WO2021093374A1 - Method for synthesizing argatroban hydrate - Google Patents

Abstract

A method for synthesizing an argatroban hydrate. A compound I argatroban monohydrate is obtained by using a compound II as a starting material and an organosilane compound as a reducing agent under the catalytic reduction of an organic amine salt and a nonmetallic boron compound. The method has mild reaction conditions, simple and convenient operation process, and low production cost; the prepared argatroban monohydrate has high purity and yield; and the ratio of the 21(R) and 21(S) isomers is in the range of 64 to 65 : 36 to 35, meeting the pharmaceutical standard.

Description

A kind of synthetic method of argatroban hydrate Technical field

The invention belongs to the technical field of drug synthesis, and specifically relates to a method for synthesizing argatroban hydrate.

Background technique

Argatroban monohydrate is an antithrombotic drug developed by the Mitsubishi Institute of Chemistry in Japan. It was first marketed in Japan in 1990, approved by the US FDA in 2000, and launched in my country in 2002. Argatroban is a synthetic monovalent small molecule direct thrombin inhibitor that can selectively and reversibly bind to the catalytic site of thrombin. It can not only inactivate liquid-phase thrombin, but also inactivate fibrin Thrombin-bound thrombin is mainly used clinically for heparin-induced thrombocytopenia and thrombosis, percutaneous coronary intervention, stroke thrombolysis and other thrombotic diseases, and has a good market prospect.

The chemical name of Argatroban: (2 R ,4 R )-4-methyl-1-[ N -[(3-methyl-1,2,3,4-tetrahydro-8-quinolinyl) Sulfonyl]-L-arginyl]-2-piperidine carboxylic acid; its hydrate is the most commonly used monohydrate, and its chemical composition is a mixture of 21 (R ) and 21 ( S ), usually 64~65:36 ~35(US 6440417B1), its structural formula is:

There are 4 chiral centers in the argatroban molecule. Among them, the chiral centers at position 5 of the arginine fragment and the 7 and 9 positions of the pipecolic acid fragment have a definite configuration, and the tetrahydroquinoline ring is at position 21. There is no definite configuration for the chiral center of. Such chiral centers are prone to racemization when pH and temperature conditions change, which increases the difficulty of argatroban synthesis. Refer to the synthetic methods of argatroban reported in patents EP0008746A1, US4258192A, US4201863A, and EP0823430A1, which mainly mention two synthetic routes, namely the amino-protected method and the non-protected method. These two routes are both formed with nitro-L-arginine as the starting material and formed by different order of condensation with piperidine carboxylate or quinolinsulfonyl chloride. The specific synthesis route is as follows:

Amino protection method:

After the amino group of nitro-L-arginine is protected by Boc, it is condensed with piperidine carboxylic acid ester, the Boc protecting group is removed, and it is condensed with quinoline sulfonyl chloride, ester hydrolyzed, hydrogenated to remove the nitro group and reduce the quinoline ring to obtain Aga Quban (EP0008746A1, CN1951916A, US4258192A, US4201863A, etc.). As shown in route l:

Non-protection law:

Nitro-L-arginine is first condensed with quinoline sulfonyl chloride, then condensed with piperidine carboxylic acid ester, and then subjected to ester hydrolysis, hydrogenation to remove the nitro group and reduction of the quinoline ring to obtain argatroban (US4117127A, EP0823430A1, EP0008746A1 , CN101348481A, etc.). As shown in Route 2:

In the above route 1 and route 2, it is necessary to pass (2 R , 4 R )-1-[(2 S )-5-[[imino(nitroamino)methyl]amino]-2-[[(3 -Methyl-8-quinolinyl)sulfonyl]amino]-1-oxopentyl]-4-methyl-2-piperidine carboxylic acid by hydrogenation reduction to prepare argatroban.

According to patents WO2009124906A2, CN1951916A, CN103509084A, CN105837658A, CN101560244A and the document Bioorganic & Medicinal Chemistry Letters , 11 (2001) 1989-1992, Liu Xiaoli, etc., "Study on the production process and quality standards of anticoagulant argatroban"[D] 2018 , Zhou Ding et al. "Study on the Synthesis Method of Anticoagulant Argatroban" [D] reported in 2013: This process is usually catalyzed by precious metal catalysts (palladium, platinum, ruthenium, rhodium), and hydrogenation reduction reaction takes place to obtain Argatroban. Crude Gajuba. In this type of chemical reaction, the hydrogenation pressure is usually 4-10 MPa, which is a medium-high pressure reaction. It has strict requirements on production sites and production equipment, and the product yield is unstable, which is not conducive to industrialized large-scale production, and hydrogen is flammable and flammable. Explosion is not conducive to safe production.

