WO2011095125A1 - Procédés de synthèse et procédés de purification de dasatinib - Google Patents

Procédés de synthèse et procédés de purification de dasatinib Download PDF

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Publication number
WO2011095125A1
WO2011095125A1 PCT/CN2011/070826 CN2011070826W WO2011095125A1 WO 2011095125 A1 WO2011095125 A1 WO 2011095125A1 CN 2011070826 W CN2011070826 W CN 2011070826W WO 2011095125 A1 WO2011095125 A1 WO 2011095125A1
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compound
formula
group
dasatinib
hydrazine
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PCT/CN2011/070826
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English (en)
Chinese (zh)
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严荣
杨浩
侯雯
许永翔
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南京卡文迪许生物工程技术有限公司
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Priority claimed from CN201010177587A external-priority patent/CN101845045A/zh
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Publication of WO2011095125A1 publication Critical patent/WO2011095125A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to the field of medicinal chemistry, and in particular to a novel method for synthesizing dasatinib. Background technique
  • Dasatinib trade name SPRYCELTM, is an oral tyrosine kinase inhibitor developed by BMS for adult chronic myeloid leukemia (CML) and can also be used to treat Philadelphia chromosome-positive acute Lymphocytic leukemia.
  • CML chronic myeloid leukemia
  • SPRYCELTM an oral tyrosine kinase inhibitor developed by BMS for adult chronic myeloid leukemia (CML) and can also be used to treat Philadelphia chromosome-positive acute Lymphocytic leukemia.
  • Its chemical name is N-(2-chloro-6-mercaptophenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-mercapto-4- Pyrimidinyl]amino]-5-thiazolylamide, the chemical structure is as follows:
  • a method of synthesizing dasatinib is disclosed in Chinese Patent Application No. Hei 1348370A, which is incorporated by reference in its entirety. This method uses 2-tert-butoxy-aminoaminothiazole-5-carboxylic acid ethyl ester as a starting material to synthesize dasatinib by the following route:
  • the inventors have succeeded in developing a method suitable for industrial large-scale production and synthesizing dasatinib with readily available starting materials, and overcome the deficiencies in the prior art.
  • a second object of the present invention is to provide a process for the preparation of high purity dasatinib.
  • the invention provides a method for synthesizing dasatinib, comprising the following steps:
  • the compound of formula IV is acylated with an acid chlorinating reagent to give a compound of formula V:
  • the compound of formula V is reacted with 2-chloro-6-mercaptoaniline to give a compound of formula VI:
  • an alkoxy group of dC 6 or a substituted alkoxy group of dC 6 a substituent in the alkoxy group of the substituent substituted dC 6 Selected from dC 6 alkyl, aryl and substituted aryl; said aryl is selected from phenyl; said substituted aryl is selected from one or more dC 4 alkyl or alkoxy, halogen and nitro substituted Phenyl, preferably, decyloxy, benzyloxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, sec-butoxy, isobutoxy, pentoxide Base or hexyloxy.
  • the acid chloride reagent is selected from the group consisting of phosphorus trichloride, phosphorus pentachloride, thionyl chloride and oxalyl chloride, preferably oxalyl chloride.
  • the amide condensing agent is selected from the group consisting of phenyl diphosphate (PDCP), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 2-( 7-Azobenzotriazole)- ⁇ , ⁇ , ⁇ ', ⁇ '-tetradecylurea hexafluorophosphate (HATU) and 1-(3-diamidinopropyl)-3-ethyl Carbodiimide (EDCI).
  • PDCP phenyl diphosphate
  • DCC dicyclohexylcarbodiimide
  • DIC diisopropylcarbodiimide
  • the present invention also provides another method for synthesizing dasatinib, in which, after obtaining a compound of formula III, a compound of formula VII:
  • the Pg in the compound of the formula IX and the compound of the formula X is a hydroxy protecting group, and the compound of the formula X is reacted with 2-chloro-6-mercaptoaniline, and then the hydroxy protecting group Pg is removed, thereby obtaining dasatinib;
  • the compound of the formula IX is reacted with 2-chloro-6-mercaptoaniline in the presence of an amide condensing agent, and then the hydroxy protecting group Pg is removed to obtain dasatinib.
