CN111499640A

CN111499640A - Chiral resolution method of piperazinotriazole derivatives

Info

Publication number: CN111499640A
Application number: CN201910101113.3A
Authority: CN
Inventors: 李建其; 陈晓文; 阮乐军; 齐阳历; 许珺玮
Original assignee: Shanghai Institute of Pharmaceutical Industry; China State Institute of Pharmaceutical Industry
Current assignee: Shanghai Institute of Pharmaceutical Industry; China State Institute of Pharmaceutical Industry
Priority date: 2019-01-31
Filing date: 2019-01-31
Publication date: 2020-08-07

Abstract

The invention discloses a chiral resolution method of piperazinotriazole derivatives, which comprises the following steps: taking chiral acid as a resolving reagent, carrying out acid-base salt formation reaction on a racemate compound (I) and the chiral acid to obtain a mixture of diastereoisomers, collecting a single chiral isomer from the mixture, and dissociating under an alkaline condition to obtain the piperazinotriazole derivative with the R configuration of the structural general formula II. Compared with the preparation method of chiral synthesis and chiral column separation, the preparation method of the invention has the advantages of easily available raw materials, simple and convenient operation, high optical purity, low preparation cost, environmental protection and easy industrial scale preparation. The structural general formulas of the racemic compound (I) and the R configuration compound (II) are as follows:

Description

Chiral resolution method of piperazinotriazole derivatives

Technical Field

The invention relates to a chiral resolution method of piperazinotriazole derivatives.

Background

The R isomer is mainly reported to be used for preparing DPP 4(Dipeptidyl Peptidase IV) inhibitor (J.Med.chem.2008,51, 589-.

At present, the preparation method of the chiral isomer of the piperazinotriazole derivative is mainly chiral preparation chromatography, and the method has high cost, uses a large amount of organic solvents and is not suitable for large-scale preparation. The chiral synthesis method needs protecting group grafting and protecting group removing processes (CN 105175421 Aad CN 103906750A), and has long reaction steps, complex operation and poor atom economy.

In the prior art, Chinese patents CN 102906093A, CN105175421A, CN103570725A, CN106749261A and U.S. patents US2018118749A1, US2005107390A1, US2006052382A1 disclose the preparation of chiral isomers of piperazinotriazole derivatives by a chiral preparation method, meanwhile, documents J.Med.chem.2008,51, 589-.

Chinese patents CN105175421a and CN 103906750a report chiral synthesis methods of chiral isomers of piperazinotriazole derivatives. The method takes chiral (3-substituted) -piperazine-2-ketone as a starting material to prepare the chiral pure piperazinotriazole derivative through four-step reaction. Chiral (3-substituted) -piperazin-2-one is expensive and not readily available; protecting group grafting and protecting group removing reaction are needed, and atom economy is poor; with the risk of racemization side reactions occurring. Therefore, this method is not suitable for R₁Is the directed synthesis of a series of derivatives of methyl.

Compared with chiral column separation preparation and chiral synthesis methods, the chiral reagent resolution method has the advantages of wide applicable substance range, low cost, simple and convenient operation, easy laboratory implementation and industrial amplification realization. At present, chiral isomers of piperazinotriazole derivatives prepared by a chiral reagent resolution method are not reported. Therefore, the search for a proper chiral resolution reagent to realize the cheap and efficient synthesis and large-scale amplification preparation of the chiral isomer of the piperazinotriazole derivative is a very important technical problem and has great scientific significance and application value.

Disclosure of Invention

The invention provides a chiral resolution method of piperazinotriazole derivatives, which overcomes the defects in the prior art.

The chiral resolution method of the piperazinotriazole derivative is characterized in that chiral acid is used as a resolution reagent, a racemic compound (I) and the chiral acid are subjected to acid-base salt formation reaction to obtain a mixture of diastereoisomers, the mixture is recrystallized, separated and purified to obtain a single chiral isomer, and then the mixture is separated under an alkaline condition to obtain the piperazinotriazole derivative (II) with an R configuration:

wherein:

R₁is methyl, R₂Is hydrogen;

or R₁Is hydrogen, R₂Is methyl;

R₃represents trifluoromethyl, heteroaryl or methyl-substituted heteroaryl;

the chiral acid comprises D- (+) -dibenzoyltartaric acid, D- (+) -di-p-methylbenzoyltartaric acid, D- (+) -camphorsulfonic acid, D- (+) -camphoric acid, D-malic acid, D- (-) -citramalic acid or D-mandelic acid;

the salt formed by the racemic body compound (I) and the chiral acid is D- (+) -dibenzoyl tartrate, D- (+) -di-p-methyl benzoyl tartrate, D- (+) -camphorsulfonate, D- (+) -camphorate, D-malate, D- (-) -citramalate or D-mandelate.

The solvent for acid-base salt formation is methanol, ethanol, isopropanol, n-butanol, acetone, tetrahydrofuran, dichloromethane or chloroform;

the recrystallization separation and purification comprises primary recrystallization or secondary recrystallization;

the recrystallization solvent is methanol, ethanol, isopropanol, acetonitrile, water or a mixture of methanol, ethanol, isopropanol, acetonitrile and water;

the ratio of the dosage (mol) of the compound (I) salified by acid and alkali to the dosage (mol) of the resolving agent is 1: 1.0-1: 1.5;

the volume ratio of the dosage (g) of the compound (I) to the dosage (m L) of the solvent is 1: 5-1: 30;

the volume ratio of the dosage (g) of the salt formed by the compound (I) and the resolving agent to the dosage (m L) of the recrystallization solvent is 1: 5-1: 30;

the heteroaryl group comprises pyridyl, thiazolyl and 1,2, 4-thiadiazolyl;

preferably, the piperazinotriazole derivative with R configuration is:

a-1(R) -8-methyl-3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazine,

A-2(R) -8-methyl-3- (pyridin-2-yl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazine,

A-3(R) -2-methyl-4- (8-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) thiazole,

A-4(R) -3-methyl-5- (8-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) -1,2, 4-thiadiazole,

B-1(R) -5-methyl-3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazine,

B-2(R) -5-methyl-3- (pyridin-2-yl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazine or

B-3(R) -2- (5-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) thiazole.

The structures of the preferred compounds are shown in the following table:

the chiral resolution method of the piperazinotriazole derivative comprises the following steps:

(1) carrying out salt forming reaction on a racemate of the piperazinotriazole derivative and chiral acid in an organic solvent to obtain a salt formed by the piperazinotriazole derivative racemate and the chiral acid, wherein the reaction conditions comprise that the temperature is 20-100 ℃, and the stirring time is 1-9 h;

(2) carrying out recrystallization purification on the salt separated in the step (1) in a solvent for 1-2 times;

(3) reacting the purified salt obtained in the step (2) with alkali, adjusting the pH value to 9-11, extracting with an organic solvent, drying and concentrating to obtain the piperazinotriazole derivative with the R configuration.