CN101033223A also reported that when argatroban is prepared through catalytic hydrogenation reaction, a difficult by-product is formed, and its structural formula is as follows:

.

In addition, patent CN105837658A uses (2 R , 4 R )-1-[(2 S )-5-[[imino(nitroamino)methyl]amino]-2-[[(3-methyl-8- Quinolinyl)sulfonyl]amino]-1-oxopentyl]-4-methyl-2-piperidinecarboxylic acid as the starting material, formic acid or formate as the hydrogen donor, catalyzed by 10% palladium on carbon Under the catalytic hydrogen transfer hydrogenation reaction, argatroban is obtained.

Although this reaction avoids the technical and safety problems caused by the use of hydrogen, this type of reduction reaction still uses a relatively expensive metal catalyst, the reaction time is longer, and the reduction of the pyridine ring of the quinoline is not complete, and post-treatment is required. Repeated refining also makes the product yield low.

Patent CN101519429A uses (2 R ,4 R ) -N -Fmoc-4-methyl-2-piperidine carboxylic acid, polymer resin, protected amino acid, coupling reagent and organic base as starting materials to obtain (2 R ,4 R ) -N -Fmoc-4-methyl-2-piperidine carboxylic acid-resin, de-Fmoc protection, and then coupled with Fmoc-Arg(X)-OH, continue de-Fmoc protection, and with 3-methyl-1 , 2,3,4-tetrahydrofuran-8-sulfonyl chloride was condensed, and the side chain protection group was finally removed to obtain crude argatroban.

This method is a solid-phase method to synthesize argatroban. Compared with the liquid-phase method, although the conditions of medium and high pressure reactions are avoided, the synthesis route is more complicated, and the reagents (DMSO, DMF) used have high boiling points, high toxicity, and difficult to recover; In addition, raw materials such as polymer resins and protective amino acids are expensive and costly, and cannot meet the requirements of industrial production.

Patent CN103936821A is based on (2 R , 4 R )-1-[(2 S )-5-[[imino(nitroamino)methyl]amino]-2-[[(3-methyl-8-quinoline Yl)sulfonyl]amino]-1-oxopentyl]-4-methyl-2-piperidinecarboxylic acid as the starting material, formic acid, formate or hydrogen as the hydrogen source, in the chiral catalyst ( A hydrogen transfer reduction reaction occurs under the catalysis of a chiral phosphoric acid catalyst and a chiral sulfonic acid catalyst, and is further purified to obtain the formula I argatroban.

Although this method can effectively obtain the target product with higher ee value, the hand-shaped phosphoric acid or hand-shaped sulfonic acid and other chiral catalysts used in the process are expensive and difficult to recycle, which makes the production cost higher and is not suitable for industrial production. .

Patent CN101914133A uses (2 R , 4 R )-1-[ N ^G -nitro-L-arginyl]-4-methyl-2-piperidinecarboxylic acid ethyl ester hydrochloride as raw material, and (3 S ) -1,2,3,4-tetrahydro-3-methyl-8-quinolinesulfonyl chloride is reacted to obtain intermediate (2 R ,4 R )-1-[ N ^G -nitro- N ² -[(3 S )-1,2,3,4-tetrahydro-3-methyl-8-quinolinesulfonyl]-L-arginyl]-4-methyl-2-piperidinecarboxylate, then in hydrogen Hydrolysis and acidification in sodium oxide aqueous solution, and finally catalytic hydrogenation on palladium-carbon to obtain a single diastereomer 21( S )-argatroban.

The disadvantage of this method is that the raw material (3 S )-1,2,3,4-tetrahydro-3-methyl-8-quinolinesulfonyl chloride is expensive and difficult to obtain, and the catalytic hydrogenation reaction with palladium on carbon needs to be under high pressure conditions. The operation risk is high, which is not conducive to production safety and labor protection.

In summary, in the reported technical methods for preparing argatroban, there are mainly the following problems:

(1) The precious metal catalysts (palladium, platinum, ruthenium, rhodium) used in the reduction of nitro and quinoline rings are expensive, which makes the cost higher and reduces the detection limit of the finished product;

(2) When hydrogen is used as the hydrogen source for the reduction reaction, the reaction conditions are harsh, the equipment requirements are high, and the product yield is unstable;

(3) The 21-position chiral center of the tetrahydroquinoline ring is prone to racemization during the synthesis process, which increases the difficulty of the synthesis of argatroban;

(4) The solid-phase synthesis of argatroban requires expensive raw materials and high cost, which is not conducive to industrial production.

