WO2023109213A1 - Method for preparing chiral amine compound - Google Patents

Abstract

A method for preparing a chiral amine compound B or C, which can be used for synthesizing an optically pure repotrectinib intermediate, wherein 2-hydroxy-5-fluorophenylalkylketone compound A is used as a raw material, and a corresponding chiral amine compound B or lactam compound C is obtained by means of a one-step reaction in the presence of a ruthenium-based metal catalyst, an ammonia source and hydrogen. The ammonia source is selected from at least one of ammonium acetate, ammonium benzoate, and ammonium salicylate, or ammonia; and the ruthenium-based metal catalyst is: Ru(OAc)2(L) or [RuCl(p-cymene)(L)]Cl.

Description

A kind of preparation method of chiral amine compound

cross reference

This application requires Chinese patent application No. 202111524360.8, submitted on December 14, 2021, titled a method for preparing chiral amine compounds. The entire content of this Chinese patent application is hereby incorporated by reference into this application.

technical field

The invention relates to the technical field of medicine and chemical industry, in particular to a method for preparing chiral amine compounds in one step.

Background technique

Repotrectinib is a broad-spectrum next-generation drug that inhibits the activities of ROS1 (sarcoma oncogenic factor-receptor tyrosine kinase), TRK (tropomyosin receptor kinase) and ALK (anaplastic lymphoma kinase) TRKI (Tropomyosin Receptor Kinase Inhibitor) is currently in Phase II clinical trials. It can overcome a variety of gene mutations that are resistant to other TRKIs and kill a variety of tumor cells carrying ROS1 or NTRK (neurotrophic receptor tyrosine kinase) gene fusions, so it has the potential to treat ROS1-positive non-small cell lung cancer , and solid tumors positive for ROS1, NTRK, and ALK. On September 1, 2020, the phase I clinical data of TRIDENT-1 for Repotrectinib in the treatment of ROS1 fusion non-small cell lung cancer was announced at the ASCO conference, suggesting that the drug is well tolerated by patients with advanced ROS1 fusion positive non-small cell lung cancer sex and effectiveness. On December 8, 2020, the U.S. Food and Drug Administration granted repotrectinib the "Breakthrough Therapy" designation for the treatment of ROS1-positive metastatic non-small cell lung cancer.

Compound S is the third-generation TRKI developed on the basis of lopretinib and larotretinib, which can overcome a variety of gene mutations that are resistant to other TRKIs, and it has shown better efficacy than larotretinib in mouse experiments. Good ability to inhibit tumor growth, and has oral potential (J. Med. Chem. 2021, 64, 15503).

Optically pure (R)-I is a key intermediate for the preparation of lopretinib and active compound S, and the currently reported method for synthesizing this intermediate is as follows:

(1) Route 1 reported in CN 108026109 A: Starting from commercially available aldehydes, the hydrochloride of chiral amine I was obtained in three steps. This route uses a stoichiometric and expensive chiral prosthetic group (R)-tert-butylsulfinamide, and the stereochemical control of the Grignard reagent addition step is not added. Purification by column chromatography can only obtain the desired compound in a yield of 58%. Amine intermediate to be configured. The overall route is long, the yield is low, and the production cost is high, resulting in a lot of waste.

(2) WO 2019/201282 Al; PCT/CN2019/083086 literature report Route 2: Starting from commercially available ketones to obtain chiral amine I in four steps, this route uses a stoichiometric and expensive chiral prosthetic group (S )-tert-butylsulfinamide and slow dropwise addition of tetrahydrofuran solution of lithium triethylborohydride and corrosive reagent boron tribromide at low temperature, the reaction operation and post-treatment are relatively cumbersome. The overall route is long, the yield is low, and the production cost is high, resulting in a lot of waste.

In summary, the method for preparing the chiral amine I, the key intermediate of loprtinib, reported in the prior art has the disadvantages of long overall route, low yield, high production cost, and many wastes.

Contents of the invention

In order to solve the deficiencies of the prior art, the present invention provides a new preparation method of chiral amine compounds. Starting from simple and easy-to-obtain raw materials, optically pure chiral amines can be prepared in one step under the chiral metal catalyst. Amine compounds, so as to shorten the reaction process, reduce production costs and reduce environmental pollution, and ultimately help the green economic preparation of related active compounds.

