CN107304186B - Refining method of olaparib - Google Patents
Refining method of olaparib Download PDFInfo
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- CN107304186B CN107304186B CN201610258238.3A CN201610258238A CN107304186B CN 107304186 B CN107304186 B CN 107304186B CN 201610258238 A CN201610258238 A CN 201610258238A CN 107304186 B CN107304186 B CN 107304186B
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- C07—ORGANIC CHEMISTRY
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- 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
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Abstract
The invention belongs to the technical field of medicine purification, and particularly relates to a refining method of olaparib, which comprises the following steps: 1) adding the crude olaparib product into a mixed solvent of dichloromethane and acetonitrile, heating, refluxing, cooling and crystallizing; 2) adding the crystals obtained in step 1) into dichloromethane and C1‑5Recrystallizing in a mixed solvent of fatty alcohol; 3) distilling to evaporate dichloromethane, cooling to separate out solid, filtering, washing with water and drying. The olaparib obtained by the method has the characteristic of high purity.
Description
Technical Field
The invention belongs to the technical field of medicine purification, and particularly relates to a refining method of olaparib.
Background
Olaparib (Olaparib) is a small molecule, potent oral PARP inhibitor developed by KuDOS pharmaceutical company, a Quanzizi company of AstraZeneca, which can enhance the therapeutic effects of radiotherapy and alkylating agent and platinum drug chemotherapy by inhibiting the repair of DNA damage of tumor cells and promoting the apoptosis of tumor cells, and is mainly used for treating the gene mutation cancers of the breast cancer gene I (BRCA-1) and the breast cancer gene II (BRCA-2), and mainly exists in breast cancer, ovarian cancer and prostate cancer.
The following synthetic route is disclosed in WO 2004/080976A:
a preparation method of olaparib crystal form a is disclosed in CN101528714B by kudos pharmaceutical limited: the crystal form A is obtained by crystallizing the olaparib in a dichloromethane or acetonitrile solvent, treating the crystal form A with ethanol and water respectively and drying the crystal form A, wherein although most impurities can be removed by the method, the impurity C can be hardly removed, and the structural formula of the impurity C is as follows:
the impurity C is caused by impurities in the cyclopropane formyl chloride raw material in the preparation process, and if the impurities cannot be effectively controlled, the quality of a finished product of the preparation can be influenced.
Disclosure of Invention
In order to solve the defects in the prior art, the invention provides a method for refining high-purity olaparib.
A refining method of Olaparib is characterized by comprising the following steps:
1) adding the crude olaparib product into a mixed solvent of dichloromethane and acetonitrile, heating, refluxing, cooling and crystallizing;
2) adding the crystals obtained in step 1) into dichloromethane and C1-5Recrystallizing in a mixed solvent of fatty alcohol;
3) distilling to evaporate dichloromethane, cooling to separate out solid, filtering, washing with water and drying.
The adding sequence of the mixed solvent of the step 1) and the step 2) can be interchanged, namely that:
1) adding the crude olaparib product into a mixed solvent of dichloromethane and fatty alcohol for crystallization;
2) adding the crystals obtained in the step 1) into a mixed solvent of dichloromethane and acetonitrile for recrystallization.
Preferably, the volume liter amount of the mixed solvent in the step 1) is 8 to 20 times, more preferably 8 to 15 times of the mass gram amount of the crude olaparib.
Preferably, the volume ratio of dichloromethane to acetonitrile in step 1) is 1:1 to 20, more preferably 1:5 to 1: 12.
Preferably, the volume ratio of the dichloromethane to the ethanol in the mixed solvent in the step 2) is 1:0.5-5, and more preferably 1: 0.5-2.
Preferably, step 2) is to add the crystals obtained in step 1) to dichloromethane and C1-5Mixing the mixture in a mixed solvent of fatty alcohol, heating and refluxing to clarify, adding active carbon, press-filtering while the mixture is hot, continuously heating and refluxing the filtrate, cooling and precipitating crystals.
Preferably, step 3) is to add the crystals obtained in step 2) to dichloromethane and C1-5Mixing the mixture with fatty alcohol, distilling under reduced pressure to evaporate dichloromethane, and cooling to crystallize. By this procedure, the residual solvent dichloromethane in the crystallization was removed while increasing the yield of olaparib.
The crude olaparib product can be obtained by adopting the method disclosed by WO2004/080976A, namely the crude olaparib product is obtained by reacting a compound B with cyclopropyl formyl chloride; but the adopted cyclopropyl formyl chloride raw material is easy to absorb moisture and is difficult to store in the storage process, so that the method is not beneficial to large-scale production, and the material feeding process is harsh and causes certain pollution to the environment.
