CN105348148A - Method for preparing impurity oxalate of intermediate condensation compound of pradaxa - Google Patents

Method for preparing impurity oxalate of intermediate condensation compound of pradaxa Download PDF

Info

Publication number
CN105348148A
CN105348148A CN201510862480.7A CN201510862480A CN105348148A CN 105348148 A CN105348148 A CN 105348148A CN 201510862480 A CN201510862480 A CN 201510862480A CN 105348148 A CN105348148 A CN 105348148A
Authority
CN
China
Prior art keywords
impurity
oxalate
add
water
reaction
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201510862480.7A
Other languages
Chinese (zh)
Other versions
CN105348148B (en
Inventor
翟吉胜
郑忠辉
于磊
窦国华
翟光新
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shandong Xinhua Pharmaceutical Co Ltd
Original Assignee
Shandong Xinhua Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shandong Xinhua Pharmaceutical Co Ltd filed Critical Shandong Xinhua Pharmaceutical Co Ltd
Priority to CN201510862480.7A priority Critical patent/CN105348148B/en
Publication of CN105348148A publication Critical patent/CN105348148A/en
Application granted granted Critical
Publication of CN105348148B publication Critical patent/CN105348148B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention belongs to the field of medicinal chemistry and particularly relates to a method for preparing the impurity oxalate of an intermediate condensation compound of pradaxa. Hexyl chloroformate, dichloromethane, sodium hydroxide and water are added into a reaction flask, a 4-aminobenzamidine dihydrochloride solid is added, and a reaction is carried out; water is added after the reaction is finished, stirring and standing are carried out, and a water layer is separated and removed; an organic layer is steamed for removing dichloromethane, and a thick solid is obtained; the thick solid is added with acetone, heated and dissolved, added with oxalic acid dihydrate, cooled for crystallization, filtered and dried, and the impurity oxalate of the intermediate condensation compound of pradaxa is obtained. The HPLC content of the impurity oxalate (IIa), prepared and obtained through the preparing method, of the intermediate condensation compound of pradaxa is higher than 98%; synthesis of the impurity oxalate of the intermediate condensation compound of pradaxa is beneficial to impurity research of pradaxa, and the technological progress of synthesizing pradaxa is promoted.

