CN114591246A - Purification method of enzalutamide - Google Patents
Purification method of enzalutamide Download PDFInfo
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- CN114591246A CN114591246A CN202210305500.0A CN202210305500A CN114591246A CN 114591246 A CN114591246 A CN 114591246A CN 202210305500 A CN202210305500 A CN 202210305500A CN 114591246 A CN114591246 A CN 114591246A
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- enzalutamide
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- WXCXUHSOUPDCQV-UHFFFAOYSA-N enzalutamide Chemical compound C1=C(F)C(C(=O)NC)=CC=C1N1C(C)(C)C(=O)N(C=2C=C(C(C#N)=CC=2)C(F)(F)F)C1=S WXCXUHSOUPDCQV-UHFFFAOYSA-N 0.000 title claims abstract description 61
- 229960004671 enzalutamide Drugs 0.000 title claims abstract description 61
- 238000000746 purification Methods 0.000 title claims abstract description 35
- 238000000034 method Methods 0.000 title claims abstract description 23
- 239000011541 reaction mixture Substances 0.000 claims abstract description 33
- 239000002904 solvent Substances 0.000 claims abstract description 32
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims abstract description 21
- 238000001816 cooling Methods 0.000 claims abstract description 19
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims abstract description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000012535 impurity Substances 0.000 claims abstract description 9
- 238000002425 crystallisation Methods 0.000 claims abstract description 8
- 230000008025 crystallization Effects 0.000 claims abstract description 8
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229940126062 Compound A Drugs 0.000 claims description 15
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 15
- 150000001875 compounds Chemical class 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 2
- 238000009776 industrial production Methods 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 16
- 238000005406 washing Methods 0.000 description 9
- 238000010438 heat treatment Methods 0.000 description 8
- 230000010354 integration Effects 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 238000001035 drying Methods 0.000 description 7
- 239000012065 filter cake Substances 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 4
- 229940011051 isopropyl acetate Drugs 0.000 description 4
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- TYXKOMAQTWRDCR-UHFFFAOYSA-N 4-isothiocyanato-2-(trifluoromethyl)benzonitrile Chemical compound FC(F)(F)C1=CC(N=C=S)=CC=C1C#N TYXKOMAQTWRDCR-UHFFFAOYSA-N 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000009167 androgen deprivation therapy Methods 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- MLHUTKWFDCMHQO-UHFFFAOYSA-N methyl 2-[3-fluoro-4-(methylcarbamoyl)anilino]-2-methylpropanoate Chemical compound CNC(=O)C1=CC=C(NC(C)(C)C(=O)OC)C=C1F MLHUTKWFDCMHQO-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/86—Oxygen and sulfur atoms, e.g. thiohydantoin
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the field of chemical pharmacy, and particularly relates to a purification method of enzalutamide. The invention provides a purification method of enzalutamide, which comprises the following steps: dissolving the enzalutamide reaction mixture in a good solvent, adding a poor solvent, and cooling for crystallization; the good solvent at least comprises methanol or ethanol; the poor solvent at least comprises any one of n-hexane, n-heptane and cyclohexane; the enzalutamide reaction mixture includes enzalutamide and polymeric impurities. The purification method is simple and easy to operate, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the field of chemical pharmacy, and particularly relates to a purification method of enzalutamide.
Background
Enzalutamide (formula I), chemically known as 4- {3- [ 4-cyano-3- (trifluoromethyl) phenyl ] -5, 5-dimethyl-4-oxo-2-thioneimidazol-1-yl } -2-fluoro-N-methylbenzamide, was developed by Medivation, Inc in cooperation with Astellas pharmaceutical limited (Astellas) and marketed in the us in 2012 under the trade name xtani for the treatment of adult metastatic castration-resistant prostate cancer (CRPC) patients who are asymptomatic or mildly symptomatic after failure of Androgen Deprivation Therapy (ADT) and who have not received chemotherapy.
