WO1999045012A1 - Procede de production de derives d'avermectine b¿1? - Google Patents

Procede de production de derives d'avermectine b¿1? Download PDF

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Publication number
WO1999045012A1
WO1999045012A1 PCT/JP1999/001001 JP9901001W WO9945012A1 WO 1999045012 A1 WO1999045012 A1 WO 1999045012A1 JP 9901001 W JP9901001 W JP 9901001W WO 9945012 A1 WO9945012 A1 WO 9945012A1
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WO
WIPO (PCT)
Prior art keywords
substituted
general formula
unsubstituted
same
hydroxyl
Prior art date
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PCT/JP1999/001001
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English (en)
Japanese (ja)
Inventor
Shiro Terashima
Tadashi Katoh
Etsuko Saitoh
Original Assignee
Kyowa Hakko Kogyo Co., Ltd.
Sagami Chemical Research Center
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Kyowa Hakko Kogyo Co., Ltd., Sagami Chemical Research Center filed Critical Kyowa Hakko Kogyo Co., Ltd.
Priority to AU32740/99A priority Critical patent/AU3274099A/en
Publication of WO1999045012A1 publication Critical patent/WO1999045012A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
    • C07D493/20—Spiro-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a manufacturing method suitable for industrial production of Eibameku Chin B 1 derivatives are veterinary anthelmintic ivermectin and its raw material.
  • Ivamectin an animal anthelmintic agent represented by [Antimicrobial Agents and Chemotherapy]
  • Evamectin B la represented by the following formula (V ila)
  • the method for converting an aivamectin B 2a derivative into an aivamectin B la derivative is as follows: 1) A method for thermally decomposing an 23-0- (4-methoxyphenoxyloxythiocarbonyl) aivamectin B 2a derivative [tetrahedron. (Tetrahedron Lett.), 23, 2377-2378 (1982)], 2) Oxidative cleavage of C22 and C23 positions with 5,4 "-bis (O-t-butyldimethylsilyl) eivamectin B 2a derivative A method for reconstructing a spiro ring system (EP 0, 428, 286) has been reported.
  • a method for obtaining an ibamectin derivative by directly removing the hydroxyl group at the C23 position of the aivamectin B 2a derivative includes a method of preparing a 23-O— (4-methoxyphenoxyloxycarbonyl) aivamectin B 2a derivative by hydrogenating triptyltin. [Tetrahedron Lett., 2372-2378 (1982)], but is not suitable as an industrial production method because highly toxic triptyltin hydride is used. It is.
  • An object of the present invention is to provide a production method suitable for industrial production of an anthelmintic agent for animals, ibamectin, and an aivamectin Bi derivative as a raw material for producing the same. Disclosure of the invention
  • the present invention provides a compound represented by the general formula (I):
  • R 1 represents a substituted or unsubstituted lower alkylsulfonyl or a substituted or unsubstituted arylsulfonyl
  • R 2 and R 3 are the same or different and represent a hydroxyl-protecting group
  • R 4 Represents a methyl or ethyl
  • 23-O-sulfonyl eivamectin B 2 derivative represented by the general formula (II) which is subjected to a desulfonate reaction in the presence of a dibasic acid diammonium.
  • the present invention provides a compound represented by the general formula (IV):
  • R 4 has the same meaning as described above.
  • the alkyl in the substituted or unsubstituted alkylsulfonyl represents a linear or branched alkyl having 1 to 8 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl. , Sec-butyl, tert-butynole, pentinole, isopentinole, neopentinole, 2-pentinole, 3-pentyl, hexyl, heptyl, octyl, 2-ethylpropyl, 2-methylpentyl, 2-ethylbutyl, 2-ethylpentyl, etc. .
  • aryl in the substituted or unsubstituted arylsulfonyl examples include phenyl, naphthyl, anthryl and the like.
  • Substituents on substituted alkylsulfonyl include one to three halogen atoms.
  • substituent of the substituted arylsulfonyl include 1 to 3 halogen atoms, nitro, and alkyl.
  • halogen atom include fluorine, chlorine, bromine, and iodine atoms.
  • alkyl include those similar to the above.
  • R 1 preferred specific examples include, as substituted or unsubstituted alkylsulfonyl, methanesulfonyl, chloromethanesulfonyl, bromomethanesulfonyl, trifluoromethanesulfonyl, and the like.
  • substituted arylsulfonyl include benzenesulfonyl, p-chlorobenzenesensolephoninole, p-bromobenzenesnorefoninole, p-nitrobenzenesulfonyl, p-toluenesulfonyl and the like.
  • hydroxyl-protecting group those usually used as a hydroxyl-protecting group can be used, and examples thereof include benzyl, p-chlorobenzyl, trityl, and t-butyl, and preferably, trimethylsilyl and t-butyl.
  • Alkyl- or aryl-substituted silyls such as butyldimethylsilyl, triethylsilyl, triisopropylsilyl, t-butyldiphenylsilyl and the like can be mentioned. Among them, t-butyldimethylsilyl is more preferably used.
  • alkyl or aryl represents the same as above.
  • Compound (III) has the general formula (VII)
  • R 4 is as defined above.
  • R 4 is is Eibamekuchin B 2a ones Echiru, also, R 4 is is Eibamekuchin B 2b as methyl
  • Compound (I) can be prepared by substituting a sulfonyl substituted or unsubstituted at the C23 hydroxyl group of compound (III) by a known method, for example, TW Green (Greene) et al., Protective Groups 'in' Organic Synthesis (Protective Synthesis). Groups in Organic Synthesis) Second Edition, John-Wiley & Sons, New York, 1991, p117-118.
  • the compound (VII) (Eivamectin B 2a or B 2b ) as a raw material can be obtained as a secondary metabolite of an actinomycete belonging to the genus Streptomyces. ([Anti-micro vial. Agent 'and' Chemotherapy
  • the compound (VII) is typically remain force mixture obtained as a mixture containing Eibamekuchin B 2 a and Eibamekuchin B 2 b, it may be used as a raw material for the production method of the present invention.
  • the Eibamekuchin B 2 a or Eibamekuchin B 2 b may be as a raw material for manufacturing methods of the present invention isolated.
  • examples of the dibasic acid diammonium used in the desulfonate reaction include dicarboxylic acid di (quaternary ammonium), and in particular, the compound represented by the general formula (V)
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , shaku ⁇ !! are the same or different and are alkyl, cycloalkyl, substituted or unsubstituted aralkyl, substituted Or an unsubstituted aryl or a substituted or unsubstituted heterocyclic group,
  • X is a single bond, methylene, alkylidene, hydroxyl-substituted or unsubstituted alkylene, cycloalkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted Alkynylene or a substituted or unsubstituted arylene) is preferably used.
  • the alkyl includes a linear or branched alkyl having 1 to 15 carbon atoms, for example, methyl, ethyl, propyl, isopropyline, butynole, sec-butyl. Tert-butyl, pentynole, isopentinole, neopentyl, hexyl, heptyl, octinole, decyl, dodecinole, pentadodecyl and the like.
  • cycloalkyl having 3 to 12 carbon atoms, for example, cyclopropyl, cycloalkyl Pentyl, cyclohexyl, cyclododecanyl, decalyl and the like.
  • aralkyl include those having 7 to 15 carbon atoms, such as benzyl, phenethyl, and naphthylmethyl.
  • aryl and arylene portion of arylene examples include phenyl, naphthyl, and antril.
  • heterocyclic group examples include an aromatic heterocyclic group and a saturated or partially unsaturated heterocyclic group.
  • aromatic heterocyclic group examples include a 5-membered or 6-membered monocyclic aromatic heterocyclic group containing 1 to 4 nitrogen atoms, a fused bicyclic aromatic heterocyclic group composed of 5 and 6 members, or Examples include 6-membered and 6-membered fused bicyclic aromatic heterocyclic groups.
  • Specific examples include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and pyrrolyl.
  • saturated or partially unsaturated heterocyclic group examples include a 5-membered, 6-membered or 7-membered monocyclic heterocyclic group, a 6-membered and 6-membered condensed heterocyclic group, and the like.
  • Alkylidene includes those having 2 to 8 carbon atoms, for example, ethylidene, propylidene, butylidene, pentylidene, hexylidene, otatilidene and the like.
  • alkylene examples include straight or branched ones having 2 to 8 carbon atoms, for example, ethylene, propylene, butylene, pentylene, hexylene, octylene and the like.
  • cycloalkylene examples include those having 3 to 8 carbon atoms, for example, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cyclooctylene and the like.
  • Alkenylene includes straight or branched ones having 2 to 8 carbon atoms, such as ethenylene, propenylene, butenylene, octenylene and the like.
  • Alkynylene includes straight or branched ones having 2 to 8 carbon atoms, such as ethynylene, propynylene, butynylene, octynylene and the like.
  • Examples of the substituent of the substituted aralkyl, aryl, heterocyclic group, alkenylene, alkynylene or arylene include the same or different one to three halogens or alkoxy.
  • the halogen may be the same as described above.
  • Examples of the alkyl moiety of the alkoxy include the same alkyl groups as those described above.
  • Specific examples of the substituted aralkyl include 4-methoxybenzyl and 4-chloromethyl benzyl.
  • Specific examples of the substituted aralkyl include 4-methoxyphenyl,
  • hydroxyl-substituted alkylene refers to alkylene substituted with 1 to 3 hydroxyl groups.
  • the compound (V) preferably, bis (oxalate oxalate), bis (malonate) (tetrabutynoleammonium), bis (methylenomalonate)
  • tetrabutylammonium salt is preferred, and bis (tetrabutylammonium) oxalate is more preferably used.
  • Compound (V) can be obtained by purchasing a commercially available product or by synthesizing it by a known method.
  • bis (tetrabutylammonium oxalate) can be obtained by using hydroxytetrabutylammonium hydroxide. It can be obtained by neutralizing the aqueous solution with oxalic acid dihydrate, concentrating to dryness, and azeotropically evaporating with toluene to completely remove water (Tetrahedron Lett. ), 111-113 (1972)] Further, other dibasic acid diammonium can be prepared in substantially the same manner.
  • dibasic acids Jianmoniumu relative to compound (I) (2 3- O- sulfonyl Rays fit cutin B 2 derivatives) used 1-5 0 equivalents, preferably 2-2 0 equivalent, more preferably 10 equivalent is used.
  • the desulfonate reaction is carried out in a solvent, and any solvent can be used as long as it does not participate in the reaction.
  • the reaction solvent include ketones such as acetone and ethyl methyl ketone, ethers such as acetonitrile, tetrahydrofuran, 1,2 dimethyloxetane and dioxane, aromatic compounds such as benzene, toluene and xylene, and pyridine.
  • fatty acid esters such as ethyl acetate, and alcohols such as isopropyl alcohol and t-butyl alcohol.
  • aromatic compounds such as benzene and toluene and alcohols such as t-butyl alcohol are preferable.
  • benzene, toluene, ethyl acetate and t-butyl alcohol are preferable, and t-butyl alcohol is more preferably used.
  • the reaction is usually performed at 150 to 120 ° C, preferably at 10 to 60 ° C, and more preferably at 10 to 60 ° C.
  • Protecting groups for the C5 and C4 "hydroxyl groups of the compound (II) obtained by the desulfonate reaction can be determined by known methods, for example, TW Green et al., Protective Gnorapes in Organic Synthesis. (Protective Groups in Organic Synthesis) 2nd edition, John-Wiley & Sons, New York, 1991, ⁇ 68-86. (VI)
  • R 4 is as defined above. Wherein a is Eibamekuchin B la those wherein R 4 is Echiru, R 4 those methyl and is Eibamekuchin B lb) Eibameku Chin B i a or Eibamekuchin B represented by b can be obtained.
  • the method of the present invention Eibamekuchin from mixed compounds of Eibamekuchin B 2a and Eibamekuchin B 2b B, can also produce a mixture of a and Eibamekuchin B i b, such embodiments are also within the scope of the present invention Things.
  • unreacted raw materials eivamectin B 2a and / or eivamectin B 2b can be recovered after the desulfonate reaction, and the recovered raw material is further subjected to the desulfonate reaction. Can be.
  • Compound (IV) can be produced by hydrogenating the double bond between carbons 22 and 23 according to the method described in the gazette.
  • ivamectin in which R 4 is ethyl / is useful for applications such as an anthelmintic for animals.
  • the hydrogenation reaction conditions are, for example, a range from room temperature to 75 ° C. and atmospheric pressure to about 4 atm using a hydrogenation catalyst with respect to compound (VI) in a molar ratio of 0.05 to 0.5. It is preferably carried out in a reaction solvent under an ambient hydrogen atmosphere for about 1 to 48 hours.
  • a mixture of Eibamekuchin B i a and Eibamekuchin B i b can also be used as a veterinary anthelmintic agent.
  • Ibamectin can also be produced by reversing the order of the hydroxyl-protecting group deprotection step and the hydrogenation reaction step, in which case it can be carried out under the same reaction conditions as described above.
  • the reaction mixture was diluted with ethyl acetate, washed with water and saturated saline in that order, and dried over anhydrous sodium sulfate.
  • the solvent was distilled off under reduced pressure, and the obtained crude product was subjected to preparative thin-layer silica gel chromatography.
  • the production method of the present invention is suitable for industrial production of an aivamectin Bi derivative, which is a raw material for producing an animal anthelmintic agent, ibamectin.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

L'invention concerne un procédé conçu pour la production industrielle de dérivés d'avermectine B1, lesquels constituent des matériaux de départ servant à produire l'abamectine, utile en tant qu'antiparasitaire destiné aux animaux. Ce procédé consiste à désulfoner un dérivé de 23-O-sulfonyl-avermectine B2, en présence d'un sel diammonique d'un acide dibasique, afin de produire un dérivé d'avermectine B1 représenté par la formule générale (II) dans laquelle Me représente méthyle, R2 et R3 sont semblables ou différents et représentent chacun un groupe hydroxyle-protecteur, et R4 représente méthyle ou éthyle.
PCT/JP1999/001001 1998-03-05 1999-03-03 Procede de production de derives d'avermectine b¿1? WO1999045012A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU32740/99A AU3274099A (en) 1998-03-05 1999-03-03 Process for producing avermectin b1 derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP10/53010 1998-03-05
JP5301098 1998-03-05

Publications (1)

Publication Number Publication Date
WO1999045012A1 true WO1999045012A1 (fr) 1999-09-10

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Application Number Title Priority Date Filing Date
PCT/JP1999/001001 WO1999045012A1 (fr) 1998-03-05 1999-03-03 Procede de production de derives d'avermectine b¿1?

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113735924A (zh) * 2021-09-01 2021-12-03 河北威远生物化工有限公司 一种23-酮阿维菌素B2a/B2b衍生物的制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS59141582A (ja) * 1983-01-28 1984-08-14 メルク　エンド　カムパニー　インコーポレーテッド アベルメクチン及びミルベマイシンのリン酸エステル類
JPH05163277A (ja) * 1991-03-28 1993-06-29 Merck & Co Inc ４″及び４′−アルキルチオ−アベルメクチン誘導体

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS59141582A (ja) * 1983-01-28 1984-08-14 メルク　エンド　カムパニー　インコーポレーテッド アベルメクチン及びミルベマイシンのリン酸エステル類
JPH05163277A (ja) * 1991-03-28 1993-06-29 Merck & Co Inc ４″及び４′−アルキルチオ−アベルメクチン誘導体

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113735924A (zh) * 2021-09-01 2021-12-03 河北威远生物化工有限公司 一种23-酮阿维菌素B2a/B2b衍生物的制备方法

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