METHOD FOR RACEMIC PREPARATION OF CHIRAL B-AMINO ACIDS AND DERIVATIVES THEREOF

Abstract

The present disclosure relates to the field of medicine synthesis, and relates to a method for a racemic preparation of chiral h β-amino acids and derivatives thereof, and in particular to a method for racemizing sitagliptin intermediates.

##STR00001##

where R.sub.1 is hydrogen, alkyl or aryl; R.sub.2 is hydrogen, alkyl or aryl; R.sub.3 is hydrogen, alkyl, aryl or acyl; R.sub.4 is alkyl, aryl, OR′, SR′, NHR′ or NR′R″, wherein R′, R″ are hydrogen, alkyl or aryl.

Claims

1. A method for a racemic preparation of chiral β-amino acids and derivatives thereof, comprising the steps of: racemizing a compound of formula I under conditions of initiator, sulfide and solvent to obtain a compound of formula II, wherein a reaction equation is: ##STR00033## where R.sub.1 or R.sub.2 is hydrogen, alkyl or aryl; is hydrogen, alkyl, aryl or acyl; R.sub.4 is alkyl, aryl, OR, SR, NHR′ or NR′R″, where R′ or R″ is hydrogen, alkyl or aryl.

2. A method for a racemic preparation of chiral β-amino acids and derivatives thereof, comprising the steps of: racemizing a compound of formula I′ under conditions of initiator, sulfide and solvent to obtain a compound of formula II, wherein a reaction equation is: ##STR00034## where definitions of R.sub.1, R.sub.2, R.sub.3, R.sub.4 are the same as that according to claim 1.

3. A method for a racemic preparation of chiral β-amino acids and derivatives thereof, comprising the steps of: racemizing a compound of formula I″ under conditions of initiator, sulfide and solvent to obtain a compound of formula II, wherein a reaction equation is: ##STR00035## where definitions of R.sub.1, R.sub.2, R.sub.3, R.sub.4 are the same as that according to claim 1.

4. A method for racemizing ethyl 3β-amino-4-(2,4,5-trifluorophenyl) butyrate, obtained by racemizing (S)-3β-amino-′4-(2,4,5-ethyl trifluorophenyl) butyrate under conditions of pentaerythritol tetra-3-mercaptopropionate (PETMP), azobisisobutyronitrile (AIBN) and toluene; wherein a reaction equation is: ##STR00036##

5. The method according to claim 1 or 2 or 3, wherein the sulfide is selected from a group consisting of methyl mercaptoacetate, methyl mercaptopropionate, methyl mercaptobutyrate, ethyl mercaptoacetate, 1-hexyl mercaptan, 1-heptane mercaptan, 1-octyl mercaptan, 1-nonane mercaptan, 1-decane mercaptan, benzyl mercaptan, phenyl ethyl mercaptan, furfuryl mercaptan, dodecane mercaptan and other alkyl mercaptans; 1,6-hexanedithiol, 3-propanedithiol, dimercaptoethyl sulfide, pentaerythritol tetra-3-mercaptopropionate (PETMP), trimethylolpropane tris(3-mercaptopropionate) (TMMP) and other polythiols; mercaptopropyltrimethoxysilane, 3-mercaptopropyltriethoxysilane and other mercapto-containing compounds; dialkyl disulfide, thiophenol, substituted thiophenol and various aromatic thiophenol, diphenyl disulfide and diary′ disulfide.

6. The method according to claim 1 or 2 or 3, wherein the solvent is selected one or more from a group consisting of benzene, toluene, o-xylene, m-xylene, p-xylene, nitrobenzene, chlorobenzene, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, anisole, acetonitrile, chloroform, carbon tetrachloride; n-heptane, and n-octane.

