Preparation method of dabigatran etexilate intermediate compound

Abstract

The preparation method comprises the following steps: 1, dissolving a compound I in an organic solvent, adding a dehydrating agent, stirring and mixing, adding a compound II, adding an alkali reagent, reacting at room temperature for 6-8 hours, and separating a product after the reaction is finished to obtain a compound III; and 2, dissolving the reactant III in an organic solvent, adding a catalyst, adding a compound IV, carrying out a heating reaction at 100-120 DEG C, and after the reaction is finished, separating the product to obtain a target product compound V. The method has the beneficial effects that the reaction route does not need cyclization reaction, the key intermediate compound V can be obtained with high yield and high purity, and the reaction yield is effectively improved; the process steps are few, the synthesis process can be simplified, and the reaction steps are reduced; reaction raw materials are easy to obtain, reaction products are easy to separate, and by-products are few.

Description

Technical Field

[0001] The invention relates to the technical field related to pharmaceutical synthesis, and in particular to a method for preparing a dabigatran etexilate intermediate compound. Background Art

[0002] Dabigatran etexilate, chemical name is 3-[[[2-[[[4-[[[(hexyloxy)carbonyl]amino]iminomethyl]phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester, chemical formula is C34H41N7O5, is the most advanced new generation of oral anticoagulant drugs direct thrombin inhibitors (DTIs) in clinical practice, is a thrombin inhibitor dabigatran etexilate capsule (trade name Pradaxa) developed by Boehringer Ingelheim, Germany, first launched in Germany and the United Kingdom in April 2008, and was approved by the FDA on October 19, 2010, for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation. Its chemical structure is as follows: used to prevent stroke and systemic embolism in patients with non-valvular atrial fibrillation, its chemical structure is as follows: Several synthetic methods for the preparation of dabigatran etexilate have been reported, as follows: 1. Boehringer Ingelheim disclosed the synthesis route of dabigatran etexilate for the first time in patent WO9837075, and the synthesis method is as follows: The synthesis method is as follows: 3. Boehringer Ingelheim disclosed a new synthesis route in patent WO2011061080A, and the synthesis method is as follows: The above routes all contain imidazole cyclization steps. Routes 1 and 2 are condensed by carboxylic acid and ortho-diamine. The yield of the imidazole ring synthesized by the method is low, and this step usually requires the use of a condensing agent, which is expensive. It is expensive and not conducive to reducing costs. At the same time, the reaction temperature is high, the reaction time is long, and the use of condensation agents to form rings The intermediate yield is low and a large amount of impurities will be introduced, resulting in low intermediate purity, which ultimately leads to The purity of bicamphenicol is also very low, and purification is not likely to affect the final product yield. Route 3 is a direct reaction of Route 1, 2 is an optimization and improvement, but this route requires the use of a cyclization reagent, and the cyclization reagent generally used is ethyl chloride. Acid, chloroacetyl chloride, chloroacetic anhydride or chloroacetic acid. The reaction yield is only 30% when chloroacetic acid is used; When chloroacetyl chloride is used for cyclization, diacetylated impurities are easily produced, and the yield is low, only 71%; chloroacetic anhydride The price is high, which increases the production cost to a large extent; and chloroacetate needs to be made by itself, which leads to The entire synthesis process is complicated, which increases the process cost, and the cyclization reaction takes a long time. Summary of the invention

[0003] Summary of the invention In view of the above-mentioned disadvantages, the present invention aims to provide a kind of preparation method of dabigatran etcxilate intermediate compound, replace original cyclization process by new synthesis technique, avoid cyclization yield too low and waste generation more, the technical problem of product separation difficulty, technical scheme of the present invention is as follows: A kind of preparation method of dabigatran etcxilate intermediate compound, it is characterized in that comprising the following steps: The first step is to dissolve compound I in an organic solvent, add a dehydrating agent, add compound II, and Add an alkali reagent and react at -20°C for 4 to 6 hours. After the reaction is complete, separate the product to obtain compound III; In the second step, reactant III is dissolved in an organic solvent, a catalyst is added, compound IV is added, and the mixture is heated at 100-120° C. to react. After the reaction is completed, the product is separated to obtain the target product compound V.

[0004] Furthermore, the organic solvent in the first step reaction is tetrahydrofuran.

[0005] Furthermore, in the first step reaction, the dehydrating agent is thionyl chloride, and the amount of thionyl chloride used is 1.5 to 2 eq of compound I.

[0006] Furthermore, in the first step reaction, the alkaline reagent is pyridine, and the amount of pyridine used is 1 to 2 eq of compound I.

[0007] Furthermore, in the first step reaction, the molar ratio of compound I to compound II is 1:1.0-1.1.

[0008] Furthermore, the organic solvent in the second step reaction is DMSO or DMF.

[0009] Furthermore, the catalyst in the second step reaction is sodium acetate.

[0010] Furthermore, the amount of catalyst used in the second step reaction is 10-20 wt % of compound III.

[0011] Furthermore, the molar ratio of compound III to compound IV in the second step reaction is 1:1.

