CN110981934A

CN110981934A - Synthetic method of argatroban hydrate

Info

Publication number: CN110981934A
Application number: CN201911097907.3A
Authority: CN
Inventors: 于成彬; 王秀娟
Original assignee: Lunan Pharmaceutical Group Corp
Current assignee: Lunan Pharmaceutical Group Corp
Priority date: 2019-11-12
Filing date: 2019-11-12
Publication date: 2020-04-10
Anticipated expiration: 2039-11-12
Also published as: WO2021093374A1; CN110981934B

Abstract

The invention belongs to the technical field of drug synthesis, and particularly relates to a synthesis method of argatroban hydrate. The method disclosed by the invention has the advantages of mild reaction conditions, simple and convenient operation process and low production cost, and the prepared argatroban monohydrate has higher purity and yield; the ratio of the 21(R) isomer to the 21(S) isomer is 64-65: 36-35, and meets the pharmaceutical standard.

Description

Synthetic method of argatroban hydrate

Technical Field

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

Background

Argatroban (argatroban monohydrate) is an antithrombotic drug developed by Mitsubishi chemical research institute in japan and first marketed in 1990, approved by the U.S. FDA in 2000, and marketed in 2002. Argatroban is a synthetic monovalent small molecule direct thrombin inhibitor, can be selectively and reversibly combined with thrombin catalytic sites, can inactivate liquid phase thrombin, can inactivate thrombin combined with fibrin thrombus, is mainly used for heparin-induced thrombocytopenia and thrombosis, percutaneous coronary intervention treatment, cerebral apoplexy thrombolysis and other thrombotic diseases clinically, and has good market prospect.

Chemical name of argatroban: (2R,4R) -4-methyl-1- [ N- [ (3-methyl-1, 2,3, 4-tetrahydro-8-quinolinyl) sulfonyl ] -L-arginyl ] -2-piperidinecarboxylic acid; the hydrate is the most common monohydrate, the chemical composition of the hydrate is a mixture of 21(R) and 21(S), usually 64-65: 36-35 (US 6440417B1), and the structural formula is as follows:

the argatroban molecule has 4 chiral centers, wherein the chiral centers at the 5-position of the arginine fragment and the 7-and 9-positions of the piperidinecarboxylic acid fragment have a defined configuration, while the chiral center at the 21-position of the tetrahydroquinoline ring has no defined configuration. When the conditions of pH and temperature are changed, the chiral center is easy to racemize, so that the synthesis difficulty of argatroban is increased. With reference to the synthesis of argatroban reported in patents EP0008746a1, US4258192A, US4201863A, EP0823430a1, two synthetic routes are mainly mentioned, respectively amino-protected and unprotected. The two routes are both formed by taking nitro-L-arginine as a starting material and condensing with piperidine carboxylate or quinuclidine chloride in different orders.

The specific synthetic route is as follows:

amino protection method:

amino of nitro-L-arginine is Boc protected, condensed with piperidine carboxylate, Boc protecting group removed, condensed with quinoline sulfonyl chloride, ester hydrolyzed, and hydrogenated to remove nitro and reduce quinoline ring to obtain argatroban (EP0008746A1, CN1951916A, US4258192A, US4201863A, etc.). As shown in route i:

a non-protection method:

the nitro-L-arginine is firstly condensed with quinoline sulfonyl chloride, then condensed with piperidine carboxylate, and then subjected to ester hydrolysis, hydrogenation for removing nitro and reducing quinoline ring to obtain argatroban (US4117127A, EP0823430A1, EP0008746A1, CN101348481A and the like).

As shown in scheme 2:

in both scheme 1 and scheme 2 above, argatroban is prepared by the hydrogenation reduction of (2R,4R) -1- [ (2S) -5- [ [ imino (nitroamino) methyl ] amino ] -2- [ [ (3-methyl-8-quinolinyl) sulfonyl ] amino ] -1-oxopentyl ] -4-methyl-2-piperidinecarboxylic acid.

The methods for producing anticoagulant argatroban and the research on the quality standards thereof, such as WO2009124906A2, CN1951916A, CN103509084A, CN105837658A and CN101560244A, and the research on the synthetic method of anticoagulant argatroban, such as Liu Xiao & Medicinal Chemistry Letters,11(2001) 1989-: the process usually carries out hydrogenation reduction reaction under the catalysis of noble metal catalysts (palladium, platinum, ruthenium and rhodium) to obtain the argatroban crude product. In the chemical reaction, the hydrogenation pressure is usually 4-10 MPa, the reaction belongs to medium-high pressure reaction, strict requirements are imposed on production places and production equipment, the product yield is unstable, the industrial large-scale production is not facilitated, and hydrogen is flammable and explosive, and the safety production is not facilitated.