Description

The method of the oxalate of the impurity of preparation dabigatran etexilate intermediate condenses
Technical field
The invention belongs to medicinal chemistry art, be specifically related to a kind of method preparing the oxalate of the impurity of dabigatran etexilate intermediate condenses.
Background technology
Dabigatran etcxilate (commodity are called Pradaxa) is taken the lead in going on the market in Germany and Britain in April, 2008 by German Boehringer Ingelheim company, and dabigatran etcxilate is a kind of direct thrombin inhibitor.
US8399678B2 provides the preparation method of dabigatran etcxilate, when preparing dabigatran etexilate intermediate condenses (I), being reacted, obtain Compound I by the just own ester (III) of chloroformic acid and p-Aminobenzamidine (IV).Reaction equation is as follows:
In the reaction, have a large amount of unknown impurities 1 to generate, therefore, in order to quality approach and technical progress, it is necessary for preparing the higher unknown impuritie 1 of purity and confirming its structure.
Summary of the invention
For the deficiencies in the prior art, the object of this invention is to provide a kind of method preparing the oxalate of the impurity of dabigatran etexilate intermediate condenses, HPLC content is greater than 98%, is beneficial to the impurity research of dabigatran etcxilate, and promotes the technical progress of synthesis dabigatran etcxilate.
The method of the oxalate of the impurity of preparation dabigatran etexilate intermediate condenses of the present invention, the just own ester of p-Aminobenzamidine dihydrochloride and chloroformic acid reacts, then obtains product with oxalic acid dihydrate salify.
The method of the oxalate of the impurity of preparation dabigatran etexilate intermediate condenses of the present invention, preferably includes following steps:
(1) just own for chloroformic acid ester (III), methylene dichloride, sodium hydroxide, water are added reaction flask, add p-Aminobenzamidine dihydrochloride (IV) solid, reaction;
(2) add water after completion of the reaction, stir and leave standstill, branch vibration layer; Organic layer steaming vibrating dichloromethane obtains sticky solid;
(3) in sticky solid, add acetone, heating for dissolving, add oxalic acid dihydrate, cooling crystallization, filters, the dry oxalate (IIa) obtaining the impurity of dabigatran etexilate intermediate condenses.
The present invention is through being separated and structural analysis, and confirm the i.e. Compound II per of above-mentioned unknown impuritie 1, the structure of Compound II per and oxalate compound IIa thereof is as follows:
Reaction equation of the present invention is as follows:
Wherein:
The mol ratio 0.1:0.045-0.055 of the just own ester of chloroformic acid and p-Aminobenzamidine dihydrochloride.
The feed ratio of the just own ester of chloroformic acid, methylene dichloride, sodium hydroxide, water is 0.1:100-105:0.18-0.22:30-35, and wherein the just own ester of chloroformic acid and sodium hydroxide are in mol, and methylene dichloride and water are in ml.
Adding p-Aminobenzamidine dihydrochloride solid in step (1) is: at 18-22 DEG C, gradation adds p-Aminobenzamidine dihydrochloride solid, within 1 hour, adds.
In step (1), the reaction times is 3.5-4.5 hour.
As a kind of preferred version, the method of the oxalate of the impurity of preparation dabigatran etexilate intermediate condenses of the present invention, comprise the following steps: just own for 0.1mol chloroformic acid ester, 100-105ml methylene dichloride, 0.18-0.22mol sodium hydroxide, 30-35ml water are added reaction flask, divide at 18-22 DEG C and add 0.045-0.055mol p-Aminobenzamidine dihydrochloride solid for 15 ~ 20 times, within 1 hour, add, at 10 ~ 30 DEG C of reaction 3.5-4.5 hour; Add 100-105ml water after completion of the reaction, leave standstill after stirring, branch vibration layer; The 100-105ml that adds water washs once again, and organic layer steaming vibrating dichloromethane is obtained sticky solid; In sticky solid, add 45-55ml acetone, heating for dissolving, add 0.045-0.55mol oxalic acid dihydrate, cooling crystallization, filters, with washing with acetone, and the dry oxalate obtaining the impurity of dabigatran etexilate intermediate condenses.
The present invention has the following advantages:
(1) oxalate (IIa) the HPLC content of the impurity of the dabigatran etexilate intermediate condenses adopting preparation method of the present invention to prepare is greater than 98%, and productive rate reaches more than 46.5%.
(2) Compound II per and oxalate IIa thereof there is not yet bibliographical information, and the present invention has synthesized its oxalate IIa, are beneficial to the impurity research of dabigatran etcxilate, and promote the technical progress of synthesis dabigatran etcxilate.
Embodiment
Below in conjunction with embodiment, the present invention will be further described.
Embodiment 1
Just own for 16.4g (0.1mol) chloroformic acid ester (III), 100ml methylene dichloride, 8.0g sodium hydroxide (0.2mol), 32ml water are added reaction flask, divide at 20 DEG C and add 10.5g (0.05mol) p-Aminobenzamidine dihydrochloride (IV) solid for 20 times, within 1 hour, add, add reaction 4 hours.Add 100ml water after completion of the reaction, leave standstill after stirring several minutes, branch vibration layer, the 100ml that adds water washs once again, and organic layer steaming vibrating dichloromethane obtains sticky solid (II).In sticky solid, add 50ml acetone, heating for dissolving, add 6.30g (0.05mol) oxalic acid dihydrate, cooling crystallization, filters, with washing with acetone, dry oxalate (IIa) the HPLC content obtaining the impurity of condenses is 98.92%, and productive rate is 47.89%. 1HNMR：δ：0.88(s，2H)，1.34(t，12H)，1.62(s，4H)，4.06(d，4H)，7.56(d，2H)，7.90(d，2H)，9.38(s，1H)，9.98(s，1H)； 13CNMR：δ14.35，δ14.37，δ22.50(2C)，δ25.49，δ25.62，δ28.85，δ28.89，δ31.37，δ31.44，δ64.97，δ65.16，δ117.64(2C)，δ126.99，δ129.40(2C)，δ143.60，δ153.93，δ162.65(2C)，δ162.93，δ166.11。
Embodiment 2
Just own for 0.1mol chloroformic acid ester, 105ml methylene dichloride, 0.22mol sodium hydroxide, 35ml water are added reaction flask, divides at 22 DEG C and add 0.055mol p-Aminobenzamidine dihydrochloride solid for 18 times, within 1 hour, add, add reaction 4.5 hours; Add 105ml water after completion of the reaction, leave standstill after stirring, branch vibration layer; The 100ml that adds water washs once again, and organic layer steaming vibrating dichloromethane is obtained sticky solid; In sticky solid, add 55ml acetone, heating for dissolving, add 0.55mol oxalic acid dihydrate, cooling crystallization, filters, with washing with acetone, and the oxalate (IIa) of the impurity of dry dabigatran etexilate intermediate condenses.
HPLC content is 98.09%, and productive rate is 46.88%.
Embodiment 3
Just own for 0.1mol chloroformic acid ester, 102ml methylene dichloride, 0.18mol sodium hydroxide, 30ml water are added reaction flask, divides at 18 DEG C and add 0.045mol p-Aminobenzamidine dihydrochloride solid for 15 times, within 1 hour, add, add reaction 3.5 hours; Add 100ml water after completion of the reaction, leave standstill after stirring, branch vibration layer; The 105ml that adds water washs once again, and organic layer steaming vibrating dichloromethane is obtained sticky solid; In sticky solid, add 45ml acetone, heating for dissolving, add 0.045mol oxalic acid dihydrate, cooling crystallization, filters, with washing with acetone, and the oxalate (IIa) of the impurity of dry dabigatran etexilate intermediate condenses.
HPLC content is 98.50%, and productive rate is 47.34%.

