CN107304186A - A kind of process for purification of olaparib - Google Patents
A kind of process for purification of olaparib Download PDFInfo
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- CN107304186A CN107304186A CN201610258238.3A CN201610258238A CN107304186A CN 107304186 A CN107304186 A CN 107304186A CN 201610258238 A CN201610258238 A CN 201610258238A CN 107304186 A CN107304186 A CN 107304186A
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- dichloromethane
- mixed solvent
- olaparib
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
- C07D237/30—Phthalazines
- C07D237/32—Phthalazines with oxygen atoms directly attached to carbon atoms of the nitrogen-containing ring
Abstract
The invention belongs to drug purification technical field, more particularly to a kind of process for purification of olaparib comprises the following steps：1）Olaparib crude product is added to the mixed solvent of dichloromethane and acetonitrile, is heated to reflux, crystallisation by cooling；2）By step 1）Gained crystallization is added to dichloromethane and C1‑5The in the mixed solvent recrystallization of fatty alcohol；3）Distillation evaporation dichloromethane, cooling separates out solid, filtered, wash, dries.Olaparib obtained by the inventive method has the characteristics of purity is high.
Description
Technical field
The invention belongs to drug purification technical field, more particularly to a kind of process for purification of olaparib.
Background technology
Olaparib (Olaparib) is by AstraZeneca
(AstraZeneca) a kind of small molecule of KuDOS drugmakers of wholly-owned subsidiary research and development, potent oral PARP
Inhibitor, it is by suppressing DNA of tumor cell injury repair, promote apoptosis of tumor cells, so as to strengthen the curative effect of radiotherapy and alkylating agent and platinum-based chemotherapy, it is mainly used in treatment mastocarcinoma gene one (BRCA-1), the gene mutation cancer of mastocarcinoma gene two (BRCA-2), it is primarily present in breast cancer, oophoroma and prostate cancer.
Following synthetic route is disclosed in WO2004/080976A：
Olaparib crystal formation A preparation method is disclosed in CN101528714B by Kudos Pharm Ltd：Olaparib is crystallized in dichloromethane or acetonitrile solvent, then respectively with being drying to obtain crystal formation A after ethanol, water process, although this method can remove most of impurity, but can hardly remove removal of impurity C, and impurity C-structure formula is as follows：
And what impurity C was brought by impurity in preparation process middle ring the third formyl chloride raw material, if cannot effectively control, it will the quality of influence finished dosage form.
The content of the invention
In order to solve the deficiency of prior art presence, the invention provides a kind of method that high-purity olaparib is refined.
A kind of process for purification of olaparib, it is characterised in that comprise the following steps：
1）Olaparib crude product is added to the mixed solvent of dichloromethane and acetonitrile, is heated to reflux, crystallisation by cooling；
2）By step 1）Gained crystallization is added to dichloromethane and C1-5The in the mixed solvent recrystallization of fatty alcohol；
3）Distillation evaporation dichloromethane, cooling separates out solid, filtered, wash, dries.
Step 1 of the present invention）With step 2）The addition sequence of mixed solvent can exchange, be：
1）Olaparib crude product is added to the in the mixed solvent crystallization of dichloromethane and fatty alcohol；
2）By step 1）Gained crystallization is added to the in the mixed solvent recrystallization of dichloromethane and acetonitrile.
It is preferred that, the step 1）The volume in liters amount of middle mixed solvent is 8-20 times, more preferably 8-15 times of the quality grams amount of olaparib crude product.
It is preferred that, the step 1）The volume ratio of middle dichloromethane and acetonitrile is 1:1-20, more preferably 1:5 -1:12.
It is preferred that, the step 2）The volume ratio of in the mixed solvent dichloromethane and ethanol is 1:0.5-5, more preferably 1:0.5-2.
It is preferred that, step 2）For by step 1）Gained crystallization is added to dichloromethane and C1-5The in the mixed solvent of fatty alcohol is mixed, is heated to reflux to clarification, adds activated carbon, and filtrate is continued to be heated to reflux, cools down precipitation crystallization by press filtration while hot.
It is preferred that, step 3）For by step 2）Gained crystallization is added to dichloromethane and C1-5The in the mixed solvent mixing of fatty alcohol, vacuum distillation evaporation dichloromethane, crystallisation by cooling.By the step, except the middle residual solvent dichloromethane that decrystallizes, while improving the yield of olaparib.