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

in addition, patent CN105837658A discloses that argatroban is obtained by subjecting (2R,4R) -1- [ (2S) -5- [ [ imino (nitroamino) methyl ] amino ] -2- [ [ (3-methyl-8-quinolyl) sulfonyl ] amino ] -1-oxopentyl ] -4-methyl-2-piperidinecarboxylic acid as a starting material and formic acid or a formate salt as a hydrogen donor to catalytic hydrogen transfer hydrogenation under the catalysis of 10% palladium on charcoal.

Although the reaction avoids the technical and safety problems caused by using hydrogen, the reduction reaction still uses a metal catalyst with higher price, the reaction time is longer, the reduction of the pyridine ring of quinoline is not complete, the aftertreatment needs to be repeatedly refined, and the product yield is lower.

Patent CN101519429A uses (2R,4R) -N-Fmoc-4-methyl-2-piperidinecarboxylic acid, polymer resin, protected amino acid, coupling reagent and organic base as starting materials to obtain (2R,4R) -N-Fmoc-4-methyl-2-piperidinecarboxylic acid-resin, removes Fmoc protection, couples with Fmoc-Arg (X) -OH, continues to remove Fmoc protection, and condenses with 3-methyl-1, 2,3, 4-tetrahydrofuran-8-sulfonyl chloride, finally removes side chain protecting group to obtain crude argatroban.

Compared with a liquid phase method, the method for synthesizing argatroban by a solid phase method avoids medium-high pressure reaction conditions, but has a complex synthetic route, and used reagents (DMSO and DMF) have high boiling points and high toxicity and are not easy to recover; and the raw materials such as the polymer resin, the protected amino acid and the like are expensive and have higher cost, and the requirements of industrial production cannot be met.

Patent CN103936821A takes (2R,4R) -1- [ (2S) -5- [ [ imino (nitroamino) methyl ] amino ] -2- [ [ (3-methyl-8-quinolyl) sulfonyl ] amino ] -1-oxopentyl ] -4-methyl-2-piperidinecarboxylic acid as an initiator, and one of formic acid, formate or hydrogen as a hydrogen source, and performs hydrogen transfer reduction reaction under the catalysis of a chiral catalyst (a chiral phosphoric acid catalyst and a chiral sulfonic acid catalyst) to further purify to obtain the argatroban of formula I.

Although the method can effectively obtain the target product with higher ee value, chiral catalysts such as chiral phosphoric acid or chiral sulfonic acid used in the process are higher in price and difficult to recover, so that the production cost is higher, and the method is not suitable for industrial production.

Patent CN101914133A with (2R,4R) -1- [ N ]^G-nitro-L-arginyl]The (4-methyl-2-ethyl piperidine) formate hydrochloride is used as a raw material to react with (3S) -1,2,3, 4-tetrahydro-3-methyl-8-quinoline sulfonyl chloride to obtain an intermediate (2R,4R) -1- [ N^G-nitro-N²- [ (3S) -1,2,3, 4-tetrahydro-3-methyl-8-quinolinesulfonyl]-L-arginyl]4-methyl-2-piperidine formate, hydrolyzing in sodium hydroxide water solution, acidifying, and catalytic hydrogenation with palladium-carbon to obtain the final productThe single diastereomer, 21(S) -argatroban.

The method has the disadvantages that the raw material (3S) -1,2,3, 4-tetrahydro-3-methyl-8-quinoline sulfonyl chloride is expensive and difficult to obtain, and the catalytic hydrogenation reaction by palladium-carbon needs to be carried out under high pressure, so that the operation danger is high, and the production safety and labor protection are not facilitated.

In summary, in the reported technical process for the preparation of argatroban, the following problems mainly exist:

(1) noble metal catalysts (palladium, platinum, ruthenium and rhodium) used in the reduction of the nitro group and the quinoline ring are expensive, so that the cost is high, and the detection limit of a finished product is reduced;

(2) when hydrogen is used as hydrogen source to carry out reduction reaction, the reaction conditions are harsh, the requirements on equipment are high, and the product yield is unstable;

(3) the 21-site chiral center of the tetrahydroquinoline ring is easy to racemize in the synthesis process, so that the synthesis difficulty of argatroban is increased;

(4) the solid phase method for synthesizing argatroban has expensive raw materials and higher cost, and is not beneficial to industrial production.

In view of more problems in the prior art, the research and search for a preparation method which has mild reaction conditions, simple and convenient operation process, high product yield, high purity and low production cost and is suitable for the industrial production of argatroban still needs to solve the problems at present.

Disclosure of Invention

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

The specific technical scheme of the invention is as follows:

a synthesis method of argatroban monohydrate takes a compound II as an initial raw material, takes an organosilane compound as a reducing agent, and obtains the argatroban monohydrate of the compound I under the catalytic reduction of organic amine salt and a non-metallic boron compound, wherein the reaction formula is as follows:

a synthetic method of argatroban monohydrate specifically comprises the following steps:

under the protection of inert gas, adding organic amine salt, a non-metal boron compound and a compound II into a reaction solvent, stirring for dissolving, slowly adding a hydrogen source (an organosilane compound), and controlling the temperature until the reaction is finished; the argatroban monohydrate is prepared by purification and hydration treatment.

Preferably, the organic amine salt is diphenylamine hydrochloride (Ph)₂NH₂Cl), methylphenylamine hydrochloride (PhMeNH)₂Cl), diisopropylamine hydrochloride (i-Pr)₂NH₂Cl), particularly preferably diisopropylamine hydrochloride (i-Pr)₂NH₂Cl); wherein the molar ratio of the compound II to the organic amine salt is 1: 3.5 to 5.0, particularly preferably 1: 4.0.

preferably, the non-metallic boron-based compound is triethylboron or tris (pentafluorophenyl) boron; of these, tris (pentafluorophenyl) boron is particularly preferable.

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

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

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

Preferably, the reaction temperature is controlled to be 40-120 ℃.

Preferably, the reaction time can be determined according to the detection process, and the reaction time is generally 16-24 h.

In a preferable scheme, the post-treatment step is that the reaction solution is cooled to room temperature, then the pH value is adjusted to be neutral, the reaction solution is kept stand for layering, and the organic phase is subjected to pressure reduction and concentration to be dry to obtain the argatroban crude product. Further recrystallizing and hydrating to obtain the compound I argatroban monohydrate. Preferably, the recrystallization solvent is one of ethanol/water, acetonitrile/water; among them, ethanol/water is particularly preferable.

Preferably, the inert gas is nitrogen or argon.

Compared with the prior art, the invention has the following technical effects:

(1) the non-metal boron compound is used as the catalyst for reduction reaction, so that the application of heavy metal palladium compound with high toxicity or other complex catalysts can be effectively avoided, the yield is improved, and the cost is reduced;

(2) the product obtained by the method has good appearance, and the ratio of 21(R) isomers to 21(S) isomers is 64-65: 36-35, so that the product meets the medicinal standard;

(3) the method has the advantages of mild reaction, simple operation, no need of harsh reaction conditions such as high pressure, high temperature and the like, and no need of multiple crystallization and other steps in the post-treatment process.

Drawings

FIG. 1 HPLC chromatogram of crude argatroban obtained in example 1 of the present invention.

FIG. 2 HPLC chromatogram of Argatroban monohydrate obtained in example 1 of the present invention.

FIG. 3 is a chart showing the measurement of 21-position isomer of argatroban monohydrate obtained in example 1 of the present invention.

Detailed Description

The invention is further illustrated by the following examples, which should be properly understood: the examples of the present invention are merely illustrative and not restrictive, and therefore, the present invention may be modified in a simple manner without departing from the scope of the invention as claimed.

Materials used in the experiment: the compound II has a CAS number of 74874-10-5 and is named as (2R,4R) -1- [ (2S) -5- [ [ imino (nitroamino) methyl ] amino ] -2- [ [ (3-methyl-8-quinolyl) sulfonyl ] amino ] -1-oxopentyl ] -4-methyl-2-piperidinecarboxylic acid, and can be obtained by market purchase or preparation according to the existing literature. Materials used in other experiments are of no source and no specification and are all of commercial analytical purity or chemical purity; can be purchased from the market or prepared by referring to the existing literature.

The invention adopts HPLC to measure the purity of argatroban, and the chromatographic conditions are as follows:

a chromatographic column: welch Ultimate XB-C₁₈(4.6mm×150mm,3.0μm)；

Mobile phase: acetonitrile-water (60:40)

Column temperature: 25 ℃;

detection wavelength: 259 nm;

flow rate: 1.5 mL/min;

sample introduction amount: 10 μ L.

In the following examples, various procedures and methods not described in detail are conventional methods well known in the art.