7. The method according to claim 1 or 2 or 3, wherein the initiator is selected from a group consisting of azobisisobutyronitrile (AIBN), azobisisovaleronitrile (AMBN), azobisisoheptonitrile (ABVN), azobisisobutamidine hydrochloride (MBA), dimethyl azobisisobutyrate (V601, AIBME), azobisisobuimidazoline hydrochloride (AIBI), azo isobutylcyanide formamide and other azo initiator (V30); dibenzoyl peroxide (BM), lauryl peroxide (LPO), Diisopropyl peroxydicarbonate (IPP), dicyclohexyl peroxydicarbonate (DCPD), di-tert-butyl peroxide (DTB), m-chloroperoxybenzoic acid (m-CPBA), potassium persulfate (K.sub.2S.sub.2O.sub.8) and other peroxide initiators.

8. The method according to claim 1 or 2 or 3 or 4, wherein a reaction temperature is 30° C. to 120° C. 9, The method according to claim 1 or 2 or 3 or 4, wherein a reaction time is 4 to 36 hours.

10. The method according to claim 1 or 2 or 3 or 4, wherein a molar ratio of the initiator, the sulfide and a chiral β-amino substrate required for the reaction is that: initiator: sulfide: substrate is (0.01˜0.20): (0.01˜0.20):1.

Description

DETAILED DESCRIPTION

[0050] In order to better understand the content of the present disclosure, further description will be given below in conjunction with specific embodiments, but the specific implementation is not a limitation on the content of the present disclosure.

EXAMPLE 1

[0051] ##STR00012##

[0052] (S)-3β-amino-4-(2,4,5-trifluorophenyl) methyl butyrate (4.94 g, 0.020 mol, ee>99%), toluene (20 ml), trimethylolpropane tris(3-mercaptopropionate) (TMMP, 160 mg, 0.40 mmol) and azobisisobutyronitrile (AIBN, 33 mg, 0.20 mmol) are put into a 100 ml of three-necked flask, magnetic stirring is turned on. Under nitrogen protection, the temperature rises slowly to 80° C., the progress of the reaction is tracked by HPLC, and the reaction is complete after 20 h. 20 mL of water is added to the reaction solution, the pH value is adjusted to 4˜5 with 2N dilute hydrochloric acid, the liquids are separated, the organic phase is discarded. The pH value of the water phase is adjusted to 9˜10 with 2N sodium hydroxide solution, and extracting is performed twice with isopropyl acetate (2×20 ml). The organic phases is combined, washed once with saturated brine (20 ml), dried with anhydrous sodium sulfate (10 g), filtered, and the filtrate is concentrated to dryness under reduced pressure at 35˜40° C. to obtain a colorless oil (4.81 g, 0.0195 mol), which is the target product compound 1, with a yield of 97.4%; ee=0.78%. MS(ESI): m/z 248.0817[M+H].sup.+.

EXAMPLE 2

[0053] ##STR00013##

[0054] (S)-3β-amino-4-(2,4,5-trifluorophenyl) ethyl butyrate (5.22 g, 0.020 mol, ee>99%), toluene (20 ml), pentaerythritol tetra-3-mercaptopropionate (PETMP, 98 mg, 0.20 mmol) and azobisisobutyronitrile (AIBN, 33 mg, 0.20 mmol) are put into a 100 ml of three-necked flask, magnetic stirring is turned on. Under nitrogen protection, the temperature rises slowly to 80° C., the progress of the reaction is tracked by HPLC, and the reaction is complete after 20 h. 20 mL of water is added to the reaction solution, the pH value is adjusted to 4˜5 with 2N dilute hydrochloric acid, the liquids are separated, the organic phase is discarded. The pH value of the water phase is adjusted to 9˜10 with 2N sodium hydroxide solution, and extracting is performed twice with isopropyl acetate (2×20 ml). The organic phases is combined, washed once with saturated brine (20 ml), dried with anhydrous sodium sulfate (10 g), filtered, and the filtrate is concentrated to dryness under reduced pressure at 35˜40° C. to obtain a colorless oil (4.88 g, 0.0187 mol), which is the target product compound 2, with a yield of 93.5%; ee=0.65%. MS(ESI): m/z 262.0972[M+H].sup.+.

