CN103709142B

CN103709142B - preparation method of dabigatran intermediate

Info

Publication number: CN103709142B
Application number: CN201310567975.8A
Authority: CN
Inventors: 漆志文; 叶银梅; 万新强; 罗威; 秦闯; 陈立芳
Original assignee: JIANGSU ALPHA PHARMACEUTICAL CO Ltd
Current assignee: Suqian Shengji Pharmaceutical Technology Co ltd
Priority date: 2013-11-14
Filing date: 2013-11-14
Publication date: 2019-12-06
Anticipated expiration: 2033-11-14
Also published as: CN103709142A

Description

Preparation method of dabigatran intermediate

Technical Field

the invention provides a novel preparation method of a dabigatran intermediate (a compound of a formula (I)) and belongs to the field of pharmaceutical chemicals.

Background

Dabigatran etexilate is a novel synthetic direct thrombin inhibitor, is a prodrug of dabigatran, and belongs to a non-peptide thrombin inhibitor. After oral, gastrointestinal absorption, it is converted in vivo into dabigastran with direct anticoagulant activity. dabigatran binds to the fibrin-specific binding site of thrombin, preventing cleavage of fibrinogen to fibrin, thereby blocking the final step of the coagulation cascade network and thrombus formation. dabigatran can be dissociated from fibrin-thrombin conjugate to exert reversible anticoagulation.

Patent US6087380 reports a process for the preparation of dabigatran etexilate, wherein the synthesis of dabigatran intermediates (compounds of formula [ i ]) is referred to, as follows:

The method uses bromoacetic acid with extremely high corrosivity as a raw material, has high operation risk, incomplete reaction of the raw materials during the reaction in the STEP3 STEP, low product yield and the key point that the final product of the formula (I) compound obtained by preparation has a lot of impurities, is not suitable for purification and is not suitable for industrial production.

Disclosure of Invention

The invention aims to provide a novel preparation method of a dabigatran etexilate intermediate through a great amount of experimental efforts aiming at the defects of the prior art, and the method is short in steps, simple to operate and suitable for industrial mass production.

The object of the invention can be achieved by the following measures:

A process for the preparation of a compound of formula I: reacting a compound shown in a formula V with a compound shown in a formula VI in the presence of alkali to obtain a compound III, reacting the compound III with p-aminobenzonitrile in the presence of alkali to synthesize a compound II, and finally performing hydrogenation cyclization reaction in the presence of a catalyst to obtain a compound I; the reaction route is as follows:

in the formula, X is selected from one or more halogens.

Reaction a relates to a process for the preparation of a compound of formula III,

X in each of the above formulae is preferably selected from one or two of chlorine and bromine.

The reaction solvent of reaction a may be a single solvent or a mixed solvent such as ethyl acetate, phenyl toluene, xylene, dichloromethane, dichloroethane, acetonitrile, DMF, etc., and among them, ethyl acetate and dichloromethane are preferred.

The base in reaction a may be an inorganic base such as sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, etc., or an organic base such as triethylamine, pyridine, etc.

In the present invention, the compound of formula VI may be bromoacetyl bromide, bromoacetyl chloride, chloroacetyl chloride, or the like.

in the present invention, the temperature for dropping the compound of formula VI in the main reaction is not too high, and may be-5 deg.C to 40 deg.C, and generally room temperature or low temperature, preferably-5 deg.C to 15 deg.C.

the specific steps of the reaction a are as follows: mixing the compound of formula V, alkali and an anhydrous solvent, dropwise adding the compound of formula VI under stirring at a controlled temperature, continuously stirring for reaction after dropwise adding, adding water after reaction, stirring for layering, extracting a water layer with an organic solvent, combining organic layers, washing with saline solution, drying, filtering, and concentrating the filtrate under reduced pressure until the filtrate is dry to obtain the compound of formula III.

Reaction b relates to a process for the preparation of a compound of formula II,

In the reaction b, the base can be inorganic base, such as sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, and the like, or organic base, such as triethylamine, pyridine, and the like. The temperature of the reaction can be 0-50 ℃, and is generally controlled to be between room temperature and the boiling point of the solvent, and the preferred temperature is 20-40 ℃.