Example 1

Diisopropylamine hydrochloride (27.5g, 0.2mol), tris (pentafluorophenyl) (2.6g, 5.0mmol), boron, (2R,4R) -1- [ (2S) -5- [ [ imino (nitroamino) methyl ] are reacted under nitrogen]Amino group]-2- [ [ (3-methyl-8-quinolinyl) sulfonyl ] sulfonyl]Amino group]-1-oxopentyl radical]Adding 4-methyl-2-piperidinecarboxylic acid (compound II, 27.5g, 0.05mol) into toluene (250mL), stirring to dissolve completely, slowly dropwise adding a toluene solution (450mL) of diphenylsilane (46.0g, 0.25mol), controlling the temperature to be 105-110 ℃ after dropwise adding, reacting for 20 hours, cooling the reaction liquid to room temperature, adjusting the pH value to be neutral by using a saturated sodium bicarbonate solution, standing for layering to obtain an organic phase, washing the organic phase by using saturated saline (200mL), drying over anhydrous magnesium sulfate, filtering, concentrating the filtrate under reduced pressure to be dry to obtain 24.21g of crude argatroban, wherein the yield is 95.2% (calculated by the compound II); HPLC: 96.835 percent. Then ethanol/purified water (V)_Ethanol:V_{Water (W)}1:3, 130mL) to obtain a white-like solid, namely, argatroban monohydrate 24.16g, the yield is 96.4% (based on argatroban crude product), and HPLC: 99.866 percent; the ratio of the 21(R) and 21(S) isomers was about 64.4: 35.6.

Example 2

Under the protection of nitrogen, adding diisopropylamine hydrochloride (24.1g, 0.175mol), tris (pentafluorophenyl) boron (2.6g, 5.0mmol) and a compound II (27.5g, 0.05mol) into toluene (250mL), stirring to dissolve, slowly dropwise adding a toluene (450mL) solution of diphenylsilane (46.0g, 0.25mol), controlling the temperature to be 105-110 ℃ to react for 22 hours, cooling the reaction liquid to room temperature, adjusting the pH to be neutral by using a saturated sodium bicarbonate solution, standing for layering to obtain an organic phase, washing the organic phase by using saturated saline (200mL), drying by anhydrous magnesium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness to obtain a crude product of argatroban (24.03 g), wherein the yield is 94.5% (based on the compound II); HPLC: 96.634 percent. Then acetonitrile/purified water (V)_Acetonitrile:V_{Water (W)}1:3, 130mL) to obtain a white-like solid, namely argatroban monohydrate 23.71g, the yield is 95.3% (calculated on argatroban crude product), and HPLC: 99.842 percent; the ratio of the 21(R) and 21(S) isomers was about 64.3: 35.7.

Example 3

Under the protection of nitrogen, adding diisopropylamine hydrochloride (20.6g, 0.15mol), tris (pentafluorophenyl) boron (2.6g, 5.0mmol) and a compound II (27.5g, 0.05mol) into toluene (250mL), stirring to dissolve, slowly dropwise adding a toluene (450mL) solution of diphenylsilane (46.0g, 0.25mol), controlling the temperature to be 105-110 ℃ to react for 24 hours, cooling the reaction liquid to room temperature, adjusting the pH to be neutral by using a saturated sodium bicarbonate solution, standing for layering to obtain an organic phase, washing the organic phase by using saturated saline (200mL), drying by anhydrous magnesium sulfate, filtering, and concentrating the filtrate under reduced pressure to dryness to obtain a crude product of argatroban (22.96 g) with a yield of 90.3% (based on the compound II); HPLC: 94.625 percent. Then acetonitrile/purified water (V)_Acetonitrile:V_{Water (W)}1:3, 130mL) to obtain a white-like solid, namely argatroban monohydrate 22.02g, the yield is 92.6% (calculated on argatroban crude product), HPLC: 99.762 percent; the ratio of the 21(R) and 21(S) isomers was about 64.2: 35.8.

Example 4

Diisopropylamine hydrochloride (34.4g, 0.25mol), tris (pentafluorophenyl) boron (2.6g, 5.0mmol), compound II (27.5g, 0.05mol) were added to toluene (250mL) under argon, the mixture was stirred to dissolve the clear, and the di-tert-butyl ether was slowly added dropwiseAfter finishing dripping, controlling the temperature to be 105-110 ℃ to react for 20 hours, cooling the reaction liquid to room temperature, adjusting the pH to be neutral by using a saturated sodium carbonate solution, standing for layering to obtain an organic phase, washing the organic phase by using saturated saline solution (200mL), drying by using anhydrous magnesium sulfate, filtering, and concentrating the filtrate under reduced pressure until the filtrate is dried to obtain 23.85g of crude argatroban, wherein the yield is 93.8 percent (calculated by a compound II); HPLC: 96.562 percent. Then ethanol/purified water (V)_Ethanol:V_{Water (W)}1:3, 130mL) to obtain a white-like solid, namely argatroban monohydrate 23.71g, the yield is 96.0% (calculated on argatroban crude product), HPLC: 99.845 percent; the ratio of the 21(R) and 21(S) isomers was about 64.3: 35.7.

