Preparation method of heteroatom-containing chiral amine

Abstract

The invention belongs to the technical field of organic synthesis, and provides a preparation method of heteroatom-containing chiral amine. The preparation method provided by the invention comprises the following steps: mixing imine containing heteroatoms, an ammonia borane compound, a chiral amino benzimidazole manganese catalyst and a solvent, and carrying out asymmetric transfer hydrogenation reaction to obtain the chiral amine containing heteroatoms. According to the preparation method disclosed by the invention, the optical activity of the heteroatom-containing chiral amine is improved, and data of the embodiment shows that the optical activity of the obtained heteroatom-containing chiral amine is 85-99% ee, and the separation yield is 65-99%; meanwhile, compared with an existing chiral phosphine ligand precious metal catalytic system, the preparation method has the advantages that the chiral amino benzimidazole manganese catalyst is used as the catalyst, so that the production cost and environmental pollution of the catalyst are reduced, and green preparation of key chiral drug intermediates can be realized.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a method for preparing heteroatom-containing chiral amine. Background Art

[0002] Chiral amines containing heteroatoms (N, O, S) are a very important class of chiral amine compounds, widely present in natural products, bioactive molecules, and pharmaceutical molecules. For example, tovorafenib is a type II RAF kinase inhibitor targeting mutant BRAF V600E, wild-type BRAF, and wild-type CRAF kinases, demonstrating antitumor activity in cultured cells and xenograft tumor models harboring BRAF V600E and V600D mutations, as well as in xenograft models harboring BRAF fusions. Common methods for preparing chiral amines include asymmetric hydrogenation of imines or enamines, asymmetric reductive amination of aldehydes or ketones, asymmetric C-H bond amination, and asymmetric hydroamination of alkenes. Asymmetric hydrogenation of imines is one of the most direct and efficient methods for obtaining chiral amines. However, due to the coordination effect of heteroatoms and the instability of aromatic heterocycles, asymmetric hydrogenation of heteroatom-containing imines has been rarely reported, and has primarily focused on noble metal catalytic systems with chiral phosphine ligands. For example, in 2018, Zhang Xumu's group achieved a reductive amination of 2-acetylfuran using chiral bisphosphine ligands and ruthenium acetate, achieving an ee value of 80%. This suggests that the optical activity of heteroatom-containing amines needs to be further improved. Summary of the Invention

[0003] In view of this, an object of the present invention is to provide a method for preparing heteroatom-containing chiral amines, wherein the obtained heteroatom-containing chiral amines have high optical activity.

[0004] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0005] The present invention provides a method for preparing a heteroatom-containing chiral amine, comprising the following steps:

[0006] Mixing an imine containing a heteroatom having a structure shown in Formula 1, an ammonia borane compound, a chiral aminobenzimidazole manganese catalyst, and a solvent, and performing an asymmetric transfer hydrogenation reaction to obtain the heteroatom-containing chiral amine, wherein the heteroatom includes one or more of N, O, and S;

[0007]

[0008] In formula 1, Ar 1 and Ar 2 are independently aryl, substituted aryl, aromatic heterocycle or substituted aromatic heterocycle;

[0009] R is an alkyl group, an aryl group or an aromatic heterocycle;

[0010] Ar 1 、Ar 2 and at least one of R is an aromatic heterocycle or a substituted aromatic heterocycle.

[0011] Preferably, the Ar 1 、Ar 2 and the aromatic heterocyclic ring in R is independently furan Thiophene Benzothiophene Benzofuran Pyridine Pyrazine Pyrimidine or quinoline

[0012] Preferably, the Ar 1 and Ar 2 The substituents in the substituted aryl group and the substituents in the substituted aromatic heterocycle independently include alkyl, halogen, alkoxy, cyano, nitro, trifluoromethyl, allyl or alkynyl, and the number of carbon atoms of the alkyl group is 1 to 6.

[0013] Preferably, the ammonia borane compound includes one or more of ammonia borane, dimethylamine borane, diisopropylamine borane, morpholine borane and pyridine borane.

[0014] Preferably, the chiral aminobenzimidazole manganese catalyst has a structure shown in Formula I or Formula II:

[0015]

[0016] In Formula I, R 1 is tert-butyl, isopropyl, phenyl, benzyl or adamantyl;

[0017] In Formula I and Formula II, R 2 are independently hydrogen, methyl, ethyl, isopropyl or benzyl; R 3 are independently hydrogen, aryl or substituted aryl, R 4 are independently hydrogen, aryl, or substituted aryl.

[0018] Preferably, the chiral aminobenzimidazole manganese catalyst has the following structure:

[0019]

[0020] Preferably, the solvent comprises one or more of methanol, ethanol, isopropanol, ethyl acetate, dichloromethane, n-hexane, ethyl ether, isopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, cyclohexyl methyl ether, tert-butyl methyl ether and water.

[0021] Preferably, the molar ratio of the heteroatom-containing imine to the aminoborane compound is 1:(0.1-3).

[0022] Preferably, the molar ratio of the chiral aminobenzimidazole manganese catalyst to the heteroatom-containing imine is (0.001-5):100.

