 (s, 2H). 13C NMR (125 MHz, CDCl3): δ (ppm) 200.8, 163.3, 142.7, 135.6, 133.9, 133.6, 131.6, 130.8, 129.3, 122.9, 119.9, 118.8, 117.6, 45.2. HRMS TOF MS (m/z): [M+H]+ calcd for [C14H9BrCl2O2 H] 358.9241; found 358.9240. FTIR(neat): 3074 (br), 1627, 1605, 1567, 1461, 1410, 1352, 1260 cm−1.
A solution of ammonia (7 M in methanol) was added to compound 7b (10 g) and the resulting reaction was allowed to stir at room temperature for 20 hours. The slurry formed was filtered and the collected solid was washed with methanol then dried in vacuo to provide compound 7c as a solid 8.6 g, 86% yield.
3 g of 4A molecular sieves (60 wt/wt %) is suspensed in 2-Methyl-THF (300 ml) under nitrogen atmosphere and cooled to 0° C., stirred for 10 min. 2-(2-(2-bromo-5-chlorophenyl)-1-iminoethyl)-5-chlorophenol (5 g, 13.9 mmol), aldehyde (15.3 mmol) and imine (1.39 mmol) is added, stirred for 2 minutes while maintaining reaction temperature at 0-5° C. Trifluoromethanesulfonic acid (0.418 g, 2.79 mmol) was added dropwise over 1 minute, then the mixture was warmed to room temperature and allowed to stir at this temperature for about 15 hours. The reaction mixture was filtered and the collected sieves were washed with 2-MeTHF(5 mL). The organic phase was then washed sequentially with 5 wt % NaHCO3 solution(25 mL), then water (25 mL). The organic phase was collected and concentrated in vacuo. The resulting residue was purified via crystallization from MeOH (25 mL) to give 4-(2-bromo-5-chlorobenzyl)-7-chloro-2-phenyl-2H-benzo[e][1,3]oxazine (1a) as a solid (82% yield). 1H NMR (500 MHz, CDCl3): δ (ppm) 7.55-7.52 (m, 3H), 7.42-7.34 (m, 3H), 7.30 (d, 1H, J=3.5 Hz,) 7.29 (s, 1H), 7.13-7.10 (dd, 1H, J=8.5 Hz, 2.5 Hz), 6.95-6.91 (m, 2H), 6.57 (1H, s), 4.16 (ABq, 2H,J=16.5 Hz). 13C NMR (125 MHz, CDCl3): δ (ppm) 161.5, 155.8, 139.2, 138.9, 138.1, 133.8, 133.5, 130.6, 128.8, 128.7, 128.5, 127.0, 126.3, 122.6, 121.9, 117.3, 116.2, 88.9, 40.8. HRMS TOF MS (m/z): [M+H]+ calcd for [C21H14BrCl2NO H] 445.9709; found 445.9713. FTIR(neat): 3060, 1633, 1596, 1454, 1364, 1344 cm−1.
In a glove box, a solution of compound 7e (commercially available, 2.47 mg, 0.0074 mmol, 2.2%) and diacetoxypalladium (1.51 mg, 0.0067 mmol, 2% cat.) in toluene (200 uL) was heated at 40° C. for 2 hours. The resulting solution was then transferred into a mixture of compound 7d (15 mg, 0.034 mmol) and K3PO4 (53 mg, 0.252 mmol) in toluene (0.75 mL). The resulting reaction was heated at 60° C. for 15 hours. Then the mixture was cooled and filtered. The residue was concentrated in vacuo and purified using preparative TLC to provide compound 9. The ee was determined using SFC under the following conditions:
Compound 9: (˜11 mg, 99% yield, in 95% ee). 1H NMR (CDCl3, 400 MHz): δ 7.64 (d, J=2.0 Hz, 1H), 7.62-7.60 (m, 1H), 7.37-7.30 (m, 3H), 7.14 (s, 1H), 7.13-7.10 (m, 2H), 7.07 (t, J=1.9 Hz, 1H), 7.06-7.05 (m, 2H), 6.86 (s, 1H), 6.76 (d, J=8.8 Hz, 1H).
In a dry 100 mL RB flask was placed powder MS4A (3.3 g). The flask was evacuated and heated with a heat gun in vacuo. After cooling to room temperature, dichloromethane (15 mL) was added. To the resulting solution was added Compound 8a (0.81 g) and compound 5 (1.0 g). To the resulting reaction was added trifluoroacetic acid (0.41 mL) and the reaction was allowed to stir at room temperature for about 15 hours. Additional trifluoroacetic acid (0.20 mL) was added and the reaction was allowed to stir for an additional 6 hours, then was quenched using triethylamine (1.85 mL). The resulting mixture was filtered, and concentrated in vacuo. The residue obtained was purified using flash column chromatography to provide 0.22 g of compound 8b. LRMS=512 (M+H).
In the glove box, a resulting solution of compound 7e (4.68 mg, 0.014 mmol, 2.2%) and diacetoxypalladium (2.86 mg, 0.013 mmol, 2% cat.) in toluene (400 uL) was heated at 40° C. for 2 hours. Then the resulting solution was transferred into a mixture of compound 8b (30 mg, 0.064 mmol) and K3PO4 (101 mg, 0.48 mmol) in toluene (1.0 mL). The resulting mixture was heated at 60° C. for 15 hours. Then the mixture was cooled and filtered. The reaction mixture was filtered and concentrated in vacuo. The residue obtained was purified using silica-gel column chromatography to provide compound 10. The ee was determined by using SFC under the following conditions:
For purified compound 10: (18 mg, 85.6%, 86% ee). 1H NMR (CDCl3, 400 MHz, ppm): 7.65 (d, J=1.8 Hz, 1H), 7.31 (s, 1H), 7.16 (dd, J=2.0, 8.8 Hz, 1H), 7.03-7.01 (m, 2H), 6.92-6.89 (m, 2H), 6.48 (d, J=3.6 Hz, 1H), 6.36 (d, J=3.5 Hz, 1H), 2.00-1.93 (m, 1H), 0.98-0.93 (m, 2H), 0.68-0.64 (m, 2H).