Example 5

Under the protection of argon, adding diisopropylamine hydrochloride (37.8g, 0.275mol), tris (pentafluorophenyl) boron (2.6g, 5.0mmol) and a compound II (27.5g, 0.05mol) into toluene (250mL), stirring to dissolve, slowly dropwise adding a toluene (450mL) solution of diphenylsilane (46.0g, 0.25mol), controlling the temperature to be 105-110 ℃ to react for 18 hours, cooling the reaction liquid to room temperature, adjusting the pH to be neutral by using a sodium hydroxide solution, standing for layering to obtain an organic phase, washing the organic phase by using saturated saline (200mL), drying by using anhydrous magnesium sulfate, filtering, concentrating the filtrate under reduced pressure to be dry to obtain 23.47g of crude argatroban, and obtaining the yield of 92.3% (based on the compound II); HPLC: 93.732 percent. Then ethanol/purified water (V)_Ethanol:V_{Water (W)}1:3, 130mL) to obtain an off-white solid, namely, the argatroban monohydrate 22.92g, with a yield of 94.3% (based on the crude argatroban product), HPLC: 99.730 percent; the ratio of the 21(R) and 21(S) isomers was about 64.3: 35.7.

Example 6

Adding diphenylamine hydrochloride (41.1g, 0.2mol), tris (pentafluorophenyl) boron (2.6g, 5.0mmol) and a compound II (27.5g, 0.05mol) into toluene (250mL) under the protection of nitrogen, stirring to dissolve, slowly dropwise adding a toluene (450mL) solution of diphenylsilane (46.0g, 0.25mol), controlling the temperature to be 105-110 ℃ for reaction for 22 hours after dropwise adding, cooling the reaction liquid to room temperature, adjusting the pH to be neutral by using a saturated sodium bicarbonate solution, standing for layering to obtain an organic phase, washing the organic phase by using saturated saline (200mL), and using anhydrous sulfuric acid to wash the organic phaseDrying magnesium, filtering, and concentrating the filtrate under reduced pressure to dryness to obtain crude argatroban 23.93g with yield of 94.1% (based on compound II); HPLC: 96.544 percent. Then ethanol/purified water (V)_Ethanol:V_{Water (W)}1:3, 130mL) to obtain an off-white solid, namely argatroban monohydrate 23.68g, with a yield of 95.6% (based on argatroban crude product), HPLC: 99.843 percent; the ratio of the 21(R) and 21(S) isomers was about 64.4: 35.6.

Example 7

Under the protection of argon, adding methylphenylamine hydrochloride (28.7g, 0.2mol), tris (pentafluorophenyl) boron (2.6g, 5.0mmol) and a compound II (27.5g, 0.05mol) into benzene (250mL), stirring to dissolve, slowly dropwise adding a benzene (450mL) solution of diphenylsilane (46.0g, 0.25mol), controlling the temperature to be 80-85 ℃ to react for 24 hours, cooling the reaction liquid to room temperature, adjusting the pH to be neutral by using a saturated sodium bicarbonate solution, standing for layering to obtain an organic phase, washing the organic phase by using saturated saline (200mL), drying by anhydrous magnesium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness to obtain 23.19g of crude argatroban product with the yield of 91.2% (calculated by the compound II); HPLC: 95.941 percent. Then acetonitrile/purified water (V)_Acetonitrile:V_{Water (W)}1:3, 130mL) to obtain a white-like solid, namely argatroban monohydrate 22.64g, the yield is 94.3% (calculated on argatroban crude product), HPLC: 99.795 percent; the ratio of the 21(R) and 21(S) isomers was about 64.2: 35.8.