Olaparib crude product of the present invention can be obtained using method disclosed in WO2004/080976A, i.e., obtained by compound B with Cyclopropyl carbonyl chloride reaction；But due to Cyclopropyl carbonyl chloride raw material used during storage the easy moisture absorption, it is not easy to maintain, be unfavorable for large-scale production, and during feeding intake, it is also relatively more pungent, have certain pollution to environment.
The problem of existing for more than, the applicant synthesizes olaparib crude product using ethylene-acetic acid and compound B under the conditions of dichloromethane and DIPEA, and equation is as follows：
Concrete operation step is：
Compound B, cyclopropanecarboxylic acid, O- BTAs-tetramethylurea hexafluorophosphate and acetonitrile are added in reaction vessel, temperature is maintained at 10-30 DEG C, and DIPEA is added dropwise, 15-30h is reacted, olaparib crude product will be obtained after gained mixture extract and separate, drying.
It is preferred that, the washing is first to elute filter cake obtained by suction filtration with acetonitrile, then uses water wash.
It is preferred that, the temperature is maintained at 20-30 DEG C.
It is preferred that, the drying temperature is 40-60 DEG C, more preferably, 50-60 DEG C.
It is preferred that, the extract and separate, addition solvent is water.
The advantageous effects of the present invention：
The process for purification that the present invention is provided first is crystallized with the mixed solvent of dichloromethane and acetonitrile to olaparib crude product, then is recrystallized with the mixed solvent of dichloromethane and fatty alcohol, has obtained the olaparib of high-purity.Its reason is：The mixed solvent of dichloromethane and acetonitrile can increase the solubility of relative substance in a solvent beyond removal of impurity C, effectively remove other most of impurity in olaparib crude product beyond removal of impurity C；Reuse dichloromethane and fatty alcohol mixed solvent, particularly C1-5Fatty alcohol, the mixed solvent is good to impurity C dissolubility, and olaparib indissoluble, therefore, it is possible to effectively remove the impurity C in olaparib.The two combination can be improved into olaparib purity, simultaneously effective control impurity C, test result indicates that, the olaparib highly finished product purity that the process for purification that the present invention is provided is obtained is up to more than 99.92%, impurity C content is no more than 0.03%, always miscellaneous to be no more than 0.08%, present invention gained olaparib highly finished product are and CN101528714B crystal formation A identical crystal formations.
The preparation method of olaparib crude product of the present invention, stores convenient with raw material, the advantage of ready access upon use, and environmental pollution is small in use, suitable for industrial-scale production.
Embodiment
Compound B can be prepared by the method described in WO2004/080976A specifications.
Olaparib crude product of the present invention is the product of compound B gained after the formyl chloride of ring third or cyclopropanecarboxylic acid addition.
Embodiment
1
1mol compounds B, 1.25mol cyclopropanecarboxylic acid, 5lHBTU (O- BTAs-tetramethylurea hexafluorophosphate) and 5l acetonitriles are added in reaction vessel, temperature is maintained at 10 DEG C, 2molN is added dropwise, N- diisopropylethylamine, reacts 15h, and gained mixture is added into water extract and separate, extract obtains olaparib crude product in 40 DEG C of drying, detected through HPLC, purity 99.58%, it is maximum single miscellaneous（Impurity C）0.28%, total miscellaneous 0.42%.
Embodiment
2
1mol compounds B, 1.5mol cyclopropanecarboxylic acid, 2lO- BTAs-tetramethylurea hexafluorophosphate and 10l acetonitriles are added in reaction vessel, temperature is maintained at 30 DEG C, 2molN is added dropwise, N- diisopropylethylamine, reacts 30h, and gained mixture is added into water extract and separate, extract obtains olaparib crude product in 50 DEG C of drying, detected through HPLC, purity 99.62%, it is maximum single miscellaneous（Impurity C）0.24%, total miscellaneous 0.38%.
Embodiment
3
1mol compounds B, 1mol cyclopropanecarboxylic acid, 5lO- BTAs-tetramethylurea hexafluorophosphate and 8l acetonitriles are added in reaction vessel, temperature is maintained at 20 DEG C, 3molN is added dropwise, N- diisopropylethylamine, reacts 20h, and gained mixture is added into water extract and separate, extract obtains olaparib crude product in 60 DEG C of drying, detected through HPLC, purity 99.6%, it is maximum single miscellaneous（Impurity C）0.25%, total miscellaneous 0.4%.