[0023] Preferably, the temperature of the asymmetric transfer hydrogenation reaction is -80-80°C, and the time is 5 minutes to 48 hours.

[0024] The present invention provides a method for preparing heteroatom-containing chiral amine.

[0025] The preparation method provided by the present invention improves the optical activity of heteroatom-containing chiral amines. Data from the examples show that the optical activity of the obtained heteroatom-containing chiral amines is 85-99% ee, and the separation yield is 65-99%. At the same time, compared with the existing noble metal catalytic system of chiral phosphine ligands, the preparation method of the present invention uses a chiral aminobenzimidazole manganese catalyst as a catalyst, which reduces the production cost and environmental pollution of the catalyst, and can achieve green preparation of key chiral drug intermediates. DETAILED DESCRIPTION

[0026] The present invention provides a method for preparing a heteroatom-containing chiral amine, comprising the following steps:

[0027] Mixing an imine containing a heteroatom having a structure shown in Formula 1, an ammonia borane compound, a chiral aminobenzimidazole manganese catalyst, and a solvent, and performing an asymmetric transfer hydrogenation reaction to obtain the heteroatom-containing chiral amine, wherein the heteroatom includes one or more of N, O, and S;

[0028]

[0029] In formula 1, Ar 1 and Ar 2 are independently aryl, substituted aryl, aromatic heterocycle or substituted aromatic heterocycle;

[0030] R is an alkyl group, an aryl group or an aromatic heterocycle;

[0031] Ar 1 、Ar 2 and at least one of R is an aromatic heterocycle or a substituted aromatic heterocycle.

[0032] Unless otherwise specified, the raw materials used in the present invention are preferably commercially available products.

[0033] In the present invention, in Formula 1, Ar 1 and Ar 2are independently aryl, substituted aryl, aromatic heterocycle or substituted aromatic heterocycle; R is alkyl, aryl or aromatic heterocycle, preferably alkyl or aryl; Ar 1 、Ar 2 and at least one of R is an aromatic heterocycle or a substituted aromatic heterocycle.

[0034] In the present invention, in Formula 1, Ar 1 and Ar 2 The aryl groups in are independently preferably phenyl or naphthyl, and the naphthyl group is preferably 3-naphthyl.

[0035] In the present invention, the Ar 1 、Ar 2 The aromatic heterocyclic ring in R is preferably furan Thiophene Benzothiophene Benzofuran Pyridine Pyrazine Pyrimidine or quinoline

[0036] In the present invention, the Ar 1 and Ar 2 The substituents in the substituted aryl group and the substituents in the substituted aromatic heterocycle independently preferably include alkyl, halogen, alkoxy, cyano, nitro, trifluoromethyl, allyl or alkynyl, and the number of carbon atoms in the alkyl group is preferably 1-6.

[0037] In the present invention, the number of carbon atoms in the alkyl group in R is preferably 1 to 6, and more preferably a methyl group.

[0038] In a specific embodiment of the present invention, the Ar 1 Specifically, phenyl, naphthyl, pyridyl, benzofuranyl, benzothienyl, pyrazinyl, o-methylphenyl, 2-bromo-6-pyridyl or pyrimidinyl is preferred.

[0039] In a specific embodiment of the present invention, the Ar 2 Specifically, a thienyl group, a furyl group, a pyridyl group or a phenyl group is preferred.

[0040] In one embodiment of the present invention, R is preferably a methyl group or an aryl group.

[0041] In a specific embodiment of the present invention, the heteroatom-containing imine specifically has the following structure:

[0042]

[0043] In the present invention, the ammonia borane compound preferably includes one or more of ammonia borane, dimethylamine borane, diisopropylamine borane, morpholine borane and pyridine borane, and is more preferably ammonia borane.

[0044] In the present invention, the chiral aminobenzimidazole manganese catalyst preferably has a structure shown in Formula I or Formula II:

[0045]

[0046] In Formula I, R 1 Preferably tert-butyl, isopropyl, phenyl, benzyl or adamantyl;

[0047] In Formula I and Formula II, R 2 R is independently preferably hydrogen, methyl, ethyl, isopropyl or benzyl; 3 R is independently preferably hydrogen, aryl or substituted aryl, 4 Independently, preferably hydrogen, aryl or substituted aryl.

[0048] In some embodiments of the present invention, in Formula I, R 1 Specifically, tert-butyl is preferred, R 2 Specifically, methyl group is preferred. 3 Specifically, hydrogen or phenyl is preferred, and R 4 Specifically, hydrogen is preferred.

[0049] In some embodiments of the present invention, in Formula II, R 2 Specifically, methyl group is preferred. 3 Specifically, hydrogen or phenyl is preferred, and R 4 Specifically, hydrogen is preferred.

[0050] In some specific embodiments of the present invention, the chiral aminobenzimidazole manganese catalyst has the following structure:

[0051]

[0052] In the present invention, the solvent preferably includes one or more of methanol, ethanol, isopropanol, ethyl acetate, dichloromethane, n-hexane, ether, isopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, cyclohexyl methyl ether, tert-butyl methyl ether and water, and is more preferably tert-butyl methyl ether.