Example 8

Under the protection of argon, adding diisopropylamine hydrochloride (27.5g, 0.2mol), tris (pentafluorophenyl) boron (1.28g, 2.5mmol) and a compound II (27.5g, 0.05mol) into toluene (250mL), stirring to dissolve, slowly dropwise adding a toluene (450mL) solution of diphenylsilane (46.0g, 0.25mol), controlling the temperature to be 105-110 ℃ to react for 23 hours, cooling the reaction liquid to room temperature, adjusting the pH to be neutral by using a saturated sodium bicarbonate solution, standing for layering to obtain an organic phase, washing the organic phase by using saturated saline (200mL), drying by anhydrous magnesium sulfate, filtering, concentrating the filtrate under reduced pressure to be dry to obtain 23.44g of crude argatroban, and obtaining the yield of 92.2% (based on the compound II); HPLC: 95.734 percent. Then ethanol/purified water (V)_Ethanol:V_{Water (W)}1:3, 130mL) system to obtain off-white solid after recrystallization hydrationNamely, the argatroban monohydrate 22.67g, the yield is 93.4% (based on argatroban crude product), HPLC: 99.783 percent; the ratio of the 21(R) and 21(S) isomers was about 64.4: 35.6.

Example 9

Under the protection of nitrogen, adding diisopropylamine hydrochloride (27.5g, 0.2mol), tris (pentafluorophenyl) boron (1.0g, 2.0mmol) and a compound II (27.5g, 0.05mol) into benzene (250mL), stirring to dissolve, slowly dropwise adding a benzene (450mL) solution of diphenylsilane (46.0g, 0.25mol), controlling the temperature to be 80-85 ℃ to react for 28 hours, cooling the reaction liquid to room temperature, adjusting the pH to be neutral by using a saturated sodium bicarbonate solution, standing for layering to obtain an organic phase, washing the organic phase by using saturated saline (200mL), drying by using anhydrous magnesium sulfate, filtering, concentrating the filtrate under reduced pressure to be dry to obtain 21.67g of crude argatroban, and obtaining the yield of 85.2% (based on the compound II); HPLC: 94.394 percent. Then ethanol/purified water (V)_Ethanol:V_{Water (W)}1:3, 130mL) to obtain a white-like solid, namely, 21.20g of argatroban monohydrate, with a yield of 94.5% (based on argatroban crude product), HPLC: 99.765 percent; the ratio of the 21(R) and 21(S) isomers was about 64.4: 35.6.

Example 10

Under the protection of nitrogen, adding diisopropylamine hydrochloride (27.5g, 0.2mol), tris (pentafluorophenyl) boron (5.1g, 10.0mmol) and a compound II (27.5g, 0.05mol) into toluene (250mL), stirring to dissolve, slowly dropwise adding a toluene (450mL) solution of diphenylsilane (46.0g, 0.25mol), controlling the temperature to be 105-110 ℃ to react for 16 hours, cooling the reaction liquid to room temperature, adjusting the pH to be neutral by using a saturated sodium bicarbonate solution, standing for layering to obtain an organic phase, washing the organic phase by using saturated saline (200mL), drying by anhydrous magnesium sulfate, filtering, concentrating the filtrate under reduced pressure to be dry to obtain 23.32g of crude argatroban, and obtaining the yield of 91.7% (based on the compound II); HPLC: 96.184 percent. Then acetonitrile/purified water (V)_Acetonitrile:V_{Water (W)}1:3, 130mL) to obtain a white-like solid, namely argatroban monohydrate 22.63g, the yield is 93.7% (calculated on argatroban crude product), HPLC: 99.734 percent; the ratio of the 21(R) and 21(S) isomers was about 64.1: 35.9.

Example 11

Under the protection of nitrogenAdding diisopropylamine hydrochloride (27.5g, 0.2mol), tris (pentafluorophenyl) boron (6.4g, 12.5mmol) and a compound II (27.5g, 0.05mol) into 1, 4-dioxane (250mL), stirring for dissolving, slowly dropwise adding a1, 4-dioxane (450mL) solution of diphenylsilane (46.0g, 0.25mol), controlling the temperature to be 100-105 ℃ for reaction for 14 hours after dripping, cooling a reaction liquid to room temperature, adjusting the pH to be neutral by using a saturated sodium bicarbonate solution, extracting dichloromethane (300mL multiplied by 3), drying an organic phase anhydrous magnesium sulfate, filtering, and concentrating a filtrate under reduced pressure until the filtrate is dried to obtain 23.80g of crude argatroban with the yield of 93.6% (calculated by the compound II); HPLC: 94.627 percent. Then acetonitrile/purified water (V)_Acetonitrile:V_{Water (W)}1:3, 130mL) to obtain a white-like solid, namely argatroban monohydrate 22.90g, the yield is 92.9% (calculated on argatroban crude product), HPLC: 99.742 percent; the ratio of the 21(R) and 21(S) isomers was about 64.2: 35.8.

