CN101033232A - Method of preparing olanzapine crystal system I - Google Patents
Method of preparing olanzapine crystal system I Download PDFInfo
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- CN101033232A CN101033232A CN 200710067892 CN200710067892A CN101033232A CN 101033232 A CN101033232 A CN 101033232A CN 200710067892 CN200710067892 CN 200710067892 CN 200710067892 A CN200710067892 A CN 200710067892A CN 101033232 A CN101033232 A CN 101033232A
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- zyprexa
- olanzapine crystal
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Abstract
The invention discloses a preparation method of olanzapine crystal form I, which is as followed: take olanzapine crude purified in organic solvent to get one with HPLC more than 99.5%, and after it is resolved in dichloromethane, solid olanzapine crystal I is produced through heating enrichment or spray drying. Compared with the existing technology, the method has a substantial increase in product yield, and can effectively reduce the formation of impurity, which is a low-cost preparation method suitable for industrial production with the good purity of product.
Description
(1) technical field
The present invention relates to the preparation method of a kind of 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno-[2,3-b] [1,5] benzodiazepine (being called Zyprexa among the present invention) crystal formation I.
(2) background technology
The structure of 2-methyl-4-of the present invention (4-methyl isophthalic acid-piperazinyl)-10H-thieno-[2,3-b] [1,5] benzodiazepine (being called Zyprexa among the present invention) is as follows:
Zyprexa is widely used for treating in mental patient and all kinds of research as a kind of antipsychotic drug, and its preparation method can be referring to US 5229382, in this patent it is incorporated by reference in this text and examines.The crystal formation problem that does not relate to Zyprexa among the US 5229382.In US 5736541, at first mention crystal formation, in this patent the refining product called after crystal form II that obtains from ethyl acetate, and among the US 5229382 by the product called after crystal formation I that obtains behind the acetonitrile refining.The X-RPD data of measuring are as follows:
The spacing relative intensity figure of crystal form II:
| d | I/I 1 |
| 10.2689 8.577 7.4721 7.125 6.1459 6.071 5.4849 5.2181 5.1251 4.9874 4.7665 4.7158 4.4787 4.3307 4.2294 4.141 3.9873 3.7206 3.5645 3.5366 3.3828 3.2516 3.134 3.0848 3.0638 3.0111 2.8739 2.8102 2.7217 2.6432 2.6007 | 100.00 7.96 1.41 6.50 3.12 5.12 0.52 6.86 2.47 7.41 4.03 6.80 14.72 1.48 23.19 11.28 9.01 14.04 2.27 4.85 3.47 1.25 0.81 0.45 1.34 3.51 0.79 1.47 0.20 1.26 0.77 |
The spacing relative intensity figure of crystal formation I:
| d | I/I 1 |
| 9.9463 8.5579 8.2445 6.8862 6.3787 6.2439 5.5895 5.3055 4.98l5 4.8333 4.7255 4.6286 4.533 4.4624 4.2915 4.2346 4.0855 3.8254 | 100.00 15.18 1.96 14.73 4.25 5.21 1.10 0.95 6.14 68.37 21.88 3.82 17.83 5.02 9.19 18.88 17.29 6.49 |
| 3.7489 3.6983 3.5817 3.5064 3.3392 3.2806 3.2138 3.1118 3.0507 2.948 2.8172 2.7589 2.6597 2.6336 2.5956 | 10.64 14.65 3.04 9.23 4.67 1.96 2.52 4.81 1.96 2.40 2.89 2.27 1.86 1.10 1.73 |
In WO 0218390, mention, by not being crystal formation I in fact with obtaining product behind the acetonitrile refining among the US 5229382, but crystal form II.
In WO 9638151, mention and can use toluene, THF, ethyl acetate, trimethyl carbinol crystallization obtains crystal formation I, but the crystal form X-RPD data that provide in this patent are the same with the data of the crystal form II that front US5736541 mentions.What promptly obtained by above solvent crystallization is crystal form II in fact.