Embodiment
4
Olaparib crude product is prepared using the method in CN101528714B：
The solution of the triethylamine 34ml and cyclopropanecarbonyl chloride 22ml that are pre-mixed in dichloromethane 100ml is added dropwise in the suspension that 100g compounds B is added in 1.2l dichloromethane, kept for 15 DEG C, insulation 15 minutes, gained mixture is added into water extract and separate, extract obtains olaparib crude product in 50 DEG C of drying, detected through HPLC, purity 99.5%, it is maximum single miscellaneous（Impurity C）0.31%, total miscellaneous 0.5%.
It can be seen that by embodiment 1-4, condensation reaction either is carried out with compound B with cyclopropanecarboxylic acid or the formyl chloride of ring third, miscellaneous maximum list is impurity C, and impurity C alreadys exceed always miscellaneous 60%, therefore removal of impurity C is removed, the lifting for olaparib quality has great importance.
Embodiment
5
1）The mixed solvent that 100g olaparib crude products as obtained by implementing 2 are added into 1.2l dichloromethane and acetonitrile is mixed, and wherein the volume ratio of in the mixed solvent dichloromethane and acetonitrile is 1:12, backflow is heated to, 5h is incubated, natural cooling crystallization, suction filtration is dried under vacuum to constant weight, obtains primary crystallization；
2）Primary crystallization is added to the in the mixed solvent of 1.2l dichloromethane and methanol, the volume ratio of the in the mixed solvent dichloromethane and methanol is 1:0.5；It is heated to reflux to clarification, adds activated carbon, filtrate is continued to be heated to backflow, is incubated 3h, natural cooling crystallization, suction filtration is dried under vacuum to constant weight, obtains secondary crystallization by press filtration while hot；
3）Secondary crystallization is added in dichloromethane and methanol mixed solvent, the mixed solvent is with step 2）, distillation evaporation dichloromethane, then natural cooling crystallization, filtering, washing, 58 DEG C of drying, obtain solid powder 95.2g, yield 95.2% is detected through HPLC, purity 99.96%, maximum single miscellaneous（Impurity C）0.012%, total miscellaneous 0.04%.
Embodiment
6
1）The in the mixed solvent that 100g olaparib crude products as obtained by implementing 1 are added into 0.8l dichloromethane and acetonitrile is crystallized, and wherein the volume ratio of in the mixed solvent dichloromethane and acetonitrile is 1:20, backflow is heated to, 3h is incubated, natural cooling crystallization, suction filtration is dried under vacuum to constant weight, obtains primary crystallization；
2）Primary crystallization is added to the in the mixed solvent of 0.8l dichloromethane and ethanol, the volume ratio of the in the mixed solvent dichloromethane and ethanol is 1:5；Backflow is heated to, 2h is incubated, natural cooling crystallization, suction filtration is dried under vacuum to constant weight, obtains secondary crystallization；
3）Secondary crystallization is added in dichloromethane and alcohol mixed solvent, the mixed solvent is with step 2）, distillation evaporation dichloromethane, then natural cooling crystallization, filtering, washing, 50 DEG C of drying, obtain solid powder 96.5g, yield 96.5% is detected through HPLC, purity 99.94%, maximum single miscellaneous（Impurity C）0.015%, total miscellaneous 0.06%.
Embodiment
7
1）The in the mixed solvent that 100g olaparib crude products as obtained by implementing 3 are added into 1.5l dichloromethane and acetonitrile is crystallized, and wherein the volume ratio of in the mixed solvent dichloromethane and acetonitrile is 1:1, backflow is heated to, 4h is incubated, natural cooling crystallization, suction filtration is dried under vacuum to constant weight, obtains primary crystallization；
2）Primary crystallization is added to the in the mixed solvent of 1.5l dichloromethane and propyl alcohol, the volume ratio of the in the mixed solvent dichloromethane and methanol is 1:2；Backflow is heated to, 3h is incubated, natural cooling crystallization, suction filtration is dried under vacuum to constant weight, obtains secondary crystallization；
3）Secondary crystallization is added in dichloromethane and propanol solvent mixture, the mixed solvent is with step 2）, distillation evaporation dichloromethane, then natural cooling crystallization, filtering, washing, 60 DEG C of drying, obtain solid powder 95.6g, yield 95.6% is detected through HPLC, purity 99.944%, maximum single miscellaneous（Impurity C）0.013%, total miscellaneous 0.056%.
