CN103387566B - Preparation of 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino] Ethyl propionate method - Google Patents

Abstract

The open one of the present invention prepares the method for 3-[[[2-[[(4-cyano-phenyl) amino] methyl]-1-methyl isophthalic acid H-benzoglyoxaline-5-base] carbonyl] (pyridine-2-base) is amino] ethyl propionate, it is characterized in that described method comprises and makes (4-cyano-phenyl) amino] the first step of reacting with 3-[(3-amino-4-methylamino benzoyl) (pyridine-2-base) is amino] ethyl propionate again with pair (trichloromethyl) carbonate reaction of acetic acid.Described method is simple, and cost is low.

Description

Preparation of 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino] Ethyl propionate method

technical field

The present invention belongs to the field of drug synthesis, specifically, relates to a method for preparing 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazole-5 -yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester.

Background technique

Thrombosis is mainly divided into arterial thrombosis and venous thrombosis. Venous thromboembolism is induced by various reasons in venous blood vessels, which can lead to venous thromboembolism (VET), and its main clinical manifestations are deep venous thrombosis (DVT) and pulmonary embolism (pulmonary embolism, PE). A disease that seriously endangers human health. Pulmonary embolism is one of the common respiratory and cardiovascular diseases. Deep vein thrombosis mainly occurs after major orthopedic surgery. Anticoagulant drug treatment is the basic method to control thrombosis, which can effectively reduce mortality , to prevent recurrence.

Dabigatran etexilate (Dabigatran etexilate, formula 1 below) is a new type of oral direct thrombin inhibitor, after oral absorption, it is converted into the active part dabigatran (dabigatran) by esterase to produce thrombin inhibitory effect. It is mainly used for the prevention of venous thrombosis in adult patients undergoing elective total hip or total knee replacement surgery and the prevention of stroke and thrombosis in patients with atrial fibrillation. 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propane Ethyl acetate (the following formula 2, referred to as compound 2 herein) is an important intermediate for the synthesis of dabigatran etexilate.

The prior art generally adopts [(4-cyanophenyl) amino] acetic acid (following formula 3, referred to as compound 3 herein) and 3-[(3-amino-4-methylaminobenzoyl) (pyridine -2-base) amino] propionic acid ethyl ester (following formula 4, referred to as compound 4 herein) as raw material synthetic compound 2:

WO98/37075 and document J.Med.Chem, 2002, 45, 1757-1766 mentioned using tetrahydrofuran (THF) as solvent, N, N'-carbonyldiimidazole (CDI) as condensation agent, reflux in acetic acid, dichloro Extracted with methane, evaporated to dryness, and obtained compound 2 through column chromatography (yield: 61%).

CN1861596 mentions selecting DMF as solvent, 1-hydroxybenzotriazole (HOBT) and 1-ethyl-3-(3-dimethylpropyl) carbodiimide hydrochloride (EDCI) as condensation agent, Reflux in acetic acid, neutralize with ammonia water, extract with dichloromethane, evaporate to dryness, and obtain compound 2 by column chromatography. (Yield: 83%).

WO2008095928 mentioned that THF was used as solvent, CDI or EDCI was used as condensation agent, refluxed in acetic acid, and compound 2 was obtained by forming a salt with HBr.

WO2009111997 mentions using dried THF as a solvent, CDI as a condensation agent, reflux in acetic acid, extraction with dichloromethane, evaporation to dryness, oxalate in ethyl acetate, recrystallization, and free compound 2 (yield: 57.2%, HPLC: 97.8%).

The Chinese Journal of Pharmaceutical Industry published by Xing Songsong et al., 2010, 42(5): 321-325 mentions that compound 3 reacts in a mixture of DMF and THF, reacts with EDCI and HOBT, evaporates to dryness, and then uses dichloromethane to make Solvent, reacted with compound 4, refluxed with acetic acid, neutralized with ammonia water, extracted with dichloromethane, evaporated to dryness, and obtained compound 2 by column chromatography (yield: 67%).

In the existing method, by-products such as imidazole and hydroxybenzotriazole are unavoidable in the reaction system, and the product is difficult to purify by simple crystallization. In the literature, column chromatography or salt formation and then freeing are used to obtain relatively pure products. .

Contents of the invention

The object of the present invention is to provide a method for synthesizing the intermediate which is simple and easy to implement and low in cost.

Therefore, the present invention provides a method for preparing 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridine -2-yl) amino] the method of ethyl propionate, it is characterized in that described method comprises making (4-cyanophenyl) amino] acetic acid react with two (trichloromethyl) carbonate earlier and 3-[ (3-Amino-4-methylaminobenzoyl)(pyridin-2-yl)amino]propionic acid ethyl ester reaction step.

