CN111793017B - Preparation method of lactam compound - Google Patents

Abstract

The invention relates to a preparation method of a lactam compound, belonging to the field of pharmaceutical chemistry. The preparation method comprises the steps of carrying out asymmetric hydrogenation reaction on raw materials under the action of a ruthenium catalyst and a hydrogen donor reagent, and then carrying out post-treatment to obtain the target compound. The product obtained by the method has high ee value, and the method is simple and convenient, thereby being beneficial to simply and efficiently obtaining the target compound.

Description

A method for preparing lactam compound

Technical Field

The invention relates to a preparation method of a lactam compound and belongs to the technical field of pharmaceutical chemistry.

Background Art

The lactam compound shown in the following formula III is an intermediate in the preparation process of various drugs, which includes two chiral centers. How to easily obtain a single-configuration compound III has an important impact on the preparation process of drugs that need to use this compound III as an intermediate.

In the prior art, compound III is prepared by hydrogenation reduction reaction to obtain a mixture of different configurations, and then a target compound of a single configuration is obtained by splitting and other processes. Due to different conditions, the proportions of compounds of different configurations in the obtained products of these hydrogenation reduction reactions are different, but the proportion of the main product is not high, which is not conducive to the preparation of the final drug. Therefore, it is necessary to develop a simple and high-yield preparation method for compound III.

Summary of the invention

After research, the inventors have developed a method for preparing compound III, which can easily obtain products with more single configurations and high ee values, avoids the use of hydrogen, and is simple and safe to operate.

The present invention provides a method for preparing compound III, comprising: subjecting compound II to an asymmetric hydrogenation reaction under the action of a ruthenium catalyst and a hydrogen donor reagent, and then subjecting compound II to post-treatment to obtain compound III.

in,

n is 1, 2 or 3;

R ¹ is an optionally substituted linear or branched alkyl, ester, aryl, heteroaryl, or R ¹ is hydrogen;

^R2 is an optionally substituted linear or branched alkyl, benzyl, aryl, heteroaryl, or ^R2 is hydrogen.

The alkyl group may be an optionally substituted C1-C6 (1 carbon to 6 carbon) alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc.;

The ester group may be an optionally substituted C2-C12 (2 carbons to 12 carbons) ester group, such as methyl formate (COOMe), ethyl formate (COOC ₂ H ₅ ), methyl acetate (CH ₂ COOMe), ethyl acetate (CH ₂ COOC ₂ H ₅ ), phenol formate (COOPh), etc.;

The aryl group may be an optionally substituted C6-C12 (6 carbons to 12 carbons) aryl group, such as an optionally substituted phenyl group, an optionally substituted benzyl group, an optionally substituted naphthyl group, an optionally substituted naphthylmethyl group, etc.;

The heteroaryl group is an optionally substituted five-membered or six-membered heterocyclic group containing nitrogen, oxygen or sulfur elements, such as an optionally substituted thienyl group, an optionally substituted pyrrolyl group, an optionally substituted furanyl group, an optionally substituted pyrimidinyl group, an optionally substituted pyrimidinyl group, an optionally substituted piperidinyl group, an optionally substituted piperazinyl group, and the like.

In some embodiments, ^R1 is an optionally substituted linear or branched C1-C6 (1 carbon to 6 carbon) alkyl group, a C2-C12 (2 carbon to 12 carbon) ester group, an optionally substituted C6-C12 (6 carbon to 12 carbon) aryl group, an optionally substituted five-membered or six-membered heterocyclic group containing nitrogen, oxygen or sulfur elements, or ^R1 is hydrogen.

In some embodiments, ^R2 is an optionally substituted linear or branched C1-C6 (1 carbon to 6 carbon) alkyl, benzyl, an optionally substituted C6-C12 (6 carbon to 12 carbon) aryl, an optionally substituted five-membered or six-membered heterocyclic group containing nitrogen, oxygen or sulfur elements, or ^R2 is hydrogen.

In some embodiments, R ¹ is an optionally substituted linear or branched C1-C6 (1 carbon to 6 carbon) alkyl, a C2-C12 (2 carbon to 12 carbon) ester group, an optionally substituted C6-C12 (6 carbon to 12 carbon) aryl group, an optionally substituted five-membered or six-membered heterocyclic group containing nitrogen, oxygen or sulfur elements, or R ¹ is hydrogen; R ² is an optionally substituted linear or branched C1-C6 (1 carbon to 6 carbon) alkyl, a benzyl group, an optionally substituted C6-C12 (6 carbon to 12 carbon) aryl group, an optionally substituted five-membered or six-membered heterocyclic group containing nitrogen, oxygen or sulfur elements, or R ² is hydrogen.

In some embodiments, n is 1, 2 or 3; ^R1 is an optionally substituted straight or branched C1-C6 (1 carbon to 6 carbon) alkyl, a C2-C12 (2 carbon to 12 carbon) ester group, an optionally substituted C6-C12 (6 carbon to 12 carbon) aryl group, an optionally substituted five-membered or six-membered heterocyclic group containing nitrogen, oxygen or sulfur elements, or ^R1 is hydrogen; ^R2 is an optionally substituted straight or branched C1-C6 (1 carbon to 6 carbon) alkyl, a benzyl group, an optionally substituted C6-C12 (6 carbon to 12 carbon) aryl group, an optionally substituted five-membered or six-membered heterocyclic group containing nitrogen, oxygen or sulfur elements, or ^R2 is hydrogen.

The ruthenium catalyst may be a compound represented by the following formula CAT-A or CAT-B:

Wherein, A is oxygen, alkylene or absent; Q is hydrogen or alkyl; Ar is benzene, optionally substituted benzene, cyclopentadiene, optionally substituted cyclopentadiene; ^R3 is optionally substituted straight or branched C1-C6 (1 carbon to 6 carbon) alkyl, or optionally substituted phenyl, including but not limited to phenyl optionally substituted by straight or branched C1-C6 alkyl, phenyl optionally substituted by halogen, phenyl optionally substituted by C1-C6 (1 carbon to 6 carbon) haloalkyl, etc.

In some embodiments, A is oxygen, methylene, or absent.

In some embodiments, Q is a linear or branched C1-C6 (1 carbon to 6 carbon) alkyl group.

In some embodiments, R ³ is methyl, trifluoromethyl, p-methylphenyl, p-trifluoromethylphenyl, pentafluorophenyl, or perfluorobutyl.

In some embodiments, A is oxygen, methylene or absent; Q is a linear or branched C1-C6 (1 carbon to 6 carbon) alkyl; ^R3 is methyl, trifluoromethyl, p-methylphenyl, p-trifluoromethylphenyl, pentafluorophenyl, or perfluorobutyl.

In some embodiments, A is oxygen and Q is methyl. In some embodiments, A is oxygen and Q is hydrogen. In some embodiments, A is alkylene and Q is hydrogen or methyl. In some embodiments, A is methylene and Q is hydrogen or methyl. In some embodiments, A is absent and Q is hydrogen or methyl.

In some embodiments, A is oxygen, Q is methyl, and R ³ is p-methylphenyl. In some embodiments, A is absent, Q is hydrogen, and R ³ is p-methylphenyl.

In some embodiments, Ar is benzene, optionally substituted benzene, cyclopentadiene, optionally substituted cyclopentadiene; ^R3 is methyl, trifluoromethyl, p-methylphenyl, p-trifluoromethylphenyl, pentafluorophenyl, or perfluorobutyl.

In some embodiments, Ar is 4-methylisopropylbenzene and ^R3 is trifluoromethyl.

In some embodiments, the ruthenium catalyst is selected from at least one of the compounds represented by the following formulas: (R,R)-Ts-DENEB, (R,R)-Teth-TsDpen, (R,R)-CAT01 to (R,R)-CAT07, wherein i-Pr represents isopropyl, Ph represents phenyl, and Ts represents p-toluenesulfonyl:

In some embodiments, the ruthenium catalyst is (R,R)-Ts-DENEB, which is beneficial to the reaction and the acquisition of the product. In some embodiments, the ruthenium catalyst is (R,R)-Teth-TsDpen, which is beneficial to the reaction and the acquisition of the product.

The amount of the ruthenium catalyst can be any suitable catalyst amount; for example, relative to 1 mole of compound II, the amount of the ruthenium catalyst can be 0.0001 mole to 0.1 mole. In some embodiments, the molar ratio of the ruthenium catalyst to compound II is 0.0001:1-0.05:1. In some embodiments, the molar ratio of the ruthenium catalyst to compound II is 0.0005:1-0.05:1. In some embodiments, the molar ratio of the ruthenium catalyst to compound II is 0.001:1-0.02:1. In some embodiments, the molar ratio of the ruthenium catalyst to compound II is 0.008:1-0.015:1. In some embodiments, the molar ratio of the ruthenium catalyst to compound II is 0.005:1-0.01:1, which is conducive to better reaction.

The hydrogen donor reagent may be any suitable hydrogen donor reagent.

In some embodiments, the hydrogen donor reagent is formic acid and an organic amine, and the organic amine is selected from at least one of diethylamine, diisopropylamine, dicyclohexylamine, triethylamine, and N,N-diisopropylethylamine. In some embodiments, the hydrogen donor reagent is a formate, which can be sodium formate, potassium formate, or a combination thereof.

The amount of the hydrogen donor reagent may be any suitable amount.

In some embodiments, the molar ratio of the hydrogen donor reagent to compound II is 1:1-4:1, calculated based on the amount of formic acid or formate. In some embodiments, the molar ratio of the hydrogen donor reagent to compound II is 1:1-2:1, calculated based on the amount of formic acid.

The amount of the organic amine can be any suitable amount. In some embodiments, the molar ratio of the organic amine to the compound II is 10:1-1:1. In some embodiments, the molar ratio of the organic amine to the compound II is 8:1-1:1. In some embodiments, the molar ratio of the organic amine to the compound II is 5:1-1:1. In some embodiments, the molar ratio of the organic amine to the compound II is 4:1-1:1, which is conducive to better reaction.

The temperature of the asymmetric hydrogenation reaction may be 0 to 100° C. In some embodiments, the temperature of the asymmetric hydrogenation reaction is 15° C., 25° C., 30° C., 35° C., 55° C., 65° C. or 80° C. In some embodiments, the asymmetric hydrogenation reaction is carried out at a temperature of 20° C. to 45° C., which is conducive to obtaining the reaction product.

The reaction solvent of the asymmetric hydrogenation reaction can be any suitable solvent. In some embodiments, the reaction solvent of the asymmetric hydrogenation reaction can be at least one of dichloromethane, toluene, tetrahydrofuran, and 2-methyltetrahydrofuran. In some embodiments, the reaction solvent is dichloromethane, which is conducive to reaction processing.

The reaction of the present invention can be monitored by high performance liquid chromatography (HPLC) and other methods to determine the end point of the reaction. The reaction is considered complete when the HPLC content of the compound of Formula II is less than or equal to 5%. The reaction time is generally 10-80 hours depending on the substrate, catalyst, and reaction conditions.

The post-treatment may include: after the reaction is completed, washing the reaction solution with water, and removing the solvent by distillation under reduced pressure to obtain a crude compound III. In order to further improve the purity of compound III, any suitable method or method that can improve the purity of the target product, including but not limited to decolorization, adsorption, washing, crystallization, recrystallization, etc., can be used to purify the crude product.

In some embodiments, n is 1; R ¹ is methyl, n-propyl, isopropyl, ester, naphthylmethyl, benzyl, or substituted benzyl; R ² is methyl, isopropyl, n-butyl, benzyl, or p-methoxybenzyl.

In some embodiments, n is 2; ^R1 is methyl, n-propyl, isopropyl, ester, naphthylmethyl, benzyl, or substituted benzyl; ^R2 is methyl, isopropyl, n-butyl, benzyl, or p-methoxybenzyl.

In some embodiments, n is 1, ^R1 is methyl, and ^R2 is benzyl.

In some embodiments, n is 2, ^R1 is methyl, and ^R2 is benzyl.

In some embodiments, compound III can be represented by any one of the following formulae III-1 to III-19, wherein Bn represents a benzyl group, PMB represents a p-methoxyphenyl group, and Me represents a methyl group:

In some embodiments, compound III is represented by the following formula III-a or III-b, wherein Bn represents a benzyl group:

The compound III can be used as an intermediate in the preparation of drugs and applied in the drug preparation process. For example, the compound of formula III-a can be used to prepare the drug Tofacitinib (English name: Tofacitinib) after undergoing a carbonyl reduction reaction.

The compound II can be obtained by a known method, or by a cyclization reaction of compound I under certain conditions:

Wherein, R ¹ , R ² , and n are as defined above; R ₀ is a cyano group or an ester group.

In some embodiments, the compound shown in Formula IA is reacted to obtain the compound shown in Formula II-A, and then Compound II is prepared, wherein R ¹ , R ² , and n are as defined above:

The method provided by the present invention does not require the use of hydrogen, and the ee value of the obtained compound III can reach 99% or above.

DETAILED DESCRIPTION

In order to enable those skilled in the art to better understand the technical solution of the present invention, some non-limiting embodiments are further disclosed below to further illustrate the present invention in detail.

The reagents used in the present invention can be purchased from the market or prepared by the method described in the present invention.

In the present invention, g: gram; mL: milliliter; mol: mole; °C: degree Celsius; h: hour; min: minute; °C: degree Celsius; LCMS or LC-MS means liquid chromatography-mass spectrometry; GC-MS means gas chromatography-mass spectrometry; DCM means dichloromethane; TLC means thin layer chromatography.

dr (diastereomeric ratio) value calculation method: dr = (RR + SS) / (RS + SR); ee (enantiomeric excess) value calculation method: ee = ([RR] - [SS]) / ([RR] + [SS]) * 100%. In the present invention, the main product is a cis-configuration product (i.e., RR or SS configuration product), so only the ee value of the main product is calculated; wherein RR represents the content of RR configuration product, SS represents the content of SS configuration product, RS represents the content of RS configuration product, and SR represents the content of SR configuration product.

In the present invention, room temperature refers to ambient temperature, which is 0°C-30°C or 0°C-25°C or 15°C-25°C.

Example 1

Preparation of compound I-1:

Benzylamine (10.12 g, 1.00 eq) and methyl acrylate (8.13 g, 1.0 eq) were added to the reaction bottle, stirred at room temperature for 30 h, and the reaction was monitored by gas chromatography. After the reaction, the reaction solution was concentrated to obtain a transparent oily substance: Compound I-1, 18.03 g, detected by LC-MS: M+H ⁺ =194.2.

Preparation of compound I-2:

p-Benzylamine (14.13 g, 1.10 eq), methyl methacrylate (12.00 g, 1.0 eq) and lithium perchlorate (12.75 g, 1.00 eq) were added to a reaction flask and stirred at room temperature for 26 h. After the reaction was completed, DCM (150 mL) was added for dilution, filtered, and the filtrate was concentrated to obtain a crude compound I-2. The crude product was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:2, volume ratio) to obtain compound I-2: 11.91 g of a transparent oil; detection, LC-MS: M+H ⁺ = 208.2.

Example 2

Preparation of compound II-A1:

Compound I-1 (18.00 g, 1.0 eq), dimethyl oxalate (13.20 g, 1.20 eq), and 30% sodium methoxide solution (20.13 g, 1.20 eq) were added to a reaction flask, and the temperature was raised to reflux for reaction for 6 h. The reaction was controlled to be complete by TLC, and the methanol was concentrated to remove the methanol. 200 ml of water was added to the residual liquid and stirred for 5 min. HCl solution was added dropwise to adjust the pH to 6, and stirred for 30 min. The filter cake crude product (19.2 g) was obtained by suction filtration. 200 ml of methanol was added to the crude product and the temperature was raised to reflux for 1 h. After cooling to room temperature, the compound II-A1 was obtained by suction filtration: 16.8 g of a white solid with a yield of 88.37%. The detection was LC-MS, M+H ⁺ =248.2.

Preparation of compound II-A2:

Compound I-2 (11.91 g, 1.0 eq), diethyl oxalate (10.08 g, 1.2 eq), and 20% sodium ethoxide solution (23.46 g, 1.20 eq) were added to a reaction flask, and the temperature was raised to reflux for reaction for 6 h. The reaction was controlled to be complete by TLC. The ethanol was concentrated to remove the ethanol, and 100 ml of water was added to the residual liquid, and stirred for 5 min. HCl solution was added dropwise to adjust the pH to 6. The mixture was stirred for 30 min and filtered. The crude filter cake was subjected to silica gel column chromatography to obtain compound II-A2: 6.12 g of white solid, with a yield of 52.66%; detection, LC-MS: M+H ⁺ =204.2.

Preparation of compound II-A3:

17.0 g of methyl 5-chlorovalerate, 14.7 g (2 eq) of sodium azide, and 68 ml of N,N-dimethylformamide were added to a 250 mL single-mouth bottle, and the reaction was stopped at 60 ° C for 24 h, and the temperature was cooled to room temperature; 200 mL of water was added, and dichloromethane was extracted (100 mL*3), and the organic phase was dried at 40 ° C to obtain 14.00 g of a light yellow oil. GC-MS detection showed that M = 157.1, which was compound I-3-02;

12g of compound I-3-02 and 13.75g of methyl formate (3eq) were dissolved in 100ml of dichloromethane, the system was cooled to 0°C, 31.9g of titanium tetrachloride (2.2eq) was added dropwise, and 20g of triethylamine (2.6eq) was added dropwise at 0-10°C after the addition was complete. After the addition was complete, the mixture was reacted at 0°C for 2 hours, the reaction was stopped, 100mL of water was slowly added, and the mixture was extracted with ethyl acetate (100mL*3). The organic phase was dried at 40°C to obtain compound I-3-03, 11.8g, with a yield of 83%;

5.0 g of compound I-3-03 and 2.89 g of benzylamine (1.0 eq) were dissolved in 30 ml of acetic acid, and 6.18 g of sodium cyanoborohydride (4.5 eq) were added in batches at room temperature. After the addition, the mixture was reacted at room temperature for 2 hours. The reaction was stopped, and the acetic acid was removed at 50° C., 100 mL of ethyl acetate was added, and the mixture was washed with 1 mol/L sodium hydroxide solution (100 mL*2), and washed once with water (100 mL); the obtained organic phase was dried over anhydrous sodium sulfate, and then dried at 40° C. to obtain compound I-3: 4.5 g of oil, LC-MS: M+H ⁺ =277.3.

Compound I-3 (0.3 g, 1.0 eq), diethyl oxalate (0.19 g, 1.2 eq), and 20% sodium ethoxide solution (0.44 g, 1.20 eq) were added to a reaction flask, and the temperature was raised to reflux for reaction for 3 h. The reaction was completed by TLC control. The ethanol was concentrated to remove the ethanol, and 20 ml of water was added to the residual liquid and stirred for 5 min. HCl solution was added dropwise to adjust the pH to 6. The mixture was stirred for 30 min and filtered. The crude filter cake was subjected to silica gel column chromatography (EA: n-hexane = 1:10, volume ratio) to obtain compound II-A3: 0.12 g of white solid, with a yield of 40%; detection, LC-MS: M+H ⁺ = 273.3.

Preparation of compound II-B1:

Compound II-A1 (5.00 g, 1.0 eq), benzaldehyde (2.03 g, 1.00 eq), and 50 ml of 20% HCl aqueous solution (mass fraction) were added to a reaction flask, heated to 80°C for 6 h, the reaction was completed by TLC, concentrated to remove ethanol, 100 ml of water was added to the residual liquid and stirred for 5 min, extracted with DCM three times, and the organic phases were combined and concentrated to obtain 5.00 g of crude solid. The crude product was recrystallized from 95% ethanol to obtain 3.96 g of pure product with a yield of 79.2%; the obtained intermediate (0.96 g, 1.00 eq) and 10% palladium carbon (50 mg) were added to 50 ml of methanol, and reacted at room temperature under normal hydrogen pressure for 16 h. The reaction was completed by HPLC monitoring, palladium carbon was filtered out, and the filtrate was concentrated to obtain a crude product II-B1. The crude product was recrystallized from anhydrous ethanol to obtain compound II-B1: 0.48 g of white solid, yield: 50%, detection, LC-MS: M+H ⁺ =280.3.

Preparation of compound II-B2:

Compound II-A1 (7.00 g, 1.0 eq), 4-chlorobenzaldehyde (3.77 g, 1.00 eq) and 140 ml of 20% HCl aqueous solution (mass fraction) were added to a reaction bottle, heated to 100 °C for 6 h, and controlled by TLC. After the reaction, the temperature was lowered to 0 °C, filtered, and the filter cake was washed with 50 mL of water and dried in vacuo at 50 °C to obtain 6.0 g of solid.

The obtained intermediate (6.0 g, 1.00 eq) and 10% palladium on carbon (1.2 g) were added to 600 ml of tetrahydrofuran, and the reaction was carried out at room temperature under normal hydrogen pressure for 16 h. The reaction was completed by HPLC monitoring, and the palladium on carbon was filtered out. The filtrate was concentrated to dryness to obtain a crude product II-B2. The crude product was recrystallized from anhydrous ethanol to obtain compound II-B2: 5.0 g of a white solid, with a yield of 83%. Detection, LC-MS: M+H ⁺ =314.1.

Preparation of compound II-B3:

Compound II-A1 (10 g, 1.0 eq), 4-chlorobenzaldehyde (4.29 g, 1.00 eq) and 200 ml of 20% HCl aqueous solution (mass fraction) were added to a reaction bottle, heated to 100°C for 4 h, controlled by TLC, and cooled to 0°C after the reaction was completed. The filter cake was washed with 50 mL of water and dried in vacuo at 50°C to obtain 6.8 g of a solid intermediate.

The obtained intermediate (6.8 g, 1.00 eq) and 10% palladium carbon (6.8 g) were added to 150 ml methanol, and reacted at room temperature under normal hydrogen pressure for 16 h. The reaction was completed by HPLC monitoring, palladium carbon was filtered off, and the filtrate was concentrated to dryness to obtain a crude product II-B3. The crude product was recrystallized from anhydrous ethanol to obtain compound II-B3: 5.2 g white solid, yield: 76.5%. Detection, LC-MS: M+H ⁺ = 285.2.

Preparation of compound II-C1:

Add 5.9g to a 250ml single-mouth bottle N-benzyl-4-methylpiperidine, 150ml tetrahydrofuran and 0.5ml water, slowly add 15.8g iodine under stirring in a water bath, and then slowly add diiodobenzene acetate (20g, 2.0eq); after the addition, transfer to 25°C oil bath for insulation, react for 30min, add diiodobenzene acetate (10g, 1.0eq), continue to react for 1 hour, take a sample for LCMS detection, add saturated sodium thiosulfate (200ml) to the reaction solution after the reaction is complete, extract with DCM (100ml*4), combine the organic phases, dry with anhydrous sodium sulfate, filter, and evaporate the filtrate to dryness under reduced pressure to obtain a crude product II-C1; the crude product is purified by gradient column chromatography with an eluent of n-hexane: ethyl acetate = 10:1→8:1→6:1→4:1→2:1 (volume ratio) to obtain compound II-C1: 7.14g yellow solid, yield 83.4%; detection, LC-MS: M+H ⁺ =218.2.

Example 3

Catalyst screening experiment:

Compound II-A2 (2mmol, 1.00eq), ruthenium catalyst (0.02mmol, 1%eq), and triethylamine (6.5mmol, 3.25eq) were dissolved in 6ml of dichloromethane, and formic acid (2.60mmol, 1.30eq) was slowly added at room temperature. The temperature was then raised to reflux for reaction for 16h. The reaction was monitored by HPLC. After the reaction was completed, the reaction solution was washed three times with water and concentrated by rotary evaporation to obtain a crude product. The crude product was sent for sampling and the isomer content was detected by normal phase HPLC. After silica gel column chromatography, III-1 was obtained: 364mg white solid with a yield of 88.76%. The isomer content was detected by normal phase HPLC, and the ee value and dr value were calculated.

Except for the different catalyst conditions, the reactions were carried out under the same conditions and operations as above. The results obtained with different catalysts are shown in Table 1 below, wherein, except for the catalyst No. 10 which was 0.01 mmol, 0.5% eq, the other catalysts were 0.02 mmol, 1% eq; the conversion rate data were determined by HPLC detection, the isomer content was determined by normal phase HPLC detection, and the ee value and dr value were calculated from the normal phase HPLC data.

Table 1: Reaction results of different catalysts

It can be seen from Table 1 that the reaction results are slightly different for different catalysts. When the catalyst dosage is reduced from 1% eq to 0.5% eq, the raw material is still completely converted and the isomer content is basically unchanged.

Example 4

Preparation of compound III-1

Compound II-A2 (406 mg, 1.00 eq), catalyst (R, R)-Ts-DENEB (7 mg, 0.5% eq), triethylamine (657 mg, 3.25 eq) were added to 6 ml of DCM solvent, and then formic acid (120 mg, 2.60 eq) was slowly added, and the temperature was raised to reflux for reaction; the reaction was terminated by HPLC control for 16 h, the reaction solution was washed three times with water, and concentrated to dryness to obtain a crude product, and the crude product was chromatographed on a silica gel column to obtain compound III-1: 364 mg of a white solid, detection: yield 88.76%, normal phase HPLC detection chiral purity: ee value 98.7%, dr value 98:2; melting point: 70.8 ° C; specific rotation

LC-MS, M+H ⁺ : 206.11;

¹ H NMR (600MHz, CDCl ₃ ) δ7.34 (q, J＝7.2Hz, 2H), 7.30 (dd, J＝12.6, 5.3Hz, 1H), 7.24 (d, J＝7.2Hz, 2H), 4.53 (d,J＝14.6Hz,1H),4.41(dd,J＝13.8,11.2Hz,2H),3.34(dd,J＝9.9,6.3Hz,1H),2.87(dd,J＝9.9,1.9Hz, 1H),2.62-2.54(m,1H),1.01(d,J＝7.0Hz,3H);

¹³ C NMR (101MHz, CDCl ₃ ) δ174.42(s), 135.84(s), 128.74(s), 128.18(s), 127.75(s), 72.17(s), 50.70(s), 46.94(s) ,32.09(s),12.46(s);

HRMS [M+H] ⁺ : C ₁₂ H ₁₅ NO ₂ , calcd: 206.1176, found: 206.1187.

Example 5

Compound III-2 was prepared by referring to the above method: white solid, yield 95.7%, ee value: 96.2%, dr value: 97:3; melting point: 117.1°C; specific rotation

¹ H NMR (400MHz, CDCl ₃ ) δ7.34–7.23(m,3H),7.22–7.16(m,2H),7.14–7.03(m,3H),6.77(d,J＝6.9Hz,2H), 4.59(d,J＝14.5Hz,1H),4.40(d,J＝5.1Hz,1H),4.12(d,J＝14.4Hz,1H),3.87(s,1H),3.05–3.00(m,1H ),2.99(d,J＝4.0Hz,1H),2.87(dd,J＝10.3,2.5Hz,1H),2.66–2.55(m,1H),2.13(dd,J＝13.5,11.6Hz,1H) ;

¹³ C NMR (101MHz, CDCl ₃ ) δ174.23(s), 139.65(s), 135.88(s), 129.05(s), 128.84(s), 128.57(s), 128.40(s), 127.91(s) ,126.12(s),71.95(s),46.94(s),46.85(s),39.71(s),31.91(s);

HRMS [M+H] ⁺ : C ₁₈ H ₁₉ NO ₂ , calcd: 282.1489, found 282.1491.

Example 6

Compound III-3 was prepared by referring to the above method to obtain a white solid with a yield of 89.5%, ee value: 99.1%, dr value: 92:8; melting point: 152.9°C; specific rotation

¹ H NMR (600MHz, CDCl ₃ ) δ7.41–7.32(m,3H),7.26(t,J＝3.0Hz,3H),7.13(d,J＝8.3Hz,2H),6.71(d,J＝ 8.3Hz,2H),4.71(t,J＝14.1Hz,1H),4.43(dd,J＝7.0,1.7Hz,1H),4.12(d,J＝14.4Hz,1H ),3.15(d,J＝2.1Hz,1H),3.09(dd,J＝10.3,6.0Hz,1H),2.99(dd,J＝14.0,4.7Hz,1H),2.87(dd,J＝10.4, 2.4Hz,1H),2.69–2.60(m,1H),2.11(dd,J=14.0,11.1Hz,1H);

¹³ C NMR (101MHz, CDCl ₃ ) δ173.64(s), 137.92(s), 135.80(s), 132.01(s), 130.35(s), 128.91(s), 128.68(s), 128.51(s) ,128.01(s),71.86(s),46.81(s),46.41(s),39.62(s),31.20(s);

HRMS [M+H] ⁺ : calcd. for C ₁₈ H ₁₈ ClNO ₂ : 316.1099; found 316.1106.

Example 7

According to the above method, compound III-4 was prepared as a dark oil with a yield of 76.6%, ee value: 98.5%, dr value: 98:2; specific rotation

¹ H NMR (400MHz, CDCl ₃ ) δ7.41–7.30 (m, 3H), 7.24 (d, J = 7.0Hz, 2H), 4.55–4.41 (m, 2H), 4.39 (d, J = 6.8Hz, 1H),4.19(s,1H),3.34–3.18(m,3H),3.01(dd,J＝10.0,4.5Hz,1H),2.39(dq,J＝13.6,6.9Hz,1H),1.83–1.71 (m,1H),1.68–1.46(m,2H),1.32(ddd,J＝15.8,9.5,4.7Hz,2H);

¹³ C NMR (101MHz, CDCl ₃ ) δ174.45(s), 135.68(s), 128.81(s), 128.19(s), 127.86(s), 71.49(s), 51.46(s), 49.03(s) ,46.84(s),37.17(s),26.79(s),23.98(s);

HRMS [M+H] ⁺ : C ₁₄ H ₁₈ N ₄ O ₂ , calcd: 275.1503; found 275.1492.

Example 8

Compound III-5 was prepared by referring to the above method. The product was a white solid with a yield of 88.1%, ee value of 100%, dr value of 93:7, melting point of 99.6°C, and specific rotation of

¹ H NMR (400 MHz, CDCl ₃ )δ7.42–7.32(m,3H),7.31–7.23(m,2H),7.11(d,J＝5.0Hz,1H),6.89–6.83(m,1H),6.49(d,J＝2.8Hz,1H),4.63(d,J＝14.5Hz,1H),4.50(dd,J＝7.0,2.2Hz ,1H),4.30(d,J＝14.5Hz,1H),3.74(d,J＝2.4Hz,1H),3.30–3.18(m,2H),3.06(dd,J＝10.3,2.6Hz,1H),2.79–2.69(m,1H),2.58(dd,J＝14.8,10.9Hz,1H);

¹³ C NMR (101MHz, CDCl ₃ ) δ173.93(s), 142.00(s), 135.77(s), 128.85(s), 128.39(s), 127.91(s), 126.81(s), 125.67(s) ,123.77(s),71.66(s),47.36(s),46.87(s),39.84(s),26.51(s);

HRMS [M+H] ⁺ : calcd. for C ₁₆ H ₁₇ NO ₂ S: 288.1053; found 288.1044.

Example 9

Referring to the above method, compound III-6 was prepared as a white solid with a yield of 88.3%, ee value: 100%, dr value: 98:2; melting point: 135.9°C; specific rotation

¹ H NMR (400MHz, CDCl ₃ ) δ7.31–7.21(m,3H),7.18(d,J＝7.6Hz,2H),4.52(dd,J＝7.6,4.1Hz,1H),4.49–4.37( m,2H),4.00(d,J＝3.4Hz,1H),3.63(s,3H),3.49(dd,J＝9.9,3.5Hz,1H),3.32(td,J＝7.5,3.6Hz,1H ),3.26(dd,J=9.7,7.5Hz,1H);

¹³ C NMR (101MHz, CDCl ₃ ) δ172.23(s), 170.60(s), 135.26(s), 128.77(s), 128.23(s), 127.89(s), 70.60(s), 52.18(s) ,46.97(s),45.70(s),42.93(s);

HRMS [M+H] ⁺ : Calcd. for C ₁₃ H ₁₅ NO ₄ : 250.1074; found 250.1059.

Example 10

According to the above method, compound III-7 was prepared as a colorless transparent oil with a yield of 82%, ee value: 97.8%, dr value: 98:2; specific rotation

¹ H NMR (400MHz, CDCl ₃ ) δ4.32(t,J＝11.2Hz,1H),3.91(d,J＝15.2Hz,1H),3.43(dt,J＝15.5,7.7Hz,1H),3.28 (t,J＝7.3Hz,2H),2.95(dt,J＝9.6,4.8Hz,1H),2.59(hd,J＝7.0,2.5Hz,1H),1.55–1.45(m,2H),1.32( dt,J＝14.9,7.4Hz,2H),1.05(d,J＝7.1Hz,3H),0.93(t,J＝7.3Hz,3H);

¹³ C NMR (101MHz, CDCl ₃ ) δ174.23(s),72.18(s),51.23(s),42.59(s),32.21(s),29.14(s),19.95(s),13.69(s) ,12.63(s);

HRMS [M+H] ⁺ : C ₉ H ₁₇ NO ₂ , calcd: 172.1332; found 172.1346.

Embodiment 11

According to the above method, compound III-a was prepared as a transparent oil with a yield of 83%, ee value: 99.8%, dr value: 93:7, and specific rotation:

¹ H NMR (400MHz, CDCl ₃ ) δ7.33 (dd, J＝13.7, 6.4Hz, 2H), 7.27 (t, J＝6.9Hz, 3H), 4.69–4.61 (m, 1H), 4.51 (d, J＝14.5Hz,1H),4.18(d,J＝5.3Hz,1H),3.81(s,1H),3.31–3.21(m,1H),3.20–3.11(m,1H),2.48–2.36(m ,1H),2.07–1.95(m,1H),1.77–1.70(m,1H),0.95(d,J＝7.0Hz,3H);

¹³ C NMR (151MHz, CDCl ₃ ) δ172.21(s), 136.58(s), 128.71(s), 128.19(s), 127.68(s), 70.85(s), 50.44(s), 43.59(s) ,30.78(s),26.17(s),11.79(s);

HRMS [M+H] ⁺ : Calcd. for C ₁₃ H ₁₇ NO ₂ : 220.1332; found 220.1314.

Example 12

Lithium aluminum hydride (281 mg, 2.50 eq) was suspended in 6 ml tetrahydrofuran, replaced with nitrogen, protected with nitrogen, and stirred at 0°C; Compound III-a (650 mg, 1.00 eq) was dissolved in 10 ml tetrahydrofuran and added dropwise to the reaction bottle via a syringe. After 15 min of complete addition, stirring was continued for 30 min, and then the temperature was raised to reflux for reaction. After 15 h of reaction, the reaction was monitored by thin layer chromatography, and the reaction was completed. The mixture was placed at 0°C and stirred, and 6 ml of ethyl acetate was added to quench and stir; the reaction solution was poured into 200 ml saturated sodium citrate and stirred for 30 min, 50 ml of ethyl acetate was added and stirred, the organic phases were combined and filtered through a layer of diatomaceous earth, the filtrate was separated, the aqueous phase was extracted with EA twice, and all organic phases were combined and dried over anhydrous sodium sulfate; the filtrate was filtered, and the filtrate was concentrated to dryness to obtain 800 mg of a transparent oil III-a1: (3R, 4R)-1-benzyl-4-methylpiperidin-3-ol, a transparent oil, with a yield of 74%; specific rotation

¹ H NMR (400MHz, CDCl ₃ ) δ7.37–7.24(m,5H),3.59(s,1H),3.53(s,2H),3.03–2.92(m,1H),2.83(dd,J＝11.0 ,1.7Hz,1H),2.53(s,1H),2.17(d,J＝11.2Hz,1H),2.00(td,J＝11.4,3.0Hz,1H),1.59–1.39(m,3H),1.01 (d,J=6.0Hz,3H);

¹³ C NMR (151MHz, CDCl ₃ ) δ 138.32, 128.97, 128.29, 127.12, 69.36, 62.65, 60.09, 53.30, 34.88, 28.38, 17.84;

HRMS [M+H] ⁺ : calcd for C ₁₃ H ₁₉ NO: 206.1539; found 206.1570.

The method of the present invention has been described through preferred embodiments, and relevant personnel can obviously modify or appropriately change and combine the methods and applications described herein within the content, spirit and scope of the present invention to implement and apply the technology of the present invention. Those skilled in the art can refer to the content of this article and appropriately improve the process parameters. It is particularly important to point out that all similar replacements and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention.

Claims (8)

1. A method for preparing compound III, comprising: subjecting compound II to an asymmetric hydrogenation reaction under the action of a ruthenium catalyst and a hydrogen donor reagent, and then subjecting compound II to post-treatment to prepare compound III. in, n is 1, ^R1 is methyl, n-propyl, isopropyl, methyl formate, naphthylmethyl or benzyl, ^R2 is methyl, isopropyl, n-butyl, benzyl or p-methoxybenzyl; or n is 2, ^R1 is methyl, n-propyl, isopropyl, methyl formate, naphthylmethyl or benzyl, ^R2 is methyl, isopropyl, n-butyl, benzyl or p-methoxybenzyl; or Formula II is Formula III is Alternatively, Formula II is Formula III is The ruthenium catalyst is selected from at least one of the compounds represented by the following formulas: (R,R)-Ts-DENEB, (R,R)-Teth-TsDpen, (R,R)-CAT01 to (R,R)-CAT05, and (R,R)-CAT07, wherein i-Pr represents an isopropyl group, Ph represents a phenyl group, and Ts represents a p-toluenesulfonyl group: The hydrogen donor reagent is formic acid and an organic amine, wherein the organic amine is selected from at least one of diethylamine, diisopropylamine, dicyclohexylamine, triethylamine, and N,N-diisopropylethylamine; or the hydrogen donor reagent is a formate salt selected from sodium formate, potassium formate, or a combination thereof. 2. The method according to claim 1, wherein the molar ratio of the ruthenium catalyst to the compound II is 0.0001:1-0.05:1. 3. The method according to claim 1, wherein the molar ratio of the organic amine to the compound II is 10:1-1:1. 4. The method according to claim 1, wherein the molar ratio of formic acid or formate to compound II is 1:1-4:1. 5. The method according to claim 1, wherein the temperature of the asymmetric hydrogenation reaction is 0 to 100°C. 6. The method according to claim 1, wherein the reaction solvent of the asymmetric hydrogenation reaction is at least one of dichloromethane, toluene, tetrahydrofuran, and 2-methyltetrahydrofuran. 7. The method according to claim 1, wherein the post-treatment comprises: after the reaction is completed, washing the reaction solution with water, and removing the solvent by reduced pressure distillation to obtain compound III. 8. The method according to claim 1, wherein n is 1, ^R1 is methyl, and ^R2 is benzyl; or n is 2, ^R1 is methyl, and ^R2 is benzyl.