CN105348148B - The method for preparing the oxalates of the impurity of dabigatran etexilate intermediate condensation product - Google Patents

The method for preparing the oxalates of the impurity of dabigatran etexilate intermediate condensation product Download PDF

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Publication number
CN105348148B
CN105348148B CN201510862480.7A CN201510862480A CN105348148B CN 105348148 B CN105348148 B CN 105348148B CN 201510862480 A CN201510862480 A CN 201510862480A CN 105348148 B CN105348148 B CN 105348148B
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China
Prior art keywords
impurity
oxalates
condensation product
dabigatran etexilate
intermediate condensation
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CN201510862480.7A
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Chinese (zh)
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CN105348148A (en
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翟吉胜
郑忠辉
于磊
窦国华
翟光新
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山东新华制药股份有限公司
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/04Preparation 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
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06Preparation 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
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41Preparation of salts of carboxylic acids
    • C07C51/412Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part

Abstract

The invention belongs to medicinal chemistry art, and in particular to a kind of method of the oxalates for the impurity for preparing dabigatran etexilate intermediate condensation product.The just own ester of chloro-carbonic acid, dichloromethane, sodium hydroxide, water are added into reaction bulb, adds p-Aminobenzamidine dihydrochloride solid, reacts;After completion of the reaction plus water, stirring are stood, branch vibration layer;Organic layer steaming vibrating dichloromethane obtains sticky solid;Into sticky solid plus acetone, dissolve by heating, add oxalic acid dihydrate, cool crystallization, filtering, the oxalates of dry the impurity of dabigatran etexilate intermediate condensation product.Oxalates (IIa) the HPLC contents of the impurity for the dabigatran etexilate intermediate condensation product being prepared using preparation method of the present invention are more than 98%;The oxalates for synthesizing the impurity of dabigatran etexilate intermediate condensation product is beneficial to the impurity research of dabigatran etcxilate, and promotes the technological progress of synthesis dabigatran etcxilate.

Description

The method for preparing the oxalates of the impurity of dabigatran etexilate intermediate condensation product

Technical field

The invention belongs to medicinal chemistry art, and in particular to a kind of impurity for preparing dabigatran etexilate intermediate condensation product The method of oxalates.

Background technology

Dabigatran etcxilate (trade name Pradaxa) by German Boehringer Ingelheim company in April, 2008 Germany and Britain takes the lead in listing, and dabigatran etcxilate is a kind of direct thrombin inhibitor.

US8399678B2 provides the preparation method of dabigatran etcxilate, is preparing dabigatran etexilate intermediate condensation product (I) When, reacted by the just own ester (III) of chloro-carbonic acid and p-Aminobenzamidine (IV), obtain compound I.Reaction equation is as follows:

In the reaction, there is substantial amounts of unknown impuritie 1 to generate, therefore, for quality research and technological progress, prepare pure It is necessary to spend higher unknown impuritie 1 and confirm its structure.

The content of the invention

In view of the shortcomings of the prior art, it is an object of the invention to provide a kind of dabigatran etexilate intermediate condensation product of preparing The method of the oxalates of impurity, HPLC contents are more than 98%, are studied beneficial to the impurity of dabigatran etcxilate, and promote synthesis Da Bijia The technological progress of group's ester.

The method of the oxalates of the impurity of the present invention for preparing dabigatran etexilate intermediate condensation product, p-aminophenyl first Amidine dihydrochloride reacts with the just own ester of chloro-carbonic acid, then obtains product into salt with oxalic acid dihydrate.

It is of the present invention prepare dabigatran etexilate intermediate condensation product impurity oxalates method, preferably include with Lower step:

(1) the just own ester (III) of chloro-carbonic acid, dichloromethane, sodium hydroxide, water are added into reaction bulb, adds p-Aminobenzamidine Dihydrochloride (IV) solid, reaction;

(2) water is added after completion of the reaction, stirring is stood, branch vibration layer;Organic layer steaming vibrating dichloromethane obtains sticky solid;

(3) add acetone into sticky solid, dissolve by heating, add oxalic acid dihydrate, cool crystallization, and filtering is dry to reach Than adding group oxalates of the impurity of ester intermediate condensate (IIa).

The present invention confirms above-mentioned unknown impuritie 1 i.e. compound II, compound II and its oxalic acid by separation and structural analysis Salt compound IIa structure is as follows:

Reaction equation of the present invention is as follows:

Wherein:

The mol ratio 0.1 of the just own ester of chloro-carbonic acid and p-Aminobenzamidine dihydrochloride:0.045-0.055.

The just own ester of chloro-carbonic acid, dichloromethane, sodium hydroxide, the rate of charge of water are 0.1:100-105:0.18-0.22:30- 35, wherein the just own ester of chloro-carbonic acid and sodium hydroxide are in terms of mol, and dichloromethane and water are in terms of ml.

In step (1) plus p-Aminobenzamidine dihydrochloride solid is:Add p-Aminobenzamidine two by several times at 18-22 DEG C HCl, solid, add within 1 hour.

The reaction time is 3.5-4.5 hours in step (1).

As a kind of preferred scheme, the oxalates of the impurity of the present invention for preparing dabigatran etexilate intermediate condensation product Method, comprise the following steps:By the just own ester of 0.1mol chloro-carbonic acids, 100-105ml dichloromethane, 0.18-0.22mol hydroxides Sodium, 30-35ml water add reaction bulb, point 15~20 times plus 0.045-0.055mol p-Aminobenzamidine disalts at 18-22 DEG C Hydrochlorate solid, add within 1 hour, react 3.5-4.5 hours at 10~30 DEG C;After completion of the reaction plus 100-105ml water, it is quiet after stirring Put, branch vibration layer;Add water 100-105ml to washed once again, organic layer steaming vibrating dichloromethane is obtained into sticky solid;To sticky solid In plus 45-55ml acetone, dissolve by heating, add 0.045-0.55mol oxalic acid dihydrates, cool crystallization, filtering, is washed with acetone Wash, the oxalates of dry the impurity of dabigatran etexilate intermediate condensation product.