One specific step of reaction b is: dissolving the compound shown in the formula III and p-aminobenzonitrile into solvents such as ethyl acetate, benzene, toluene, xylene, acetonitrile, dichloromethane, dichloroethane, chloroform and the like, adding alkali, stirring for reaction, adding water after the reaction is finished, stirring for demixing, extracting a water layer by using an organic solvent, combining organic layers, washing by using saturated sodium bicarbonate and saline solution respectively, drying the organic layers, and concentrating under reduced pressure until the organic layers are dried to obtain the compound shown in the formula II.

Reaction c relates to a process for the preparation of compounds of formula I,

In the reaction c, the catalyst is selected from a heavy metal catalyst or a composite catalyst of the heavy metal catalyst and an acid, wherein the heavy metal catalyst is selected from palladium carbon and palladium hydroxide, and the acid is sulfuric acid or acetic acid. In the invention, the acid is added during hydrogenation mainly for promoting intramolecular nitro transfer hydrogenation to directly form a ring, so that nitro reduction and ring formation are simultaneously completed to prepare the product compound shown in the formula (I), and the acid only needs a catalytic amount, or acetic acid can be directly used for replacing methanol, ethanol, ethyl acetate and the like and used as a solvent and a catalyst.

In the reaction c, hydrogen is introduced during hydrogenation; the reaction vessel may be either atmospheric or pressurized, the hydrogen pressure is generally controlled at 0-10 kg/cm2, and the hydrogenation reaction time is generally 8-10 hours.

the reaction solvent in reaction c may be selected from methanol, ethanol or ethyl acetate.

in the reaction c, the reaction temperature may be 0 to 60 ℃, and further may be from room temperature to the boiling point of the solvent, preferably within 20 to 50 ℃, and an excessively high temperature may cause side reactions.

The specific steps of the reaction c are as follows: dissolving the compound shown in the formula II in a solvent such as methanol, ethanol, ethyl acetate and the like, putting the mixture into a hydrogenation kettle, adding a noble metal catalyst such as palladium-carbon, palladium hydroxide and the like, adding a small amount of sulfuric acid or acetic acid, introducing N2 to replace oxygen in the kettle for three times, then using hydrogen to replace N2 in the kettle for three times, introducing hydrogen to stir for reaction after the replacement is finished, filtering the catalyst by pressure after the reaction is finished, and concentrating the catalyst by pressure reduction until the catalyst is dried to obtain the compound shown in the formula I.

The compound of formula V is used as a raw material to be prepared with a compound of formula VI to obtain a compound of formula III, then the compound of formula II is obtained with p-aminobenzonitrile under the action of alkali, and then the target product compound of formula I is obtained by transfer hydrogenation. The method has the advantages of short steps, mild conditions and high total reaction yield, and is suitable for industrial mass production.

Detailed Description

The invention will be described in detail with reference to the following non-limiting examples, which should not be construed as limiting the scope of the invention

example 1 preparation of a compound of formula iii (-X ═ Cl)

Dissolving 37.2g of a compound shown in the formula V in 200ml of dichloromethane, adding 15g of triethylamine, controlling the temperature in an ice-water bath to be 0-5 ℃, slowly dropwise adding 13.8g of chloroacetyl chloride, after about 20 minutes of dripping is finished, removing the ice bath, naturally heating to room temperature, stirring for 3-4 hours, after the reaction is finished, adding 100ml of water, stirring and layering, extracting a water layer twice by using 100ml of dichloromethane 2, combining organic layers, washing by using 100ml of saturated saline solution, drying the organic layer by using 8g of anhydrous sodium sulfate, performing suction filtration, concentrating the filtrate under reduced pressure to dryness, and recrystallizing the remainder by using 115ml of ethyl acetate to obtain 40.2g of a product.