Example 12

Under the protection of nitrogen, adding diisopropylamine hydrochloride (27.5g, 0.2mol), triethylboron (0.5g, 5.0mmol) and a compound II (27.5g, 0.05mol) into toluene (250mL), stirring to dissolve, slowly dropwise adding a toluene (450mL) solution of diphenylsilane (46.0g, 0.25mol), controlling the temperature to be 105-110 ℃ to react for 22 hours, cooling the reaction liquid to room temperature, adjusting the pH to be neutral by using a saturated sodium bicarbonate solution, standing for layering to obtain an organic phase, washing the organic phase by using saturated saline (200mL), drying by anhydrous magnesium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness to obtain a crude product of argatroban 24.05g, wherein the yield is 94.6% (based on the compound II); HPLC: 96.604 percent. Then ethanol/purified water (V)_Ethanol:V_{Water (W)}1:3, 130mL) to obtain a white-like solid, namely argatroban monohydrate 23.59g, the yield is 94.7% (calculated on argatroban crude product), HPLC: 99.846 percent; the ratio of the 21(R) and 21(S) isomers was about 64.4: 35.6.

Example 13

Under the protection of nitrogen, diisopropylamine hydrochloride (27.5g, 0.2mol), tris (pentafluorophenyl) (2.6g, 5.0mmol) boron and compound II (27.5g, 0.05mol) are added to toluene (250mL), the solution is stirred, diphenylsilane (36.9g, 0.2mol) solution in toluene (450mL) is slowly added dropwise, and the temperature is controlled at 105-110 DEG CAfter 24 hours of reaction, cooling the reaction solution to room temperature, adjusting the pH value to be neutral by using a saturated sodium bicarbonate solution, standing for layering, taking an organic phase, washing the organic phase by using saturated saline solution (200mL), drying by using anhydrous magnesium sulfate, filtering, and concentrating the filtrate under reduced pressure until the organic phase is dried to obtain 23.85g of argatroban crude product with the yield of 93.8 percent (calculated by a compound II); HPLC: 95.521 percent. Then ethanol/purified water (V)_Ethanol:V_{Water (W)}1:3, 130mL) to obtain a white-like solid, namely argatroban monohydrate 23.30g, the yield is 94.3% (calculated on argatroban crude product), HPLC: 99.786 percent; the ratio of the 21(R) and 21(S) isomers was about 64.5: 35.5.

Example 14

Under the protection of nitrogen, adding diisopropylamine hydrochloride (27.5g, 0.2mol), tris (pentafluorophenyl) (2.6g, 5.0mmol) boron and a compound II (27.5g, 0.05mol) into toluene (250mL), stirring to dissolve, slowly dropwise adding a toluene (450mL) solution of diphenylsilane (32.2g, 0.175mol), controlling the temperature to be 105-110 ℃ to react for 24 hours, cooling the reaction liquid to room temperature, adjusting the pH to be neutral by using a saturated sodium bicarbonate solution, standing for layering to obtain an organic phase, washing the organic phase by using saturated saline (200mL), drying by anhydrous magnesium sulfate, filtering, concentrating the filtrate under reduced pressure to dryness to obtain 21.51g of crude argatroban product with the yield of 84.6% (based on the compound II); HPLC: 94.726 percent. Then ethanol/purified water (V)_Ethanol:V_{Water (W)}1:3, 130mL) to obtain a white-like solid, namely argatroban monohydrate 20.85g, the yield is 93.6% (calculated on argatroban crude product), HPLC: 99.732 percent; the ratio of the 21(R) and 21(S) isomers was about 64.4: 35.6.

Example 15

Under the protection of nitrogen, adding diisopropylamine hydrochloride (27.5g, 0.2mol), tris (pentafluorophenyl) (2.6g, 5.0mmol) boron and a compound II (27.5g, 0.05mol) into 1, 4-dioxane (250mL), stirring to dissolve, slowly dropwise adding a1, 4-dioxane (450mL) solution of diphenylsilane (55.3g, 0.3mol), controlling the temperature to be 100-105 ℃ to react for 18 hours, cooling the reaction liquid to room temperature, adjusting the pH to be neutral by using a saturated sodium bicarbonate solution, extracting dichloromethane (300mL multiplied by 3), drying an organic phase anhydrous magnesium sulfate, filtering, concentrating the filtrate under reduced pressure to be dry to obtain 23.60g of crude argatroban, and collecting the crude argatrobanA rate of 92.8% (based on compound II); HPLC: 95.869 percent. Then ethanol/purified water (V)_Ethanol:V_{Water (W)}1:3, 130mL) to obtain a white-like solid, namely argatroban monohydrate 22.95g, the yield is 93.9% (calculated on argatroban crude product), HPLC: 99.757 percent; the ratio of the 21(R) and 21(S) isomers was about 64.3: 35.7.

