CN111004244A - Synthetic method of Ruipafebu camphorsulfonate - Google Patents
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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- C07C303/22—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof from sulfonic acids, by reactions not involving the formation of sulfo or halosulfonyl groups; from sulfonic halides by reactions not involving the formation of halosulfonyl groups
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Abstract
A synthetic method of Ruipafebrium camphorsulfonate comprises the following steps: 1) reacting the compound M-1 with pyridinium tribromide by using tetrahydrofuran and/or dichloromethane as a solvent to obtain a compound M-2; 2) taking N, N-dimethylacetamide as a solvent, reacting the compound M-2 with p-formylphenylboronic acid under the catalysis of 1, 1' -bis (diphenylphosphino) ferrocene palladium dichloride to obtain a compound M-3, wherein the reaction temperature is more than or equal to 90 ℃; 3) taking methanol and/or ethanol as a solvent, reacting the compound M-3 with methylamine under the catalysis of p-toluenesulfonic acid, and then adding sodium borohydride for reduction to obtain a compound M-4; 4) reacting the compound M-4 with alkali by using water as a solvent to obtain a compound M-5; 5) and (3) taking methanol and/or ethanol as a solvent, and reacting the compound M-5 with camphorsulfonic acid to obtain the licarpan camphorsulfonate. The compounds M-1, M-3 and M-4 of the invention all react at room temperature, the conditions are mild and controllable, the reaction period is short, the synthesis efficiency can be effectively improved, the production cost is reduced, and the purity of the obtained product reaches 99.95-99.98%.
Description
Technical Field
The invention relates to the field of medicines, and particularly relates to a synthetic method of Ruipafenib camphorsulfonate.
Background
Polyadenosyldiphosphribose polymerase (PARP) is a family of ribozymes responsible for ADP-ribosylation, in which a poly ADP-ribosyltransferase cleaves ADP-ribose moieties from NAD+Transfer to nuclear target protein repairThe side chain of a particular amino acid in the enzyme is transferred to a previously attached ADP-ribose unit. The PARP family in humans comprises 17 enzymes, of which PARP-1 is best characterized.
Rucapebamamphosulfonate (Rucaparib Camsylate) as a phosphoribosyl polymerase (PARP) inhibitor can selectively kill tumor cells with defective homologous recombination function, and has less harm to normal cells.
Rucaparib was given U.S. FDA accelerated approval to market at month 2016, for the treatment of advanced ovarian cancer patients who have undergone two or more chemotherapy treatments and whose tumors have specific genetic mutations.
Rucaparib is the second adenosine diphosphate ribose polymerase (PARP) inhibitor marketed in the United states following Ashlika Olaparib 2014 (trade name: Lynparza). Phosphate was used in early clinical trials, in which it was administered intravenously. However, because of its ease of hydration, it is desirable to use another salt in tablet formulations, and (S) -camphorsulfonate has more stable physical properties, is less hygroscopic, compressible, and has a higher melting point than several other salts ((R) -camphorsulfonate, maleate, and trihydrate hydrochloride).
Currently, there are two major routes for the synthesis of Rucapebabu Camsylate (Rucaparib Camsylate) from M-1:
a first circuit:
according to the description in WO2018140377A1, the route is a convergent synthesis route, but in the suzuki reaction, the aminomethyl group can generate substitution reaction with bromide, and more impurities are formed, so that the control of the reaction is not facilitated.
A second circuit:
adam Thomas Gillmore, Matthew Badland, Clare L look, et. organic Process research & Development 2012,16.1897-1904. the line is a straight line synthesis line, although the synthesis line is long, each site is easy to control, which is beneficial to the control of product quality. However, the synthesis method generates more impurities, the product is not suitable for refining and qualified, the content of a single impurity cannot reach 0.1%, the medicinal requirement cannot be met, the total yield is only 42.14%, and the utilization rate of raw materials is low.