In WO 0218390, mention and obtain crystal formation I with the methylene dichloride crystallization, but operation according to this patent, in treating process, Zyprexa and methylene dichloride can react generation impurity: (1-(chloromethyl)-1-methyl-4-(2-methyl isophthalic acid 0H-thiophene [2,3-b] [1,5] benzodiazepine-4-yl) piperazine-1-chlorine.This impurity can not be removed in refining, and structure is as follows:
Mention among the WO 2004006933 with Virahol and other organic solvent crystallization and prepare crystal formation I, other solvents comprise THF, methylene dichloride, toluene, DMF, DMSO, chloroform etc.But use mixed solvent crystallization in this method, solvent can not reclaim, and is very big to environmental influence.
To sum up, there are the following problems to prepare the method for olanzapine crystal system I at present: (1) productive rate is not high.As all adopting methylene dichloride to make solvent in the patent of other preparation olanzapine crystal system I, owing to the factor of impurity, mother liquor can not reclaim the continuation crystallization substantially in preparation process, and yield is about about 67%.(2) product purity is not high.Using the methylene dichloride crystallization as mentioning in other patent, substantially all is to dissolve under reflux state, and then recrystallization, but generates impurity easily when high temperature, can't remove in treating process.
(3) summary of the invention
The object of the present invention is to provide a kind of productive rate height, good product purity, help the preparation method of the I of olanzapine crystal system cheaply of suitability for industrialized production, wherein obtaining olanzapine crystal system I is the pharmaceutically pure substantially crystal formation that can be used as antipsychotic drug.
In preparation Zyprexa crude product process, this patent is done US 5229382 and is quoted in full.Obtain the Zyprexa crude product according to US 5229382 operation experiments.The crude product purity (HPLC) that obtains in the experiment is greater than 97%, more preferably greater than 99%.
For realizing goal of the invention, the present invention adopts following method to prepare olanzapine crystal system I: get the Zyprexa crude product and carry out purifying obtain purity (HPLC) greater than 99.5% Zyprexa in organic solvent, the purity (HPLC) that obtains is dissolved in methylene dichloride greater than 99.5% Zyprexa, concentrate then and make solid and be olanzapine crystal system I, described organic solvent is C
1～C
7Alcohol, C
3～C
7Ketone, C
3～C
7Ester, C
3～C
7Ether or chloroform, acetonitrile and above two kinds or the mixed solvent of two or more arbitrary proportions, described olanzapine crystal system I is using under the Cu-Ka radiation condition, and as follows with the X-ray powder diffraction spectrum characteristics data of 2 θ spacings (d value) expression: 2 θ spacings (d value) are about 9.9463, about 8.5579, about 8.2445, about 6.8862, about 6.3787, about 6.2439, about 5.5895, about 5.3055, about 4.9815, about 4.8333, about 4.7255, about 4.6286, about 4.533, about 4.4624, about 4.2915, about 4.2346, about 4.0855, about 3.8254, about 3.7489, about 3.6983, about 3.5817, about 3.5064, about 3.3392, about 3.2806, about 3.2138, about 3.1118, about 3.0507, about 2.948, about 2.8172, about 2.7589, about 2.6597, about 2.6336, about 2.5956; And survey infrared absorption spectrum with the KBr pressed disc method, at about 1456, about 1365, about 905, about 757, about 662, about 604cm
-3Characteristic peak is arranged.
Describedly concentrate that to make the solid step as follows: the dichloromethane solution of Zyprexa 20～80 ℃ of following concentrating under reduced pressure 5～30 hours, is obtained solid and is olanzapine crystal system I.
Further, describedly concentrate that to make the solid step as follows: the dichloromethane solution of Zyprexa 30～70 ℃ of following concentrating under reduced pressure 15～20 hours, is obtained solid and is olanzapine crystal system I.
Further, describedly concentrate that to make the solid step as follows: the dichloromethane solution of Zyprexa at 30 ℃ of following concentrating under reduced pressure, is waited to become all that controlled temperature is 60～70 ℃ of concentrating under reduced pressure 10～15 hours behind the solid, obtain solid and be olanzapine crystal system I.
Described concentrate made the solid step and also can carry out according to following: the dichloromethane solution of Zyprexa is carried out spraying drying, collect pressed powder and promptly get described olanzapine crystal system I.
Further, described spray-dryer temperature of inlet air is 60～150 ℃.
