CN101362746A - Separation method of argatroban single stereoisomers and polymorph - Google Patents
Separation method of argatroban single stereoisomers and polymorph Download PDFInfo
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- CN101362746A CN101362746A CNA2007100255674A CN200710025567A CN101362746A CN 101362746 A CN101362746 A CN 101362746A CN A2007100255674 A CNA2007100255674 A CN A2007100255674A CN 200710025567 A CN200710025567 A CN 200710025567A CN 101362746 A CN101362746 A CN 101362746A
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Abstract
The invention provides a polymorphic substance A and a polymorphic substance B with fixed composition of an Argatroban single stereoisomer-compound II as well as a preparation method of the polymorphic substance A and the polymorphic substance B. The invention also provides a new method for separating and purifying the compound II from Argatroban. The invention also provides the application of the polymorphic substance A and the polymorphic substance B to the preparation of anticoagulant and anti-thrombotic agents.
Description
The present invention relates to the fixing polymorphic form A that forms of having of argatroban single stereoisomers-Compound I I and polymorph b and the application in preparation anticoagulation and antithrombotic reagent thereof.
The invention still further relates to the novel method of from argatroban, separating the Compound I I that purifies out, and the preparation method of polymorphic form A and polymorph b.
Argatroban is the direct thrombin inhibitors of a kind of small molecules of chemosynthesis, has than better anticoagulation of heparin and anti thrombotic action.Argatroban goes through to treat periphery thrombus disease and acute apoplexy in Japan, and is used for the prevention and the treatment of heparin-induced thrombocytopenia by drugs approved by FDA.
The chemical name of argatroban is: (2R, 4R)-the 4-methyl isophthalic acid-[N-[(3-methyl isophthalic acid, 2,3,4-tetrahydrochysene-8-quinolyl) sulphonyl]-the L-arginyl]-Pipecolic Acid
Its structural formula is:
Argatroban
Have 4 chiral centres in the argatroban molecule, wherein, the chiral centre on arginine fragment and the piperidine carboxylic acid fragment has definite configuration, and the chiral centre on tetrahydric quinoline group does not have definite configuration.
Usually the final step of the synthetic argatroban that adopts reaction is:
In this step reaction, the toluquinoline in the compound 2 is reduced into the methyl tetrahydroquinoline, and has produced a chiral centre thus.The argatroban that obtains like this is the mixture of a diastereomer.This mixture contains about 63%-67%'s (R)-isomer I and about (S)-isomer II of 33%-37%, and the argatroban that uses clinically is exactly the mixture that isomer I and isomer II are about 65:35 at present.
Using the major side effects of anticoagulation medicine is severe haemorrhage, for example gi tract and retroperitoneal hamorrhage, and severe haemorrhage is fatal often clinically.Therefore, the using dosage of anticoagulation medicine and blood coagulation resisting function thereof need control strictly.Now known that the blood coagulation resisting function of Compound I I is higher more than 4 times than the blood coagulation resisting function of Compound I, therefore,, will increase the probability that has side effects greatly if the ratio of isomer I and isomer II can not obtain strict control.
Use single argatroban isomer will overcome the unmanageable problem of isomer proportion, be convenient to control the generation that dosage reduces the severe haemorrhage side effect.
The invention provides fixing polymorphic form A and the polymorph b of forming of having of argatroban single stereoisomers-Compound I I, and the preparation method of polymorphic form A and polymorph b is provided.
The present invention also provides the novel method of separating the Compound I I that purifies out from argatroban.
The present invention also provides polymorphic form A and the application of polymorph b in preparation anticoagulation and antithrombotic reagent.
Description of drawings:
Fig. 1 is the X-ray powder diffraction pattern of the polymorphic form A of Compound I I
Fig. 2 is the X-ray powder diffraction pattern of the polymorph b of Compound I I
Chinese patent application 200610129330.6 has disclosed a kind of method of isolating compound I I from argatroban, the method be with Argatroban adds hot reflux 5-10 hour dissolving, then cooling crystallization in the mixture of alcohol and water. The employed solvent of the method With the ratio of raw material be 15-30:1, and in order to obtain purity greater than 98% compound I I, the process of above-mentioned dissolving and crystallization Need to repeat many times. Therefore, said method need to expend a large amount of solvents and the energy.
Have been found that now a kind of method of from argatroban, isolating easily compound I I. Argatroban is dissolved in methyl alcohol, Add then the insoluble or sl. sol. solvent of argatroban in this solution and place again crystallization, the compound of compound I I that obtained enrichment The mixture of I and compound I I repeats above-mentioned steps, can obtain purity greater than 99% compound I I.