In view of the many problems existing in the prior art, research to find a preparation method suitable for industrial production of argatroban with mild reaction conditions, simple operation process, high product yield, high purity, and low production cost is still a problem that needs to be solved at present. .

Technical solutions

Aiming at the problems existing in the current preparation technology of argatroban, the present invention provides a method for synthesizing argatroban hydrate. The method can effectively avoid the use of precious metal catalysts, has mild reaction conditions, simple operation process, low production cost, and can obtain argatroban monohydrate with higher yield and purity.

The specific technical scheme of the present invention is as follows:

A method for synthesizing argatroban monohydrate, using compound II as a starting material and organosilane compound as a reducing agent to obtain compound I argatroban under the catalytic reduction of organic amine salts and non-metal boron compounds Monohydrate, the reaction formula is as follows:

.

A method for synthesizing argatroban monohydrate, which specifically includes the following steps:

Under the protection of inert gas, add organic amine salt, non-metal boron compound, compound II into the reaction solvent, stir to clear, slowly add hydrogen source (organosilane compound), control the temperature until the reaction is over; after purification hydration treatment Gatroban monohydrate.

Preferably, the organic amine salt is diphenylamine hydrochloride (Ph ₂ NH ₂ Cl), methylphenylamine hydrochloride (PhMeNH ₂ Cl), diisopropylamine hydrochloride ( i- Pr ₂ NH ₂ Cl), particularly preferably diisopropylamine hydrochloride ( i- Pr ₂ NH ₂ Cl); wherein the molar ratio of compound II to organic amine salt is 1:3.5~5.0, particularly preferably 1:4.0 .

Preferably, the non-metal boron compound is triethylboron or tris(pentafluorophenyl)boron; among them, tris(pentafluorophenyl)boron is particularly preferred.

Preferably, the organosilane compound is one of diphenylsilane, diethylsilane, and dimethylphenylsilane; among them, diphenylsilane is particularly preferred.

Preferably, the molar ratio of the compound II to the non-metal boron compound and the organosilane compound is 1:0.05 to 0.20:4.0 to 6.0; among them, 1:0.1:5.0 is particularly preferred.

Preferably, the reaction solvent is one or a combination of dichloromethane, chloroform, 1,4-dioxane, toluene, and benzene; among them, toluene is particularly preferred.

Preferably, the controlled reaction temperature is 40~120°C.

Preferably, the reaction time can determine the reaction end point according to the detection process, and the reaction time is generally 16 to 24 h.

In a preferred embodiment, the post-treatment step is to adjust the pH to neutral after the reaction solution is cooled to room temperature, stand still for layering, and concentrate the organic phase under reduced pressure to dryness to obtain crude argatroban. Further recrystallize and hydrate to obtain compound I argatroban monohydrate. Preferably, the recrystallization solvent is one of ethanol/water and acetonitrile/water; among them, ethanol/water is particularly preferred.

Preferably, the inert gas is nitrogen or argon.

Beneficial effect

Compared with the prior art, the technical effects achieved by the present invention are:

(1) Using non-metal boron compounds as catalysts for reduction reactions can effectively avoid the application of toxic heavy metal palladium compounds or other complex catalysts, improve yield and reduce costs;

(2) The product obtained by adopting the present invention has good appearance, and the ratio of 21(R ) and 21( S ) isomers is 64~65:36~35 and meets the medical standards;

(3) The reaction is mild, the operation is simple, and the harsh reaction conditions such as high pressure and high temperature are not required, and the post-treatment process does not require multiple crystallization steps.

Description of the drawings

Figure 1 HPLC related substance spectrum of crude argatroban obtained in Example 1 of the present invention.

Figure 2 HPLC related substance spectrum of argatroban monohydrate obtained in Example 1 of the present invention.

Fig. 3 The measurement spectrum of the 21-position isomer of argatroban monohydrate obtained in Example 1 of the present invention.

Embodiments of the present invention

The following examples are used to further illustrate the present invention. It should be correctly understood that the examples of the present invention are only used to illustrate the present invention, not to limit the present invention. Therefore, the present invention is simply improved on the premise of the method of the present invention. All belong to the scope of protection of the present invention.

