WO1999045012A1

WO1999045012A1 - Process for producing avermectin b1 derivatives

Info

Publication number: WO1999045012A1
Application number: PCT/JP1999/001001
Authority: WO
Inventors: Shiro Terashima; Tadashi Katoh; Etsuko Saitoh
Original assignee: Kyowa Hakko Kogyo Co., Ltd.; Sagami Chemical Research Center
Priority date: 1998-03-05
Filing date: 1999-03-03
Publication date: 1999-09-10
Also published as: AU3274099A

Abstract

A process suitable for the industrial production of avermectin B1 derivatives which are starting materials for producing abamectin useful as an antiparasitic for animals. This process comprises desulfonating a 23-O-sulfonyl avermectin B2 derivative in the presence of diammonium salt of a dibasic acid to give an avermectin B1 derivative represented by general formula (II) (Me: methyl), wherein R?2 and R3¿ are the same or different and each represents a hydroxyl-protective group; and R4 represents methyl or ethyl.

Description

Specification

Method for producing aivamectin B ₁ derivative

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. Background art

Equation (I Va)

Ivamectin, an animal anthelmintic agent represented by [Antimicrobial Agents and Chemotherapy],

15, 372 (1979)] is the formula (Via) obtained as a secondary metabolite of actinomycetes belonging to the genus Streptomyces.

Evamectin B _la represented by the following formula (V ila)

In represented Eibamekuchin by recrystallization from a mixture of B _2a isolated Eibamekuchin B _la, double bonds Journal 'O Bed' are prepared by hydrogenating Medeishinaru between the carbon 22 and 23 positions 'Chemistry (J. Med.

Chem.), 23, 1134 (1980)].

Since conventional, can convert unwanted Eibamekuchin B _2a if introduced double bond between dehydrated 23-position hydroxyl group of the unnecessary and Eibamekuchin B _{2 a} has been discarded carbon 22-23 of useful Eibamekuchin B _la, Many attempts have been made on this transformation.

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.

However, the method (1) requires a reaction temperature of 180 ° C or higher during the pyrolysis reaction, and the method (2) requires multi-steps and requires industrial processes such as lithium hexamethyldisilazide and lead tetraacetate. The problem is that reagents that are not suitable for chemical production are used. In addition, _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):

(Wherein, 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.

(Wherein, R ² , R ³ and R ⁴ are as defined above)

Provided is a method for producing a Bi derivative.

Further, the present invention provides a compound represented by the general formula (I I I):

(Wherein R ² , R ³ and R ⁴ have the same meanings as described above), wherein a substituted or unsubstituted sulfonyl is introduced into the hydroxyl group at the C23 position of the aivamectin B ₂ derivative represented by the general formula (I)

(Wherein, RR ^2, R ³ and R ⁴ the same meaning as defined above is) 23-is represented by O - give the sulfonyl rays fit cutin B ₂ derivatives, further which dibasic acids Jianmo: presence of © beam A general formula (II) characterized by a desulfonate reaction

(Wherein, R ² , R ³ and R ⁴ are as defined above)

Provided is a method for producing a Bi derivative.

Further, the present invention provides a compound represented by the general formula (I):

(Wherein, RR ² , R ³ and R ⁴ have the same meanings as described above. Hereinafter, the compound is represented by compound (I). The compounds of other formula numbers are sometimes represented in the same manner.) 23 — Also provides O-sulfonyl eibamectin B ₂ derivatives.

The present invention provides a compound represented by the general formula (IV):

(Wherein, R ⁴ has the same meaning as described above).

Wherein RR ² , R ³ and R ⁴ have the same meanings as defined above, and a 23-O-sulfonyl eibamectin B ₂ derivative is subjected to a desulfonate reaction in the presence of a dibasic acid diammonium. General formula (II)

(Wherein, R ² , R ³ and R ⁴ have the same meanings as described above).

In the definition in the general formula, 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. .

Examples of aryl in the substituted or unsubstituted arylsulfonyl include phenyl, naphthyl, anthryl and the like.

Substituents on substituted alkylsulfonyl include one to three halogen atoms. Examples of the substituent of the substituted arylsulfonyl include 1 to 3 halogen atoms, nitro, and alkyl. Here, examples of the halogen atom include fluorine, chlorine, bromine, and iodine atoms. Examples of the alkyl include those similar to the above.