In a glove box, a solution of copper(I) iodide (0.076 mg, 0.0004 mmol, 10% cat.) in acetonitrile (50 μL) was added to compound 10b (commercially available, 0.14 mg, 0.000422 mmol, 11%) and heated to about 55° C. for about 2 h. The solvent was then removed in vacuo and Cs2CO3 (9.8 mg, 0.030 mmol) was added. Compound 10a (prepared using the methods described above to make compound 7 and substituting the appropriate reactants, 2.3 mg, 0.004 mmol) was then added as a solution in 2-methyltetrahydrofuran (0.1 mL) and the resulting mixture heated to about 65° C. for 24 h to provide compound 12 in 68% ee.
In a glove box, a suspension of compound 10a (16 mg), CuI (1.37 mg, 0.25 eq.) and Cs2CO3 (28 mg, 3 eq.) in DMAc (0.5 mL) was heated to 85° C. and allowed to stand at this temperature for 18 hours. The reaction mixture was then diluted with ethyl acetate (10 mL) and washed with water (2×5 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified using flash column chromatography to provide compound 13 (racemic, 8 mg, 60% yield). 1H NMR (CDCl3, 500 MHz): δ 7.67(d, J=2.0 Hz, 1H), 7.42 (s, 1H), 7.21 (dd, J=2.0, 8.5 Hz, 1H), 7.06-7.12 (m, 5H), 2.19-2.16 (m, 1H), 1.08-1.12 (m, 2H), 1.00-1.03 (m, 2H).
The crude product of compound 8, obtained using the method described in Example 6 (21 g theoretic yield, 48.8 mmol) was dissolved in ˜50 mL of toluene and 128 mL of iPAC at 45° C. (S)-Camphorsulfonic acid (10.8 g, 46.4 mmol) was added over 2.5 hours in three portions at 45° C. It was cooled to room temperature and additional (S)-camphorsulfonic acid (0.57 g, 2.4 mmol) was added. After aging at room temperature for 16 hrs, the mixture was filtered. The solid was washed with 50 ml 1/2.5 toluene/isopropyl acetate and then 50 ml isopropyl acetate, and dried with vacuum to afford 27.1 g of 8 (40.8 mmol) as its camphorsulfonic acid (CSA) salt salt in 96 to >99%ee. A “racemic” salt was also observed sometimes, leading to lower ee (˜96% ee).
(R)-QuinoxP* (compound 7e, commercially available, 0.454 g, 1.358 mmol, 1.0 equiv) was taken up in dry tetrahydrofuran (13.5 mL) at room temperature. The resulting solution was cooled to 0° C. and BH3-SMe2 (0.14 mL, 1.494 mmol, 1.1 equiv) was added in one portion. The resulting reaction was allowed to stir at 0° C. for 40 minutes and aqueous 35 wt % H2O2 (1.4 mL, 16.3 mmol, 12 equiv) was added over 5 minutes. The resulting solution was allowed to stir at 0° C. for 2 hours and was then quenched by the addition of saturated aqueous Na2SO3 (20 mL). The mixture was then diluted with ethyl acetate (20 mL). The layers were separated and the aqueous layer was washed twice with 20 mL of ethyl acetate. The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to dryness and dried further at room temperature in vacuo with nitrogen purge for 16 hours. The residue obtained was taken up in dichloromethane (13.5 mL) and cooled to −5° C. HBF4-etherate (1.85 mL, 13.58 mL, 10 equiv) was added in one portion. Vigorous gas evolution was observed during the acid addition. The cooling bath was removed and the resulting solution was allowed to stir at room temperature for 1 hour. The mixture was quenched with 40 mL of saturated aqueous KHCO3 which had been degassed with nitrogen. The biphasic mixture was diluted with 30 mL of MTBE and the layers were separated. The aqueous layers were washed twice with 30 mL of MTBE. The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to dryness and the residue obtained was purified using flash column chromatography on silica gel chromatography (50% ethyl acetate/hexanes to 100% ethyl acetate) to provide (R)-QuinoxP* monoxide (13b, 320 mg, 67%) as a solid. 1H NMR (400 Mhz, CDCl3) δ 8.165 (dd, J=1.28, 8.36 Hz, 1H), 8.069 (dd, J=1.52, 8.17 Hz, 1H), 7.817 (m, 2H), 1.977 (d, J=12.8 Hz, 3H), 1.459 (d, J=6.9 Hz, 3H), 1.186 (d, J=13.7 Hz, 9H), 1.088 (d, J=11.8 Hz, 9H); 31P NMR(162 Mhz, CDCl3) δ 51.16 (d, J=4.1 Hz), −11.9 (d, J=3.8 Hz); LRMS calcd. for C18H29N2OP32 [M+H]+ 351; found 351.
A 3000-mL 3-necked round-bottom flask was purged and maintained with an inert atmosphere of nitrogen. 5-Bromoindolin-2-one (14a, 201 g, 947 mmol), sodium hydroxide (216.96 g, 472 mmol) and water (1139.04 mL) were added. The resulting solution was allowed to stir for 30 h at 100° C. The pH value of the solution was adjusted to 6 with hydrogen chloride (6 mol/L). The solids were collected by filtration. This resulted in compound 14b (229 g, 871 mmol, 92% yield) as a gray solid.
Into a 5-L flask was charged hydrochloric acid, 37% (1000 ml) and water (1000 mL). 2-(2-Amino-5-bromophenyl)acetic acid (230 g, 871 mmol) was added batchwise at r.t in 20 min. The suspension was stirred for 1 h, and then cooled to −5° C. A solution of sodium nitrite (66.1 g, 958 mmol) in 100 mL water was added dropwise at −5 to 0° C. over 2.5 hr. The mixture was allowed to stir for further 1 h at −5 to 0° C. The solution was labelled as solution A.