The concrete steps of the method are as follows:
Other mixed things of argatroban or Compound I and Compound I I are dissolved in the methyl alcohol, and at below 15 times of weight of the mixture of argatroban or Compound I and Compound I I, general preferred 3-10 doubly usually for the weight of the methyl alcohol that uses.Solvent temperature is between the boiling point of room temperature and methyl alcohol, usually about 60 degree.
The solution that obtains in step 1) adds the solvent of insoluble in right amount or slightly soluble argatroban, and the solvent that can select for use comprises water, the alcohol of C2-C4, the ketone of C3-C5, the ether of C2-C6, the ester of C2-C6, methylene dichloride, tetrahydrofuran (THF) and acetonitrile.Preferred solvent comprises water, ethanol, and Virahol, acetone, ethyl acetate and ether, most preferred solvent are water and ethanol.The amount that solvent adds generally is no more than 50% (volume ratio) of methyl alcohol, usually between the 10%-30% of methyl alcohol (volume ratio).Mix after adding solvent, place crystallization, can obtain the Compound I of Compound I I enrichment of enrichment and the mixture of Compound I I after the filtration.Measure the content of Compound I I in the mixture with HPLC, repeating step 1 and 2 then is till the content of Compound I I reaches desired value.
A preferred concrete grammar is:
1) other mixed things with argatroban or Compound I and Compound I I are dissolved in the methyl alcohol of about 3-10 times weight in about 60 degrees centigrade
2) in this solution, add the water of 1/3rd to 1/8th volumes
3) collect crystal after placing crystallization, measure the content of Compound I I, repeating step 1), 2), till the content of Compound I I is greater than 99%.
It is about 15% that each circulation of aforesaid method can improve Compound I I, and whole yield is about 20% in argatroban.
Method provided by the invention, the quantity of solvent of using in whole process is less than the method for bibliographical information greatly, and does not need long reflux, the consumption of having saved the energy greatly.
The detection that crystal by the Compound I I obtain purifying with the methanol-water system carries out is found, the crystal of separating out from the methanol-water system is also containing a certain amount of moisture content through after the sufficient drying, and its water content is not a fixed value, usually between 0-1, concrete water content is relevant with the ratio of methanol-water in the methanol-water system.Therefore, the crystal of separating out from the methanol-water system does not have definite composition, is unwell to as pharmaceutical raw material.
In order to obtain crystal by the Compound I I that fixedly forms, Compound I I can be dissolved in crystallization then in the anhydrous alcohols, the crystal that obtains is the polymorphic form A of Compound I I, and polymorphic form A has definite composition, do not contain crystal water, do not contain crystal alcohol yet.
Polymorphic form A is characterized as: 2 θ angles in the X-ray powder diffraction pattern are 7.0,7.6,8.2,9.3, and there is characteristic peak 9.9,10.4,11.1,12.0,16.7,18.7,21.5,26.0 ° position.Available anhydrous alcohols comprises methyl alcohol, ethanol and Virahol.The method for preparing polymorphic form A normally is dissolved in Compound I I in the anhydrous alcohol under the situation of heating, and crystal is separated out in cooling after the placement then.
With Compound I I crystallization in water, can obtain having the fixing polymorph b of forming, after the polymorph b process vacuum-drying constant weight, measure water content with Ka Er-Fei Xiuerfa and find that polymorph b is the monohydrate of Compound I I.Being characterized as of polymorph b: 2 θ angles in the X-ray powder diffraction pattern are 7.0,8.2,10.0,11.9,16.7,19.0,21.5,23.3, and there is characteristic peak 25.6 ° position.
The method for preparing polymorph b normally is dissolved in Compound I I in the pure water under the situation of reflux, and crystal is separated out in cooling after the placement then.
Compound I I dissolves relatively difficulty in water, I dissolves in water for the ease of Compound I, also Compound I I can be dissolved in earlier in a spot of dehydrated alcohol, then this drips of solution is added in the water.Usually below 5% (volume ratio) of the water yield, with this understanding, a spot of ethanol does not influence the composition and the crystal formation of the polymorph b that obtains at last to the consumption of dehydrated alcohol.