Materials used in the experiment: The CAS number of the compound II is 74874-10-5, and the name is (2 R ,4 R )-1-[(2 S )-5-[[imino(nitroamino)methyl ]Amino]-2-[[(3-methyl-8-quinolinyl)sulfonyl]amino]-1-oxopentyl]-4-methyl-2-piperidinecarboxylic acid, the compound is available on the market Purchased or prepared by referring to existing literature. The materials used in other experiments without indicating the source and specifications are commercially available for analytical or chemical purity; they can be purchased on the market or prepared by referring to existing literature.

The present invention uses HPLC to determine the purity of argatroban, and the chromatographic conditions are as follows:

Chromatographic column: Welch Ultimate XB-C ₁₈ (4.6 mm×150 mm, 3.0 μm);

Mobile phase: acetonitrile-water (60:40)

Column temperature: 25 ℃;

Detection wavelength: 259 nm;

Flow rate: 1.5 mL/min;

Injection volume: 10 μL.

In the following embodiments, various processes and methods that are not described in detail are conventional methods known in the art.

Example 1

Under the protection of nitrogen, diisopropylamine hydrochloride (27.5 g, 0.2 mol), tris(pentafluorophenyl) (2.6 g, 5.0 mmol) boron, (2 R ,4 R )-1-[(2 S )-5-[[Imino(nitroamino)methyl]amino]-2-[[(3-methyl-8-quinolinyl)sulfonyl]amino]-1-oxopentyl]- 4-Methyl-2-piperidinecarboxylic acid (Compound II, 27.5 g, 0.05 mol) was added to toluene (250 mL), stirred to dissolve, and diphenylsilane (46.0 g, 0.25 mol) in toluene solution was slowly added dropwise ( 450 mL), after dripping, the temperature was controlled at 105~110℃ and reacted for 20 hours, the reaction solution was cooled to room temperature, saturated sodium bicarbonate solution was adjusted to neutral pH, and the organic phase was separated into layers and the organic phase was passed through saturated brine ( 200 mL) was washed, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain 24.21 g of crude argatroban, with a yield of 95.2% (calculated as compound II); HPLC: 96.835%. After recrystallization and hydration with ethanol/purified water (V _ethanol : V _water = 1:3, 130 mL) system, the off-white solid is obtained as argatroban monohydrate 24.16g, with a yield of 96.4% (using argatroban) HPLC: 99.866%; the ratio of 21(R ) and 21( S ) isomers is about 64.4:35.6.

Example 2

Under nitrogen protection, add diisopropylamine hydrochloride (24.1 g, 0.175 mol), tris(pentafluorophenyl) boron (2.6 g, 5.0 mmol), and compound II (27.5 g, 0.05 mol) into toluene (250 mol) mL), stir to dissolve, and slowly add diphenylsilane (46.0 g, 0.25 mol) in toluene (450 mL) solution dropwise. After dripping, the temperature is controlled at 105~110°C and reacted for 22 hours, the reaction solution is cooled to room temperature. Adjust the pH to neutral with saturated sodium bicarbonate solution, let stand to separate the organic phase, wash the organic phase with saturated brine (200 mL), dry with anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure to dryness to obtain argatril 24.03g of crude banyan, the yield was 94.5% (based on compound II); HPLC: 96.634%. After recrystallization and hydration with acetonitrile/purified water (V _acetonitrile :V _water =1:3, 130 mL) system, the off-white solid was obtained as argatroban monohydrate 23.71g, and the yield was 95.3% (using argatroban) HPLC: 99.842%; the ratio of 21(R ) and 21( S ) isomers is about 64.3:35.7.

Example 3

Under nitrogen protection, add diisopropylamine hydrochloride (20.6 g, 0.15 mol), tris(pentafluorophenyl) boron (2.6 g, 5.0 mmol), and compound II (27.5 g, 0.05 mol) into toluene (250 mol) mL), stir to dissolve, and slowly add diphenylsilane (46.0 g, 0.25 mol) in toluene (450 mL) solution dropwise. After dripping, the temperature is controlled at 105~110°C and reacted for 24 hours, the reaction solution is cooled to room temperature. Adjust the pH to neutral with saturated sodium bicarbonate solution, let stand to separate the organic phase, wash the organic phase with saturated brine (200 mL), dry with anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure to dryness to obtain argatril The yield of 22.96g of crude ban was 90.3% (calculated as compound II); HPLC: 94.625%. After recrystallization and hydration in acetonitrile/purified water (V _acetonitrile :V _water =1:3, 130 mL) system, the off-white solid was obtained as argatroban monohydrate 22.02g, and the yield was 92.6% (with argatroban) HPLC: 99.762%; the ratio of 21(R ) and 21( S ) isomers is about 64.2:35.8.

Example 4

Under argon protection, add diisopropylamine hydrochloride (34.4 g, 0.25 mol), tris(pentafluorophenyl) boron (2.6 g, 5.0 mmol), and compound II (27.5 g, 0.05 mol) into toluene ( 250 mL), stir to dissolve, and slowly add diphenylsilane (46.0 g, 0.25 mol) in toluene (450 mL) solution dropwise. After the dripping is completed, the temperature is controlled at 105~110°C for 20 hours, and the reaction solution is cooled to room temperature. , Adjust the pH to neutral with saturated sodium carbonate solution, stand still and separate the organic phase, wash the organic phase with saturated brine (200 mL), dry with anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure to dryness to obtain argatril 23.85g of crude banyan, yield 93.8% (calculated as compound II); HPLC: 96.562%. After recrystallization and hydration in ethanol/purified water (V _ethanol : V _water =1:3, 130 mL) system, the off-white solid is obtained as argatroban monohydrate 23.71g, the yield is 96.0% (using argatroban) HPLC: 99.845%; the ratio of 21(R ) and 21( S ) isomers is about 64.3:35.7.

Example 5

Under the protection of argon, add diisopropylamine hydrochloride (37.8 g, 0.275 mol), tris(pentafluorophenyl) boron (2.6 g, 5.0 mmol), and compound II (27.5 g, 0.05 mol) into toluene ( 250 mL), stir to dissolve, and slowly add diphenylsilane (46.0 g, 0.25 mol) in toluene (450 mL) solution dropwise. After dripping, the temperature is controlled at 105~110°C for 18 hours, and the reaction solution is cooled to room temperature. , Adjust the pH to neutral with sodium hydroxide solution, stand still to separate the organic phase, wash the organic phase with saturated brine (200 mL), dry with anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure to dryness to obtain argatril 23.47g of crude bantam, yield 92.3% (calculated as compound II); HPLC: 93.732%. After recrystallization and hydration with ethanol/purified water (V _ethanol : V _water = 1:3, 130 mL) system, the off-white solid was obtained as argatroban monohydrate 22.92g, the yield was 94.3% (using argatroban) HPLC: 99.730%; the ratio of 21(R ) and 21( S ) isomers is about 64.3:35.7.

Example 6

Under nitrogen protection, add diphenylamine hydrochloride (41.1 g, 0.2 mol), tris(pentafluorophenyl) boron (2.6 g, 5.0 mmol), and compound II (27.5 g, 0.05 mol) into toluene (250 mL) After stirring, the solution of diphenylsilane (46.0 g, 0.25 mol) in toluene (450 mL) was slowly added dropwise. After the dripping was completed, the temperature was controlled at 105~110℃ and reacted for 22 hours. The reaction solution was cooled to room temperature, and saturated carbonic acid was used. Adjust the pH of the sodium hydrogen solution to neutral, stand to separate the organic phase, wash the organic phase with saturated brine (200 mL), dry with anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure to dryness to obtain crude argatroban 23.93 g, yield 94.1% (calculated as compound II); HPLC: 96.544%. After recrystallization and hydration with ethanol/purified water (V _ethanol : V _water =1:3, 130 mL) system, the off-white solid was obtained as argatroban monohydrate 23.68g, with a yield of 95.6% (using argatroban) HPLC: 99.843%; the ratio of 21(R ) and 21( S ) isomers is about 64.4:35.6.

Example 7

Under argon protection, add methylphenylamine hydrochloride (28.7 g, 0.2 mol), tris(pentafluorophenyl) boron (2.6 g, 5.0 mmol), and compound II (27.5 g, 0.05 mol) into benzene ( 250 mL), stir to dissolve, and slowly add diphenylsilane (46.0 g, 0.25 mol) in benzene (450 mL) solution dropwise. After dripping, the temperature is controlled at 80~85℃ for 24 hours and the reaction solution is cooled to room temperature. , Adjust the pH to neutral with saturated sodium bicarbonate solution, let stand to separate the organic phase, wash the organic phase with saturated brine (200 mL), dry with anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure to dryness. The crude troban was 23.19 g, and the yield was 91.2% (calculated as compound II); HPLC: 95.941%. After recrystallization and hydration in acetonitrile/purified water (V _acetonitrile :V _water =1:3, 130 mL) system, the off-white solid was obtained as argatroban monohydrate 22.64g, with a yield of 94.3% (using argatroban) HPLC: 99.795%; the ratio of 21(R ) and 21( S ) isomers is about 64.2:35.8.