Into a 5000 mL flask was charged water (1000 mL) and potassium iodide (795 g, 4.79 mmol). The solution was heated to 50° C. Solution A was added dropwise over 2 hr. The resulting solution was allowed to stir for a further 2 hr at 50° C. LCMS showed reaction completed conversion. The cake was dried under vacuum to obtain compound 14c (210 g, 616 mmol, 61.6% yield) as a yellow solid.
Into a 5000 mL flask was charged 2-(5-bromo-2-iodophenyl)acetic acid (190 g, 557 mmol) and MeCN (1900.0 mL). Oxalyl dichloride (91.9 g, 724 mmol) was added dropwise RT, then stirred for 1 h at RT. The mixture was concentrated in vacuo to give a yellow oil. Into a 5000 ml flask was charged the residue and MeCN (1900.0 mL), 3-bromophenol (92 g, 724 mmol) and DIEA (94 g, 724 mmol) were added dropwise at -10 degree. It was then stirred for about 15 hours at RT. The solvent was removed by distillation under vacuum. The residue was applied to a silica gel column with ethyl acetate/petroleum ether(1:100) to give compound 14d (170 g, 276 mmol, 61.6% yield) as a white solid.
In a 2000 mL flask, methanesulfonic anhydride (76 g, 5.74 mmol) and methanesulfonic acid (1900 g, 104 mmol) were placed. The resulting solution was heated at 90° C. for 2 hours. The solution was cooled to 70° C., and 3-bromophenyl 2-(5-bromo-2-iodophenyl)acetate (170 g, 276 mmol) was added. The resulting solution was heated at 70° C. for 30 hours. After cooling to room temperature, the mixture was diluted with water (1000 mL) and the resultant slurry of product was filtered. The product cake was slurry washed with water, 15% aqueous sodium carbonate solution and then MeOH:water (1:1). The cake was dried under vacuum to provide compound 14e (110 g, 222 mmol, 65% yield)
A solution of ammonia (1000 mL, 9 M in MeOH) was added to 1-(4-bromo-2-hydroxyphenyl)-2-(5-bromo-2-iodophenyl)ethanone (110 g, 222 mmol) and the mixture was stirred at room temperature for 20 h. The resulting slurry was filtered and the product cake was washed with MeOH. After vacuum drying, compound 14f (60 g, 121 mmol, 55% yield) was obtained as a yellow solid.
Into a 1000 ml 4-neck round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 4A molecular sieves (30 g) and 2-Methyl-THF (420 ml), the suspension was allowed to stir for 10 min. 5-bromo-2-(2-(5-bromo-2-iodophenyl)-1-iminoethyl)phenol (60 g, 0.404 mmol), benzaldehyde (14 g, 0.444 mmol), (E)-N-benzylidene-4-methoxyaniline (1.6 g, 0.040 mmol) was added. After the solution was allowed to stir for 5 min, trifluoromethanesulfonic acid (3.636 g, 0.081 mmol) was added. The resulting solution was allowed to stir for about 15 hours at room temperature. The reaction was quenched by the addition of 200 ml of NaHCO3 solution. The organic layer was separated and the aqueous was re-extracted with EA (1×200 mL). The combined organic fractions were washed with brine (1×300 mL), dried with Na2SO4, filtered and the filtrate was evaporated in vacuo. The residue obtained was recrystallized from methanol. The solid was collected and dried in vacuo at room temperature to provide compound 14g (53.5 g, 0.343 mmol, 76% yield) as a yellow solid. LC-MS (ES, m/z): (M+1)=582, 584, 586. H-NMR (400 MHz, CDCl3) δ 7.68(d, J=8.42 Hz, 1H), 7.54-7.47(m,2H), 7.42-7.28 (m, 4H), 7.17 (d, J=8.26 Hz, 1H), 7.13-7.02 (m, 3H), 6.55 (s, 1H), 4.21-4.06 (m, 2H).
A 3000-mL 4-necked round-bottom flask was purged and maintained with an inert atmosphere of nitrogen. 5-Chloroindolin-2-one (15a, 160 g, 952 mmol) and sodium hydroxide (1193 ml, 4773 mmol) were added. The resulting solution was stirred for 30 h at 100° C. The pH value of the solution was adjusted to 6 with hydrogen chloride (6 mol/L). The solid was collected by filtration to provide compound 15b (170 g, 916 mmol, 96% yield).
Into a 5-L flask was charged hydrochloric acid, 37% (850 mL) and water (1000 mL) Compound 15b (170 g, 916 mmol) was added batchwise at r.t in 20 min. The suspension was stirred for 1 h, and then cooled to −5° C. A solution of sodium nitrite (76 g, 1099 mmol) in 200 mL water was added dropwise at −5 to 0° C. over 2.5 hr. The mixture was stirred for further 1 h at −5 to 0° C. The solution was labelled as solution A.
Into a 10 L flask was charged water (850 mL), con.sulfuric acid (90 g, 916 mmol) and potassium iodide (243 g, 1465 mmol). The solution was heated to 50° C. Solution A was added dropwise for 2 hr. The resulting solution was stirred for a further 2 hr at 50° C. LCMS showed complete conversion. The reaction mixture was poured into 3 L of ice-water and extracted with ethyl acetate (3000 mL*2). The combined organic layers were washed with Na2S2O3 and dried with Na2SO4, filtered and concentrated in vacuo to provide compound 15c (176 g, 594 mmol, 64.8% yield) as a solid.
Into a 3 L flask was charged compound 15c (140 g, 472 mmol) and MeCN (1400 mL). Oxalyl dichloride (78 g, 614 mmol) was added dropwise at room temperature over 30 min .The solution was allowed to stir for 10 min at room temperature. LCMS showed complete conversion. 3-Chlorophenol (79 g, 614 mmol) was added a −10° C. over 5 min, DIEA (73.8 g, 571 mmol) was added dropwise at −10° C. over 30 min. The solution was stirred for a further 30 min at −10° C. LCMS showed complete conversion. EA/H2O(1000 mL/1000 mL) was added and stirred for other 30 min. Organic layer was separated, aqueous layer was re-extracted with EA(500 mL×2). The combined organic layers were dried with Na2SO4, filtered and concentrated in vacuo to provide crude product, which was purified on silica gel eluting with PE, to provide compound 15d (150 g, 369 mmol, 78% yield) as a solid.