At present, a plurality of reports of methods for synthesizing enzalutamide exist, such as methods of patents WO2006124118, CN201410407389, CN201410162985, CN201410036169, CN201180020668 and the like; however, the reports of the purification method of enzalutamide are few, patent WO2006124118 reports that enzalutamide is obtained by purification with a silica gel chromatographic column, and does not mention the purity, patent CN201410162985 reports that enzalutamide with the purity of 99.5% is obtained by crystallization with isopropanol, and does not mention the problems of related substances.
The HPLC purity of the enzalutamide reaction liquid mixture is only about 60 percent, and the conventional method for removing the polymeric impurity (formula II) is difficult, so that the method for purifying the enzalutamide by simple operation is necessary to meet the requirement of industrial production.
The patent CN111386257A mentions the purification process of enzalutamide, the synthetic route of which is inconsistent with that of the present invention, and the impurity spectrum is inconsistent; the purification method of this patent, which uses only an alcohol solvent as a crystallization solvent, has no ability to remove the above-mentioned impurities (compound of formula II).
Disclosure of Invention
The invention aims to provide a purification method of enzalutamide, which is simple and easy to operate and is suitable for industrial production.
In order to achieve the purpose, the invention adopts the following technical scheme:
the purification method comprises the following steps: dissolving the enzalutamide reaction mixture in a good solvent, adding a poor solvent, and cooling for crystallization; the good solvent at least comprises methanol or ethanol; the poor solvent at least comprises any one of n-hexane, n-heptane and cyclohexane; the enzalutamide reaction mixture comprises enzalutamide and polymeric impurities; the structural formula of the enzalutamide is shown as a formula I, and the structural formula of the polymerized impurity structure is shown as a formula II;
further, the conditions for dissolving the enzalutamide reaction mixture in a good solvent are as follows: controlling the temperature to be 50-80 ℃ for dissolution.
Further, the condition of adding the poor solvent is as follows: controlling the temperature to be 50-80 ℃ and dripping.
Further, the cooling crystallization is followed by filtration and drying.
Further, the good solvent is preferably ethanol.
Further, the poor solvent is preferably n-hexane.
Further, the enzalutamide reaction mixture is prepared by reacting a compound A and a compound B; the structural formula of the compound A is shown in the formula III, and the structural formula of the compound B is shown in the formula IV; the reaction is as follows:
according to the preparation method of patent document CN201180020668, the compound 2- [ 3-fluoro-4- (methylcarbamoyl) phenylamino ] -2-methyl propionic acid methyl ester (formula III) and the compound 4-isothiocyanato-2- (trifluoromethyl) benzonitrile (formula IV) are subjected to cyclization reaction, and the enzalutamide reaction mixture is prepared by washing and distillation.
Further, the dosage of the good solvent is based on the dosage of the compound A, and specifically comprises the following components: 4 ml-10 ml of good solvent corresponding to 1g of the compound A.
Further, the amount of the good solvent corresponding to 1g of Compound A was 6 ml.
Further, the dosage of the poor solvent is based on the dosage of the compound A, and specifically comprises the following components: 4ml to 30ml of poor solvent corresponding to 1g of the compound A.
Further, the amount of the poor solvent corresponding to 1g of the compound A was 18 ml.
Further, the cooling crystallization conditions are as follows: the temperature reduction time is controlled to be 3 to 6 hours.
Further, preferably, the temperature reduction time is controlled to be 4 to 5 hours.
The invention has the advantages that:
1. the invention provides a purification method of enzalutamide, which can purify an enzalutamide reaction mixture with the purity of 60% to the purity of more than 99.5% at one time.
2. The purification method provided by the invention has an excellent effect of removing polymeric impurities (formula II), and the prepared enzalutamide monohybrid HPLC is less than 0.15%.
3. The purification method provided by the invention is simple and easy to operate, has low requirements on equipment and can quickly obtain a high-purity product.
