A method for catalytically preparing a perindopril intermediate

Abstract

The present invention discloses a method for catalytically preparing an intermediate of perindopril, wherein the method uses metal ruthenium or platinum ruthenium alloy as a catalyst, can obtain a target product with high selectivity, the product ee value reaches more than 99%, and the generation of dechlorination products is effectively avoided. Continuous hydrogenation adopts a micro-filled bed filled with loaded granular ruthenium or ruthenium platinum alloy for catalysis. Compound I is cyclized in a solvent to generate (2S, 3aS, 7aS)-2-carboxylic acid octahydroindole (compound II). Similarly, the hydrogenation liquid of compound I enters a microchannel reactor through a delivery pump, and an acid binding agent is delivered by another pump for continuous production to obtain compound II.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and in particular to the preparation of compounds S-2-amino-3-((1S, 2S)-2-chlorocyclohexyl) propionic acid (or analogs) and (2S, 3aS, 7aS)-2-carboxylic acid octahydroindole (intermediate of perindopril). Background Art

[0002] Perindopril, also known as Silvastatin, is a third-generation thiol-free angiotensin-converting enzyme inhibitor (ACEI). It has high tissue affinity and a long half-life, and is widely used in the treatment of heart failure and primary hypertension. The active metabolite Perindoprilat, which is hydrolyzed after oral administration, is the main active metabolite.

[0003] At present, there is no literature report on compound I in this application, and there are many literature reports on compound II. This case only compares the synthetic routes related to this case.

[0004]

[0005] The key point of this route is the preparation of (S)-dihydroindole-2-carboxylic acid, and there are many synthetic methods in the literature.

[0006] (1) CN104672124B discloses that o-chlorobenzaldehyde and acetylglycine are used as starting materials to first obtain S-o-chlorophenylalanine, which is then cyclized to obtain (2S)-dihydroindole-2-carboxylic acid, which is then hydrogenated to obtain compound II. The yield of the cyclization step is relatively low, and copper salt catalysis is required.

[0007] (2) Racemic indole-2-carboxylic acid is used as a raw material, firstly reduced to obtain racemic dihydroindole-2-carboxylic acid, and then chiral split by a splitting method to obtain (2S)-dihydroindole-2-carboxylic acid. The reducing agent used includes tin powder / hydrogen chloride gas, etc., which is highly polluting, difficult to post-process, and has a low yield of chiral splitting, serious waste of raw materials, and poor economic benefits.

[0008] (3) Using L-phenylalanine as the starting material, a chlorination reaction is first carried out at the ortho position of the benzene ring, and a dichloro product is generated during the chlorination. Then, (2S)-dihydroindole-2-carboxylic acid is prepared through intramolecular cyclization. The yield is low, and the chlorination reaction requires the passage of chlorine gas, which is less safe. Summary of the invention

[0009] In view of the problems existing in the prior art, the purpose of the present invention is to provide a method for preparing a perindopril intermediate, and the preparation process route is as follows: the post-treatment of the present invention is simple and convenient, and the yield is high, which is not described in the currently disclosed preparation method of compound I.

[0010]

[0011] The specific preparation process is as follows:

[0012] The compound represented by o-halogenated phenylalanine is mixed in a solvent, a catalyst is added, and a hydrogenation reaction is carried out in a hydrogenation reactor or a continuous micro-packed bed. The reaction is controlled at a suitable temperature. After the reaction is complete, the obtained hydrogenated liquid can be post-treated to obtain compound I or can be directly used to prepare compound II without treatment. Compound II is obtained in high yield and the product quality is excellent.

[0013] The solvent used in the synthesis process of compound I is a mixture of one or more of methanol, ethanol, isopropanol, n-butanol, ethylene glycol, glycerol, acetonitrile, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, ethylene glycol dimethyl ether and water. The amount of solvent added is 2-20 times the weight of the raw material, and the weight ratio of the solvent during continuous hydrogenation is 10-20 times the weight of the raw material. The catalyst used in the reaction is one of ruthenium carbon, platinum carbon, and ruthenium platinum alloy carbon. The catalyst has a powdered catalyst adapted to the kettle type, a granular or columnar catalyst adapted to the micro-filled bed. The weight ratio of the catalyst to compound II is 0.005-0.05:1. The catalyst for continuous hydrogenation can meet the continuous hydrogenation for more than 2000 hours at one time, greatly reducing the amount of catalyst and labor, and can significantly reduce production costs.

[0014] The reaction temperature of the continuous hydrogenation reaction is 60°C-150°C, and the hydrogen pressure ranges from 1.5MPa to 5.0MPa. The solvent is one or more of methanol, ethanol, isopropanol, and water. The continuous hydrogenation process is as follows Figure 1 shown.

[0015] In the synthesis of compound I, the reaction temperature of the catalytic reaction is 20°C-80°C, and the hydrogen pressure ranges from 0.5MPa to 5.0MPa. The reaction temperature of the continuous hydrogenation reaction is 60°C-150°C, and the hydrogen pressure ranges from 1.5MPa to 5.0MPa.

[0016] In the synthesis method of compound II, the acid-binding agent is one or more of triethylamine, diisopropylethylamine, pyridine, DBU, sodium alcoholate, potassium alcoholate, sodium hydroxide, potassium hydroxide, potassium carbonate and other commonly used organic bases or inorganic bases. The molar ratio of the above acid-binding agent to compound I is 1-3:1. The solvent is one or more of methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, ethylene glycol dimethyl ether, dimethyl sulfoxide and water. The mass of the solvent is 2-15 times the mass of compound II. The reaction temperature range is between -10°C and 90°C.

[0017] The present invention relates to a catalytic hydrogenation synthesis method for the intermediate (compound I) of perindopril in a kettle and continuously by hydrogenation. The method uses metal ruthenium or platinum-ruthenium alloy as a catalyst, can obtain the target product with high selectivity, the product ee value reaches more than 99%, and the generation of dechlorination products is effectively avoided.

[0018] Instruction Manual

[0019] Figure 1 This is a diagram of the continuous hydrogenation process of the present invention. DETAILED DESCRIPTION

[0020] The technical solution of the present invention is described below through specific embodiments to facilitate a better understanding of the technical solution.

[0021] Example 1

[0022]

[0023] In a 2L autoclave, add 120g of S-o-chlorophenylalanine, 1000ml of methanol, and 5g of 10% ruthenium carbon (dry basis). After sealing the autoclave, nitrogen and hydrogen replacement are carried out according to the standard operating procedures of high-pressure hydrogenation standards. Raise the temperature to 60-70°C, introduce hydrogen pressure to 5.0MPa, maintain the pressure in the range of 4.5-5MPa until the pressure does not change, and then keep warm for 3h. After the insulation reaction is completed, cool to 20-30°C and replace with nitrogen according to the standard operating procedures of high-pressure hydrogenation standards. Sampling and analysis of the reaction solution require o-chlorophenylalanine <0.5% and dechlorinated impurities <0.3%. Filter to remove the catalyst, concentrate the filtrate under reduced pressure to a volume of 400-500ml, and add 1500ml of crystallization. Filter to obtain S-2-amino-3-((1S,2S)-2-chlorocyclohexyl) propionic acid (Compound I). Dry to obtain 120.6g (97.6%) of white solid. The ee value is 99.4%. 1 H NMR(400MHz, Deuterium Oxide,KOH)δ3.26(dd,J=7.9,5.8Hz,1H),3.10(m,1H),1.75–1.55(m,3H),1.52–1.40(m ,1H),1.39–1.28(m,2H),1.16(dddt,J=24.2,15.0,12.2,6.0Hz,3H),0.98–0.80(m,2H).

[0024] Add the product from the first step, 1200ml of DMF, and 125g of triethylamine to a 2L four-necked flask, heat to 60-70°C and react for 8-10h. After the reaction is complete, concentrate to dryness under reduced pressure. Add 1500ml of water to the remaining solid, adjust the pH to 8 with sodium bicarbonate, and a large amount of white solid precipitates. Filter to obtain compound II, and vacuum dry to obtain 93.3g (94.1%) of white solid, with an ee value of 99.6%. 1 HNMR(400MHz,Deuterium Oxide)δ4.05(dd,J=9.4,6.6Hz,1H),3.64(dt,J=7.5,5.4Hz,1H),2.36–2.22(m,2H),2 .01–1.88(m,J=6.0,5.5Hz,1H),1.77(ddt,J=13.3,8.5,4.3Hz,1H),1.65–1.21(m,7H).

[0025] Example 2

[0026] In a 2L autoclave, add 120g of S-o-chlorophenylalanine, 1000ml of methanol, and 7g of 5% platinum carbon (dry basis). After sealing the autoclave, nitrogen and hydrogen replacement are carried out according to the standard operating procedures of high-pressure hydrogenation standards. Heat to 60-70°C, introduce hydrogen pressure to 5.0MPa, maintain the pressure in the range of 4.5-5MPa until the pressure does not change, and then keep warm for 3h. After the insulation reaction is completed, cool to 20-30°C, and nitrogen replacement is carried out according to the standard operating procedures of high-pressure hydrogenation standards. Filter to remove the catalyst, concentrate the filtrate under reduced pressure to a volume of 400-500ml, and add 1500ml of crystallization. Filter to obtain S-2-amino-3-((1S, 2S)-2-chlorocyclohexyl) propionic acid (Compound I). Dry to obtain 117.6g (95.1%) of white solid. ee value 99.2%.

[0027] Add the product from the first step, 1200ml of DMF, and 120g of triethylamine to a 2L four-necked flask, heat to 60-70°C and react for 8-10h. After the reaction is complete, concentrate to dryness under reduced pressure. Add 1500ml of water to the remaining solid, adjust the pH to 8 with sodium bicarbonate, and a large amount of white solid precipitates. Filter to obtain compound II, and vacuum dry to obtain 90.3g (94%) of white solid, with an ee value of 99.5%.

[0028] Example 3

[0029] In a 2L autoclave, add 120g of S-o-chlorophenylalanine, 1000ml of methanol, and 5g of 10% ruthenium carbon (dry basis). After sealing the autoclave, nitrogen and hydrogen replacement are carried out according to the standard operating procedures of high-pressure hydrogenation standards. Raise the temperature to 60-70°C, introduce hydrogen pressure to 5.0MPa, maintain the pressure in the range of 4.5-5MPa until the pressure does not change, and then keep the reaction warm for 3h. After the insulation reaction is completed, cool to 20-30°C and replace with nitrogen according to the standard operating procedures of high-pressure hydrogenation standards. Sampling and analysis of the reaction solution requires o-chlorophenylalanine <0.5% and dechlorinated impurities <0.3%. The catalyst was removed by filtration, 120 g of 30% sodium hydroxide solution was added dropwise to the filtrate, the temperature was raised to 60-65°C and the reaction was carried out for 4-5 h. After the reaction, the pH value was adjusted to 8 using 5% sodium bicarbonate. A large amount of white solid was precipitated and filtered to obtain compound II. The white solid was dried in vacuo to obtain 95.7 g (two-step yield 94.1%), and the ee value was 99.5%.

[0030] Example 4

[0031] In a 5L flask, 240g of S-o-chlorophenylalanine and 3000ml of methanol were added, and stirred to dissolve and set aside. 15ml of granular 5% ruthenium carbon catalyst was filled into the micro-packed bed, hydrogen was purged and preheated to 110°C, and the liquid phase pump was turned on to pump the liquid to be hydrogenated into the gas-liquid mixer (liquid phase flow rate 1.5ml / min, gas phase flow rate 25ml / min), and then the hydrogenation liquid was obtained after catalysis by the catalyst. The sampling and analysis of the hydrogenation liquid met the requirements of the sampling and analysis of the reaction liquid for o-chlorophenylalanine <0.5%, and the requirements of dechlorination impurities <0.3%. The hydrogenation liquid after gas-liquid separation entered the plate microchannel and was pumped into 5% sodium hydroxide solution from another inlet. The reaction temperature was 85°C, and the reaction time in the microchannel was 4 minutes to complete the conversion. The reaction solution of compound II was adjusted to pH 8 with 5% sodium bicarbonate, and a large amount of white solid was precipitated. Compound II was obtained by filtration, and the ee value was 99.6%.

[0032] Example 5

[0033] At room temperature, add 600 mL of 2-methyltetrahydrofuran, 67.6 g of compound II and 35 g of triethylamine in a 2L four-necked flask, stir, and pass nitrogen protection. Add 50 g of trimethylsilyl chloride and stir at room temperature for 2 hours. Cool to -5-5°C in an ice bath, then slowly drop N-[(S)-1-butyryl chloride]-S-pentanine ethyl ester in 2-methyltetrahydrofuran solution (126 g / 500 mL). After the addition is complete, react at 0-5°C for 4 hours. HPLC monitoring shows that the content of compound II is less than 1%, and the reaction is complete. Filter, take the filtrate and concentrate to dryness, add 600 ml of dichloromethane to the residue, and adjust the pH value to 6 with 5% ammonia solution, and separate the layers. The aqueous phase is extracted twice with 100 mL of dichloromethane, the organic phases are combined, dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated under reduced pressure to obtain a red oily substance, which is perindopril. Add 400 ml of methyl isobutyl ketone to dissolve, slowly add 51.0 g of tert-butylamine dropwise to precipitate a white solid. Heat to 60-65°C and stir for 30 minutes, then slowly cool to 10-15°C to crystallize for 3 hours, filter, and wash with methyl isobutyl ketone to obtain 209.8 g of crude perindopril tert-butylamine salt, with a yield of 87.1%, a purity of 99.6%, and an ee value of 99.7%.

Claims

1. A method for preparing compound (I) by catalysis, characterized in that: The synthesis method uses S-ortho-halogen substituted phenylalanine as a raw material, adds it to a polar solvent, and prepares compound (I) under the action of a catalyst and a hydrogenation reaction. The reaction formula is as follows: Wherein, R is Cl; The catalyst is one of ruthenium carbon, platinum carbon, and ruthenium platinum alloy carbon. The catalyst is in the form of a powdered catalyst suitable for a kettle, or a granular or columnar catalyst suitable for a micro-filled bed. The weight ratio of the catalyst to compound I is 0.005-0.05:

1. In the autoclave reaction, the polar solvent is selected from one or more of methanol, ethanol, isopropanol, n-butanol, ethylene glycol, glycerol, acetonitrile, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, ethylene glycol dimethyl ether and water, and the amount of the polar solvent added is 2-20 times the mass of compound I; The reaction temperature is 20-80°C, and the hydrogen pressure ranges from 0.5 to 5.0 MPa; The reaction temperature of the continuous hydrogenation reaction is 60-150°C, and the hydrogen pressure ranges from 1.5-5.0 MPa.

2. A synthetic method for preparing compound (II), characterized in that: The synthesis method uses compound (I) as a raw material, and obtains compound (II) by heating in a solvent and under the action of an acid-binding agent. The reaction formula is as follows: ； The acid-binding agent is one or more of triethylamine, diisopropylethylamine, pyridine, DBU, sodium alcoholate, potassium alcoholate, sodium hydroxide, potassium hydroxide, and potassium carbonate; the molar ratio of the acid-binding agent to the compound (I) is 1-3:1; The solvent is one or more of methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and water, and the amount of the solvent added is 2-15 times the mass of compound II; The reaction temperature ranges from -10°C to 90°C.

3. A synthetic method for preparing compound (II) as claimed in claim 1, characterized in that: The reactor is a batch reactor or a continuous flow reactor.

Images