Technical purpose of the present invention is achieved through the following technical solutions:

A method for preparing a class of chiral amine compounds, which uses compound A as a raw material to obtain the corresponding chiral amine compound B or chiral amine compound C in one step in the presence of a ruthenium-based metal catalyst, an ammonia source and hydrogen;

Wherein, the group R in the compound A and the chiral amine compound B is selected from the group consisting of alkyl, alkyl with H optionally substituted, cycloalkyl, cycloalkyl with H optionally substituted, aryl, aryl H optionally substituted Among the group, aralkyl group, aralkyl group with optionally substituted H, heteroaryl, heteroaryl group with optionally substituted H, carboxyl, -C _n H _2n COOH, -COOR ₁ and -C _n H _2n COOR ₁ One, wherein n is an integer of 1-4, R ₁ is an alkyl group, an alkyl group optionally substituted by H, an aryl group or an aryl group optionally substituted by H;

In the chiral amine compound C, n is an integer of 1-4;

The ruthenium-based metal catalyst is: Ru(OAc) ₂ (L) or [RuCl(p-cymene)(L)]Cl, wherein L has the structure of general formula II, III or IV:

For the general formula II, Ar is Ph (the corresponding bisphosphine ligand is called Segphos), 3,5-Me ₂ C ₆ H ₃ (the corresponding bisphosphine ligand is called DM-Segphos), 4-MeO-3, 5- ^t Bu ₂ C ₆ H ₂ (the corresponding bisphosphine ligand is called DTBM-Segphos) or other aryl groups; for the general formula III, Ar is Ph (the corresponding bisphosphine ligand is called BINAP), 4-Me -C ₆ H ₄ (the corresponding bisphosphine ligand is called tolBINAP), 3,5-Me ₂ C ₆ H ₃ (the corresponding bisphosphine ligand is called xylBINAP) or other aryl groups; for the general formula IV, Ar is Ph (the corresponding bisphosphine ligand is called C ₃ *-TunePhos), 3,5-Me ₂ C ₆ H ₃ (the corresponding bisphosphine ligand is called C ₃ *-DM-TunePhos), 4-MeO-3 ,5- ^t Bu ₂ C ₆ H ₂ (the corresponding bisphosphine ligand is called C ₃ *-DTBM-TunePhos) or other aryl groups; or one of the S-configuration ligands corresponding to the above compounds;

The ammonia source is selected from at least one of ammonium acetate, ammonium benzoate, and ammonium salicylate, or ammonia gas is used.

It should be understood by those skilled in the art that in the above reactions, selecting the corresponding R-configuration ligand or S-configuration ligand can obtain the chiral compound of the corresponding configuration.

Further, in one embodiment of the present invention, the ruthenium-based metal catalyst is selected from Ru(OAc) ₂ [(R)-Segphos], Ru(OAc) ₂ [(R)-DM-Segphos], Ru (OAc) ₂ [(R)-DTBM-Segphos], Ru(OAc) ₂ [(R)-BINAP], Ru(OAc) ₂ [(R)-tolBINAP], Ru(OAc) ₂ [(R)- xylBINAP], Ru(OAc) ₂ [(R)-C ₃ *-TunePhos], Ru(OAc) ₂ [(R)-C ₃ *-DM-TunePhos], Ru(OAc) ₂ [(R)-C ₃ *-DTBM-TunePhos], [RuCl(p-cymene)((R)-Segphos)]Cl, [RuCl(p-cymene)((R)-DM-Segphos)]Cl, [RuCl(p-cymene) )((R)-BINAP))]Cl and one of the metal catalysts composed of S-configuration ligands corresponding to the above compounds.

Further, in one embodiment of the present invention, the reaction is carried out in an organic solvent, and the organic solvent is alcohol. As a more specific embodiment, at least one selected from methanol, ethanol, isopropanol, butanol, trifluoroethanol and hexafluoroisopropanol, the amount of organic solvent added is 2mL to 10mL per millimole of compound A Solvent meter.

Further, in one of the preferred embodiments of the present invention, the group R in compound A and chiral amine compound B is selected from C1-C10 alkyl, C1-C10 alkyl with H optionally substituted, C3 -C6 cycloalkyl, C3-C6 cycloalkyl with H optionally substituted, phenyl, phenyl with H optionally substituted with halogen, aralkyl, carboxyl, -C _n H _2n COOH, -COOR ₁ , - C _n H _2n COOR ₁ and one of the groups X1, X2, X3, X4, X5, X6 shown in the following formula, wherein n is an integer of 1-4, R ₁ is methyl, ethyl or propyl;

Further, in one of the more preferred embodiments of the present invention, the group R in compound A and chiral amine compound B is selected from methyl, ethyl, propyl, butyl, isopropyl, cyclohexyl , tert-butyl, methylene carboxyl, phenyl, phenyl with H optionally substituted by halogen, benzyl, phenethyl, carboxyl, -CH ₂ COOH, -CH ₂ CH ₂ COOH, -CH ₂ CH ₂ CH ₂ COOH, -COOCH ₃ , -COOCH ₂ CH ₃ , -CH ₂ COOCH ₃ , -CH ₂ COOCH ₃ , -CH ₂ COOCH ₂ CH ₃ , -CH ₂ COOCH ₂ CH ₂ CH ₃ and -CH ₂ CH ₂ COOCH ₂ One of _CH3 .

Further, in one of the preferred embodiments of the present invention, the compound A is selected from one of the compounds A1, A2, A3, A4, A5, A6, A7, A8, A9 and A10:

Further, in one embodiment of the present invention, the molar ratio of the compound A to the ruthenium-based metal catalyst is 1:0.01-1:0.001, and the molar ratio of the compound A to the ammonia source is 1:2-1 :4.

Further, in one embodiment of the present invention, the hydrogen pressure during the reaction is 30-100 atm, and the reaction temperature is 50-100°C.

Further, in one embodiment of the present invention, the reaction time is 12-48h.

Further, in one of the embodiments of the present invention, after the reaction is completed, a quenching solution is added to quench the reaction, and the quenching solution is a saturated sodium bicarbonate solution or other weakly basic inorganic salt solution, and the compound is A Quenching solution was used in an amount of 10-30 mL.

Further, in one embodiment of the present invention, after the reaction, the process of extracting the organic phase with an organic solvent and drying it is also included.

Implementing the embodiment of the present invention will have the following beneficial effects:

In the present invention, the easy-to-obtain compound A is used as a substrate, and the reductive amination involving a ruthenium-based metal catalyst and an ammonium salt can realize a one-step reaction to directly and efficiently synthesize optically pure compound B or C, wherein compound B is the key to lopratinib Intermediate I or an analog thereof. Ruthenium-based metal catalysts are easy to prepare, and the chiral ligands and metal precursors used are relatively cheap and easy to obtain. The amount of catalyst used in this reaction can be reduced to 0.1%, and the scale of the reaction is easy to expand. Compared with the method for synthesizing intermediate I in the prior art, the use of expensive and stoichiometric optically pure tert-butylsulfinamide is avoided, the process flow can be greatly shortened, and the production cost and environmental pollution caused by the protecting group operation can be reduced. Improve the yield of key intermediates, facilitate industrial application, and ultimately help the green economic preparation of related active compounds.

Detailed ways

In order to better understand the content of the present invention, the following will be further described in conjunction with specific embodiments to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention , but not all examples. Based on the embodiments of the present invention, all other embodiments obtained by persons of ordinary skill in the art without creative efforts fall within the protection scope of the present invention.

The reagents used in the examples are all conventional commercially available reagents, and the technical means used in the examples are conventional means well known to those skilled in the art.

In the following examples 1-19, the reaction product was protected by acetylation, and the enantiomeric excess value ee was measured by high performance liquid chromatography. Resolution conditions: Daicel Chiralpak OD-3, Hexane:i-PrOH=95:5, v=1.0 mL/min, T=25°C, UV 210 nm, t ₁ =12.183 min, t ₂ =18.044 min.

Example 1

Add ruthenium-based metal catalyst Ru(OAc) ₂ [(R)-Segphos] (0.001mmol), compound A1 (0.1mmol), ammonium acetate (0.2mmol) and methanol (0.5mL) in the reaction bottle of 2mL, react The bottle was placed in an autoclave and filled with hydrogen to 40 atmospheres. The reaction kettle was placed in an oil bath at 80°C and stirred for 24 hours to obtain compound B1. After the reaction, carefully release the hydrogen in the kettle in the fume hood, add 2 mL of saturated sodium bicarbonate solution to quench the reaction, extract three times with 3 mL of dichloromethane, combine the organic phases, dry with anhydrous sodium sulfate, filter and depressurize The solvent was spin-dried to obtain a crude product.

The crude product was redissolved in 5 mL of dichloromethane, washed with 1M hydrochloric acid solution, and the aqueous phase was separated. Immediately after that, saturated sodium bicarbonate solution was added to the aqueous phase until no gas was produced. Subsequently, the aqueous phase was separated and extracted with dichloromethane, and the organic phase was collected, dried with anhydrous sodium sulfate, filtered, and finally the solvent was spin-dried to obtain pure product B1. The product yields and enantiomeric excess values are shown in Table 1.

Compound B1 NMR:

¹ H NMR (400MHz, CDCl ₃ ) δ6.83(td, J=8.5, 3.0Hz, 1H), 6.75(dd, J=8.8, 4.9Hz, 1H), 6.68(dd, J=9.0, 2.9Hz, 1H), 4.26(q, J=6.6Hz, 1H), 1.47(d, J=6.7Hz, 3H).

¹³ C NMR (100MHz, CDCl ₃ ) δ156.0(d, J=236.1Hz), 153.47, 128.90(d, J=6.5Hz), 117.74(d, J=7.7Hz), 114.57(d, J=22.5 Hz), 113.54 (d, J=23.3Hz), 51.38, 23.63.

¹⁹ F NMR (400MHz, CDCl ₃ ) δ-125.955.

Example 2

Except that 0.2mmol ammonium acetate is replaced by 0.2mmol ammonium salicylate, other operating conditions and steps are the same as in Example 1. The product yields and enantiomeric excess values are shown in Table 1.

Example 3

Except that 0.2mmol ammonium acetate is replaced by 0.2mmol ammonium benzoate, other operating conditions and steps are the same as in Example 1. The product yields and enantiomeric excess values are shown in Table 1.

Example 4

Except that 0.001 mmol of ruthenium-based metal catalyst Ru(OAc) ₂ [(R)-Segphos] was replaced by 0.001 mmol of Ru(OAc) ₂ [(R)-DM-Segphos], other operating conditions and steps were the same as in Example 1. The product yields and enantiomeric excess values are shown in Table 1.

Example 5

Except that 0.001 mmol of ruthenium-based metal catalyst Ru(OAc) ₂ [(R)-Segphos] was replaced by 0.001 mmol of Ru(OAc) ₂ [(R)-DTBM-Segphos], other operating conditions and steps were the same as in Example 1. The product yields and enantiomeric excess values are shown in Table 1.

Example 6

Except that 0.001 mmol of ruthenium-based metal catalyst Ru(OAc) ₂ [(R)-Segphos] was replaced by 0.001 mmol of Ru(OAc) ₂ [(R)-BINAP], other operating conditions and steps were the same as in Example 1. The product yields and enantiomeric excess values are shown in Table 1.

Example 7

Except that 0.001 mmol of ruthenium-based metal catalyst Ru(OAc) ₂ [(R)-Segphos] was replaced by 0.001 mmol of Ru(OAc) ₂ [(R)-tolBINAP], other operating conditions and steps were the same as in Example 1. The product yields and enantiomeric excess values are shown in Table 1.

Example 8

Except that 0.001 mmol of ruthenium-based metal catalyst Ru(OAc) ₂ [(R)-Segphos] was replaced by 0.001 mmol of Ru(OAc) ₂ [(R)-xylBINAP], other operating conditions and steps were the same as in Example 1. The product yields and enantiomeric excess values are shown in Table 1.

Example 9

Except that 0.001mmol ruthenium-based metal catalyst Ru(OAc) ₂ [(R)-Segphos] was replaced by 0.001mmol Ru(OAc) ₂ [(R)-C ₃ *-TunePhos], other operating conditions and steps were the same as in Example 1 . The product yields and enantiomeric excess values are shown in Table 1.

Example 10

Except that 0.001mmol of ruthenium-based metal catalyst Ru(OAc) ₂ [(R)-Segphos] was replaced by 0.001mmol of Ru(OAc) ₂ [(R)-C ₃ *-DM-TunePhos], other operating conditions and steps were implemented example 1. The product yields and enantiomeric excess values are shown in Table 1.

Example 11

Except that 0.001mmol ruthenium-based metal catalyst Ru(OAc) ₂ [(R)-Segphos] was replaced by 0.001mmol Ru(OAc) ₂ [(R)-C ₃ *-DTBM-TunePhos], other operating conditions and steps were the same as the implementation example 1. The product yields and enantiomeric excess values are shown in Table 1.

Example 12

Except that 0.001mmol ruthenium-based metal catalyst Ru(OAc) ₂ [(R)-Segphos] is replaced by 0.001mmol [RuCl(p-cymene)((R)-Segphos)]Cl, other operating conditions and steps are the same as in the examples 1. The product yields and enantiomeric excess values are shown in Table 1.

Example 13

Except that 0.001 mmol of ruthenium-based metal catalyst Ru(OAc) ₂ [(R)-Segphos] was replaced by 0.001 mmol of [RuCl(p-cymene)((R)-DM-Segphos)]Cl, other operating conditions and steps were the same Example 1. The product yields and enantiomeric excess values are shown in Table 1.

Example 14

Except that 0.001 mmol of ruthenium-based metal catalyst Ru(OAc) ₂ [(R)-Segphos] was replaced by 0.001 mmol of [RuCl(p-cymene)((R)-BINAP))]Cl, other operating conditions and steps were implemented example 1. The product yields and enantiomeric excess values are shown in Table 1.

Example 15

Except that 0.5 mL of solvent methanol was replaced by 0.5 mL of trifluoroethanol, other operating conditions and steps were the same as in Example 1. The product yields and enantiomeric excess values are shown in Table 1.

Example 16

Except that 0.5mL solvent methanol was replaced by 0.5mL ethanol, other operating conditions and steps were the same as in Example 1. The product yields and enantiomeric excess values are shown in Table 1.

Example 17

Except that 0.5mL solvent methanol was replaced by 0.5mL isopropanol, other operating conditions and steps were the same as in Example 1. The product yields and enantiomeric excess values are shown in Table 1.

Example 18

Except that 0.001 mmol of ruthenium-based metal catalyst Ru(OAc) ₂ [(R)-Segphos] was replaced by 0.001 mmol of Ru(OAc) ₂ [(S)-Segphos], other operating conditions and steps were the same as in Example 1. The product yields and enantiomeric excess values are shown in Table 1.

Table 1.

Example 19

In this example, a scaled-up gram-scale experiment was carried out for substrate A1:

Add compound A1 (7.0mmol, 1078mg), ammonium acetate (2.0equiv, 14.0mmol, 1078mg), Ru(OAc) ₂ [(R)-Segphos] (0.035mmol, 5.8mg) and methanol (8.0 mL). Put the reaction bottle into a high-pressure hydrogenation reactor, and fill it with hydrogen gas at a pressure of 80 atmospheres. The reaction kettle was placed in an oil bath at 80° C. and stirred for 48 hours to obtain compound B1. After the reaction, the reactor was taken out from the oil bath and allowed to cool to room temperature. Carefully release the hydrogen in the kettle in a fume hood, spin the reaction solution to dryness, then dissolve it in 50 mL of dichloromethane, and wash it with saturated sodium bicarbonate solution, then separate the organic phase with a separatory funnel, and then use anhydrous Dry over sodium sulfate, filter, and finally spin dry the solvent to obtain a crude product.

The crude product was redissolved in 50 mL of dichloromethane, washed with 1M hydrochloric acid solution, and the aqueous phase was separated. Immediately after that, saturated sodium bicarbonate solution was added to the aqueous phase until no gas was produced. Subsequently, the aqueous phase was separated and extracted with dichloromethane, and the organic phase was collected, dried with anhydrous sodium sulfate, filtered, and finally the solvent was spin-dried to obtain a white solid (0.92g). The enantiomeric excess (e.e. 94%) was determined by HPLC after protection by acetylation.

Example 20

Under argon atmosphere in the glove box, add ruthenium-based metal catalyst Ru(OAc) ₂ [(R)-Segphos] (0.001mmol), compound A2 (0.1mmol), ammonium acetate (0.2mmol) and Methanol (0.5mL), put the reaction flask into a high-pressure hydrogenation reactor, and fill it with hydrogen to 40 atmospheres. The reaction kettle was placed in an oil bath at 80° C. and stirred for 24 hours to obtain compound B2. After the reaction, carefully release the hydrogen in the kettle in the fume hood, add 2 mL of saturated sodium bicarbonate solution to quench the reaction, extract three times with 3 mL of dichloromethane, combine the organic phases, dry with anhydrous sodium sulfate, filter and depressurize The solvent was spin-dried to obtain a crude product. The crude product was redissolved in 5 mL of dichloromethane, washed with 1M hydrochloric acid solution, and the aqueous phase was separated. Immediately after that, saturated sodium bicarbonate solution was added to the aqueous phase until no gas was produced. Then the aqueous phase was separated and extracted with dichloromethane, and the organic phase was collected, dried with anhydrous sodium sulfate, filtered, and finally the solvent was spin-dried to obtain pure product B2, which was detected by high performance liquid chromatography after acetylation protection Enantiomeric excess values.

B2: light brown solid, 15.9 mg, 94% yield, greater than 99% ee.

¹ H NMR (400MHz, CDCl ₃ ) δ6.83 (td, J=8.5, 3.0Hz, 1H), 6.74 (dd, J=8.8, 4.9Hz, 1H), 6.64 (dd, J=9.0, 3.0Hz, 1H), 3.95(t, J=7.0Hz, 1H), 1.77(ddd, J=20.9, 13.7, 6.5Hz, 2H), 0.92(s, 3H).

¹³ C NMR (100MHz, CDCl ₃ ) δ156.97, 154.62, 153.55(d, J=1.9Hz), 127.65(d, J=6.5Hz), 117.71(d, J=7.7Hz), 116.61–112.03(m), 58.00(d, J=1.1), 29.47, 10.68.

¹⁹ F NMR (400MHz, CDCl ₃ ) δ-126.29.

Example 21

Under argon atmosphere in the glove box, add ruthenium-based metal catalyst Ru(OAc) ₂ [(R)-Segphos] (0.001mmol), compound A3 (0.1mmol), ammonium acetate (0.2mmol) and Methanol (0.5mL), put the reaction flask into a high-pressure hydrogenation reactor, and fill it with hydrogen to 40 atmospheres. The reaction kettle was placed in an oil bath at 80° C. and stirred for 24 h to obtain compound B3. After the reaction, carefully release the hydrogen in the kettle in the fume hood, add 2 mL of saturated sodium bicarbonate solution to quench the reaction, extract three times with 3 mL of dichloromethane, combine the organic phases, dry with anhydrous sodium sulfate, filter and depressurize The solvent was spin-dried to obtain a crude product. The crude product was redissolved in 5 mL of dichloromethane, washed with 1M hydrochloric acid solution, and the aqueous phase was separated. Immediately after that, saturated sodium bicarbonate solution was added to the aqueous phase until no gas was produced. Then the aqueous phase was separated and extracted with dichloromethane, and the organic phase was collected, dried with anhydrous sodium sulfate, filtered, and finally the solvent was spin-dried to obtain pure product B3, which was detected by high-performance liquid chromatography after acetylation protection Enantiomeric excess values.

B3: Light brown solid, 17.0 mg, 94% yield, 99% ee.

¹ H NMR (400MHz, CDCl ₃ ) δ6.83(td, J=8.5, 3.1Hz, 1H), 6.74(dd, J=8.8, 4.9Hz, 1H), 6.64(dd, J=9.0, 3.0Hz, 1H),4.13–3.88(m,1H),1.90–1.53(m,2H),1.54–1.14(m,3H),0.93(t,J＝7.3Hz,3H).

¹³ C NMR (100MHz, CDCl ₃ ) δ157.00, 154.65, 153.54 (d, J = 2.0Hz), 127.98 (d, J = 6.5Hz), 117.75 (d, J = 7.7Hz), 114.45 (dd, J = 22.8 , 12.8Hz), 56.29 (d, J=1.2Hz), 38.67, 19.43, 13.85.

¹⁹ F NMR (400MHz, CDCl ₃ ) δ-126.239.

Example 22

Under an argon atmosphere in a glove box, add ruthenium-based metal catalyst Ru(OAc) ₂ [(R)-Segphos] (0.001 mmol), compound A5 (0.1 mmol), ammonium acetate (0.2 mmol) and Methanol (0.5mL), put the reaction flask into a high-pressure hydrogenation reactor, and fill it with hydrogen to 40 atmospheres. The reaction kettle was placed in an oil bath at 80° C. and stirred for 24 h to obtain compound B5. After the reaction, carefully release the hydrogen in the kettle in the fume hood, add 2 mL of saturated sodium bicarbonate solution to quench the reaction, extract three times with 3 mL of dichloromethane, combine the organic phases, dry with anhydrous sodium sulfate, filter and depressurize The solvent was spin-dried to obtain a crude product. The crude product was redissolved in 5 mL of dichloromethane, washed with 1M hydrochloric acid solution, and the aqueous phase was separated. Immediately after that, saturated sodium bicarbonate solution was added to the aqueous phase until no gas was produced. Then the aqueous phase was separated and extracted with dichloromethane, and the organic phase was collected, dried with anhydrous sodium sulfate, filtered, and finally the solvent was spin-dried to obtain the pure product B5, which was detected by high-performance liquid chromatography after being protected by acetylation Enantiomeric excess values.

B5: light brown solid, 19.5 mg, 89% yield, 99% ee.

¹ H NMR (400MHz, CDCl ₃ ) δ7.45–7.28(m,5H),6.97–6.65(m,2H),6.47(dd,J=9.2,2.6Hz,1H),5.25(s,1H).

¹³ C NMR (100MHz, CDCl ₃ ) δ157.08, 154.73, 153.83 (d, J = 1.9Hz), 142.59, 129.12, 128.10, 127.18 (d, J = 6.5Hz), 126.90, 118.01 (d, J = 7.7Hz) ,115.05(t,J=23.1Hz),59.69.

¹⁹ F NMR (400MHz, CDCl ₃ ) δ-125.499.

The above disclosures are only preferred embodiments of the present invention, and certainly cannot limit the scope of rights of the present invention. Therefore, equivalent changes made according to the claims of the present invention still fall within the scope of the present invention.

Claims (11)

1. The preparation method of a class of chiral amine compounds is characterized in that, using compound A as a raw material, in the presence of a ruthenium-based metal catalyst, ammonia source and hydrogen, one-step reaction to obtain the corresponding chiral amine compound B or chiral amine compound C ;

   

   Wherein, the group R in the compound A and the chiral amine compound B is selected from the group consisting of alkyl, alkyl with H optionally substituted, cycloalkyl, cycloalkyl with H optionally substituted, aryl, aryl H optionally substituted Among the group, aralkyl group, aralkyl group with optionally substituted H, heteroaryl, heteroaryl group with optionally substituted H, carboxyl, -C _n H _2n COOH, -COOR ₁ and -C _n H _2n COOR ₁ One, wherein n is an integer of 1-4, R ₁ is an alkyl group, an alkyl group optionally substituted by H, an aryl group or an aryl group optionally substituted by H;

   In the chiral amine compound C, n is an integer of 1-4;

   The ruthenium-based metal catalyst is: Ru(OAc) ₂ (L) or [RuCl(p-cymene)(L)]Cl, wherein L has the structure of general formula II, general formula III or general formula IV:

   

   For general formula II, Ar is Ph, 3,5-Me ₂ C ₆ H ₃ , 4-MeO-3,5- ^tBu ₂ C ₆ H ₂ or other aryl groups; for general formula III, Ar is Ph, 4 -Me-C ₆ H ₄ ,3,5-Me ₂ C ₆ H ₃ or other aryl; for formula IV, Ar is Ph, 3,5-Me ₂ C ₆ H ₃ ,4-MeO-3,5 - ^t Bu ₂ C ₆ H ₂ or other aryl groups; or one of the S-configuration ligands corresponding to the above compounds;

   The ammonia source is selected from at least one of ammonium acetate, ammonium benzoate or ammonium salicylate, or is ammonia gas.
2. The preparation method according to claim 1, wherein the ruthenium-based metal catalyst is selected from Ru(OAc) ₂ [(R)-Segphos], Ru(OAc) ₂ [(R)-DM-Segphos], Ru(OAc) ₂ [(R)-DTBM-Segphos], Ru(OAc) ₂ [(R)-BINAP], Ru(OAc) ₂ [(R)-tolBINAP], Ru(OAc) ₂ [(R) -xylBINAP], Ru(OAc) ₂ [(R)-C ₃ *-TunePhos], Ru(OAc) ₂ [(R)-C ₃ *-DM-TunePhos], Ru(OAc) ₂ [(R)- C ₃ *-DTBM-TunePhos], [RuCl(p-cymene)((R)-Segphos)]Cl, [RuCl(p-cymene)((R)-DM-Segphos)]Cl, [RuCl(p- cymene)((R)-BINAP))]Cl and the corresponding S-configuration ligands of the above compounds are one of the metal catalysts.
3. The preparation method according to claim 1, characterized in that the reaction is carried out in an organic solvent, the organic solvent is an alcohol solvent, and the amount of the organic solvent is calculated by adding 2mL to 10mL of solvent per millimole of compound A.
4. The preparation method according to claim 3, wherein the alcohol solvent is at least one selected from methanol, ethanol, isopropanol, butanol, trifluoroethanol and hexafluoroisopropanol.
5. The preparation method according to claim 1, wherein the group R in compound A and chiral amine compound B is selected from C1-C10 alkyl, C1-C10 alkyl optionally substituted by H, C3- C6 cycloalkyl, C3-C6 cycloalkyl with H optionally substituted, phenyl, phenyl with H optionally substituted with halogen, aralkyl, carboxyl, -C _n H _2n COOH, -COOR ₁ , -C _n H _2n COOR ₁ , one of the groups X1, X2, X3, X4, X5 and X6 shown in the following formula, wherein n is an integer from 1 to 4, and R ₁ is methyl, ethyl or propyl;

   
6. The preparation method according to claim 5, wherein the group R in compound A and chiral amine compound B is selected from methyl, ethyl, propyl, butyl, isopropyl, cyclohexyl, tert-butyl radical, methylene carboxyl, phenyl, phenyl with H optionally substituted by halogen, benzyl, phenethyl, carboxyl, -CH ₂ COOH, -CH ₂ CH ₂ COOH, -CH ₂ CH ₂ CH ₂ COOH, -COOCH ₃ , -COOCH ₂ CH ₃ , -CH ₂ COOCH _{3 ,} -CH ₂ COOCH ₃ , -CH 2 COOCH ₂ CH ₃ , -CH ₂ COOCH ₂ CH ₂ CH ₃ and -CH ₂ CH ₂ COOCH ₂ CH ₃ kind of.
7. The preparation method according to claim 5, wherein the compound A is selected from one of the compounds A1, A2, A3, A4, A5, A6, A7, A8, A9 and A10:

   
8. The preparation method according to claim 1, wherein the molar ratio of the compound A to the ruthenium-based metal catalyst is 1:0.01-1:0.001, and the molar ratio of the compound A to the ammonia source is 1:2- 1:4.
9. The preparation method according to claim 1, characterized in that, during the reaction, the hydrogen pressure is 30-100 atm, and the reaction temperature is 50-100°C.
10. The preparation method according to claim 1, characterized in that, after the reaction is completed, a quenching solution is added to quench the reaction, and the quenching solution is a saturated sodium bicarbonate solution or other alkaline inorganic salt solutions.
11. preparation method according to claim 1, is characterized in that, described reaction is carried out in autoclave or continuous microchannel reactor.