CN103923168B - A kind of preparation method of argatroban monohydrate - Google Patents

A kind of preparation method of argatroban monohydrate Download PDF

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Publication number
CN103923168B
CN103923168B CN201310013259.5A CN201310013259A CN103923168B CN 103923168 B CN103923168 B CN 103923168B CN 201310013259 A CN201310013259 A CN 201310013259A CN 103923168 B CN103923168 B CN 103923168B
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argatroban
white powder
ethanol water
stirring
added
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CN103923168A (en
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赵志全
吴尽
陈见见
徐冰
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Shandong New Time Pharmaceutical Co Ltd
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Shandong New Time Pharmaceutical Co Ltd
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Abstract

The invention discloses a kind of preparation methods of argatroban monohydrate, and this method comprises the following steps:(1)Crude product is taken to be added 97%(V/V)Ethanol water in, dissolving is down to room temperature, is then cooled to 05 DEG C again, and stirring and crystallizing filters, dry, obtains white powder I;(2)White powder I is repeated into step(1)Operation, obtain white powder II;(3)Extracting waste powder II is added 25%(V/V)Ethanol water in, dissolve, decolourize, filtering, the lower cooled to room temperature of filtrate stirring continues stirring and crystallizing, filters, dry, obtains argatroban monohydrate.The present invention can make the purity of final products agatroban reach 99.90% or more, and it is 65 so that the ratio of 21 R/S isomers is mainly controlled:34, to farthest play argatroban bioactivity.