[0012] Furthermore, the heating temperature in the second step reaction is 100-120°C.

[0013] The beneficial effects of the present invention are: The beneficial effects of the present invention are: 1. The reaction route of the present invention does not require a cyclization reaction, has a high yield, and has good reaction selectivity. The key intermediate compound V can be obtained in high yield and high purity, effectively improving the yield of the reaction and saving production costs; 2. At the same time, the present invention has fewer process steps, which can simplify the synthesis process and reduce the reaction steps, making it more suitable for large-scale industrial production needs; 3. The reaction raw materials of the present invention are easy to obtain, the reaction products are simple to separate, and there are few by-products. The purity of compound I and the final product compound II can also be effectively improved. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 is a schematic diagram of the chemical structure of dabigatran etexilate; Figure 2 Schematic diagram of the reaction process of route 1; Figure 3 Schematic diagram of the reaction flow of route 2; Figure 4 The reaction flow diagram of route 3 is shown; Figure 5 It is a schematic diagram of the reaction flow of the present invention. DETAILED DESCRIPTION

[0015] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0016] In the first step, 18.2 g (0.1 mol) of compound I was dissolved in 200 ml of tetrahydrofuran, an organic solvent. Stir at room temperature for 1 hour, add 0.15 mol of dehydrating agent dichlorothionyl at -20 to -10°C, stir and mix, return to room temperature, add 19.4 g (0.1 mol) of compound II, add 0.1 mol of alkaline reagent pyridine, react at room temperature for 6 to 8 hours, after the reaction is completed, evaporate under reduced pressure to remove the solvent and dehydrating agent, dissolve the product in 100 ml of dichloromethane, wash with saturated brine 2 to 3 times, separate the organic phase, evaporate the solvent, and recrystallize the product with 40 ml of chloroform to obtain 34.0 g of compound III, with a yield of 94.9% and a purity of 97.9%; In the second step, under nitrogen protection, 35.8 g (0.1 mol) of compound III was dissolved in 400 ml of DMSO as an organic solvent, anhydrous sodium sulfate was added for drying, and the mixture was filtered. 3.58 g of sodium acetate as a catalyst was added to the filtrate, and compound IV was added. The mixture was reacted at 100°C for 6 to 8 hours. After the reaction was completed, the mixture was evaporated under reduced pressure, and the product was dissolved in 100 ml of chloroform, and washed 2 to 3 times with saturated brine. The organic phase was separated, and the solvent was evaporated. The product was recrystallized with 50 ml of chloroform to obtain 38.0 g of compound III with a yield of 94.9% and a purity of 97.8%. In the first step, 18.2 g (0.1 mol) of compound I was dissolved in 200 ml of tetrahydrofuran, an organic solvent. Stir at room temperature for 1 hour, add 0.2 mol of dehydrating agent dichlorothionyl at -20 to 10°C, stir and mix, return to room temperature, add 19.4 g (0.1 mol) of compound II, add 0.1 mol of pyridine as an alkaline reagent, react at room temperature for 6 to 8 hours, after the reaction is completed, evaporate under reduced pressure to remove the solvent and dehydrating agent, dissolve the product in 100 ml of dichloromethane, wash with saturated brine 2 to 3 times, separate the organic phase, evaporate the solvent, and recrystallize the product with 40 ml of chloroform to obtain 33.6 g of compound III, with a yield of 93.8% and a purity of 97.6%; In the first step, 18.2 g (0.1 mol) of compound I was dissolved in 200 ml of tetrahydrofuran, an organic solvent. Stir at room temperature for 1 hour, add 0.15 mol of dehydrating agent dichlorothionyl at -20 to 10°C, stir and mix, return to room temperature, add 19.4 g (0.11 mol) of compound II, add 0.1 mol of alkaline reagent pyridine, react at room temperature for 6 to 8 hours, after the reaction is completed, evaporate under reduced pressure to remove the solvent and dehydrating agent, dissolve the product in 100 ml of dichloromethane, wash with saturated brine 2 to 3 times, separate the organic phase, evaporate the solvent, and recrystallize the product with 40 ml of chloroform to obtain 33.3 g of compound III, with a yield of 93.0% and a purity of 97.5%; In the first step, 18.2 g (0.1 mol) of compound I was dissolved in 200 ml of tetrahydrofuran, an organic solvent. Stir at room temperature for 1 hour, add 0.15 mol of dehydrating agent dichlorothionyl at -20 to 10°C, stir and mix, return to room temperature, add 19.4 g (0.11 mol) of compound II, add 0.2 mol of pyridine as an alkaline reagent, react at room temperature for 6 to 8 hours, after the reaction is completed, evaporate under reduced pressure to remove the solvent and dehydrating agent, dissolve the product in 100 ml of dichloromethane, wash with saturated brine 2 to 3 times, separate the organic phase, evaporate the solvent, and recrystallize the product with 40 ml of chloroform to obtain 33.6 g of compound III, with a yield of 93.8% and a purity of 97.6%; The second step, under nitrogen protection, 35.8g (0.1mol) of compound III was dissolved in 400ml of DMF, anhydrous sodium sulfate was added to dry, filtered, 3.58g of sodium acetate catalyst was added to the filtrate, compound IV was added, and the reaction was carried out at 100°C for 6-8h. After the reaction was completed, the product was evaporated under reduced pressure, and 100ml of chloroform was used to dissolve the product, saturated brine was added to wash 2-3 times, the organic phase was separated, the solvent was evaporated, and the product was recrystallized with 50ml of chloroform to obtain 37.5g of compound III, with a yield of 93.6% and a purity of 97.8%; In the second step, under nitrogen protection, 35.8 g (0.1 mol) of compound III was dissolved in 400 ml of DMSO as an organic solvent, anhydrous sodium sulfate was added for drying, and the mixture was filtered. 7.16 g of sodium acetate as a catalyst was added to the filtrate, and compound IV was added. The mixture was reacted at 100°C for 6 to 8 hours. After the reaction was completed, the mixture was evaporated under reduced pressure, and the product was dissolved in 100 ml of chloroform, and washed 2 to 3 times with saturated brine. The organic phase was separated, and the solvent was evaporated. The product was recrystallized with 50 ml of chloroform to obtain 37.6 g of compound III with a yield of 93.9% and a purity of 97.5%. The second step, under nitrogen protection, 35.8g (0.1mol) of compound III was dissolved in 400ml of DMSO as an organic solvent, anhydrous sodium sulfate was added for drying, and the mixture was filtered. 3.58g of sodium acetate catalyst was added to the filtrate, and 0.1mol of compound IV was added. The mixture was reacted at 120°C for 6-8h. After the reaction was completed, the mixture was evaporated under reduced pressure. The product was dissolved in 100ml of chloroform, and washed 2-3 times with saturated brine. The organic phase was separated, the solvent was evaporated, and the product was recrystallized with 50ml of chloroform to obtain 37.3g of compound III with a yield of 93.1% and a purity of 97.8%. It will be apparent to those skilled in the art that the invention is not limited to the details of the exemplary embodiments described above and that the invention can be implemented in other specific forms without departing from the spirit or essential features of the invention. Therefore, the embodiments should be considered exemplary and non-limiting in all respects, and the scope of the invention is defined by the appended claims rather than the foregoing description, and it is intended that all variations falling within the meaning and scope of the equivalent elements of the claims be included in the invention. Any reference numeral in a claim should not be considered as limiting the claim to which it relates.

