WO2010083752A1 - 一种高纯度的非布司他及其制备方法 - Google Patents

一种高纯度的非布司他及其制备方法 Download PDF

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WO2010083752A1
WO2010083752A1 PCT/CN2010/070271 CN2010070271W WO2010083752A1 WO 2010083752 A1 WO2010083752 A1 WO 2010083752A1 CN 2010070271 W CN2010070271 W CN 2010070271W WO 2010083752 A1 WO2010083752 A1 WO 2010083752A1
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febuxostat
methyl
solvent
purity
methylpropoxy
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PCT/CN2010/070271
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English (en)
French (fr)
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周兴国
唐雪民
石瑞娜
叶文润
罗杰
邓杰
樊斌
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重庆医药工业研究院有限责任公司
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Priority to US13/145,499 priority Critical patent/US20110282069A1/en
Publication of WO2010083752A1 publication Critical patent/WO2010083752A1/zh

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D277/00Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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
    • C07D277/56Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425Thiazoles
    • A61K31/4261,3-Thiazoles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • A61P19/06Antigout agents, e.g. antihyperuricemic or uricosuric agents

Definitions

  • the invention belongs to the technical field of medicinal chemistry, and particularly relates to 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylic acid (febuxostat).
  • febuxostat 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylic acid
  • High purity compound, and method of preparing high purity febuxostat the present invention also relates to a composition comprising the high purity febuxostat and optionally a pharmaceutically acceptable carrier and excipient, and the high purity non-woven fabric The use of sita in the preparation of pharmaceutical compositions.
  • Febuxostat is the first non-sputum type of new xanthine oxidase inhibitor that safely and effectively treats diseases associated with high levels of uric acid, such as gout. Febuxostat has been approved for marketing in the European Union, and has also submitted a new drug registration to the US FDA and has been approved.
  • Patent Application Publication No. WO 92/09279 is a compound patent application for the drug, which relates to 110 kinds of febuxostat structural analogs, as well as methods for their synthesis and purification, indications and the like.
  • Patent JP 10-45733 discloses two other synthetic processes for febuxostat.
  • JP 6-345724 discloses the synthesis of febuxostat by a bis-cyano substituted benzene compound.
  • the last step reaction is the hydrolysis of the ester intermediate. Since the ester intermediate structure also contains a hydrolyzable group such as a cyano group, the hydrolysis reaction in this step produces some impurities.
  • the product is febuxostat; in addition, hydrolysis of certain impurities entrained in the ester intermediate may also produce some impurities into the product febuxostat.
  • the present inventors have found in the research that there are three relatively high content impurities in the febuxostat finished product, and these impurities are not easily reduced or removed by the existing purification method, such as recrystallization by using a solvent such as methanol, ethanol or acetone alone. .
  • the inventors have prepared and purified these three main impurities to determine their structure; a new purification method for the purification of febuxostat by a mixed solvent has been proposed, thereby These three impurities can be effectively reduced or removed.
  • This purification method high-purity febuxostat can be obtained.
  • the high-purity febuxostat can also be used in the preparation of a pharmaceutical preparation to reduce the initial content of impurities in the preparation, which is advantageous for the storage and safety of the preparation.
  • the present invention first provides a high-purity febuxostat having a content of not less than 99.0%.
  • the high-purity febuxostat is obtained by recrystallizing febuxostat in a mixed solvent containing two or more kinds.
  • the solvent is selected from the group consisting of alcohols, heterocycles, ketones, esters, ethers, alkylenes, especially selected from alcohols, ketones, esters or heterocyclic solvents.
  • the alcohol solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol;
  • the ketone solvent is selected from the group consisting of acetone and cyclohexanone;
  • the solvent is selected from the group consisting of ethyl acetate and methyl acetate;
  • the heterocyclic solvent is selected from the group consisting of tetrahydrofuran, dioxane, and thiazole.
  • the solvent is a mixed solvent of an alcohol and a heterocyclic ring in a volume ratio of 10:1 to 1:10, preferably 10:2 to 10:5.
  • the solvent is a mixed solvent of methanol:tetrahydrofuran in a volume ratio of 5:1.
  • the present invention also provides a process for producing the above-mentioned high-purity febuxostat, which comprises recrystallizing febuxostat in a mixed solvent containing two or more kinds.
  • the solvent is preferably a mixed solvent composed of two or more solvents selected from the group consisting of solvents: alcohols, heterocyclics, ketones, esters, ethers, Alkane, wherein the more preferred class of solvents are alcohols, ketones, esters or heterocyclic solvents.
  • the alcohol solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol;
  • the ketone solvent is selected from the group consisting of acetone and cyclohexanone; From ethyl acetate, methyl acetate;
  • the heterocyclic solvent is selected from the group consisting of tetrahydrofuran, dioxane, and thiazole.
  • the solvent is a mixed solvent of an alcohol and a heterocyclic ring in a volume ratio of 10:1 to 1:10, preferably 10:2 to 10:5.
  • the solvent is a mixed solvent of methanol:tetrahydrofuran in a volume ratio of 5:1.
  • febuxostat obtained by the prior art method: 2-[3-carbamoyl-4-(2-methylpropoxy) Phenyl]-4-methyl-5-thiazolecarboxylic acid (FBZA), 2-[3-carboxy-4-(2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylic acid (FBZB) and 2-[3-formyl-4-(2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylic acid (FBZC), the structures of which are as follows:
  • the content of the high-purity febuxostat in the present invention is not less than 99.0%, and the content of the impurity FBZA contained therein is not more than 0.5%, and the content of the impurity FBZB contained is not more than 0.25%.
  • the invention also provides a pharmaceutical composition comprising the high purity febuxostat of the invention and optionally a pharmaceutically acceptable carrier and excipient. Further, the present invention provides the use of the high-purity febuxostat for the preparation of a pharmaceutical composition, particularly for the preparation of a pharmaceutical composition for preventing and treating a disease associated with excessive uric acid, such as gout. Use in.
  • the invention also provides the use of FBZA and/or FBZB as a quality control reference for the high purity febuxostat of the invention.
  • the invention also provides for the use of FBZC as a quality control reference for high purity febuxostat as described herein.
  • the quality control reference substance can be used, for example, in the determination of the content of febuxostat or related substances, for example, as an internal standard or an external standard in high performance liquid chromatography (HPLC), or they can be measured first. Correction factors were then determined in conjunction with their relative retention times in HPLC relative to febuxostat.
  • the present invention provides a method of treating a disease associated with hyperuricemia, including gout, comprising administering to a patient in need of such treatment a high-purity febuxostat of the present invention.
  • a high purity febuxostat is provided.
  • the present invention provides a high-purity febuxostat wherein the content of febuxostat is not less than 99.0%, preferably not less than 99.5%, 99.6%, 99.7%, 99.8%, 99.9%. .
  • the high-purity febuxostat according to the present invention is obtained by recrystallizing febuxostat in a mixed solvent containing two or more kinds.
  • the febuxostat which is used as a raw material for the preparation of high-purity febuxostat is a general purity of febuxostat which can be obtained by any feasible method, and its content is generally less than 99%, for example, less than 99.0%. , below 98.5%, below 98.0%, below 97.5%, below 97.0%, below 96.0%, below 95.0%, even below 90.0%.
  • the solvent is selected from the group consisting of alcohols, heterocycles, ketones, esters, ethers, halogenated alkanes; especially selected from alcohols, ketones, esters or heterocyclic solvents.
  • the alcohol solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol;
  • the ketone solvent is selected from the group consisting of acetone and cyclohexanone;
  • the solvent is selected from the group consisting of ethyl acetate and methyl acetate; and the heterocyclic solvent is selected from the group consisting of tetrahydrofuran, dioxane, and thiazole.
  • the solvent is a mixed solvent of an alcohol and a heterocyclic ring in a volume ratio of 10:1 to 1:10, preferably 10:2 to 10:5. More specifically, the solvent is a mixed solvent of methanol:tetrahydrofuran in a volume ratio of 5:1.
  • the present invention further provides a high-purity febuxostat wherein the content of febuxostat is not less than 99.0%, and the impurity 2-[3-carbamoyl-4-(2-methylpropoxy) is contained.
  • the content of phenyl]-4-methyl-5-thiazolecarboxylic acid (FBZA) is not higher than 0.5%, 0.3%, 0.2%, 0.15%, 0.1% or 0.05%, and the impurity 2-[3-carboxyl
  • the content of -4-(2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylic acid (FBZB) is not higher than 0.25%, 0.2%, 0.15%, 0.1% or 0.05%.