The method also includes the steps of crystallizing the product with a crystallization solvent and recrystallizing with a recrystallization solvent.

According to a preferred embodiment of the present invention, the preparation method comprises the following steps:

1) reacting [(4-cyanophenyl) amino] acetic acid and bis(trichloromethyl) carbonate in the presence of an organic base in a nonpolar solvent;

2) In a non-polar solvent, the product obtained in step 1) is reacted with ethyl 3-[(3-amino-4-methylaminobenzoyl)(pyridin-2-yl)amino]propionate, and after the reaction Evaporated to dryness, the residue was refluxed in acetic acid and evaporated to dryness;

3) The residue obtained in step 2) is crystallized with a crystallization solvent and then recrystallized with a recrystallization solvent to obtain 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methanol Ethyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propanoate.

According to a preferred embodiment of the present invention, the organic base is pyridine.

According to a preferred embodiment of the present invention, the non-polar solvent is selected from dichloromethane, tetrahydrofuran or toluene; more preferably dichloromethane.

According to a preferred embodiment of the present invention, the crystallization solvent is selected from ethyl acetate, butyl acetate or n-hexane, more preferably ethyl acetate.

According to a preferred embodiment of the present invention, the recrystallization solvent is selected from ethanol, acetone, acetonitrile, toluene or isopropanol, more preferably ethanol.

According to a particularly preferred embodiment of the present invention, bis(trichloromethyl)carbonate is the condensing agent, and the molar ratio of compound 4:compound 3:bis(trichloromethyl)carbonate:pyridine is 1:(1.0 -1.2): (0.33-0.55): (1.0-1.65) ratio feeding, bis(trichloromethyl)carbonate reacts with compound 3 in dichloromethane first, dichloromethane is evaporated to dryness and then dichloromethane Dissolve, add compound 4 to reflux for 15-20 h, then reflux with acetic acid for 1-2 h, extract with dichloromethane, and evaporate to dryness. The obtained crude product is directly crystallized with ethyl acetate, and then recrystallized with solvent such as ethanol.

Compared with the synthetic method of prior art, the advantages of the present invention are as follows:

1) Using bis(trichloromethyl)carbonate as the condensation agent, the cost is low, the operation is mild, and no low temperature is required;

2) Using dichloromethane as a solvent, it is easy to remove without re-distilling;

3) After treatment, use ethyl acetate for crystallization and ethanol recrystallization, without column chromatography, salt formation and free operation;

4) There are few by-products, and the obtained product has high purity.

Detailed ways

The present invention is further described by the following examples, but the examples are not intended to limit the scope of the present invention. Compounds 3 and 4 were provided by Shanghai Aobo Biomedical Technology Co., Ltd.

HPLC assay conditions are as follows:

Instrument: Waters1525-2489-2707 high performance liquid chromatography,

Column: C18,

Column length: 15cm,

Mobile phase: (methanol: acetonitrile = 55: 45): (1% diethylamine aqueous solution, phosphoric acid to adjust PH7) = 58: 42,

Flow rate: 0.6ml/min,

Wavelength: 284nm,

Column temperature: 40°C,

Injection volume: 5 μL.

Example 1

Dissolve compound 3 (3.4g, 0.0193mol) in dichloromethane (150ml), add bis(trichloromethyl)carbonate (2.3g/0.0077mol), pyridine (1.82g, 0.0231mol), at 20°C Stir for 3h. Dichloromethane was evaporated to dryness, the residue was dissolved in dichloromethane (75ml), transferred to a four-necked flask, compound 4 (6g, 0.0175mol) was dissolved in dichloromethane (75ml), and added to the above solution, Heated to reflux and reacted for 15-20h. Dichloromethane was evaporated to dryness, and acetic acid (80ml) was added to the residue to reflux for 1.5h. Evaporate acetic acid to dryness, dissolve with dichloromethane, wash with water 3-4 times, and dry the dichloromethane layer with anhydrous magnesium sulfate. Evaporate to dryness to obtain 7.8 g of slightly yellow amorphous substance. Ethyl acetate (25ml) was added for crystallization to obtain 6g of a yellowish solid, which was recrystallized by adding ethanol (30ml) to obtain 5.87g of a white solid. Yield: 70%, m.p.: 141-142°C. Purity: 99.41% (measured by HPLC), retention time: 5.429min.