Preparation method's of the present invention purification step, described organic solvent are selected from one of following or following two kinds or the mixture of two or more arbitrary proportions: methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, isopropylcarbinol, the trimethyl carbinol, acetone, methylethylketone, methyl tertbutyl ketone, ethyl acetate, isopropyl acetate, ethyl acetate, ether, diisopropyl ether, methyl tertiary butyl ether, THF, toluene, DMSO, DMF, chloroform, acetonitrile.
Further, described organic solvent is preferably one of following or following two kinds or the mixture of two or more arbitrary proportions: ethanol, DMSO, DMF, THF, ethyl acetate, toluene, acetonitrile.
Described purification process can be the purification process in the technical field routine, comprises crystallisation by cooling, adds the crystal seed crystallization, method commonly used technically such as evaporating solvent crystallization.
Further, in purge process, the processing of decolouring of gac or silica gel be can add in case of necessity, crystallization or crystallization carried out again.
Recommend described preparation method to carry out as follows:
(1) the Zyprexa crude product is added in the acetonitrile, heating for dissolving use activated carbon decolorizing, filtration, and the filtrate crystallisation by cooling, aftertreatment makes purity (HPLC) greater than 99.5% Zyprexa;
(2) purity (HPLC) that step (1) is obtained joins in the methylene dichloride greater than 99.5% Zyprexa, dissolving is filtered, and shifts out solution and carries out spraying drying, collect pressed powder and be described olanzapine crystal system I, described spray-dryer temperature of inlet air is 80～120 ℃.
Compared with prior art, innovative point of the present invention is:
(1) among the present invention, when using methylene dichloride to change crystalline substance, adopts the method for first dissolution in low temperature, can effectively reduce the generation of impurity.And utilize the spray-drying process can rapid drying, do not generate impurity substantially.
(2) adopt acetonitrile or other organic solvent to purify earlier among the present invention, mother liquor can reclaim the continuation crystallization, and yield significantly improves, and can reach more than 90%.
To sum up, utilize the preparation method of olanzapine crystal system I of the present invention, the product yield height that obtains, purity is better, and cost is low, is suitable for suitability for industrialized production.
(4) embodiment
In with the lower section, specifically set forth embodiment of the present invention by embodiment, but protection scope of the present invention is not limited thereto.
Embodiment 1: preparation technical grade Zyprexa
10g Zyprexa crude product adds in the 150ml acetonitrile, is heated to molten clearly, adds gac 0.5g, is heated to 70 ℃ and stirs 30min.Filtered while hot, the filtrate cooling and stirring maintains the temperature at about 0 ℃ and stirs 1h, separates out solid.Filtration obtains technical grade Zyprexa 6.9g.HPLC＝99.98％。
Embodiment 2: preparation olanzapine crystal system I
6.9g the technical grade Zyprexa adds in the 120ml methylene dichloride, is heated to 30 ℃, it is molten clear to be stirred to solution.Filter, filtrate is at 30 ℃ of following concentrating under reduced pressure, wait all become solid after, be warming up to 70 ℃ of concentrating under reduced pressure 15h.Get solid 6.7g.HPLC=99.96% is through verifying as olanzapine crystal system I.
Embodiment 3: preparation olanzapine crystal system I
20g technical grade Zyprexa adds in the methylene dichloride of 160ml, is heated to 30 ℃, and it is molten clear to be stirred to solution.Filter, filtrate is carried out spraying drying.Temperature of inlet air is 100 ℃.Collect solid 19.8g.Through verifying as olanzapine crystal system I.
Claims (10)
1. the preparation method of an olanzapine crystal system I, it is characterized in that described method is: get the Zyprexa crude product and in organic solvent, carry out purifying and obtain purity (HPLC) greater than 99.5% Zyprexa, the purity (HPLC) that obtains is dissolved in methylene dichloride greater than 99.5% Zyprexa, concentrate then and make solid and be olanzapine crystal system I, described organic solvent is C
1～C
7Alcohol, C
3～C
7Ketone, C
3～C
7Ester, C
3～C
7Ether or chloroform, acetonitrile and above two kinds or the mixed solvent of two or more arbitrary proportions, described olanzapine crystal system I is using under the Cu-Ka radiation condition, and as follows with the X-ray powder diffraction spectrum characteristics data of 2 θ spacings (d value) expression: 2 θ spacings (d value) are about 9.9463, about 8.5579, about 8.2445, about 6.8862, about 6.3787, about 6.2439, about 5.5895, about 5.3055, about 4.9815, about 4.8333, about 4.7255, about 4.6286, about 4.533, about 4.4624, about 4.2915, about 4.2346, about 4.0855, about 3.8254, about 3.7489, about 3.6983, about 3.5817, about 3.5064, about 3.3392, about 3.2806, about 3.2138, about 3.1118, about 3.0507, about 2.948, about 2.8172, about 2.7589, about 2.6597, about 2.6336, about 2.5956; And survey infrared absorption spectrum with the KBr pressed disc method, at about 1456, about 1365, about 905, about 757, about 662, about 604cm
-3Characteristic peak is arranged.
2. the preparation method of olanzapine crystal system I as claimed in claim 1, it is characterized in that describedly concentrating that to make the solid step as follows: the dichloromethane solution of Zyprexa 20～80 ℃ of following concentrating under reduced pressure 5～30 hours, is obtained solid and is olanzapine crystal system I.
3. the preparation method of olanzapine crystal system I as claimed in claim 2, it is characterized in that describedly concentrating that to make the solid step as follows: with the dichloromethane solution of Zyprexa at 30 ℃ of following concentrating under reduced pressure, controlled temperature is 60～70 ℃ of concentrating under reduced pressure 10～15 hours behind the solid Deng all becoming, and obtains solid and is olanzapine crystal system I.
4. the preparation method of olanzapine crystal system I as claimed in claim 1 is characterized in that, describedly concentrates that to make the solid step as follows: the dichloromethane solution of Zyprexa is carried out spraying drying, collect pressed powder and promptly get described olanzapine crystal system I.
5. the preparation method of olanzapine crystal system I as claimed in claim 4 is characterized in that described spray-dryer temperature of inlet air is 60～150 ℃.
6. as the preparation method of the described olanzapine crystal system I of one of claim 1～5, it is characterized in that described organic solvent is one of following or following two kinds or the mixture of two or more arbitrary proportions: methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, isopropylcarbinol, the trimethyl carbinol, acetone, methylethylketone, methyl tertbutyl ketone, ethyl acetate, isopropyl acetate, ethyl acetate, ether, diisopropyl ether, methyl tertiary butyl ether, THF, toluene, DMSO, DMF, chloroform, acetonitrile.
7. the preparation method of olanzapine crystal system I as claimed in claim 6 is characterized in that described organic solvent is one of following or following two kinds or the mixture of two or more arbitrary proportions: ethanol, DMSO, DMF, THF, ethyl acetate, toluene, acetonitrile.
8. the preparation method of olanzapine crystal system I as claimed in claim 1 is characterized in that described purification process is crystallisation by cooling, adds crystal seed crystallization or evaporating solvent crystallization.
9. the preparation method of olanzapine crystal system I as claimed in claim 8 is characterized in that described purifying also comprises and adds the processing of decolouring of gac or silica gel, carries out crystallization or crystallization again.
10. the preparation method of olanzapine crystal system I as claimed in claim 1 is characterized in that described preparation method carries out as follows:
(1) the Zyprexa crude product is added in the acetonitrile, heating for dissolving use activated carbon decolorizing, filtration, and the filtrate crystallisation by cooling, aftertreatment makes purity (HPLC) greater than 99.5% Zyprexa;
(2) purity (HPLC) that step (1) is obtained joins in the methylene dichloride greater than 99.5% Zyprexa, dissolving is filtered, and shifts out solution and carries out spraying drying, collect pressed powder and be described olanzapine crystal system I, described spray-dryer temperature of inlet air is 80～120 ℃.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109456337A (en) * | 2017-09-06 | 2019-03-12 | 万全万特制药江苏有限公司 | The refining methd of Olanzapine |
| CN109456336A (en) * | 2017-09-06 | 2019-03-12 | 万全万特制药江苏有限公司 | The refining methd of Olanzapine |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109456337A (en) * | 2017-09-06 | 2019-03-12 | 万全万特制药江苏有限公司 | The refining methd of Olanzapine |
| CN109456336A (en) * | 2017-09-06 | 2019-03-12 | 万全万特制药江苏有限公司 | The refining methd of Olanzapine |
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