Polymorphic form A and polymorph b all have satisfactory stability, and polymorphic form A and the solvability of polymorph b in dehydrated alcohol are also relatively good, can be prepared into the ethanolic soln that contains sorbyl alcohol easily.Therefore, polymorphic form A and polymorph b can be used to preparation
The medicinal preparations of Compound I I.Show that with experiment in vitro the anticoagulant effect of Compound I I (content is greater than 99%) is more than the twice of argatroban (Compound I I content 35%) in the body.
Embodiment
10 gram argatrobans (Compound I I content 35%) are dissolved in 80 ml methanol in 60C °, in this solution, add 16 milliliters of pure water, slowly cool to room temperature after mixing, after spending the night, placement separates out crystal, filter the collection back and under vacuum, be dried to constant weight, obtain 7.5 gram solids, HPLC analyzes and shows that Compound I I content is 45%.
1 gram argatroban (Compound I I content 35%) is dissolved in 10 ml methanol in 60C °, in this solution, add 2 milliliters of dehydrated alcohols, slowly cool to room temperature after mixing, place and separate out crystal after 1 hour, filter the collection back and under vacuum, be dried to constant weight, obtain 0.7 gram solid, HPLC analyzes and shows that Compound I I content is 41%.
1 gram argatroban (Compound I I content 35%) is dissolved in 10 ml methanol in 60C °, in this solution, add 2 milliliters of anhydrous diethyl ethers, slowly cool to room temperature after mixing, place and separate out crystal after 1 hour, filter the collection back and under vacuum, be dried to constant weight, obtain 0.78 gram solid, HPLC analyzes and shows that Compound I I content is 39%.
5 mixtures (Compound I I content 80%) that digest compound I and Compound I I are dissolved in 30 milliliters 60C ° the methyl alcohol, the pure water that in this solution, adds 5 milliliters, mix the back and place the crystallisation by cooling that spends the night, filter and collect crystal, be dried to constant weight under the vacuum, obtain 4.1 gram solids, HPLC analyzes and shows that Compound I I content is 91%.
0.5 mixture (Compound I I content 98.0%) that digests compound I and Compound I I is dissolved in 5 milliliters 55C ° the methyl alcohol, the pure water that in this solution, adds 0.7 milliliter, mix the back and place the crystallisation by cooling that spends the night, filter and collect crystal, be dried to constant weight under the vacuum, obtain 0.38 gram solid, HPLC analyzes and shows that Compound I I content is 99.2%.
The preparation of polymorphic A:
Digest compound II (content is 99%) with 2 and be dissolved under 78C ° in 8 milliliters the dehydrated alcohol, slowly cool to room temperature, place the back of spending the night and collect crystal, vacuum-drying obtains 1.8 gram polymorphic A to constant weight.
Digest compound II (content is 99%) with 2 and be dissolved under reflux temperature in 15 milliliters the anhydrous methanol, slowly cool to room temperature, place the back of spending the night and collect crystal, vacuum-drying obtains 1.7 gram polymorphic A to constant weight.
The preparation of polymorph b
Digest compound II (content is 99%) with 1 and be dissolved under reflux temperature in 250 milliliters the water, slowly cool to room temperature, place the back of spending the night and collect crystal, vacuum-drying obtains 0.87 gram polymorph b to constant weight.
Digest the solution of compound II (content is 99%) in 10 milliliters of dehydrated alcohols with 1 and slowly be added drop-wise in 250 milliliters the boiling water, slowly cool to room temperature, place the back of spending the night and collect crystal, vacuum-drying obtains 0.77 gram polymorph b to constant weight.
Claims (9)
1. the polymorphic form A of the compound shown in the formula II is characterized in that its X-ray powder diffraction pattern 7.0,7.6,8.2,9.3,9.9,10.4,11.1,12.0,16.7,18.7, and there is characteristic peak the position at 21.5,26.0 ° of 2 θ angle.
2. the polymorphic form A of the compound shown in the formula II as claimed in claim 1, the purity that it is characterized in that the compound shown in the formula II is greater than 99%.
3. method for preparing suc as formula the polymorphic form A of the compound shown in the II, this method comprises the crystallization then in anhydrous alcohols of the compound dissolution shown in the formula II.Said anhydrous alcohols comprises methyl alcohol, ethanol and Virahol.
4. the polymorph b of the compound shown in the formula II is characterized in that the X-ray powder diffraction pattern 7.0,8.2, and there is characteristic peak the position at 10.0,11.9,16.7,19.0,21.5,23.3,25.6 ° of 2 θ angles.
5. the polymorph b of the compound shown in the formula II as claimed in claim 4, the purity that it is characterized in that the compound shown in the formula II is greater than 99%.