The peak time of the optical isomer of the piperazinotriazole derivative obtained by resolution of the invention through chiral high performance liquid chromatography (HP L C) is consistent with that of the piperazinotriazole derivative with R configuration obtained by preparation and separation through a chiral column reported in literature, and the piperazinotriazole derivative obtained by resolution can be verified to be in R configuration.

In the invention, a chiral resolution reagent is very critical, and mainly depends on whether diastereoisomers with large property difference can be formed in a solvent with a racemate raw material so as to realize resolution, and recrystallization is carried out in a proper solvent so as to obtain the chiral isomers with high optical purity. Preferably, the chiral resolving agent comprises D- (+) -dibenzoyltartaric acid, D- (+) -di-p-methylbenzoyltartaric acid, D- (+) -camphorsulfonic acid, D- (+) -camphoric acid, D-malic acid, D- (-) -citramalic acid or D-mandelic acid.

The chiral resolution method of the piperazinotriazole derivative has the following remarkable advantages:

1. compared with the reported chiral synthesis method, the R isomer of the piperazinotriazole derivative is obtained by the chiral resolution method of the piperazinotriazole derivative, and the raw material is cheap and easy to obtain, the impurity content is low, and the preparation cost is low; the reaction processes of protecting group connection and protecting group removal are not needed, the operation is simple and convenient, and the atom economy is high;

2. compared with the reported chiral column separation preparation method, the R isomer of the piperazinotriazole derivative obtained by the chiral resolution method of the piperazinotriazole derivative has the advantages of simple operation, high optical purity, greatly reduced preparation cost, environmental protection and easy industrial scale preparation.

In conclusion, the technology of the invention is not reported in documents, and has novelty, creativity, practicability and obvious technological progress compared with the existing preparation method and technology.

Detailed Description

Example 1

Preparation of (R) -8-methyl-3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazine (A-1)

The racemate of 8-methyl-3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazine is prepared by the method of reference Org. L et, 7,2005, 1039-one 1042.

D- (+) -dibenzoyltartaric acid (36g,0.1mol) and ethanol (400m L) were added to a 1L single-necked flask, stirred to be clear, the racemate of 8-methyl-3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazine (20.6g,0.1mol) was added in portions at room temperature, after the addition was completed, the mixture was stirred at room temperature for 1 hour, filtered, and the filter cake was washed with absolute ethanol (50m L× 2).

Transferring the obtained salt into a 1L single-mouth bottle, adding methanol 200m L, stirring, heating to reflux, dissolving, stirring for 1h, naturally cooling to room temperature, stirring for 0.5h, and filtering.

Transferring the filter cake to a 500m L single-neck bottle, sequentially adding ethyl acetate (200m L) and water (100m L), stirring, cooling the system to 0-10 ℃, adjusting the pH of the system to 10-11 by using 20% NaOH aqueous solution, stirring for 10min, separating liquid, sequentially washing an organic layer by using water (50m L× 1) and saturated salt solution (100m L× 1), and removing anhydrous NaSO₄Drying, filtering, concentrating,to obtain (R) -8-methyl-3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4]]Triazole [4,3-a ]]Pyrazine 8.1g as a colorless oil in 39% yield.

The peak time of the resolved A-1 after further condensation with (R) -3-amino-4- (2,4, 5-trifluorophenyl) butanoic acid (prepared according to J.Med.chem.2008,51, 589-one 602) by chiral high performance liquid analysis (HP L C) was consistent with the peak time of the R-configured compound 34b obtained by separation by chiral column preparation reported in J.Med.chem.2008,51, 589-one 602.

¹H NMR(CD₃OD,:ppm):1.90(d,J＝7Hz,3H),3.70-3.80(m,1H),3.95-4.05(m,1H),4.50-4.60(m,1H),4.60-4.70(m,1H),4.80(b,1H),4.98(q,J＝7Hz,1H).ESI-MS:207[M+H⁺].

ee％(HPLC):99％.

Example 2

D- (+) -di-p-methylbenzoyl tartaric acid (39g,0.1mol) and methanol (400m L) were added to a 1L single-necked flask, stirred to be clear, the racemate (20.6g,0.1mol) of 8-methyl-3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazine was added in portions at room temperature, and after the addition, the mixture was stirred at room temperature for 2 hours, filtered, and the filter cake was washed with methanol (50m L× 2).

Transferring the filter cake to a 500m L single-neck bottle, sequentially adding ethyl acetate (200m L) and water (100m L), stirring, cooling the system to 0-10 ℃, adjusting the pH of the system to 10-11 by using 20% NaOH aqueous solution, stirring for 10min, separating liquid, sequentially washing an organic layer by using water (50m L× 1) and saturated salt solution (100m L× 1), and removing anhydrous NaSO₄Drying, filtering and concentrating to obtain (R) -8-methyl-3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4]]Triazole [4,3-a ]]Pyrazine 5.9g as a colorless oil in 29% yield.

ee％(HPLC):98.7％.

Example 3

Adding D- (+) -camphorsulfonic acid (23g,0.1mol) and isopropanol (300m L) into a 1L single-mouth bottle, stirring to be clear, adding 8-methyl-3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazine racemate (20.6g,0.1mol) in batches at room temperature, heating to an internal temperature of 80 ℃, stirring for 3h, cooling to room temperature, stirring for 1h, filtering, and washing a filter cake with isopropanol (50m L× 2).

Transferring the obtained salt into a 1L single-mouth bottle, adding ethanol 100m L, stirring, heating to reflux, dissolving, stirring for 1h, naturally cooling to room temperature, stirring for 0.5h, and filtering.

Transferring the filter cake to a 500m L single-neck bottle, sequentially adding ethyl acetate (200m L) and water (100m L), stirring, cooling the system to 0-10 ℃, adjusting the pH of the system to 10-11 by using 20% KOH aqueous solution, stirring for 10min, separating liquid, sequentially washing an organic layer by using water (50m L× 1) and saturated salt solution (100m L× 1), and removing anhydrous NaSO₄Drying, filtering and concentrating to obtain (R) -8-methyl-3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4]]Triazole [4,3-a ]]Pyrazine was 4.6g as a colorless oil in 22% yield.

ee％(HPLC):99.1％.

Example 4

Adding D- (+) -camphoric acid (20g,0.1mol) and THF (300m L) into a 1L single-mouth bottle, stirring to be clear, adding 8-methyl-3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazine racemate (20.6g,0.1mol) in batches at room temperature, heating to an internal temperature of 60 ℃, stirring for 3h, cooling to room temperature, stirring for 1h, filtering, and washing a filter cake with THF (50m L× 2).

Transferring the obtained salt into a 1L single-mouth bottle, adding methanol 100m L, stirring, heating to reflux, dissolving, stirring for 1h, naturally cooling to room temperature, stirring for 0.5h, and filtering.

Transferring the filter cake to 500m L single-neck bottle, sequentially adding ethyl acetate (200m L) and water (100m L), stirring, cooling the system to 0-10 deg.C, adjusting pH of the system to 10-11 with 20% NaOH aqueous solution, stirring for 10min, separating liquid, and addingThe organic layer was washed with water (50m L× 1) and saturated brine (100m L× 1) in this order, and anhydrous NaSO was added₄Drying, filtering and concentrating to obtain (R) -8-methyl-3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4]]Triazole [4,3-a ]]Pyrazine 7.2g as a colorless oil in 35% yield.

ee％(HPLC):99％.

Example 5

Adding D-malic acid (13.4g,0.1mol) and acetone (300m L) into a 1L single-mouth bottle, stirring to be clear, adding 8-methyl-3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazine racemate (20.6g,0.1mol) in batches at room temperature, heating to an internal temperature of 60 ℃, stirring for 3h, cooling to room temperature, stirring for 1h, filtering, and washing a filter cake with acetone (50m L× 2).

Transferring the filter cake to a 500m L single-neck bottle, sequentially adding ethyl acetate (200m L) and water (100m L), stirring, cooling the system to 0-10 ℃, adjusting the pH of the system to 10-11 by using 20% NaOH aqueous solution, stirring for 10min, separating liquid, sequentially washing an organic layer by using water (50m L× 1) and saturated salt solution (100m L× 1), and removing anhydrous NaSO₄Drying, filtering and concentrating to obtain (R) -8-methyl-3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4]]Triazole [4,3-a ]]Pyrazine 7.5g as a colorless oil in 36% yield.

ee％(HPLC):98.1％.

Example 6

Preparation of (R) -8-methyl-3- (pyridin-2-yl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazine (A-2)

Racemate reference bioorg. Med. chem. L ett.2015,25,3157-3163 for 8-methyl-3- (pyridin-2-yl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazine.

D- (+) -dibenzoyltartaric acid (36g,0.1mol) and ethanol (400m L) were added to a 1L single-necked flask, stirred to be clear, the racemate of 8-methyl-3- (pyridin-2-yl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazine (21.5g,0.1mol) was added in portions at room temperature, and after the addition, the mixture was stirred at room temperature for 1 hour, filtered, and the filter cake was washed with absolute ethanol (50m L× 2).

Transferring the filter cake to a 500m L single-neck bottle, sequentially adding dichloromethane (200m L) and water (100m L), stirring, cooling the system to 0-10 ℃, adjusting the pH of the system to 10-11 by using 20% NaOH aqueous solution, stirring for 10min, separating liquid, sequentially washing an organic layer by using water (50m L× 1) and saturated saline solution (100m L× 1), and removing anhydrous NaSO₄Drying, filtering and concentrating to obtain (R) -8-methyl-3- (pyridine-2-yl) -5,6,7, 8-tetrahydro- [1,2,4]]Triazole [4,3-a ]]Pyrazine 7.2g as a colorless oil in 33% yield.

The resolved A-2, after further condensation with 2, 3-dichlorobenzoic acid (prepared according to Bioorg. Med. chem. L ett.2015,25,3157-3163), showed a peak time consistent with that of 7l of the R-configuration compound isolated by chiral column preparation as reported in the Bioorg. Med. chem. L ett.2015,25,3157-3163, via chiral HPLC analysis.

¹H NMR(CD₃OD,:ppm):1.92(d,J＝7Hz,3H),3.71-3.80(m,1H),3.96-4.04(m,1H),4.52-4.63(m,1H),4.61-4.71(m,1H),4.82(b,1H),4.99(q,J＝7Hz,1H),7.51-7.53(m,1H),7.93-7.95(m,1H),8.34-8.37(m,2H).

ESI-MS:216[M+H⁺].

ee％(HPLC):99.2％.

Example 7

D- (+) -di-p-methylbenzoyl tartaric acid (38.6g,0.1mol) and ethanol (400m L) were added to a 1L single-necked flask, stirred to be clear, the racemate of 8-methyl-3- (pyridin-2-yl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazine (21.5g,0.1mol) was added in portions at room temperature, after the addition, the mixture was stirred at room temperature for 1 hour, filtered, and the filter cake was washed with absolute ethanol (50m L× 2).

Transferring the filter cake to a 500m L single-neck bottle, sequentially adding dichloromethane (200m L) and water (100m L), stirring, cooling the system to 0-10 ℃, adjusting the pH of the system to 10-11 by using 20% NaOH aqueous solution, stirring for 10min, separating liquid, sequentially washing an organic layer by using water (50m L× 1) and saturated saline solution (100m L× 1), and removing anhydrous NaSO₄Drying, filtering and concentrating to obtain (R) -8-methyl-3- (pyridine-2-yl) -5,6,7, 8-tetrahydro- [1,2,4]]Triazole [4,3-a ]]Pyrazine 5.9g as a colorless oil in 27% yield.

ee％(HPLC):99.4％.

Example 8

D- (-) -citramalic acid (14.8g,0.1mol) and chloroform (400m L) were added to a 1L single-necked flask, stirred to be clear, the racemate of 8-methyl-3- (pyridin-2-yl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazine (21.5g,0.1mol) was added in portions at room temperature, after the addition was completed, the mixture was stirred at room temperature for 1 hour, filtered, and the filter cake was washed with chloroform (50m L× 2).

Transferring the obtained salt into a 1L single-mouth bottle, adding ethanol 200m L and water 20m L, stirring, heating to reflux, dissolving, stirring for 1h, naturally cooling to room temperature, stirring for 0.5h, and filtering.

Transferring the filter cake to 500m L single-neck bottle, sequentially adding dichloromethane (200m L) and water (100m L), stirring, cooling the system to 0-10 deg.C, adjusting the pH of the system to 10-11 with 50% sodium bicarbonate water solution, stirring for 10min, separating, sequentially washing the organic layer with water (50m L× 1) and saturated saline (100m L× 1), and removing anhydrous NaSO₄Drying, filtering and concentrating to obtain (R) -8-methyl-3- (pyridine-2-yl) -5,6,7, 8-tetrahydro- [1,2,4]]Triazole [4,3-a ]]Pyrazine was 4.7g as a colorless oil in 22% yield.

ee％(HPLC):98.9％.

Example 9

D-mandelic acid (16.0g,0.1mol) and ethanol (400m L) were added to a 1L single-necked flask, stirred to be clear, the racemate of 8-methyl-3- (pyridin-2-yl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazine (21.5g,0.1mol) was added in portions at room temperature, and after the addition, the mixture was stirred at room temperature for 1 hour, filtered, and the filter cake was washed with ethanol (50m L× 2).

Transferring the obtained salt into a 1L single-neck bottle, adding isopropanol 150m L and water 20m L, stirring, heating to reflux, dissolving, stirring for 1h, naturally cooling to room temperature, stirring for 0.5h, and filtering.