Drawings
FIG. 1 is an HPLC chart of the reaction mixture of Enzalutamide of example 1;
FIG. 2 is an HPLC chart of purified enzalutamide of example 2;
FIG. 3 is an HPLC chart of the reaction mixture of example 7 enzalutamide;
figure 4 is an HPLC profile of purified enzalutamide from example 7.
Detailed Description
The following describes in detail preferred embodiments of the present invention. The examples are provided for better illustration of the present invention, but the present invention is not limited to the examples. Therefore, those skilled in the art should make insubstantial modifications and adaptations to the embodiments of the present invention in light of the above teachings and remain within the scope of the invention.
Example 1 preparation of Enzalutamide reaction mixture
Dissolving 20g (74.5mmol) of the compound shown in the formula III in 20ml of dimethyl sulfoxide and 40ml of isopropyl acetate, adding 34g (149.1mmol) of the compound shown in the formula IV, heating to 80-90 ℃, controlling the temperature to 80-90 ℃ to react for 12 hours, cooling to room temperature, adding 100ml of isopropyl acetate and 100ml of water to stir, separating, discarding the water phase, washing the organic phase with 100ml of water, separating, discarding the water phase, and evaporating the organic solvent under reduced pressure at 50 ℃ to obtain the remainder which is the enzalutamide reaction mixture.
The enzalutamide reaction mixture HPLC is shown in fig. 1, and the integration results are shown in table 1.
TABLE 1 Enzalutamide reaction mixture HPLC integration results
Example 2 purification of Enzalutamide reaction mixture
Adding 100ml of ethanol into the enzalutamide reaction mixture prepared in the embodiment 1, heating to 70 ℃, stirring for dissolving, controlling the temperature to be 60-70 ℃, dropwise adding 200ml of n-hexane, slowly cooling to 0 ℃ after dropwise adding, controlling the cooling time to be 4 hours, filtering, washing a filter cake by using n-hexane, and drying at 50 ℃ to obtain 27.5g, wherein the yield is as follows: 79.5 percent.
The HPLC of purified enzalutamide is shown in fig. 2, and the integration results are shown in table 2.
TABLE 2 HPLC integration results of purified enzalutamide
Example 3 purification of Enzalutamide reaction mixture
Adding 120ml of ethanol into the enzalutamide reaction mixture prepared in the example 1, heating to 70 ℃, stirring to dissolve, controlling the temperature to be 60-70 ℃, dropwise adding 200ml of n-heptane, slowly cooling to 0 ℃, controlling the cooling time to be 4 hours, filtering, washing a filter cake with n-heptane, and drying at 50 ℃ to obtain 26.0g of the product with yield: 75.1 percent.
Example 4 purification of Enzalutamide reaction mixture
Adding 80ml of methanol into the enzalutamide reaction mixture prepared in the example 1, heating to 60 ℃, stirring to dissolve, controlling the temperature to be 50-65 ℃, dropwise adding 160ml of cyclohexane, slowly cooling to 0 ℃ after dropwise adding, controlling the cooling time to be 6 hours, filtering, washing a filter cake by cyclohexane, and drying at 50 ℃ to obtain 26.9g of filter cake, wherein the yield is as follows: 77.7 percent.
Example 5 purification of Enzalutamide reaction mixture
Adding 160ml of methanol into the enzalutamide reaction mixture prepared in the example 1, heating to 70 ℃, stirring for dissolving, controlling the temperature to be 60-70 ℃, dropwise adding 160ml of n-heptane, after dropwise adding, slowly cooling to 0 ℃, controlling the cooling time to be 4 hours, filtering, washing a filter cake with n-heptane, and drying at 50 ℃ to obtain 24.9g, wherein the yield is as follows: 72.0 percent.