Claims (7)

1. prepare a method for the oxalate of the impurity of dabigatran etexilate intermediate condenses, it is characterized in that: the just own ester of p-Aminobenzamidine dihydrochloride and chloroformic acid reacts, then obtains product with oxalic acid dihydrate salify.
2. the method for the oxalate of the impurity of preparation dabigatran etexilate intermediate condenses according to claim 1, is characterized in that: comprise the following steps:
(1) just own for chloroformic acid ester, methylene dichloride, sodium hydroxide, water are added reaction flask, add p-Aminobenzamidine dihydrochloride solid, reaction;
(2) add water after completion of the reaction, stir and leave standstill, branch vibration layer; Organic layer steaming vibrating dichloromethane obtains sticky solid;
(3) in sticky solid, add acetone, heating for dissolving, add oxalic acid dihydrate, cooling crystallization, filters, the dry oxalate obtaining the impurity of dabigatran etexilate intermediate condenses.
3. the method for the oxalate of the impurity of preparation dabigatran etexilate intermediate condenses according to claim 2, is characterized in that: the mol ratio 0.1:0.045-0.055 of the just own ester of chloroformic acid and p-Aminobenzamidine dihydrochloride.
4. the method for the oxalate of the impurity of preparation dabigatran etexilate intermediate condenses according to claim 2, it is characterized in that: the feed ratio of the just own ester of chloroformic acid, methylene dichloride, sodium hydroxide, water is 0.1:100-105:0.18-0.22:30-35, wherein the just own ester of chloroformic acid and sodium hydroxide are in mol, and methylene dichloride and water are in ml.
5. the method for the oxalate of the impurity of preparation dabigatran etexilate intermediate condenses according to claim 2, it is characterized in that: adding p-Aminobenzamidine dihydrochloride solid in step (1) is: at 18-22 DEG C, gradation adds p-Aminobenzamidine dihydrochloride solid, within 1 hour, adds.
6. the method for the oxalate of the impurity of preparation dabigatran etexilate intermediate condenses according to claim 2, is characterized in that: in step (1), the reaction times is 3.5-4.5 hour.
7. the method for the oxalate of the impurity of preparation dabigatran etexilate intermediate condenses according to claim 2, it is characterized in that: just own for 0.1mol chloroformic acid ester, 100-105ml methylene dichloride, 0.18-0.22mol sodium hydroxide, 30-35ml water are added reaction flask, divide at 18-22 DEG C and add 0.045-0.055mol p-Aminobenzamidine dihydrochloride solid for 15 ~ 20 times, within 1 hour, add, at 10 ~ 30 DEG C of reaction 3.5-4.5 hour; Add 100-105ml water after completion of the reaction, leave standstill after stirring, branch vibration layer; The 100-105ml that adds water washs once again, and organic layer steaming vibrating dichloromethane is obtained sticky solid; In sticky solid, add 45-55ml acetone, heating for dissolving, add 0.045-0.55mol oxalic acid dihydrate, cooling crystallization, filters, with washing with acetone, and the dry oxalate obtaining the impurity of dabigatran etexilate intermediate condenses.
CN201510862480.7A 2015-11-30 2015-11-30 The method for preparing the oxalates of the impurity of dabigatran etexilate intermediate condensation product Active CN105348148B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201510862480.7A CN105348148B (en) 2015-11-30 2015-11-30 The method for preparing the oxalates of the impurity of dabigatran etexilate intermediate condensation product

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201510862480.7A CN105348148B (en) 2015-11-30 2015-11-30 The method for preparing the oxalates of the impurity of dabigatran etexilate intermediate condensation product

Publications (2)

Publication Number Publication Date
CN105348148A true CN105348148A (en) 2016-02-24
CN105348148B CN105348148B (en) 2017-12-26

Family

ID=55324235

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201510862480.7A Active CN105348148B (en) 2015-11-30 2015-11-30 The method for preparing the oxalates of the impurity of dabigatran etexilate intermediate condensation product

Country Status (1)

Country Link
CN (1) CN105348148B (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105732433A (en) * 2016-04-13 2016-07-06 山东新华制药股份有限公司 Refining method of Dabigatran etexilate intermediate condensation compound