  • the hydroxy protecting reagent is an agent of the following hydroxy protecting group: c r c 4 alkanoate, substituted c r c 4 alkanoate or carbonate protecting group;
  • the ester is selected from the group consisting of a decanoyl group, an acetyl group, a propionyl group, a butyryl group, a benzoyl group, and a p-phenylbenzoyl group;
  • the carbonate is selected from the group consisting of a nonyl decyl ester, a 9-fluorenyl ester, and a 2-(trimethylsilyl) group.
  • Ethyl ester isobutyl ester, vinyl ester, allyl ester and p-nitrophenyl ester or benzyl ester, see "GREENE, S PROTECTIVE GROUP IN ORGANIC SYNTHESIS” by PETER GM WUTS, etc., Fourth Edition, 2007, A John Wiley & Sons, Inc., Publication, pp. 16-366.
  • the acid chlorinating agent is selected from the group consisting of phosphorus trichloride, phosphorus pentachloride, chlorinated acid chloride and oxalyl chloride, preferably oxalyl chloride.
  • the amide condensing agent is selected from the group consisting of phenyl dichloride dichloride (PDCP), dicyclohexyl carbodiimide (DCC), diisopropyl carbodiimide (DIC), 2-(7-azobenzotriazole)- ⁇ , ⁇ , ⁇ ', ⁇ '-tetradecylurea hexafluoroantimonate (HATU) and 1-(3-diamidinopropyl)- 3-ethylcarbodiimide (EDCI).
  • PDCP phenyl dichloride dichloride
  • DCC dicyclohexyl carbodiimide
  • DIC diisopropyl carbodiimide
  • EDCI 1-(3-diamidinopropyl)- 3-ethylcarbodiimide
  • the present invention also provides an additional method for synthesizing dasatinib in which a compound of formula III is reacted with a hydroxy protected 1-(2-hydroxyethyl)piperazine to provide a compound of formula III.
  • the compound of formula IX is acylated under the action of an acid chlorinating reagent to give a compound of formula X:
  • the compound of the formula IX is reacted with 2-chloro-6-mercaptoaniline in the presence of an amide condensing agent, and then the hydroxy protecting group Pg is removed to obtain dasatinib.
  • the hydroxy protecting group is selected from an acid protecting group selected from a substituted or unsubstituted c r c 4 alkyl ether, a substituted or unsubstituted benzyl ether.
  • the substituted c r c 4 alkyl acid is preferably a self-substituted oxime ether and diethyl ether, more preferably selected from the group consisting of decyl oxime ether, tert-butoxy oxime ether, 2-oxo ethoxy oxime ether, Thiosulfonyl ether, (phenyl dithylsilyl) anthracene Ether, benzyloxyanthracene, (4-oxophenoxy) oxime ether, menthoxy oxime ether, tetrahydropyranyl ether, tetrahydrofuranyl ether, 1-ethoxyethyl ether and allyl ether
  • the substituted benzylic acid is preferably selected from the group consisting of p-methoxybenzyl ether, 3,4-dimethoxyoxybenzyl ether and p-nitrobenzyl ether; the substituted benzylic acid
  • the acid chlorinating agent is selected from the group consisting of phosphorus trichloride, phosphorus pentachloride, succinyl chloride and oxalyl chloride, preferably oxalyl chloride.
  • the amide condensing agent is selected from the group consisting of dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), and 2-(7-azobenzotriene).
  • the present invention also provides a fourth method of synthesizing dasatinib, in which, after obtaining a compound of formula III, an amine is reacted to provide a compound of formula VI:
  • the compound of formula XII is reacted with 1-(2-hydroxyethyl)piperazine to give dasatinib.
  • the removal of the hydroxy protecting group can also be referred to "GREENE, S PROTECTIVE GROUP IN ORGANIC SYNTHESIS” by PETER GM WUTS, etc., Fourth Edition, 2007, A John Wiley & Sons, Inc. ., Publication, can be used by those skilled in the art This selects the appropriate removal conditions.
  • the present invention provides a method for purifying dasatinib, comprising: adding a crude dasatinib obtained by concentration or suction filtration after completion of the reaction to an organic solvent;
  • the crude dasatinib may have a purity of 95% or more, and preferably the crude product has a purity of 97% or more.
  • the organic solvent may be an aprotic polar solvent, preferably ruthenium, osmium-dimercaptoamide, hydrazine, fluorenyl-dimercaptoacetamide, dimethyl sulfoxide or a mixture thereof.
  • the heating temperature may be selected from room temperature to reflux temperature, preferably 40 to 100 °C.
  • the compound is compounded.
  • a crude amount of dasatinib can be dissolved in a solution of dimethyl hydrazide or a dimethyl sulfoxide under heating, and a certain amount of dalsalazine can be added while maintaining a certain temperature.
  • the insoluble organic solvent or a mixture of water and an organic solvent is precipitated by a decompression method, and a solid is obtained by filtration or centrifugation, and a high-purity dasatinib is obtained by drying.
  • the weight of the crude dasatinib and the dimercapto group having an impurity content of about 3% are usually 1: 1-200 (g: ml), preferably selected from a ratio of 1:2 to 200, most preferably selected from a ratio of 1:3 to 200.
  • the crude dasatinib is dissolved from room temperature to heating, and the specific heating temperature may be below the reflux temperature, preferably from below 120 °C, most preferably from below 100 °C.
  • the volume ratio of sulfoxide is usually 1 ⁇ 200 ⁇ 200: 1 . Most preferably selected from the ratio of 3 to 200:1, the solid is precipitated under stirring, and is lowered to 0 to 10 ° C, and after 1 to 2 hours of incubation, it is filtered and dried.
  • a common commercially available raw material having a wide range of sources can be selected, for example, the common commercially available raw material 2-mercapto-4,6-dichloropyrimidine involved in the appropriate route of the present invention is selected.
  • 2-mercapto-4,6-dichloropyrimidine involved in the appropriate route of the present invention is selected.
  • 2-mercapto-4,6-dichloropyrimidine involved in the appropriate route of the present invention is selected.
  • the process used in the invention has mild reaction conditions, simple post-treatment method, simple intermediate purification, and is more suitable for process production.
  • the existing dasatinib synthesis methods are obtained by using different synthetic routes or preparation methods to obtain 2-(6-chloro-2-mercaptopyrimidin-4-amino)-N-(2-chloro-6).
  • - anthracene) thiazol-5-nonanamide which is then condensed with 1-(2-hydroxyethyl)piperazine to give dasatinib.
  • the present invention provides a novel synthetic route which avoids the simple route and method of synthesizing dasatinib in the last step using 4-hydroxyethylpiperazine, which is more conducive to the quality control and improvement of the finished product.
  • the synthesis method provided by the present invention has a high yield in each step.
  • the yield of each of the existing methods described in the published materials is between 15% and 49%.
  • the most simple synthetic route in the present invention is selected, for example, selecting 2-mercapto-4,6-dichloropyrimidine and 2-aminothiazole-5-decanoic acid decyl ester in Examples 1 to 8 of the present invention.
  • the total yield of dasatinib synthesized by four steps of condensation and hydrolysis is higher than that of the existing method.
  • FIG. 1 shows the chromatogram of dasatinib. The results of the analysis are as follows: Peak number retention time peak area
  • Figure 2 shows the reaction of a compound of formula I with a compound of formula II to give a compound of formula III.
  • Example 2 Preparation of 2-(6-chloro-2-mercaptopyrimidin-4-amino)thiazole-5-decanoic acid (Compound 5)
  • 2-(6-Chloro-2-indolylpyrimidine-4-amino Ethyl thiazole-5-decanoate (Compound 4, R5 is a mercapto group) (31.0 g, Ol lmol) is added to a pre-formed NaOH (10.Og, 0.25 mol) in water (250 ml) and stirred at room temperature. The reaction was overnight.
  • R5 is fluorenyl) (0.57g, 2mmol), potassium carbonate (0.3g, 3mmol) and 2-chloro-6-mercaptoaniline (compound 7) (0.2ml, 2mmol) are added to acetonitrile (10ml), warming up To reflux reaction. After completion of the reaction, the temperature was lowered, and 1N hydrochloric acid was added thereto, followed by suction filtration. Dry at 60 ° C to constant weight. The target compound 8, 0.3 g (yield: 38.0%) was obtained.
  • the crude dasatinib (Compound 1) was added to DMF (40 ml), and the temperature was raised to 60 ° C to dissolve. A mixture of 120 ml of water and acetone (1:1) was added under heat, and the crystals were precipitated with stirring, and then cooled to 0 ° C for 2 hours. After suction filtration, the filter cake was rinsed with water and then rinsed with water and acetone (1:1) and drained. The cake was dried under reduced pressure (-0.095 MPa) at about 50 ° C, and dried with pentoxide pentoxide. (Yield 68.4%, 99.0%)
  • Example 6 Preparation of dasatinib (Compound 1) 2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-mercaptopyrimidin-4-amino)thiazole-5-decanoate (Compound 10, under nitrogen)
  • R5 is fluorenyl) (0.5g, 1.3mmol), potassium carbonate (0.2g, 2.0mmol) and 2-chloro-6-mercaptoaniline (Compound 7) (0.18ml, 1.5mmol) are added to acetonitrile (10ml).
  • the temperature was raised to reflux reaction, the reaction was completed, the temperature was lowered, 1N hydrochloric acid was added, and suction filtration was applied. Dry at 60 ° C to constant weight.
  • the filter cake was taken out and added to water (300 ml) and stirred for 30 minutes, suction filtered, and the cake was washed with water.
  • the filter cake was taken out and added to 80% ethanol-water (600 ml), heated to dissolve, and 1.5 g of activated carbon was added for decolorization, suction filtration, and the filtrate was recrystallized overnight. After suction filtration, drying, and purification of the cake, dasatinib (Compound 1), 35.4 g (yield: 72.5%, purity: 99.7%) was obtained.
  • the filter cake was taken out and added to water (300 ml) and stirred for 30 minutes, suction filtered, and the cake was washed with water.
  • the filter cake was dried under reduced pressure (-0.095 MPa) at about 50 ° C, and dried with phosphorus pentoxide to obtain dasatinib (Compound 1), 38.6 g (yield: 79.1%, purity: 99.91%).
  • the filter cake was added to dimethyl sulfoxide (36 ml), and the temperature was raised to 60-70 ° C under stirring. After the solution was dissolved, 145 ml of a mixture of water and ethanol (1:1) was added thereto, and the crystals were precipitated and cooled. 10 ° C for 10 minutes. After suction filtration, the filter cake was rinsed with water, rinsed with water and ethanol (1:1) and drained. The filter cake was dried under reduced pressure (-0.095 MPa) at about 50 °C, and dried with phosphorus pentoxide to obtain dasatinib (Compound 1), 7.9 g (yield: 80.9%, purity: 99.95%, see figure 1) .
  • Example 12 2-(6-(4-(2-Benzyloxyethyl)piperazin-1-yl)-2-mercaptopyrimidine-4-amino)thiazole
  • Ethyl decanoate (Compound 4, R5 is a mercapto group) (4.3 g, 0.015 mol)
  • benzyloxyethylpiperazine (Compound 15, Pg is benzyl) (llg, 0.05 mol) and n-butanol (55 ml) .
  • Example 13 2-(6-(4-(2-Benzyloxyethyl)piperazin-1-yl)-2-mercaptopyrimidine-4-amino)thiazole-5-decanoic acid (Compound 12, Pg is Preparation of benzyl)
  • Example 14 Preparation of benzyl protected dasatinib (compound 14, Pg is benzyl) 2-(6-(4-benzyloxyethyl)piperazin-1-yl under nitrogen protection -2-mercaptopyrimidin-4-amino)thiazole-5-decanoic acid (Compound 12, Pg is benzyl) (13.6 g, 0.03 mol), PDCP (5.4 ml, 0.036 mol) and 2-chloro-6- The mercaptoaniline (Compound 7) (4.4 ml, 0.036 mol) was added to dichloromethane (55 ml), stirred, and triethylamine (12.3 ml, 0.09 mol) was added dropwise at 0 °C.
