US20070105760A1 - Process for the preparation of echinocandin derivatives - Google Patents

Process for the preparation of echinocandin derivatives Download PDF

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Publication number
US20070105760A1
US20070105760A1 US11/591,898 US59189802A US2007105760A1 US 20070105760 A1 US20070105760 A1 US 20070105760A1 US 59189802 A US59189802 A US 59189802A US 2007105760 A1 US2007105760 A1 US 2007105760A1
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formula
compound
carried out
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hours
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Philippe Boffelli
Agnes Brouillard
Colette Colladant
Serge Droux
Michel Elter
Didier Ferroud
Guy Lemaitre
Joseph Paladino
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Priority to US11/591,898 priority Critical patent/US20070105760A1/en
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Priority to US12/830,941 priority patent/US20100273977A1/en
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems

Definitions

  • a subject of the present invention is a process for the preparation of echinocandin derivatives, the intermediates and the products obtained and their use as an antifungal medicament.
  • the objective of the present invention is to provide a new process for the preparation of echinocandin derivatives and to obtain new salts of the latter.
  • Echinocandin can be presented in the form of two epimers called isomer A and isomer B corresponding to the R and S configurations of the substituent in position 4.
  • One of the subjects of the present invention is to obtain during the process, a majority of one of the two isomers, i.e. at least greater than 50% (isomer called form A, corresponding to the pharmacologically active compound of formula (I), which is not the case for the process according to WO99/29716 during which the active isomer A obtained during the process before purification on a chromatographic column is in the minority.
  • Another objective of the present invention is to avoid purifications of the intermediate products by chromatography and to obtain crystallized products which allows a significant improvement in yields.
  • a subject of the invention is a process for the preparation of compounds of formula (I) in which R represents a linear or branched or cyclic chain containing up to 30 carbon atoms, optionally containing one or more heteroatoms and one or more heterocycles comprising the following stages a) A compound of formula (II) is subjected to the action of an acid of formula R—CO 2 H, R being as defined above, said acid being, if appropriate, in an isolated or non isolated activated form, in order to obtain the compound of formula (III) b) if appropriate, the compound of formula (III) is subjected to an alkylation reaction of the alcohol in position 5 by the action of an alcohol of formula Alk—OH in the presence of PPTS, Alk being an Alkyl radical containing 1 to 4 carbon atoms, in order to obtain the compound of formula (III′) c) the compound of formula (III) or (III′) is subjected to a dehydration reaction, in order to obtain a compound of formula (IV) d)
  • a subject of the invention is a process as defined previously in which the compounds of formulae (I), (III), (III′) or (IV) contain an R radical representing the following groups:
  • a subject of the invention is a process as defined previously in which the compounds of formulae (I), (III), (III′) or (IV) contain an R radical representing the following group:
  • the compound of formula (II) is prepared according to the method described in the International Application WO99/29716 page 18 (Preparation 2, “nucleus of deoxymulundocandin”).
  • Activation of the acid of formula R—CO 2 H is carried out according to standard methods known to a person skilled in the art (Journet M. et al, J. Org. Chem. (1999), 64, 2411-2417; Pöchlauer P. et al. Tetrahedron 54(1998) 3489-3494; Kunushima et al. Tetrahedron (1999) 55 13159-13170).
  • pentaflurophenol is used in order to obtain the activated ester of pentafluorophenol which is isolated before being used in the acylation reaction of the amine.
  • Another method is the use of N-hydroxysuccinimide (optionally N-hydroxybenzotriazole) in order to obtain the activated ester of N-hydroxysuccinimide (optionally N-hydroxybenzotriazole) which is also isolated.
  • the acylation stage which follows in order to obtain a compound of formula (III) is carried out in the presence of a base according to methods known to a person skilled in the art and is illustrated in the examples described hereafter. It is also possible to carry out the acylation without isolating the active ester and without an added base by operating in the presence of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-myl-morpholinium chloride (DMTMM). This last alternative has the advantage of suppressing an isolation stage and therefore of improving yields.
  • DTMM 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-myl-morpholinium chloride
  • the compound obtained after the dehydration reaction is then purified by crystallization from a mixture of DMF (dimethylformamide)/MeCN (acetonitile). Mixtures of the following solvents: DMF/acetone and DMF/AcOEt (ethyl acetate) can also be used.
  • DMF dimethylformamide
  • MeCN acetonitile
  • ethylenediamine is used in the presence of NaBH 3 CN by coupling with TiCl 4 or any other Lewis acid or in the presence of NaBH(OCOR′)3, OCOR′ representing Boc-L-Pro, Bzl-L-Pro or any other optically active amino acid as well as any other chiral or non chiral carboxylic acid.
  • Coupling the reduction reagent NaBH 3 CN with a Lewis acid, in particular TiCl 4 is an essential element for selectivity and therefore in order to obtain a mixture of isomer A and isomer B in which the active isomer A is in the majority.
  • a ratio of isomer A of greater than 70%, and in particular comprised between 80 and 85% is obtained. The situation is similar with the other reagents mentioned above.
  • reaction intermediate before reduction can if appropriate, be isolated, and is therefore a subject of the present invention. It is an imidazolidine of formula (IV′) or (IV′a) when R represents a —Ph—Ph—O— C 8 H 17 group
  • the salification reaction is carried out according to the usual methods known to a person skilled in the art.
  • Preparation of the hydrochloride or of the di-hydrochloride is carried out in the presence of hydrochloric acid in methanol.
  • a subject of the present invention is a process for the preparation of the compounds of formula (Ia) comprising the following stages a) A compound of formula (II) is subjected to the action of an acid of formula C 8 H 17 —O—Ph—Ph—CO 2 H, said acid being, if appropriate, in an activated, isolated or non isolated form, in order to obtain the compound of formula (IIIa) b) if appropriate the compound of formula (IIIa) is subjected to an alkylation reaction of the alcohol in position 5 by the action of methanol in the presence of PPTS in order to obtain the compound of formula (IIIa′) c) the compound of formula (IIIa) or (IIIa′) is subjected to a dehydration reaction, in order to obtain a compound of formula (IVa), d) the compound of formula (IVa) is subjected to a reducing amination reaction by the action of ethylene diamine in the presence of a reducing agent such as NaBH 3 CN coupled with TiC
  • the compound of formula (Ia) can be found in the form of a mixture of two epimers (asymmetrical carbon in position 4) which are called isomer A or isomer B.
  • the compound of formula (I) obtained according to the process as defined above allows a mixture of isomer A/isomer B of approximately 70-85%/30-15% to be obtained.
  • the compound of formula (Ia) is purified by chromatography on silica then by reversed-phase chromatography using a mixture of organic solvents, water and trifluoroacetic acid in order to obtain the trifluoroacetic acid salt of the compound of formula (Ia).
  • This salt is then subjected to the action of a base, for example by the action of an aqueous solution of sodium bicarbonate, in order to obtain the compound of formula (Ia) in the form of a base.
  • the base obtained is salified by the action of hydrochloric acid in order to obtain the corresponding salt namely the dihydrochloride of the compound of formula (Ia).
  • a quite particular subject of the invention is a process as defined previously characterized in that the activation reaction of the acid is carried out in the presence of pentafluorophenol, N-hydroxysuccinimide or optionally N-hydroxybenzotriazole.
  • a quite particular subject of the invention is a process as defined previously characterized in that the acylation reaction in the presence of an isolated activated acid, is carried out in the presence of diisopropylethylamine.
  • a quite particular subject of the invention is a process as defined previously characterized in that the activation reaction then the acylation reaction in the presence of an isolated activated acid, is carried out in the presence of N-methyl pyrrolidone and DMTMM.
  • a quite particular subject of the invention is a process as defined previously characterized in that the dehydration reaction is carried out in the presence of AIBB and if appropriate MgI 2 .
  • a quite particular subject of the invention is a process as defined previously characterized in that the dehydration reaction is carried out in the presence of HBr-AcOH and MgI 2 .
  • a quite particular subject of the invention is a process as defined previously characterized in that the product originating from the dehydration is purified by crystallization from a dimethylformamide (DMF)/acetonitrile, DMF/acetone or DMF/AcOEt mixture.
  • DMF dimethylformamide
  • a quite particular subject of the invention is a process as defined previously characterized in that the reducing amination reaction is carried out in the presence of a reducing agent chosen from NaBH 3 CN coupled with TiCl 4 , NaBH(Boc-L-Pro) 3 or NaBH(Bzl-L-Pro) 3 .
  • a reducing agent chosen from NaBH 3 CN coupled with TiCl 4 , NaBH(Boc-L-Pro) 3 or NaBH(Bzl-L-Pro) 3 .
  • a subject of the invention is also the dihydrochloride of 1-[4-[(2-aminoethyl)amino]-N-2-[[4′-(octyloxy)[1,1 ′-biphenyl]-4-yl]carbonyl]-L-ornithine]-4-[4-(4-hydroxyphenyl)-L-threonine]-5-L-serine echinocandin B in 4S or 4R form or in the form of a mixture of the two stereoisomers.
  • a subject of the invention is also the dihydrochloride of 1-[4-[(2-aminoethyl)amino]-N2-[[4′-(octyloxy)[1,1 ′-biphenyl]-4-yl]carbonyl]-L-ornithine]-4-[4-(4-hydroxyphenyl)-L-threonine]-5-L-serine echinocandin B in the form of the active isomer A obtained by the process as described previously.
  • a subject of the invention is also the dihydrochloride of 1-[4-[(2-aminoethyl)amino]-N2-[[4′-(octyloxy)[1,1′-biphenyl]-4-yl]carbonyl]-L-ornithine]-4-[4-(4-hydroxyphenyl)-L-threonine]-5-L-serine echinocandin B in 4S or 4R form or in the form of a mixture of the two stereoisomers, as a medicament and in particular as and antifungal medicament.
  • a subject of the invention is the pharmaceutical compositions containing the dihydrochloride of 1-[4-[(2-aminoethyl)amino]-N2-[[4′-(octyloxy)[1,1′-biphenyl]-4-yl]carbonyl]-L-ornithine]-4-[4-(4-hydroxyphenyl)-L-threonine]-5-L-serine echinocandin B in 4S or 4R form or in the form of a mixture of the two stereoisomers and a pharmaceutically acceptable vehicle.
  • Threonine 8.16 (1H), 4.85 (1H), 4.41 (1H), 1.13 (3H); ⁇ Hydroxyproline: 4.42 (1H), 1.92-2.28 (2H), 4.44 (1H), 3.86-3.70 (2H); ⁇ Hydroxy homo tyrosine 7.36 (1H), 4.23 (1H), 4.20 (1H), 2.53-2.46 (2H), 6.98 (2H), 6.68 (2H); Serine: 7.40 (1H), 4.86 (1H), 3.66-3.60 (2H), ⁇ Hydroxy ⁇ methyl proline: 4.27 (1H), 4.03 (1H), 2.38 (1H), 0.99 (3H), 3.25-3.93 (2H), ⁇ ornithine >>: 7.98 (1H), 5.16 (1H), 3.96 (1H), 8.54 (1H), 4.44 (1H), 1.98 (2H); Aromatic and octyloxy chain: 7.98 (2H), 7.71 (2H), 7.68 (2H), 7.02 (2H), 4.00 (2H), 1.72 (2H), 1.41 (2H), 1.
  • deoxymuluncandin prepared according to Preparation 2 of WO 99/29716
  • 8.3 ml of N-myl pyrolidone 1.12 g of octyloxybiphenyl acid and 0.95 g of 4-(4,6-Dimoxy-1,3,5-triazin-2-yl)-4-m-yl-morpholinium chloride (DMTMM) is added.
  • DTMM 4-(4,6-Dimoxy-1,3,5-triazin-2-yl)-4-m-yl-morpholinium chloride
  • the reaction medium is poured into 133 ml of water under agitation. Agitated is carried out for 20 minutes, the solid is filtered and rinsed 3 times with water (3 times 7 ml). After drying under vacuum at 40° C., 2.66 g of expected product 4 is obtained in the form of beige solid.
  • Second Stage Dehydration (Obtaining a Compound of Formula (IVa)
  • the Product is Crystallized According to the Preparation Described below.
  • Route 2 Starting from Product (IIIa) Obtained in Stage a by the Action of AIBB/MgI 2 /dioxane
  • Agitation is carried out for 2 hours, followed by distilling under vacuum to a residual volume of 250 ml at an internal temperature of less than 35° C. Atmospheric pressure of nitrogen is reestablished, and 200 ml of dimethylformamide is added, followed by distilling under vacuum to a residual volume of 250 ml and this solution is poured at ambient temperature into 2.8 litres of water. After rinsing with DMF, agitation is carried out for 1 hour. The solid is filtered and rinsed with water. The solid is dried for 24 hours under vacuum at 30° C. 46 g of expected product is obtained in the form of beige solid.
  • the Product is then Crystallized According to the Method Described below.
  • Route 3 Starting From Product IIIa Obtained in the First Stage by the Action of HBr-AcOH/MgI 2 /MEK
  • Agitating is carried out for 10 minutes, followed by decanting, reextracting the aqueous phase with a mixture of ethyl acetate/methanol and distilling all the organic phases under vacuum to a residual volume of 40 ml.
  • 40 ml of DMF is introduced and distilling is continued to a residual volume of 60 ml.
  • This solution is poured into 320 ml of water over 20 minutes and agitated for 15 hours at ambient temperature. If necessary the pH is adjusted to 9-9.5 with dilute soda, followed by filtering and rinsing with an aqueous solution of 1.2 g of sodium bicarbonate (pH 9-9.5). After drying the solid in an oven under vacuum at 30 C. for 18 hours, 8.55 g of expected crude base is obtained in the form of a white solid.
  • Hyflosupercel Kieselguhr filtration agent 20 g is added to the suspension and agitation is carried out for 16 hours at ambient temperature, followed by filtering and washing with water. The cake is dissolved by passing through 100 ml of methanol four times. The methanolic filtrate is concentrated to dryness under vacuum without exceeding 40° C. 21.25 g of expected product is obtained.
  • a suspension of the product of formula (IVa) obtained in Stage II) in 40 ml of dichloromethane and 0.32 ml of ethylene diamine is agitated for 18 hours.
  • 80 ml of diethyl ether is added and agitation is carried out for 5 hours.
  • the solid is filtered and rinsed several times with diethyl ether. After drying in an oven under vacuum for 15 hours at ambient temperature, 076 g of expected compound is obtained in the form of a white solid.
  • This intermediate is then subjected to the action of a reducing reaction according to preceding routes 1 or 2.
  • This isolated compound is new and forms part of the present invention
  • a Prochrom LC 200 column is conditioned with 2.5 g of merck 11763 silica using a methylene chloride (43)-acetonitrile (50)-methanol (7)-water (5)-trifluoroacetic acid (1) mixture as mobile phase.
  • 24 g of the compound obtained above (Stage III, route 1) is dissolved in 126 ml of a mixture composed of acetonitrile (50)-methanol (7)-water (5)-TFA (1).
  • the solution is filtered and 86 ml of methylene chloride is added. This solution is injected into the column. Elution is carried out a flow rate of 76 1/h and a pressure of 14 bars.
  • a Prochrom LC 50 column is conditioned with 300 g of reversed-phase Daisogel SP 120 n° 5/1502 silica, using a water (90)-acetonitrile (10)-trifluoroacetic acid (0.1) mixture as mobile phase. 36.75 g of the salt obtained above in the first chromatography is dissolved in a mixture comprising 57.3 ml of water (90)-acetonitrile (10)-trifluoroacetic acid (0.1) and 26.8 ml of pure acetonitrile. The solution is filtered and this solution is injected into the column.
  • Elution is carried out with water (90)-acetonitrile (10)-trifluoroacetic acid (0.1) in the first instance to remove the mineral salts, then with water (50)-acetonitrile (50)-trifluoroacetic acid (0.1) to remove the product.
  • the fractions collected are distilled under vacuum at an external temperature of less than 40° C.
  • the resultant limpid aqueous solution is lyophilized. 15.59 g of expected product is obtained in the form of a Lacty white solid di-salt of TFA.
  • 10.53 g of compound obtained in the preceding stage is dissolved in 263 ml of methanol whilst agitating for 30 minutes at ambient temperature, followed by filtering and rinsing with twice 31.6 ml of methanol.
  • 2.1 ml of 36% hydrochloric acid is added agitation and under nitrogen at ambient temperature. Agitation is carried out for 30 minutes, followed by distilling to dryness under vacuum without exceeding 35° C.
  • the dry extract is taken up in 105.3 ml of diisopropyl oxide.
  • the suspension obtained is agitated for 2 hours, followed by filtering and washing with twice 21.1 ml of diisopropyl oxide. After drying the solid in an oven under vacuum at 40.° C., 10.52 g of expected product is obtained in the form of a white powder.

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  • Animal Behavior & Ethology (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
US11/591,898 2001-12-14 2002-12-12 Process for the preparation of echinocandin derivatives Abandoned US20070105760A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US11/591,898 US20070105760A1 (en) 2001-12-14 2002-12-12 Process for the preparation of echinocandin derivatives
US12/830,941 US20100273977A1 (en) 2001-12-14 2010-07-06 Process for the preparation of echinocandin derivatives

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
FR0116230A FR2833596B1 (fr) 2001-12-14 2001-12-14 Procede de preparation de derives d'echinocandine
FR0116230 2001-12-14
US11/591,898 US20070105760A1 (en) 2001-12-14 2002-12-12 Process for the preparation of echinocandin derivatives
PCT/FR2002/004308 WO2003054001A2 (fr) 2001-12-14 2002-12-12 Procede de preparation de derives d'echinocandines et leurs compositions
US10/867,070 US7148322B2 (en) 2001-12-14 2004-06-14 Process for the preparation of echinocandin derivatives

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US11/591,898 Abandoned US20070105760A1 (en) 2001-12-14 2002-12-12 Process for the preparation of echinocandin derivatives
US10/867,070 Expired - Fee Related US7148322B2 (en) 2001-12-14 2004-06-14 Process for the preparation of echinocandin derivatives
US12/830,941 Abandoned US20100273977A1 (en) 2001-12-14 2010-07-06 Process for the preparation of echinocandin derivatives

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US10/867,070 Expired - Fee Related US7148322B2 (en) 2001-12-14 2004-06-14 Process for the preparation of echinocandin derivatives
US12/830,941 Abandoned US20100273977A1 (en) 2001-12-14 2010-07-06 Process for the preparation of echinocandin derivatives

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EP (1) EP1456229B1 (sl)
JP (1) JP4510461B2 (sl)
KR (1) KR20040066167A (sl)
CN (2) CN1326872C (sl)
AR (1) AR037827A1 (sl)
AT (1) ATE441662T1 (sl)
AU (1) AU2002364991B9 (sl)
BR (1) BR0214937A (sl)
CA (1) CA2469918A1 (sl)
CO (1) CO5590934A2 (sl)
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DE (1) DE60233589D1 (sl)
DK (1) DK1456229T3 (sl)
EA (1) EA007964B1 (sl)
ES (1) ES2333784T3 (sl)
FR (1) FR2833596B1 (sl)
HK (2) HK1071900A1 (sl)
HU (1) HUP0402602A3 (sl)
IL (1) IL162385A0 (sl)
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PT (1) PT1456229E (sl)
SI (1) SI1456229T1 (sl)
TW (1) TWI322820B (sl)
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US20100197928A1 (en) * 2007-09-14 2010-08-05 Novexel Method for preparing disubstituted piperidine and intermediates

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FR2833596B1 (fr) * 2001-12-14 2005-02-18 Aventis Pharma Sa Procede de preparation de derives d'echinocandine
TW200826957A (en) * 2006-10-16 2008-07-01 Teva Gyogyszergyar Zartkoruen Mukodo Reszvenytarsasag Purification processes for echinocandin-type compounds
FR2936798B1 (fr) * 2008-10-03 2012-09-28 Novexel Nouveaux composes heterocycliques azotes, leur preparation et leur utilisation comme medicaments antibacteriens.
FR2937034B1 (fr) * 2008-10-10 2012-11-23 Novexel Nouveaux composes heterocycliques azotes, leur preparation et leur utilisation comme medicaments antibacteriens
FR2936951B1 (fr) * 2008-10-10 2010-12-03 Novexel Nouvelles combinaisons de composes heterocycliques azotes antibacteriens avec d'autres composes antibacteriens et leur utilisation comme medicaments
CN101928670B (zh) 2009-09-24 2012-02-22 上海天伟生物制药有限公司 一种抗生素的高产菌株及其制备方法和用途
CN102659930B (zh) * 2012-03-30 2014-04-23 上海天伟生物制药有限公司 一种高纯度环肽类物质的晶体及其制备方法和用途
CN102627689B (zh) * 2012-03-30 2014-08-06 上海天伟生物制药有限公司 一种环肽类化合物的水合物及其制备方法和用途
CN102627688B (zh) * 2012-03-30 2014-12-31 上海天伟生物制药有限公司 一种高纯度环肽化合物及其制备方法和用途
EP3464319A4 (en) * 2014-10-07 2020-02-26 Alaparthi, Lakshmi Prasad INTERMEDIATES AND PROCESSES FOR THE PREPARATION OF ANIDULAFUNGIN
CN112646854B (zh) * 2020-12-11 2022-10-11 浙江工业大学 一种棘白菌素b合成培养基及应用
CN115785226A (zh) * 2021-09-09 2023-03-14 上海天伟生物制药有限公司 一种棘白菌素药物杂质及其制备、纯化方法和应用

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EP1456229B1 (fr) 2009-09-02
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TW200301133A (en) 2003-07-01
DE60233589D1 (de) 2009-10-15
AR037827A1 (es) 2004-12-09
AU2002364991A1 (en) 2003-07-09
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CN1326872C (zh) 2007-07-18
EA200400806A1 (ru) 2004-12-30
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