  • a high-purity febuxostat wherein the febuxostat content is not less than 99.5%, and the impurity 2-[3-carbamoyl-4 is contained
  • the content of -(2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylic acid (FBZA) is not higher than 0.5%, 0.4%, 0.3%, 0.2%, 0.15%, 0.1% or 0.05 %
  • the content of the impurity 2-[3-carboxy-4-(2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylic acid (FBZB) is not higher than 0.25%, 0.2%, 0.15%, 0.1% or 0.05%.
  • a high-purity febuxostat is provided, wherein the febuxostat content is not less than 99.6%, and the impurity 2-[3-carbamoyl-4-
  • the content of (2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylic acid (FBZA) is not higher than 0.4%, 0.3%, 0.2%, 0.15%, 0.1% or 0.05%
  • the content of the impurity 2-[3-carboxy-4-(2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylic acid (FBZB) is not higher than 0.25%, 0.2%, 0.15%, 0.1. % or 0.05%.
  • a high-purity febuxostat wherein the febuxostat content is not less than 99.7%, and the impurity 2-[3-carbamoyl-4 is contained.
  • -(2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylic acid (FBZA) is not more than 0.3%, 0.2%, 0.15%, 0.1% or 0.05%, and contains impurities 2 -[3-carboxy-4-(2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylic acid (FBZB) content is not Above 0.25%, 0.2%, 0.15%, 0.1% or 0.05%.
  • a high-purity febuxostat wherein the febuxostat content is not less than 99.8%, and the impurity 2-[3-carbamoyl-4 is contained -(2-methylpropoxy)phenyl]_4-methyl-5-thiazolecarboxylic acid (FBZA) content not higher than 0.2%, 0.15%, 0.1% or 0.05%, containing impurities 2-[3- The content of carboxy-4-(2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylic acid (FBZB) is not higher than 0.2%, 0.15%, 0.1% or 0.05%.
  • FBZA carboxy-4-(2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylic acid
  • the content of febuxostat is not less than 99.9%, and the impurity 2-[3-carbamoyl-4-(2-methylpropoxy)phenyl] is contained.
  • the content of -4-methyl-5-thiazolecarboxylic acid (FBZA) is not higher than 0.1% or 0.05%, and the impurity 2-[3-carboxy-4-(2-methylpropoxy)phenyl] -4 is contained.
  • the content of methyl-5-thiazolecarboxylic acid (FBZB) is not more than 0.1% or 0.05%.
  • the present invention also provides a high-purity febuxostat wherein the content of febuxostat is not less than 99.0%, and the impurity 2-[3-carbamoyl-4-(2-methylpropoxy) is contained.
  • the content of phenyl]-4-methyl-5-thiazolecarboxylic acid is not higher than 0.5%, 0.3%, 0.2%, 0.15%, 0.1% or 0.05%, and the impurity 2-[3-carboxyl
  • the content of -4-(2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylic acid (FBZB) is not higher than 0.25%, 0.2%, 0.15%, 0.1% or 0.05%
  • the content of the impurity 2-[3-formyl-4-(2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylic acid (FBZC) is not higher than 0.25%, 0.2%, 0.15%, 0.1% or 0.05%.
  • a high-purity febuxostat wherein the febuxostat content is not less than 99.5%, and the impurity 2-[3-carbamoyl-4 is contained
  • the content of -(2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylic acid (FBZA) is not higher than 0.5%, 0.4%, 0.3%, 0.2%, 0.15%, 0.1% or 0.05 %
  • the content of the impurity 2-[3-carboxy-4-(2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylic acid (FBZB) is not higher than 0.25%, 0.2%, 0.15%, 0.1% or 0.05%
  • the content of the impurity 2-[3-formyl-4-(2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylic acid (FBZC) is not Above 0.25%, 0.2%, 0.15%, 0.1% or 0.05%.
  • a high-purity febuxostat wherein the febuxostat content is not less than 99.6%, and the impurity 2-[3-carbamoyl-4 is contained -(2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylic acid (FBZA) is not more than 0.4%, 0.3%, 0.2%, 0.15%, 0.1% or 0.05%,
  • the content of impurity-containing 2-[3-carboxy-4-(2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylic acid (FBZB) is not higher than 0.25%, 0.2%, 0.15%, 0.1% or 0.05%
  • the content of the impurity 2-[3-formyl-4-(2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylic acid (FBZC) is not higher than 0.25 %, 0.2%, 0.15%, 0.1% or 0.05%
  • a high-purity febuxostat wherein the febuxostat content is not less than 99.7%, and the impurity 2-[3-carbamoyl-4 is contained.
  • -(2-methylpropoxy)benzene The content of -4-methyl-5-thiazolecarboxylic acid (FBZA) is not higher than 0.3%, 0.2%, 0.15%, 0.1% or 0.05%, and the impurity 2-[3-carboxy-4-(2-)
  • the content of methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylic acid (FBZB) is not higher than 0.25%, 0.2%, 0.15%, 0.1% or 0.05%, and the impurities 2-[3- The content of formyl-4-(2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylic acid (FBZC) is not higher than 0.25%, 0.2%, 0.15%, 0.1% or 0.05%.
  • a high-purity febuxostat wherein the febuxostat content is not less than 99.8%, and the impurity 2-[3-carbamoyl-4 is contained -(2-methylpropoxy)phenyl]_4-methyl-5-thiazolecarboxylic acid (FBZA) content not higher than 0.2%, 0.15%, 0.1% or 0.05%, containing impurities 2-[3- The content of carboxy-4-(2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylic acid (FBZB) is not higher than 0.2%, 0.15%, 0.1% or 0.05%, and contains impurities 2 -[3-formyl-4-(2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylic acid (FBZC) is not more than 0.2%, 0.15%, 0.1% or 0.05% .
  • FBZA carboxy-4-(2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylic
  • a high-purity febuxostat wherein the febuxostat content is not less than 99.9%, and the impurity 2-[3-carbamoyl-4 is contained -(2-methylpropoxy)phenyl]_4-methyl-5-thiazolecarboxylic acid (FBZA) content of not more than 0.1% or 0.05%, containing impurities 2-[3-carboxy_4-(2 -Methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylic acid (FBZB) content of not more than 0.1% or 0.05%, containing impurities 2-[3-formyl-4-(2- The content of methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylic acid (FBZC) is not more than 0.1% or 0.05%.
  • FBZA 2-methylpropoxy)phenyl]_4-methyl-5-thiazolecarboxylic acid
  • Another object of the present invention is to provide a process for preparing the above-mentioned high-purity febuxostat.
  • the present invention provides a process for producing high-purity febuxostat as described below, which comprises recrystallizing febuxostat in a mixed solvent containing two or more kinds.
  • the method specifically includes:
  • the separated product is dried.
  • the mixed solvent in the above purification method preferably contains at least two of an alcohol, a heterocyclic ring, a ketone, an ester, an ether, and a halogenated alkane, and among them, an alcohol, a ketone, an ester, and a heterocyclic ring are preferable.
  • the mixed solvent may also contain some other types of solvents such as alkanes, water, amides, sulfones and the like.
  • the above alcohol solvent includes methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, etc.;
  • the heterocyclic solvent includes tetrahydrofuran, dioxane, thiazole;
  • the ester solvent is ethyl acetate, Methyl acetate, etc.;
  • the ketones are acetone, cyclohexanone and the like.
  • the ratio of the alcohol to the heterocyclic ring in the mixed solvent is usually 10:1 to 1:10 (volume ratio), more preferably 10:2 to 10:5 (volume ratio).
  • a lower amount of solvent is generally used to dissolve the febuxostat at a higher temperature.
  • the amount of the solvent is generally from about just 1 part to the excess, preferably just about 0.5 times the excess; the dissolution temperature is generally selected from half the boiling point of the solvent to the boiling temperature, preferably the boiling point.
  • a hot filtration operation may be carried out to remove some of the insoluble impurities.
  • the cooling and crystallization in the step (2) of the above purification method may be stirred and crystallization, or may be static crystallization.
  • the final temperature of crystallization is generally from -20 ° C to room temperature, preferably from -5 ° C to room temperature.
  • the above purification step (3) generally involves an operation of washing the separated solid with a certain amount of a suitable solvent such as a crystallization solvent or one of them.