In view of the above problems, the applicant of the present invention synthesizes crude olaparib by using cyclopropyl formic acid and compound B under the conditions of dichloromethane and N, N-diisopropylethylamine, and the following equation:
the specific operation steps are as follows:
adding the compound B, cyclopropanecarboxylic acid, O-benzotriazole-tetramethylurea hexafluorophosphate and acetonitrile into a reaction vessel, keeping the temperature at 10-30 ℃, dropwise adding N, N-diisopropylethylamine, reacting for 15-30h, and extracting, separating and drying the obtained mixture to obtain crude Olaparib.
Preferably, the washing is to wash the filter cake obtained by suction filtration with acetonitrile and then with water.
Preferably, the temperature is maintained at 20-30 ℃.
Preferably, the drying temperature is 40 to 60 ℃, more preferably, 50 to 60 ℃.
Preferably, the solvent added for the extraction separation is water.
The invention has the beneficial technical effects that:
according to the refining method provided by the invention, the crude Olaparib product is crystallized by using a mixed solvent of dichloromethane and acetonitrile, and then the mixed solvent of dichloromethane and fatty alcohol is recrystallized, so that the high-purity Olaparib is obtained. The reason for this is that: the mixed solvent of dichloromethane and acetonitrile can increase the solubility of related impurities except the impurity C in the solvent, and effectively remove most of other impurities except the impurity C in the crude product of the olaparib; reusing a mixed solvent of methylene chloride and fatty alcohol, especially C1-5The fatty alcohol, which is a mixed solvent, has good solubility for the impurity C, but the olaparib is hardly soluble, so that the impurity C in the olaparib can be effectively removed. Combine the twoThe purity of the Olaparib refined product obtained by the refining method provided by the invention can be improved, and meanwhile, the impurity C is effectively controlled, experimental results show that the purity of the Olaparib refined product obtained by the refining method provided by the invention is over 99.92%, the content of the impurity C is not more than 0.03%, the total impurity content is not more than 0.08%, and the Olaparib refined product obtained by the refining method provided by the invention is in a crystal form the same as the crystal form A of CN 101528714B.
The preparation method of the crude Olaparib product has the advantages of convenient raw material storage and convenient use and taking at any time, has small environmental pollution in the using process, and is suitable for industrial mass production.
Detailed Description
Compound B can be prepared by the methods described in the description of WO 2004/080976A.
The crude olaparib product is obtained by adding cyclopropane formyl chloride or cyclopropane formic acid to a compound B.
Example 1
Adding 1mol of compound B, 1.25mol of cyclopropanecarboxylic acid, 5l of HBTU (O-benzotriazole-tetramethyluronium hexafluorophosphate) and 5l of acetonitrile into a reaction vessel, keeping the temperature at 10 ℃, dropwise adding 2mol of N, N-diisopropylethylamine, reacting for 15h, adding water into the obtained mixture, extracting and separating, drying the extract at 40 ℃ to obtain crude Olaparib, and detecting by HPLC (high performance liquid chromatography), wherein the purity is 99.58%, the maximum single impurity (impurity C) is 0.28%, and the total impurity is 0.42%.
Example 2
Adding 1mol of compound B, 1.5mol of cyclopropanecarboxylic acid, 2 lO-benzotriazole-tetramethylurea hexafluorophosphate and 10l of acetonitrile into a reaction vessel, keeping the temperature at 30 ℃, dropwise adding 2mol of N, N-diisopropylethylamine, reacting for 30h, adding water into the obtained mixture, extracting and separating, drying the extract at 50 ℃ to obtain crude Olaparib, and detecting by HPLC, wherein the purity is 99.62%, the maximum single impurity (impurity C) is 0.24%, and the total impurity is 0.38%.
Example 3
Adding 1mol of compound B, 1mol of cyclopropanecarboxylic acid, 5 lO-benzotriazole-tetramethylurea hexafluorophosphate and 8l of acetonitrile into a reaction vessel, keeping the temperature at 20 ℃, dropwise adding 3mol of N, N-diisopropylethylamine, reacting for 20h, adding water into the obtained mixture, extracting and separating, drying the extract at 60 ℃ to obtain crude olaparib, and detecting by HPLC (high performance liquid chromatography), wherein the purity is 99.6%, the maximum single impurity (impurity C) is 0.25%, and the total impurity is 0.4%.
