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A kind of preparation method of dabigatran etexilate intermediate

A technology for dabigatran etexilate and intermediates, which is applied in the field of preparation of dabigatran etexilate intermediates, and can solve the problems of long reaction cycle, high corrosion of production equipment, and low purity of compound 1

Active Publication Date: 2018-03-23
LEPU PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The use of hydrogen chloride gas brings great inconvenience to the production operation, there is a great potential safety hazard, and it is highly corrosive to the production equipment
[0010] The preparation of compound 1 in route 2 is under the catalysis of Pd / C, and the reduction reaction is carried out with hydrogen, which has the problems of long reaction cycle, poor selectivity, and low purity of compound 1.

Method used

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  • A kind of preparation method of dabigatran etexilate intermediate
  • A kind of preparation method of dabigatran etexilate intermediate
  • A kind of preparation method of dabigatran etexilate intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] A kind of preparation method of dabigatran etexilate intermediate, comprises the steps:

[0028] (1) Dissolve 480g of compound 2 in 2500mL of tetrahydrofuran (stir at room temperature until completely dissolved), cool the reaction solution to -5°C, slowly add 1mol / L lithium hexamethyldisilazide tetrahydrofuran solution 1200mL dropwise, About 50 minutes to drip;

[0029] (2) After the dropwise addition, keep the temperature of the reaction solution at 15-20°C, detect by HPLC, if the remaining amount of compound 2 is below 1.0%, stop the reaction (timed reaction time is about 2 hours);

[0030] (3) Continue to cool down to below 5°C, add concentrated hydrochloric acid (density 1.179g / cm 3 ) until the pH of the reaction solution is between 2-3, add 1200mL water and 800mL methyl tert-butyl ether, stir and mix, separate the water phase (add concentrated hydrochloric acid: the basic impurities generated can be removed, compound 1 is dissolved in acidic conditions In water, ...

Embodiment 2

[0033] Replace the 1 mol / L tetrahydrofuran solution of lithium hexamethyldisilazide in step (1) with the tetrahydrofuran solution of 1 mol / L sodium hexamethyldisilazide, and refer to Embodiment 1 for others to obtain light yellow Oil 442g, yield 88.6%.

Embodiment 3

[0035] The tetrahydrofuran in step (1) was replaced with acetonitrile, and other references were made to Implementation 1 to obtain 376 g of light yellow oil, with a yield of 75.3%.

[0036] The compound 1 oil obtained in any of the above examples was dissolved in acetone, and an equimolar p-toluenesulfonic acid was added to obtain a white solid powder, which was the p-toluenesulfonate of compound 1. 1 HNMR (DMSO) see figure 1 , 1 HNMR(DMSO, 30℃400MHz)[ppm] δ1.12 (t, 3H), δ2.29(s, 3H) ,δ2.68(t,2H),δ3.76(s,3H),δ3.98 (t,2H),δ4.22(t,2H),δ4.65(d,2H),δ6.86(m,2H),δ6.90(m,1H),δ7.12(m,3H) ,δ7.16(m,1H),δ7.36(m,1H),δ7.40(m,1H),δ7.49(m,3H),δ7.55(m,1H),δ7.62( m, 2H), δ8.38 (m, 3H) δ8.80 (s, 2H).

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Abstract

The invention discloses a preparation method of a Dabigatran midbody of a compound 1. According to a specific preparation process, in MN(TMS)2, M is equal to Li, Na or K, and TMS is equal to (CH3)3Si; the preparation process comprises the steps of 1) dissolving a compound 2 in an organic solvent, dropwise adding the MN(TMS)2 at minus 10 DEG C-5 DEG C, after the dropwise adding is completed, reacting at 15-20 DEG C, and ending; 2) under 5 DEG C, dropwise adding an acidification reagent into reaction liquid for acidification, adjusting pH to 2-3, adding water and organic ether for washing, and separating out an aqueous phase; 3) adding dichloromethane into the aqueous phase obtained in step 2), adjusting pH to 8-10 by using alkali liquor, separating out an aqueous phase, extracting the aqueous phase by using dichloromethane, and combining organic phases; 4) drying the organic phases obtained in step 3), then removing the solvent to obtain the compound 1. The method is simple to operate, free of production safety loopholes, good in reaction selectivity, and suitable for scale production.

Description

technical field [0001] The invention belongs to the field of organic synthesis, in particular to a preparation method of a dabigatran etexilate intermediate. Background technique [0002] Dabigatran etexilate was developed by Boehringer Ingelheim, Germany, and was first launched in Germany and the United Kingdom in April 2008. It is the first new class of oral anticoagulant drugs to be marketed in 50 years after the waring method. [0003] There are many literatures and patent reports about its synthesis, and there are two common synthetic routes, [0004] Synthetic Route 1: Patents WO2014 / 12880 A1, US6087380 A1, WO2012 / 77136 A2, WO2004 / 14894 A1, US2013 / 30023 A1, WO2014 / 192030 A2, Journal of Medicinal Chemistry, 2002, vol. 45(9), p. 1757 – 1766; [0005] [0006] Synthetic route 2: WO2007 / 71742 A1, US2011 / 118471 A1, EP1609784 A1, etc.; [0007] [0008] In the process report of the above routes, compound 1 is a key intermediate for the synthesis of dabigatran etexil...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 李海峰刘娜娜孔巍王振卫张帮浩王庆鹏
Owner LEPU PHARMACEUTICAL CO LTD