6. method for preparing suc as formula the polymorph b of the compound shown in the II, this method comprises the compound crystallization in water shown in the formula II.
7. as claim 1, the application in preparation anticoagulation and antithrombotic reagent of 2,4,5 described polymorphic form A and polymorph b.
8. method of isolating Compound I I from argatroban, this method comprises
A. other mixed things with argatroban or Compound I and Compound I I are dissolved in the methyl alcohol, and at below 15 times of weight of the mixture of argatroban or Compound I and Compound I I, general preferred 3-10 doubly usually for the weight of the methyl alcohol that uses.Solvent temperature is between the boiling point of room temperature and methyl alcohol, usually about 60 degree.
B. the solution that obtains in steps A adds the solvent of insoluble in right amount or slightly soluble argatroban, and the solvent that can select for use comprises water, the alcohol of C2-C4, the ketone of C3-C5, the ether of C2-C6, the ester of C2-C6, methylene dichloride, tetrahydrofuran (THF) and acetonitrile.Preferred solvent comprises water, ethanol, and Virahol, acetone, ethyl acetate and ether, most preferred solvent are water and ethanol.The amount that solvent adds generally is no more than 50% (volume ratio) of methyl alcohol, usually between the 10%-30% of methyl alcohol (volume ratio).Mix after adding solvent, place crystallization, can obtain the Compound I of Compound I I enrichment of enrichment and the mixture of Compound I I after the filtration.C. measure the content of Compound I I in the mixture with HPLC, repeating step 1 and 2 then is till the content of Compound I I reaches desired value.
9. method as claimed in claim 8, wherein said solvent insoluble or the slightly soluble argatroban is a water.
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| CN2007100255674A CN101362746B (en) | 2007-08-06 | 2007-08-06 | Separation method of argatroban single stereoisomers and polymorph |
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|---|---|---|---|
| CN 201110281988 Division CN102329371B (en) | 2007-08-06 | 2007-08-06 | Method for separating single stereoisomer of Argatroban and polymorphic substance |
| CN 201110281947 Division CN102382169B (en) | 2007-08-06 | 2007-08-06 | Argatroban single stereoisomer separation method and polymorph |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102240393A (en) * | 2010-05-14 | 2011-11-16 | 北京润德康医药技术有限公司 | Injection preparation containing argatroban |
| CN105218626A (en) * | 2015-08-04 | 2016-01-06 | 天津市亨必达化学合成物有限公司 | A kind of argatroban new crystal and preparation method thereof |
| CN105367622A (en) * | 2014-08-26 | 2016-03-02 | 四川科瑞德制药有限公司 | Argatroban compound |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6440417B1 (en) * | 1998-11-06 | 2002-08-27 | Conjuchem, Inc. | Antibodies to argatroban derivatives and their use in therapeutic and diagnostic treatments |
| CN100427480C (en) * | 2006-11-10 | 2008-10-22 | 天津市炜杰科技有限公司 | Process for preparing argatroban hydrate |
| CN100586946C (en) * | 2006-11-10 | 2010-02-03 | 天津市炜杰科技有限公司 | Argatroban separation method |
-
2007
- 2007-08-06 CN CN2007100255674A patent/CN101362746B/en active Active
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102240393A (en) * | 2010-05-14 | 2011-11-16 | 北京润德康医药技术有限公司 | Injection preparation containing argatroban |
| CN105367622A (en) * | 2014-08-26 | 2016-03-02 | 四川科瑞德制药有限公司 | Argatroban compound |
| CN105218626A (en) * | 2015-08-04 | 2016-01-06 | 天津市亨必达化学合成物有限公司 | A kind of argatroban new crystal and preparation method thereof |
| 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 |
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Application publication date: 20090211 Assignee: Borui Biomedicine Taixing Co., Ltd. Assignor: Borui Bio-medical Technology (Jiangsu) Co., Ltd. Contract record no.: 2013320010013 Denomination of invention: Separation method of argatroban single stereoisomers and polymorph Granted publication date: 20111228 License type: Exclusive License Record date: 20130304 |
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Address after: Suzhou City, Jiangsu Province, Suzhou Industrial Park 215123 Xinghu Street No. 218 Nano Technology Park building C25 Patentee after: Borui Pharmaceutical (Suzhou) Limited by Share Ltd Address before: Xinghu Street Industrial Park of Suzhou city in Jiangsu province 215123 No. 218 nano technology park A3 building 420 room Patentee before: Borui Bio-medical Technology (Jiangsu) Co., Ltd. |