EXAMPLE 3

[0055] ##STR00014##

[0056] (S)-3β-amino-4-(2,4,5-trifluorophenyl) isopropyl butyrate (5.51 g, 0.020 mol, ee>99%), toluene (20 ml), pentaerythritol tetra-3-mercaptopropionate (PETMP, 98 mg, 0.20 mmol) and azobisisobutyronitrile (AIBN, 33 mg, 0.20 mmol) are put into a 100 ml of three-necked flask, magnetic stirring is turned on. Under nitrogen protection, the temperature rises slowly to 80° C., the progress of the reaction is tracked by HPLC, and the reaction is complete after 20 h. 20 mL of water is added to the reaction solution, the pH value is adjusted to 4˜5 with 2N dilute hydrochloric acid, the liquids are separated, the organic phase is discarded. The pH value of the water phase is adjusted to 9˜10 with 2N sodium hydroxide solution, and extracting is performed twice with isopropyl acetate (2×20 ml). The organic phases is combined, washed once with saturated brine (20 ml), dried with anhydrous sodium sulfate (10 g), filtered, and the filtrate is concentrated to dryness under reduced pressure at 35˜40° C. to obtain a colorless oil (5.07 g, 0.0184 mol), which is the target product compound 3, with a yield of 92%; ee=1.2%. MS(ESI): m/z 276.1128[M+H].sup.+.

EXAMPLE 4

[0057] ##STR00015##

[0058] (S)-3β-amino-4-(2,4,5-trifluorophenyl) tert-butyl butyrate (5.79 g, 0.020 mol, ee>99%), toluene (30 ml), pentaerythritol tetra-3-mercaptopropionate (PETMP, 98 mg, 0.20 mmol) and azobisisobutyronitrile 33 mg, 0.20 mmol) are put into a 100 ml of three-necked flask, magnetic stirring is turned on. Under nitrogen protection, the temperature rises slowly to 80° C., the progress of the reaction is tracked by HPLC, and the reaction is complete after 20 h. 20 mL of water is added to the reaction solution, the pH value is adjusted to 5˜6 with 2N dilute hydrochloric acid, the liquids are separated, the organic phase is discarded. The pH value of the water phase is adjusted to 9˜10 with 2N sodium hydroxide solution, and extracting is performed twice with isopropyl acetate (2×20 ml). The organic phases is combined, washed once with saturated brine (20 ml), dried with anhydrous sodium sulfate (10 g), filtered, and the filtrate is concentrated to dryness under reduced pressure at 35˜40° C. to obtain a colorless oil (5.18 g, 0.0179 mol), which is the target product compound 4, with a yield of 89.5%; ee=1.9%. MS(ESI): m/z 290.1293[M+H].sup.+.

EXAMPLE 5

[0059] ##STR00016##

[0060] (S)-3β-amino-1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolone[4,3-a]pyrazine-7(8H)-4-(2,4,5-trifluorophenyl)butanone ((S)-sitagliptin, 8.15 g, 0.020 mol, ee>99%), toluene (30 ml), pentaerythritol tetra-3-mercaptopropionate (PETMP, 98 mg, 0.20 mmol) and azobisisobutyronitrile (AIBN, 33 mg, 0.20 mmol) are put into a 100 ml of three-necked flask, magnetic stirring is turned on. Under nitrogen protection, the temperature rises slowly to 80° C., the progress of the reaction is tracked by HPLC, and the reaction is complete after 22 h. 20 mL of water is added to the reaction solution, the pH value is adjusted to 4˜5 with 2N dilute hydrochloric acid, the liquids are separated, the organic phase is discarded. The pH value of the water phase is adjusted to 9˜10 with 2N sodium hydroxide solution, and extracting is performed twice with isopropyl acetate (2×20 ml). The organic phases is combined, washed once with saturated brine (20 ml), dried with anhydrous sodium sulfate (10 g), filtered, and the filtrate is concentrated to dryness under reduced pressure at 35˜40° C. to obtain a white solid (7.13 g, 0.0175 mol), which is the target product compound 5, with a yield of 87.5%; ee=4%. MS(ESI): m/z 408.1179[M+H].sup.+.