Example 4
The crude olaparib was prepared by the method in CN 101528714B:
adding 100g of the compound B into a suspension of 1.2l of dichloromethane, dropwise adding a solution of 34ml of premixed triethylamine and 22ml of premixed cyclopropanecarbonyl chloride in 100ml of dichloromethane, keeping the temperature at 15 ℃, keeping the temperature for 15 minutes, adding water into the obtained mixture for extraction and separation, drying the extract at 50 ℃ to obtain crude olaparib, and detecting by HPLC (high performance liquid chromatography), wherein the purity is 99.5%, the maximum single impurity (impurity C) is 0.31%, and the total impurity is 0.5%.
It can be seen from examples 1-4 that, no matter whether cyclopropanecarboxylic acid or cyclopropanecarbonyl chloride is used for condensation reaction with the compound B, the largest single impurity is the impurity C, and the impurity C is more than 60% of the total impurity, so that the removal of the impurity C has important significance for improving the quality of the olaparib.
Example 5
1) Adding 100g of crude olaparib product obtained by the implementation 2 into 1.2l of mixed solvent of dichloromethane and acetonitrile for mixing, wherein the volume ratio of dichloromethane to acetonitrile in the mixed solvent is 1:12, heating to reflux, preserving heat for 5 hours, naturally cooling for crystallization, performing suction filtration, and drying in vacuum to constant weight to obtain primary crystals;
2) adding the primary crystals into 1.2l of a mixed solvent of dichloromethane and methanol, wherein the volume ratio of the dichloromethane to the methanol in the mixed solvent is 1: 0.5; heating and refluxing to clarify, adding activated carbon, hot press filtering, heating the filtrate to reflux, keeping the temperature for 3h, naturally cooling for crystallization, suction filtering, and vacuum drying to constant weight to obtain secondary crystals;
3) and (3) adding the secondary crystal into a mixed solvent of dichloromethane and methanol, wherein the mixed solvent is the same as the mixed solvent in the step 2), distilling and evaporating dichloromethane, then naturally cooling and crystallizing, filtering, washing with water, and drying at 58 ℃ to obtain 95.2g of solid powder, wherein the yield is 95.2%, and the purity is 99.96%, the maximum single impurity (impurity C) is 0.012%, and the total impurity is 0.04% by HPLC detection.
Example 6
1) Adding 100g of crude olaparib product obtained by the implementation of the step 1 into 0.8l of mixed solvent of dichloromethane and acetonitrile for crystallization, wherein the volume ratio of dichloromethane to acetonitrile in the mixed solvent is 1:20, heating to reflux, preserving heat for 3 hours, naturally cooling for crystallization, performing suction filtration, and drying in vacuum to constant weight to obtain primary crystals;
2) adding the primary crystals into 0.8l of a mixed solvent of dichloromethane and ethanol, wherein the volume ratio of the dichloromethane to the ethanol in the mixed solvent is 1: 5; heating to reflux, keeping the temperature for 2h, naturally cooling for crystallization, performing suction filtration, and vacuum drying to constant weight to obtain secondary crystals;
3) and (3) adding the secondary crystal into a mixed solvent of dichloromethane and ethanol, wherein the mixed solvent is the same as the mixed solvent in the step 2), distilling and evaporating dichloromethane, naturally cooling and crystallizing, filtering, washing with water, and drying at 50 ℃ to obtain 96.5g of solid powder, wherein the yield is 96.5%, and the purity is 99.94%, the maximum single impurity (impurity C) is 0.015% and the total impurity is 0.06% through HPLC detection.
Example 7
1) Adding 100g of crude olaparib product obtained by the implementation of the step 3 into 1.5l of mixed solvent of dichloromethane and acetonitrile for crystallization, wherein the volume ratio of dichloromethane to acetonitrile in the mixed solvent is 1:1, heating to reflux, preserving heat for 4 hours, naturally cooling for crystallization, performing suction filtration, and drying in vacuum to constant weight to obtain primary crystals;
2) adding the primary crystals into 1.5l of a mixed solvent of dichloromethane and propanol, wherein the volume ratio of dichloromethane to methanol in the mixed solvent is 1: 2; heating to reflux, keeping the temperature for 3h, naturally cooling for crystallization, performing suction filtration, and vacuum drying to constant weight to obtain secondary crystals;
3) and (3) adding the secondary crystals into a mixed solvent of dichloromethane and propanol, wherein the mixed solvent is the same as the mixed solvent in the step 2), distilling and evaporating dichloromethane, then naturally cooling and crystallizing, filtering, washing with water, and drying at 60 ℃ to obtain 95.6g of solid powder, wherein the yield is 95.6%, and the solid powder has the purity of 99.944%, the maximum single impurity (impurity C) is 0.013% and the total impurity is 0.056% by HPLC detection.