Example 8

Under argon protection, add diisopropylamine hydrochloride (27.5 g, 0.2 mol), tris(pentafluorophenyl) boron (1.28 g, 2.5 mmol), and compound II (27.5 g, 0.05 mol) into toluene ( 250 mL), stir to dissolve, and slowly add diphenylsilane (46.0 g, 0.25 mol) in toluene (450 mL) solution dropwise. After dripping, the temperature is controlled at 105~110℃ and reacted for 23 hours, and the reaction solution is cooled to room temperature. , Adjust the pH to neutral with saturated sodium bicarbonate solution, let stand to separate the organic phase, wash the organic phase with saturated brine (200 mL), dry with anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure to dryness. The crude troban was 23.44g, the yield was 92.2% (calculated as compound II); HPLC: 95.734%. After recrystallization and hydration in ethanol/purified water (V _ethanol : V _water =1:3, 130 mL) system, the off-white solid is obtained as argatroban monohydrate 22.67g, with a yield of 93.4% (using argatroban) HPLC: 99.783%; the ratio of 21(R ) and 21( S ) isomers is about 64.4:35.6.

Example 9

Under nitrogen protection, add diisopropylamine hydrochloride (27.5 g, 0.2 mol), tris(pentafluorophenyl) boron (1.0 g, 2.0 mmol), and compound II (27.5 g, 0.05 mol) into benzene (250 g, 0.05 mol). mL), stir to dissolve, and slowly add diphenylsilane (46.0 g, 0.25 mol) in benzene (450 mL) solution dropwise. After the dripping is completed, the temperature is controlled at 80~85℃ for 28 hours, and the reaction solution is cooled to room temperature. Adjust the pH to neutral with saturated sodium bicarbonate solution, let stand to separate the organic phase, wash the organic phase with saturated brine (200 mL), dry with anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure to dryness to obtain argatril 21.67 g of crude bantam, yield 85.2% (calculated as compound II); HPLC: 94.394%. After recrystallization and hydration in ethanol/purified water (V _ethanol : V _water =1:3, 130 mL) system, the off-white solid is obtained as argatroban monohydrate 21.20g, the yield is 94.5% (using argatril HPLC: 99.765%; the ratio of 21(R ) and 21( S ) isomers is about 64.4:35.6.

Example 10

Under nitrogen protection, add diisopropylamine hydrochloride (27.5 g, 0.2 mol), tris(pentafluorophenyl) boron (5.1 g, 10.0 mmol), and compound II (27.5 g, 0.05 mol) into toluene (250 mL), stir to dissolve, and slowly add diphenylsilane (46.0 g, 0.25 mol) in toluene (450 mL) solution dropwise. After dripping, the temperature is controlled at 105~110℃ for 16 hours, and the reaction solution is cooled to room temperature. Adjust the pH to neutral with saturated sodium bicarbonate solution, let stand to separate the organic phase, wash the organic phase with saturated brine (200 mL), dry with anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure to dryness to obtain argatril 23.32 g of crude banyan, with a yield of 91.7% (calculated as compound II); HPLC: 96.184%. After recrystallization and hydration in acetonitrile/purified water (V _acetonitrile :V _water =1:3, 130 mL) system, the off-white solid was obtained as argatroban monohydrate 22.63g, and the yield was 93.7% (with argatrole HPLC: 99.734%; the ratio of 21(R ) and 21( S ) isomers is about 64.1:35.9.

Example 11

Under nitrogen protection, add diisopropylamine hydrochloride (27.5 g, 0.2 mol), tris(pentafluorophenyl) boron (6.4 g, 12.5 mmol), and compound II (27.5 g, 0.05 mol) into 1,4 -Dioxane (250 mL), stir to dissolve, and slowly add diphenylsilane (46.0 g, 0.25 mol) in 1,4-dioxane (450 mL) solution dropwise, after dripping, control the temperature to 100 After reacting at ~105℃ for 14 hours, the reaction solution was cooled to room temperature, adjusted to neutral pH with saturated sodium bicarbonate solution, extracted with dichloromethane (300 mL×3), the organic phase was dried with anhydrous magnesium sulfate, filtered, and the filtrate was depressurized Concentrate to dryness to obtain 23.80 g of crude argatroban, with a yield of 93.6% (calculated as compound II); HPLC: 94.627%. After recrystallization and hydration with acetonitrile/purified water (V _acetonitrile :V _water =1:3, 130 mL) system, the off-white solid was obtained as argatroban monohydrate 22.90g, and the yield was 92.9% (with argatroban) HPLC: 99.742%; the ratio of 21(R ) and 21( S ) isomers is about 64.2:35.8.