Example 16

Under the protection of nitrogen, adding diisopropylamine hydrochloride (27.5g, 0.2mol), tris (pentafluorophenyl) (2.6g, 5.0mmol) boron and a compound II (27.5g, 0.05mol) into toluene (250mL), stirring to dissolve, slowly dropwise adding a toluene (450mL) solution of diethylsilane (21.5g, 0.25mol), controlling the temperature to be 105-110 ℃ to react for 22 hours, cooling the reaction liquid to room temperature, adjusting the pH to be neutral by using a saturated sodium bicarbonate solution, standing for layering to obtain an organic phase, washing the organic phase by using saturated saline (200mL), drying by anhydrous magnesium sulfate, filtering, and concentrating the filtrate under reduced pressure to dryness to obtain 23.32g of crude argatroban with the yield of 91.7% (calculated by the compound II); HPLC: 96.586 percent. Then ethanol/purified water (V)_Ethanol:V_{Water (W)}1:3, 130mL) to obtain a white-like solid, namely argatroban monohydrate 22.33g, the yield is 92.5% (calculated on argatroban crude product), HPLC: 99.823 percent; the ratio of the 21(R) and 21(S) isomers was about 64.3: 35.7.

Example 17

Under the protection of argon, adding diisopropylamine hydrochloride (27.5g, 0.2mol), tris (pentafluorophenyl) (2.6g, 5.0mmol) boron and a compound II (27.5g, 0.05mol) into chloroform (250mL), stirring to dissolve, slowly dropwise adding a chloroform (450mL) solution of dimethylphenylsilane (34.0g, 0.25mol), controlling the temperature to be 60-65 ℃ to react for 24 hours, cooling the reaction liquid to room temperature, adjusting the pH to be neutral by using a saturated sodium bicarbonate solution, standing for layering to obtain an organic phase, washing the organic phase by using saturated saline (200mL), drying by anhydrous magnesium sulfate, filtering, and concentrating the filtrate under reduced pressure to dryness to obtain 23.04g of crude argatroban product with the yield of 90.6% (calculated by the compound II); HPLC: 96.384 percent. Then ethanol/purified water (V)_Ethanol:V_{Water (W)}1:3, 130mL) to obtain a white solid, namely argatroban 22.45g, with a yield of 94.1% (based on argatroban)Crude product basis), HPLC: 99.796 percent; the ratio of the 21(R) and 21(S) isomers was about 64.4: 35.6.

Claims

1. The synthesis method of the argatroban hydrate is characterized in that a compound II is used as an initial raw material, an organosilane compound is used as a reducing agent, and the argatroban hydrate of the compound I is obtained under the catalytic reduction of an organic amine salt and a non-metal boron compound, wherein the reaction formula is as follows:

2. the synthesis method according to claim 1, characterized by comprising in particular the following steps: under the protection of inert gas, adding organic amine salt, a non-metal boron compound and a compound II into a reaction solvent, stirring for dissolving, slowly adding a hydrogen source, namely an organosilane compound, controlling the temperature until the reaction is finished, and performing purification hydration post-treatment to obtain a compound I argatroban monohydrate.

3. A synthesis method according to claim 1 or 2, characterized in that the organic amine salt is one of diphenylamine hydrochloride, methylphenyl amine hydrochloride and diisopropylamine hydrochloride.

4. The synthesis method according to claim 1 or 2, wherein the non-metallic 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 preferable.

6. The synthesis method according to claim 2, wherein the reaction solvent is one of dichloromethane, chloroform, 1, 4-dioxane, toluene, benzene or their combination.

7. The synthesis method according to claim 2, wherein the molar ratio of the compound II to the organic amine salt, the non-metallic boron compound and the organosilane compound is 1: 3.5-5.0: 0.05-0.20: 4.0 to 6.0.

8. The synthesis method according to claim 2, wherein the reaction temperature is 40-120 ℃.

9. The synthesis method of claim 2, wherein the post-treatment step comprises the steps of reducing the temperature of the reaction solution to room temperature, adjusting the pH value to be neutral, standing for layering, and concentrating the organic phase under reduced pressure to be dry to obtain a crude argatroban product; further purifying and hydrating to obtain argatroban monohydrate.