In the general formula, preferred specific examples of R ¹ include, as substituted or unsubstituted alkylsulfonyl, methanesulfonyl, chloromethanesulfonyl, bromomethanesulfonyl, trifluoromethanesulfonyl, and the like. Examples of the substituted arylsulfonyl include benzenesulfonyl, p-chlorobenzenesensolephoninole, p-bromobenzenesnorefoninole, p-nitrobenzenesulfonyl, p-toluenesulfonyl and the like.

As the 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. Here, alkyl or aryl represents the same as above. Compound (III) has the general formula (VII)

(Wherein, 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) C 5 of the compound represented by Known methods for hydroxyl groups at the C 4 "position, such as TW Greene et al., Protective Groups in Protective Groups in Organic Syntnesis, 2nd Edition, Chillon-Williant Kens Publication (John-Wiley & Sons), New York, 1991, pp. 68-86, can be obtained by introducing a hydroxyl-protecting group as described above. The compound can be introduced into the hydroxyl group at the C5 position and the C4 "position of the compound (VII) in one or more steps. After the introduction of the protecting group for the hydroxyl group, it is preferable to extract the reaction solution, purify by silica gel column chromatography, etc. to obtain the compound (III), and then introduce the next sulfonyl. preferable. 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.

In addition, 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

(Antimicrobial Agents and Chemotherapy), 15, 361 (1979), Antimicrobial Agents and Chemotherapy.

Chemotherapy), 15, 368 (1979))]. In the above method, 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.

Further, recrystallization from these mixtures, was purified operations silica gel chromatography, the Eibamekuchin B _{2 a} or Eibamekuchin B _{2 b} may be as a raw material for manufacturing methods of the present invention isolated.

In the method of the present invention, 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 ^ R ¹ ^ ¹² ^) (OOC-X-COO ")

(V)

(Wherein, R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , shaku 尺 !! 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.

In the definition in the formula of the general formula (V), 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.

As cycloalkyl, having 3 to 12 carbon atoms, for example, cyclopropyl, cycloalkyl Pentyl, cyclohexyl, cyclododecanyl, decalyl and the like. Examples of aralkyl include those having 7 to 15 carbon atoms, such as benzyl, phenethyl, and naphthylmethyl.

Examples of aryl and arylene portion of arylene include phenyl, naphthyl, and antril.

Examples of the heterocyclic group include an aromatic heterocyclic group and a saturated or partially unsaturated heterocyclic group.

Examples of the aromatic heterocyclic group 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. , Pyrazolyl, imidazolyl, triazolyl, tetrazolyl, chenyl, furyl, thiazolyl, oxazolyl, indolyl, indazolyl, benzimidazolyl, benzotriazolyl, prenyl and the like.

Examples of the saturated or partially unsaturated heterocyclic group include a 5-membered, 6-membered or 7-membered monocyclic heterocyclic group, a 6-membered and 6-membered condensed heterocyclic group, and the like. And pyrrolidinyl, piperidino, piperazinyl, morpholino, thiomorpholino, homopiperidino, homopiperazinyl, tetrahydropyridinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl and the like.

Alkylidene includes those having 2 to 8 carbon atoms, for example, ethylidene, propylidene, butylidene, pentylidene, hexylidene, otatilidene and the like.

Examples of the alkylene include straight or branched ones having 2 to 8 carbon atoms, for example, ethylene, propylene, butylene, pentylene, hexylene, octylene and the like.

Examples of the cycloalkylene 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. In this case, 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,

4 Monophenyl phenyl and the like.

The term “hydroxyl-substituted alkylene” refers to alkylene substituted with 1 to 3 hydroxyl groups.

As specific examples of the compound (V), preferably, bis (oxalate oxalate), bis (malonate) (tetrabutynoleammonium), bis (methylenomalonate)

(Tetrabutylammonium), bisethylmalonate (tetrabutylammonium), bisbutylmalonate (tetrabutylammonium), bissuccinate (tetrabutylammonium), D- or L-tartrate (Tetrabutylammonium), bis (tetrabutylammonium) 1,3-propanedicarboxylate, bis (tetrabutylammonium) fumarate, bis (tetrabutylammonium) maleate, bis (acetylenedicarboxylate) (Tetrabutylammonium), bis (tetrabutylammonium) 1,2-cyclopropanedicarboxylate, bis (tetrabutylammonium) 1,2-cyclopentanedicarboxylate, 1,2-cyclohexane Bis (tetrabutylammonium) dicarboxylate, bis (phthalate) Examples thereof include bis (tetrabutylammonium), bis (tetrabutylammonium) terephthalate or bis (tetrabutylammonium) naphthalenedicarboxylate, and other quaternary ammonium salts of the above dicarboxylic acids. Among them, 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. For example, 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.