Example 6 preparation and purification of Enzalutamide reaction mixture
Dissolving 100g (0.37mol) of the compound shown in the formula III in 100ml of dimethyl sulfoxide and 200ml of isopropyl acetate, adding 170.1g (0.75mol) of the compound shown in the formula IV, heating to 80-90 ℃, controlling the temperature to 80-90 ℃ to react for 11 hours, cooling to room temperature, adding 500ml of isopropyl acetate and 500ml of water to stir, separating, discarding the water phase, washing the organic phase with 500ml of water, separating, discarding the water phase, and evaporating the organic solvent at 50 ℃ under reduced pressure to obtain the remainder, namely the enzalutamide reaction mixture.
Adding 600ml of ethanol into the enzalutamide reaction mixture, heating to 70 ℃, stirring for dissolving, controlling the temperature to be 60-70 ℃, dropwise adding 1800ml of n-hexane, slowly cooling to 0 ℃, controlling the cooling time to be 4 hours after dropwise adding, filtering, washing a filter cake by using n-hexane, and drying at 50 ℃ to obtain 142.5g, wherein the yield is as follows: 82.3 percent.
Example 7 purification of Enzalutamide reaction mixture (see CN201180020668 purification method)
Adding 220ml of isopropanol into the enzalutamide reaction mixture prepared in example 1, heating to 70 ℃, stirring to dissolve, slowly cooling to 0 ℃, controlling the cooling time to be 4 hours, filtering, washing a filter cake with isopropanol, and drying at 50 ℃ to obtain 24.0g of the product with yield: 69.4 percent.
The enzalutamide reaction mixture HPLC is shown in fig. 3, and the integration results are shown in table 3.
TABLE 3 HPLC INTEGRATION OF ENZUMU AMINE REACTION MIXTURES
The HPLC of purified enzalutamide is shown in fig. 4, and the integration results are shown in table 4.
TABLE 4 HPLC integration results of purified enzalutamide
Examples 2-7 enzalutamide HPLC purity before and after purification and formula II compound HPLC purity before and after purification, as shown in table 5 below.
TABLE 5 comparison of results before and after purification of Enzalutamide reaction mixture
Claims (10)
1. A purification method of enzalutamide, comprising: dissolving the enzalutamide reaction mixture in a good solvent, adding a poor solvent, and cooling for crystallization; the good solvent at least comprises methanol or ethanol; the poor solvent at least comprises any one of n-hexane, n-heptane and cyclohexane; the enzalutamide reaction mixture comprises enzalutamide and polymeric impurities; the structural formula of the enzalutamide is shown as a formula I, and the structural formula of the polymerized impurity structure is shown as a formula II;
2. the purification method according to claim 1, wherein the good solvent is ethanol.
3. The purification method according to claim 1, wherein the poor solvent is n-hexane.
4. The purification process according to claim 1, wherein the enzalutamide reaction mixture is prepared by reacting compound a and compound B; the structural formula of the compound A is shown in the formula III, and the structural formula of the compound B is shown in the formula IV; the reaction is as follows:
5. the purification method according to claim 4, wherein the amount of the good solvent is, based on the amount of the compound A, specifically: 4 ml-10 ml of good solvent corresponding to 1g of the compound A.
6. The purification process according to claim 5, wherein the amount of the good solvent corresponding to 1g of Compound A is 6 ml.
7. The purification process according to claim 4, wherein the amount of the poor solvent is, based on the amount of compound A: 4ml to 30ml of poor solvent corresponding to 1g of the compound A.
8. The purification process according to claim 7, wherein the amount of poor solvent corresponding to 1g of Compound A is 18 ml.
9. The purification method according to claim 1, wherein the conditions for temperature-reduced crystallization are as follows: the temperature reduction time is controlled to be 3 to 6 hours.
10. The purification method according to claim 9, wherein the controlled temperature reduction time is 4 to 5 hours.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115536591A (en) * | 2022-09-27 | 2022-12-30 | 爱斯特（成都）生物制药股份有限公司 | Method for preparing enzalutamide by continuous flow |
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Application publication date: 20220607 |