Dry methanesulfonic acid (750 g, 7804 mmol) was added to compound 15d (100 g, 246 mmol) and the resulting solution was heated at 70° C. for about 15 hours. After cooling to room temperature, the mixture was diluted with water (1000 mL). The mixture was extracted with EA (500 mL×2). The combined organic layers were washed with water (500 mL×2) and brine (200 mL×1), dried with Na2SO4, filtered and concentrated in vacuo to provide crude product, which was purified using flash column chromatography on silica gel eluting with petroleum ether to provide compound 15e (52 g, 128 mmol, 52.0% yield) as a solid.
A solution of ammonia (7 M in MeOH) was added to compound 15e (50 g, 123 mmol) and the mixture was allowed to stir at room temperature for 20 hours. The resulting slurry was filtered and the product cake was washed with MeOH (100 mL×2). After vacuum drying, compound 15f was obtained as a solid (35 g, 94 mmol, 77% yield).
Into a 500 ml flask was charged 4 Å molecular sieves (18 g) and isopropyl acetate (245 mL). The solution was stirred for 2 hour at 20° C. Compound 15f (35 g, 86 mmol), (E)-N-benzylidene-4-methoxyaniline (1.821 g, 8.62 mmol) and benzaldehyde (10.06 g, 95 mmol) were added at room temperature. After 10 min, trifluoromethanesulfonic acid (2.59 g, 17.24 mmol) was added. The mixture was stirred at room temperature for 15 h. LCMS showed complete conversion. 5% NaHCO3 (500 ml) was added and stirred for other 30 minutes. The organic layer was separated and the aqueous layer was re-extracted with EA(200 mL×1). The combined organic layers were dried with Na2SO4, filtered and concentrated in vacuo. The solid obtained was suspended in MeOH(100 mL) and stirred for a further 1 hour. The resulting slurry was filtered and the collected solid was washed with MeOH(100 mL×2), then dried in vacuo to provide compound 15g (36.5 g, 73.9 mmol, 86% yield) as a solid. LC-MS: (ES, m/z): 494 [M+H]+H-NMR: (400 MHz, CDCl3, ppm): δ 7.80 (1H, d), 7.55 (2H, d), 7.47-7.37(3H, m), 7.31-7.20 (2H, m), 7.05-6.98 (3H, m), 6.65 (1H, s), 4.23 (2H, s).
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed [3-bromo-4-[(1R)-1-(dimethylamino)ethyl]cyclopenta-2,4-dien-1-yl](cyclopenta-2,4-dien-1-yl)iron (Compound 16a, 5 g, 14.88 mmol, 1.00 equiv), acetic acid (10 mL), and dicyclohexylphosphane (3.3 g, 16.64 mmol, 1.10 equiv). The resulting solution was heated to reflux for 2 hours, then cooled to room temperature and concentrated in vacuo and diluted with acetonitrile. The resulting solution was filtered and the collected solid dried in vacuo to provide 4.7 g (65%) of compound 16b as a solid.
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed compound 16b (1 g, 2.04 mmol, 1.00 equiv), tetrahydrofuran (10 mL). This was followed by the addition of butyllithium (200 mg, 3.12 mmol, 1.50 equiv) dropwise with stirring at −60° C. To this was added diphenylphosphinoyl chloride (730 mg, 3.08 mmol, 1.50 equiv) dropwise with stirring at −60° C. The reaction was allowed to stir for 2 hours at −60° C., then 40% HBF4 solution(2.2 g, 5.00 equiv) was added. The resulting solution was allowed to stir for 2 hours at room temperature, then was diluted with 10 mL of H2O. The resulting solution was extracted with dichloromethane and the organic layer was concentrated in vacuoThe residue obtained was purified using flash column chromatography on silica gel eluted with dichloromethane/methanol (100:1). The crude product was re-crystallized from a 10:1 mixture of pentane:tetrahydrofuran to provide 0.67 g (47%) of compound 16c as a solid.
LC-MS: (ES, m/z): 611 [M+H]+H-NMR: (300 MHz, DMSO, ppm): δ 7.96 (dd, J=12.3, 7.1 Hz, 2H), 7.66 (ddt, J=24.8, 21.7, 8.2 Hz, 9H), 5.01 (s, 1H), 4.75 (d, J=14.8 Hz, 2H), 4.07 (s, 5H), 2.69 (s, 1H), 2.33 (s, 1H), 1.84-1.63 (m, 7H), 1.52 (s, 6H), 1.26 (s, 6H), 1.12 (s, 6H).
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed compound 16d (2 g, 4.09 mmol, 1.00 equiv), propan-2-one (20 mL) and 30% hydrogen peroxide (930 mg, 8.17 mmol, 2.00 equiv). The reaction was allowed to stir for 4 hours at 40° C., then the reaction mixture was concentrated in vacuo to provide 2 g (92%) of compound 16e as a solid.
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed compound 16e (1.5 g, 2.97 mmol, 1.00 equiv), tetrahydrofuran (15 mL). This was followed by the addition of butyllithium (228 mg, 3.56 mmol, 1.20 equiv) dropwise with stirring at −60° C. To this was added chlorodiphenylphosphane (786 mg, 3.56 mmol, 1.20 equiv) dropwise with stirring at −60° C. The solution was stirred for 2 h at −60° C. To the mixture was added 40% HBF4 solution (3.3 g, 15.2 mmol, 5.00 equiv) and the resulting reaction was allowed to stir for 2 hours at room temperature. The resulting solution was diluted with of H2O and extracted with 20 mL of dichloromethane and the organic layer was collected and concentrated in vacuo. The residue obtained was purified using flash column chromatography on silica gel, eluting with dichloromethane/methanol (100:1). This resulted in 1.3 g crude HBF4 salt. The crude salt was taken up in MTBE (10 mL) and stirred for 1 hour under nitrogen atmosphere, then the reaction was filtered and the collected solids were dried to provide 0.85 g (43%) of 16f as a solid.