Example 2

Dissolve compound 3 (12.g, 0.0679mol) in 600ml of dichloromethane, add bis(trichloromethyl)carbonate (8.1g, 0.0272mol), pyridine (6.45g, 0.0816mol), and stir at 24°C 3h. Evaporate dichloromethane to dryness, dissolve the residue in dichloromethane (300ml), transfer to a four-necked flask, dissolve compound 4 (21.1g, 0.0617mol) in dichloromethane (300ml), add to the above solution , heated to reflux, and reacted for 15-20h. Dichloromethane was evaporated to dryness, and acetic acid (350ml) was added to the residue to reflux for 1.5h. Evaporate acetic acid to dryness, dissolve with dichloromethane, wash with water 3-4 times, and dry the dichloromethane layer with anhydrous magnesium sulfate. Evaporate to dryness to obtain 38.8 g of slightly yellow amorphous substance. Ethyl acetate (150ml) was added for crystallization to obtain 25g of a yellowish solid, which was recrystallized by adding ethanol (120ml) to obtain 22g of a white solid. Yield 74%, m.p.: 141-142°C. Purity: 99.61% (measured by HPLC), retention time: 5.479min.

Example 3

Dissolve compound 3 (24.7g, 0.140mol) in 1300ml of dichloromethane, add bis(trichloromethyl)carbonate (16.6g/0.056mol), pyridine (13.3g, 0.168mol), and stir at 25°C for 3h . Evaporate dichloromethane to dryness, dissolve the residue in 600ml dichloromethane, transfer to a four-necked flask, dissolve compound 4 (40g/0.117mol) in dichloromethane (700m) 1, add in the above solution, heat To reflux, react for 15-20h. Dichloromethane was evaporated to dryness, and 80ml of acetic acid was added to the residue to reflux for 1.5h. Evaporate acetic acid to dryness, dissolve in dichloromethane, wash with water three times, and dry the dichloromethane layer with anhydrous magnesium sulfate. Evaporate to dryness to obtain 66 g of slightly yellow amorphous substance. Ethyl acetate (260ml) was added for crystallization to obtain 46g of yellowish solid, which was recrystallized by adding ethanol (230ml) to obtain 43g of white solid, yield: 76% m.p.: 141-142°C. Purity: 99.5% (measured by HPLC), retention time: 5.508min.

Example 4

Compound 3 (10g, 0.0568mol) was dissolved in redistilled THF450ml, N ₂ protected, bis(trichloromethyl)carbonate (6.7g/0.0227mol), pyridine (5.4g, 0.0681mol), 20 Stir at ℃ for 3h. THF was evaporated to dryness, the residue was dissolved in THF (200ml), transferred to a four-neck flask, compound 4 (17.6g, 0.0516mol) was dissolved in THF (250ml), added to the above solution, heated to reflux, Reaction 15-20h. THF was evaporated to dryness, and acetic acid (240ml) was added to the residue to reflux for 1.5h. Evaporate acetic acid to dryness, dissolve with dichloromethane, wash with water 3-4 times, and dry the dichloromethane layer with anhydrous magnesium sulfate. Evaporate to dryness to obtain 22.6 g of slightly yellow amorphous substance. Ethyl acetate (80ml) was added for crystallization to obtain 18g of a yellowish solid, which was recrystallized by adding ethanol (90ml) to obtain 16.4g of a white solid. Yield: 66%, mp: 141-142°C, purity: 98.54% (measured by HPLC), retention time: 5.419.

Claims (6)

1. Preparation of 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl) The method of amino] ethyl propionate, it is characterized in that described method comprises the following steps: 1) reacting [(4-cyanophenyl)amino]acetic acid and bis(trichloromethyl)carbonate in the presence of an organic base in dichloromethane; 2) In dichloromethane, make the product obtained in step 1) react with ethyl 3-[(3-amino-4-methylaminobenzoyl) (pyridin-2-yl) amino] propionate, and distill Dry, the residue was refluxed in acetic acid and evaporated to dryness; 3) The residue obtained in step 2) is crystallized with a crystallization solvent and then recrystallized with a recrystallization solvent to obtain 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methanol Base-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester, Wherein said ethyl 3-[(3-amino-4-methylaminobenzoyl)(pyridin-2-yl)amino]propionate: [(4-cyanophenyl)amino]acetic acid: bis(tri The molar ratio of chloromethyl)carbonate is 1:1.0-1.2:0.33-0.55. 2. The method of claim 1, wherein the organic base is pyridine. 3. The method according to claim 1, characterized in that the crystallization solvent is selected from ethyl acetate, butyl acetate or n-hexane. 4. The method according to claim 3, characterized in that the crystallization solvent is ethyl acetate. 5. The method of claim 1, wherein the recrystallization solvent is selected from ethanol, acetone, acetonitrile, toluene or isopropanol. 6. The method of claim 5, wherein the recrystallization solvent is ethanol.