EXAMPLE 2 preparation of the Compound of formula II

22.4g of the compound of the formula III prepared in example 1 (-X ═ Cl) was dissolved in 120ml of acetonitrile, 6.3g of p-aminobenzonitrile and 10g of potassium carbonate were added, the temperature was slowly raised to about 35 ℃ with stirring, the mixture was stirred for about 5 hours, after completion of the reaction by TLC, the acetonitrile was concentrated under reduced pressure to dryness, 120ml of water was added, extraction was performed with 150ml of ethyl acetate 2, the organic layers were combined, 50ml of saturated brine was washed, and then dried over 10g of anhydrous sodium sulfate, suction filtration was performed, the filtrate was concentrated under reduced pressure to dryness, 70ml of ethanol was added to the residue, and after heating, crystallization was performed by cooling, and after suction filtration, 23.8g of the product was obtained.

EXAMPLE 3 preparation of the Compound of formula I

20g of the compound of the formula II prepared in the example 2 and 200ml of ethyl acetate are put into a hydrogenation kettle and stirred for dissolution, 0.4g of 5% palladium hydroxide is added, 1ml of glacial acetic acid is added, N2 is used for replacement for three times and then replaced with hydrogen for three times, and hydrogen is introduced to control the pressure to be about 1kg/cm2 for reaction for 4-6 hours. After the reaction is finished, replacing hydrogen with nitrogen, discharging, performing suction filtration, concentrating the filtrate under reduced pressure to dryness, adding 95ml of ethanol into the residue, heating to dissolve the residue, cooling, and crystallizing to obtain 14.9g of a product.

Claims

1. A process for the preparation of a compound of formula I, characterized in that the reaction scheme is:

Wherein, -X ═ Cl; the reaction steps comprise:

1) Preparation of a Compound of formula III: dissolving 37.2g of a compound shown in the formula V in 200ml of dichloromethane, adding 15g of triethylamine, controlling the temperature in an ice-water bath to be 0-5 ℃, slowly dropwise adding 13.8g of chloroacetyl chloride, after about 20 minutes of dropwise adding, removing the ice bath, naturally heating to room temperature, stirring for 3-4 hours, after the reaction is finished, adding 100ml of water, stirring, layering, extracting a water layer twice by using 100ml of dichloromethane 2, combining organic layers, washing by using 100ml of saturated saline solution, drying the organic layer by using 8g of anhydrous sodium sulfate, performing suction filtration, concentrating the filtrate under reduced pressure to dryness, and recrystallizing the remainder by using 115ml of ethyl acetate to obtain 40.2g of a product;

2) Preparation of a Compound of formula II: dissolving 22.4g of the prepared compound shown in the formula III in 120ml of acetonitrile, adding 6.3g of p-aminobenzonitrile and 10g of potassium carbonate, slowly heating to about 35 ℃ under stirring, stirring for reaction for about 5 hours, performing TLC (thin layer chromatography) to show that the acetonitrile is concentrated under reduced pressure till the reaction is dry after the reaction is finished, adding 120ml of water, extracting with 150ml of ethyl acetate 2, combining organic layers, washing with 50ml of saturated saline water, drying with 10g of anhydrous sodium sulfate, performing suction filtration, performing reduced pressure concentration on the filtrate till the filtrate is dry, adding 70ml of ethanol into the residue, heating, cooling, crystallizing, performing suction filtration and drying to obtain 23.8g of a product;

3) preparation of a Compound of formula I: putting 20g of the prepared compound shown in the formula II and 200ml of ethyl acetate into a hydrogenation kettle, stirring and dissolving, adding 0.4g of 5% palladium hydroxide, adding 1ml of glacial acetic acid, replacing for three times by N2, replacing for three times by hydrogen, introducing hydrogen, controlling the pressure to be 1kg/cm2, and reacting for 4-6 hours; after the reaction is finished, replacing hydrogen with nitrogen, discharging, performing suction filtration, concentrating the filtrate under reduced pressure to dryness, adding 95ml of ethanol into the residue, heating to dissolve the residue, cooling, and crystallizing to obtain 14.9g of a product.