LC-MS: (ES, m/z): 611 [M+H]+ H-NMR: (300 MHz, DMSO, ppm): δ 7.64 (ddt, J=7.8, 5.2, 2.8 Hz, 2H), 7.39 (td, J=3.1, 1.5 Hz, 3H), 7.27-7.15 (m, 5H), 4.63 (t, J=2.6 Hz, 1H), 4.51 (t, J=2.5 Hz, 1H), 4.38-4.30 (m, 1H), 3.28 (s, 3H), 1.79 (s, 1H), 1.61 (dt, J=16.1, 8.1 Hz, 5H), 1.44 (dd, J=22.4, 12.6 Hz, 9H), 1.28-0.91 (m, 11H), 0.75 (s, 3H).
In a glove box, a slurry of copper(II) bromide (14.3 mg, 0.064 mmol) and compound 17b (commercially available, 25.2 mg, 0.064 mmol) in toluene (4 mL) was agitated about 16 h at room temperature. A portion of the resulting catalyst slurry (0.038 mL; about 4 mol % catalyst) was then added into a mixture of compound 14g (8.8 mg, 0.015 mmol) in toluene (0.225 mL) with stirring followed by K3PO4 (12.7 mg, 0.06 mmol). The resulting mixture was heated to about 55° C. and held at about 55° C. with stirring for about 27 h to provide compound 26 in 78% ee.
Under a nitrogen atmosphere inside a glovebox, a 0.025 M solution of palladium acetate in anhydrous toluene was added to 1.0 mole equivalent of the ligand and the mixture was agitated at room temperature between 0.5 and 2 h (8 mL catalyst stock solution was prepared for 7e and 2 mL of stock solution was prepared for Ligand 18c, which is commercially available). A portion of the catalyst mixture (0.14 mL; 1 mol % catalyst) was then added to a mixture of compound 18a (0.35 mmol) in toluene (6.86 mL) followed by K3PO4 (409 mg, 1.93 mmol). The resulting mixture was heated to about 55° C. and held at about 55° C. with agitation at 1200 rpm for about 24 h to provide compound 18b. The absolute configurations of the compounds of 18b, where indicated, were confirmed was using X-ray analysis.
Wherein the structure of Ligand 7e and Ligand 18c are as follows:
The solution of N-(2-(2-(2-bromophenyl)acetyl)phenyl)-4-methylbenzenesulfonamide (27) (1.9 g, 4.28 mmol) in ammonia (19.55 ml, 137 mmol) (7N in MeOH) was stirred at rt for overnight. There are lots of pricipitates generated (yellow). The solid was collected by vacumm filtration and washed with MeOH, then the solid was dried under with N2 flow at rt. to give N-(2-(2-(2-bromophenyl)-1-iminoethyl)phenyl)-4-methylbenzenesulfonamide (28) (1.54 g, 81% yield). The product was used for next step without any further purification. 1H NMR (500 MHz, CDCl3): δ (ppm) 14.0 (br, 1H), 9.46 (br, 1H), 7.74-7.67 (m, 5H), 7.36 (qd, 2H, J=7.5, 1.0 Hz), 7.27 (td, 1H, J=8.0, 2.0 Hz), 7.20 (d, 2H, J=8.5 Hz), 7.15 (dd, 1H, J=7.5, 1.5 Hz), 7.05 (td, 1H, J=8.0, 1.0 Hz), 4.17 (s, 2H), 2,37 (s, 3H). 13C NMR (125 MHz, CDCl3): δ (ppm) 175.6, 143.2, 140.3, 137.3, 133.6, 133.5, 132.5, 132.0, 129.9, 129.4, 128.9, 128.2, 127.2, 125.8, 122.1, 121.7, 119.2, 44.6, 21.5. HRMS TOF MS (m/z): [M+H]+ calcd for [C21H19BrN2O2S H] 443.0423; found 443.0426. FTIR(neat): 3059 (br), 1601, 1535, 1481, 1438, 1278, 1253 cm−1.
The suspension of 4A MS (3 g), 4-methoxyaniline (0.167 g, 1.353 mmol), RCHO (6.77 mmol), N-(2-(2-(2-bromophenyl)-1-iminoethyl)phenyl)-4-methylbenzenesulfonamide (1.50 g, 3.38 mmol) in DCM (15.00 ml) was charge trifluoromethanesulfonic acid (0.118 ml, 1.353 mmol). Then the mixture was heated to around 40 C for 48 hs. The mixture was filtered through filter aid. And the solution was concentrated under vacuum and purified by flash chromatograph. (Hex/EA: from 92/8 to 95/5).
4-(2-bromobenzyl)-2-phenyl-1-tosyl-1,2-dihydroquinazoline (29a): off-white solid in 78% yield. 1H NMR (500 MHz, CDCl3): δ (ppm) 7.83 (dd, 1H, J=8.0, 1.0 Hz), 7.57-7.55 (m, 1H), 7.47-7.39 (m, 5H), 7.33 (dd, 1H, J=8.0, 1.5 Hz), 7.27-7.15 (m, 7H), 7.11-7.06 (m, 2H), 6.55-6.53 (m, 1H), 4.11 (d, J=15.0 Hz), 3.68 (d, 1H, J=15.0 Hz), 2.45 (s, 3H). 13C NMR (125 MHz, CDCl3): δ (ppm) 162.9, 143.8, 137.5, 136.4, 136.1, 134.7, 132.7, 132.3, 130.7, 129.5, 128.3, 128.0, 127.9, 127.5, 127.18, 127.17, 127.0, 126.4, 125.0, 124.8, 124.4, 72.5, 41.1, 21.6. HRMS TOF MS (m/z): [M+H]+ calcd for [C28H23BrN2O2S H] 531.0736; found 531.0756. FTIR(neat): 3055, 1635, 1598, 1449, 1346, 1167 cm−1.