EXAMPLE 6

[0061] ##STR00017##

[0062] (R)-1-(2β-amino-4-(2,4-bis(trifluoromethyl)-5,8-dihydropyrido[3,4-D]pyrimidin-7(6H)-yl)-4-oxobutyl)-5,5-difluoropiperidin-2-one ((R)-gigliptin, 9.79 g, 0.020 mol, ee>99%), p-xylene (30 ml), trimethylolpropane tris(3-mercaptopropionate) (TMMP, 160 mg, 0.40 mmol) and azobisisoheptonitrile (ABVN, 50 mg, 0.20 mmol) are put into a 100 ml of three-necked flask, magnetic stirring is turned on. Under nitrogen protection, the temperature rises slowly to 70° C., the progress of the reaction is tracked by HPLC, and the reaction is complete after 22 h. 20 mL of water is added to the reaction solution, the pH value is adjusted to 4˜5 with 2N dilute hydrochloric acid, the liquids are separated, the organic phase is discarded. The pH value of the water phase is adjusted to 9˜10 with 2N sodium hydroxide solution, and extracting is performed twice with ethyl acetate (2×20 ml). The organic phases is combined, washed once with saturated brine (20 ml), dried with anhydrous sodium sulfate (10 g), filtered, and the filtrate is concentrated to dryness under reduced pressure at 35˜40° C. to obtain a colorless oil (8.27 g, 0.0169 mol), which is the target product compound 6, with a yield of 84.5%; ee=1.6%. MS(ESI): m/z 490.1408[M+H].sup.+.

EXAMPLE 7

[0063] ##STR00018##

[0064] (S)-4((S)-3β-amino-4-(2,4,5-trifluorophenyl)butyryl)-3-(tert-butyl methyl ether methyl) piperazin-2-one ((S)-itagliptin, 7.99 g, 0.020 mol, ee>99%), m-xylene (30 ml), pentaerythritol tetra-3-mercaptopropionate (PETMP, 98 mg, 0.20 mmol) and azobisisoheptonitrile (ABVN, 50 mg, 0.20 mmol) are put into a 100 ml of three-necked flask, magnetic stirring is turned on. Under nitrogen protection, the temperature rises slowly to 70° C., the progress of the reaction is tracked by HPLC, and the reaction is complete after 24 h. 20 mL of water is added to the reaction solution, the pH value is adjusted to 4˜5 with 2N dilute hydrochloric acid, the liquids are separated, the organic phase is discarded. The pH value of the water phase is adjusted to 9˜10 with 2N sodium hydroxide solution, and extracting is performed twice with ethyl acetate (2×20 ml). The organic phases is combined, washed once with saturated brine (20 ml), dried with anhydrous sodium sulfate (10 g), filtered, and the filtrate is concentrated to dryness under reduced pressure at 35˜40° C. to obtain a colorless oil (6.78 g, 0.0170 mol), which is the target product compound 7, with a yield of 85%; ee=2.2%. MS(ESI): m/z 400.2137[M+H].sup.+.

EXAMPLE 8

[0065] ##STR00019##

[0066] (S)-3β-amino-N-methyl-4-butanamide (2.32 g, 0.020 mol, ee>99%), dry benzene (20 ml), n-octyl mercaptan (0.29 g, 0.002 mol), azobisisobutyronitrile (AIBN, 66 mg, 0.40 mmol) are put into a 100 ml of three-necked flask, magnetic stirring is turned on. Under nitrogen protection, the temperature rises slowly to 60° C., the progress of the reaction is tracked by HPLC, and the reaction is complete after 20 h. 20 mL of water is added to the reaction solution, the pH value is adjusted to 4˜5 with 2N dilute hydrochloric acid, the liquids are separated, the organic phase is discarded. The pH value of the water phase is adjusted to 9˜10 with 2N sodium hydroxide solution, and extracting is performed twice with ethyl acetate (2×20 ml). The organic phases is combined, washed once with saturated brine (20 ml), dried with anhydrous sodium sulfate (10 g), filtered, and the filtrate is concentrated to dryness under reduced pressure at 35˜40° C. to obtain a colorless oil (2.21 g, 0.0191 mol), which is the target product compound 8, with a yield of 95.3%; ee=2.4%. MS(ESI): m/z 117.0944[M+H].sup.+.