[0053] In the present invention, the molar ratio of the heteroatom-containing imine to the aminoborane compound is preferably 1:(0.1-3), specifically preferably 1:0.1, 1:0.5, 1:1, 1:1.5, 1:2, 1:2.5 or 1:3.

[0054] In the present invention, the molar ratio of the chiral aminobenzimidazole manganese catalyst to the heteroatom-containing imine is (0.001-5):100, specifically preferably 0.001:100, 0.01:100, 0.1:100, 0.5:100, 1:100, 2:100, 3:100, 4:100 or 5:100.

[0055] In the present invention, the temperature of the asymmetric transfer hydrogenation reaction is preferably -80 to 80 ° C, more preferably room temperature, that is, no additional heating or additional cooling is required, and the time is preferably 5 min to 48 h, specifically preferably 5 min, 10 min, 20 min, 0.5 h, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 11 h, 12 h, 13 h, 14 h, 15 h, 16 h, 17 h, 18 h, 19 h, 20 h, 21 h, 22 h, 23 h, 24 h, 27 h, 30 h, 33 h, 36 h, 39 h, 42 h, 45 h or 48 h. In the present invention, the asymmetric transfer hydrogenation reaction is preferably carried out under a protective atmosphere, and the protective atmosphere is preferably argon.

[0056] After the asymmetric transfer hydrogenation reaction, the present invention preferably further comprises: quenching the reaction, performing extraction, and combining the organic phases; drying the organic phases with a desiccant, and then purifying by column chromatography to obtain the heteroatom-containing chiral amine. In the present invention, the reagent for quenching the reaction is preferably a saturated sodium bicarbonate solution. In the present invention, the extractant for the extraction is preferably dichloromethane, and the number of extractions is preferably three. In the present invention, the desiccant is preferably anhydrous sodium sulfate. In the present invention, the eluent for the column chromatography purification is preferably a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of ethyl acetate to petroleum ether in the mixed solvent of ethyl acetate and petroleum ether is preferably 1:0→1:10.

[0057] In the present invention, the preparation formula of the heteroatom-containing chiral amine is as follows:

[0058]

[0059] The preparation method of the heteroatom-containing chiral amine provided by the present invention is described in detail below with reference to the examples, but they should not be construed as limiting the scope of protection of the present invention.

[0060] Example 1

[0061] Under an argon atmosphere, imine 1a (0.5 mmol), ammonia borane (0.5 mmol), Mn-1 (0.01 mmol), and 2 mL of solvent (specifically tert-butyl methyl ether) were added to a 25 mL Shrek tube. The Shrek tube was left to react at room temperature for 2 h. After the reaction, 2 mL of saturated sodium bicarbonate solution was added to quench the reaction. The mixture was extracted three times with 5 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and then purified by flash column chromatography (eluent: a mixed solvent of ethyl acetate and petroleum ether, with a volume ratio of ethyl acetate to petroleum ether of 1:0 → 1:10) to obtain chiral amine 2a. The product was a colorless liquid with a 92% isolated yield. The optical rotation value was:

[0062] 1 H NMR (400MHz, CDCl3) δ7.39-7.28(m,4H),7.27-7.19(m,1H),7.16(dd,J=5.2,1.2Hz,1H),6.90(d d,J=5.2,1.2Hz,1H),6.86-6.79(m,1H),3.89-3.73(m,3H),1.68(s,1H),1.34(d,J=6.8Hz,3H).

[0063] 13 C NMR (101MHz, CDCl3) δ145.29,144.51,128.61,127.12,126.82,126.68,124.79,124.32,57.14,46.15,24.49.

[0064] The enantioselectivity of the obtained 2a was determined by HPLC, and the test result was 98% ee. The test conditions were: Chiralcel AD-H column, 210 nm, hexane / i-PrOH = 98 / 2; flow rate: 1.0 mL / min; t1 = 5.997 min, t2 = 6.566 min, t R =6.029min(minor), t R =6.584min(major).

[0065]

[0066] Example 2

[0067] Under an argon atmosphere, imine 1b (0.5 mmol), ammonia borane (0.5 mmol), Mn-1 (0.01 mmol), and 2 mL of solvent (specifically tert-butyl methyl ether) were added to a 25 mL Shrek tube. The Shrek tube was left to react at room temperature for 2 h. After completion of the reaction, 2 mL of saturated sodium bicarbonate solution was added to quench the reaction. The mixture was extracted three times with 5 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and then purified by flash column chromatography (eluent: a mixed solvent of ethyl acetate and petroleum ether, with a volume ratio of ethyl acetate to petroleum ether of 1:0 → 1:10) to obtain chiral amine 2b. The product was a colorless liquid with a 92% isolated yield. The optical rotation values ​​were:

[0068] 1 H NMR (400MHz, CDCl3) δ7.37-7.28(m,5H),7.27-7.19(m,1H),6.27(dd,J=2.8,1.2Hz,1H),6.08(d,J=2 .8Hz, 1H), 3.77 (q, J = 6.8Hz, 1H), 3.60 (dd, J = 36.4, 14.4Hz, 2H), 1.76 (s, 1H), 1.34 (d, J = 6.4Hz, 3H).

[0069] 13 C NMR (101MHz, CDCl3) δ154.07,145.12,141.78,128.55,127.09,126.83,110.12,106.86,57.12,44.04,24.35.