Example 8
1) Adding 100g of crude olaparib product obtained by the implementation 2 into 2l of mixed solvent of dichloromethane and acetonitrile for crystallization, wherein the volume ratio of dichloromethane to acetonitrile in the mixed solvent is 1:5, heating to reflux, preserving heat for 4 hours, naturally cooling for crystallization, performing suction filtration, and drying in vacuum to constant weight to obtain primary crystals;
2) adding the primary crystal into 2l of mixed solvent of dichloromethane and amyl alcohol, wherein the volume ratio of dichloromethane to ethanol in the mixed solvent is 1: 3; heating to reflux, keeping the temperature for 2h, naturally cooling for crystallization, performing suction filtration, and vacuum drying to constant weight to obtain secondary crystals;
3) and (3) adding the secondary crystals into a mixed solvent of dichloromethane and pentanol, wherein the mixed solvent is the same as the step 2), distilling and evaporating dichloromethane, naturally cooling and crystallizing, filtering, washing with water, and drying at 65 ℃ to obtain 95.5g of solid powder, wherein the yield is 95.5%, and the purity is 99.945%, the maximum single impurity (impurity C) is 0.018%, and the total impurity content is 0.055% by HPLC (high performance liquid chromatography).
Example 9
The difference from example 5 is that the miscible solvents of step 1) and step 2) are exchanged and the remaining conditions are unchanged; 95.2g of solid powder are obtained in 95.2% yield and, by HPLC, 99.96% purity, maximum single impurity (impurity C) 0.012%, total impurity 0.04%.
Example 10
1) Adding 100g of the crude olaparib product obtained in example 4 into 2l of a mixed solvent of dichloromethane and acetonitrile for crystallization, wherein the volume ratio of dichloromethane to acetonitrile in the mixed solvent is 1:7, heating to reflux, preserving heat for 4 hours, naturally cooling for crystallization, performing suction filtration, and drying in vacuum to constant weight to obtain primary crystals;
2) adding the primary crystal into 2l of mixed solvent of dichloromethane and butanol, wherein the volume ratio of dichloromethane to ethanol in the mixed solvent is 1: 3; heating to reflux, keeping the temperature for 2h, naturally cooling for crystallization, performing suction filtration, and vacuum drying to constant weight to obtain secondary crystals;
3) and (3) adding the secondary crystals into a mixed solvent of dichloromethane and butanol, wherein the mixed solvent is the same as the mixed solvent obtained in the step 2), distilling and evaporating dichloromethane, naturally cooling and crystallizing, filtering, washing with water, and drying at 60 ℃ to obtain 88.2g of solid powder, wherein the yield is 88.2%, and the purity is 99.92%, the maximum single impurity (impurity C) is 0.03% and the total impurity is 0.08% through HPLC detection.
Example 11
1) Adding 100g of the crude olaparib product obtained in example 4 into 1.2l of a mixed solvent of dichloromethane and acetonitrile for crystallization, wherein the volume ratio of dichloromethane to acetonitrile in the mixed solvent is 1:1, heating to reflux, preserving heat for 5 hours, naturally cooling for crystallization, performing suction filtration, and drying in vacuum to constant weight to obtain primary crystals;
2) adding the primary crystals into 1.2l of a mixed solvent of dichloromethane and methanol, wherein the volume ratio of the dichloromethane to the methanol in the mixed solvent is 1: 0.5; heating to reflux, keeping the temperature for 3h, naturally cooling for crystallization, performing suction filtration, and vacuum drying to constant weight to obtain secondary crystals;
3) and (3) adding the secondary crystal into a mixed solvent of dichloromethane and methanol, wherein the mixed solvent is the same as the mixed solvent obtained in the step 2), distilling and evaporating dichloromethane, naturally cooling and crystallizing, filtering, washing with water, and drying at 40 ℃ to obtain 88.0g of solid powder, wherein the yield is 88.0%, and the solid powder has the purity of 99.92%, the maximum single impurity (impurity C) of 0.028% and the total impurity of 0.08% by HPLC (high performance liquid chromatography).