4-(2-bromobenzyl)-2-phenethyl-1-tosyl-1,2-dihydroquinazoline (29b): yellowish syrup in 64% yield. 1H NMR (500 MHz, CD3CN): δ (ppm) 7.74 (dd, 1H, J=8.0, 1.0 Hz), 7.60-7.56 (m, 1H), 7.54-7.51 (m, 2H), 7.36 (td, 1H, J=7.5, 1.0 Hz), 7.26-7.18 (m, 7H), 7.16-7.09 (m, 4H), 6.66 (dd, 1H, J=7.5, 2.0 Hz), 5.84 (dd, 1H, J=8.5, 5.0 Hz), 4.01 (d, 1H, J=15.0 Hz), 3.33 (d, 1H, J=15.0 Hz), 2.73-2.64 (m, 2H), 2.41 (s, 3H), 1.84-1.77 (m, 1H), 1.54-1.46 (m, 1H). 13C NMR (125 MHz, CD3CN): δ (ppm) 161.7, 145.5, 142.6, 138.0, 136.8, 135.2, 133.4, 133.2, 132.7, 130.7, 129.5, 129.42, 129.39, 128.5, 128.4, 128.3, 128.0, 126.9, 126.1, 125.9, 125.2, 72.5, 41.5, 34.8, 32.1, 21.7. HRMS TOF MS (m/z): [M+H]+ calcd for [C30H27BrN2O2S H] 559.1049; found 559.1063. FTIR(neat): 3023, 1629, 1596, 1451, 1347 cm−1.
Under a nitrogen atmosphere inside a glovebox, a 0.025 M solution of palladium acetate in anhydrous toluene was added to 5.0 mole equivalent of the ligand and the mixture was agitated at room temperature between 0.5 and 2 h (2 mL of stock solution was prepared for Ligand 2). A portion of the catalyst mixture (0.14 mL; 1 mol % catalyst) was then added to a mixture of compound 29 (0.35 mmol) in toluene (6.86 mL) followed by K3PO4 (409 mg, 1.93 mmol). The resulting mixture was heated to about 55° C. and held at about 55° C. with agitation at 1200 rpm for about 24 h to provide a compound of formula 30. The absolute configurations of the compounds of 30, where indicated, were confirmed was using X-ray analysis.
In a glovebox under nitrogen atmosphere, a 0.1 M solution of KOtBu in toluene (700 μl, 70 μmol, 1.0 eq.) was slowly added to a mixture of Ligand 19a (commercially available, 49 mg, 70 μmol, 1.0 eq.) in 700 μl toluene at about 25° C. To a portion of the resulting mixture (350 μl) was added a solution of tris(dibenzylideneacetone)dipalladium(O) (8.0 mg, 8.8 μmol, 1.0 eq. Pd relative to ligand) in 350 μL anhydrous toluene. The mixture was agitated for about 0.5 h at about 25° C. The catalyst mixture (700 μl, about 5 mol % loading Pd) was then added to a solution of 7d (157 mg, 0.35 mmol, 1.0 eq.) in 6.30 mL toluene with agitation at room temperature followed by K3PO4 (409 mg, 1.93 mmol, 5.5 eq.) with agitation prior to heating to 55° C. The resulting mixture agitated at about 55° C. for about 20 h to provide compound 9 in 87% ee.
In a glovebox under nitrogen atmosphere, a 0.1 M solution of KOtBu in toluene (700 μl, 70 μmol, 1.0 eq.) was slowly added to a mixture of Ligand 16f (49 mg, 70 μmol, 1.0 eq.) in 700 μl toluene at about 25° C. To portion of the resulting mixture (700 μl) was added a solution of palladium acetate (3.9 mg, 18 μmol, 0.5 eq. Pd relative to ligand) in 350 μL anhydrous toluene. The mixture was agitated for about 0.5 h at about 25° C. The catalyst mixture (1.05 ml, about 5 mol % loading Pd) was then added to a solution of 7d (157 mg, 0.35 mmol, 1.0 eq.) in 6.30 mL toluene with agitation at room temperature followed by K3PO4 (409 mg, 1.93 mmol, 5.5 eq.) with agitation prior to heating to 55° C. The resulting mixture agitated at about 55° C. for about 20 h to provide compound 9 in about 87% ee.
In a glovebox under nitrogen atmosphere, a 0.1 M solution of KOtBu in toluene (700 μl, 70 μmol, 1.0 eq.) was slowly added to a mixture of Ligand 16c (49 mg, 70 μmol, 1.0 eq.) in 700 μl tetrahydrofuran at about 25° C. To a portion of the resulting mixture (350 μl) was added a solution of tris(dibenzylideneacetone)dipalladium(0) (8.0 mg, 8.8 μmol, 1.0 eq. Pd relative to ligand) in 350 μL anhydrous toluene. The mixture was agitated for about 0.5 h at about 25° C. The catalyst mixture (700 μl, about 5 mol % loading Pd) was then added to a solution of 7d (157 mg, 0.35 mmol, 1.0 eq.) in 6.30 mL toluene with agitation at room temperature followed by K3PO4 (409 mg, 1.93 mmol, 5.5 eq.) with agitation prior to heating to 55° C. The resulting mixture was agitated at 55° C. for about 20 hours to provide compound 9 in about 4% ee.
