Asymmetric synthesis of alpha-branched chiral amines

Abstract

The present invention relates to an improved asymmetric synthesis of alpha-branched amines (hereafter referred to as the compound) and relative chiral amines (1″) or its pharmaceutically acceptable salt and derivatives. The process comprises an unusual substrate specific regioselective ortho lithiation of substituted arene compounds, followed by its highly diastereoselective addition to N-tert-butanesulfinylimines resulting in the selective formation of alpha-branched sulfinyl amine and chiral amine; which on subsequently removing the sulfinyl group provides corresponding alpha-branched amines or relative chiral amines (1″).

Claims

1. A process for the preparation of a branched amine compound (1″) or a salt thereof; of the following formula, ##STR00024## wherein, R.sub.1, R.sub.2 and R.sub.3 are independently selected from H, C.sub.1-C.sub.10 linear or branched or cyclic alkyl, substituted or unsubstituted aryl, ester, ether, hetero aryl, halo, haloalkyl comprising the steps of; (x) reacting substituted arene compound (5) of the following formula, ##STR00025## with N-tert-butanesulfinylimine compound (3) of the following formula, ##STR00026## in the presence of a lithiating agent; (y) removing the sulfinyl group from the compound sulfinyl amine (6) of stage (x) represented by the following formula, ##STR00027##

2. The process according to the claim 1, wherein the step (x) of claim 1 involves formation of cyclic lithiated compound (5-Li) of the following formula, ##STR00028## wherein, R.sub.1 is as defined herein.

3. The process according to the claim 1, wherein the lithiating agent used in step (x) of claim 1 is an organolithium compound selected from n-butyl lithium (n-BuLi), phenyllithium, methyllithium, tert-butyllithium or a mixture thereof.

4. The process according to the claim 1, wherein the step (y) of claim 1 involves the cleaving of the sulfinyl substitution of the amine by treatment of the sulfinyl amine compound (5) with an acid selected from hydrochloric acid, hydrobromic acid, hydrofluoric acid, nitric acid, sulfuric acid, phosphoric acid or a mixture thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) Accordingly, the present invention relates to an improved process for the preparation of alpha-branched amine (1) or its salts, represented by the following formula,

(2) ##STR00006##
wherein, R.sub.1, R.sub.2 and R.sub.3 is independently selected from H, C.sub.1-C.sub.10 linear or branched or cyclic alkyl, substituted or unsubstituted aryl, ester, ether hetero aryl, halo, haloalkyl comprising the steps of;

(3) (a) reacting substituted arene compound (2) represented by the following formula,

(4) ##STR00007##
with N-tert-butanesulfinylimine compound (3) represented by the following formula,

(5) ##STR00008##
in the presence of a lithiating agent;

(6) (b) removing the sulfinyl group from the compound alpha-branched sulfinyl amine compound (4) of stage (a) represented by the following formula,

(7) ##STR00009##
The compound (1) obtained by the afore described process is optionally converted into various therapeutically active drugs or advanced drug intermediates.

(8) In an embodiment, the lithiating agent used at step (a) is an organolithium compound selected from n-butyl lithium (n-BuLi), phenyllithium, methyllithium, tert-butyllithium or mixture thereof.

(9) In an embodiment, the lithiating agent used is n-Butyl Lithium (n-BuLi). Accordingly, the present invention relates to an improved process for the preparation of alpha-branched sulfinyl amine compound (4) represented by the following formula,

(10) ##STR00010##
wherein, R.sub.1, R.sub.2 and R.sub.3 is independently selected from H, C.sub.1-C.sub.10 linear or branched or cyclic alkyl, substituted or unsubstituted aryl, ester, ether, hetero aryl, halo, haloalkyl comprising, reacting cyclic lithiated compound (2-Li) represented by the following formula,

(11) ##STR00011##
with N-tert-butanesulfinylimine compound (3) represented by the following formula,

(12) ##STR00012##
The compound (4) obtained by the afore described process is optionally converted into alpha-branched amine (1) by removing the sulfinyl group from the compound alpha-branched sulfinyl amine (4).