The present invention has advantages below:

(1) grass of the impurity for the dabigatran etexilate intermediate condensation product being prepared using preparation method of the present invention Hydrochlorate (IIa) HPLC contents are more than 98%, and yield reaches more than 46.5%.

(2) compound II and its oxalates IIa has been there is not yet document report, the present invention have synthesized its oxalates IIa, beneficial to up to Than adding the impurity of group ester to study, and promote the technological progress of synthesis dabigatran etcxilate.

Embodiment

With reference to embodiment, the present invention will be further described.

Embodiment 1

By the just own ester (III) of 16.4g (0.1mol) chloro-carbonic acid, 100ml dichloromethane, 8.0g sodium hydroxides (0.2mol), 32ml water adds reaction bulb, point 20 times plus 10.5g (0.05mol) p-Aminobenzamidine dihydrochloride (IV) solid at 20 DEG C, and 1 Hour adds, and adds reaction 4 hours.After completion of the reaction plus 100ml water, stood after stirring a few minutes, branch vibration layer, add water 100ml washed once again, and organic layer steaming vibrating dichloromethane obtains sticky solid (II).Add 50ml acetone, heating into sticky solid Dissolving, adds 6.30g (0.05mol) oxalic acid dihydrate, and cool crystallization, filtering, is washed with acetone, the impurity of dry condensation product Oxalates (IIa) HPLC contents be 98.92%, yield 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:δ 14.35, δ 14.37, δ 22.50 (2C), δ 25.49, δ 25.62, δ 28.85, δ 28.89, δ 31.37, δ 31.44, δ 64.97, δ 65.16, δ 117.64 (2C), δ 126.99, δ 129.40 (2C), δ 143.60, δ 153.93, δ 162.65 (2C), δ 162.93, δ 166.11。

Embodiment 2

The just own ester of 0.1mol chloro-carbonic acids, 105ml dichloromethane, 0.22mol sodium hydroxides, 35ml water are added into reaction bulb, Point 18 times plus 0.055mol p-Aminobenzamidine dihydrochloride solids, are added for 1 hour at 22 DEG C, add reaction 4.5 hours;Instead Add 105ml water after answering, stood after stirring, branch vibration layer;Add water 100ml to washed once again, organic layer is boiled off into dichloromethane Alkane obtains sticky solid;Add 55ml acetone into sticky solid, dissolve by heating, add 0.55mol oxalic acid dihydrates, cool crystallization, Filtering, is washed with acetone, dries the oxalates (IIa) of the impurity of dabigatran etexilate intermediate condensation product.

HPLC contents are 98.09%, yield 46.88%.

Embodiment 3

The just own ester of 0.1mol chloro-carbonic acids, 102ml dichloromethane, 0.18mol sodium hydroxides, 30ml water are added into reaction bulb, Point 15 times plus 0.045mol p-Aminobenzamidine dihydrochloride solids, are added for 1 hour at 18 DEG C, add reaction 3.5 hours;Instead Add 100ml water after answering, stood after stirring, branch vibration layer;Add water 105ml to washed once again, organic layer is boiled off into dichloromethane Alkane obtains sticky solid;Add 45ml acetone into sticky solid, dissolve by heating, add 0.045mol oxalic acid dihydrates, cool crystallization, Filtering, is washed with acetone, dries the oxalates (IIa) of the impurity of dabigatran etexilate intermediate condensation product.

HPLC contents are 98.50%, yield 47.34%.

Claims (1)

  1. A kind of 1. method of the oxalates for the impurity for preparing dabigatran etexilate intermediate condensation product, it is characterised in that:P-aminophenyl Carbonamidine dihydrochloride reacts with the just own ester of chloro-carbonic acid, then obtains product into salt with oxalic acid dihydrate:The structure of the product is such as Under:
    Comprise the following steps:
    The just own ester of 0.1mol chloro-carbonic acids, 100-105mL dichloromethane, 0.18-0.22mol sodium hydroxides, 30-35mL water are added Reaction bulb, point 15~20 times plus 0.045-0.055mol p-Aminobenzamidine dihydrochloride solids at 18-22 DEG C, adds for 1 hour It is complete, react 3.5-4.5 hours at 10~30 DEG C;After completion of the reaction plus 100-105mL water, stood after stirring, branch vibration layer;Add water 100-105mL be washed once again, and organic layer steaming vibrating dichloromethane is obtained into sticky solid;Add 45-55mL acetone into sticky solid, Dissolve by heating, add 0.045-0.55mol oxalic acid dihydrates, cool crystallization, filtering, is washed with acetone, dry dabigatran The oxalates of the impurity of ester intermediate condensate.
CN201510862480.7A 2015-11-30 2015-11-30 The method for preparing the oxalates of the impurity of dabigatran etexilate intermediate condensation product CN105348148B (en)

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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

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DK2297132T3 (en) * 2008-06-16 2015-05-26 Boehringer Ingelheim Int Process for preparing an intermediate of dabigatran etexilate
US8399678B2 (en) * 2009-11-18 2013-03-19 Boehringer Ingelheim International Gmbh Process for the manufacture of dabigatran etexilate
CN102633713B (en) * 2012-03-22 2013-12-11 南京工业大学 Dabigatran etexilate intermediate, preparation method for same and method for preparing dabigatran etexilate
CN104031031B (en) * 2014-05-05 2017-01-11 南通常佑药业科技有限公司 Dabigatran etexilate preparation method
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