In a glovebox under nitrogen atmosphere, a solution of palladium acetate (14.4 mg, 64 μmol) in 8 mL anhydrous toluene was prepared. A 50 μL portion of this solution (0.09 mg, 4.0 μmol, about 0.10 eq. palladium acetate) was then added to 73 (0.42 μmol, 0.11 eq.). The resulting mixture was agitated for about 2 hours at about 35° C. A solution of 7d (1.8 mg, 4.0 μmol, 1.0 eq.) in 60 μL toluene was then added to a 50 μL portion of the catalyst mixture (about 10 mol % loading Pd) at room temperature followed by the base (30 μmol, 7.5 eq.) prior to heating to 55° C. The resulting mixture was agitated at about 55° C. for about 18 hours to provide compound 9 in 93-96% ee for the following bases: K3PO4, K2CO3, KHCO3, KOAc, KF, LiOH, Li2CO3, Na2CO3, Rb2CO3, and Cs2CO3
In a glovebox under nitrogen atmosphere, a solution of palladium acetate (14.4 mg, 64 μmol) in 8 mL anhydrous toluene was prepared. A 50 μL portion of this solution (0.09 mg, 4.0 μmol, about 0.10 eq. palladium acetetate) was then added to 7e (0.42 μmol, 0.11 eq.). The resulting mixture was agitated for about 2 hours at about 35° C. Substrate-Base Mixture Prep: A 0.15 M solution of base in toluene (1.0 ml, 4.4 μmol, 1.1 eq.) was added to a solution of compound 7d (59.2 mg, 132 μmole, 1.0 eq.) in 1 mL toluene portionwise at about −5° C. over about 10 min. and the mixture agitated about 0.5 hour. Reaction: 60 μl of the resulting substrate-base mixture (4 μmol substrate) was added to a 50 μL portion of catalyst mixture solution at room temp. with agitation prior to heating to 55° C. The resulting mixture agitated at about 55° C. for about 18 hours to provide compound 9 in 90-96% ee for the following bases: KOtBu, NaOtBu, KHMDS, NaHMDS, and LiHMDS.
In a glovebox under nitrogen atmosphere, a solution of palladium acetate (14.4 mg, 64 μmol) in 8 mL anhydrous toluene was prepared and added to 7e (22.5 mg, 67 μmol, 1.05 eq.). The resulting mixture was agitated for about 2 hours at about 25° C. A solution of 7d (1.8 mg, 4.0 μmol, 1.0 eq.) in 60 μL toluene was then added to a 50 μL portion of the catalyst mixture (about 10 mol % loading Pd) at room temperature with agitation. Finally, a 0.44 M solution of the base in tert-butyl methyl ether (18 μl, 8 μmol, 2 eq.) was added to this mixture with agitation prior to heating to 55° C. The resulting mixture was agitated at about 55° C. for about 18 hours to provide compound 9 in 90-97% ee using the following bases: triethylamine, t-butylamine, polyvinylpyridine, 2,6-lutidine, 2,4,6-tri-t-butylpyridine, quinuclidine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,2,2,6,6-pentamethylpiperidine, 1,1,3,3-tetramethyl guanidine (TMG), t-butyl-1,1,3,3-tetramethylguanidine (t-Bu-TMG), 2-tert-Butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine (BEMP), and 1-ethyl-2,2,4,4,4-pentakis(dimethylamino)2,4-catendi(phosphazene).
In a glovebox under nitrogen atmosphere, a solution of palladium acetate (44.9 mg, 0.20 mmol) in 8 mL anhydrous toluene was prepared and was then added to 7e (66.9 mg, 0.20 mmol, 1.0 eq.). The resulting mixture was agitated for about 1.5 hours at about 25° C. A portion of the resulting catalyst mixture (700 μl, about 5 mol % loading Pd) was then added to a solution of 7d (157 mg, 0.35 mmol, 1.0 eq.) in 6.3 mL toluene with agitation at room temperature. Finally, 2-tert-butyl-1,1,3,3-tetramethylguanidine (73 μl, 61 mg, 357 μmol, 1.02 eq.) was added to this mixture with agitation prior to heating to 55° C. The resulting mixture was agitated at about 55° C. for about 24 hours to provide compound 9 in about 94% ee.
In a glovebox under nitrogen atmosphere, a solution of palladium acetate (44.9 mg, 0.20 mmol) in 8 mL anhydrous toluene was prepared and was then added to 7e (66.9 mg, 0.20 mmol, 1.0 eq.). The resulting mixture was agitated for about 1.5 hours at about 25° C. A portion of the resulting catalyst mixture (1.47 mL, about 3.5 mol % loading Pd) was then added to a solution of compound 7d (470 mg, 1.05 mmol, 1.0 eq.) in 3.79 mL toluene with agitation at room temperature. Finally, 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphirine, polymer-bound (580 mg, 2.0-2.5 mmole/g loading, 1.2-1.5 mmol, 1.1-1.4 eq.) was added to this mixture with agitation prior to heating to 55° C. The resulting mixture was agitated at about 55° C. for about 21 hours, cooled to room temperature, the reaction filtered, the filtered solids washed with toluene (16 mL), and the combined filtrates concentrated in vacuo to provide 340 mg of compound 9 in about 94% ee.
In a glove box, a slurry of copper(II) bromide (14.3 mg, 0.064 mmol) and compound 27a (commercially available, 24.8 mg, 0.067 mmol) in toluene (8 mL) was agitated about 19 hours at 50° C. A portion of the resulting catalyst slurry (0.019 mL; about 3.8 mol % catalyst) was then added into a mixture of compound 7d (1.8 mg, 0.004 mmol) in toluene (0.1 mL) with stirring followed by K3PO4 (6.4 mg, 0.03 mmol). The resulting mixture was heated to about 60° C. and held at about 60° C. with stirring for about 19 hours to provide compound 9 in 55% ee.
In a glove box, a slurry of copper(I) iodide (2.285 mg, 0.012 mmol, 6% cat.) and compound 17a (commercially available, 2.361 mg, 0.006 mmol, 3%) in toluene (3 mL) was heated to about 55° C. for about 2 h. The resulting catalyst slurry was then added into a mixture of compound 15g (99 mg, 0.2 mmol) and K3PO4 (170 mg, 0.8 mmol) in toluene (2 mL) with stirring. The resulting mixture was heated to about 55° C. and held at about 55° C. with stirring for about 19 hours to provide compound 9 in 76% ee.
