CN107304187B - Recrystallization method of olaparib - Google Patents

Recrystallization method of olaparib Download PDF

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CN107304187B
CN107304187B CN201610258239.8A CN201610258239A CN107304187B CN 107304187 B CN107304187 B CN 107304187B CN 201610258239 A CN201610258239 A CN 201610258239A CN 107304187 B CN107304187 B CN 107304187B
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olaparib
mixed solvent
recrystallization method
acetonitrile
temperature
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CN107304187A (en
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章微华
蔡鸿飞
金远锋
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Hangzhou Rongli Pharmaceutical Technology Co ltd
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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

Hair brushBelongs to the technical field of medicine purification, and particularly relates to a recrystallization method of olaparib. The method comprises the following steps: 1) adding the crude olaparib product into a mixed solvent of methyl tertiary ether and acetonitrile, mixing, heating for refluxing, and cooling for crystallization; 2) adding into ethyl acetate and C1‑5Mixing the mixture in alcohol solvent, heating and refluxing, cooling and recrystallizing. The obtained product has high purity.

Description

Recrystallization method of olaparib
Technical Field
The invention belongs to the technical field of medicine purification, and particularly relates to a recrystallization 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 first breast cancer gene (BRCA-1) and the second breast cancer gene (BRCA-2), and the given genes mainly exist in breast cancer, ovarian cancer and prostate cancer.
The following synthetic route is disclosed in WO 2004/080976A:
Figure 377387DEST_PATH_IMAGE001
Figure 917959DEST_PATH_IMAGE002
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:
Figure 450572DEST_PATH_IMAGE003
the impurity C is inevitable for impurities in the cyclopropane formyl chloride raw material in the preparation process, and the quality of a finished product of the preparation can be influenced if the impurity C cannot be effectively controlled.
Disclosure of Invention
In order to solve the defects in the prior art, the invention provides a method for recrystallizing high-purity olaparib.
A recrystallization method of olaparib is characterized by comprising the following steps:
1) adding the crude Olaparib product into a mixed solvent of methyl tertiary ether and acetonitrile, mixing, heating and refluxing, keeping the temperature at 60-95 ℃ for 3-5h, and cooling to 20-40 ℃ for crystallization;
2) adding the crystals obtained in step 1) to ethyl acetate and C1-5Mixing with mixed solvent of alcohol, heating and refluxing, keeping the temperature at 40-80 deg.C for 0.5-3h, cooling, recrystallizing, filtering, and adding C1-5Washing with alcohol, and drying at 40-70 deg.C.
Preferably, the volume liter amount of the mixed solvent in the step 1) is 6 to 20 times, more preferably 6 to 12 times of the mass gram amount of the crude olaparib.
Preferably, the heat preservation temperature in the step 1) is 60-70 ℃.
Preferably, the temperature of the temperature reduction in the step 1) is 30-40 ℃.
Preferably, the volume ratio of methyl tertiary ether to acetonitrile in the step 1) is 1:1-15, more preferably 1: 1-5.
Preferably, the dichloromethane and C in the mixed solvent of the step 2)1-5The volume ratio of the alcohol is 1:0.5-5, more preferably 1: 0.5-2.
Preferably, the heat preservation temperature in the step 2) is 55-70 ℃.
Preferably, the drying temperature in the step 2) is 50-60 ℃.
Preferably, the cooling mode in the step 2) is natural cooling.
The raw material of the cyclopropyl formyl chloride is easy to absorb moisture and is difficult to store in the storage process, so that the cyclopropyl formyl chloride is not beneficial to large-scale production, and the cyclopropyl formyl chloride is harsh in the feeding process and causes certain pollution to the environment.
The applicant synthesizes crude olaparib by using cyclopropyl formic acid and a compound B under the conditions of dichloromethane and N, N-diisopropylethylamine, and the equation is as follows:
Figure 852734DEST_PATH_IMAGE004
the method comprises the following specific steps:
adding the compound B, cyclopropanecarboxylic acid, O-benzotriazole-tetramethylurea hexafluorophosphate and dichloromethane into a reaction vessel, keeping the temperature at 10-30 ℃, dropwise adding N, N-diisopropylethylamine, reacting for 15-30h, adding water into the obtained mixture, extracting, separating, washing and concentrating to obtain crude Olaparib.
Preferably, the temperature is maintained at 20-30 ℃.
Preferably, the drying temperature is 40-65 ℃, more preferably, 50-65 ℃.
The invention has the beneficial technical effects that:
the recrystallization method provided by the invention comprises the steps of mixing methyl tertiary ether and acetonitrile mixed solvent, heating and refluxing, keeping the temperature for 3-5h at 60-95 ℃ to enable the mixed solution to be in a supersaturated state, then cooling to 20-40 ℃ to crystallize crude Olaparib, and then using ethyl acetate and C1-5Mixing the mixed solvents of alcohol, heating and refluxing, keeping the temperature at 40-80 ℃ for 0.5-3h to ensure that the mixed solution is in a supersaturated state, and naturally cooling and recrystallizing to obtain the high-purity olaparib. The reason for this is that: the mixed solvent of methyl tertiary ether and acetonitrile can increase the solubility of related impurities except the impurity C in the mixed solvent, and effectively remove most of other impurities except the impurity C in the crude product of the olaparib; reuse of ethyl acetate and C1-5And an alcohol-mixed solvent, which has good solubility for the impurity C and is almost insoluble in Olaparib, and thus can effectively remove the impurity C from Olaparib. The purity of the Olaparib can be improved by combining the two, and meanwhile, the impurity C is effectively controlled, and experimental results show that the refining yield of the Olaparib refined product obtained by the recrystallization method reaches over 90 percent, the purity reaches over 99.93 percent, the content of the impurity C is not more than 0.02 percent, and the total impurity is not more than 0.07 percent. The olaparib obtained by the invention is in the same crystal form as CN101528714B crystal form A.