Example 12

Under nitrogen protection, add diisopropylamine hydrochloride (27.5 g, 0.2 mol), triethylboron (0.5 g, 5.0 mmol), and compound II (27.5 g, 0.05 mol) into toluene (250 mL), Stir and dissolve, slowly add diphenylsilane (46.0 g, 0.25 mol) in toluene (450 mL) solution dropwise. After dripping, the temperature is controlled at 105~110°C and reacted for 22 h, the reaction solution is cooled to room temperature, and saturated hydrogen carbonate is used. Adjust the pH of the sodium solution to neutral, stand still and separate into layers to take the organic phase. The organic phase is washed with saturated brine (200 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate is concentrated under reduced pressure to dryness to obtain 24.05g of crude argatroban. , The yield is 94.6% (calculated as compound II); HPLC: 96.604%. After recrystallization and hydration in ethanol/purified water (V _ethanol : V _water = 1:3, 130 mL) system, the off-white solid is obtained as argatroban monohydrate 23.59g, the yield is 94.7% (using argatroban) HPLC: 99.846%; the ratio of 21(R ) and 21( S ) isomers is about 64.4:35.6.

Example 13

Under nitrogen protection, add diisopropylamine hydrochloride (27.5 g, 0.2 mol), tris(pentafluorophenyl) (2.6 g, 5.0 mmol) boron, and compound II (27.5 g, 0.05 mol) into toluene (250 mol) mL), stir to dissolve, and slowly add diphenylsilane (36.9 g, 0.2 mol) in toluene (450 mL) solution dropwise. After dripping, the temperature is controlled at 105~110°C and reacted for 24 hours, the reaction solution is cooled to room temperature. Adjust the pH to neutral with saturated sodium bicarbonate solution, let stand to separate the organic phase, wash the organic phase with saturated brine (200 mL), dry with anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure to dryness to obtain argatril 23.85g of crude banyan, yield 93.8% (calculated as compound II); HPLC: 95.521%. After recrystallization and hydration with ethanol/purified water (V _ethanol : V _water =1:3, 130 mL) system, the off-white solid is obtained as argatroban monohydrate 23.30g, the yield is 94.3% (using argatroban) HPLC: 99.786%; the ratio of 21(R ) and 21( S ) isomers is about 64.5:35.5.

Example 14

Under nitrogen protection, add diisopropylamine hydrochloride (27.5 g, 0.2 mol), tris(pentafluorophenyl) (2.6 g, 5.0 mmol) boron, and compound II (27.5 g, 0.05 mol) into toluene (250 mol) mL), stir to dissolve, and slowly add diphenylsilane (32.2 g, 0.175 mol) in toluene (450 mL) solution dropwise. After dripping, the temperature is controlled at 105~110°C and reacted for 24 hours, the reaction solution is cooled to room temperature. Adjust the pH to neutral with saturated sodium bicarbonate solution, let stand to separate the organic phase, wash the organic phase with saturated brine (200 mL), dry with anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure to dryness to obtain argatril 21.51 g of crude bantam, yield 84.6% (calculated as compound II); HPLC: 94.726%. After recrystallization and hydration with ethanol/purified water (V _ethanol : V _water =1:3, 130 mL) system, the off-white solid was obtained as 20.85g of argatroban monohydrate, with a yield of 93.6% (using argatroban) HPLC: 99.732%; the ratio of 21(R ) and 21( S ) isomers is about 64.4:35.6.

Example 15

Under nitrogen protection, add diisopropylamine hydrochloride (27.5 g, 0.2 mol), tris(pentafluorophenyl) (2.6 g, 5.0 mmol) boron, and compound II (27.5 g, 0.05 mol) into 1,4 -In dioxane (250 mL), stir to dissolve, slowly add diphenylsilane (55.3 g, 0.3 mol) in 1,4-dioxane (450 mL) solution dropwise, and control the temperature to 100 After 18 hours of reaction at ~105℃, the reaction solution was cooled to room temperature, adjusted to neutral pH with saturated sodium bicarbonate solution, extracted with dichloromethane (300 mL×3), the organic phase was dried with anhydrous magnesium sulfate, filtered, and the filtrate was depressurized After being concentrated to dryness, 23.60 g of crude argatroban was obtained, with a yield of 92.8% (calculated as compound II); HPLC: 95.869%. After recrystallization and hydration with ethanol/purified water (V _ethanol : V _water = 1:3, 130 mL) system, the off-white solid was obtained as argatroban monohydrate 22.95g, with a yield of 93.9% (using argatroban) Based on crude product), HPLC: 99.757%; the ratio of 21(R ) and 21( S ) isomers is about 64.3:35.7.

Example 16

Under the protection of nitrogen, add diisopropylamine hydrochloride (27.5 g, 0.2 mol), tris(pentafluorophenyl) (2.6 g, 5.0 mmol) boron, compound II (27.5 g, 0.05 mol) into toluene (250 mL), stir to dissolve, and slowly add diethylsilane (21.5 g, 0.25 mol) in toluene (450 mL) solution dropwise. After dripping, the temperature is controlled at 105~110℃ and reacted for 22 hours, the reaction solution drops to At room temperature, adjust the pH to neutral with saturated sodium bicarbonate solution, stand still to separate the organic phase, wash the organic phase with saturated brine (200 mL), dry with anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure to dryness. The crude gatroban was 23.32g, the yield was 91.7% (calculated as compound II); HPLC: 96.586%. After recrystallization and hydration in ethanol/purified water (V _ethanol : V _water =1:3, 130 mL) system, the off-white solid is obtained as argatroban monohydrate 22.33g, with a yield of 92.5% (using argatril HPLC: 99.823%; the ratio of 21(R ) and 21( S ) isomers is about 64.3:35.7.

Example 17

Under the protection of argon, add diisopropylamine hydrochloride (27.5 g, 0.2 mol), tris(pentafluorophenyl) (2.6 g, 5.0 mmol) boron, compound II (27.5 g, 0.05 mol) into chloroform (250 mL), stir to dissolve, and slowly add dimethylphenylsilane (34.0 g, 0.25 mol) in chloroform (450 mL) solution dropwise. After the dripping is completed, the temperature is controlled at 60~65℃ and reacted for 24 hours. Cool down to room temperature, adjust the pH to neutral with saturated sodium bicarbonate solution, let stand to separate the organic phase, wash the organic phase with saturated brine (200 mL), dry with anhydrous magnesium sulfate, filter, and concentrate the filtrate to dryness under reduced pressure 23.04g of crude argatroban was obtained, with a yield of 90.6% (calculated as compound II); HPLC: 96.384%. After recrystallization in ethanol/purified water (V _ethanol :V _water =1:3, 130 mL) system, the off-white solid is 22.45g argatroban, the yield is 94.1% (calculated as the crude argatroban) , HPLC: 99.796%; the ratio of 21(R ) and 21( S ) isomers is about 64.4:35.6.

Claims (9)

1. A method for synthesizing argatroban hydrate, which is characterized in that compound II is used as a starting material, an organosilane compound is used as a reducing agent, and compound I is obtained under the catalytic reduction of an organic amine salt and a non-metal boron compound. Gatroban monohydrate, the reaction formula is as follows:

   

   .
2. The synthesis method according to claim 1, characterized in that it specifically comprises the following steps: under the protection of an inert gas, adding organic amine salts, non-metal boron compounds, and compound II to the reaction solvent, stirring to dissolve, and slowly adding a hydrogen source That is, the organosilane compound, the temperature is controlled to the end of the reaction, and the compound I argatroban monohydrate is obtained after purification and hydration.
3. The synthesis method according to claim 1 or 2, wherein the organic amine salt is one of diphenylamine hydrochloride, methylphenylamine hydrochloride, and diisopropylamine hydrochloride.
4. The synthesis method according to claim 1 or 2, wherein the non-metal boron compound is triethylboron or tris(pentafluorophenyl)boron.
5. The synthesis method according to claim 1 or 2, wherein the organosilane compound is one of diphenylsilane, diethylsilane, and dimethylphenylsilane; among them, diphenylsilane is particularly preferred .
6. The synthesis method according to claim 2, wherein the reaction solvent is one or a combination of dichloromethane, chloroform, 1,4-dioxane, toluene, and benzene.
7. The synthesis method according to claim 2, wherein the molar ratio of compound II to organic amine salt, non-metal boron compound, and organosilane compound is 1:3.5~5.0:0.05~0.20:4.0~6.0.
8. The synthesis method according to claim 2, wherein the reaction temperature is 40~120°C.
9. The synthesis method according to claim 2, characterized in that the post-treatment step is to adjust the pH to neutral after the reaction solution is cooled to room temperature, stand still for layering, and concentrate the organic phase under reduced pressure to dry to obtain the crude argatroban; Argatroban monohydrate is obtained by purified hydration.