Disclosure of Invention
The invention aims to provide a synthetic method of Ruipafebrium camphorsulfonate aiming at the defects of the prior art, wherein compounds M-1, M-3 and M-4 of the Ruipafebrium camphorsulfonate are reacted under the room temperature condition (10-30 ℃), the conditions are mild and controllable, the reaction period is short, the synthetic efficiency can be effectively improved, the production cost is reduced, and the purity of the obtained product reaches 99.95-99.98%.
The technical scheme of the invention is as follows: the synthesis method of the Ruipafebrium camphorsulfonate comprises the following steps:
1) taking tetrahydrofuran and/or dichloromethane as a solvent, reacting the compound M-1 with pyridinium tribromide to obtain a compound M-2, wherein the structural formula of the compound M-1 is shown in the specification
2) Taking N, N-dimethylacetamide as a solvent, reacting the compound M-2 with p-formylphenylboronic acid under the catalysis of 1, 1' -bis (diphenylphosphino) ferrocene palladium dichloride to obtain a compound M-3, wherein the reaction temperature is more than or equal to 90 ℃;
3) taking methanol and/or ethanol as a solvent, reacting the compound M-3 with methylamine under the catalysis of p-toluenesulfonic acid, and then adding sodium borohydride for reduction to obtain a compound M-4;
4) reacting the compound M-4 with alkali by using water as a solvent to obtain a compound M-5;
5) and (3) taking methanol and/or ethanol as a solvent, and reacting the compound M-5 with camphorsulfonic acid to obtain the licarpan camphorsulfonate.
That is, the reaction flow of the present invention is:
further, the reaction temperature of the step 1) is 10-30 ℃, and the molar ratio of the compound M-1 to the pyridinium tribromide is 1: 1.2, after the reaction is finished, carrying out suction filtration, adding a filter cake into a 5% sodium bicarbonate aqueous solution, stirring, carrying out suction filtration, washing the filter cake with water to be neutral, and drying to obtain a compound M-2 with the yield of 90-92%.
Further, the reaction of step 2) is carried out under the protective atmosphere, the reaction temperature is 90-100 ℃, the solvent is a mixed solution of N, N-dimethylacetamide and water, after the reaction is finished, the temperature is reduced to 10-30 ℃, water is added for crystallization, then the filtration is carried out, the filter cake is washed to be neutral by water, the drying is carried out, ethanol is added for stirring at the temperature of 75-80 ℃, the temperature is reduced to 10-30 ℃, the filtration is carried out, the filter cake is dried to obtain the compound M-3, and the yield is 93-95%.
Further, the reaction temperature of the step 3) is 10-30 ℃, and the molar ratio of the compound M-3, methylamine and sodium borohydride is 1: 2: and 2, adding methylamine into methylamine ethanol solution in batches, adding sodium borohydride into the methylamine ethanol solution in batches, reducing the solution for 1 hour, adding hydrochloric acid into the solution to quench the solution, distilling the solution to remove a solvent, performing suction filtration, drying a filter cake to obtain a M-4 crude product, adding the M-4 crude product into ethanol, stirring the mixture, heating the mixture to 65-70 ℃, adding water into the mixture, cooling the mixture to 10-30 ℃, stirring the mixture, filtering the mixture, and drying the mixture to obtain a compound M-4, wherein the purity of the M-4 is 99.5-99.8%, and the yield is 90-92%.
Further, the alkali in the step 4) is sodium hydroxide solution, the reaction temperature is 10-30 ℃, the sodium hydroxide solution is added dropwise, after the reaction is finished, the filtration is carried out, the filter cake is washed by water to be neutral, and the compound M-5 is obtained by drying, wherein the yield is 90-92%.
Further, the camphorsulfonic acid in the step 5) is a methanol-camphorsulfonic acid solution, and is added dropwise, after the dropwise addition, the temperature is raised to 75-80 ℃, after the reaction is finished, water is added dropwise, the solution is dissolved clearly, decolored and filtered, the filtrate is cooled to 10-30 ℃ for crystallization, the filtrate is filtered, and the filter cake is dried to obtain the white-like solid Ruipaba camphorsulfonate with the yield of 88-90%.
Adopt above-mentioned technical scheme to have following beneficial effect:
1. the method has the advantages that the reaction period of each step is short, the synthesis efficiency can be effectively improved, the multi-step reaction is carried out at room temperature (10-30 ℃), the reaction condition is mild and controllable, and the production cost of the licarpan camphorsulfonate can be effectively reduced.
2. The purity of the finally obtained white solid Ruipafebu camphorsulfonate reaches 99.95-99.98%, and the single impurity is less than 0.1%, so that the pharmaceutical requirements can be effectively met.
3. The final synthesized Ruipafeba camphorsulfonate has the yield of 60-65%, high utilization rate of raw materials and effectively reduced production cost.
The following is a further description with reference to specific examples.
Detailed Description
The details of the main compounds used in the present invention are shown in the following table
Example one
The method comprises the following steps: compound M-1(80g, 0.392mol) was added to 600mL of tetrahydrofuran, followed by pyridinium tribromide (150.36g, 0.468mol) and reacted at 10 ℃ for 1 hour, followed by suction filtration, the cake was added to a 5% aqueous sodium bicarbonate solution (400mL), stirred for 1 hour, then suction filtered, the cake was washed with water (200mL), and air-dried to give a pale yellow compound M-2(100.54g) with a yield of 90.65%.
Step two: compound M-2(90g, 0.318mol) was added to a mixed solution of 900mL of N-dimethylacetamide and 135mL of water, and p-formylphenylboronic acid (57.20g, 0.382mol), sodium carbonate (84.24g, 0.795mol) and Pd (dppf) Cl were added2(6.98g, 9.54mmol), heating to 90-100 ℃ for reaction for 2h (the process is carried out under the protection of nitrogen), after the reaction is finished, adding water (1800mL), crystallizing at 10 ℃ for 1h, then carrying out suction filtration, washing a filter cake with water to be neutral, drying, adding into absolute ethyl alcohol (720mL), stirring at 75-80 ℃ for 1h, cooling to room temperature, carrying out suction filtration, and carrying out vacuum drying on the filter cakePale yellow compound M-3(91.93g) was obtained in 93.80% yield.
Step three: adding a compound M-3(85g, 0.292mol) into 3780mL of absolute ethyl alcohol, adding p-toluenesulfonic acid (0.85g, 4.94mmol) and a 30% methylamine ethanol (60.44g, 0.584mol) solution, reacting at 10 ℃ for 2h, adding sodium borohydride (22.09g, 0.584mol) in batches, reacting for 1h, adding a hydrochloric acid aqueous solution (concentrated hydrochloric acid 340mL + water 1360mL), quenching, distilling to remove tetrahydrofuran and absolute ethyl alcohol, filtering, drying to obtain a crude M-4 product, adding the crude M-4 product into 580mL of ethanol, stirring and heating to 65-70 ℃, adding water (190mL), cooling to 10-30 ℃, stirring, filtering, and drying to obtain a compound M-4(90.77g), wherein the yield is 91.5%.
Step four: the compound M-4(75g, 0.208mol) was added to water (1500mL), 40% sodium hydroxide solution (9.17g NaOH in 13.76g water) was added dropwise, stirred at 10 ℃ for 2h and filtered, the filter cake was washed with water to neutrality, and the filter cake was dried under vacuum to give M-5(61.22g) as a white solid with a yield of 90.83%.
Step five: adding a compound M-5(50g, 0.155mol) into methanol (300mL), dropwise adding a methanol (100mL) -camphorsulfonic acid (39.51g, 0.170mol) solution, heating to 60-65 ℃ after dropwise adding, stirring for 30min, dropwise adding water (130mL) to dissolve the solution, adding activated carbon to decolorize for 1h after the solution is clear, then carrying out suction filtration, cooling the filtrate to 10 ℃ for crystallization for 2h, carrying out suction filtration, and drying a filter cake to obtain a white-like crystal Ruipababucamphorsulfonate (77.21g), wherein the purity is 99.98%, the yield is 89.86%, and the overall yield is 63.5%.
Example two
The method comprises the following steps: taking the compound M-1(80g, 0.39mol), adding the compound into 600mL tetrahydrofuran, then adding pyridinium tribromide (150.36g, 0.468mol), reacting at 20 ℃ for 1h, then carrying out suction filtration, adding the filter cake into a 5% sodium bicarbonate aqueous solution, stirring for 1h, carrying out suction filtration, washing the filter cake with water to be neutral, and carrying out forced air drying to obtain a light yellow compound M-2(101.29g) with the yield of 91.23%.
Step two: compound M-2(90g, 0.318mol) was added to a mixed solution of 900mL of N, N-dimethylacetamide and 135mL of water, and p-formylphenylboronic acid (57.20g, 0.382mol) and sodium carbonate (8 mol) were added4.24g, 0.795mol) and Pd (dppf) Cl2(6.98g, 9.54mmol), heating to 90-100 ℃ for reaction for 2h (the process is carried out under the protection of nitrogen), after the reaction is finished, adding water (1800mL), crystallizing at 10 ℃ for 1h, then carrying out suction filtration, washing a filter cake with water to be neutral, drying, adding the filter cake into absolute ethyl alcohol (720mL), stirring at 75-80 ℃ for 1h, cooling to room temperature, carrying out suction filtration, and carrying out vacuum drying on the filter cake to obtain a light yellow compound M-3(92.33g), wherein the yield is 94.21%.
Step three: adding a compound M-3(85g, 0.292mol) into 3780mL of absolute ethyl alcohol, adding p-toluenesulfonic acid (0.85g, 4.94mmol) and a 30% methylamine ethanol (60.44g, 0.584mol) solution, reacting at 10 ℃ for 2h, adding sodium borohydride (30.02g, 0.794mol) in batches, reacting for 1h, adding a hydrochloric acid aqueous solution (340 mL of concentrated hydrochloric acid and 1360mL of water), quenching, distilling to remove tetrahydrofuran and absolute ethyl alcohol, filtering, drying to obtain a crude M-4 product, adding the crude M-4 product into 580mL of ethanol, stirring and heating to 65-70 ℃, adding water (190mL), cooling to 10-30 ℃, stirring, filtering, drying to obtain a white solid M-4 (89.78g), wherein the yield is 90.5%.
Step four: taking the compound M-4(75g, 0.208mol), adding the compound into water (1500mL), dropwise adding 40% sodium hydroxide solution (9.17g NaOH is added into 13.76g water), stirring at 10 ℃ for 2h, then carrying out suction filtration, adding water into a filter cake, washing the filter cake to be neutral, and carrying out vacuum drying on the filter cake to obtain white solid M-5(62.06g) with the yield of 92.08%.
Step five: adding a compound M-5(50g, 0.155mol) into a methanol (300mL) solution, dropwise adding a methanol (100mL) -camphorsulfonic acid (39.51g, 0.170mol) solution, heating to 60-65 ℃ after dropwise adding, stirring for 30min, dropwise adding water (130mL) to dissolve the solution, adding activated carbon to decolor for 1h after dissolving, then performing suction filtration, cooling the filtrate to 10 ℃ for crystallization for 2h, performing suction filtration, and drying a filter cake to obtain a white-like crystal Ruipababucamphorsulfonate (76.18g), wherein the purity is 99.97%, the yield is 88.67%, and the overall yield is 63.5%.
Claims (6)
1. The synthesis method of the Ruipafenac camphorsulfonate is characterized by comprising the following steps:
1) taking tetrahydrofuran and/or dichloromethane as solventThe compound M-1 reacts with pyridinium tribromide to obtain a compound M-2, wherein the structural formula of the compound M-1 is shown in the specification
2) Taking N, N-dimethylacetamide as a solvent, reacting the compound M-2 with p-formylphenylboronic acid under the catalysis of 1, 1' -bis (diphenylphosphino) ferrocene palladium dichloride to obtain a compound M-3, wherein the reaction temperature is more than or equal to 90 ℃;
3) taking methanol and/or ethanol as a solvent, reacting the compound M-3 with methylamine under the catalysis of p-toluenesulfonic acid, and then adding sodium borohydride for reduction to obtain a compound M-4;
4) reacting the compound M-4 with alkali by using water as a solvent to obtain a compound M-5;
5) and (3) taking methanol and/or ethanol as a solvent, and reacting the compound M-5 with camphorsulfonic acid to obtain the licarpan camphorsulfonate.
2. The synthesis process according to claim 1, wherein the reaction temperature in step 1) is 10-30 ℃ and the molar ratio of compound M-1 to pyridinium tribromide is 1: 1.2, after the reaction is finished, carrying out suction filtration, adding the filter cake into a 5% sodium bicarbonate aqueous solution, stirring, carrying out suction filtration, washing the filter cake with water to be neutral, and drying to obtain a compound M-2.
3. The synthesis method of claim 1, wherein the reaction in step 2) is carried out under a protective atmosphere, the reaction temperature is 90-100 ℃, the solvent is a mixed solution of N, N-dimethylacetamide and water, after the reaction is finished, the temperature is reduced to 10-30 ℃, water is added for crystallization, then the filtration is carried out, the filter cake is washed to be neutral by water, the drying is carried out, ethanol is added for stirring at 75-80 ℃, the temperature is reduced to 10-30 ℃, the filtration is carried out, and the filter cake is dried to obtain the compound M-3.
4. The synthesis method according to claim 1, wherein the reaction temperature in step 3) is 10-30 ℃, and the molar ratio of the compound M-3, methylamine and sodium borohydride is 1: 2: and 2, adding methylamine into methylamine ethanol solution in batches, adding sodium borohydride into the methylamine ethanol solution in batches, reducing the solution for 1h, adding hydrochloric acid into the solution to quench the solution, distilling the solution to remove a solvent, performing suction filtration, drying a filter cake to obtain a M-4 crude product, adding the M-4 crude product into ethanol, stirring and heating the mixture to 65-70 ℃, adding water into the mixture, cooling the mixture to 10-30 ℃, stirring the mixture, filtering the mixture, and drying the mixture to obtain a compound M-4.
5. The synthesis method of claim 1, wherein the alkali in the step 4) is sodium hydroxide solution, the reaction temperature is 10-30 ℃, the sodium hydroxide solution is added dropwise, after the reaction is finished, the filtration is carried out, the filter cake is washed to be neutral by adding water, and the compound M-5 is obtained by drying.
6. The synthesis method of claim 1, wherein the camphorsulfonic acid in the step 5) is methanol-camphorsulfonic acid solution, and is added dropwise, after the dropwise addition, the temperature is raised to 75-80 ℃, after the reaction is finished, water is added dropwise, the solution is decolored, filtered, the filtrate is cooled to 10-30 ℃ for crystallization, filtered, and the filter cake is dried to obtain the white-like solid rebamipramic acid salt.
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Citations (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101027306A (en) * | 2004-09-22 | 2007-08-29 | 辉瑞有限公司 | Method of preparing poly(ADP-ribose) polymerases inhibitors |
CN101133061A (en) * | 2004-09-22 | 2008-02-27 | 辉瑞有限公司 | Polymorphic and amorphous forms of the phosphate salt of 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6h-azepino[5,4,3-ce]indol-6-one |
CN102884066A (en) * | 2010-02-12 | 2013-01-16 | 辉瑞公司 | Salts and polymorphs of 8-fluoro-2-{4-[(methylamino}methyl]phenyl}-1,3,4,5-tetrahydro-6h-azepino[5,4,3-cd]indol-6-one |
WO2018140377A1 (en) * | 2017-01-24 | 2018-08-02 | Assia Chemical Industries Ltd. | Solid state forms of rucaparib and of rucaparib salts |
WO2019020508A1 (en) * | 2017-07-26 | 2019-01-31 | Olon S.P.A. | Method for the preparation of high-purity rucaparib |
CN109824677A (en) * | 2019-04-03 | 2019-05-31 | 江苏开元药业有限公司 | The preparation method for treating ovarian cancer Rui Kapabu |
WO2019130229A1 (en) * | 2017-12-28 | 2019-07-04 | Mylan Laboratories Ltd | Methods and intermediates for preparing rucaparib |
US20190233428A1 (en) * | 2018-01-30 | 2019-08-01 | RK Pharma Solutions LLC | Polymorphs of rucaparib camsylate and methods of making same |
CN110229162A (en) * | 2018-03-05 | 2019-09-13 | 新发药业有限公司 | A kind of simple and convenient process for preparing of Rui Kapabu |
WO2019207596A1 (en) * | 2018-04-25 | 2019-10-31 | Mylan Laboratories Limited | Novel crystalline forms of rucaparib (s)-camsylate salt and rucaparib free base |
WO2019207498A1 (en) * | 2018-04-25 | 2019-10-31 | Biophore India Pharmaceuticals Pvt. Ltd | Solid forms of 8-fluoro-2-{4-[(methylamino)methyl] phenyl}-1,3,4,5-tetrahydro-6h-azepino[5,4,3-cd] indol-6-one ((1s,4r)-7,7dimethyl-2-oxobicyclo [2.2.1] hept-1-yl) methanesulfonic acid salt (rucaparib camsylate) and the prerparation thereof |
-
2019
- 2019-12-27 CN CN201911373692.3A patent/CN111004244A/en not_active Withdrawn
Patent Citations (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101027306A (en) * | 2004-09-22 | 2007-08-29 | 辉瑞有限公司 | Method of preparing poly(ADP-ribose) polymerases inhibitors |
CN101133061A (en) * | 2004-09-22 | 2008-02-27 | 辉瑞有限公司 | Polymorphic and amorphous forms of the phosphate salt of 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6h-azepino[5,4,3-ce]indol-6-one |
CN102884066A (en) * | 2010-02-12 | 2013-01-16 | 辉瑞公司 | Salts and polymorphs of 8-fluoro-2-{4-[(methylamino}methyl]phenyl}-1,3,4,5-tetrahydro-6h-azepino[5,4,3-cd]indol-6-one |
WO2018140377A1 (en) * | 2017-01-24 | 2018-08-02 | Assia Chemical Industries Ltd. | Solid state forms of rucaparib and of rucaparib salts |
US20190389871A1 (en) * | 2017-01-24 | 2019-12-26 | Assia Chemical Industries Ltd. | Solid state forms of rucaparib and of rucaparib salts |
WO2019020508A1 (en) * | 2017-07-26 | 2019-01-31 | Olon S.P.A. | Method for the preparation of high-purity rucaparib |
WO2019130229A1 (en) * | 2017-12-28 | 2019-07-04 | Mylan Laboratories Ltd | Methods and intermediates for preparing rucaparib |
US20190233428A1 (en) * | 2018-01-30 | 2019-08-01 | RK Pharma Solutions LLC | Polymorphs of rucaparib camsylate and methods of making same |
CN110229162A (en) * | 2018-03-05 | 2019-09-13 | 新发药业有限公司 | A kind of simple and convenient process for preparing of Rui Kapabu |
WO2019207596A1 (en) * | 2018-04-25 | 2019-10-31 | Mylan Laboratories Limited | Novel crystalline forms of rucaparib (s)-camsylate salt and rucaparib free base |
WO2019207498A1 (en) * | 2018-04-25 | 2019-10-31 | Biophore India Pharmaceuticals Pvt. Ltd | Solid forms of 8-fluoro-2-{4-[(methylamino)methyl] phenyl}-1,3,4,5-tetrahydro-6h-azepino[5,4,3-cd] indol-6-one ((1s,4r)-7,7dimethyl-2-oxobicyclo [2.2.1] hept-1-yl) methanesulfonic acid salt (rucaparib camsylate) and the prerparation thereof |
CN109824677A (en) * | 2019-04-03 | 2019-05-31 | 江苏开元药业有限公司 | The preparation method for treating ovarian cancer Rui Kapabu |
Non-Patent Citations (2)
Title |
---|
ADAM T. GILLMORE等: "Multkilogram Scale-Up of a Reductive Alkylation Route to a Novel PARP Inhibitor", 《ORG. PROCESS RES. DEV.》 * |
余从煊,欧育湘,温敬铨: "《物理有机化学》", 31 July 1991 * |
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