Description

A kind of preparation method of argatroban monohydrate
Technical field
The invention belongs to drug technical field of refinement, in particular to a kind of preparation side of argatroban monohydrate Method.
Technical background
Argatroban monohydrate (argatroban monohydrate, 1) is a kind of high activity, highly selective blood coagulation Enzyme inhibitor, blood coagulation resisting function does not depend on internal antithrombase, but is directly combined simultaneously with the fibrin ferment to dissociate in blood Make its inactivation.
It is smaller additionally, due to argatroban molecular weight, can be directly entered inside thrombus, inactivation with fibrin knot The fibrin ferment of conjunction inhibits the generation of fibrin ferment indirectly, therefore the argatroban of extremely low concentration can inhibit by thrombin induction Platelet aggregation response.Since argatroban can substantially reduce the level of thrombin-antithrombin complex in blood plasma, effectively change The hypercoagulative state of kind patient, therefore have extraordinary clinical effectiveness in the treatment of chronic thromboembolic disease.
Chemistry entitled (2R, 4R) -4- methyl-1s-[N ~ 2- (3- methyl-1s, the 2,3,4- tetrahydrochysenes-of argatroban monohydrate 8- quinoline sulfonyl)-L- arginyl-s] -2 piperidine carboxylic acid monohydrate, typically 21(R)With 21(S)The mixing of argatroban Object, structural formula are as follows:
As X=CH3, Y=H, which is 21(S)Argatroban, as X=H, Y=CH3, the compound It is 21(R)Argatroban.Existing literature has disclosed first obtain anhydrous argatroban after through hydration become argatroban one be hydrated Object, and medical argatroban monohydrate needs to meet:21(R)With 21(S)The content ratio of position is located at R:S=63 ~ 67:37 In ~ 33 ranges.
There are many document report, EP 8746, US 4 258 192, JP by the preparation process of argatroban monohydrate 81-15,267, Application Publication flat 1-35000, EP 823 430 15% ethyl alcohol recrystallization of equal documents, R/S isomer proportions It changes greatly, and final products purity is not high, it is low to refine yield.
Patent ZL 200610129332.5 provides a kind of preparation method of medical argatroban monohydrate, using water It recrystallizes anhydrous argatroban and obtains argatroban monohydrate.The method uses solvent(Water)It is more, it is cumbersome, it is final to produce Product purity is not high, and 21 R/S isomer proportions change greatly.
Invention content
In view of the deficiencies in the prior art, the purpose of the present invention is to provide a kind of Ah adding easy to operate, refining effect is good The preparation method of bent class's monohydrate.
The present inventor is studied by a large number of experiments, has unexpectedly obtained the following technical solution of realization the object of the invention:
A kind of preparation method of argatroban monohydrate, includes the following steps:
(1)Argatroban crude product is taken, is added 97%(V/V)Ethanol water in, be heated to reflux dissolving, it is complete it is molten after be down to Then room temperature is cooled to 0-5 DEG C again, stirring and crystallizing filters, dry, obtains white powder I;
(2)White powder I is repeated into step(1)Operation, obtain white powder II;
(3)Extracting waste powder II is added 25%(V/V)Ethanol water in, be heated to reflux dissolving, it is de- that activated carbon be added Color, filtering, the lower cooled to room temperature of filtrate stirring continue stirring and crystallizing, filter, dry, obtain argatroban monohydrate.
Preferably, the preparation method of the argatroban monohydrate, wherein step(1)Middle argatroban crude product and 97% (V/V)The mass/volume ratio of ethanol water is 1:15-25.
It is further preferred that the preparation method of the argatroban monohydrate, wherein step(1)Middle argatroban crude product With 97%(V/V)The mass/volume ratio of ethanol water is 1:20.
Preferably, the preparation method of the argatroban monohydrate, wherein step(3)Middle white powder II and 25%(V/ V)The mass/volume ratio of ethanol water is 1:10-15.
It is further preferred that the preparation method of the argatroban monohydrate, wherein step(3)Middle white powder II with 25%(V/V)The mass/volume ratio of ethanol water is 1:12.
Compared with prior art, argatroban monohydrate preparation method of the present invention passes through to without hydration A Jiaqu Class's crude product is refined twice, rehydrated to become agatroban, can make the purity of final products agatroban Reach 99.90% or more, and the ratio of 21 R/S structure bodies is made to control 65:34 or so, to farthest played Ah Add bent class's bioactivity.
Specific embodiment
Beneficial effects of the present invention are now further described by following embodiment, embodiment is only used for the purpose of illustration, It does not limit the scope of the invention, while the obvious change and modification that those of ordinary skill in the art are made according to the present invention It is also contained within the scope of the invention.
Embodiment 1
20L ethyl alcohol/purifying water mixed solvent is added to 1019g argatroban crude products(Volume ratio shared by ethyl alcohol is 97%), add Heat reflux dissolving.It is complete it is molten after be cooled to room temperature, be then cooled to 0-5 DEG C of stirring and crystallizing again 3 hours.It filters, 50 DEG C of constant pressure and dries 6 Hour.Obtain 704g white powders.
14L ethyl alcohol/purifying water mixed solvent is added(Volume ratio shared by ethyl alcohol is 97%), it is heated to reflux dissolving.Complete molten rear drop It warms to room temperature, is then cooled to 0-5 DEG C of stirring and crystallizing again 3 hours.It filters, 50 DEG C of constant pressure and dries 12 hours.Obtain 600.5g whites Powder.
7.2L ethyl alcohol/purified water is added(Volume ratio shared by ethyl alcohol is 25%), it is heated with stirring to reflux, 60g activated carbons are added Continue to stir 0.5h.Filtering, the lower cooled to room temperature of filtrate stirring, is stirred for crystallization 4 hours.Filtering, 50 DEG C of vacuum drying Obtain white powder 514.6g within 24 hours.Ratio through high performance liquid chromatography detection, purity 99.97%, 21 R/S isomers is 65:34.
Embodiment 2
2L ethyl alcohol/purifying water mixed solvent is added to 100g argatroban crude products(Volume ratio shared by ethyl alcohol is 97%), heating Reflux dissolving.It is complete it is molten after be cooled to room temperature, be then cooled to 0-5 DEG C of stirring and crystallizing again 3 hours.It filters, 50 DEG C of constant pressure and dries 8 are small When.Obtain 71.2g white powders.
1.4L ethyl alcohol/purifying water mixed solvent is added(Volume ratio shared by ethyl alcohol is 97%), it is heated to reflux dissolving.It is complete it is molten after It is cooled to room temperature, is then cooled to 0-5 DEG C of stirring and crystallizing again 3 hours.It filters, 50 DEG C of constant pressure and dries 14 hours.Obtain 62g white powder End.
740mL ethyl alcohol/purified water is added(Volume ratio shared by ethyl alcohol is 25%), it is heated with stirring to reflux, 6.2g activity is added Charcoal continues to stir 0.5h.Filtering, the lower cooled to room temperature of filtrate stirring, is stirred for crystallization 7 hours.Filtering, 50 DEG C of vacuum are dry Obtain white powder 53g within dry 28 hours.Ratio through high performance liquid chromatography detection, purity 99.99%, 21 R/S isomers is 64:35.
Embodiment 3
1.2L ethyl alcohol/purifying water mixed solvent is added to 60g argatroban crude products(Volume ratio shared by ethyl alcohol is 97%), add Heat reflux dissolving.It is complete it is molten after be cooled to room temperature, be then cooled to 0-5 DEG C of stirring and crystallizing again 3 hours.It filters, 50 DEG C of constant pressure and dries 7 Hour.Obtain 42.6g white powders.
850mL ethyl alcohol/purifying water mixed solvent is added(Volume ratio shared by ethyl alcohol is 97%), it is heated to reflux dissolving.It is complete it is molten after It is cooled to room temperature, is then cooled to 0-5 DEG C of stirring and crystallizing again 3 hours.It filters, 50 DEG C of constant pressure and dries 12 hours.Obtain 38g white powder End.
460mL ethyl alcohol/purified water is added(Volume ratio shared by ethyl alcohol is 25%), it is heated with stirring to reflux, 3.5g activity is added Charcoal continues to stir 0.5h.Filtering, the lower cooled to room temperature of filtrate stirring, is stirred for crystallization 5 hours.Filtering, 50 DEG C of vacuum are dry Obtain white powder 32.3g within dry 24 hours.Ratio through high performance liquid chromatography detection, purity 99.98%, 21 R/S isomers is 65:34.