  • the drying step (5) is generally carried out at a temperature of 50 to 150 ° C, preferably 70 to 90 ° C; the degree of vacuum is generally 0 to 0.098 MPa, preferably 0.08 to 0.095 MPa; and the drying time is generally 2 to 24 hours, preferably 8 ⁇ 16 hours.
  • the purification method can effectively reduce or remove the impurity content in the febuxostat product.
  • the FBZA content in the febuxostat before purification is about 1%
  • the FBZB content is about 0.5%
  • the FBZC content is about 0.5%.
  • the methanol/tetrahydrofuran (volume ratio 5/1) in the solvent is recrystallized once, and the content of FBZA, FBZB, and FBZC in the obtained febuxostat product can reach less than 0.2%, 0.1%, and 0.1%, respectively. Not higher than 0.1%.
  • the febuxostat purification method provided by the present invention is a novel method for the purification of febuxostat which is simple in operation, high in efficiency, and easy to industrialize.
  • the present invention also provides a method of preparing the above three impurity compounds FBZA, FBZB and FBZC.
  • the above three impurity compounds having a purity of not less than 90%, preferably not less than 95% can be obtained.
  • the method for preparing 2-[3-carbamoyl-4-(2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylic acid is as follows: 2-[3-cyano- Ethyl 4- or 2-(2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylate or methyl ester (prepared according to the method of JP10-45733) in a mixed solution of an alkali solution and an organic solvent Hydrolysis, after hydrolysis, neutralized with acid, separated, and dried. The resulting product can be further purified by recrystallization.
  • the alkali solution is preferably sodium hydroxide or potassium hydroxide aqueous solution, and the concentration is 0.5 to 5.0 mol/L, preferably 2 to 3 mol/L; the organic solvent is preferably tetrahydrofuran, methanol, ethanol or acetone; and the reaction temperature is preferably 70 to 80°. C; hydrolysis time is 18 ⁇ 36 hours, preferably 20 ⁇ 30 hours; neutralizing acid is preferred hydrochloric acid; recrystallization agent optional methanol, B The alcohol or the like; the drying temperature is usually 50 to 150 ° C, preferably 70 to 90 ° C; the degree of vacuum is generally 0 to 0.098 MPa, preferably 0.08 to 0.095 MPa.
  • the method for preparing 2-[3-carboxy-4-(2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylic acid is as follows: 2-[3-cyano-4- Ethyl (ethyl 2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylate or methyl ester (prepared according to the method of JP 10-45733) and hydrolyzed in a mixed solution of an alkali solution and an organic solvent After the hydrolysis is completed, it is neutralized with an acid, separated, and dried. The resulting product can be further purified by recrystallization.
  • the alkali solution is preferably sodium hydroxide or potassium hydroxide aqueous solution, and the concentration is 0.5 to 5.0 mol/L, preferably 2 to 3 mol/L; the organic solvent is preferably tetrahydrofuran, methanol, ethanol or acetone; and the reaction temperature is preferably 80 to 90. °C; hydrolysis time is 36 ⁇ 72 hours, preferably 44 ⁇ 52 hours; neutralizing acid is preferred hydrochloric acid; recrystallization agent can choose methanol, ethanol, etc.; drying temperature is generally 50 ⁇ 150 °C, preferably 70 ⁇ 90 °C
  • the degree of vacuum is generally from 0 to 0.098 MPa, preferably from 0.08 to 0.095 MPa.
  • the lye is preferably sodium hydroxide or potassium hydroxide solution, and has a concentration of 0.5 to 5.0 mol/L, preferably 2 to 3 mol/L; the organic solvent is preferably tetrahydrofuran, methanol, ethanol or acetone; and the reaction temperature is 60 to 90°. C;
  • the hydrolysis time is 0.5 to 20 hours, preferably 1 to 6 hours;
  • the acid for neutralization is preferably hydrochloric acid;
  • the recrystallization agent may be selected from ethyl acetate, methanol, ethanol, etc.;
  • the drying temperature is generally 50 to 150 ° C, preferably 70 ⁇ 90°C;
  • the degree of vacuum is generally from 0 to 0.098 MPa, preferably from 0.08 to 0.095 MPa.
  • the content of febuxostat and impurities therein in the present invention is determined by high-performance liquid chromatography (HPLC, detection wavelength of about 220 nm) area normalization method, and the detection limit thereof is not less than 0.02%, and the limit of quantification is not lower than 0.05%.
  • HPLC high-performance liquid chromatography
  • the purity of FBZA, FBZB and FBZC was also determined by high performance liquid chromatography (HPLC, detection wavelength of about 220 nm) area normalization method. The value of the content or purity is obtained by rounding off the detected data.
  • the present invention also provides the use of the above impurities as a quality control reference for the high purity febuxostat described in the present invention.
  • the invention provides the use of said impurities FBZA and/or FBZB as a quality control reference for said high purity febuxostat as described herein.
  • the invention provides the use of said impurities FBZA and / or FBZB and / or FBZC as a quality control reference for said high purity febuxostat in the present invention.
  • a pharmaceutical composition comprising the above-described high-purity febuxostat.
  • the pharmaceutical composition contains the above-described high purity febuxostat and optional pharmaceutical excipients, including excipients and carriers.
  • the pharmaceutical composition may be in the form of a pharmaceutical preparation such as a tablet, a capsule, and other solid or dry pharmaceutical preparations. Among them, a tablet form is preferred. These formulations may be known to those of ordinary skill in the art.
  • the corresponding excipients are prepared by the corresponding well-known pharmaceutical preparation techniques.
  • the tablet may contain an excipient such as a filler, a binder, a disintegrant, a lubricant, etc.; the filler may be selected from the group consisting of microcrystalline cellulose, lactose, pregelatinized starch, mannitol, starch or sorbitol.
  • the disintegrant may be selected from croscarmellose sodium, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch or cross-linked poly-dimensional One or more of the ketones, preferably croscarmellose sodium; the binder may be selected from one or more of povidone, starch syrup or hydroxypropylmethylcellulose, preferably hydroxypropyl Methylcellulose; the lubricant may be magnesium stearate or the like.
  • the febuxostat tablet of the present invention is a wet granulation tableting process. It is prepared by pulverizing, sieving, mixing, granulating, drying, granulating, tableting and other processes.
  • the present invention also provides the use of the above-mentioned high-purity febuxostat or a pharmaceutical composition containing the above-mentioned high-purity febuxostat for the manufacture of a medicament for preventing or treating a disease associated with hyperuricemia, said
  • the diseases associated with high uric acid mainly refer to gout caused by hyperuricemia of blood, hyperuricemia caused by radiotherapy and chemotherapy in cancer patients, and other conditions of hyperuricemia.
  • the present invention provides a method of treating or preventing a disease associated with excessive uric acid in the blood, including gout, comprising administering to a patient in need of such treatment a high purity febuxostat as described herein.
  • Example 1 is intended to illustrate the invention, but are not to be construed as limiting the scope of the invention.
  • Example 1
  • the filter cake is recrystallized from absolute ethanol, suction filtered, and the filter cake is dried under reduced pressure (-0.090 ⁇ -0.095 MPa) at 75-85 ° C to give 2-[3-carboxy-4-(2-methylpropoxy). Phenyl]-4-methyl-5-thiazolecarboxylic acid (FBZB) 8.7 g, off-white solid. HPLC purity: 98%.

