CN107304187A - A kind of recrystallization method of olaparib - Google Patents
A kind of recrystallization method of olaparib Download PDFInfo
- Publication number
- CN107304187A CN107304187A CN201610258239.8A CN201610258239A CN107304187A CN 107304187 A CN107304187 A CN 107304187A CN 201610258239 A CN201610258239 A CN 201610258239A CN 107304187 A CN107304187 A CN 107304187A
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- Prior art keywords
- mixed solvent
- olaparib
- recrystallization method
- acetonitrile
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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 recrystallization method of olaparib.Including step：1）The in the mixed solvent that olaparib crude product is added into the tertiary ether of first and acetonitrile is mixed, and is heated to reflux, decrease temperature crystalline；2）It is added to ethyl acetate and C1‑5The in the mixed solvent mixing of alcohol, is heated to reflux, cooling recrystallization.Products obtained therefrom has the characteristics of purity is high.
Description
Technical field
The invention belongs to drug purification technical field, more particularly to a kind of recrystallization method of olaparib.
Background technology
Olaparib (Olaparib) is wholly-owned subsidiary's KuDOS systems by AstraZeneca (AstraZeneca)
Medicine company research and development a kind of small molecule, potent oral PARP inhibitor, it 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, be mainly used in treatment breast
The gene mutation cancer of gland cancer gene one (BRCA-1), mastocarcinoma gene two (BRCA-2), breast is primarily present in gene
Gland 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：Aura
Pa Ni is crystallized in dichloromethane or acetonitrile solvent, then respectively with being drying to obtain crystal formation A after ethanol, water process, although the party
Method can remove most of impurity, but can hardly remove removal of impurity C, impurity C-structure formula：
And what impurity C came for impurity band in preparation process middle ring the third formyl chloride raw material, it is inevitable, if cannot be effective
Control, it will influence finished dosage form quality.
The content of the invention
In order to solve the deficiency of prior art presence, the invention provides a kind of side of high-purity olaparib recrystallization
Method.
A kind of recrystallization method of olaparib, it is characterised in that comprise the following steps：
1）The in the mixed solvent that olaparib crude product is added into the tertiary ether of first and acetonitrile is mixed, and is heated to reflux, and is protected at 60-95 DEG C
Warm 3-5h, cools to 20-40 DEG C of crystallization；
2）By step 1）Gained crystallization is added to ethyl acetate and C1-5The in the mixed solvent mixing of alcohol, is heated to reflux, in 40-80
DEG C insulation 0.5-3h, cooling recrystallization, filtering, use C1-5Alcohol is washed, in 40-70 DEG C of drying.
It is preferred that, the step 1）The volume in liters amount of middle mixed solvent is the 6-20 of the quality grams amount of olaparib crude product
Times, more preferably 6-12 times.
It is preferred that, the step 1）Middle holding temperature is 60-70 DEG C.
It is preferred that, the step 1）Middle cooling temperature is 30-40 DEG C.
It is preferred that, the step 1）The volume ratio of the middle tertiary ether of first and acetonitrile is 1:1-15, more preferably 1:1-5.
It is preferred that, the step 2）In the mixed solvent dichloromethane and C1-5The volume ratio of alcohol is 1:0.5-5, more preferably 1:
0.5-2。
It is preferred that, the step 2）Middle holding temperature is 55-70 DEG C.
It is preferred that, the step 2）Middle drying temperature is 50-60 DEG C.
It is preferred that, the step 2）The middle type of cooling is natural cooling.
Due to being obtained using method disclosed in WO2004/080976A, but because Cyclopropyl carbonyl chloride raw material used exists
The easy moisture absorption, not easy to maintain during storage, is unfavorable for large-scale production, and during feeding intake, it is also relatively more pungent, have to environment
Certain pollution.
The applicant is closed using ethylene-acetic acid and compound B under the conditions of dichloromethane and N, N- diisopropylethylamine
Into olaparib crude product, equation is as follows：
Concretely comprise the following steps：
Compound B, cyclopropanecarboxylic acid, O- BTAs-tetramethylurea hexafluorophosphate and dichloromethane are added into reaction to hold
In device, temperature is maintained at 10-30 DEG C, and DIPEA is added dropwise, and reacts 15-30h, by gained mixture add water extraction,
Divide liquid, wash, be concentrated to give olaparib crude product.