[0070] The enantioselectivity of the obtained 2b was determined by HPLC, and the test result was 92% ee. The test conditions were: Chiralcel AD-H column, 210 nm, hexane / i-PrOH = 98 / 2; flow rate: 1.0 mL / min; t1 = 5.689 min, t2 = 6.652 min, t R =5.704min(minor), t R =6.675min(major).

[0071]

[0072] Example 3

[0073] Under an argon atmosphere, imine 1c (0.5 mmol), ammonia borane (0.5 mmol), Mn-1 (0.01 mmol), and 2 mL of solvent (specifically tert-butyl methyl ether) were added to a 25 mL Shrek tube. The Shrek tube was left to react at room temperature for 2 h. After completion of the reaction, 2 mL of saturated sodium bicarbonate solution was added to quench the reaction. The mixture was extracted three times with 5 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and then purified by flash column chromatography (eluent: a mixed solvent of ethyl acetate and petroleum ether, with a volume ratio of ethyl acetate to petroleum ether of 1:0 → 1:10) to obtain chiral amine 2c. The product was a colorless liquid with a 70% isolated yield. The optical rotation values ​​were:

[0074] 1 H NMR (400MHz, CDCl3) δ8.54(d,J=4.4Hz,1H),7.58(td,J=8.0,2.0Hz,1H),7.40-7.29(m,4H),7. 28-7.07(m,3H),3.82(q,J=6.4Hz,1H),3.79-3.70(m,2H),2.40(s,1H),1.41(d,J=6.8Hz,3H).

[0075] 13 C NMR (101MHz, CDCl3) δ159.82,149.30,145.40,136.32,128.48,126.98,126.79,122.43,121.85,58.04,53.10,24.48.

[0076] The enantioselectivity of the obtained 2c was determined by HPLC, and the test result was 95% ee. The test conditions were: Chiralcel AD-H column, 210 nm, hexane / i-PrOH = 85 / 15; flow rate: 1.0 mL / min; t1 = 4.879 min, t2 = 5.230 min, t R =4.868min(minor), t R =5.203min(major).

[0077]

[0078] Example 4

[0079] Under an argon atmosphere, imine 1d (0.5 mmol), ammonia borane (0.5 mmol), Mn-1 (0.01 mmol), and 2 mL of solvent (specifically tert-butyl methyl ether) were added to a 25 mL Shrek tube. The Shrek tube was left to react at room temperature for 2 h. After completion of the reaction, 2 mL of saturated sodium bicarbonate solution was added to quench the reaction. The mixture was extracted three times with 5 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and then purified by flash column chromatography (eluent: a mixed solvent of ethyl acetate and petroleum ether, with a volume ratio of ethyl acetate to petroleum ether of 1:0 → 1:10) to obtain chiral amine 2d. The product was a colorless liquid with an 81% isolated yield. The optical rotation values ​​were:

[0080] 1 H NMR (400MHz, CDCl3) δ7.81(dd,J=8.4,5.6Hz,3H),7.74(s,1H),7.49(dd,J=8.4,1.6Hz,1H),7.47-7.38(m,2H),7.17(dd,J=5.2,0.8Hz ,1H),6.90(dd,J=4.8,3.2Hz,1H),6.82(d,J=3.2Hz,1H),3.99(q,J=6.4Hz,1H),3.90-3.73(m,2H),1.77(s,1H),1.41(d,J=6.4Hz,3H).

[0081] 13 C NMR (101MHz, CDCl3) δ144.48,142.69,133.60,133.00,128.49,127.89,127.80, 126.74,126.11,125.65,125.58,125.00,124.88,124.39,57.25,46.19,24.48.

[0082] The enantioselectivity of 2d was determined by HPLC, and the result was 86% ee. The test conditions were: Chiralcel OD-H column, 254 nm, hexane / i-PrOH = 97 / 3; flow rate: 1.0 mL / min; t1 = 6.819 min, t2 = 7.248 min, t R =6.798min(minor), t R =7.205min(major).

[0083]

[0084] Example 5

[0085] Under an argon atmosphere, imine 1e (0.5 mmol), ammonia borane (0.5 mmol), Mn-1 (0.01 mmol), and 2 mL of solvent (specifically tert-butyl methyl ether) were added to a 25 mL Shrek tube. The Shrek tube was left to react at room temperature for 2 h. After completion of the reaction, 2 mL of saturated sodium bicarbonate solution was added to quench the reaction. The mixture was extracted three times with 5 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and then purified by flash column chromatography (eluent: a mixed solvent of ethyl acetate and petroleum ether, with a volume ratio of ethyl acetate to petroleum ether of 1:0 → 1:10) to obtain chiral amine 2e. The product was a colorless liquid with a 92% isolated yield. The optical rotation values ​​were:

[0086] 1 H NMR (400MHz, CDCl3) δ8.55(d,J=2.0Hz,1H),7.62(t,J=7.2Hz,1H),7.31(d,J=7.6Hz,1H),7.21-7.06(m ,2H),6.96-6.76(m,2H),3.93(d,J=6.4Hz,1H),3.88-3.72(m,2H),2.19(s,1H),1.38(d,J=6.4Hz,3H).

[0087] 13 C NMR (101MHz, CDCl3) δ164.24,149.42,144.32,136.54,126.57,124.71,124.26,121.99,121.32,58.26,46.30,22.89.

[0088] HRMS(ESI)[M+H] + :calculated for[C 17 H 18 NS] + :268.1154,found:268.1148.

[0089] The enantioselectivity of the obtained 2e was determined by HPLC, and the test result was 94% ee. The test conditions were: Chiralcel AD-H column, 210 nm, hexane / i-PrOH = 90 / 10; flow rate: 1.0 mL / min; t1 = 6.454 min, t2 = 6.966 min, t R =6.444min(major), t R =7.009min(minor).

[0090]

[0091] Example 6

[0092] Under an argon atmosphere, imine 1f (0.5 mmol), ammonia borane (0.5 mmol), Mn-1 (0.01 mmol), and 2 mL of solvent (specifically tert-butyl methyl ether) were added to a 25 mL Shrek tube. The Shrek tube was left to react at room temperature for 2 h. After completion of the reaction, 2 mL of saturated sodium bicarbonate solution was added to quench the reaction. The mixture was extracted three times with 5 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and then purified by flash column chromatography (eluent: a mixed solvent of ethyl acetate and petroleum ether, with a volume ratio of ethyl acetate to petroleum ether of 1:0 → 1:10) to obtain chiral amine 2f. The resulting product was a white solid with a 99% isolated yield and an optical rotation value of:

[0093] 1 H NMR (400MHz, CDCl3) δ7.78(d,J=8.0Hz,1H),7.66(d,J=7.6Hz,1H),7.34-7.21(m,2H),7.17(dd,J=4.8,0.6Hz,1H),7.11(s,1H),6. 91(dd,J=4.8,3.6Hz,1H),6.86(d,J=2.8Hz,1H),4.19(q,J=6.8Hz,1H),3.92(q,J=14.4Hz,2H),1.74(s,1H),1.48(d,J=6.8Hz,3H).

[0094] 13 C NMR (101MHz, CDCl3) δ151.47,144.03,139.85,139.36,126.77,125.10,124.57,124.22,123.95,123.22,122.67,120.37,53.17,45.93,24.65.

[0095] HRMS(ESI)[M+H] + :calculated for[C 12 H 15 N2S] + :219.0950,found:219.0955.

[0096] The enantioselectivity of 2f was determined by HPLC, and the result was 99% ee. The test conditions were: Chiralcel AD-H column, 210 nm, hexane / i-PrOH = 98 / 2; flow rate: 1.0 mL / min; t1 = 9.784 min, t2 = 10.632 min, tR =9.892min(minor), t R =10.657min(major).

[0097]

[0098] Example 7

[0099] Under argon, imine 1f (4.0 mmol), ammonia borane (4.0 mmol), Mn-1 (0.02 mmol), and 10 mL of solvent (specifically tert-butyl methyl ether) were added to a 100 mL Shrek tube. The tube was left to react at room temperature for 12 h. After completion, the reaction was quenched by adding 20 mL of saturated sodium bicarbonate solution and extracted three times with 25 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and purified by flash column chromatography (eluent: a mixed solvent of ethyl acetate and petroleum ether, with a volume ratio of ethyl acetate to petroleum ether of 1:0 → 1:10) to afford chiral amine 2f as a white solid in 99% isolated yield and 99% ee.

[0100] The difference between Examples 6 and 7 is that the reaction substrate is scaled up to gram level, the amount of catalyst is reduced to 0.5%, and the separation yield and enantioselectivity remain unchanged.

[0101] Example 8

[0102] Under an argon atmosphere, 1 g (0.5 mmol) of imine, ammonia borane (0.5 mmol), Mn-1 (0.01 mmol), and 2 mL of solvent (specifically tert-butyl methyl ether) were added to a 25 mL Shrek tube. The Shrek tube was left to react at room temperature for 2 h. After the reaction, 2 mL of saturated sodium bicarbonate solution was added to quench the reaction. The mixture was extracted three times with 5 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and then purified by flash column chromatography (eluent: a mixed solvent of ethyl acetate and petroleum ether, with a volume ratio of ethyl acetate to petroleum ether of 1:0→1:10) to obtain 2 g of chiral amine. The product was a colorless liquid with a 92% isolated yield. The optical rotation value was:

[0103] 1 H NMR (400MHz, CDCl3) δ7.56-7.48(m,1H),7.45(d,J=8.0Hz,1H),7.28-7.10(m,3H),6. 99-6.79(m,2H),6.53(s,1H),4.10-3.80(m,3H),1.87(s,1H),1.49(d,J=6.4Hz,3H).

[0104] 13C NMR (101MHz, CDCl3) δ160.26,154.86,143.98,128.45,126.73,125.06,124.55,123.82,122.73,120.82,111.24,102.81,50.63,45.88,20.64.

[0105] HRMS(ESI)[M+H] + :calculated for[C 15 H 16 NOS] + :258.0947,found:258.0943.

[0106] The enantioselectivity of the obtained 2 g was determined by HPLC, and the test result was 97% ee. The test conditions were: Chiralcel AD-H column, 210 nm, hexane / i-PrOH = 98 / 2; flow rate: 1.0 mL / min; t1 = 8.225 min, t2 = 11.001 min, t R =8.231min(minor), t R =10.738min(major).

[0107]

[0108] Example 9

[0109] Under an argon atmosphere, imine 1h (0.5 mmol), ammonia borane (0.5 mmol), Mn-1 (0.01 mmol), and 2 mL of solvent (specifically tert-butyl methyl ether) were added to a 25 mL Shrek tube and allowed to react at room temperature for 2 h. After completion of the reaction, 2 mL of saturated sodium bicarbonate solution was added to quench the reaction. The mixture was extracted three times with 5 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and then purified by flash column chromatography (eluent: a mixed solvent of ethyl acetate and petroleum ether, with a volume ratio of ethyl acetate to petroleum ether of 1:0→1:10) to obtain chiral amine 2h. The product was a colorless liquid with a 92% isolated yield. The optical rotation value was:

[0110] 1 H NMR (400MHz, Chloroform-d) δ9.44(d,J=1.5Hz,1H),8.64-8.46(m,2H),7.43-7.21(m,1H),7.09-6.96(m,2H),4.95(s,2H),2.44(s,3H).

[0111] 13 C NMR (101MHz, CDCl3) δ166.25,151.84,144.76,143.75,143.47,142.62,126.81,124.33,123.87,51.55,14.06.

[0112] HRMS(ESI)[M+H] + :calculated for[C 11 H 14 N3S]+:220.0903,found:220.0904.

[0113] The enantioselectivity of 2h was determined by HPLC, and the test result was 97% ee. The test conditions were: Chiralcel AD-H column, 254 nm, hexane / i-PrOH = 97 / 3; flow rate: 1.0 mL / min; t1 = 12.299 min, t2 = 14.253 min, t R =12.320min(minor), t R =14.244min(major).

[0114]

[0115] Example 10

[0116] Under an argon atmosphere, imine 1i (0.5 mmol), ammonia borane (0.5 mmol), Mn-1 (0.01 mmol), and 2 mL of solvent (specifically tert-butyl methyl ether) were added to a 25 mL Shrek tube. The Shrek tube was left to react at room temperature for 2 h. After completion of the reaction, 2 mL of saturated sodium bicarbonate solution was added to quench the reaction. The mixture was extracted three times with 5 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and then purified by flash column chromatography (eluent: a mixed solvent of ethyl acetate and petroleum ether, with a volume ratio of ethyl acetate to petroleum ether of 1:0 → 1:10) to obtain chiral amine 2i. The product was a colorless liquid with a 92% isolated yield. The optical rotation values ​​were:

[0117] 1 H NMR (400MHz, CDCl3) δ7.88(d,J=7.8Hz,1H),7.75(d,J=7.3Hz,1H),7.60(d,J=7.2Hz ,2H),7.54-7.32(m,10H),7.23(s,1H),5.25(s,1H),4.20-3.72(m,2H),2.22(s,1H).

[0118] 13 C NMR (101MHz, CDCl3) δ150.24,142.88,140.12,139.86,139.82,128.81,128.60,128. 37,127.84,127.55,127.24,124.23,123.99,123.39,122.56,120.99,62.63,51.73.

[0119] HRMS(ESI)[M+H] + :calculated for[C 22 H 20 NS] + :330.1311,found:330.1316.

[0120] The enantioselectivity of the obtained 2i was determined by HPLC, and the test result was 85% ee. The test conditions were: Chiralcel OJ column, 254 nm, hexane / i-PrOH = 50 / 50; flow rate: 1.0 mL / min; t1 = 21.828 min, t2 = 28.856 min, t R =22.223min(minor), t R =28.425min(major).

[0121]

[0122] Example 11

[0123] Under an argon atmosphere, imine 1j (0.5 mmol), ammonia borane (0.5 mmol), Mn-1 (0.01 mmol), and 2 mL of solvent (specifically tert-butyl methyl ether) were added to a 25 mL Shrek tube. The Shrek tube was left to react at room temperature for 2 h. After completion of the reaction, 2 mL of saturated sodium bicarbonate solution was added to quench the reaction. The mixture was extracted three times with 5 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and then purified by flash column chromatography (eluent: a mixed solvent of ethyl acetate and petroleum ether, with a volume ratio of ethyl acetate to petroleum ether of 1:0 → 1:10) to obtain chiral amine 2j. The product was a colorless liquid with a 92% isolated yield. The optical rotation values ​​were:

[0124] 1H NMR(400MHz, CDCl3) δ7.64(d,J=7.5Hz,1H),7.39-7.05(m,9H),6.30(dd,J=3.1,1 .9Hz,1H),6.18-6.01(m,1H),5.01(s,1H),3.73(s,2H),2.20(s,3H),1.95(s,1H).

[0125] 13 C NMR (101MHz, CDCl3) δ154.00,142.69,141.88,141.07,135.95,130.58,128.48, 128.17,127.11,126.89,126.83,126.28,110.20,107.23,61.47,44.30,19.47.

[0126] HRMS(ESI)[M+H] + :calculated for[C 19 H 20 NO] + :278.1539,found:278.1538.