Embodiment
8
1）The in the mixed solvent that 100g olaparib crude products as obtained by implementing 2 are added into 2l dichloromethane and acetonitrile is crystallized, and wherein the volume ratio of in the mixed solvent dichloromethane and acetonitrile is 1:5, backflow is heated to, 4h is incubated, natural cooling crystallization, suction filtration is dried under vacuum to constant weight, obtains primary crystallization；
2）Primary crystallization is added to the in the mixed solvent of 2l dichloromethane and amylalcohol, the volume ratio of the in the mixed solvent dichloromethane and ethanol is 1:3；Backflow is heated to, 2h is incubated, natural cooling crystallization, suction filtration is dried under vacuum to constant weight, obtains secondary crystallization；
3）Secondary crystallization is added to dichloromethane and amylalcohol in the mixed solvent, the mixed solvent is with step 2）, distillation evaporation dichloromethane, then natural cooling crystallization, filtering, washing, 65 DEG C of drying, obtain solid powder 95.5g, yield 95.5% is detected through HPLC, purity 99.945%, maximum single miscellaneous（Impurity C）0.018%, total miscellaneous 0.055%.
Embodiment
9
It is with the difference of embodiment 5, by step 1）With step 2）Miscible solvent exchange, remaining condition is constant；Solid powder 95.2g is obtained, yield 95.2% is detected through HPLC, purity 99.96%, it is maximum single miscellaneous（Impurity C）0.012%, total miscellaneous 0.04%.
Embodiment
10
1）By 100g, the olaparib crude product as obtained by embodiment 4 is added to the in the mixed solvent crystallization of 2l dichloromethane and acetonitrile, and the wherein volume ratio of in the mixed solvent dichloromethane and acetonitrile is 1:7, backflow is heated to, 4h is incubated, natural cooling crystallization, suction filtration is dried under vacuum to constant weight, obtains primary crystallization；
2）Primary crystallization is added to the in the mixed solvent of 2l dichloromethane and butanol, the volume ratio of the in the mixed solvent dichloromethane and ethanol is 1:3；Backflow is heated to, 2h is incubated, natural cooling crystallization, suction filtration is dried under vacuum to constant weight, obtains secondary crystallization；
3）Secondary crystallization is added to dichloromethane and butanol in the mixed solvent, the mixed solvent is with step 2）, distillation evaporation dichloromethane, then natural cooling crystallization, filtering, washing, 60 DEG C of drying, obtain solid powder 88.2g, yield 88.2% is detected through HPLC, purity 99.92%, maximum single miscellaneous（Impurity C）0.03%, total miscellaneous 0.08%.
Embodiment
11
1）By 100g, the olaparib crude product as obtained by embodiment 4 is added to the in the mixed solvent crystallization of 1.2l dichloromethane and acetonitrile, and the wherein volume ratio of in the mixed solvent dichloromethane and acetonitrile is 1:1, backflow is heated to, 5h is incubated, natural cooling crystallization, suction filtration is dried under vacuum to constant weight, obtains primary crystallization；
2）Primary crystallization is added to the in the mixed solvent of 1.2l dichloromethane and methanol, the volume ratio of the in the mixed solvent dichloromethane and methanol is 1:0.5；Backflow is heated to, 3h is incubated, natural cooling crystallization, suction filtration is dried under vacuum to constant weight, obtains secondary crystallization；
3）Secondary crystallization is added in dichloromethane and methanol mixed solvent, the mixed solvent is with step 2）, distillation evaporation dichloromethane, then natural cooling crystallization, filtering, washing, 40 DEG C of drying, obtain solid powder 88.0g, yield 88.0% is detected through HPLC, purity 99.92%, maximum single miscellaneous（Impurity C）0.028%, total miscellaneous 0.08%.
Embodiment 12
It is with the difference of embodiment 11, step 1）With step 2）In mixed solvent exchange, remaining condition is constant.Obtain solid powder 88.0
G, yield 88.0%, is detected through HPLC, purity 99.92%, maximum single miscellaneous（Impurity C）0.028%, total miscellaneous 0.08%.