It is preferred that, the temperature is maintained at 20-30 DEG C.
It is preferred that, the drying temperature is 40-65 DEG C, more preferably, 50-65 DEG C.
The advantageous effects of the present invention：
The recrystallization method that the present invention is provided first is mixed with the mixed solvent of the tertiary ether of first and acetonitrile, is heated to reflux, at 60-95 DEG C
3-5h is incubated, mixed solution is in hypersaturated state, is then cooled to 20-40 DEG C and olaparib crude product is crystallized, then
With ethyl acetate and C1-5The mixed solvent mixing of alcohol, is heated to reflux, is incubated 0.5-3h at 40-80 DEG C, is in mixed solution
Hypersaturated state, natural cooling recrystallization, has obtained the olaparib of high-purity.Its reason is：The tertiary ether of first and acetonitrile it is mixed
Bonding solvent can increase solubility of the relative substance beyond removal of impurity C in the mixed solvent, effectively remove in olaparib crude product
Other most of impurity beyond removal of impurity C；Reuse ethyl acetate and C1-5Alcohol mixed solvent, the mixed solvent is to impurity C's
Dissolubility is good, and olaparib is almost insoluble, therefore, it is possible to effectively remove the impurity C in olaparib.The two is combined can be with
Olaparib purity is improved, impurity C is simultaneously effective controlled, test result indicates that, the recrystallization method that the present invention is provided is obtained
Olaparib highly finished product refined yield up to more than 90%, purity is up to more than 99.93%, and impurity C content is no more than
0.02%, it is always miscellaneous to be no more than 0.07%.Olaparib is and CN101528714B crystal formation A identical crystal formations obtained by of the invention.
The preparation method of olaparib crude product of the present invention, stores convenient with raw material, the advantage of ready access upon use, and
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 cyclopropanecarboxylic acid addition.
Embodiment 1
By 1mol compounds B, 1.25mol cyclopropanecarboxylic acid, 5l O- BTAs-tetramethylurea hexafluorophosphate and 5l dichloros
Methane is added in reaction vessel, and temperature is maintained at 30 DEG C, and 2molN is added dropwise, and N- diisopropylethylamine reacts 15h, gained is mixed
Compound add water extraction, point liquid, washing, 40 DEG C be concentrated to give olaparib crude product.
Embodiment 2
By 1mol compounds B, 1.5mol cyclopropanecarboxylic acid, 2l O- BTAs-tetramethylurea hexafluorophosphate and 10l dichloros
Methane is added in reaction vessel, and temperature is maintained at 10 DEG C, and 2molN is added dropwise, and N- diisopropylethylamine reacts 30h, gained is mixed
Compound add water extraction, point liquid, washing, 50 DEG C be concentrated to give olaparib crude product.
Embodiment 3
By 1mol compounds B, 1mol cyclopropanecarboxylic acid, 5l O- BTAs-tetramethylurea hexafluorophosphate and 8l dichloromethane
It is added in reaction vessel, temperature is maintained at 20 DEG C, 3molN is added dropwise, N- diisopropylethylamine reacts 20h, by gained mixture
Add water extraction, point liquid, washing, 65 DEG C be concentrated to give olaparib crude product.
Embodiment 4
1）The in the mixed solvent that 100g olaparib crude products as obtained by implementing 2 are added into the tertiary ether of 1.2l first and acetonitrile is crystallized,
Wherein the volume ratio of the tertiary ether of in the mixed solvent first and acetonitrile is 1:1, backflow is heated to, 5h, natural cooling analysis are incubated at 80 DEG C
Crystalline substance, 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 in the mixed solvent dichloromethane and
The volume ratio of methanol is 1:0.5；Be heated to backflow, 50 DEG C be incubated 1h, natural cooling crystallization, suction filtration, 60 DEG C are dried under vacuum to
Constant weight, obtains solid powder 94g, and yield 94%, purity 99.95% is maximum single miscellaneous（Impurity C）0.012%, total miscellaneous 0.05%.