Transferring the filter cake to a 500m L single-neck bottle, sequentially adding dichloromethane (200m L) and water (100m L), stirring, cooling the system to 0-10 ℃, adjusting the pH of the system to 10-11 by using 20% NaOH aqueous solution, stirring for 10min, separating liquid, sequentially washing an organic layer by using water (50m L× 1) and saturated saline solution (100m L× 1), and removing anhydrous NaSO₄Drying, filtering and concentrating to obtain (R) -8-methyl-3- (pyridine-2-yl) -5,6,7, 8-tetrahydro- [1,2,4]]Triazole [4,3-a ]]Pyrazine 6.1g as a colorless oil in 28% yield.

ee％(HPLC):99％.

Example 10

Preparation of (R) -2-methyl-4- (8-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) thiazole (A-3)

2-methyl-4- (8-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) thiazole, by the method of reference J.Med.chem.2015,58(7), 3060-propanoic acid 3082.

D- (+) -dibenzoyltartaric acid (36g,0.1mol) and ethanol (400m L) were added to a 1L single-necked flask, stirred to be clear, the racemate of 2-methyl-4- (8-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) thiazole (23.5g,0.1mol) was added in portions at room temperature, after the addition, stirred at room temperature for 5 hours, filtered, and the filter cake was washed with absolute ethanol (50m L× 2).

Transferring the obtained salt into a 1L single-mouth bottle, adding ethanol 200m L, stirring, heating to reflux, dissolving, stirring for 1h, naturally cooling to room temperature, stirring for 0.5h, and filtering.

Transferring the filter cake to a 500m L single-neck bottle, sequentially adding dichloromethane (150m L) and water (100m L), stirring, cooling the system to 0-10 deg.C, adding 20% NaOH waterAdjusting pH of the solution to 10-11, stirring for 10min, separating, sequentially washing organic layer with water (50m L× 1) and saturated saline solution (100m L× 1), and anhydrous NaSO₄Drying, filtering and concentrating to obtain (R) -2-methyl-4- (8-methyl-5, 6,7, 8-tetrahydro- [1,2,4]]Triazole [4,3-a ]]Pyrazin-3-yl) thiazole 8.3g as a colorless oil in 35% yield.

The resolved A-3 has a liquid phase peak-out time (t) consistent with that of the compound of R configuration obtained by chiral column preparative separation as reported in J.Med.chem.2015,58(7),3060-_R(S)＝9.4min,t_R(R)＝10.6min)。

¹H NMR(CD₃OD,:ppm):1.91(d,J＝6.6Hz,3H),2.83(s,3H),3.82-3.90(m,2H),4.04(m,1H),4.79(m,2H),5.08(m,2H).

ESI-MS:236[M+H⁺].

ee％(HPLC):99.1％.

Example 11

D- (+) -di-p-methylbenzoyl tartaric acid (39g,0.1mol) and methanol (400m L) were added to a 1L single-necked flask, stirred to be clear, the racemate (23.5g,0.1mol) of 2-methyl-4- (8-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) thiazole was added in portions at room temperature, after addition, the mixture was stirred at room temperature for 4 hours, filtered, and the filter cake was washed with methanol (50m L× 2).

Transferring the filter cake to a 500m L single-neck bottle, sequentially adding chloroform (150m L) and water (100m L), stirring, cooling the system to 0-10 deg.C, adjusting the pH of the system to 10-11 with 20% NaOH aqueous solution, stirring for 10min, separating, sequentially washing the organic layer with water (50m L× 1) and saturated saline (100m L× 1), and removing anhydrous NaSO₄Drying, filtering and concentrating to obtain (R) -2-methyl-4- (8-methyl-5, 6,7, 8-tetrahydro- [1,2,4]]Triazole [4,3-a ]]Pyrazin-3-yl) thiazole in a 30% yield as a colorless oil 7.1 g.

ee％(HPLC):98.3％.

Example 12

Adding D- (+) -camphorsulfonic acid (24g,0.1mol) and ethanol (400m L) into a 1L single-mouth bottle, stirring to be clear, adding racemate (23.5g,0.1mol) of 2-methyl-4- (8-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) thiazole in batches at room temperature, stirring for 4 hours at room temperature after adding, filtering, and washing a filter cake with ethanol (50m L× 2).

Transferring the filter cake to a 500m L single-neck bottle, sequentially adding dichloromethane (150m L) and water (100m L), stirring, cooling the system to 0-10 deg.C, adjusting the pH of the system to 10-11 with 20% NaOH aqueous solution, stirring for 10min, separating, sequentially washing the organic layer with water (50m L× 1) and saturated salt solution (100m L× 1), and removing anhydrous NaSO₄Drying, filtering and concentrating to obtain (R) -2-methyl-4- (8-methyl-5, 6,7, 8-tetrahydro- [1,2,4]]Triazole [4,3-a ]]Pyrazin-3-yl) thiazole 5.8g as a colorless oil in 25% yield.

ee％(HPLC):98.3％.

Example 13

Adding D-mandelic acid (16g,0.1mol) and acetone (400m L) into a 1L single-mouth bottle, stirring to be clear, adding racemate (23.5g,0.1mol) of 2-methyl-4- (8-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) thiazole in batches at room temperature, heating to reflux after the addition is finished, stirring for 8h, cooling to room temperature, filtering, and washing a filter cake with acetone (50m L× 2).

Transferring the obtained salt into a 1L single-mouth bottle, adding 100m of ethanol L and 30m of water L, stirring, heating to reflux, dissolving, stirring for 2h, naturally cooling to room temperature, stirring for 0.5h, and filtering.

The filter cake was transferred to a 500m L single neck flask, dichloromethane (150m L) and water (100m L) were added in sequence, and stirring was carried outStirring, cooling to 0-10 deg.C, adjusting pH to 10-11 with 20% NaOH water solution, stirring for 10min, separating, sequentially washing organic layer with water (50m L× 1) and saturated saline solution (100m L× 1), and anhydrous NaSO₄Drying, filtering and concentrating to obtain (R) -2-methyl-4- (8-methyl-5, 6,7, 8-tetrahydro- [1,2,4]]Triazole [4,3-a ]]Pyrazin-3-yl) thiazole 6.2g as a colorless oil in 26% yield.

ee％(HPLC):99.5％.

Example 14

Preparation of (R) -3-methyl-5- (8-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) -1,2, 4-thiadiazole (A-4)

3-methyl-5- (8-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) -1,2, 4-thiadiazole is prepared by the method of ACS Med. chem. L ett.2015,6, 736-.

D- (+) -dibenzoyltartaric acid (36g,0.1mol) and dichloromethane (400m L) were added to a 1L single-necked flask, stirred to be clear, the racemate of 3-methyl-5- (8-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) -1,2, 4-thiadiazole (23.6g,0.1mol) was added in portions at room temperature, after addition, stirred at room temperature for 7h, filtered, and the filter cake was washed with dichloromethane (50m L× 2).