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Description

一种高纯度的非布司他及其制备方法 技术领域
本发明属于药物化学技术领域, 具体涉及包含 2-[3-氰基 -4-(2-甲基丙氧基) 苯基] -4-甲基 -5-噻唑甲酸(非布司他) 的高纯度化合物, 以及制备高纯度非布司 他的方法,本发明还涉及含有所述高纯度非布司他和任选的可药用载体和赋形剂 的组合物以及所述高纯度非布司他在制备药物组合物中的用途。
技术背景
非布司他 (Febuxostat)化学名为: 2-[3-氰基 -4-(2-甲基丙氧基)苯基] -4-甲基 -5- 噻唑甲酸。 化学结构式为:
Figure imgf000002_0001
非布司他是第一个非嘌呤类型的新型黄嘌呤氧化酶抑制剂,能安全有效的治 疗与尿酸过高有关的疾病, 如痛风。非布司他已在欧盟获上市批准, 同时也向美 国 FDA提交了新药注册, 并获得批准推荐。
专利申请公开 WO92/09279为该药物的化合物专利申请,该发明专利申请涉 及了 110 种非布司他结构类似物, 以及其合成和精制方法、 适应症等。 专利 JP10-45733公开了非布司他的另两种合成工艺。 JP6-345724公开了以双氰基取代 苯类化合物合成非布司他。 这些发明专利文件提供了多种合成非布司他的途径, 并提供了结构类似物的合成方法。 专利 JP10-45733提供的合成工艺, 由于反应 步骤较短、原材料易得 (不涉及管控剧毒原材料),反应条件温和,工艺收率较高, 无特殊三废, 较适用于工业化。上述非布司他的现有制备技术中, 最后一步反应 均为酯中间体的水解, 由于酯中间体结构中还含有氰基等可水解的基团, 因此该 步水解反应会产生一些杂质引入产品非布司他;另外,酯中间体中夹带的某些杂 质的水解也可能产生一些杂质进入产品非布司他。因此,产品非布司他中通常会 存在多种杂质,但现有技术未涉及非布司他中的杂质情况及对其研究。杂质的存 在会给药品安全性带来潜在的隐患,例如可能与某些不良反应相关联;甚至还可 能影响到药品的长期稳定性。 发明内容 为了进一步提高非布司他产 JPlO-45733的方法制备得到非布司他,并对其中的杂质进行了研究。本发明人在 研究中发现,非布司他成品中有三种含量相对较高的杂质,并且这些杂质不易通 过现有的精制方法有效降低或除去,如单独采用甲醇、乙醇、丙酮等溶剂重结晶。
因此,针对研究中发现的这些问题,本发明人已制备并纯化了这三种主要杂 质,确定它们的物质结构;提出了一种采用混合溶剂对非布司他进行精制的新纯 化方法, 从而可有效降低或除去这三种杂质。通过该精制方法, 可得到高纯度的 非布司他。还可将该高纯度非布司他用于制备药物制剂, 以降低制剂中杂质的初 始含量, 有利于制剂的储存和安全性的提高。
因此, 本发明首先提供了一种高纯度非布司他, 其含量不低于 99.0%。在一 个方面,所述高纯度非布司他是通过使非布司他在含两种或两种以上的混合溶剂 中重结晶而得到的。在一个优选的方面, 所述溶剂选自醇类、杂环类、酮类、酯 类、 醚类、 ^代烷烃, 尤其是选自醇类、 酮类、 酯类或杂环类溶剂。 在一个更优 选的方面, 所述醇类溶剂选自甲醇、 乙醇、 丙醇、 异丙醇、 正丁醇、 异丁醇; 所 述酮类溶剂选自丙酮、环已酮; 所述酯类溶剂选自乙酸乙酯、 乙酸甲酯; 所述杂 环类溶剂选自四氢呋喃、二氧六环、 噻唑。在一个特别优选的方面, 所述溶剂是 体积比为 10:1〜1:10、优选 10:2〜10:5的醇类和杂环类的混合溶剂。在一个更特 别优选的方面, 所述溶剂是体积比为 5:1的甲醇: 四氢呋喃的混合溶剂。
本发明还提供了一种制备上述高纯度非布司他的方法,所述方法包括使非布 司他在含两种或两种以上的混合溶剂中重结晶。在本发明的方法中,所述溶剂优 选是由选自以下类别溶剂中的两种或更多种以上的溶剂组成的混合溶剂: 醇类、 杂环类、 酮类、 酯类、 醚类、 ^代烷烃, 其中更优选的溶剂类别是醇类、 酮类、 酯类或杂环类溶剂。 其中, 优选地, 所述醇类溶剂选自甲醇、 乙醇、 丙醇、 异丙 醇、 正丁醇、异丁醇; 所述酮类溶剂选自丙酮、环已酮; 所述酯类溶剂选自乙酸 乙酯、 乙酸甲酯; 所述杂环类溶剂选自四氢呋喃、 二氧六环、 噻唑。 在一个特别 优选的方面, 所述溶剂是体积比为 10:1〜1:10、优选 10:2〜10:5的醇类和杂环类 的混合溶剂。 在一个更特别优选的方面, 所述溶剂是体积比为 5:1的甲醇: 四氢 呋喃的混合溶剂。
另一方面,本发明人还制备、纯化并鉴定了现有技术方法得到的非布司他中 的 3种主要杂质成分: 2-[3-氨甲酰基 -4-(2-甲基丙氧基)苯基] -4-甲基 -5-噻唑甲酸 (FBZA)、 2-[3-羧基 -4-(2-甲基丙氧基)苯基] -4-甲基 -5-噻唑甲酸(FBZB)和 2-[3- 甲酰基 -4-(2-甲基丙氧基)苯基] -4-甲基 -5-噻唑甲酸 (FBZC),其结构分别如下所示:
Figure imgf000004_0001
FBZA
Figure imgf000004_0002
FBZB
Figure imgf000004_0003
FBZC
优选地, 本发明中的所述高纯度非布司他的含量不低于 99.0%, 并且其所含 杂质 FBZA的含量不高于 0.5%, 所含杂质 FBZB的含量不高于 0.25%。
在又一方面,本发明还提供了一种药物组合物,其含有本发明所述的高纯度 非布司他和任选的可药用载体和赋形剂。另外,本发明还提供了所述高纯度非布 司他在制备药物组合物中的用途,特别是在用于制备用于预防和治疗与尿酸过高 有关的疾病 (例如痛风) 的药物组合物中的用途。
在另一方面, 本发明还提供了 FBZA和 /或 FBZB在用作本发明所述高纯度 非布司他的质量控制对照品中的用途。类似地,本发明也提供了 FBZC在用作本 发明所述高纯度非布司他的质量控制对照品中的用途。所述质量控制对照品例如 可以用在非布司他的含量或有关物质测定上, 例如可以作为高效液相色谱法 (HPLC) 中的内标或外标对照品, 也可以先测量出它们的校正因子, 然后结合 它们在 HPLC中相对于非布司他的相对保留时间进行测定。
此外,本发明还提供了一种治疗包括痛风在内的与尿酸过高有关的疾病的方 法, 包括给需要此治疗的患者施用本发明所述的高纯度非布司他。 具体实施方式 在本发明的第一个方面, 提供了一种高纯度的非布司他。
为了实现该目的,本发明提供了一种高纯度的非布司他,其中非布司他的含 量不低于 99.0%, 优选不低于 99.5%、 99.6%、 99.7%、 99.8%、 99.9%。
在一个方面,本发明所述的高纯度非布司他是通过使非布司他在含两种或两 种以上的混合溶剂中重结晶而得到的。其中用作制备高纯度非布司他的原料的非 布司他是具有一般纯度的非布司他,其可通过任何可行的方法制得,其含量一般 低于 99%,例如低于 99.0%,低于 98.5%,低于 98.0%,低于 97.5%,低于 97.0%, 低于 96.0%, 低于 95.0%, 甚至低于 90.0%等。 在一个优选的方面中, 所述溶剂 选自醇类、 杂环类、 酮类、 酯类、 醚类、 卤代烷烃; 尤其是选自醇类、 酮类、 酯 类或杂环类溶剂。 在一个更优选的方面, 所述醇类溶剂选自甲醇、 乙醇、 丙醇、 异丙醇、 正丁醇、 异丁醇; 所述酮类溶剂选自丙酮、 环已酮; 所述酯类溶剂选自 乙酸乙酯、 乙酸甲酯; 所述杂环类溶剂选自四氢呋喃、二氧六环、噻唑。特别地, 所述溶剂是体积比为 10:1〜1:10、 优选 10:2〜10:5的醇类和杂环类的混合溶剂。 更特别地, 所述溶剂是体积比为 5:1的甲醇: 四氢呋喃的混合溶剂。
本发明进一步提供了一种高纯度的非布司他, 其中非布司他的含量不低于 99.0%, 并且所含杂质 2-[3-氨甲酰基 -4-(2-甲基丙氧基)苯基] -4-甲基 -5-噻唑甲酸 (FBZA) 的含量不高于 0.5%、 0.3%、 0.2%、 0.15%、 0.1%或 0.05%, 所含杂质 2-[3-羧基 -4-(2-甲基丙氧基)苯基] -4-甲基 -5-噻唑甲酸 (FBZB ) 的含量不高于 0.25%、 0.2%、 0.15%、 0.1%或 0.05%。
在本发明的另一个具体实施方案中,提供了一种高纯度的非布司他,其中非 布司他的含量不低于 99.5%, 并且所含杂质 2-[3-氨甲酰基 -4-(2-甲基丙氧基)苯 基] -4-甲基 -5-噻唑甲酸(FBZA)的含量不高于 0.5%、 0.4%、 0.3%、 0.2%、 0.15%、 0.1%或 0.05%, 所含杂质 2-[3-羧基 -4-(2-甲基丙氧基)苯基] -4-甲基 -5-噻唑甲酸 (FBZB) 的含量不高于 0.25%、 0.2%、 0.15%、 0.1%或 0.05%。
在本发明的一个具体实施方案中,提供了一种高纯度的非布司他,其中非布 司他的含量不低于 99.6%,并且所含杂质 2-[3-氨甲酰基 -4-(2-甲基丙氧基)苯基] -4- 甲基 -5-噻唑甲酸 (FBZA) 的含量不高于 0.4%、 0.3%、 0.2%、 0.15%、 0.1%或 0.05%, 所含杂质 2-[3-羧基 -4-(2-甲基丙氧基)苯基] -4-甲基 -5-噻唑甲酸 (FBZB) 的含量不高于 0.25%、 0.2%、 0.15%、 0.1%或 0.05%。
在本发明的另一个具体实施方案中,提供了一种高纯度的非布司他,其中非 布司他的含量不低于 99.7%, 并且所含杂质 2-[3-氨甲酰基 -4-(2-甲基丙氧基)苯 基] -4-甲基 -5-噻唑甲酸(FBZA)的含量不高于 0.3%、 0.2%、 0.15%、 0.1%或 0.05%, 所含杂质 2-[3-羧基 -4-(2-甲基丙氧基)苯基] -4-甲基 -5-噻唑甲酸(FBZB)的含量不 高于 0.25%、 0.2%、 0.15%、 0.1%或 0.05%。
在本发明的又一个具体实施方案中,提供了一种高纯度的非布司他,其中非 布司他的含量不低于 99.8%, 并且所含杂质 2-[3-氨甲酰基 -4-(2-甲基丙氧基)苯 基 ]_4-甲基 -5-噻唑甲酸(FBZA) 的含量不高于 0.2%、 0.15%、 0.1%或 0.05%, 所 含杂质 2-[3-羧基 -4-(2-甲基丙氧基)苯基] -4-甲基 -5-噻唑甲酸(FBZB)的含量不高 于 0.2%、 0.15%、 0.1%或 0.05%。
在本发明的又一个具体实施方案中, 非布司他的含量不低于 99.9%, 并且所 含杂质 2-[3-氨甲酰基 -4-(2-甲基丙氧基)苯基] -4-甲基 -5-噻唑甲酸 (FBZA) 的含 量不高于 0.1%或 0.05%, 所含杂质 2-[3-羧基 -4-(2-甲基丙氧基)苯基] -4-甲基 -5-噻 唑甲酸 (FBZB) 的含量不高于 0.1%或 0.05%。
本发明还提供了一种高纯度的非布司他, 其中非布司他的含量不低于 99.0%, 并且所含杂质 2-[3-氨甲酰基 -4-(2-甲基丙氧基)苯基] -4-甲基 -5-噻唑甲酸 (FBZA) 的含量不高于 0.5%、 0.3%、 0.2%、 0.15%、 0.1%或 0.05%, 所含杂质 2-[3-羧基 -4-(2-甲基丙氧基)苯基] -4-甲基 -5-噻唑甲酸 (FBZB ) 的含量不高于 0.25%、 0.2%、 0.15%、 0.1%或 0.05%, 所含杂质 2-[3-甲酰基 -4-(2-甲基丙氧基) 苯基] -4-甲基 -5-噻唑甲酸 (FBZC)的含量不高于 0.25%、 0.2%、 0.15%、 0.1%或 0.05%。
在本发明的另一个具体实施方案中,提供了一种高纯度的非布司他,其中非 布司他的含量不低于 99.5%, 并且所含杂质 2-[3-氨甲酰基 -4-(2-甲基丙氧基)苯 基] -4-甲基 -5-噻唑甲酸(FBZA)的含量不高于 0.5%、 0.4%、 0.3%、 0.2%、 0.15%、 0.1%或 0.05%, 所含杂质 2-[3-羧基 -4-(2-甲基丙氧基)苯基] -4-甲基 -5-噻唑甲酸 (FBZB) 的含量不高于 0.25%、 0.2%、 0.15%、 0.1%或 0.05%, 所含杂质 2-[3- 甲酰基 -4-(2-甲基丙氧基)苯基] -4-甲基 -5-噻唑甲酸 (FBZC)的含量不高于 0.25%、 0.2%、 0.15%、 0.1%或 0.05%。
在本发明的另一个具体实施方案中,提供了一种高纯度的非布司他,其中非 布司他的含量不低于 99.6%, 并且所含杂质 2-[3-氨甲酰基 -4-(2-甲基丙氧基)苯 基] -4-甲基 -5-噻唑甲酸(FBZA)的含量不高于 0.4%、 0.3%、 0.2%、 0.15%、 0.1% 或 0.05%,所含杂质 2-[3-羧基 -4-(2-甲基丙氧基)苯基] -4-甲基 -5-噻唑甲酸(FBZB) 的含量不高于 0.25%、 0.2%、 0.15%、 0.1%或 0.05%, 所含杂质 2-[3-甲酰基 -4-(2- 甲基丙氧基)苯基] -4-甲基 -5-噻唑甲酸 (FBZC)的含量不高于 0.25%、 0.2%、 0.15%、 0.1%或 0.05%
在本发明的另一个具体实施方案中,提供了一种高纯度的非布司他,其中非 布司他的含量不低于 99.7%, 并且所含杂质 2-[3-氨甲酰基 -4-(2-甲基丙氧基)苯 基] -4-甲基 -5-噻唑甲酸(FBZA)的含量不高于 0.3%、 0.2%、 0.15%、 0.1%或 0.05%, 所含杂质 2-[3-羧基 -4-(2-甲基丙氧基)苯基] -4-甲基 -5-噻唑甲酸(FBZB)的含量不 高于 0.25%、 0.2%、 0.15%、 0.1%或 0.05%, 所含杂质 2-[3-甲酰基 -4-(2-甲基丙氧 基)苯基] -4-甲基 -5-噻唑甲酸 (FBZC)的含量不高于 0.25%、 0.2%、 0.15%、 0.1%或 0.05%。
在本发明的另一个具体实施方案中,提供了一种高纯度的非布司他,其中非 布司他的含量不低于 99.8%, 并且所含杂质 2-[3-氨甲酰基 -4-(2-甲基丙氧基)苯 基 ]_4-甲基 -5-噻唑甲酸(FBZA) 的含量不高于 0.2%、 0.15%、 0.1%或 0.05%, 所 含杂质 2-[3-羧基 -4-(2-甲基丙氧基)苯基] -4-甲基 -5-噻唑甲酸(FBZB)的含量不高 于 0.2%、 0.15%、 0.1%或 0.05%,所含杂质 2-[3-甲酰基 -4-(2-甲基丙氧基)苯基] -4- 甲基 -5-噻唑甲酸 (FBZC)的含量不高于 0.2%、 0.15%、 0.1%或 0.05%。
在本发明的另一个具体实施方案中,提供了一种高纯度的非布司他,其中非 布司他的含量不低于 99.9%, 并且所含杂质 2-[3-氨甲酰基 -4-(2-甲基丙氧基)苯 基 ]_4-甲基 -5-噻唑甲酸 (FBZA) 的含量不高于 0.1%或 0.05%, 所含杂质 2-[3-羧 基 _4-(2-甲基丙氧基)苯基] -4-甲基 -5-噻唑甲酸 (FBZB ) 的含量不高于 0.1%或 0.05%, 所含杂质 2-[3-甲酰基 -4-(2-甲基丙氧基)苯基] -4-甲基 -5-噻唑甲酸 (FBZC) 的含量不高于 0.1%或 0.05%。
本发明的另一个目的是提供一种制备上述高纯度非布司他的方法。
为此,本发明提供了一种如下所述的制备高纯度非布司他的方法, 该方法包 括使非布司他在含两种或两种以上的混合溶剂中重结晶。
该方法具体可包括:
( 1 ) 将 2-[3-氰基 -4-(2-甲基丙氧基)苯基] -4-甲基 -5-噻唑甲酸 (非布司他) 在 混合溶剂中加热溶解;
(2) 冷却析晶;
(3 ) 过滤或离心分离析出的 2-[3-氰基 -4-(2-甲基丙氧基)苯基] -4-甲基 -5-噻唑 甲酸 (非布司他);
(4) 任选地, 根据纯度要求重复上述步骤;
(5) 任选地, 对分离的产品进行干燥。
上述纯化方法中的混合溶剂优选至少包含醇类、杂环类、酮类、酯类、醚类、 卤代烷烃中的两类, 其中优选醇类、 酮类、 酯类和杂环类。 在此基础上, 该混合 溶剂还可以包含一些其他类型的溶剂, 如烷烃类、 水、 酰胺类、 砜类等。