Embodiment 5
1）The in the mixed solvent that 100g olaparib crude products as obtained by implementing 1 are added into the tertiary ether of 0.6l first and acetonitrile is crystallized,
Wherein the volume ratio of the tertiary ether of in the mixed solvent first and acetonitrile is 1:8, backflow is heated to, 3h is incubated at 60 DEG C, is cooled to 40 DEG C
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 0.6l dichloromethane and ethanol, the in the mixed solvent dichloromethane and
The volume ratio of ethanol is 1:5；Be heated to backflow, 80 DEG C be incubated 0.5h, natural cooling crystallization, suction filtration, 50 DEG C are dried under vacuum to
Constant weight, obtains solid powder 92g, and yield 92%, purity 99.94% is maximum single miscellaneous（Impurity C）0.011%, total miscellaneous 0.06%.
Embodiment 6
1）The in the mixed solvent that 100g olaparib crude products as obtained by implementing 3 are added into the tertiary ether of 1.5l first and acetonitrile is crystallized,
Wherein the volume ratio of the tertiary ether of in the mixed solvent first and acetonitrile is 1:7, backflow is heated to, 4h is incubated at 70 DEG C, is cooled to 25 DEG C
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 in the mixed solvent dichloromethane and
The volume ratio of methanol is 1:2；Be heated to backflow, 40 DEG C be incubated 3h, natural cooling crystallization, suction filtration, 55 DEG C are dried under vacuum to perseverance
Weight, obtains solid powder 94.6g, and yield 94.6%, purity 99.944% is maximum single miscellaneous（Impurity C）0.012%, total miscellaneous 0.056%.
Embodiment 7
1）The in the mixed solvent that 100g olaparib crude products as obtained by implementing 2 are added into the tertiary ether of 2l first and acetonitrile is crystallized, its
The volume ratio of the middle tertiary ether of in the mixed solvent first and acetonitrile is 1:5, backflow is heated to, 5h is incubated at 65 DEG C, is cooled to 35 DEG C of analysis
Crystalline substance, 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 in the mixed solvent dichloromethane and second
The volume ratio of alcohol is 1:3；Be heated to backflow, 40 DEG C be incubated 2h, natural cooling crystallization, suction filtration, 70 DEG C are dried under vacuum to constant weight,
Solid powder 92.5g is obtained, yield 92.5%, purity 99.94% is maximum single miscellaneous（Impurity C）0.015%, total miscellaneous 0.06%.
Embodiment 8
1）The gained olaparib crude product of 100g embodiments 3 is added to the in the mixed solvent crystallization of the tertiary ether of 2l first and acetonitrile, wherein
The volume ratio of the tertiary ether of in the mixed solvent first and acetonitrile is 1:15, backflow is heated to, 3h is incubated at 90 DEG C, is cooled to 30 DEG C of analysis
Crystalline substance, 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 in the mixed solvent dichloromethane and second
The volume ratio of alcohol is 1:3；Be heated to backflow, 70 DEG C be incubated 1.5h, natural cooling crystallization, suction filtration, 40 DEG C are dried under vacuum to perseverance
Weight, obtains solid powder 90.15g, and yield 90.15%, purity 99.93% is maximum single miscellaneous（Impurity C）0.02%, total miscellaneous 0.07%.
Embodiment 9
1）The gained olaparib crude product of 100g embodiments 2 is added to the in the mixed solvent crystallization of the tertiary ether of 1.2l first and acetonitrile, its
The volume ratio of the middle tertiary ether of in the mixed solvent first and acetonitrile is 1:1, backflow is heated to, 2h is incubated at 95 DEG C, is cooled to 20 DEG C of analysis
Crystalline substance, 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 in the mixed solvent dichloromethane and
The volume ratio of methanol is 1:0.5；Be heated to backflow, 65 DEG C be incubated 3h, natural cooling crystallization, suction filtration, 50 DEG C are dried under vacuum to
Constant weight, obtains solid powder 90g, and yield 90%, purity 99.93% is maximum single miscellaneous（Impurity C）0.016%, total miscellaneous 0.07%.