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 cyclopropanecarboxylic acid to a compound B.
Example 1
Adding 1mol of compound B, 1.25mol of cyclopropanecarboxylic acid, 5l O-benzotriazole-tetramethylurea hexafluorophosphate and 5l of dichloromethane into a reaction vessel, keeping the temperature at 30 ℃, dropwise adding 2mol of N, N-diisopropylethylamine, reacting for 15h, adding water into the obtained mixture, extracting, separating, washing and concentrating at 40 ℃ to obtain crude Olaparib.
Example 2
Adding 1mol of compound B, 1.5mol of cyclopropanecarboxylic acid, 2l O-benzotriazole-tetramethylurea hexafluorophosphate and 10l of dichloromethane into a reaction vessel, keeping the temperature at 10 ℃, dropwise adding 2mol of N, N-diisopropylethylamine, reacting for 30h, adding water into the obtained mixture, extracting, separating, washing and concentrating at 50 ℃ to obtain crude Olaparib.
Example 3
Adding 1mol of compound B, 1mol of cyclopropanecarboxylic acid, 5l O-benzotriazole-tetramethylurea hexafluorophosphate and 8l of dichloromethane into a reaction vessel, keeping the temperature at 20 ℃, dropwise adding 3mol of N, N-diisopropylethylamine, reacting for 20 hours, adding water into the obtained mixture for extraction, separating, washing and concentrating at 65 ℃ to obtain crude Olaparib.
Example 4
1) Adding 100g of crude Olaparib obtained by the implementation 2 into 1.2l of mixed solvent of methyl tertiary ether and acetonitrile for crystallization, wherein the volume ratio of methyl tertiary ether to acetonitrile in the mixed solvent is 1:1, heating to reflux, preserving the temperature for 5 hours at 80 ℃, naturally cooling for crystallization, performing suction filtration, and performing vacuum drying 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 at 50 ℃ for 1h, naturally cooling for crystallization, performing suction filtration, and vacuum drying at 60 ℃ to constant weight to obtain 94g of solid powder, wherein the yield is 94%, the purity is 99.95%, the maximum single impurity (impurity C) is 0.012%, and the total impurity content is 0.05%.
Example 5
1) Adding 100g of crude Olaparib obtained by the implementation of the step 1 into 0.6l of mixed solvent of methyl tertiary ether and acetonitrile for crystallization, wherein the volume ratio of methyl tertiary ether to acetonitrile in the mixed solvent is 1:8, heating to reflux, preserving the temperature for 3h at 60 ℃, cooling to 40 ℃ for crystallization, carrying out suction filtration, and carrying out vacuum drying to constant weight to obtain primary crystals;
2) adding the primary crystals into 0.6l 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 at 80 ℃ for 0.5h, naturally cooling for crystallization, performing suction filtration, and vacuum drying at 50 ℃ to constant weight to obtain 92g of solid powder, wherein the yield is 92%, the purity is 99.94%, the maximum single impurity (impurity C) is 0.011%, and the total impurity is 0.06%.
Example 6
1) Adding 100g of crude olaparib obtained by the implementation of the step 3 into 1.5l of mixed solvent of methyl tertiary ether and acetonitrile for crystallization, wherein the volume ratio of the methyl tertiary ether to the acetonitrile in the mixed solvent is 1:7, heating to reflux, preserving the temperature for 4h at 70 ℃, cooling to 25 ℃ for crystallization, carrying out suction filtration, and carrying out vacuum drying 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 at 40 ℃ for 3h, naturally cooling for crystallization, performing suction filtration, and vacuum drying at 55 ℃ to constant weight to obtain 94.6g of solid powder, wherein the yield is 94.6%, the purity is 99.944%, the maximum single impurity (impurity C) is 0.012%, and the total impurity content is 0.056%.
Example 7
1) Adding 100g of crude olaparib obtained by the implementation 2 into 2l of mixed solvent of methyl tertiary ether and acetonitrile for crystallization, wherein the volume ratio of methyl tertiary ether to acetonitrile in the mixed solvent is 1:5, heating to reflux, preserving heat at 65 ℃ for 5h, cooling to 35 ℃ for crystallization, performing suction filtration, and performing vacuum drying 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 at 40 ℃ for 2h, naturally cooling for crystallization, performing suction filtration, and vacuum drying at 70 ℃ to constant weight to obtain 92.5g of solid powder, wherein the yield is 92.5%, the purity is 99.94%, the maximum single impurity (impurity C) is 0.015%, and the total impurity is 0.06%.
Example 8
1) Adding 100g of the crude olaparib product obtained in the example 3 into 2l of a mixed solvent of methyl tertiary ether and acetonitrile for crystallization, wherein the volume ratio of the methyl tertiary ether to the acetonitrile in the mixed solvent is 1:15, heating to reflux, preserving heat at 90 ℃ for 3h, cooling to 30 ℃ for crystallization, performing suction filtration, and performing vacuum drying 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 at 70 ℃ for 1.5h, naturally cooling for crystallization, performing suction filtration, and vacuum drying at 40 ℃ to constant weight to obtain 90.15g of solid powder, wherein the yield is 90.15%, the purity is 99.93%, the maximum single impurity (impurity C) is 0.02%, and the total impurity content is 0.07%.
Example 9
1) Adding 100g of the crude olaparib product obtained in the example 2 into 1.2l of a mixed solvent of methyl tertiary ether and acetonitrile for crystallization, wherein the volume ratio of methyl tertiary ether to acetonitrile in the mixed solvent is 1:1, heating to reflux, preserving the temperature for 2h at 95 ℃, cooling to 20 ℃ for crystallization, performing suction filtration, and performing vacuum drying 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 at 65 ℃ for 3h, naturally cooling for crystallization, performing suction filtration, and vacuum drying at 50 ℃ to constant weight to obtain 90g of solid powder, wherein the yield is 90%, the purity is 99.93%, the maximum single impurity (impurity C) is 0.016%, and the total impurity content is 0.07%.
Through the examples 4-9, the crude olaparib product is crystallized by a mixed solvent of methyl tertiary ether and acetonitrile (volume ratio is 1: 1-15), and then recrystallized by a mixed solvent of dichloromethane and organic alcohol (volume ratio is 1: 0.5-5), the purity of the obtained crystal can reach more than 99.93%, the content of impurity C can be controlled within 0.02%, and the content of total impurities is controlled within 0.07%.
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 (8)

