CN102382169A - Argatroban single stereoisomer separation method and polymorph - Google Patents
Argatroban single stereoisomer separation method and polymorph Download PDFInfo
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- CN102382169A CN102382169A CN2011102819470A CN201110281947A CN102382169A CN 102382169 A CN102382169 A CN 102382169A CN 2011102819470 A CN2011102819470 A CN 2011102819470A CN 201110281947 A CN201110281947 A CN 201110281947A CN 102382169 A CN102382169 A CN 102382169A
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Abstract
The invention provides Argatroban single stereoisomer compound II polymorph A which has a fixed composition, a preparation method thereof, and an application of the polymorph A in the preparation of anticoagulant and antithrombotic medicaments.
Description
Technical field
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.
Background technology
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)-4-methyl isophthalic acid-[N-[(3-methyl isophthalic acid, 2,3,4-tetrahydrochysene-8-quinolyl) sulphonyl]-L-arginyl]-Pipecolic Acid
Its structural formula is:
Have 4 chiral centres in the argatroban molecule, wherein, the chiral centre on l-arginine fragment and the piperidine carboxylic acid fragment has definite configuration, and the chiral centre on tetrahydric quinoline group does not have definite configuration.
The final step reaction of the synthetic argatroban that adopts usually 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 compound of a black corresponding isomer.This mixture contains (S)-isomer II of about 63%-67% (R)-isomer I and about 33%-37%, and the argatroban that uses clinically at present is exactly the mixture that isomer I and isomer II were about 65: 35.
Using the major side effects of anticoagulation medicine is severe haemorrhage, for example gi tract and retroperitoneal hamorrhage, and serious hemorrhage 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, if the ratio of isomer I and isomer II can not obtain strict control, with increasing the probability that has side effects greatly.
Use single argatroban isomer will overcome the unmanageable problem of isomer proportion, be convenient to control the generation of the less severe haemorrhage spinoff of dosage.
Summary of the invention
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 from argatroban, separating the compound I I that purifies out.
The present invention also provides polymorphic form A and the application of polymorph b in preparation anticoagulation and antithrombotic reagent.
One Chinese patent application 20061012933.6 has disclosed a kind of method of from argatroban, isolating compound I I, and this method is that argatroban has been added backflow 5-10 hour dissolving, cooling crystallization then in the mixture of alcohol and water.The ratio of employed solvent of this method and raw material is 15-30: 1, and also in order to obtain purity greater than 98% compound I I, above-mentioned dissolving and crystalline process need repeat many times.Therefore, aforesaid method needs the solvent and the energy of labor.
Have been found that a kind of method of from argatroban, isolating compound I I easily now.Argatroban is dissolved in methyl alcohol; In this solution, add the insoluble or sl. sol. solvent of argatroban then and place crystallization again; Compound I and the mixture of compound I I of compound I I that obtained enrichment repeats above-mentioned steps, can obtain purity greater than 99% compound I I.
These method concrete steps are following:
Other mixed things of argatroban or compound I and compound I I are dissolved in the methyl alcohol, and the weight of employed methyl alcohol is usually at below 15 times of weight of the mixture of argatroban or compound I and compound I I, general preferred 3～10 times.Solvent temperature is between the boiling point of room temperature and methyl alcohol, usually about 60 degree.
The solution that in step 1), obtains 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, THF and acetonitrile.Preferred solvent comprises water, ethanol, and Virahol, acetone, ETHYLE 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 enrichment and the compound of compound I I after the filtration.
Measure the content of compound I I in the mixed solution 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 60 deg.c
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%.
Each circulation of aforesaid method can improve compound I I about 15%, and whole yield is about 20% in argatroban.
Method provided by the invention, the quantity of solvent of in whole process, using is less than the method for bibliographical information greatly, and does not need long reflux, the consumption of having saved the energy greatly.
Crystal through the compound I I obtain purifying with the methanol-water system detects discovery; The crystal of from the methanol-water system, separating out is also containing a certain amount of moisture through after the sufficient drying; And its water cut is not a fixed value; Usually between 0-1, concrete water cut is relevant with the ratio of methanol-water in the methanol-water system.Therefore, the crystal of from the methanol-water system, separating out 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; Can compound I I 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 1 dry constant weight, measure water cut 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 can compound I I be dissolved in earlier in a spot of absolute ethyl 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 absolute ethyl alcohol.
Polymorphic form A and polymorph b all have satisfactory stability property, and polymorphic form A and the solvability of polymorph b in absolute ethyl 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 prepare the medicinal prepns 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.
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
Embodiment
Embodiment 1
10g argatroban (compound I I content 35%) is dissolved in 80 ml methanol in 60 ℃; In this solution, add 16 milliliters of pure water; Slowly cool to room temperature after mixing, separate out crystal after placement is spent the night, 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%.
1g argatroban (compound I I content 35%) is dissolved in 10 ml methanol in 60 ℃; In this solution, add 2 milliliters of absolute ethyl 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%.
Embodiment 3
1g argatroban (compound I I content 35%) is dissolved in 10 ml methanol in 60 ℃; 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%.
Embodiment 4
With 5 digest compound I and compound I I mixture (compound I I content 80%) be dissolved in 30 milliliters 60 ℃ 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%.
Embodiment 5
With 0.5 digest compound I and compound I I mixture (compound I I content 98.0%) be dissolved in 5 milliliters 55 ℃ 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:
Embodiment 6
Digest compound II (content is 99%) with 2 and under 78 ℃, be dissolved in 8 milliliters the absolute ethyl 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.
Embodiment 7
Digest compound II (content is 99%) with 2 and under reflux temperature, be dissolved 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
Embodiment 8
Digest compound II (content is 99%) with 1 and under reflux temperature, be dissolved in 250 ml waters, 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.
Embodiment 9
Digest the solution of compound II (content is 99%) in 10 milliliters of absolute ethyl 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 (4)
1. the polymorphic form A of the compound shown in the formula
; It is characterized in that its X-ray powder diffraction pattern is as shown in Figure 1:
2. method for preparing suc as formula the polymorphic form A of the compound shown in
; This method comprises the compound dissolution crystallization then in anhydrous alcohols shown in the formula
; Said anhydrous alcohols comprises methyl alcohol, ethanol and Virahol.
3. the method for the polymorphic form A suc as formula the compound shown in
according to claim 2; It is characterized in that described anhydrous alcohols is methyl alcohol or ethanol.
4. the application of polymorphic form A as claimed in claim 1 in preparation anticoagulation and antithrombotic reagent.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN110452285A (en) * | 2019-09-12 | 2019-11-15 | 北京悦康科创医药科技股份有限公司 | A kind of argatroban monocrystalline and its cultural method and application |
-
2007
- 2007-08-06 CN CN 201110281947 patent/CN102382169B/en active Active
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN110452285A (en) * | 2019-09-12 | 2019-11-15 | 北京悦康科创医药科技股份有限公司 | A kind of argatroban monocrystalline and its cultural method and application |
| CN110452285B (en) * | 2019-09-12 | 2021-05-25 | 北京悦康科创医药科技股份有限公司 | Argatroban single crystal and culture method and application thereof |
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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: Suzhou City, Jiangsu Province, Suzhou Industrial Park 215123 Xinghu Street No. 218 nano technology park A3 building 420 room Patentee before: Borui Bio-medical Technology (Jiangsu) Co., Ltd. |
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Effective date of registration: 20201218 Address after: 22 Binjiang South Road, Taixing Economic Development Zone, Taizhou City, Jiangsu Province Patentee after: BRIGHTGENE BIO-MEDICAL TECHNOLOGY Co.,Ltd. Patentee after: Borui biomedical (Suzhou) Co.,Ltd. Address before: Building C25, nanotechnology Park, 218 Xinghu street, Suzhou Industrial Park, Jiangsu Province Patentee before: Borui biomedical (Suzhou) Co.,Ltd. |
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