[0127] The enantioselectivity of 2j was determined by HPLC, and the result was 94% ee. The test conditions were: Chiralcel AD-H column, 254 nm, hexane / i-PrOH = 97 / 3; flow rate: 1.0 mL / min; t1 = 5.138 min, t2 = 5.482 min, t R =5.118min(major), t R =5.476min(minor).

[0128]

[0129] Example 12

[0130] Under an argon atmosphere, imine 1k (0.5 mmol), ammonia borane (0.5 mmol), Mn-1 (0.01 mmol), and 2 mL of solvent (specifically tert-butyl methyl ether) were added to a 25 mL Shrek tube. The Shrek tube was left to react at room temperature for 2 h. After completion of the reaction, 2 mL of saturated sodium bicarbonate solution was added to quench the reaction. The mixture was extracted three times with 5 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and then purified by flash column chromatography (eluent: a mixed solvent of ethyl acetate and petroleum ether, with a volume ratio of ethyl acetate to petroleum ether of 1:0 → 1:10) to obtain chiral amine 2k. The product was a colorless liquid with an 83% isolated yield. The optical rotation values ​​were:

[0131] 1 H NMR(400MHz,Chloroform-d)δ7.40(t,J=7.6Hz,1H),7.29-7.21(m,2H),7.13-7.04(m,1H),6.82(dd,J=5.1 ,3.4Hz,1H),6.77(d,J=3.4Hz,1H),3.83(q,J=6.7Hz,1H),3.74(s,2H),2.03(s,1H),1.28(d,J=6.7Hz,3H).

[0132] 13 C NMR (101MHz, CDCl3) δ166.33,144.03,141.90,138.98,126.64,126.31,124.81,124.40,119.99,57.99,46.33,22.86.

[0133] HRMS(ESI)[M+H] + :calculated for[C 12 H 14 BrN2S]+:297.0056,found:297.0050.

[0134] The enantioselectivity of 2k was determined by HPLC, and the test result was 92% ee. The test conditions were: Chiralcel AD-H column, 254 nm, hexane / i-PrOH = 97 / 3; flow rate: 1.0 mL / min; t1 = 7.421 min, t2 = 7.938 min, t R =7.415min(major), t R =7.910min(minor).

[0135]

[0136] Example 13

[0137] Under an argon atmosphere, imine 1l (0.5 mmol), ammonia borane (0.5 mmol), Mn-1 (0.01 mmol), and 2 mL of solvent (specifically tert-butyl methyl ether) were added to a 25 mL Shrek tube. The Shrek tube was left to react at room temperature for 2 h. After completion of the reaction, 2 mL of saturated sodium bicarbonate solution was added to quench the reaction. The mixture was extracted three times with 5 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and then purified by flash column chromatography (eluent: a mixed solvent of ethyl acetate and petroleum ether, with a volume ratio of ethyl acetate to petroleum ether of 1:0 → 1:10) to obtain chiral amine 2l. A colorless liquid with a 65% isolated yield and optical rotation values ​​were:

[0138] 1 H NMR(400MHz,Chloroform-d)δ9.17(d,J=1.4Hz,1H),8.68(d,J=5.2Hz,1H),7.43(dd,J=5.1,1.4Hz,1H),7.21(dd,J=5.1,1.2H z,1H),6.93(dd,J=5.1,3.4Hz,1H),6.90-6.83(m,1H),3.92(q,J=6.7Hz,1H),3.87(s,2H),2.21(s,1H),1.40(d,J=6.8Hz,3H).

[0139] 13 C NMR (101MHz, CDCl3) δ172.95,158.83,157.23,143.59,126.66,124.98,124.55,118.73,57.71,46.35,22.38.

[0140] The enantioselectivity of the obtained 2l was determined by HPLC, and the test result was 96% ee. The test conditions were: Chiralcel AD-H column, 254 nm, hexane / i-PrOH = 97 / 3; flow rate: 1.0 mL / min; t1 = 7.421 min, t2 = 7.938 min, t R =7.415min(major), t R =7.910min(minor).

[0141]

[0142] Example 14

[0143] The difference from Example 1 is that the catalyst is Mn-2, and the rest is the same as Example 1.

[0144] The results were as follows: the isolated yield was 93%; the enantioselectivity of the obtained 2a was determined by high performance liquid chromatography, and the test result was 85% ee.

[0145] Example 15

[0146] The difference from Example 1 is that the catalyst is Mn-3, and the rest is the same as Example 1.

[0147] The results were as follows: the isolated yield was 94%; the enantioselectivity of the obtained 2a was determined by high performance liquid chromatography, and the test result was 89% ee.

[0148] Example 16

[0149] The difference from Example 1 is that the catalyst is Mn-4, and the rest is the same as Example 1.

[0150] The results were as follows: the isolated yield was 95%; the enantioselectivity of the obtained 2a was determined by high performance liquid chromatography, and the test result was 93% ee.

[0151] Example 17

[0152] The difference from Example 2 is that the catalyst is Mn-2, and the rest is the same as Example 2.

[0153] The results were as follows: the isolated yield was 97%; the enantioselectivity of the obtained 2b was determined by high performance liquid chromatography, and the test result was 90% ee.