EXAMPLE 9

[0067] ##STR00020##

[0068] (S)-3β-amino-N,N-dimethyl-4-butanamide (2.60 g, 0.020 mol, ee>99%), dimethyltetrahydrofuran (20 ml), dodecanethiol (0.41 g, 0.002 mol), azobisisobutyronitrile (AIBN, 66 mg, 0.40 mmol) are put into a 100 ml of three-necked flask, magnetic stirring is turned on. Under nitrogen protection, the temperature rises slowly to 60° C., the progress of the reaction is tracked by HPLC, and the reaction is complete after 20 h. 20 mL of water is added to the reaction solution, the pH value is adjusted to 4˜5 with 2N dilute hydrochloric acid, the liquids are separated, the organic phase is discarded. The pH value of the water phase is adjusted to 9˜10 with 2N sodium hydroxide solution, and extracting is performed twice with ethyl acetate (2×20 ml).

[0069] The organic phases is combined, washed once with saturated brine (20 ml), dried with anhydrous sodium sulfate (10 g), filtered, and the filtrate is concentrated to dryness under reduced pressure at 35˜40° C. to obtain a colorless oil (2.43 g, 0.0187 mol), which is the target product compound 9, with a yield of 95.3%; ee=2.7%. MS(ESI): m/z 131.1102[M+H].sup.+.

EXAMPLE 10

[0070] ##STR00021##

[0071] (R)-3β-amino-3-phenyl-N-methyl-butyramide (3.56 g, 0.020 mol, ee>99%), toluene (20 ml), methyl thioglycolate (0.42 g, 0.004 mol), azobisisobutyronitrile (AIBN, 66 mg, 0.40 mmol) are put into a 100 ml of three-necked flask, magnetic stirring is turned on. Under nitrogen protection, the temperature rises slowly to 80° C., the progress of the reaction is tracked by HPLC, and the reaction is complete after 22 h. 20 mL of water is added to the reaction solution, the pH value is adjusted to 4˜5 with 2N dilute hydrochloric acid, the liquids are separated, the organic phase is discarded. The pH value of the water phase is adjusted to 9˜10 with 2N sodium hydroxide solution, and extracting is performed twice with isopropyl acetate (2×20 ml). The organic phases is combined, washed once with saturated brine (20 ml), dried with anhydrous sodium sulfate (10 g), filtered, and the filtrate is concentrated to dryness under reduced pressure at 35˜40° C. to obtain a colorless oil (3.25 g, 0.0183 mol), which is the target product compound 10, with a yield of 91.2%; ee=2.8%. MS(ESI): m/z 179.1114[M+H].sup.+.

EXAMPLE 11

[0072] ##STR00022##

[0073] (R)-3β-amino-4-phenyl-N,N-dimethylbutanamide (4.12 g, 0.020 mol, ee>99%), benzene (20 ml), n-octyl mercaptan (0.29 g, 0.002 mol), azobisisobutyronitrile (AIBN, 66 mg, 0.40 mmol) are put into a 100 ml of three-necked flask, magnetic stirring is turned on. Under nitrogen protection, the temperature rises slowly to 80° C., the progress of the reaction is tracked by HPLC, and the reaction is complete after 22 h. 20 mL of water is added to the reaction solution, the pH value is adjusted to 4˜5 with 2N dilute hydrochloric acid, the liquids are separated, the organic phase is discarded. The pH value of the water phase is adjusted to 9˜10 with 2N sodium hydroxide solution, and extracting is performed twice with isopropyl acetate (2×20 ml). The organic phases is combined, washed once with saturated brine (20 ml), dried with anhydrous sodium sulfate (10 g), filtered, and the filtrate is concentrated to dryness under reduced pressure at 35˜40° C. to obtain a colorless oil (3.61 g, 0.0175 mol), which is the target product compound 11, with a yield of 87.6%; ee=2.6%. MS(ESI): m/z 207.1413[M+H].sup.+.