[0017] In addition, it should be understood that although the present specification is described according to implementation modes, not every implementation mode contains only one independent technical solution. This description of the specification is only for the sake of clarity. Those skilled in the art should regard the specification as a whole. The technical solutions in each embodiment may also be appropriately combined to form other implementation modes that can be understood by those skilled in the art.

Claims

1. a preparation method of dabigatran etcxilate intermediate compound, it is characterized in that The following steps are involved: The first step is to dissolve compound I in an organic solvent, add a dehydrating agent, stir and mix, and add a chemical Compound II is added with an alkali reagent and reacted at room temperature for 6 to 8 hours. After the reaction is completed, the product is separated to obtain compound III; In the second step, reactant III is dissolved in an organic solvent, a catalyst is added, compound IV is added, and the reaction is heated. After the reaction is completed, the product is separated to obtain the target product compound V.

2. the preparation method of a kind of dabigatran etcxilate intermediate compound according to claim 1, is characterized in that: The organic solvent in the first step reaction is tetrahydrofuran.

3. the preparation method of a kind of dabigatran etcxilate intermediate compound according to claim 1, is characterized in that: In the first step reaction, the dehydrating agent is thionyl chloride, and the amount of thionyl chloride used is 1.5 to 2 eq of compound I.

4. the preparation method of a kind of dabigatran etcxilate intermediate compound according to claim 1, is characterized in that: In the first step reaction, the alkaline reagent is pyridine, and the amount of pyridine used is 1 to 2 eq of compound I.

5. the preparation method of a kind of dabigatran etcxilate intermediate compound according to claim 1, is characterized in that: In the first step reaction, the molar ratio of compound I to compound II is 1:1.0-1.

1.

6. the preparation method of a kind of dabigatran etcxilate intermediate compound according to claim 1, is characterized in that: The organic solvent in the second step reaction is dichloromethane (DCM) or tetrahydrofuran (THF).

7. the preparation method of a kind of dabigatran etcxilate intermediate compound according to claim 1, is characterized in that: The catalyst in the second step reaction is sodium acetate.

8. the preparation method of a kind of dabigatran etcxilate intermediate compound according to claim 1, is characterized in that: The amount of catalyst used in the second step reaction is 10-20 wt% of compound III.

9. the preparation method of a kind of dabigatran etcxilate intermediate compound according to claim 1, is characterized in that: The molar ratio of compound III to compound IV in the second step reaction is 1:

1.

10. The method for preparing a dabigatran etexilate intermediate compound according to claim 1, wherein: The heating temperature in the second step reaction is 100-120°C.

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