(13) In the context of the present invention, the term “optionally” when used in reference to any element; including a process step e.g. optionally converted; it is intended to mean that the subject compound is subsequently converted, or alternatively, is not converted into the compound (1). Both alternatives are intended to be within the scope of the present invention.

(14) In a specific embodiment, the process for the preparation of alpha-branched amine (1) comprises the steps of; (i) dissolving substituted arene compound (2) in a solvent; (ii) cooling the reaction mixture of stage (i) to a temperature of about 0° C.; (iii) adding n-Butyl Lithium (n-BuLi) to the stirring solution of stage (ii); (iv) cooling the reaction mixture of stage (iii) to a temperature of about −78° C.; (v) adding N-tert-butanesulfinylimine (3) to the stirring solution of stage (iv); (vi) stirring the reaction mixture of stage (v) at a temperature of about −78° C.; (vii) isolating the alpha-branched sulfinyl amine compound (4); (viii) removing the sulfinyl group.

(15) The process of the present invention as per the specific embodiment described above is illustrated in the following Scheme (A);

(16) ##STR00013##
wherein, R.sub.1, R.sub.2 and R.sub.3 is independently selected from H, C.sub.1-C.sub.10 linear or branched or cyclic alkyl, substituted or unsubstituted aryl, ester, ether, hetero aryl, halo, haloalkyl.

(17) The solvent used in any of the process steps from the step (i) to step (viii) of the above process (as depicted in the Scheme (A)) is selected from an ether solvent such as tetrahydrofuran, cyclopentyl methyl ether, 2-methyltetrahydrofuran, diethyl ether, dioxane, 1,4-dioxane, 1,2-dioxane and 1,3-dioxane; an alcoholic solvent such as methanol, ethanol, isopropanol, t-amyl alcohol, t-butyl alcohol and hexanol; halogenated solvent such as dichloromethane, 4-bromotoluene, diiodomethane, carbon tetrachloride, chlorobenzene and chloroform; ketone such as acetone; an aprotic solvent such as acetonitrile, N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide, dimethyl sulfoxide (DMSO) and N-methylpyrrolidone (NMP); an aromatic solvent such as toluene, xylene and benzene; water or a mixture thereof.

(18) The term ‘temperature of about 0° C.’ referred to in the step (ii) of the above process (as depicted in the Scheme (A)) can range from −5° C. to +5° C.

(19) The term ‘temperature of about −78° C.’ referred to in the step (iv) or (vi) of the above process (as depicted in the Scheme (A)) can range from −70° C. to −90° C.

(20) The term ‘isolating’ the compound referred to in any process step from step (i) to step (viii) corresponds to the isolating or separating the obtained product using methods that corresponds to the steps involving addition of water, biphasic solvent workup, separation of solvent layers or precipitation, evaporation of solvent, filtration, washing and drying.

(21) The term ‘removing the sulfinyl group’ the compound referred to in any process step (viii) corresponds to the cleaving of the sulfinyl substitution of the amine and producing the free amine compound. The removal of the sulfinyl group is achieved by treatment of the compound (4) with an acid, for example hydrochloric acid, hydrobromic acid, hydrofluoric acid, nitric acid, sulfuric acid, phosphoric acid or mixture thereof.

(22) The inventors of the instant invention reasoned that a direct method to access alpha-branched amine would be an asymmetric synthesis comprising direct ortho lithiation of anisoles and similar relative substituted arene compounds followed by addition to the Ellman's Imines, which has not been explicitly reported in the art on the currently considered chemical moieties. These reaction conditions, however, surprisingly led to an unusual substrate specific regioselective lithiation of substituted arene compounds such as anisole, involves formation of compounds with Lithiumcycles. The inventors envisages that these synthetic effort could be of value in a variety of research applications, including the discovery of the known as well as new bioactive substances; many drugs, investigational drug candidates, and natural products and so on.