It can be drawn by embodiment 4-9, olaparib crude product is passed through into the tertiary ether of first and acetonitrile（Volume ratio is 1:1-15）
Mixed solvent crystallization, then pass through dichloromethane and Organic Alcohol（Volume ratio is 1:0.5-5）Mixed solvent is recrystallized, gained crystal
Purity is up to more than 99.93%, and impurity C's can be controlled within the scope of 0.02%, and total miscellaneous control is within the scope of 0.07%.
Above example is only intended to help and understands the present invention, is not construed as limiting the invention, for this area
For those of ordinary skill, 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 (8)
1. a kind of recrystallization method of olaparib, it is characterised in that comprise the following steps：
1）The in the mixed solvent that olaparib crude product is added into the tertiary ether of first and acetonitrile is mixed, and is heated to reflux, and is protected at 60-95 DEG C
Warm 3-5h, cools to 20-40 DEG C of crystallization；
2）By step 1）Gained crystallization is added to ethyl acetate and C1-5The in the mixed solvent mixing of alcohol, is heated to reflux, in 40-80
DEG C insulation 0.5-3h, cooling recrystallization, filtering, use C1-5Alcohol is washed, in 40-70 DEG C of drying.
2. recrystallization method according to claim 1, it is characterised in that the step 1）The volume in liters of middle mixed solvent
Measure the quality grams amount for olaparib crude product 6-20 times.
3. recrystallization method according to claim 2, it is characterised in that the step 1）The volume in liters of middle mixed solvent
Measure the quality grams amount for olaparib crude product 6-12 times.
4. recrystallization method according to claim 1, it is characterised in that the step 1）The volume of the middle tertiary ether of first and acetonitrile
Than for 1:1-15.
5. recrystallization method according to claim 4, it is characterised in that the step 1）The volume of the middle tertiary ether of first and acetonitrile
Than for 1:1-5.
6. recrystallization method according to claim 1, it is characterised in that the step 2）In the mixed solvent ethyl acetate and
C1-5The volume ratio of alcohol is 1:0.5-5.
7. recrystallization method according to claim 6, it is characterised in that the step 2）In the mixed solvent ethyl acetate and
C1-5The volume ratio of alcohol is 1:0.5-2.
8. recrystallization method according to claim 1, it is characterised in that the step 1）Middle holding temperature is 60-70 DEG C.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201610258239.8A CN107304187B (en) | 2016-04-25 | 2016-04-25 | Recrystallization method of olaparib |
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| CN201610258239.8A CN107304187B (en) | 2016-04-25 | 2016-04-25 | Recrystallization method of olaparib |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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| CN101528714A (en) * | 2006-10-17 | 2009-09-09 | 库多斯药物有限公司 | Polymorphic form of 4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2h-phthalazin-1-one |
| CN105061328A (en) * | 2015-08-27 | 2015-11-18 | 北京科莱博医药开发有限责任公司 | Refining method for olaparib |
| CN105503739A (en) * | 2016-02-24 | 2016-04-20 | 上海今寅生物科技有限公司 | Preparation method of high-purity olaparib |
-
2016
- 2016-04-25 CN CN201610258239.8A patent/CN107304187B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101528714A (en) * | 2006-10-17 | 2009-09-09 | 库多斯药物有限公司 | Polymorphic form of 4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2h-phthalazin-1-one |
| CN105061328A (en) * | 2015-08-27 | 2015-11-18 | 北京科莱博医药开发有限责任公司 | Refining method for olaparib |
| CN105503739A (en) * | 2016-02-24 | 2016-04-20 | 上海今寅生物科技有限公司 | Preparation method of high-purity olaparib |
Non-Patent Citations (1)
| Title |
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| FILIP ZMUDA等: "Synthesis and Evaluation of a Radioiodinated Tracer with Specificity for Poly(ADP-ribose) Polymerase‑1 (PARP-1) in Vivo", 《J. MED. CHEM.》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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| CN107304187B (en) | 2021-07-09 |
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