Transferring the obtained salt into a 1L single-mouth bottle, adding methanol 200m L, stirring, heating to reflux, dissolving, stirring for 2h, naturally cooling to room temperature, stirring for 0.5h, and filtering.

Transferring the filter cake to a 500m L single-neck bottle, sequentially adding dichloromethane (150m L) and water (100m L), stirring, cooling the system to 0-10 deg.C, adjusting the pH of the system to 10-11 with 50% potassium carbonate aqueous solution, stirring for 10min, separating, sequentially washing the organic layer with water (50m L× 1) and saturated saline (100m L× 1), and removing anhydrous NaSO₄Drying, filtering and concentrating to obtain (R) -3-methyl-5- (8-methyl-5, 6,7, 8-tetrahydro- [1,2,4]]Triazole [4,3-a ]]Pyrazin-3-yl) -1,2, 4-thiadiazole 7.3g as a colorless oil in 31% yield.

The A-4 obtained by the resolution is consistent with the liquid phase peak-out time (t) of an R-configuration compound obtained by the preparation and separation of a chiral column reported in the documents ACS Med. chem. L ett.2015,6,736- & 740 (t)_R(R)＝11.1min,t_R(S)＝12.7min)。

¹H NMR(CD₃OD,:ppm):1.90(d,J＝6.6Hz,3H),2.82(s,3H),3.81-3.88(m,2H),4.77(m,2H),5.06(m,2H).

ESI-MS:237[M+H⁺].

ee％(HPLC):99.4％.

Example 15

Preparation of (R) -3-methyl-5- (8-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) -1,2, 4-thiadiazole (A-4) D- (+) -di-p-methylbenzoyl tartaric acid (39g,0.1mol) and chloroform (400m L) were added to a 1L single vial, stirred to clarify, and at room temperature, the racemate (23.6g,0.1mol) of 3-methyl-5- (8-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) -1,2, 4-thiadiazole was added in portions, after completion, stirred at room temperature for 6 hours, filtered, and the filter cake was washed with dichloromethane (50m L× 2).

Transferring the filter cake to a 500m L single-neck bottle, sequentially adding dichloromethane (150m L) and water (100m L), stirring, cooling the system to 0-10 deg.C, adjusting the pH of the system to 10-11 with 20% NaOH aqueous solution, stirring for 10min, separating, sequentially washing the organic layer with water (50m L× 1) and saturated salt solution (100m L× 1), and removing anhydrous NaSO₄Drying, filtering and concentrating to obtain (R) -3-methyl-5- (8-methyl-5, 6,7, 8-tetrahydro- [1,2,4]]Triazole [4,3-a ]]Pyrazin-3-yl) -1,2, 4-thiadiazole 5.9g as a colorless oil in 25% yield.

ee％(HPLC):99％.

Example 16

Preparation of (R) -3-methyl-5- (8-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) -1,2, 4-thiadiazole (A-4) D-malic acid (14g,0.1mol), THF (400m L) were added to a 1L one-neck flask, stirred to be clear at room temperature, 3-methyl-5- (8-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) -1,2, 4-thiadiazole racemate (23.6g,0.1mol) was added in portions at room temperature, stirred at room temperature for 5 hours, filtered, and the filter cake was washed with THF (50m L× 2).

Transferring the obtained salt into a 1L single-mouth bottle, adding acetonitrile 200m L, stirring, heating to reflux, dissolving clearly, stirring for 3h, naturally cooling to room temperature, stirring for 0.5h, and filtering.

Transferring the filter cake to a 500m L single-neck bottle, sequentially adding dichloromethane (150m L) and water (100m L), stirring, cooling the system to 0-10 deg.C, adjusting the pH of the system to 10-11 with 20% NaOH aqueous solution, stirring for 10min, separating, sequentially washing the organic layer with water (50m L× 1) and saturated salt solution (100m L× 1), and removing anhydrous NaSO₄Drying, filtering and concentrating to obtain (R) -3-methyl-5- (8-methyl-5, 6,7, 8-tetrahydro- [1,2,4]]Triazole [4,3-a ]]6.7g of pyrazin-3-yl) -1,2, 4-thiadiazole as a colorless oil in 28% yield.

ee％(HPLC):98.8％.

Example 17

Preparation of (R) -3-methyl-5- (8-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) -1,2, 4-thiadiazole (A-4) D- (-) -citramalic acid (15g,0.1mol), acetone (400m L) were added to a 1L single vial, stirred to clarify, the racemate (23.6g,0.1mol) of 3-methyl-5- (8-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) -1,2, 4-thiadiazole was added portionwise at room temperature, warmed to reflux, stirred for 5h, filtered, and the filter cake was washed with acetone (50m L× 2).

Transferring the obtained salt into a 1L single-neck bottle, adding acetonitrile 200m L and water 10m L, stirring, heating to reflux, dissolving, stirring for 5h, naturally cooling to room temperature, stirring for 0.5h, and filtering.

ee％(HPLC):99.7％.

Example 18

Preparation of (R) -5-methyl-3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazine (B-1)

5-methyl-3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazine by the method of reference CN 103570725A.

D- (+) -dibenzoyltartaric acid (36g,0.1mol) and isopropanol (400m L) were added to a 1L single-necked flask, stirred to be clear, 5-methyl-3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazine racemate (20.6g,0.1mol) was added in portions at room temperature, and after the addition, the mixture was stirred at room temperature for 6 hours, filtered, and the filter cake was washed with isopropanol (50m L× 2).

Transferring the filter cake to a 500m L single-neck bottle, sequentially adding dichloromethane (150m L) and water (100m L), stirring, cooling the system to 0-10 deg.C, adjusting the pH of the system to 10-11 with 20% NaOH aqueous solution, stirring for 10min, separating, sequentially washing the organic layer with water (50m L× 1) and saturated salt solution (100m L× 1), and removing anhydrous NaSO₄Drying, filtering and concentrating to obtain (R) -5-methyl-3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4]]Triazole [4,3-a ]]Pyrazine 8.4g as a colorless oil in 41% yield.

After the resolved B-1 is further condensed with 2-fluoro-5- ((4-oxo-3, 4-dihydrophthalazin-1-yl) methyl) benzoic acid (prepared according to CN 103570725A), the liquid phase peak-out time of the R configuration compound S3- (+) prepared and separated by a chiral column reported in the document CN103570725A is consistent.

¹H NMR(CDCl₃,:ppm):1.55(t,J＝5.9Hz,3H),2.37-1.97(m,1H),3.06(dd,J＝13.4,1.6Hz,1H),3.21(dd,J＝13.4,4.0Hz,1H),4.14(dd,J＝15.9,7.7Hz,1H),4.35(d,J＝16.8Hz,1H),4.57-4.41(m,1H),6.79(t,J＝51.6Hz,1H).

ESI-MS:207[M+H⁺].

ee％(HPLC):99.1％.