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5693636A (en) * 1991-06-28 1997-12-02 Smithkline Beecham Corporation Bicyclic fibrinogen antagonists
CN101845017A (en) * 2009-03-24 2010-09-29 天津市炜杰科技有限公司 Preparation method of atracurium besilate intermediates
CN102066355A (en) * 2008-06-16 2011-05-18 贝林格尔.英格海姆国际有限公司 Method for producing an intermediate product of dabigatran etexilate
US20110275824A1 (en) * 2009-11-18 2011-11-10 Boehringer Ingelheim International Gmbh Process for the manufacture of dabigatran etexilate
CN102633713A (en) * 2012-03-22 2012-08-15 南京工业大学 Dabigatran etexilate intermediate, preparation method for same and method for preparing dabigatran etexilate
CN104031031A (en) * 2014-05-05 2014-09-10 南通常佑药业科技有限公司 Dabigatran etexilate preparation method
CN104910047A (en) * 2015-05-11 2015-09-16 常州市阳光药业有限公司 Preparation method of dabigatran etexilate intermediate

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5693636A (en) * 1991-06-28 1997-12-02 Smithkline Beecham Corporation Bicyclic fibrinogen antagonists
CN102066355A (en) * 2008-06-16 2011-05-18 贝林格尔.英格海姆国际有限公司 Method for producing an intermediate product of dabigatran etexilate
CN101845017A (en) * 2009-03-24 2010-09-29 天津市炜杰科技有限公司 Preparation method of atracurium besilate intermediates
US20110275824A1 (en) * 2009-11-18 2011-11-10 Boehringer Ingelheim International Gmbh Process for the manufacture of dabigatran etexilate
CN102633713A (en) * 2012-03-22 2012-08-15 南京工业大学 Dabigatran etexilate intermediate, preparation method for same and method for preparing dabigatran etexilate
CN104031031A (en) * 2014-05-05 2014-09-10 南通常佑药业科技有限公司 Dabigatran etexilate preparation method
CN104910047A (en) * 2015-05-11 2015-09-16 常州市阳光药业有限公司 Preparation method of dabigatran etexilate intermediate

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ANON.: "Impurities of Ethyl 3-{[(2-{[(4-{N-[(hexyloxy)carbonyl]carbamimidoyl}-phenyl)amino]methyl}-1-methyl-1H-benzimidazol-5-yl)carbonyl](2-pyridinyl)-amino}propanoate mesylate", 《IP.COM》 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105732433A (en) * 2016-04-13 2016-07-06 山东新华制药股份有限公司 Refining method of Dabigatran etexilate intermediate condensation compound

Also Published As

Publication number Publication date
CN105348148B (en) 2017-12-26

Similar Documents

Publication Publication Date Title
KR20130129180A (en) Process for preparing aminobenzoylbenzofuran derivatives
JP2012255005A (en) Method for producing 5-(4-[4-(5-cyano-3-indolyl)butyl]-1-piperazinyl)benzofuran-2-carboxamide
JP5256029B2 (en) Method for producing 3,7-diaza-bicyclo [3.3.1] nonane compound
CN110724100B (en) Preparation method of cisatracurium besilate intermediate
EP3444244B1 (en) Preparation process for high-purity dabigatran etexilate
JP2011527330A5 (en)
CN105348148A (en) Method for preparing impurity oxalate of intermediate condensation compound of pradaxa
CN110526813B (en) Process for producing isoquinoline compounds and intermediates thereof
CN112778200B (en) Preparation method and application of cisatracurium besilate
CN109928933B (en) 2-chloro-5-aldehyde pyrimidine and preparation method thereof
EA022300B1 (en) Separation of 2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine enantiomers using tartaric acid
CN113603670A (en) Method for preparing 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethyl-1-one
CN105153211B (en) Method for synthesis of 1-(N-Boc-4-piperidine)-4-pyrazoleboronic acid pinaol ester
CN105481831B (en) A kind of method for preparing dabigatran etexilate intermediate
CN110386928B (en) Azilsartan synthesis process
CN105399683B (en) Benzimidizole derivatives and preparation method thereof
CN108558676B (en) Preparation method of N, N-dibenzylethylenediamine diacetate
EP2557077B1 (en) Method for making donepezil
CN111217735B (en) Preparation method of silodosin intermediate
US8552195B2 (en) Method for making donepezil
KR101558742B1 (en) New synthetic method of natural product moracin Y
CN102648185A (en) Methods of preparing 1-(4-((1r,2s,3r)-1,2,3,4-tetrahydroxybutyl)-1h-imidazol-2-yl)ethanone
CN101747280B (en) Method for preparing detomidine and the intermediate thereof
CN114394955A (en) Preparation method of esomeprazole impurity H193/61
CN105777646A (en) Novel preparation method of 5-iodine-2-phenyl-1-methyl imidazole

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant