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WO2010064219A1 - Procédé de préparation d'un nouvel intermédiaire de la caspofungine - Google Patents

Procédé de préparation d'un nouvel intermédiaire de la caspofungine Download PDF

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Publication number
WO2010064219A1
WO2010064219A1 PCT/IB2009/055526 IB2009055526W WO2010064219A1 WO 2010064219 A1 WO2010064219 A1 WO 2010064219A1 IB 2009055526 W IB2009055526 W IB 2009055526W WO 2010064219 A1 WO2010064219 A1 WO 2010064219A1
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Prior art keywords
formula
compound
acid
process according
alkyl
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Inventor
Ramendra S. Rathore
Angadi Surender
Ram Chander Aryan
Chandra Has Khanduri
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Ranbaxy Laboratories Ltd
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Ranbaxy Laboratories Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/50—Cyclic peptides containing at least one abnormal peptide link
    • C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
    • C07K7/56—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation not occurring through 2,4-diamino-butanoic acid

Definitions

  • the present invention provides a process for preparing a novel intermediate of Formula IV,
  • antifungal agent such as caspofungin, derivatives, and pharmaceutically acceptable salts thereof.
  • Echinocandins and echinocandin-like cyclohexapeptide compounds are described in literature as highly effective antifungal agents, particularly against yeast causing myotic infections such as Candida albicans, Candida parapsilosis, and the like.
  • Some of these compounds are natural products produced by the cultivation of microorganisms, such as Aspergillus rugulosus, Aspergillus nidulans and Acrophialophoria lemonispora described in U.S. Patent Nos. 4,024,245; 4,024,246; and 4,173,629 respectively.
  • Some of these compounds are semisynthetic and can be produced by modifying the natural products as described in U.S. Patent Nos. 4,293,489; 4,320,053; 4,370,054; 4,322,338; 5,378,804; 5,965,525; and 5,376,634.
  • Cancidas® (caspofungin acetate), l-[(4R,5S)-5-[(2-aminoethyl)amino]-N 2 -(10,12- dimethyl-loxotetradecyl)-4-hydroxy-L-ornithine]-5-[(3R)-3-hydroxy-L-ornithine] pneumocandin Bo diacetate (salt), is the first of a new class of antifungal drugs (echinocandins) that inhibit the synthesis of ⁇ (l,3)-D-glucan, an integral component of the fungal cell wall.
  • echinocandins antifungal drugs
  • Candida infections like: intra-abdominal abscesses, peritonitis and pleural space infections. It is also indicated for the treatment of invasive aspergillosis in patients who are refractory to or intolerant of other therapies (i.e., amphotericin B, lipid Formulations of amphotericin B, and/or itraconazole). It is further indicated for the treatment of esophageal candidiasis.
  • U.S. Patent No. 5,378,804 discloses the reaction of pneumocandin B 0 with 2- aminoethanethiol in the presence of an acid, followed by oxidation to give sulfone which is made to react with ethylene diamine to give caspofungin in low yields; resulting from the lack of stereoselectivity and chemoselectivity of the process.
  • U.S. Patent No. 5,552,521 describes the process for the preparation of caspofungin involving the reduction of the pneumocandin Bo followed by the reaction with thiophenol and displacement of phenyl-thio group with ethylene diamine.
  • U.S. Patent No. 5,936,062 describes the process involving the reaction of pneumocandin B 0 with boronic acid, followed by reduction and then reaction with thiophenol, which upon displacement with ethylene diamine, provides caspofungin.
  • the present invention provides a process for preparing a novel intermediate which can be effectively used for the preparation of antifungal agents such as caspofungin, derivatives, and pharmaceutically acceptable salt thereof.
  • the present invention provides a process for preparing a novel intermediate of Formula IV,
  • Ri is hydrogen, Ci -C 4 alkyl, halogen, nitro, hydroxy, Ci-C 4 alkoxy;
  • R 2 is Ci_C 2 o alkyl, C 1 -C 2 0 alkoxy, C 2 -C 2 0 alkenyl, aryl optionally substituted with Rx, wherein Rx is hydrogen, halogen, amino, hydroxyl, Ci-Ci 0 alkyl, Ci-Ci 0 alkoxy, aryl or Cs-Coheteroaryl, which can be effectively used for the preparation of antifungal agents.
  • the invention further provides a process for preparing caspofungin, derivatives, and pharmaceutically acceptable salts thereof.
  • One aspect of the present invention provides a process for preparing a novel intermediate of Formula IV,
  • R x is hydrogen, C 1 -C 4 alkyl, halogen, nitro, hydroxy, C 1 -C 4 alkoxy
  • R 2 is Ci-C 20 alkyl, Ci-C 20 alkoxy, C 2 -C 20 alkenyl, aryl optionally substituted with Rx, wherein Rx is hydrogen, halogen, amino, hydroxyl, Ci-Ci 0 alkyl, Ci-Ci 0 alkoxy, aryl or Cs-Ceheteroaryl,
  • the process comprises the steps of: a) converting a compound of Formula I
  • R2 is C1-C20 alkyl, C1-C20 alkoxy, C2- C 20 alkenyl, aryl optionally substituted with Rx, wherein Rx is hydrogen, halogen, amino, hydroxyl, C1-C10 alkyl, C1-C10 alkoxy, aryl or C5-C6 heteroaryl.
  • the process comprises the steps of: a) reacting a compound of Formula I with cyanuric chloride
  • the present invention provides a novel intermediate of Formula IV,
  • Ri is hydrogen, Ci -C 4 alkyl, halogen, nitro, hydroxy, Ci-C 4 alkoxy
  • R 2 is Ci C 2 0 alkyl, C 1 -C 2 0 alkoxy, C 2 -C 2 0 alkenyl, aryl optionally substituted with Rx, wherein Rx is hydrogen, halogen, ammo, hydroxyl, Q-Cio alkyl, Ci-Ci 0 alkoxy, aryl or Cs-Cgheteroaryl.
  • a pharmaceutical composition comprising: a) a compound of Formula V
  • R 2 is -(CH 2 )SCH(CH 3 )CH 2 CH(CH 3 )CH 2 CH 3 ); and b) one or more compound selected from
  • the compounds in component b) are present in an amount up to 2% (suitably up to 0.2%), based upon 100% total weight of components a) and b).
  • the compound in component a), i.e., the active ingredient is preferably present in an amount greater than 95% and more preferably greater than 98% or 99% based upon 100% total weight of component a) and b).
  • alkyl refers to a straight or branched chain alkyl group optionally substituted with 1-3 halogen, C 1 -C 5 alkoxy, hydroxy or amino.
  • Representative examples include C 1 -C 2 0 alkyl such as methyl, ethyl, propyl, butyl or - (CH 2 )SCH(CH 3 )CH 2 CH(CH 3 )CH 2 CH 3 ).
  • alkoxy includes straight or branched alkyl as defined above attached via an oxygen linkage to the rest of the molecule. Representative examples include methoxy or ethoxy.
  • alkenyl includes straight or branched alkyl group as defined above having unsaturation.
  • aryl includes aromatic radicals having in the range of 6 to 14 carbon atoms such as phenyl, napthyl, biphenyl, and the like.
  • heteroaryl includes saturated or unsaturated 5 or 6 membered cyclic radical where-in one or two carbon atoms in the ring may be replaced by N or O; which may be optionally substituted with C 1 -C 1 0 alkyl, C 1 -C 1 0 alkoxy, halogen or amino.
  • halogen includes fluorine, chlorine, bromine or iodine.
  • room temperature means a temperature range of about 25° C to about 30 0 C.
  • pharmaceutically acceptable salts includes the acid addition salts of inorganic acids, (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid or the like), or organic acids, (e.g., acetic acid, trifluoroacetic acid fumaric acid, citric acid, succinic acid, tartaric acid, maleic acid, oxalic acid, malic acid, glutamic acid, or the like).
  • inorganic acids e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid or the like
  • organic acids e.g., acetic acid, trifluoroacetic acid fumaric acid, citric acid, succinic acid, tartaric acid, maleic acid, oxalic acid, malic acid, glutamic acid, or the like.
  • the present invention provides a process for preparing a novel intermediate of
  • Ri is hydrogen, Ci -C 4 alkyl, halogen, nitro, hydroxy, Ci-C 4 alkoxy
  • R 2 is Ci-C 2 O alkyl, Ci-C 2 O alkoxy, C 2 -C 2 O alkenyl, aryl optionally substituted with Rx, wherein Rx is hydrogen, halogen, amino, hydroxyl, Ci-Cio alkyl, Ci-Cio alkoxy, aryl or Cs-Ceheteroaryl.
  • the process comprises the steps of: a) converting a compound of Formula I
  • the step a) involves converting a compound of Formula I to a compound of Formula III, wherein the conversion can be effected by dehydrating the compound of Formula I to give a compound of Formula II, which upon reduction gives a compound of Formula III.
  • the dehydrating agent used in step a) can be selected from anhydrides (e.g., acetic anhydride or trifluoroacetic anhydride); acid chlorides (e.g., cyanuric chloride, oxalyl chloride, phosphorus oxychloride, thionyl chloride, p- toluenesulfonyl chloride or chlorosulfonyl isocyanate); phosphonium reagents (e.g., phosphorus pentaoxide, phosphorus pentachloride, triphenylphosphine/carbon tetrachloride, triphenylphosphonium ditriflate or triphenylphosphonium dichloride); carbodiimides (e.g., dicyclohexylcarbodiimide or the like) or other dehydrating agents (e.g., aluminum chloride, titanium tetrachloride or ethyl(carboxysulfamoyl
  • Suitable solvents used in the dehydration step may include from polar aprotic solvents (e.g., dimethylformamide, dimethylsulf oxide, N-methylpyrrolidine or dime thy lacetamide), weakly basic solvents (e.g., pyridine, collidine or the like).
  • the reducing agent used in this step may include metal hydrides (e.g., sodium borohydride, sodium borohydride with cobaltous chloride, sodium borohydride with nickel chloride hexahydrate, lithium aluminum hydride, diborane, diisobutyl aluminum hydride or the like), catalytic reducing agents (e.g., palladium on carbon, platinum oxide, or rhodium on alumina or the like).
  • Step a) may also be carried out by reducing a compound of Formula I directly to a compound of Formula III, wherein the reducing agents may include borane complex (e.g., borane in tetrahydrofuran, dimethylsulfide, diphenylsulfide, dibenzylsulfide, 1 ,4-oxathiane or chloroborohydride in dimethylsulfide), metal boride (sodium borohydride with zirconium chloride or titanium chloride, titanium or zirconium borides), or as exemplified in U.S. Patent Nos. 5,348,940; 5,378,804, or 6,030,944.
  • borane complex e.g., borane in tetrahydrofuran, dimethylsulfide, diphenylsulfide, dibenzylsulfide, 1 ,4-oxathiane or chloroborohydride in dimethylsulfide
  • metal boride
  • Step b) can be carried out in presence of an acid in a polar aprotic solvent to give a compound of Formula IV.
  • the acid may be organic acids (e.g., acetic acid, formic acid, camphor sulfonic acid, methane sulfonic acid, trifluoromethanesufonic acid, monochloroacetic acid, dichloroacetic acid, trichloroacetic acid or trifluoroacetic acid), inorganic acids (e.g., hydrochloric acid, sulfuric acid or phosphoric acid), or a mixture thereof.
  • organic acids e.g., acetic acid, formic acid, camphor sulfonic acid, methane sulfonic acid, trifluoromethanesufonic acid, monochloroacetic acid, dichloroacetic acid, trichloroacetic acid or trifluoroacetic acid
  • inorganic acids e.g., hydrochloric acid, sulfuric acid or phospho
  • the polar aprotic solvent may include dimethylformamide, dimethylsulf oxide, acetate (e.g., ethyl acetate or the like), nitriles (e.g., acetonitrile, propionitrile, or the like), ketones (e.g., acetone, diethylketone, methylethylketone or the like) or a mixture thereof.
  • a compound of Formula I may be treated with acid chloride such as cyanuric chloride, oxalyl chloride, phosphorus oxychloride or thionyl chloride, suitably cyanuric chloride in dimethylformamide at low temperature to give a compound of Formula II.
  • the compound of Formula II may be reduced using any reducing agent known to a person of ordinary skill in the art including for example, sodium borohydride in the presence of nickel chloride hexahydrate.
  • the compound of Formula III is reacted with a compound of Formula VI, (e.g., 1-hydroxybenzotriazole) in the presence of triflouroacetic acid in acetonitrile to give an intermediate of Formula IV.
  • a compound of Formula VI e.g., 1-hydroxybenzotriazole
  • the intermediate of Formula IV may be prepared by reacting a compound of Formula I with a compound of Formula VI to give a compound of Formula Ha,
  • the intermediate of Formula IV may be prepared by dehydrating a compound of Formula I to give a compound of Formula II, which upon reaction with a compound of Formula VI, gives a compound of Formula Ilia.
  • the above process further comprises converting an intermediate of Formula IV to a compound of Formula V (e.g., caspofungm), or pharmaceutically acceptable salts thereof.
  • a compound of Formula V e.g., caspofungm
  • Ri is hydrogen and R 2 is Ci-C 20 alkyl group, preferably -(CH 2 ) S CH(CH 3 )CH 2 CH(CH 3 )CH 2 CH 3 ).
  • the present invention also provides a process for preparing a compound of Formula V,
  • R 2 is Ci C 2 o alkyl, Ci-C 2O alkoxy, C 2 -C 2O alkenyl, aryl optionally substituted with Rx, wherein Rx is hydrogen, halogen, ammo, hydroxyl, Ci-Cio alkyl, Ci-Cio alkoxy, aryl or Cs-Ceheteroaryl.
  • the process comprises the steps of: a) reacting a compound of Formula I with cyanuric chloride
  • step a) may be carried out in a solvent including a polar aprotic solvent (e.g., dimethylformamide, dimethylsulfoxide, N-methylpyrrolidine or dimethylacetamide), weakly basic solvent (e.g., pyridine, collidine or the like), or a mixture thereof.
  • a polar aprotic solvent e.g., dimethylformamide, dimethylsulfoxide, N-methylpyrrolidine or dimethylacetamide
  • weakly basic solvent e.g., pyridine, collidine or the like
  • Step b) may be carried out in presence of one or more reducing agents including metal hydrides (e.g., sodium borohydride, sodium borohydride with cobaltous chloride, sodium borohydride with nickel chloride hexahydrate, aluminum hydride, diborane, diisobutyl aluminum hydride or the like), catalytic reducing agents (e.g., palladium on carbon, platinum oxide, or rhodium on alumina or the like), or a mixture thereof.
  • metal hydrides e.g., sodium borohydride, sodium borohydride with cobaltous chloride, sodium borohydride with nickel chloride hexahydrate, aluminum hydride, diborane, diisobutyl aluminum hydride or the like
  • catalytic reducing agents e.g., palladium on carbon, platinum oxide, or rhodium on alumina or the like
  • Step c) may be carried out in the presence of an acid in a polar aprotic solvent.
  • the acid may include organic acids (e.g., acetic acid, formic acid, camphor sulfonic acid, methane sulfonic acid, trifluoromethanesufonic acid, monochloroacetic acid, dichloroacetic acid, trichloroacetic acid or trifluoroacetic acid), inorganic acids (e.g., hydrochloric acid, sulfuric acid or phosphoric acid), or mixtures thereof.
  • organic acids e.g., acetic acid, formic acid, camphor sulfonic acid, methane sulfonic acid, trifluoromethanesufonic acid, monochloroacetic acid, dichloroacetic acid, trichloroacetic acid or trifluoroacetic acid
  • inorganic acids e.g., hydrochloric acid, sulfuric acid or phosphoric acid
  • the polar aprotic solvent may include dimethylformamide, dimethylsulfoxide, acetate (e.g., ethyl acetate or the like), nitriles (e.g., acetonitrile, propionitrile or the like), ketones (e.g., acetone, diethylketone, methylethylketone or the like), or mixtures thereof.
  • Step d) involves reacting a compound of Formula IV with ethylene diamine and optionally converting the compound of Formula V (wherein Ri is hydrogen, R 2
  • the present invention further provides a compound having the structure of
  • Ri is hydrogen, C 1 -C 4 alkyl, halogen, nitro, hydroxy, Ci-C 4 alkoxy
  • R 2 is Ci_C 2 o alkyl, Ci-C 2 O alkoxy, C 2 -C 2 O alkenyl, aryl optionally substituted with Rx, wherein Rx is hydrogen, halogen, amino, hydroxyl, Ci-Cio alkyl, Ci-Ci 0 alkoxy, aryl or C5-C6 heteroaryl.
  • R x is hydrogen and R 2 is Ci- C 20 alkyl group, preferably -(CH 2 )8CH(CH3)CH 2 CH(CH3)CH 2 CH3).
  • Example 1 Preparation of a Compound of Formula II (wherein R 2 is - (CH 2 )RCH(CH 3 )CH 2 CH(CH 3 )CH 2 CH 3 )
  • Cyanuric chloride (3.11 g; 16.90 mmole) was added to a solution of Pneumocandin B 0 (20 g, 18.78 mmole) in dry dimethylformamide (200 mL; water content below 0.10% (w/w)) at about -30° C for about 20 hours. After the completion of reaction, water (200 mL) was added over 15 minutes and the mixture was warmed to room temperature. The above mixture was slowly poured into vigorously stirred water (2400 mL) at ambient temperature. The suspension was stirred for about 2 hours and filtered.
  • reaction mixture was poured into ortho phosphoric acid solution in water (7%; 373 mL) at about 0° C.
  • tetrahydrofuran 200 mL
  • the above suspension was stirred at about 0° C to 5° C for 3 to 4 hours.
  • the above solution was saturated with sodium chloride (55 g).
  • the organic layer was separated and mixed with water (300 mL) at a temperature range of about 5° C to 10° C.
  • the pH of the mixture was adjusted to about 6.5 using sodium bicarbonate solution in water (5%; 140 mL).
  • the above suspension was stirred at a temperature range of about 5° C to 10° C for about 1 hour.
  • the solid was isolated by filtration further washed with acetonitrile (50 mL) and dried at room temperature.
  • the pH of the above suspension was adjusted to about 6.5 using saturated dipotassium hydrogen phosphate (K 2 HP ⁇ 4 ; 100 mL) at 0° C. After decanting the upper clear solution, sticky solid thus obtained was stirred with water (50 ml) at room temperature for 1 hour and the solid was filtered. The solid was collected and dried at room temperature.
  • K 2 HP ⁇ 4 saturated dipotassium hydrogen phosphate
  • the above solid was purified by reverse phase chromatography using the acetonitrile and orthophosphoric acid (0.1% in water) as eluent in the ratio 20:80.
  • the rich cuts were combined and concentrated to provide 0.5 g of compound of Formula V with 97% HPLC purity.
  • the above solid can be purified by reverse phase chromatography using acetonitrile and acetic acid (0.1% in water) as eluent in the ratio 20:80.