Example 19

D- (+) -camphoric acid (22g,0.1mol) and THF (400m L) were added to a 1L single-necked flask, stirred to be clear, 5-methyl-3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazine racemate (20.6g,0.1mol) was added in portions at room temperature, after the addition was completed, stirred at room temperature for 6 hours, filtered, and the filter cake was washed with THF (50m L× 2).

Transferring the obtained salt into a 1L single-mouth bottle, adding ethanol 100m L, stirring, heating to reflux, dissolving, stirring for 3h, naturally cooling to room temperature, stirring for 0.5h, and filtering.

Transferring the filter cake to a 500m L single-neck bottle, sequentially adding dichloromethane (150m L) and water (100m L), stirring, cooling the system to 0-10 ℃, adjusting the pH of the system to 10-11 by using 20% KOH aqueous solution, stirring for 10min, separating liquid, sequentially washing an organic layer by using water (50m L× 1) and saturated saline (100m L× 1), and removing anhydrous NaSO₄Drying, filtering and concentrating to obtain (R) -5-methyl-3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4]]Triazole [4,3-a ]]Pyrazine 7.1g as a colorless oil in 34% yield.

ee％(HPLC):99％.

Example 20

D-malic acid (15g,0.1mol) and acetone (400m L) were added to a 1L single-necked flask, stirred to be clear, 5-methyl-3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazine racemate (20.6g,0.1mol) was added in portions at room temperature, and after the addition, stirred at room temperature for 6 hours, filtered, and the filter cake was washed with acetone (50m L× 2).

Transferring the obtained salt into a 1L single-mouth bottle, adding isopropanol 200m L, stirring, heating to reflux, dissolving, stirring for 6h, naturally cooling to room temperature, stirring for 0.5h, and filtering.

Transferring the filter cake to a 500m L single-neck bottle, sequentially adding dichloromethane (150m L) and water (100m L), stirring, cooling the system to 0-10 deg.C, adjusting the pH of the system to 10-11 with 20% NaOH aqueous solution, stirring for 10min, separating, sequentially washing the organic layer with water (50m L× 1) and saturated salt solution (100m L× 1), and removing anhydrous NaSO₄Drying, filtering and concentrating to obtain (R) -5-methyl-3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4]]Triazole [4,3-a ]]Pyrazine 6.9g as a colorless oil in 33% yield.

ee％(HPLC):99.3％.

Example 21

Preparation of (R) -5-methyl-3- (pyridin-2-yl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazine (B-2)

5-methyl-3- (pyridin-2-yl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazine by the method of reference CN 106749261A.

D- (+) -di-p-methylbenzoyl tartaric acid (39g,0.1mol) and methanol (400m L) were added to a 1L single-necked flask, stirred to be clear, the racemate of 5-methyl-3- (pyridin-2-yl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazine (21.5g,0.1mol) was added in portions at room temperature, after the addition was completed, stirred at room temperature for 9 hours, filtered, and the filter cake was washed with methanol (50m L× 2).

Transferring the obtained salt to a 1L single-neck bottle, adding methanol 150m L, stirring, heating to reflux, dissolving clearly, stirring for 2h, naturally cooling to room temperature, stirring for 0.5h, filtering, transferring the filter cake to a 500L single-neck bottle, adding methanol 150m L, stirring, heating to reflux, dissolving clearly, stirring for 2h, naturally cooling to room temperature, stirring for 0.5h, and filtering.

Transferring the filter cake to a 500m L single-neck bottle, sequentially adding dichloromethane (150m L) and water (100m L), stirring, cooling the system to 0-10 deg.C, adjusting the pH of the system to 10-11 with 20% NaOH aqueous solution, stirring for 10min, separating, sequentially washing the organic layer with water (50m L× 1) and saturated salt solution (100m L× 1), and removing anhydrous NaSO₄Drying, filtering and concentrating to obtain (R) -5-methyl-3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4]]Triazole [4,3-a ]]Pyrazine was 4.7g as a colorless oil in 22% yield.

After the resolved B-2 is further condensed with 2-fluoro-5- ((4-oxo-3, 4-dihydrophthalazin-1-yl) methyl) benzoic acid (prepared according to CN 106749261A), the liquid phase peak-out time of the R configuration compound S13- (+) prepared and separated by a chiral column reported in the document CN106749261A is consistent.

¹H NMR(CDCl₃,:ppm):1.33(d,J＝6.8Hz,3H),3.03(d,J＝12Hz,1H),3.17(d,J＝4.2Hz,1H),3.63(d,J＝7.0Hz,1H),4.02(d,J＝5.2Hz,1H),4.27(d,J＝3.6Hz,1H),4.68(ddd,J＝6.8,4.4,2.2Hz,1H),6.51(dd,J＝3.4,1.8Hz,1H),7.20(d,J＝1.6Hz,1H),7.00(d,J＝3.4Hz,1H),8.75(d,J＝2.0Hz,1H).ESI-MS:216[M+H⁺].

ee％(HPLC):99.6％.

Example 22

D-mandelic acid (16g,0.1mol) and ethanol (400m L) were added to a 1L single-necked flask, stirred to be clear, 5-methyl-3- (pyridin-2-yl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazine racemate (21.5g,0.1mol) was added in portions at room temperature, after the addition was completed, stirred at room temperature for 5 hours, filtered, and the filter cake was washed with ethanol (50m L× 2).

Transferring the obtained salt into a 1L single-mouth bottle, adding methanol 150m L, stirring, heating to reflux, dissolving, stirring for 2h, naturally cooling to room temperature, stirring for 0.5h, and filtering.

Transferring the filter cake to a 500m L single-neck bottle, sequentially adding dichloromethane (150m L) and water (100m L), stirring, cooling the system to 0-10 deg.C, adjusting the pH of the system to 10-11 with 50% sodium carbonate aqueous solution, stirring for 10min, separating, sequentially washing the organic layer with water (50m L× 1) and saturated salt solution (100m L× 1), and removing anhydrous NaSO₄Drying, filtering and concentrating to obtain (R) -5-methyl-3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4]]Triazole [4,3-a ]]Pyrazine 7.9g as a colorless oil in 37% yield.

ee％(HPLC):98.8％.

Example 23

Preparation of (R) -2- (5-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) thiazole (B-3)

2- (5-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) thiazole by the method of reference CN 106749261A.

D- (+) -dibenzoyltartaric acid (37g,0.1mol) and dichloromethane (400m L) were added to a 1L single-necked flask, stirred to be clear, the racemate (22.1g,0.1mol) of 2- (5-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) thiazole was added in portions at room temperature, after completion of the addition, stirred at room temperature for 8 hours, filtered, and the filter cake was washed with dichloromethane (50m L× 2).