  • Compound 14 Pg is benzyl) 2-(6-(4-benzyloxyethyl)piperazin-1-yl under nitrogen protection -2-mercaptopyrimidin-4-amino)thiazole-5-decan
  • the ethoxylated ethyl group-protected dasatinib (Compound 14, Pg is an ethoxyethyl group) was prepared to reach satinib: Compound 1 (yield: 72.5%, purity: 99.53%).
  • Dasatinib (Compound 14, Pg is a sulfonylthio group) protected by a sulfhydryl sulfhydryl group was prepared to reach satinib: Compound 1 (yield: 80.7%, purity: 99.61%).
  • the dasatinib synthesis route and method provided by the invention are simple, high in yield and more suitable for industrial production.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention porte sur des procédés de synthèse de dasatinib, qui comprennent les étapes suivantes : la réaction d'un composé de formule I avec un composé de formule II pour obtenir un composé de formule III, puis la liaison du composé de formule III avec de la 2-chloro-6-méthylaniline et de la 1-(2-hydroxyéthyl)pipérazine dans n'importe quel ordre pour donner du dasatinib. En outre, l'invention porte également sur des procédés de purification du dasatinib.
PCT/CN2011/070826 2010-02-02 2011-01-30 Procédés de synthèse et procédés de purification de dasatinib WO2011095125A1 (fr)

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CN201010104295 2010-02-02
CN201010104295.9 2010-02-02
CN201010177587A CN101845045A (zh) 2010-02-02 2010-05-07 一种新的达沙替尼合成方法
CN201010177587.5 2010-05-07

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CN102161660A (zh) * 2010-02-21 2011-08-24 中国医学科学院药物研究所 2-(6-氯-2-甲基嘧啶-4-胺基)-n-(2-氯-6-甲基苯基)-5-噻唑甲酰胺的制备方法
WO2014102759A2 (fr) 2012-12-31 2014-07-03 Ranbaxy Laboratories Limited Procédé de préparation de dasatinib et de ses intermédiaires
CN108299417A (zh) * 2018-02-09 2018-07-20 安庆奇创药业有限公司 一种达沙替尼关键中间体的合成方法
CN109265455A (zh) * 2018-11-09 2019-01-25 新发药业有限公司 一种达沙替尼的制备方法

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102161660A (zh) * 2010-02-21 2011-08-24 中国医学科学院药物研究所 2-(6-氯-2-甲基嘧啶-4-胺基)-n-(2-氯-6-甲基苯基)-5-噻唑甲酰胺的制备方法
CN102161660B (zh) * 2010-02-21 2015-05-20 中国医学科学院药物研究所 2-(6-氯-2-甲基嘧啶-4-胺基)-n-(2-氯-6-甲基苯基)-5-噻唑甲酰胺的制备方法
WO2014102759A2 (fr) 2012-12-31 2014-07-03 Ranbaxy Laboratories Limited Procédé de préparation de dasatinib et de ses intermédiaires
WO2014102759A3 (fr) * 2012-12-31 2014-10-30 Ranbaxy Laboratories Limited Procédé de préparation de dasatinib et de ses intermédiaires
US9365526B2 (en) 2012-12-31 2016-06-14 Sun Pharmaceutical Industries Limited Process for the preparation of dasatinib and its intermediates
CN108299417A (zh) * 2018-02-09 2018-07-20 安庆奇创药业有限公司 一种达沙替尼关键中间体的合成方法
CN109265455A (zh) * 2018-11-09 2019-01-25 新发药业有限公司 一种达沙替尼的制备方法
CN109265455B (zh) * 2018-11-09 2020-08-18 新发药业有限公司 一种达沙替尼的制备方法

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