  • Example 4 The compound of Formula V (Example 4; 0.20 g) was dissolved in ethanol (2.30 mL) and water (0.20 mL) at room temperature. To this solution was added acetic acid (0.012 mL) at about 10° C followed by slow addition (1 hour) of ethyl acetate (5.0 mL). After stirring at room temperature for 30 minutes, the solid was filtered under inert atmosphere to get caspofungin diacetate.

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Abstract

La présente invention concerne un procédé de préparation d'un nouvel intermédiaire de Formule (IV) qui peut être employé de façon efficace dans la synthèse d'un agent antifongique comme la caspofungine, ainsi que ses dérivés et ses sels de qualité pharmaceutique.
PCT/IB2009/055526 2008-12-04 2009-12-04 Procédé de préparation d'un nouvel intermédiaire de la caspofungine Ceased WO2010064219A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012010092A1 (fr) * 2010-07-20 2012-01-26 上海天伟生物制药有限公司 Méthode de synthèse et applications d'un cristal de substance peptidique
WO2012062213A1 (fr) 2010-11-10 2012-05-18 上海天伟生物制药有限公司 Analogue de la casponfungine et ses applications
DE112011103711T5 (de) 2010-11-10 2013-08-08 Shanghai Techwell Biopharmaceutical Co., Ltd. Caspofungin-Analogen Herstellungsverfahren dafür und Verwendung desselben
DE112011103715T5 (de) 2010-11-10 2013-08-29 Shanghai Techwell Biopharmaceutical Co., Ltd. Herstellungsverfahren für Caspofungin
US9446091B2 (en) 2011-04-22 2016-09-20 Shanghai Techwell Biopharmaceutical Co., Ltd. Caspofungin or salts thereof with high purity, as well as preparation method and use thereof
CN109721640A (zh) * 2017-10-31 2019-05-07 鲁南制药集团股份有限公司 一种卡泊芬净中间体及其合成方法

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012010092A1 (fr) * 2010-07-20 2012-01-26 上海天伟生物制药有限公司 Méthode de synthèse et applications d'un cristal de substance peptidique
KR20130060267A (ko) * 2010-07-20 2013-06-07 샹하이 테크웰 바이오파마슈티컬 컴퍼니, 리미티드 펩타이드계 물질의 결정체 및 그의 제조방법과 용도
US8969309B2 (en) 2010-07-20 2015-03-03 Shanghai Techwell Biopharmaceutical Co., Ltd. Crystal of peptide substance as well as the preparation method and use thereof
KR101596554B1 (ko) 2010-07-20 2016-02-22 샹하이 테크웰 바이오파마슈티컬 컴퍼니, 리미티드 펩타이드계 물질의 결정체 및 그의 제조방법과 용도
WO2012062213A1 (fr) 2010-11-10 2012-05-18 上海天伟生物制药有限公司 Analogue de la casponfungine et ses applications
DE112011103711T5 (de) 2010-11-10 2013-08-08 Shanghai Techwell Biopharmaceutical Co., Ltd. Caspofungin-Analogen Herstellungsverfahren dafür und Verwendung desselben
DE112011103715T5 (de) 2010-11-10 2013-08-29 Shanghai Techwell Biopharmaceutical Co., Ltd. Herstellungsverfahren für Caspofungin
US9446091B2 (en) 2011-04-22 2016-09-20 Shanghai Techwell Biopharmaceutical Co., Ltd. Caspofungin or salts thereof with high purity, as well as preparation method and use thereof
DE112012001839B4 (de) 2011-04-22 2019-02-07 Shanghai Techwell Biopharmaceutical Co., Ltd. Caspofungindiacetat mit hoher Reinheit sowie Herstellungsverfahren und Verwendung dafür
CN109721640A (zh) * 2017-10-31 2019-05-07 鲁南制药集团股份有限公司 一种卡泊芬净中间体及其合成方法

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