Example 12
The difference from example 11 is that the mixed solvent in step 1) and step 2) is exchanged and the remaining conditions are unchanged. 88.0g of solid powder was obtained in 88.0% yield, 99.92% purity by HPLC, 0.028% maximum single impurity (impurity C), 0.08% total impurity.
By comparing example 5 with example 9 and example 11 with example 12, that is, by interchanging the mixed solvents used for crystallization in step 1) and step 2), the detection results of the obtained products are consistent.
From examples 5 to 12, it can be seen that crude olaparib was purified by passing it through a mixed solvent of dichloromethane and acetonitrile, dichloromethane and C1-5The secondary crystallization of the fatty alcohol mixed solvent can lead the purity of the obtained crystal to be more than 99.92 percent, the content of the impurity C can be controlled within the range of 0.03 percent, and the content of the total impurities is controlled within the range of 0.08 percent.
Further, it can be found by comparing examples 5 to 9 with examples 10 to 12 that the purification yield of crude olaparib obtained by reacting compound B with cyclopropanecarboxylic acid is significantly higher than that of crude olaparib obtained by condensing compound B with cyclopropanecarboxylic acid chloride, probably because cyclopropanecarboxylic acid chloride is prepared from cyclopropanecarboxylic acid, impurities are also generated during the preparation process, and the types and contents of impurities of cyclopropanecarboxylic acid chloride are more than those of cyclopropanecarboxylic acid, so that the impurities participate in the condensation reaction with compound B, and the yield is influenced during the purification process of olaparib.
The above embodiments are only for understanding the invention, and do not limit the invention, and it will be obvious to those skilled in the art that the invention can be modified or modified without departing from the principle of the invention, and the modified or modified embodiments also fall into the protection scope of the claims of the invention.
Claims (9)
1. A refining method of Olaparib is characterized by comprising the following steps:
1) adding the crude olaparib product into a mixed solvent of dichloromethane and acetonitrile, heating, refluxing, cooling and crystallizing;
2) adding the crystals obtained in step 1) into dichloromethane and C1-5Recrystallizing in a mixed solvent of fatty alcohol;
3) distilling and evaporating dichloromethane, cooling to separate out a solid, filtering, washing with water, and drying;
the mixed solvents in the step 1) and the step 2) can be exchanged;
the crude olaparib product is prepared by the following method:
adding the compound B, cyclopropanecarboxylic acid, O-benzotriazole-tetramethylurea hexafluorophosphate and acetonitrile into a reaction vessel, keeping the temperature at 10-30 ℃, dropwise adding N, N-diisopropylethylamine, reacting for 15-30h, and extracting, separating and drying the obtained mixture to obtain crude Olaparib.
2. The refining method as claimed in claim 1, wherein the volume liter amount of the mixed solvent in the step 1) is 8 to 20 times the mass gram amount of the crude olaparib.
3. The purification process according to claim 1, wherein the volume ratio of dichloromethane to acetonitrile in the step 1) is 1: 1-20.
4. The purification process according to claim 1, wherein the methylene chloride and C in the mixed solvent of step 2) are1-5The volume ratio of the fatty alcohol is 1: 0.5-5.
5. The purification process according to claim 4, wherein the methylene chloride and C in the mixed solvent of step 2) are1-5The volume ratio of the fatty alcohol is 1: 0.5-2.
6. The refining method according to claim 1, wherein the crystals obtained in step 1) are added to dichloromethane and C in step 2)1-5Mixing the mixture in a mixed solvent of fatty alcohol, heating and refluxing to clarify, adding active carbon, press-filtering while the mixture is hot, continuously heating and refluxing the filtrate, cooling and separating out solids.
7. The preparation method of the crude Olaparib product is characterized by comprising the following steps:
adding the compound B, cyclopropanecarboxylic acid, O-benzotriazole-tetramethylurea hexafluorophosphate and acetonitrile into a reaction vessel, keeping the temperature at 10-30 ℃, dropwise adding N, N-diisopropylethylamine, reacting for 15-30h, and extracting, separating and drying the obtained mixture to obtain crude Olaparib.
8. The method of claim 7, wherein the temperature is maintained at 20-30 ℃.
9. The method according to claim 7, wherein the drying temperature is 40 to 60 ℃.
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| CA3031777A1 (en) | 2018-01-31 | 2019-07-31 | Apotex Inc. | Crystalline form of olaparib |
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| 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 |
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| CN105985294A (en) * | 2015-02-11 | 2016-10-05 | 四川科伦药物研究院有限公司 | Preparation method for olaparib |
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