Claims (5)

1. a kind of preparation method of argatroban monohydrate, it is characterised in that include the following steps:
(1)Argatroban crude product is taken, is added 97%(V/V)Ethanol water in, be heated to reflux dissolving, it is complete it is molten after be down to room temperature, Then it is cooled to 0-5 DEG C again, stirring and crystallizing filters, dry, obtains white powder I;
(2)White powder I is repeated into step(1)Operation, obtain white powder II;
(3)Extracting waste powder II is added 25%(V/V)Ethanol water in, be heated to reflux dissolving, activated carbon decolorizing, mistake be added Filter, the lower cooled to room temperature of filtrate stirring, continues stirring and crystallizing, filters, dry, obtains argatroban monohydrate.
2. the preparation method of argatroban monohydrate according to claim 1, it is characterised in that:Step(1)Middle Ah add'sing song Class's crude product and 97%(V/V)The mass/volume ratio of ethanol water is 1:15-25.
3. the preparation method of argatroban monohydrate according to claim 2, it is characterised in that:Step(1)Middle Ah add'sing song Class's crude product and 97%(V/V)The mass/volume ratio of ethanol water is 1:20.
4. the preparation method of argatroban monohydrate according to claim 1, it is characterised in that:Step(3)Middle white powder End II and 25%(V/V)The mass/volume ratio of ethanol water is 1:10-15.
5. the preparation method of argatroban monohydrate according to claim 4, it is characterised in that:Step(3)Middle white powder End II and 25%(V/V)The mass/volume ratio of ethanol water is 1:12.
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Publication number Priority date Publication date Assignee Title
CN104558103B (en) * 2013-10-24 2019-02-26 四川科瑞德制药股份有限公司 A kind of preparation method of argatroban intermediate
CN104558104B (en) * 2014-12-24 2018-04-17 天津药物研究院药业有限责任公司 A kind of process for purification of argatroban refinement mother liquor recovery article
CN105218626B (en) * 2015-08-04 2018-12-25 天津市亨必达化学合成物有限公司 A kind of argatroban novel crystal forms and preparation method thereof
CN105601704A (en) * 2015-11-19 2016-05-25 天津市亨必达化学合成物有限公司 Novel industrial refining method of high-pure chiral argatroban
CN111961114A (en) * 2020-08-03 2020-11-20 扬州中宝药业股份有限公司 Argatroban intermediate and preparation method and application thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1951936A (en) * 2006-11-10 2007-04-25 天津市炜杰科技有限公司 Argatroban separation method
CN101348481A (en) * 2007-12-25 2009-01-21 天津泰普药品科技发展有限公司 Argatroban and preparation thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1951936A (en) * 2006-11-10 2007-04-25 天津市炜杰科技有限公司 Argatroban separation method
CN101348481A (en) * 2007-12-25 2009-01-21 天津泰普药品科技发展有限公司 Argatroban and preparation thereof

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