Compared by embodiment 5 with embodiment 9, embodiment 11 with embodiment 12, i.e., by step 1）With step 2）In exchanged to the mixed solvent that crystallizes, products obtained therefrom testing result is consistent.
It can be drawn by embodiment 5-12, olaparib crude product is passed through into dichloromethane and acetonitrile mixed solvent, dichloromethane and C1-5Fatty alcohol mixed solvent secondary crystallization, the purity of gained crystal is up to more than 99.92%, and impurity C's can be controlled within the scope of 0.03%, and total miscellaneous control is within the scope of 0.08%.
Further, it is can be found that by comparative example 5-9 and embodiment 10-12, the refined yield of obtained olaparib crude product is reacted apparently higher than the olaparib crude product obtained by compound B and ring the third formyl chloride condensation reaction by compound B and cyclopropanecarboxylic acid, it is probably because the formyl chloride of ring third is prepared by cyclopropanecarboxylic acid, impurity can be also produced in preparation process, cause the dopant species and content of the formyl chloride of ring third more than cyclopropanecarboxylic acid, so as to participate in the condensation reaction with compound B, in olaparib subtractive process, yield have impact on.
Above example is only intended to help and understands the present invention; it is not construed as limiting the invention; for the person of ordinary skill of the art; under the premise without departing from the principles of the invention; some improvement or modification can also be carried out to the present invention, these are improved or modification also falls into the protection domain of the claims in the present invention.
Claims (10)
1. a kind of process for purification of olaparib, it is characterised in that comprise the following steps：
1）Olaparib crude product is added to the in the mixed solvent of dichloromethane and acetonitrile, is heated to reflux, crystallisation by cooling；
2）By step 1）Gained crystallization is added to dichloromethane and C1-5The in the mixed solvent recrystallization of fatty alcohol；
3）Distillation evaporation dichloromethane, cooling separates out solid, filtered, wash, dries；
The step 1）With step 2）Middle mixed solvent can be exchanged.
2. process for purification according to claim 1, it is characterised in that the step 1）The volume in liters amount of middle mixed solvent is 8-20 times of the quality grams amount of olaparib crude product.
3. process for purification according to claim 1, it is characterised in that the step 1）The volume ratio of middle dichloromethane and acetonitrile is 1:1-20.
4. process for purification according to claim 1, it is characterised in that the step 2）In the mixed solvent dichloromethane and C1-5The volume ratio of fatty alcohol is 1:0.5-5.
5. process for purification according to claim 4, it is characterised in that the step 3）In the mixed solvent dichloromethane and C1-5The volume ratio of fatty alcohol is 1:0.5-2.
6. process for purification according to claim 1, it is characterised in that step 2）For by step 1）Gained crystallization is added to dichloromethane and C1-5The in the mixed solvent of fatty alcohol is mixed, is heated to reflux to clarification, adds activated carbon, and filtrate is continued to be heated to reflux, cools down precipitation solid by press filtration while hot.
7. a kind of preparation method of olaparib crude product, it is characterised in that including following reaction：
。
8. preparation method according to claim 7, it is characterised in that comprise the following steps：
Compound B, cyclopropanecarboxylic acid, O- BTAs-tetramethylurea hexafluorophosphate and acetonitrile are added in reaction vessel, temperature is maintained at 10-30 DEG C, and DIPEA is added dropwise, 15-30h is reacted, olaparib crude product will be obtained after gained mixture extract and separate, drying.
9. preparation method according to claim 8, it is characterised in that the temperature is maintained at 20-30 DEG C.
10. preparation method according to claim 8, it is characterised in that the drying temperature is 40-60 DEG C.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109293576A (en) * | 2018-11-08 | 2019-02-01 | 威海贯标信息科技有限公司 | A kind of preparation method of small grain size olaparib |
| US10662178B2 (en) | 2018-01-31 | 2020-05-26 | Apotex Inc. | Crystalline form of Olaparib |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US10662178B2 (en) | 2018-01-31 | 2020-05-26 | Apotex Inc. | Crystalline form of Olaparib |
| CN109293576A (en) * | 2018-11-08 | 2019-02-01 | 威海贯标信息科技有限公司 | A kind of preparation method of small grain size olaparib |
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