(23) The process of the present invention as per the specific embodiment described above is illustrated in the following Scheme (B);

(24) ##STR00014##
wherein R.sub.2 represents variable as listed in below Table-1.

(25) In the representative case illustrated below wherein the addition of anisole (2a-Li) lithiumcycle to various N-tert-Butanesulfinyl aldimines (3a-k) was studied. For instance, the reaction of 3a-k with lithiumcycle (2a-Li) in THF at −78° C. for 2 h afforded alpha-branched sulfinyl amine (4a-k) in about 92% yield and with a high diasteromeric ratio (dr 98:2). The diastereoselectivity of the reaction was determined to be 98:2 by .sup.1H NMR analysis. The obtained compound (4a-k) was further treated with hydrochloric acid to remove the sulfinyl group.

(26) TABLE-US-00001 TABLE 1 Diastereoselective addition of ortho-lithiated anisole (lithiumcycle) (2a-Li) to various N-tert-Butanesulfinyl Aldimines.sup.a yield Substrate (R.sub.2) product (%).sup.b dr.sup.c 3a: R.sub.2 = Ph 4a 90 >95:5 3b: R.sub.2 = o-ClC.sub.6H.sub.5 4b 91 >95:5 3c: R.sub.2 = p-MeC.sub.6H.sub.5 4c 90 >95:5 3d: R.sub.2 = p-MeoC.sub.6H.sub.5 4d 89 >95:5 3e: R.sub.2 = 2-Furyl 4e 90 >95:5 3f: R.sub.2 = 2-Thiophenyl 4f 92 >95:5 3g: R.sub.2 = Cinnamyl 4g 82  90:10 3h: R.sub.2 = 3-ph-propionyl 4h 85  90:10 3i: R.sub.2 = Isopropyl 4i 88 >98:2 3j: R.sub.2 = Isovaleryl 4j 84  92:8 3k: R.sub.2 = n-Butyl 4k 80  91:9 .sup.aAll the reactions performed with 1.0 equiv of 3 and 5.0 equiv of 2a and n-BuLi (3.0 equiv)at 0 to −78° C. for 2 h, unless stated otherwise indicate; .sup.bIsolated yield; .sup.cThe diastereoselectivity was determined by .sup.1H NMR analysis. The “>95:5” dr denotes that signal for only one diastereomer were observed

(27) In another embodiment, there is provided an improved process for the preparation of branched amine (1″) comprising, reacting cyclic lithiated compound (5-Li) with N-tert-butanesulfinylimine (3) to produce branched sulfinyl amine (6); and subsequently removing the sulfinyl group.

(28) In a further embodiment, there is provided an improved process for the preparation of branched sulfinyl amine (6) comprising, reacting cyclic lithiated compound (5-Li) with N-tert-butanesulfinylimine (3).

(29) Accordingly, the present invention relates to an improved process for the preparation of a branched amine compound (1″) or its salts, represented by the following formula,

(30) ##STR00015##
wherein, R.sub.1, R.sub.2 and R.sub.3 is independently selected from H, C.sub.1-C.sub.10 linear or branched or cyclic alkyl, substituted or unsubstituted aryl, ester, ether, hetero aryl, halo, haloalkyl comprising the steps of;

(31) (x) reacting substituted arene compound (5) represented by the following formula,

(32) ##STR00016##
with N-tert-butanesulfinylimine compound (3) represented by the following formula,

(33) ##STR00017##
in the presence of a lithiating agent;

(34) (y) removing the sulfinyl group from the compound sulfinyl amine (6) of stage (x) represented by the following formula,

(35) ##STR00018##
The compound (1″) obtained by the afore described process is optionally converted into various therapeutically active drugs or advanced drug intermediates.