1. A recrystallization method of olaparib is characterized by comprising the following steps:
1) adding the crude Olaparib product into a mixed solvent of methyl tertiary ether and acetonitrile, mixing, heating and refluxing, keeping the temperature at 60-95 ℃ for 3-5h, and cooling to 20-40 ℃ for crystallization;
2) adding the crystals obtained in step 1) to ethyl acetate and C1-5Mixing with mixed solvent of alcohol, heating and refluxing, keeping the temperature at 40-80 deg.C for 0.5-3h, cooling, recrystallizing, filtering, and adding C1-5Washing with alcohol, and drying at 40-70 deg.C;
the recrystallization method is used for removing impurities in crude Olaparib;
the impurities include, but are not limited to, olaparib impurity C of the structure:
Figure FDA0003016800080000011
2. the recrystallization method as claimed in claim 1, wherein the volume liter amount of the mixed solvent in the step 1) is 6 to 20 times the mass gram amount of the crude olaparib.
3. The recrystallization method as claimed in claim 2, wherein the volume liter amount of the mixed solvent in the step 1) is 6 to 12 times the mass gram amount of the crude olaparib.
4. The recrystallization method according to claim 1, wherein the volume ratio of methyl tert-ether to acetonitrile in step 1) is 1:1 to 15.
5. The recrystallization method according to claim 4, wherein the volume ratio of methyl tert-ether to acetonitrile in step 1) is 1:1 to 5.
6. The recrystallization method according to claim 1, wherein the mixed solvent of step 2) is composed of ethyl acetate and C1-5The volume ratio of the alcohol is 1: 0.5-5.
7. The recrystallization method according to claim 6, wherein the mixed solvent of step 2) is composed of ethyl acetate and C1-5The volume ratio of the alcohol is 1: 0.5-2.
8. The recrystallization method according to claim 1, wherein the holding temperature in step 1) is 60 to 70 ℃.
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CA3031777A1 (en) 2018-01-31 2019-07-31 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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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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