优选地, 上述醇类溶剂包括甲醇、 乙醇、丙醇、异丙醇、正丁醇、异丁醇等; 杂环类溶剂包括四氢呋喃、二氧六环、噻唑;酯类溶剂为乙酸乙酯、乙酸甲酯等; 酮类为丙酮、 环已酮等。 混合溶剂中醇类和杂环类的比例一般为 10: 1〜1: 10 (体积比), 更优选 10: 2〜10: 5 (体积比)。
为了得到较高的纯化收率,一般使用较少量的溶剂在较高的温度下来溶解非 布司他。 溶剂量一般是从刚好溶解量至过量约 1 倍, 优选刚好溶解量至过量约 0.5倍; 溶解温度一般选择溶剂沸点温度的一半至沸点温度, 优选沸点温度。
上述纯化方法步骤 (1)中在非布司他溶解完全后, 可进行趁热过滤操作来除 去其中的一些不溶性杂质。
上述纯化方法步骤 (2)中冷却析晶可以是搅拌析晶, 也可是静置析晶。 析晶 最终温度一般是 -20°C至室温, 优选 -5°C至室温。
上述纯化方法步骤 (3)中一般涉及用一定量的适宜溶剂 (如结晶溶剂或其中的 一种)洗涤分离出的固体的操作。
上述纯化方法步骤 (5)干燥温度一般为 50〜150°C, 优选 70〜90°C ; 真空度 一般为 0〜0.098MPa, 优选 0.08〜0.095 MPa; 干燥时间一般为 2〜24小时, 优 选 8〜16小时。
该纯化方法能有效的降低或除去非布司他成品中的杂质含量。例如,用醇类 /杂环类混合溶剂纯化非布司他时, 纯化前非布司他中 FBZA含量为 1%左右、 FBZB含量为 0.5%左右、 FBZC含量为 0.5%左右, 选用该类混合溶剂中的甲醇 / 四氢呋喃 (体积比 5/1)重结晶一次, 所得的非布司他产品中 FBZA、 FBZB, FBZC 的含量能达到分别低于 0.2%、 0.1%、 0.1%, 其它杂质含量也不高于 0.1%。 若按 文献方法(如 WO9209279所述)纯化非布司他, 需重结晶多次才能获得纯度较 高的非布司他, 这必将导致产品收率降低, 工业成本大大增加。 因此, 本发明提 供的非布司他纯化方法是一种操作简便,效率较高,易于工业化的非布司他纯化 新方法。
本发明还同时提供了上述三种杂质化合物 FBZA、 FBZB和 FBZC的制备方 法。 通过所述方法, 可得到纯度不低于 90%, 优选不低于 95%的上述三种杂质 化合物。
制备 2-[3-氨甲酰基 -4-(2-甲基丙氧基)苯基] -4-甲基 -5-噻唑甲酸(FBZA) 的 方法如下:将 2-[3-氰基 -4-(2-甲基丙氧基)苯基] -4-甲基 -5-噻唑甲酸乙酯或甲酯 (可 按 JP10-45733 中的方法制备)在碱溶液与有机溶剂的混合溶液中水解, 水解完 毕后用酸中和, 分离, 干燥。所得产品可经重结晶进一步纯化。其中, 碱液优选 氢氧化钠、 氢氧化钾水溶液, 浓度为 0.5〜5.0mol/L, 优选浓度为 2~3mol/L; 有 机溶剂优选四氢呋喃、 甲醇、 乙醇、 丙酮; 反应温度优选 70〜80°C ; 水解时间 为 18〜36小时, 优选 20〜30小时; 中和用酸优选盐酸; 重结晶剂可选甲醇、 乙 醇等;干燥温度一般为 50〜150°C,优选 70〜90°C ;真空度一般为 0〜0.098MPa, 优选 0.08〜0.095 MPa。
制备 2-[3-羧基 -4-(2-甲基丙氧基)苯基] -4-甲基 -5-噻唑甲酸(FBZB)的方法如 下: 将 2-[3-氰基 -4-(2-甲基丙氧基)苯基] -4-甲基 -5-噻唑甲酸乙酯或甲酯 (可按 JP10-45733中的方法制备)与在碱溶液与有机溶剂的混合溶液中水解,水解完毕 后用酸中和, 分离, 干燥。所得产品可经重结晶进一步纯化。其中, 碱液优选氢 氧化钠、 氢氧化钾水溶液, 浓度为 0.5〜5.0mol/L, 优选浓度为 2~3 mol/L; 有机 溶剂优选四氢呋喃、 甲醇、 乙醇、 丙酮; 反应温度优选 80〜90°C ; 水解时间为 36〜72小时, 优选 44〜52小时; 中和用酸优选盐酸; 重结晶剂可选甲醇、 乙醇 等; 干燥温度一般为 50〜150°C, 优选 70〜90°C ; 真空度一般为 0〜0.098MPa, 优选 0.08〜0.095 MPa。
制备 2-[3-甲酰基 -4-(2-甲基丙氧基)苯基] -4-甲基 -5-噻唑甲酸(FBZC)的方法 如下: 将 2-[3-甲酰基 -4-(2-甲基丙氧基)苯基] -4-甲基 -5-噻唑甲酸乙酯或甲酯 (可 按 JP10-45733 中的方法制备) 与在碱溶液与有机溶剂的混合溶液中水解, 水解 完毕后用酸中和, 分离, 干燥。所得产品可经重结晶进一步纯化。其中, 碱液优 选氢氧化钠、 氢氧化钾溶液, 浓度为 0.5〜5.0mol/L, 优选浓度为 2~3mol/L; 有 机溶剂优选四氢呋喃、 甲醇、 乙醇、 丙酮; 反应温度为 60〜90°C ; 水解时间为 0.5〜20小时, 优选 1〜6小时; 中和用酸优选盐酸;; 重结晶剂可选乙酸乙酯、 甲醇、 乙醇等; 干燥温度一般为 50〜150°C,优选 70〜90°C ; 真空度一般为 0〜 0.098MPa, 优选 0.08〜0.095 MPa。
本发明中涉及的非布司他和其中杂质的含量是用高效液相色谱 (HPLC,检测 波长约 220nm)面积归一化法测定的, 其检测限不低于 0.02%, 定量限不低于 0.05%。 FBZA、 FBZB和 FBZC的纯度也是通过高效液相色谱 (HPLC, 检测波长 约 220nm)面积归一化法测定的。含量或纯度的数值是经检测数据四舍五入所得。
相应地,本发明还提供了上述杂质用作本发明中所述高纯度非布司他的质量 控制对照品的用途。 在一个实施方案中, 本发明提供了所述杂质 FBZA和 /或 FBZB用作本发明中所述高纯度非布司他的质量控制对照品的用途。在另一个实 施方案中, 本发明提供了所述杂质 FBZA和 /或 FBZB和 /或 FBZC用作本发明中 所述高纯度非布司他的质量控制对照品的用途。
根据本发明的再一方面, 提供了一种含有上述高纯度非布司他的药物组合 物。所述药物组合物含有上述高纯度非布司他和任选的药用辅料,包括赋形剂和 载体。所述药物组合物可以是药物制剂的形式, 例如片剂、胶囊及其他固体或干 燥药物制剂。其中,优选片剂形式。这些制剂可采用本领域一般技术人员公知的 相应的辅料, 采用相应的公知的药物制剂制备技术制得。例如, 片剂可含有填充 剂、 黏合剂、 崩解剂、 润滑剂等赋形剂; 所述填充剂可选自微晶纤维素、 乳糖、 预胶化淀粉、甘露醇、淀粉或山梨醇中的一种或者几种,优选乳糖、微晶纤维素; 所述崩解剂可选自交联羧甲基纤维素钠、低取代羟丙基纤维素、羧甲基淀粉钠或 交联聚维酮中的一种或者几种,优选交联羧甲基纤维素钠; 所述粘合剂可选自聚 维酮、淀粉浆或羟丙甲基纤维素的一种或者几种, 优选羟丙甲基纤维素; 所述润 滑剂可以为硬脂酸镁等。本发明所述的非布司他片剂为湿法制粒压片工艺。经过 粉碎、 过筛、 混合、 制粒、 干燥、 整粒、 压片等工艺过程制得。
本发明还提供了上述高纯度非布司他或含有上述高纯度非布司他的药物组 合物在制造用于预防或治疗与血尿酸过高有关的疾病的药物中的用途,所说的与 尿酸过高相关的疾病主要指血尿酸过高引起的痛风、癌症患者放化疗引起的高血 尿酸以及其他血尿酸过高的病症。
本发明和提供了一种治疗或预防包括痛风在内的与血液中尿酸过高有关的 疾病的方法, 包括给需要此治疗的患者施用本发明所述的高纯度非布司他。 实施例
下述实施例是举例说明本发明, 但不应当理解为是对本发明的范围的限制。 实施例 1
2-[3-氨甲酰基 -4-(2-甲基丙氧基)苯基] -4-甲基 -5-噻唑甲酸 (FBZA)的制备
在 500ml的三颈瓶中, 加入, 2-[3-氰基 -4-(2-甲基丙氧基)苯基] -4-甲基 -5-噻 唑甲酸乙酯 20.0g、 10%氢氧化钠 200ml溶解和四氢呋喃 70ml, 于 75〜80°C搅 拌反应约 24h, 冷却, 用浓盐酸, 调 pH至 3左右, 析出白色固体, 过滤, 滤饼 经水洗涤后, 用甲醇重结晶,过滤收集析出物, 滤饼在 80〜85°C下减压 (-0.085〜 -0.090MPa)干燥, 得 2-[3-氨甲酰基 -4-(2-甲基丙氧基)苯基] -4-甲基 -5-噻唑甲酸 (FBZA)9.4g, 白色晶体。 HPLC纯度: 98%。 IR (KBr): 3464, 3399, 3190, 2963, 1693, 1646, 1598, 1505, 1411, 1256, 1161, 1016cm-1。 ^-NMR^OOMHz, DMSO-d6) δ (ppm): 8.342〜8.346 ( 1H, d), 8.013〜8.035 ( 1H, m), 7.255〜7.273 ( 1H, d), 3.972〜3.985 (2H, d), 2.095〜2.148 ( 1H, s), 2.656 (3H, m), 0.997— 1.010 (6H, d)。 实施例 2
2-[3-羧基 -4-(2-甲基丙氧基)苯基] -4-甲基 -5-噻唑甲酸 (FBZB) 的制备
在 500ml的三颈瓶中, 2-[3-氰基 -4-(2-甲基丙氧基)苯基] -4-甲基 -5-噻唑甲酸 乙酯 22.0g、 10%氢氧化钠 220ml溶解和四氢呋喃 80ml, 加热至剧烈回流, 反应 约 48小时, 停止加热, 冷却, 缓慢滴加浓盐酸, 调节 pH至 3左右, 析出固体, 抽滤, 滤饼经水洗涤至中性后, 抽干。 滤饼用无水乙醇重结晶, 抽滤, 滤饼在 75〜85°C下减压干燥 (-0.090〜- 0.095MPa)得 2-[3-羧基 -4-(2-甲基丙氧基)苯基] -4- 甲基 -5-噻唑甲酸 (FBZB)8.7g,类白色固体。 HPLC 纯度: 98%。 IR (KBr): 3396, 2959, 2874, 1692, 1604, 1508, 1422, 1377, 1293, 1252, 1223, 1167, 1111, 1092, 1017, 825cm-1 1H-NMR(500MHz, DMSO-d6) δ (ppm): 8.185〜8.181 ( 1H, d), 7.958〜7.938 ( 1H, m), 7.125〜7.107 ( 1H, d), 3.825〜3.812 (2H, d), 2.614 (3H, s), 2.031〜1.979 ( 1H, m), 0.971〜0.958 (6H, d)。 实施例 3
2-[3-甲酰基 -4-(2-甲基丙氧基)苯基] -4-甲基 -5-噻唑甲酸 (FBZC) 的制备
在 500ml的三颈瓶中, 加入 2-[3-甲酰基 -4-(2-甲基丙氧基)苯基] -4-甲基 -5-噻 唑甲酸乙酯 28.0g、 10%氢氧化钠 280ml溶解和乙醇 90ml, 于 80°C左右搅拌反 应约 4h, 停止反应, 冷却, 缓慢滴加盐酸, 调节 pH至 3, 析出白色固体过滤, 滤饼用水洗涤, 抽干。 滤饼用乙酸乙酯重结晶, 过滤, 滤饼在 70~75°C下减压 (-0.080〜- 0.085MPa)干燥得 2-[3-甲酰基 -4-(2-甲基丙氧基)苯基] -4-甲基 -5-噻唑甲 酸 (FBZC)11.2g, 白色晶体。 HPLC 纯度: 99%。 IR (KBr): 3432, 2966, 2871 , 1679, 1652, 1605, 1513, 1447, 1427, 1371 , 1179, 1111, 1014cm-1
Figure imgf000011_0001
DMSO-d6) δ (ppm): 13.360 ( 1H, s), 10.397 ( 1H, s), 8.191〜8.153 (2H, m), 7.337〜7.319 ( 1H, d), 3.990〜3.977 (2H, d), 2.659 (3H, s), 2.163〜2.084 ( 1H, s), 1.045〜1.031 (6H, d)。 实施例 4
高纯度非布司他的制备
在 1L 反应瓶中加入非布司他粗品 (HPLC: 98.1%, 下同) 70g、 甲醇 480ml 和四氢呋喃 95ml。 加热回流溶解, 趁热过滤, 滤液静置析晶, 有白色晶体析出, 过滤。 滤饼经减压干燥 (80〜85°C、 -0.080〜- 0.090MPa) 8h 以上, 得白色晶体 59.6g。 HPLC: 99.9%, FBZA: 0.02%, FBZB: 0.03%, FBZC: 0.03%。 实施例 5
高纯度非布司他的制备
在 200ml反应瓶中加入非布司他粗品 10g、 甲醇 60ml和四氢呋喃 24ml。 加 热回流溶解,趁热过滤,滤液搅拌析晶,过滤。滤饼经减压干燥 (75〜80°C、-0.090〜 -0.095MPa) 15h以上,得白色晶体 7.91g。 HPLC: 99.9%, FBZA: 0.02%, FBZB: 0.01%, FBZC: 0.02%。 实施例 6
高纯度非布司他的制备
在 200ml反应瓶中加入非布司他粗品 10g、 乙醇 80ml和四氢呋喃 20ml。 加 热回流溶解, 冷却滤液至 0~5°C, 过滤。 滤饼经减压干燥 (70〜75°C、 -0.08〜 -0.09MPa) 8h以上, 得白色晶体 7.54g。 HPLC: 99.8%, FBZA: 0.04%, FBZB: 0.06%, FBZC: 0.06%。 实施例 7
高纯度非布司他的制备
在 100ml反应瓶中加入非布司他粗品 10g、 丙酮 50ml和四氢呋喃 15ml。 加 热回流溶解, 趁热过滤, 搅拌冷却滤液 5~10°C, 过滤。 用少量丙酮洗滤饼, 滤 饼经减压干燥(85〜90°C、-0.085〜-0.095MPa)9h以上,得白色晶体 7.25g。HPLC: 99.6%, FBZA: 0.15%, FBZB: 0.08%, FBZC: 0.12%。 实施例 8
高纯度非布司他的制备
在 200ml反应瓶中加入非布司他粗品 10g、 甲醇 50ml、 水 10ml和四氢呋喃 24ml。 加热回流溶解, 趁热过滤, 冷却滤液, 过滤, 用少量甲醇洗滤饼。滤饼经 减压干燥(70〜75°C、 -0.080〜- 0.085MPa) 16h以上, 得白色晶体 8.11g。 HPLC: 99.5%, FBZA: 0.30%, FBZB: 0.11%, FBZC: 0.07%。 实施例 9
高纯度非布司他的制备
在 200ml反应瓶中加入非布司他粗品 10g、 丙酮 60ml和乙酸乙酯 30ml。 加 热回流溶解,趁热过滤,冷却滤液,过滤。滤饼经减压干燥(80〜85°C、 -0.085〜 -0.095MPa) 10h以上,得白色晶体 7.89g。 HPLC: 99.7%, FBZA: 0.12%, FBZB: 0.07%, FBZC: 0.10%。 实施例 10 高纯度非布司他片
每片处方:
Figure imgf000013_0001
制备工艺:
1、 将非布司他微粉化使成粒径为 0〜10μηι, 备用;
2、 分别将乳糖、 微晶纤维素、 交联羧甲基纤维素钠和硬脂酸镁过 80 目筛 备用;
3、 将羟丙甲纤维素用纯化水配成 1%的浓度备用;
4、 将非布司他、 乳糖、 微晶纤维素和内加部分的交联羧甲基纤维素钠混合 均匀, 加入粘合剂制软材, 软材过 20 目筛制得湿粒, 在 50°C〜60°C干 燥, 将干粒过筛整粒, 加入硬脂酸镁和外加交联羧甲基纤维素钠混匀, 得半成品。 测定含量, 计算片重。 依据半成品含量调节片重压片, 即得 成品。

Claims

1. 一种高纯度的非布司他, 其特征在于: 非布司他的含量不低于 99.0%。
2. 权利要求 1 的高纯度非布司他, 其是通过使非布司他在含两种或两种以上的 混合溶剂中重结晶而得到的。
3. 权利要求 2 的高纯度非布司他, 其中所述溶剂选自醇类、 杂环类、 酮类、 酯 类、 醚类、 卤代烷烃。 权
4. 权利要求 3 的高纯度非布司他, 其中所述溶剂选自醇类、 酮类、 酯类或杂环 类溶剂。
5. 权利要求 2 的高纯度非布司他, 其中所述醇类溶剂选自甲醇、 乙醇、 丙醇、 异丙醇、 正丁醇、 异丁醇; 所述酮类溶剂选自丙酮、 环已酮; 所述酯类溶剂选自 求
乙酸乙酯、 乙酸甲酯; 所述杂环类溶剂选自四氢呋喃、 二氧六环、 噻唑。
6. 权利要求 3-5 中任一项所述的高纯度非布司他, 其中所述溶剂是体积比为 10:1〜1:10、 优选 10:2〜10:5的醇类和杂环类的混合溶剂。
7. 权利要求 6的高纯度非布司他,其中所述溶剂是体积比为 5:1的甲醇: 四氢呋 喃的混合溶剂。
8. 权利要求 1-2中任一项所述的高纯度非布司他, 其所含有的杂质 2-[3-氨甲酰 基 -4-(2-甲基丙氧基)苯基] -4-甲基 -5-噻唑甲酸(FBZA)的含量不高于 0.5%, 2-[3- 羧基 _4-(2-甲基丙氧基)苯基] -4-甲基 -5-噻唑甲酸 (FBZB) 的含量不高于 0.25%。
9. 权利要求 1-2中任一项所述的高纯度非布司他, 其所含有的杂质 2-[3-氨甲酰 基 -4-(2-甲基丙氧基)苯基] -4-甲基 -5-噻唑甲酸(FBZA)的含量不高于 0.5%, 2-[3- 羧基 _4-(2-甲基丙氧基)苯基] -4-甲基 -5-噻唑甲酸 (FBZB) 的含量不高于 0.25%, 并且 2-[3-甲酰基 -4-(2-甲基丙氧基)苯基] -4-甲基 -5-噻唑甲酸 (FBZC)的含量不高 于 0.25%。
10.权利要求 8或 9所述的高纯度非布司他,其所含有的杂质 FBZA的含量不高 于 0.2%, FBZB的含量不高于 0.1%。
11. 权利要求 9所述的高纯度非布司他, 其所含有的杂质 FBZC 的含量不高于 0.1%。
12. 一种制备权利要求 1的高纯度非布司他的方法,所述方法包括使非布司他在 含两种或两种以上的混合溶剂中重结晶。
13. 权利要求 12所述的制备方法, 其中所述溶剂选自醇类、 杂环类、 酮类、 酯 类、 醚类、 ^代烷烃, 尤其是醇类、 酮类、 酯类或杂环类溶剂。
14. 权利要求 13所述的制备方法, 其中所述溶剂是体积比为 10:1〜1:10、 优选 10:2〜10:5的醇类和杂环类的混合溶剂。
15. 权利要求 13所述的制备方法, 其中所述醇类溶剂选自甲醇、 乙醇、 丙醇、 异丙醇、 正丁醇、 异丁醇; 所述酮类溶剂选自丙酮、 环已酮; 所述酯类溶剂选自 乙酸乙酯、 乙酸甲酯; 所述杂环类溶剂选自四氢呋喃、 二氧六环、 噻唑。
16. 2-[3-氨甲酰基 -4-(2-甲基丙氧基)苯基] -4-甲基 -5-噻唑甲酸(FBZA)和 /或 2-[3- 羧基 _4-(2-甲基丙氧基)苯基] -4-甲基 -5-噻唑甲酸 (FBZB) 用作权利要求 1-11 中 任一项所述的高纯度非布司他的质量控制对照品的用途。
17. 2-[3-氨甲酰基 -4-(2-甲基丙氧基)苯基] -4-甲基 -5-噻唑甲酸(FBZA)和 /或 2-[3- 羧基 _4-(2-甲基丙氧基)苯基] -4-甲基 -5-噻唑甲酸(FBZB)和 /或 2-[3-甲酰基 -4-(2- 甲基丙氧基)苯基] -4-甲基 -5-噻唑甲酸 (FBZC)用作权利要求 1-11中任一项所述的 高纯度非布司他的质量控制对照品的用途。
18. 一种药物组合物, 含有权利要求 1~11中任一项的高纯度非布司他和任选的 可药用载体和赋形剂。
19. 权利要求 1~11中任一项的高纯度非布司他在制备药物组合物中的用途。
20. 一种治疗包括痛风在内的与尿酸过高有关的疾病的方法, 包括给需要此治疗 的患者施用权利要求 1~11中任一项的高纯度非布司他或权利要求 18的组合物。
21. 2-[3-氨甲酰基 -4-(2-甲基丙氧基)苯基] -4-甲基 -5-噻唑甲酸。
22. 2-[3-羧基 -4-(2-甲基丙氧基)苯基] -4-甲基 -5-噻唑甲酸。
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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Families Citing this family (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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WO2011139886A2 (en) * 2010-04-29 2011-11-10 Dr. Reddy's Laboratories Ltd. Preparation of febuxostat
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WO2012131590A1 (en) 2011-03-31 2012-10-04 Sandoz Ag An improved process for preparation of febuxostat and its polymorphic crystalline form c thereof
CN102267957B (zh) * 2011-08-24 2013-04-24 山东齐都药业有限公司 非布司他a晶型的制备方法
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2614520A (en) * 1950-03-30 1952-10-21 Cameron Iron Works Inc Mechanical advantage operator
JP2003261548A (ja) * 2002-03-07 2003-09-19 Teijin Ltd 2−(3−シアノ−4−イソブチルオキシフェニル)−4−メチル−5−チアゾールカルボン酸の結晶多形体の製造方法
CN101085761A (zh) * 2007-06-29 2007-12-12 上海华拓医药科技发展股份有限公司 非布他特微晶及其组合物
WO2007148787A1 (ja) * 2006-06-23 2007-12-27 Teijin Pharma Limited 2-(3-シアノ-4-イソブチルオキシフェニル)-4-メチル-5-チアゾールカルボン酸の結晶多形体の製造方法
CN101139325A (zh) * 2006-09-07 2008-03-12 上海医药工业研究院 2-(3-氰基-4-异丁氧基苯基)-4-甲基-5-噻唑甲酸晶型及其制备方法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992009279A1 (en) * 1990-11-30 1992-06-11 Teijin Limited 2-arylthiazole derivative and pharmaceutical composition containing the same

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2614520A (en) * 1950-03-30 1952-10-21 Cameron Iron Works Inc Mechanical advantage operator
JP2003261548A (ja) * 2002-03-07 2003-09-19 Teijin Ltd 2−(3−シアノ−4−イソブチルオキシフェニル)−4−メチル−5−チアゾールカルボン酸の結晶多形体の製造方法
WO2007148787A1 (ja) * 2006-06-23 2007-12-27 Teijin Pharma Limited 2-(3-シアノ-4-イソブチルオキシフェニル)-4-メチル-5-チアゾールカルボン酸の結晶多形体の製造方法
CN101139325A (zh) * 2006-09-07 2008-03-12 上海医药工业研究院 2-(3-氰基-4-异丁氧基苯基)-4-甲基-5-噻唑甲酸晶型及其制备方法
CN101085761A (zh) * 2007-06-29 2007-12-12 上海华拓医药科技发展股份有限公司 非布他特微晶及其组合物

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105372372A (zh) * 2012-12-14 2016-03-02 贵州信邦制药股份有限公司 一种非布索坦片剂的检测方法
CN105372372B (zh) * 2012-12-14 2018-05-01 贵州信邦制药股份有限公司 一种非布索坦片剂的检测方法

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