Transferring the obtained salt into a 1L single-neck bottle, adding ethanol 150m L and water 30m L, stirring, heating to reflux, dissolving, stirring for 2 hours, naturally cooling to room temperature, stirring for 0.5 hour, filtering, transferring the filter cake into a 500L single-neck bottle, adding ethanol 100m L and water 20m L, stirring, heating to reflux, dissolving, stirring for 1 hour, naturally cooling to room temperature, stirring for 0.5 hour, and filtering.

Transferring the filter cake to a 500m L single-neck bottle, sequentially adding dichloromethane (150m L) and water (100m L), stirring, cooling the system to 0-10 deg.C, adjusting the pH of the system to 10-11 with 20% NaOH aqueous solution, stirring for 10min, separating, sequentially washing the organic layer with water (50m L× 1) and saturated salt solution (100m L× 1), and removing anhydrous NaSO₄Drying, filtering and concentrating to obtain (R) -2- (5-methyl-5, 6,7, 8-tetrahydro- [1,2,4]]Triazole [4,3-a ]]Pyrazin-3-yl) thiazole 5.1g as a colorless oil in 23% yield.

Chiral liquid phase conditions:

chromatographic column, CHIRA L PAK-AD-H, mobile phase, ethanol/n-hexane (40:60), wavelength of 220nm

Retention time: t is t_R(R)＝12.8min,t_R(S)＝14.9min¹H NMR(CDCl₃,:ppm):1.13(d,J＝6.5Hz,3H),2.08(s,2H),2.96(dd,J＝12,3.5Hz,1H),3.2(dd,J＝13.4,4.5Hz,1H),3.84(d,J＝4.0Hz,9H),4.10(d,J＝16Hz,1H),4.23(d,J＝16.2Hz,1H),4.46(dt,J＝7.8,5.6Hz,1H),6.81(s,2H).ESI-MS:222[M+H⁺].

ee％(HPLC):99.4％.

Example 24

D- (+) -di-p-methylbenzoyl tartaric acid (39g,0.1mol) and chloroform (400m L) were added to a 1L single-necked flask, stirred to be clear, the racemate (22.1g,0.1mol) of 2- (5-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) thiazole was added in portions at room temperature, after completion of addition, stirred at room temperature for 6 hours, filtered, and the filter cake was washed with chloroform (50m L× 2).

Transferring the obtained salt to a 1L single-neck bottle, adding methanol 150m L, stirring, heating to reflux, dissolving clearly, stirring for 2h, naturally cooling to room temperature, stirring for 0.5h, filtering, transferring the filter cake to a 500L single-neck bottle, adding methanol 100m L, stirring, heating to reflux, dissolving clearly, stirring for 1h, naturally cooling to room temperature, stirring for 0.5h, and filtering.

Transferring the filter cake to a 500m L single-neck bottle, sequentially adding dichloromethane (150m L) and water (100m L), stirring, cooling the system to 0-10 deg.C, adjusting the pH of the system to 10-11 with 20% NaOH aqueous solution, stirring for 10min, separating, sequentially washing the organic layer with water (50m L× 1) and saturated salt solution (100m L× 1), and removing anhydrous NaSO₄Drying, filtering and concentrating to obtain (R) -2- (5-methyl-5, 6,7, 8-tetrahydro- [1,2,4]]Triazole [4,3-a ]]Pyrazin-3-yl) thiazole 5.5g as a colorless oil in 25% yield.

ee％(HPLC):99.1％.

Example 25

Adding D- (+) -camphorsulfonic acid (25g,0.11mol) and ethanol (400m L) into a 1L single-mouth bottle, stirring to be clear, adding 2- (5-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) thiazole racemate (22.1g,0.1mol) in batches at room temperature, heating to reflux after the addition is finished, stirring for 2h, cooling to room temperature, filtering, and washing a filter cake with ethanol (50m L× 2).

Transferring the obtained salt into a 1L single-mouth bottle, adding ethanol 150m L and water 10m L, stirring, heating to reflux, dissolving, stirring for 2h, naturally cooling to room temperature, stirring for 0.5h, and filtering.

Transferring the filter cake to a 500m L single-neck bottle, sequentially adding dichloromethane (150m L) and water (100m L), stirring, cooling the system to 0-10 deg.C, adjusting the pH of the system to 10-11 with 20% NaOH aqueous solution, stirring for 10min, separating, sequentially washing the organic layer with water (50m L× 1) and saturated salt solution (100m L× 1), and removing anhydrous NaSO₄Drying, filtering and concentrating to obtain (R) -2- (5-methyl-5, 6,7, 8-tetrahydro- [1,2,4]]Triazole [4,3-a ]]Pyrazin-3-yl) thiazole 9.1g as a colorless oil in 41% yield.

ee％(HPLC):99％.

Example 26

Adding D- (+) -camphoric acid (23g,0.12mol) and isopropanol (400m L) into a 1L single-mouth bottle, stirring to be clear, adding 2- (5-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) thiazole racemate (22.1g,0.1mol) in batches at room temperature, heating to reflux after the addition is finished, stirring for 3h, cooling to room temperature, filtering, and washing a filter cake with isopropanol (50m L× 2).

Transferring the obtained salt into a 1L single-neck bottle, adding methanol 150m L, stirring, heating to reflux, dissolving clearly, stirring for 2h, naturally cooling to room temperature, stirring for 0.5h, filtering, transferring the product into a 500L single-neck bottle, adding ethanol 150m L and water 10m L, stirring, heating to reflux, dissolving clearly, stirring for 1h, naturally cooling to room temperature, stirring for 0.5h, and filtering.

Transferring the filter cake to a 500m L single-neck bottle, sequentially adding dichloromethane (150m L) and water (100m L), stirring, cooling the system to 0-10 ℃, adjusting the pH of the system to 10-11 by using a 20% L iOH aqueous solution, stirring for 10min, separating liquid, sequentially washing an organic layer by using water (50m L× 1) and saturated saline (100m L× 1), and removing anhydrous NaSO₄Drying, filtering and concentrating to obtain (R) -2- (5-methyl-5, 6,7, 8-tetrahydro- [1,2,4]]Triazole [4,3-a ]]Pyrazin-3-yl) thiazole 3.9g as a colorless oil in 18% yield.

ee％(HPLC):98.9％.

Example 27

D-malic acid (16g,0.12mol) and dichloromethane (600m L) were added to a 1L single-neck flask, stirred to be clear, the racemate of 2- (5-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) thiazole (22.1g,0.1mol) was added in portions at room temperature, after the addition, the mixture was stirred at room temperature for 7 hours, filtered, and the filter cake was washed with dichloromethane (50m L× 2).

Transferring the obtained salt into a 1L single-neck bottle, adding methanol 150m L, stirring, heating to reflux, dissolving clearly, stirring for 2h, naturally cooling to room temperature, stirring for 0.5h, filtering, transferring the product into a 500L single-neck bottle, adding ethanol 150m L and water 15m L, stirring, heating to reflux, dissolving clearly, stirring for 1h, naturally cooling to room temperature, stirring for 0.5h, and filtering.