(36) In an embodiment, the lithiating agent used is n-Butyl Lithium (n-BuLi). Accordingly, the present invention relates to an improved process for the preparation of branched sulfinyl amine compound (6) represented by the following formula,

(37) ##STR00019##
wherein, R.sub.1, R.sub.2 and R.sub.3 is independently selected from H, C.sub.1-C.sub.10 linear or branched or cyclic alkyl, substituted or unsubstituted Aryl, ester, ether, hetero aryl, halo, haloalkyl comprising, reacting cyclic lithiated compound (5-Li) represented by the following formula,

(38) ##STR00020##
with N-tert-butanesulfinylimine compound (3) represented by the following formula,

(39) ##STR00021##

(40) The compound (6) obtained by the afore described process is optionally converted into branched amine (1″) by removing the sulfinyl group from the compound branched sulfinyl amine (6).

(41) In the context of the present invention, the term “optionally” when used in reference to any element; including a process step e.g. optionally converted; it is intended to mean that the subject compound is subsequently converted, or alternatively, is not converted into the compound (1″). Both alternatives are intended to be within the scope of the present invention.

(42) In a specific embodiment, the process for the preparation of a chiral amine compound (1″) comprises the steps of;

(43) (xi) dissolving substituted arene compound (5) in a solvent;

(44) (xii) cooling the reaction mixture of stage (xi) to a temperature of about 0° C.;

(45) (xiii) adding n-Butyl Lithium (n-BuLi) to the stirring solution of stage (xii);

(46) (xiv) cooling the reaction mixture of stage (xiii) to a temperature of about −78° C.;

(47) (xv) adding N-tert-butanesulfinylimine (3) to the stirring solution of stage (xiv);

(48) (xvi) stirring the reaction mixture of stage (xv) at a temperature of about −78° C.;

(49) (xvii) isolating the sulfinyl amine compound (6);

(50) (xviii) removing the sulfinyl group.

(51) The process of the present invention as per the specific embodiment described above is illustrated in the following Scheme (C);

(52) ##STR00022##
wherein, R.sub.1, R.sub.2 and R.sub.3 is independently selected from H, C.sub.1-C.sub.10 linear or branched or cyclic alkyl, substituted or unsubstituted aryl, ester, ether, hetero aryl, halo, haloalkyl.

(53) The solvent used in any of the process steps from the step (xi) to step (xviii) of the above process (as depicted in the Scheme (C)) is selected from an ether solvent such as tetrahydrofuran, cyclopentyl methyl ether, 2-methyltetrahydrofuran, diethyl ether, dioxane, 1,4-dioxane, 1,2-dioxane and 1,3-dioxane; an alcoholic solvent such as methanol, ethanol, isopropanol, t-amyl alcohol, t-butyl alcohol and hexanol; halogenated solvent such as dichloromethane, 4-bromotoluene, diiodomethane, carbon tetrachloride, chlorobenzene and chloroform; ketone such as acetone; an aprotic solvent such as acetonitrile, N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide, dimethyl sulfoxide (DMSO) and N-methylpyrrolidone (NMP); an aromatic solvent such as toluene, xylene and benzene; water or a mixture thereof.

(54) The term ‘temperature of about 0° C.’ referred to in the step (xii) of the above process (as depicted in the Scheme (C)) can range from −5° C. to +5° C.

(55) The term ‘temperature of about −78° C.’ referred to in the step (xiv) or (xvi) of the above process (as depicted in the Scheme (C)) can range from −70° C. to −90° C.

(56) The term ‘isolating’ the compound referred to in any process step from step (xi) to step (xviii) corresponds to the isolating or separating the obtained product using methods that corresponds to the steps involving addition of water, biphasic solvent workup, separation of solvent layers or precipitation, evaporation of solvent, filtration, washing and drying.

(57) The term ‘removing the sulfinyl group’ the compound referred to in any process step (xviii) corresponds to the cleaving of the sulfinyl substitution of the amine and producing the free amine compound. The removal of the sulfinyl group is achieved by treatment of the compound (5) with an acid, for example hydrochloric acid, hydrobromic acid, hydrofluoric acid, nitric acid, sulfuric acid, phosphoric acid or a mixture thereof.

(58) The process of the present invention as per the specific embodiment described above is illustrated in the following Scheme (D);

(59) ##STR00023##
wherein R.sub.2 represents variable as listed in below Table-2.

(60) In the representative case illustrated below wherein the addition of anisole (5a-Li) lithiumcycle to various N-tert-Butanesulfinyl aldimines (3a,d,e,f,I,k) was studied. For instance, the reaction of 3a,d,e,f,I,k with lithiumcycle (5a-Li) in THF at −78° C. for 2 h afforded branched sulfinyl amine (6a,d,e,f,I,k) in about 90% yield and with a high diastereomeric ratio (dr 98:2). The diastereoselectivity of the reaction was determined to be 95:5 by .sup.1H NMR analysis. The obtained compound (6a,d,e,f,I,k) was further treated with hydrochloric acid to remove the sulfinyl group.

(61) TABLE-US-00002 TABLE 2 Diastereoselective addition of lithiated ortho-methylanisole (lithiumcycle) (5a-Li) to various N-tert-Butanesulfinyl Aldimines.sup.a yield Substrate (R.sub.2) product (%).sup.b dr.sup.c 3a: R.sub.2 = Ph 6a 86 >95:5 3d: R.sub.2 = p-MeoC.sub.6H.sub.5 6d 90 >94:6 3e: R.sub.2 = 2-Furyl 6e 85 >93:7 3f: R.sub.2 = 2-Thiophenyl 6f 88 >93:7 3i: R.sub.2 = Isopropyl 6i 90 >95:5 3k: R.sub.2 = n-Butyl 6k 80  90:10 .sup.aAll the reactions performed with 1.0 equiv of 3 and 5.0 equiv of 2a and n-BuLi (3.0 equiv)at 0 to −78° C. for 2 h, unless stated otherwise indicate; .sup.bIsolated yield; .sup.cThe diastereoselectivity was determined by .sup.1H NMR analysis. The “>95:5” dr denotes that signal for only one diastereomer were observed

(62) It is evident that, the instantly presented invention is an unusual substrate specific regioselective lithiation of arene compounds with the formation of Lithiumcycles, and followed by highly diastereoselective addition to N-tert-butanesulfinylimines resulting in the selective formation of chiral amines (4) and (6) and further converted to corresponding amine (1) and (1″) respectively.

(63) Advantageously, the above identified elements of the process of the instant invention effectively contribute to the reduction of overall cost of the process.

(64) The invention is further illustrated by the following examples which are provided to be exemplary of the invention, and do not limit the scope of the invention. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

EXAMPLES

Example-1: (R)—N—((S)-(2-methoxyphenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide (4a)

(65) Charged 2.5 mL of tetrahydrofuran (THF) in a flask followed by the addition of anisole (2a) (5.0 mmol) and n-butyl lithium (1.6 M in cyclohexane, 3 mmol) at a temperature of about 0° C. The reaction mixture was further cooled down to a temperature of about −78° C. and to the stirring solution was added N-tert-butanesulfinyl aldimine (3a) (200 mg, 0.96 mmol). The reaction mixture was continued for stirring for about 2 h at −78° C. temperature; followed by the dropwise addition of water (5 mL) at same temperature. The reaction mixture was extracted with ethyl acetate (5 mL×3) and the separated organic layer was evaporated to provide compound (4a) with yield (273 mg, 90%).

Example-2: (R)—N—((R)-(2-chlorophenyl)(2-methoxyphenyl)methyl)-2-methylpropane-2-sulfinamide (4b)

(66) Charged 2.5 mL of tetrahydrofuran (THF) in a flask followed by the addition of anisole (2a) (5.0 mmol) and n-butyl lithium (1.6 M in cyclohexane, 3 mmol) at a temperature of about 0° C. The reaction mixture was further cooled down to a temperature of about −78° C. and to the stirring solution was added N-tert-butanesulfinyl aldimine (3b) (200 mg, 0.82 mmol). The reaction mixture was continued for stirring for about 2 h at −78° C. temperature; followed by the dropwise addition of water (5 mL) at same temperature. The reaction mixture was extracted with ethyl acetate (5 mL×3) and the separated organic layer was evaporated to provide compound (4b) with yield (262 mg, 91%).

Example-3: (S)-(2-Methoxyphenyl)(Phenyl)Methanamine (1a)

(67) Charged 0.7 mL of Dioxane in a flask followed by the addition of (R)—N—((S)-(2-methoxyphenyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide (4a) (100 mg, 0.28 mmol) and hydrochloric acid solution (4.0 M in dioxane, 2.8 mmol, 0.7 mL). The reaction mixture was stirred for 2 h at room temperature and the reaction mixture was concentrated under vacuum. To the crude residue was added water (2 mL), followed by the addition of 6 M NaOH aqueous solution to adjust the pH 12-13. The reaction mixture was extracted with ethyl acetate (5 mL×3) and the separated organic layer was evaporated to provide free amine compound (1a) with yield (68 mg, 98%).

Example-4: (R)—N—((R)-2-(2-Methoxyphenyl)-1-(4-Methoxyphenyl)Ethyl)-2-Methylpropane-2-Sulfinamide (6d)

(68) Charged 2.5 mL of tetrahydrofuran (THF) in a flask followed by the addition of ortho-methyl anisole (5a) (5.59 mmol) and n-butyl lithium (1.6 M in cyclohexane, 3.35 mmol) at a temperature of about 0° C. The reaction mixture was further cooled down to a temperature of about −78° C. and to the stirring solution was added N-tert-butanesulfinyl aldimine (3d) (200 mg, 1.11 mmol). The reaction mixture was continued for stirring for about 1 h at −78° C. temperature; followed by the dropwise addition of water (5 mL) at same temperature. The reaction mixture was extracted with ethyl acetate (5 mL×3) and the separated organic layer was evaporated to provide compound (6d) with yield (272 mg, 90%).

Example-5: (R)—N—((R)-2-(2-Methoxyphenyl)-1-(Thiophen-2-Yl)Ethyl)-2-Methylpropane-2-Sulfinamide (6f)

(69) Charged 2.5 mL of tetrahydrofuran (THF) in a flask followed by the addition of ortho-methyl anisole (5a) (6.27 mmol) and n-butyl lithium (1.6 M in cyclohexane, 3.76 mmol) at a temperature of about 0° C. The reaction mixture was further cooled down to a temperature of about −78° C. and to the stirring solution was added N-tert-butanesulfinyl aldimine (3f) (200 mg, 1.25 mmol). The reaction mixture was continued for stirring for about 1 h at −78° C. temperature; followed by the dropwise addition of water (5 mL) at same temperature. The reaction mixture was extracted with ethyl acetate (5 mL×3) and the separated organic layer was evaporated to provide compound (6f) with yield (276 mg, 88%).

Example-6: (R)-2-(2-Methoxyphenyl)-1-Phenylethan-1-Amine (1″a)

(70) Charged 0.7 mL of Dioxane in a flask followed by the addition of sulfinyl amine compound (6a) (100 mg, 0.28 mmol) and hydrochloric acid solution (4.0 M in dioxane, 2.8 mmol, 0.7 mL). The reaction mixture was stirred for 2 h at room temperature and the reaction mixture was concentrated under vacuum. To the crude residue was added water (2 mL), followed by the addition of 6 M NaOH aqueous solution to adjust the pH 12-13. The reaction mixture was extracted with ethyl acetate (5 mL×3) and the separated organic layer was evaporated to provide free amine compound (1″a) with yield (70 mg, 99%).