Trifluoromethanesulfonic acid (526 g, 3507 mmol) was added to 2-(5-bromo-2-chlorophenyl)acetic acid (30a, 35 g, 140 mmol) and 3-bromophenol (21.84 g, 126 mmol). The resulting solution was heated to 55° C. and allowed to stir at this temperature overnight. After cooling to room temperature, the mixture was diluted with water (1000 mL) then extracted with ethyl acetate(500 mL×2). The combined organic layers were washed with water (500 mL×2) then brine (200 mL×1), dried with Na2SO4, filtered and concentrated in vacuo to provide compound 30b (42 g, 104 mmol, 74.0% yield) as a solid, which was used without further purification.
A solution of ammonia (400 mL, 7 M in MeOH) was added to compound 30b (42 g, 104 mmol) and the mixture was allowed to stir at room temperature for 20 hours. The resulting slurry was filtered and the collected product cake was washed with MeOH (100 mL×2). After vacuum drying, compound 30c (36 g, 89 mmol, 86% yield) was obtained as a solid.
To a 500 mL flask was charged 4A MS (18 g) and Me-THF (252 ml). The solution was cooled to 20° C. and allowed to stir at this temperature for 2 hours. Compound 30c (36 g, 89 mmol) and N-benzylidene-4-methoxyaniline (1.885 g, 8.92 mmol) and benzaldehyde (10.42 g, 98 mmol) were then added and the reaction was allowed to warm to room temperature. After 10 minutes, trifluoromethanesulfonic acid (2.68 g, 17.84 mmol) was added and the resulting reaction was allowed to stir at room temperature for 15 hours. 5% NaHCO3 (500 mL) was added and the reaction was allowed to stir for an additional 30 minutes. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (200 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified using Flash column chromatography on silica gel (elutent A: WATER(0.05% NH4HCO3), elutent B: ACN, 85%-100%, 15 minutes) to provide compound 30d (29 g, 59.0 mmol, 66.1% yield) as an oil.
To a 1-L round bottomed flask equipped with an overhead stirrer and a nitrogen inlet was charged dimethoxyethane (290 ml), which was degassed with nitrogen. Compound 30d (29 g, 59.0 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (33.0 g, 130 mmol) and potassium acetate (34.7 g, 354 mmol) were charged to the flask as solids, and the flask was further purged with nitrogen.
To a 3-neck 500 mL round bottomed flask equipped with an overhead stirrer and a nitrogen inlet was charged dimethoxyethane (290 ml) which was then degassed with nitrogen. Ad2(n-Bu)Pd HBF4 (1.273 g, 3.54 mmol), t-BuOK (0.397 g, 3.54 mmol) and palladium acetate (0.397 g, 1.770 mmol) were then charged and the mixture was allowed to age under nitrogen for 30 minutes.
The palladium catalyst solution was transferred to the 1 L flask under nitrogen, and the resulting reaction solution was heated to reflux (80-83° C.) and aged at this temperature for 4 hours. The reaction was then cooled to room temperature and filtered. The filtrate was concentrated in vacuo to provide compound 30e as a syrup which was used without further purification.
To a 50 mL round bottomed flask equipped with an overhead stirrer and a nitrogen inlet was charged THF (20 mL), which was degassed with nitrogen. Methyl ((S)-1-((S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate (500 mg, 1.340 mmol), compound 30e (942 mg, 1.608 mmol), K3PO4 (569 mg, 2.68 mmol), water (5 ml) and 1,1′-BIS(di-tert-butylphosphino)ferrocene palladium dichloride (61.1 mg, 0.094 mmol) were charged to the flask, and the flask was further purged with nitrogen. The solution was heated to reflux (77° C.) and allowed to age at this temperature for 5 hours. The reaction was cooled to room temperature and purified using flash column chromatography on silica gel then lyophilized to provide compound 31 (122 mg, 0.133 mmol, 18% yield). LC-MS: (ES, m/z): 918 [M+H]+. 1H-NMR: 1H NMR (400 MHz, Methanol-d4) δ 7.66 (s, 1H), 7.55 (s, 3H), 7.47 (s, 1H), 7.43-7.32 (m, 5H), 7.16 (s, 1H), 6.48 (s, 1H), 5.11 (q, J=7.2, 5.9 Hz, 1H), 4.25-4.14 (m, 2H), 3.96 (s, 2H), 3.83 (s, 2H), 3.63 (d, J=1.8 Hz, 4H), 3.34 (s, 1H), 2.34-2.23 (m, 3H), 2.14 (s, 2H), 2.01 (tt, J=15.9, 8.1 Hz, 4H), 0.99-0.80 (m, 11H).
Compound 31 (161 mg, 0.175 mmol) and 3 mL toluene were charged to a vial. A catalyst solution was prepared in a separate vessel by dissolving 19.6 mg Pd(OAc)2 in 5 mL toluene followed by addition of 24.7 mg of (R,R)-(+)-1,2-bis(t-butylmethylphosphino)benzene. After aging at room temperature for 30 minutes, 0.50 mL of the catalyst solution (0.0088 mmol, 0.050 equiv) was added to the starting material solution in toluene followed by 205 mg of K3PO4 (0.96 mmol, 5.5 equiv). The mixture was heated to 90° C. and allowed to stir at this temperature for 25 hours. The reaction mixture was then cooled to room temperature and directly purified to provide compound 32. The d.e. was determined to be 92%. The Chiral separation method used was as follows: Regiscell 250×4.6 mm, 5 μm, MeOH with 25 mM IBA, 35% modifier/65% CO2, 3.0 mL/min, 200 bar, 35° C., compound 32: 10.0 minutes, undesired diastereomer: 8.2 minutes.
While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, the practice of the invention encompasses all of the usual variations, adaptations and/or modifications that come within the scope of the following claims. All publications, patents and patent applications cited herein are incorporated by reference in their entirety into the disclosure.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/CN2015/083786 | 7/10/2015 | WO | 00 |
| Number | Date | Country | |
|---|---|---|---|
| 62023395 | Jul 2014 | US | |
| 62171012 | Jun 2015 | US |