EXAMPLE 12

[0074] ##STR00023##

[0075] (R)-3β-amino-4-phenyl-1-piperidinyl butanone (4.97 g, 0.020 mol, ee>99%), toluene (20 ml), methyl thioglycolate (0.42 g, 4.0 mmol), azobisisobutyronitrile (AIBN, 66 mg, 0.4 mmol) are put into a 100 ml of three-necked flask, magnetic stirring is turned on. Under nitrogen protection, the temperature rises slowly to 80° C., the progress of the reaction is tracked by HPLC, and the reaction is complete after 20 h. 20 mL of water is added to the reaction solution, the pH value is adjusted to 4˜5 with 2N dilute hydrochloric acid, the liquids are separated, the organic phase is discarded. The pH value of the water phase is adjusted to 9˜10 with 2N sodium hydroxide solution, and extracting is performed twice with isopropyl acetate (2×20 ml). The organic phases is combined, washed once with saturated brine (20 ml), dried with anhydrous sodium sulfate (10 g), filtered, and the filtrate is concentrated to dryness under reduced pressure at 35˜40° C. to obtain a colorless oil (4.23 g, 0.0170 mol), which is the target product compound 12, with a yield of 85.1%; ee=2.3%. MS(ESI): m/z 249.1517[M+H].sup.+.

EXAMPLE 13

[0076] ##STR00024##

[0077] (S)-3-ethyl aminobutyrate (2.62 g, 0.020 mol, ee>99%), toluene (20 ml), methyl mercaptopropionate (0.49 g, 4.0 mmol), azobisisoheptanitrile (ABVN, 99 mg, 0.40 mmol) are put into a 100 ml of three-necked flask, magnetic stirring is turned on. Under nitrogen protection, the temperature rises slowly to 60° C., the progress of the reaction is tracked by HPLC, and the reaction is complete after 26 h. 20 mL of water is added to the reaction solution, the pH value is adjusted to 4˜5 with 2N dilute hydrochloric acid, the liquids are separated, the organic phase is discarded. The pH value of the water phase is adjusted to 9˜10 with 2N sodium hydroxide solution, and extracting is performed twice with isopropyl acetate (2×20 ml). The organic phases is combined, washed once with saturated brine (20 ml), dried with anhydrous sodium sulfate (10 g), filtered, and the filtrate is concentrated to dryness under reduced pressure at 35˜40° C. to obtain a colorless oil (2.53 g, 0.0193 mol), which is the target product compound 13, with a yield of 96.6%; ee=0.8%. MS(ESI): m/z 132.0951[M+H].sup.+.

EXAMPLE 14

[0078] ##STR00025##

[0079] (R)-3β-aminobutyric acid (2.06 g, 0.020 mol, ee>99%), tetrahydrofuran (20 ml), water (2 mL), mercaptopropyltrimethoxysilane (0.79 g, 4.0 mmol), azobis isobutyronitrile (AIBN, 66 mg, 0.40 mmol) are put into a 100 ml of three-necked flask, magnetic stirring is turned on. Under nitrogen protection, the temperature rises slowly to 60° C., the progress of the reaction is tracked by HPLC, and the reaction is complete after 24 h. 20 mL of water is added to the reaction solution, the pH value is adjusted to 2-3 with 2N dilute hydrochloric acid, the liquids are separated, the organic phase is discarded. The pH value of the water phase is adjusted to about 4.5 with 2N sodium hydroxide solution, a solid is precipitated, filtered to obtain a white viscous solid (1.55 g, 0.0150 mol), which is the target product compound 14, with a yield of 75.2%; ee=5.9%. MS(ESI): m/z 104.0631[M+H].sup.+.

EXAMPLE 15

[0080] ##STR00026##

[0081] (R)-3β-amino-3-phenylpropionic acid (3.31 g, 0.020 mol, ee>99%), tetrahydrofuran (20 ml), mercaptopropyltrimethoxysilane (0.79 g, 4.0 mmol), azobis isobutyronitrile (AIBN, 66 mg, 0.40 mmol) are put into a 100 ml of three-necked flask, magnetic stirring is turned on. Under nitrogen protection, the temperature rises slowly to 60° C., the progress of the reaction is tracked by HPLC, and the reaction is complete after 24 h. 20 mL of water is added to the reaction solution, the pH value is adjusted to 2-3 with 2N dilute hydrochloric acid, the liquids are separated, the organic phase is discarded. The pH value of the water phase is adjusted to about 4.5 with 2N sodium hydroxide solution, a solid is precipitated, filtered to obtain a white crystal (2.60 g, 0.0157 mol), which is the target product compound 15, with a yield of 78.5%; ee=6.2%. MS(ESI): m/z 166.0787[M+H].sup.+.