Transferring the filter cake to a 500m L single-neck bottle, sequentially adding dichloromethane (150m L) and water (100m L), stirring, cooling the system to 0-10 deg.C, adjusting the pH of the system to 10-11 with 20% NaOH aqueous solution, stirring for 10min, separating, sequentially washing the organic layer with water (50m L× 1) and saturated salt solution (100m L× 1), and removing anhydrous NaSO₄Drying, filtering and concentrating to obtain (R) -2- (5-methyl-5, 6,7, 8-tetrahydro- [1,2,4]]Triazole [4,3-a ]]Pyrazin-3-yl) thiazole 4.2g as a colorless oil in 19% yield.

ee％(HPLC):99.7％.

Example 28

D- (-) -citramalic acid (19g,0.13mol) and chloroform (500m L) were added to a 1L single-necked flask, stirred to be clear, the racemate (22.1g,0.1mol) of 2- (5-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) thiazole was added in portions at room temperature, after completion of the addition, stirred at room temperature for 9 hours, filtered, and the filter cake was washed with chloroform (50m L× 2).

Transferring the obtained salt into a 1L single-mouth bottle, adding ethanol 150m L and water 25m L, stirring, heating to reflux, dissolving, stirring for 2h, naturally cooling to room temperature, stirring for 0.5h, and filtering.

Transferring the filter cake to a 500m L single-neck bottle, sequentially adding dichloromethane (150m L) and water (100m L), stirring, cooling the system to 0-10 deg.C, adjusting the pH of the system to 10-11 with 20% NaOH aqueous solution, stirring for 10min, separating, sequentially washing the organic layer with water (50m L× 1) and saturated salt solution (100m L× 1), and removing anhydrous NaSO₄Drying, filtering and concentrating to obtain (R) -2- (5-methyl-5, 6,7, 8-tetrahydro- [1,2,4]]Triazole [4,3-a ]]Pyrazin-3-yl) thiazole 7.8g as a colorless oil in 35% yield.

ee％(HPLC):99％.

Example 29

D-mandelic acid (18g,0.12mol) and acetone (500m L) were added to a 1L single-necked flask, stirred to be clear, the racemate (22.1g,0.1mol) of 2- (5-methyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazin-3-yl) thiazole was added in portions at room temperature, after the addition, the mixture was stirred at room temperature for 4 hours, filtered, and the filter cake was washed with acetone (50m L× 2).

Transferring the obtained salt into a 1L single-mouth bottle, adding ethanol 150m L and water 25m L, stirring, heating to reflux, dissolving, stirring for 2 hours, naturally cooling to room temperature, stirring for 0.5 hour, filtering, transferring the product into a 500m L single-mouth bottle, adding ethanol 100m L and water 15m L, stirring, heating to reflux, dissolving, stirring for 2 hours, naturally cooling to room temperature, stirring for 0.5 hour, and filtering.

Transferring the filter cake to a 500m L single-neck bottle, sequentially adding dichloromethane (150m L) and water (100m L), stirring, cooling the system to 0-10 deg.C, adjusting the pH of the system to 10-11 with 20% NaOH aqueous solution, stirring for 10min, separating, sequentially washing the organic layer with water (50m L× 1) and saturated salt solution (100m L× 1), and removing anhydrous NaSO₄Drying, filtering and concentrating to obtain (R) -2- (5-methyl-5, 6,7, 8-tetrahydro- [1,2,4]]Triazole [4,3-a ]]Pyrazin-3-yl) thiazole 3.5g as a colorless oil in 16% yield.

ee％(HPLC):99.8％。

Claims

1. The chiral resolution method of the piperazinotriazole derivative is characterized by comprising the following steps: taking chiral acid as a resolving reagent, carrying out acid-base salt formation reaction on a racemate compound (I) and the chiral acid to obtain a mixture of diastereoisomers, collecting a single chiral isomer from the mixture, and dissociating under an alkaline condition to obtain a piperazinotriazole derivative (II) with an R configuration:

wherein:

R₁is methyl, R₂Is hydrogen;

or R₁Is hydrogen, R₂Is methyl;

R₃represents trifluoromethyl, heteroaryl or methyl-substituted heteroaryl;

the chiral acid comprises D- (+) -dibenzoyl tartaric acid, D- (+) -di-p-methylbenzoyl tartaric acid, D- (+) -camphorsulfonic acid, D- (+) -camphoric acid, D-malic acid, D- (-) -citramalic acid or D-mandelic acid.

2. The method of claim 1, wherein said heteroaryl group comprises a pyridyl, thiazolyl, or 1,2, 4-thiadiazolyl group.

3. The method according to claim 1, wherein the salt of the racemic compound (I) with a chiral acid is D- (+) -dibenzoyl tartrate, D- (+) -di-p-methylbenzoyl tartrate, D- (+) -camphorsulfonate, D- (+) -camphorate, D-malate, D- (-) -citramalate, or D-mandelate.

4. The method according to claim 1, wherein the solvent for acid-base salt formation is methanol, ethanol, isopropanol, n-butanol, acetone, tetrahydrofuran, dichloromethane or chloroform.

5. The method of claim 1, wherein the collection of the single chiral isomer from the mixture is a recrystallization method.

6. The method according to claim 1, wherein the ratio of the amount (mol) of the compound (I) salified by acid and base to the amount (mol) of the resolving agent is 1: 1.0-1: 1.5;

the volume ratio of the dosage (g) of the compound (I) to the dosage (m L) of the solvent is 1: 5-1: 30.

7. The method according to claim 4, wherein the volume ratio of the amount (g) of the salt formed by the compound (I) and the resolving agent to the amount (m L) of the recrystallization solvent is 1:5 to 1: 30.

8. The chiral resolution method of the piperazinotriazole derivative is characterized by comprising the following steps:

(1) carrying out salt forming reaction on a racemate of the piperazinotriazole derivative and chiral acid in an organic solvent to obtain a salt of the piperazinotriazole derivative racemate, wherein the reaction temperature is 20-100 ℃, and the reaction time is 1-9 h;

(2) recrystallizing and purifying the piperazine triazole derivative racemate separated in the step (1) and a salt formed by chiral acid in a solvent for 1-2 times;

9. The method according to claim 8, wherein the base in step (3) is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, and sodium bicarbonate. The organic solvent in the step (1) is selected from methanol, ethanol, isopropanol, n-butanol, acetone, tetrahydrofuran, dichloromethane or chloroform.

10. The method according to claim 8, wherein the ratio of the amount (mol) of the compound (I) salified by acid and base to the amount (mol) of the resolving agent is 1: 1.0-1: 1.5;

the volume ratio of the dosage (g) of the salt formed by the compound (I) and the resolving agent to the dosage (m L) of the recrystallization solvent is 1: 5-1: 30.

11. The method according to any one of claims 1 to 10, wherein the piperazinotriazole derivative with R configuration comprises: