CN113773322B - Preparation method of Filgotinib - Google Patents
Preparation method of Filgotinib Download PDFInfo
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- CN113773322B CN113773322B CN202111323179.0A CN202111323179A CN113773322B CN 113773322 B CN113773322 B CN 113773322B CN 202111323179 A CN202111323179 A CN 202111323179A CN 113773322 B CN113773322 B CN 113773322B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
The invention discloses a preparation method of Filgotinib. The preparation method comprises the following steps: in a mixed solvent of an alcohol solvent and water, in the presence of a palladium catalyst and alkali, a compound A (N- (5-bromo- [1,2,4] triazolo [1,5-a ] pyridin-2-yl) cyclopropylformamide) and a compound B (4- [4- (4,4,5, 5-tetramethyl [1,3,2] dioxaborolan-2-yl) benzyl ] thiomorpholine-1, 1-dioxide) are reacted to obtain the catalyst. The preparation method has the advantages of environmental friendliness, low cost, simple and convenient operation, high product purity, low impurity content, contribution to industrialization and the like.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a preparation method of Filgotinib.
Background
Filgotinib is a JAK1 inhibitor, and has the chemical name of N- [5- [4- [ (1, 1-dioxo-4-thiomorpholinyl) methyl ] phenyl ] [1,2,4] triazolo [1,5-A ] pyridin-2-yl ] cyclopropanecarboxamide, and the chemical structural formula is as follows:
filgotinib is a novel once daily oral JAK kinase inhibitor that preferentially inhibits JAK 1. Jesseca @ (filling maleate 200mg and 100mg tablets) are marketed in the European Union and Japan for the treatment of Rheumatoid Arthritis (RA) 11 months in 2020, approved by the European Union Committee and the Japan Yard labor province. In addition, a new indication application for the oral JAK1 inhibitor Jyseleca (filigotib, 200mg) has been accepted and has been under scrutiny by the European Medicines Authority (EMA), which is intended for the treatment of: adult patients with moderate to severe Ulcerative Colitis (UC) who are inadequately responsive, unresponsive, or intolerant to conventional or biological therapies.
Filgotinib was first disclosed in patent CN102105471 and reported the following two synthetic routes:
the phosphorus tribromide with strong toxicity is used in the route 2, and is not suitable for industrial production.
In the route 1, the synthesis of Filgotinib is carried out by using a Suzuki reaction, the catalyst causes higher Pd residue, and meanwhile, the Filgotinib has poor solubility and the product is difficult to purify. In patent CN102105471, column chromatography is adopted to obtain the target product, which is not suitable for industrial production. The post-treatment mode of route 1 is improved in patent CN 102482273: adding compound B to a solution of compound A in 1, 4-dioxane/water (4/1), and adding K to the solution2CO3(2 eq.) and Pd (dppf) Cl2(0.03 eq.). The resulting mixture was stirred at N2Under the atmosphere at 90oC heating in oil bath for 16 hrs. After the reaction was completed, the Pd-removing reagent "1, 2-bis (diphenylphosphino) ethane" was added, and the reaction mixture was cooled and filtered. And suspending the filter cake in acetone, stirring, filtering, leaching with acetone, and drying. The resulting solid was suspended in water, aqueous HCl was added, the mixture was stirred at room temperature, and the resulting solution was filtered through celite. Then, adding NaOH aqueous solution into the filtrate to obtain suspension, stirring at room temperature, performing suction filtration, and leaching with water to obtain a crude product. Finally, the crude product is dissolved in THF/H2In O mixture, using Pd removing reagent at 50oC, filtering the suspension, concentrating to remove the organic solvent, adding water and methanol to the resulting slurry, stirring at room temperature, filtering, and drying to obtain Filgotinib.
The post-treatment process is complicated to operate, the used reaction solvent 1, 4-dioxane has high toxicity, the catalyst has high use amount, and the Filgotinib hydrochloride has poor solubility, so that the experimental operation is not easy to repeat. The byproduct "impurity 1" produced by the reaction is not easy to be removed in the above process, and in addition, THF is easy to generate peroxide during storage, and "impurity 2" is easy to be produced during the above Pd removal operation, and the two impurities can affect the product purity of Filgotinib.
Therefore, the technology for preparing the Filgotinib, which is environment-friendly, lower in cost, simple and convenient to operate, better in quality control and suitable for large-scale production, is urgently needed to be developed in the field.
Disclosure of Invention
The invention aims to solve the technical problems of environment unfriendliness, complex treatment, low product purity and the like in the preparation of Filgotinib in the prior art, and provides a preparation method of Filgotinib. The preparation method has the advantages of environmental friendliness, low cost, simplicity and convenience in operation, high product purity, contribution to industrialization and the like.
The invention provides a preparation method of Filgotinib, which comprises the following steps:
in a mixed solvent of an alcohol solvent and water, in the presence of a palladium catalyst and an alkali, carrying out the following reaction on a compound A and a compound B;
the alcoholic solvent may be any of those conventional in the art for carrying out such reactions, and is preferably C1~C5More preferably one or more of methanol, ethanol and isopropanol.
In the mixed solvent, the volume ratio of the alcohol solvent to water can be conventional in the art, and is preferably 1:1 to 20:1, for example, 4:1 or 10: 1.
The mixed solvent can be used in an amount which is conventional in the art for carrying out such a reaction, and preferably has a volume molar ratio of 2.0-4.0L/mol, for example, 2.78L/mol, to the compound A.
The palladium-based catalyst may be one which is used in the art to carry out such reactionsConventional palladium-based catalyst, preferably PdppfCl2、Pd(PPh3)2Cl2And Pd (OAc)2One or more of (a). The dosage of the palladium catalyst can be the conventional dosage for carrying out the reaction in the field, and the preferred molar ratio of the palladium catalyst to the compound A is 0.01-0.03.
The base may be a conventional base used in the art to carry out such reactions, preferably an alkali metal carbonate and/or an alkali metal bicarbonate. The alkali metal is preferably one or more of sodium, potassium and cesium. The carbonate of the alkali metal is preferably one or more of sodium carbonate, potassium carbonate and cesium carbonate. The bicarbonate of an alkali metal is preferably sodium bicarbonate and/or potassium bicarbonate.
The base may be used in an amount conventionally used in the art for carrying out such reactions, preferably in a molar ratio to compound a of 1.0 to 1.5, e.g., 1.22.
The amount of the compound B can be the conventional amount for carrying out the reaction in the field, and the molar ratio of the compound B to the compound A is preferably 0.9-1.2, for example, 1.03.
The reaction is preferably carried out in an atmosphere of protective gas. The protective gas is preferably nitrogen and/or argon.
The reaction temperature of the reaction is preferably 60 to 100 ℃, for example, 70 to 80 ℃.
The progress of the reaction can be monitored by monitoring methods conventional in the art (e.g., TLC, HPLC, or NMR), typically with the disappearance of compound a as the end point of the reaction. The reaction time can be 10-24 hours.
After the reaction is finished, the reaction preferably further comprises post-treatment. The post-treatment preferably comprises the steps of:
(1) after the reaction is finished, cooling and carrying out suction filtration to obtain a filter cake;
（2）65~80oc, dissolving the filter cake in a mixed solvent of acetonitrile and water, mixing with a palladium removal reagent, and performing suction filtration to obtain a filtrate; the volume mol ratio of the mixed solvent of acetonitrile and water to the compound A is preferably 15.0-20.0L/mol, for example, 178L/mol; in the mixed solvent of acetonitrile and water, the volume ratio of acetonitrile to water is preferably 2.0-8.0, for example, 7.0;
(3) concentrating the filtrate to a volume A of 0-10oC, carrying out suction filtration to obtain a final product; the volume molar ratio of the volume A to the compound A is 6.0-13.0L/mol (for example, 8.3-11.1L/mol).
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The positive progress effects of the invention are as follows:
1. the preparation method adopts the alcohol solvent with lower toxicity as the reaction solvent, so that the raw materials are completely converted, and the generated impurities are less;
2. the generation of the impurity 1 can be effectively reduced through nitrogen replacement, and the product purity can be improved;
3. the catalyst is less in usage amount, the residual amount of Pd in the crude product is reduced, and the reduction of the residue of Pd in the product is facilitated;
4. acetonitrile is used as a solvent in the Pd removing process, so that the generation of impurity 2 can be avoided, and the product purity can be improved;
5. the post-treatment process is simple and convenient, the operation is easy, and the product yield is high.
Detailed Description
The present invention will be explained in more detail with reference to examples, which are provided only for illustrating the technical solutions of the present invention and the spirit and scope of the present invention are not limited thereto. Unless otherwise indicated, percentages and parts are percentages and parts by weight.
The Pd residue detection method comprises the following steps: the microwave digestion instrument climbs to 190 by 30mins at the power of 800WoAnd C, keeping the temperature for 40mins, digesting the sample, diluting the sample after digestion, and measuring the content of Pd in the sample by using an inductively coupled plasma mass spectrometer (ICP-MS).
Example 1:
compound A (75.0g, 0.27mol), compound B (98.4g, 0.28mol), NaHCO3(27.7g， 0.33mol)、Pd(dppf)Cl2(2.0g, 2.7mmol), ethanol (600mL) and water (150mL) were added to a reaction flask, replaced with nitrogen, heated to 70-80 ℃ for 15-20 hrs, and followed by HPLC until the reaction was complete.
Cooling the reaction solution to 15-30 ℃, and stirring for 2-3 hr. And (4) carrying out suction filtration, leaching a filter cake by using ethanol (150mL multiplied by 2), and leaching by using water to obtain a crude product of Filgotinib.
Adding the crude Filgotinib into a reaction bottle, adding acetonitrile (4200mL) and water (600mL), and heating to 65-80 ℃ under stirringoC, obtaining a clear solution, adding a palladium removing reagent, and keeping the temperature for 60-70 DEGoC, stirring, performing suction filtration, leaching a filter cake with acetonitrile (75mL multiplied by 2), concentrating to 2250 mL-3000 mL, and reducing the volume to 0-10oC, stirring for 1-2 hrs. And (3) carrying out suction filtration, and leaching a filter cake with acetonitrile (150mL multiplied by 2) to obtain 98.5g of a white solid, wherein the HPLC purity is 99.7%, the yield is 86.8%, the content of the impurity 1 is 0.14%, the content of the impurity 2 is 0.05%, and the content of Pd is 2 ppm.
Example 2
Mixing compound A (7.50g, 27mmol), compound B (9.84g, 28mmol) and K2CO3(4.55g，33mmol)、Pd(dppf)Cl2(0.2g, 0.27mmol), isopropanol (60mL) and water (6mL) were added to a reaction flask, replaced with nitrogen, heated to 80-90 ℃ for 10-15 hrs, and followed by HPLC until the reaction was complete.
Cooling the reaction solution to 15-30 ℃, and stirring for 2-3 hr. And (4) carrying out suction filtration, leaching a filter cake by using ethanol (150mL multiplied by 2), and leaching by using water to obtain a crude product of Filgotinib.
Adding the Filgotinib crude product into a reaction bottle, adding acetonitrile (420mL) and water (60mL), and heating to 65-80 ℃ under stirringoC, obtaining a clear solution, adding a palladium removing reagent, and keeping the temperature for 60-70 DEGoC, stirring, performing suction filtration, leaching a filter cake with acetonitrile (7.5mL multiplied by 2), concentrating to 225 mL-300 mL, and reducing the volume to 0-10%oC, stirring for 1-2 hrs. And (3) carrying out suction filtration, and leaching a filter cake with acetonitrile (15mL multiplied by 2) to obtain 102.2g of a white solid, wherein the HPLC purity is 99.8%, the yield is 88.8%, the content of the impurity 1 is 0.15%, the content of the impurity 2 is 0.06%, and the content of Pd is 3 ppm.
Example 3
Compound A (75.0g, 0.27mol), compound B (98.4g, 0.28mol), NaHCO3(27.7g，0.33mol)、Pd(dppf)Cl2(6.0g, 8.1mmol), ethanol (600mL) and water (150mL) were added to a reaction flask, replaced with nitrogen, heated to 70-80 ℃ for 15-20 hrs, and followed by HPLC until the reaction was complete.
Cooling the reaction solution to 15-30 ℃, and stirring for 2-3 hr. And (4) carrying out suction filtration, leaching a filter cake by using ethanol (150mL multiplied by 2), and leaching by using water to obtain a crude product of Filgotinib.
Adding the crude Filgotinib into a reaction bottle, adding acetonitrile (4200mL) and water (600mL), and heating to 65-80 ℃ under stirringoC, obtaining a clear solution, adding a palladium removing reagent, and keeping the temperature for 60-70 DEGoC, stirring, performing suction filtration, leaching a filter cake with acetonitrile (75mL multiplied by 2), concentrating to 2250 mL-3000 mL, and reducing the volume to 0-10oC, stirring for 1-2 hrs. And (3) carrying out suction filtration, and leaching a filter cake by using acetonitrile (150mL multiplied by 2) to obtain 96.0g of white solid, wherein the HPLC purity is 99.7%, the yield is 84.6%, the content of the impurity 1 is 0.17%, the content of the impurity 2 is 0.07%, and the content of Pd is 25 ppm.
Example 4
Compound A (75.0g, 0.27mol), compound B (98.4g, 0.28mol), NaHCO3(27.7g，0.33mol)、Pd(dppf)Cl2(2.0g, 2.7mmol), ethanol (600mL) and water (150mL) were added to a reaction flask, replaced with nitrogen, heated to 70-80 ℃ for 15-20 hrs, and followed by HPLC until the reaction was complete.
Cooling the reaction solution to 15-30 ℃, and stirring for 2-3 hr. And (4) carrying out suction filtration, leaching a filter cake by using ethanol (150mL multiplied by 2), and leaching by using water to obtain a crude product of Filgotinib.
Adding the Filgotinib crude product into a reaction bottle, adding acetonitrile (3000mL) and water (600mL), and heating to 65-80 ℃ under stirringoC, obtaining a clear solution, adding a palladium removing reagent, and keeping the temperature for 60-70 DEGoC, stirring, performing suction filtration, leaching a filter cake with acetonitrile (75mL multiplied by 2), concentrating to 2250 mL-3000 mL, and reducing the volume to 0-10oC, stirring for 1-2 hrs. And (3) carrying out suction filtration, and leaching a filter cake with acetonitrile (150mL multiplied by 2) to obtain 98.5g of a white solid, wherein the HPLC purity is 99.7%, the yield is 86.8%, the content of the impurity 1 is 0.17%, the content of the impurity 2 is 0.06%, and the content of Pd is 18 ppm.
Example 5
A mixture of 75.0g (0.27 mol) of Compound A, 98.4g (0.28 mol) of Compound B and NaHCO3(27.7g，0.33mol)、Pd(dppf)Cl2(2.0g, 2.7mmol), ethanol (600mL) and water (150mL) were added to a reaction flask, replaced with nitrogen, heated to 70-80 ℃ for 15-20 hrs, and followed by HPLC until the reaction was complete.
Cooling the reaction solution to 15-30 ℃, and stirring for 2-3 hr. And (4) carrying out suction filtration, leaching a filter cake by using ethanol (150mL multiplied by 2), and leaching by using water to obtain a crude product of Filgotinib.
Adding the Filgotinib crude product into a reaction bottle, adding acetonitrile (4800mL) and water (600mL), and heating to 65-80 ℃ under stirringoC, obtaining a clear solution, adding a palladium removing reagent, and keeping the temperature for 60-70 DEGoC, stirring, performing suction filtration, leaching a filter cake with acetonitrile (75mL multiplied by 2), concentrating to 2250 mL-3000 mL, and reducing the volume to 0-10oC, stirring for 1-2 hrs. And (3) carrying out suction filtration, and leaching a filter cake with acetonitrile (150mL multiplied by 2) to obtain 98.5g of a white solid, wherein the HPLC purity is 99.7%, the yield is 86.8%, the content of the impurity 1 is 0.17%, the content of the impurity 2 is 0.06%, and the content of Pd is 26 ppm.
Claims (10)
1. A preparation method of Filgotinib is characterized by comprising the following steps: in a mixed solvent of an alcohol solvent and water, in the presence of a palladium catalyst and an alkali, carrying out the following reaction on a compound A and a compound B;
the alcohol solvent is one or more of methanol, ethanol and isopropanol;
the volume ratio of the alcohol solvent to water is 1: 1-20: 1;
the palladium catalyst is PddppfCl2、Pd(PPh3)2Cl2And Pd (OAc)2One or more of;
the alkali is carbonate and/or bicarbonate of alkali metal;
the molar ratio of the compound B to the compound A is 0.9-1.2;
the reaction is carried out in the atmosphere of protective gas;
the reaction temperature of the reaction is 60-100 ℃;
and the method also comprises post-treatment after the reaction is finished; the post-treatment comprises the following steps:
(1) after the reaction is finished, cooling and carrying out suction filtration to obtain a filter cake; and
（2）65~80oc, dissolving the filter cake in a mixed solvent of acetonitrile and water, mixing with a palladium removal reagent, and performing suction filtration to obtain a filtrate;
concentrating the filtrate to a volume A of 0-10oAnd C, carrying out suction filtration to obtain a final product.
2. The method according to claim 1, wherein the volume molar ratio of the mixed solvent to the compound A is 2.0 to 4.0L/mol.
3. The method according to claim 2, wherein the alcoholic solvent is ethanol or isopropanol.
4. The method according to claim 1, wherein the palladium-based catalyst is PddppfCl2(ii) a And/or the molar ratio of the palladium catalyst to the compound A is 0.01-0.03.
5. The method according to claim 1, wherein the molar ratio of the base to the compound A is 1.0 to 1.5.
6. The method according to claim 1, wherein the reaction mixture,
the alkali metal is one or more of sodium, potassium and cesium;
and/or, the carbonate of the alkali metal is one or more of sodium carbonate, potassium carbonate and cesium carbonate;
and/or the bicarbonate of the alkali metal is sodium bicarbonate and/or potassium bicarbonate.
7. The method according to claim 1, wherein the reaction mixture,
the reaction temperature of the reaction is 70-80 ℃.
8. The preparation method according to claim 1, wherein the temperature is reduced to 15-30 ℃.
9. The method according to claim 1, wherein the volume molar ratio of the volume A to the compound A is 6.0 to 13.0L/mol.
10. The preparation method according to claim 1, wherein the volume molar ratio of the mixed solvent of acetonitrile and water to the compound A is 15.0-20.0L/mol;
and/or in the mixed solvent of acetonitrile and water, the volume ratio of acetonitrile to water is 2.0-8.0.
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| CN202111323179.0A CN113773322B (en) | 2021-11-10 | 2021-11-10 | Preparation method of Filgotinib |
| PCT/CN2022/119524 WO2023082839A1 (en) | 2021-11-10 | 2022-09-19 | Filgotinib preparation method |
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| JO3041B1 (en) * | 2008-07-25 | 2016-09-05 | Galapagos Nv | Novel compounds useful for the treatment of degenerative and inflammatory diseases |
| TWI462920B (en) * | 2009-06-26 | 2014-12-01 | 葛萊伯格有限公司 | Novel compound useful for the treatment of degenerative and inflammatory diseases |
| GB201402071D0 (en) * | 2014-02-07 | 2014-03-26 | Galapagos Nv | Novel salts and pharmaceutical compositions thereof for the treatment of inflammatory disorders |
| WO2017012773A1 (en) * | 2015-07-23 | 2017-01-26 | Ratiopharm Gmbh | Solid forms of filgotinib free base |
| WO2017133423A1 (en) * | 2016-02-02 | 2017-08-10 | 深圳市塔吉瑞生物医药有限公司 | Substituted picolinamide compound and use thereof |
| CN107759587B (en) * | 2016-08-19 | 2021-01-26 | 中国医药研究开发中心有限公司 | [1,2,4] triazolo [1,5-a ] pyridine compound and preparation method and medical application thereof |
| CN108341814B (en) * | 2017-01-23 | 2021-09-03 | 上海翔锦生物科技有限公司 | JAK kinase inhibitors and uses thereof |
| CN110204542B (en) * | 2019-05-23 | 2022-05-20 | 四川伊诺达博医药科技有限公司 | Synthetic method of JAK1 inhibitor Filgotinib |
| CN113773322B (en) * | 2021-11-10 | 2022-02-11 | 奥锐特药业(天津)有限公司 | Preparation method of Filgotinib |
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