EXAMPLE 16

[0082] ##STR00027##

[0083] (S)-4β-amino-2-pentanone (2.02 g, 0.020 mol, ee>99%), dry TOL (20 ml), pentaerythritol tetra-3-mercaptopropionate (PETMP, 98 mg, 0.20 mmol), azobisisobutyronitrile (AIBN, 33 mg, 0.20 mmol) are put into a 100 ml of three-necked flask, magnetic stirring is turned on. Under nitrogen protection, the temperature rises slowly to 80° C., the progress of the reaction is tracked by HPLC, and the reaction is complete after 26 h. 20 mL of water is added to the reaction solution, the pH value is adjusted to 4˜5 with 2N dilute hydrochloric acid, the liquids are separated, the organic phase is discarded. The pH value of the water phase is adjusted to 9˜10 with 2N sodium hydroxide solution, and extracting is performed twice with isopropyl acetate (2×20 ml). The organic phases is combined, washed once with saturated brine (20 ml), dried with anhydrous sodium sulfate (10 g), filtered, and the filtrate is concentrated to dryness under reduced pressure at 35˜40° C. to obtain a colorless oil (1.87 g, 0.0185 mol), which is the target product compound 16, with a yield of 92.6%; ee=1.8%. MS(ESI): m/z 102.0847[M+H].sup.+.

EXAMPLE 17

[0084] ##STR00028##

[0085] (R)-4β-amino-4-phenyl-2-butanone (3.26 g, 0.020 mol, ee>99%), dry TOL (20 ml), pentaerythritol tetra-3-mercaptopropionate (PETMP, 98 mg, 0.20 mmol), azobisisobutyronitrile (AIBN, 33 mg, 0.20 mmol) are put into a 100 ml of three-necked flask, magnetic stirring is turned on. Under nitrogen protection, the temperature rises slowly to 100° C., the progress of the reaction is tracked by HPLC, and the reaction is complete after 20 h. 20 mL of water is added to the reaction solution, the pH value is adjusted to 4˜5 with 2N dilute hydrochloric acid, the liquids are separated, the organic phase is discarded. The pH value of the water phase is adjusted to 9˜10 with 2N sodium hydroxide solution, and extracting is performed twice with isopropyl acetate (2×20 ml). The organic phases is combined, washed once with saturated brine (20 ml), dried with anhydrous sodium sulfate (10 g), filtered, and the filtrate is concentrated to dryness under reduced pressure at 35˜40° C. to obtain a colorless oil (3.17 g, 0.0194 mol), which is the target product compound 17, with a yield of 97.2%; ee=1.5%. MS(ESI): m/z 164.0995 [M+H].sup.+.

EXAMPLE 18

[0086] ##STR00029##

[0087] (S)-3β-amino-1,3-diphenyl-1-one (4.51 g, 0.020 mol, ee>99%), toluene (20 ml), pentaerythritol tetra-3-mercaptopropionate (PETMP, 98 mg, 0.20 mmol), azobisisobutyronitrile (AIBN, 33 mg, 0.20 mmol) are put into a 100 ml of three-necked flask, magnetic stirring is turned on. Under nitrogen protection, the temperature rises slowly to 120° C., the progress of the reaction is tracked by HPLC, and the reaction is complete after 18 h. 20 mL of water is added to the reaction solution, the pH value is adjusted to 4˜5 with 2N dilute hydrochloric acid, the liquids are separated, the organic phase is discarded. The pH value of the water phase is adjusted to 9˜10 with 2N sodium hydroxide solution, and extracting is performed twice with isopropyl acetate (2×20 ml). The organic phases is combined, washed once with saturated brine (20 ml), dried with anhydrous sodium sulfate (10 g), filtered, and the filtrate is concentrated to dryness under reduced pressure at 35˜40° C. to obtain a colorless oil (4.41 g, 0.0196 mol), which is the target product compound 18, with a yield of 97.8%; ee=1.3%. MS(ESI): m/z 226.1157[M+H].sup.+.

EXAMPLE 19

[0088] ##STR00030##

[0089] (S)-3-methylamino-4-(2,4,5-trifluorophenyl) butyric acid methyl ester (5.22 g, 0.020 mol, ee>99%), pentaerythritol tetra-3-mercaptopropionate (PETMP, 0.30 g, 0.60 mmol), azobisisobutyronitrile (AIBN, 66 mg, 0.40 mmol) are put into a 100 ml of three-necked flask, magnetic stirring is turned on. Under nitrogen protection, the temperature rises slowly to 80° C., the progress of the reaction is tracked by HPLC, and the reaction is complete after 20 h. 20 mL of water is added to the reaction solution, the pH value is adjusted to 4˜5 with 2N dilute hydrochloric acid, the liquids are separated, the organic phase is discarded. The pH value of the water phase is adjusted to 9˜10 with 2N sodium hydroxide solution, and extracting is performed twice with isopropyl acetate (2×20 ml). The organic phases is combined, washed once with saturated brine (20 ml), dried with anhydrous sodium sulfate (10 g), filtered, and the filtrate is concentrated to dryness under reduced pressure at 35˜40° C. to obtain a colorless oil (4.87 g, 0.0187 mol), which is the target product compound 19, with a yield of 93.3%; ee=4.8%. MS(ESI): m/z 262.0973[M+H].sup.+.

EXAMPLE 20

[0090] ##STR00031##

[0091] (R)-3β-amino-butyric acid methyl ester (3.87 g, 0.020 mol, ee>99%), toluene (20 ml), pentaerythritol tetra-3-mercaptopropionate (PETMP, 0.49 g, 0.010 mol), azodiisobutyronitrile (AIBN, 66 mg, 0.40 mmol) are put into a 100 ml of three-necked flask, magnetic stirring is turned on. Under nitrogen protection, the temperature rises slowly to 100° C., the progress of the reaction is tracked by HPLC, and the reaction is complete after 22 h. 20 mL of water is added to the reaction solution, the pH value is adjusted to 4˜5 with 2N dilute hydrochloric acid, the liquids are separated, the organic phase is discarded. The pH value of the water phase is adjusted to 9˜10 with 2N sodium hydroxide solution, and extracting is performed twice with isopropyl acetate (2×20 ml). The organic phases is combined, washed once with saturated brine (20 ml), dried with anhydrous sodium sulfate (10 g), filtered, and the filtrate is concentrated to dryness under reduced pressure at 35˜40° C. to obtain a colorless oil (3.54 g, 0.0183 mol), which is the target product compound 20, with a yield of 91.5%; ee=9.7%. MS(ESI): m/z 194.1108 [M+H].sup.+.

EXAMPLE 21

[0092] ##STR00032##

[0093] (S)-3-methyl acetaminobutyrate (3.18 g, 0.020 mol, ee>99%), toluene (20 ml), pentaerythritol tetra-3-mercaptopropionate (PETMP, 0.98 g, 0.002 mol), azodiisobutyronitrile (AIBN, 0.17 g, 0.002 mol) are put into a 100 ml of three-necked flask, magnetic stirring is turned on. Under nitrogen protection, the temperature rises slowly to 120° C., the progress of the reaction is tracked by HPLC, and the reaction is complete after 24 h. 20 mL of water is added to the reaction solution, the pH value is adjusted to 4˜5 with 2N dilute hydrochloric acid, the liquids are separated, the organic phase is discarded. The pH value of the water phase is adjusted to 9˜10 with 2N sodium hydroxide solution, and extracting is performed twice with isopropyl acetate (2×20 ml). The organic phase is concentrated to dryness under reduced pressure, and separated by fast column chromatography to obtain a colorless oil (2.46 g, 0.0155 mol), which is the target product compound 21, with a yield of 77.3%; ee=16.5%. MS(ESI): m/z 160.0897[M+H].sup.+.