[0154] Example 18

[0155] The difference from Example 2 is that the catalyst is Mn-3, and the rest is the same as Example 2.

[0156] The results were as follows: the isolated yield was 95%; the enantioselectivity of the obtained 2b was determined by high performance liquid chromatography, and the test result was 90% ee.

[0157] Example 19

[0158] The difference from Example 2 is that the catalyst is Mn-4, and the rest is the same as Example 2.

[0159] The results were as follows: the isolated yield was 93%; the enantioselectivity of the obtained 2b was determined by high performance liquid chromatography, and the test result was 89% ee.

[0160] Example 20

[0161] The difference from Example 3 is that the catalyst is Mn-2, and the rest is the same as Example 3.

[0162] The results were as follows: the isolated yield was 95%; the enantioselectivity of the obtained 2c was determined by high performance liquid chromatography, and the test result was 89% ee.

[0163] Example 21

[0164] The difference from Example 3 is that the catalyst is Mn-3, and the rest is the same as Example 3.

[0165] The results were as follows: the isolated yield was 94%; the enantioselectivity of the obtained 2c was determined by high performance liquid chromatography, and the test result was 90% ee.

[0166] Example 22

[0167] The difference from Example 3 is that the catalyst is Mn-4, and the rest is the same as Example 3.

[0168] The results were as follows: the isolated yield was 95%; the enantioselectivity of the obtained 2c was determined by high performance liquid chromatography, and the test result was 85% ee.

[0169] Example 23

[0170] The difference from Example 4 is that the catalyst is Mn-2, and the rest is the same as Example 4.

[0171] The results were as follows: the isolated yield was 95%; the enantioselectivity of the obtained 2d was determined by high performance liquid chromatography, and the test result was 93% ee.

[0172] Example 24

[0173] The difference from Example 4 is that the catalyst is Mn-3, and the rest is the same as Example 4.

[0174] The results were as follows: the isolated yield was 97%; the enantioselectivity of the obtained 2d was determined by high performance liquid chromatography, and the test result was 90% ee.

[0175] Example 25

[0176] The difference from Example 4 is that the catalyst is Mn-4, and the rest is the same as Example 4.

[0177] The results were as follows: the isolated yield was 90%; the enantioselectivity of the obtained 2d was determined by high performance liquid chromatography, and the test result was 89% ee.

[0178] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. A method for preparing a heteroatom-containing chiral amine, characterized in that: The following steps are involved: Mixing an imine containing a heteroatom having a structure shown in Formula 1, an ammonia borane compound, a chiral aminobenzimidazole manganese catalyst, and a solvent, and performing an asymmetric transfer hydrogenation reaction to obtain the heteroatom-containing chiral amine, wherein the heteroatom includes one or more of N, O, and S; In formula 1, Ar 1 and Ar 2 are independently aryl, substituted aryl, aromatic heterocycle or substituted aromatic heterocycle; R is an alkyl group, an aryl group or an aromatic heterocycle; Ar 1 、Ar 2 and at least one of R is an aromatic heterocycle or a substituted aromatic heterocycle.

2. The preparation method according to claim 1, characterized in that The Ar 1 、Ar 2 The aromatic heterocyclic ring in R and R is independently furan, thiophene, benzothiophene, benzofuran, pyridine, pyrazine, pyrimidine or quinoline.

3. The preparation method according to claim 1, characterized in that The Ar 1 and Ar 2 The substituents in the substituted aryl group and the substituents in the substituted aromatic heterocycle independently include alkyl, halogen, alkoxy, cyano, nitro, trifluoromethyl, allyl or alkynyl, and the number of carbon atoms of the alkyl group is 1 to 6.

4. The preparation method according to claim 1, characterized in that The ammonia borane compound includes one or more of ammonia borane, dimethylamine borane, diisopropylamine borane, morpholine borane and pyridine borane.

5. The preparation method according to claim 1, characterized in that The chiral aminobenzimidazole manganese catalyst has a structure shown in Formula I or Formula II: In Formula I, R 1 is tert-butyl, isopropyl, phenyl, benzyl or adamantyl; In Formula I and Formula II, R 2 are independently hydrogen, methyl, ethyl, isopropyl or benzyl; R 3 are independently hydrogen, aryl or substituted aryl, R 4 are independently hydrogen, aryl, or substituted aryl.

6. The preparation method according to claim 5, characterized in that The chiral aminobenzimidazole manganese catalyst has the following structure:

7. The preparation method according to claim 1, characterized in that The solvent includes one or more of methanol, ethanol, isopropanol, ethyl acetate, dichloromethane, n-hexane, ethyl ether, isopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, cyclohexyl methyl ether, tert-butyl methyl ether and water.

8. The preparation method according to claim 1, characterized in that The molar ratio of the heteroatom-containing imine to the aminoborane compound is 1:(0.1-3).

9. The preparation method according to claim 1, characterized in that The molar ratio of the chiral aminobenzimidazole manganese catalyst to the imine containing a heteroatom is (0.001-5):

100.

10. The preparation method according to claim 1, characterized in that The temperature of the asymmetric transfer hydrogenation reaction is -80-80°C, and the time is 5 minutes to 48 hours.

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