In desulfonation acid reaction, 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. Examples of 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. And fatty acid esters such as ethyl acetate, and alcohols such as isopropyl alcohol and t-butyl alcohol. Among them, aromatic compounds such as benzene and toluene and alcohols such as t-butyl alcohol are preferable. Further, 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, ρ 68-86. (VI)

M e: methyl

(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.

Incidentally, 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.

Further, according to the method of the present invention, 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.

Furthermore, using the Eibamekuchin B _la or Eibamekuchin B _lb, by known methods, for example, Journal O Bed Medicinal Chemistry (J. Med. Chem.), 23, 1134 (1980), JP 54 - No. 61198 Compound (IV) can be produced by hydrogenating the double bond between carbons 22 and 23 according to the method described in the gazette. Here, in the compound (IV), 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.

Tris (triphenylphosphine) -rhodium (1) Molerides are preferred, and benzene, toluene, petroleum ether or aliphatic saturated hydrocarbons are preferred as the reaction solvent.

Further, for those obtained by hydrogenating in the same way 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. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in detail with reference to Examples and Reference Examples. However, the present invention is not limited to these.

Reference example 1

Under an argon atmosphere, dissolve evamectin B _2a [compound (Vila)] (9.5 mg, 10.7 / mol) in dimethylformamide methylene chloride mixed solvent (2: 1) (0.3 mL), and cool under ice cooling. (13.7 / zL, 94.2 μιηοΐ) and t-butyldimethylchlorosilane (13.5 mg, 85.6 / zmol) were sequentially added, and the mixture was stirred at 0 for 3 hours and then left in a refrigerator (5 ° C) for 64 hours. The reaction solution was diluted with ethyl acetate, washed twice with a saturated saline-water (1: 1) solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was purified by preparative thin-layer silica gel chromatography-(ethyl hexane monoacetate = 2: 1) to give 5,4 "-bis (O-t over butyldimethylsilyl) Eibamekuchin B _{2 a:} to give compound (III) R ² and R ³ = t-butyldimethylsilyl, R ⁴ = Echiru] a (6.7 mg, 55%) as a colorless amorphous solid.

IR (liquid film) / cm— ¹ 3525, 3470, 2950, 2930, 2850, 1720, 1460, 1380, 1250, 1165, 1120, 1100, 980, 840, 780.

'H-NMR (400MHz, CDC1 3) δ = 0.08 (3Η, s), 0.10 (3Η, s), 0.13 (6H, s), 0.89 (9H, s), 0.93 (9H, s), 3.14 (1H , t, J = 8.8 Hz), 3.53 (1H, d, J = 10.1 Hz), 4.05 (1H, s), 4.43 (1H, d, J = 5.5 Hz).

SIMS (TEA + NaCl solution) (m / z): 1141 (M-Na) +.

TEA: Trietano monoamine

Example 1

In an argon atmosphere, 5,4'-bis (O-t-butyldimethylsilyl) eivamectin B _2a obtained in Reference Example 1 [Compound (III): R ² and R ³ = t-butyldimethylsilyl, R ⁴ = Ethyl) (164 · 7 mg, 0.144 mmol) in pyridine

(1.5 ml), methanesulfonyl chloride (56.0 μm, 0.721 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 6.5 hours. After the reaction solution was diluted with ethyl acetate, it was washed three times with 1% hydrochloric acid, further sequentially with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane monoacetate = 3: 1) to give 5,4 "-bis (O-t-butyldimethylsilyl). ) Single 23- O-methanesulfonyl rays Bamekuchin B _2a [compound (I) '.R ^1: methanesulfonyl, R ² and R ³ = t-butyldimethylsilyl, R ⁴ = Echiru] a (142.9 mg, 81%) Obtained as a colorless amorphous solid.

IR (liquid film) / cm— ¹ 3450, 2960, 2940, 2855, 1720, 1460, 1385, 1340, 1255, 1180, 1125, 1100, 990, 900, 840, 780.

- Anonymous _{(400MHz, CDC1 3): δ} = 0.08 (3Η, s), 0.10 (3H, s), 0.13 (6H, s), 0.89 (9H, s), 0.93 (9H, s), 1.68 (1H, (dd, J = 15.1, 3.2 Hz), 1.74 to 1.84 (5H, m), 3.03 (3H, s), 3.14 (1H, t, J = 8.8 Hz), 3.66 to 3.76 (3H, m), 4.05 (1H, s), 4.3 (1H, d, J = 5.5 Hz).

MS (m / z): 776 (M—Ole—Ole—OTBDMS) +, 719 (M—Ole—Ole—OTBDMS—t—Bu) 680 (M-Ole-Ole-OTBDMS-MsOH) ⁺ , 623 (M -Ole- Ole -OTBDMS- MsOH-t-Bu) TBDMS: t-butyldimethylsilyl, MsOH: methanesulfonic acid

Ole: Oleandrosyl group

Example 2

Under an argon atmosphere, bis (tetrabutylammonium) oxalate (43.9 mg, 76.7 μπιοΐ) was dissolved in t-butyl alcohol (0.3 mL), and the 5,4-bis (oxalate) obtained in Example 1 was added thereto. (T-butyldimethylsilyl) -23-O-methanesulfonyl eivamectin B _2a [Compound (I): R ¹ : methanesulfonyl, R ² and R ³ = t-butyldimethylsilyl, R ⁴ = (10.5 mg, 8.8 / mol) and stirred at room temperature for 16 hours. 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. 5,3 "-bis (O-t-butyldimethylsilyl) eivamectin B _la [Compound (II): R ² and R ³ = t-butyldimethylsilyl, R ⁴ = Ethyl) (4.1 mg, 43%) was obtained as a colorless amorphous solid, and the raw material 5,4〃-bis (O-t-butyldimethylsilyl) -1-23-O-methanesulfonyl eivamectin was obtained. B _2a (3.7 mg, 35%) was recovered.

IR (liquid film) / cm— ¹ 3460, 2955, 2930, 2900, 2850, 1715, 1460, 1385, 1255, 1120, 1100, 990, 840.

^{X H-NMR (400MHz, CDC1} 3): δ = 0.08 (3Η, s), 0.10 (3Η, s), 0.13 (6H, s), 0.89 (9H, s), 0.93 (9H, s), 3.14 ( 1H, t, J = 8.8 Hz), 4.43 to 4.44 (1H, m), 5.55 (1H, dd, J = 9.9, 2.5 Hz), 5.76 (1H, dd, J = 9.9, 1.7 Hz).

MS (m / z): 680 (M- Ole- Ole- OTBDMS) +

TBDMS: t-butyldimethylsilyl, Ole: Oleandrosyl group Examples 3-21

The reaction and purification were performed in the same manner as in Example 2 except that the reaction conditions (reagent, solvent, temperature, and time) were changed as shown in Tables 1-1 and 1-2. was obtained (O one t one heptyl dimethylsilyl) Eibamekuchin B i _a. In each example, 5,4 "-bis (O-t-butyldimethylsilyl) -123-0-methanesulfonyl eivamectin B _2a as a raw material was recovered. "- bi scan yield (% of (O-t-butyldimethylsilyl) Eibamekuchin B _la)) and material recovery rate (%) of also shown in Table 1 one 1, 1 one 2.

Reaction conditions and yield of desulfonate reaction

Example Catalyst Reaction solvent Temperature Time Product Raw material

No. (° C) (hour) Yield Recovery rate

(%) (%)

3 Bis oxalate acetone 1 3 2 4 2 2

(Tetrafu Chill Ammonium)

4 "acetonitrile 1 3 1 5 1 5

5 II Tetrahydrofuran 1 3 1 1 0

6 II 1, 2-S 'Toxitan II 1 3 2 1 1 0

7 II ンセ, II II 1 3 4 3 4 6

8 II Toluene II 1 5 3 0 2 3

9 II Pilisin II 1 3 5 2 0

1 0 II) 1 6 4 3 7 0

1 1 II U; Rain II 6 4 3 8 0

1 2 II Petil II 6 4 3 4 4 8

1 3 II t-f, chill alcohol 40 50 7 5 1 0

1 4 II t-f, chill alcohol 1 0 0 4 8 0

1 5 II Isofu ° p-pill alcohol 1 2 0 1 5 6 4

• 2: Reaction conditions and yield for desulfonate reaction Example Example Catalyst Reaction solvent Temperature Time Product raw material No. (° C) (Time recovery ratio) (%) (%)

1 6 Bis malonate Toluene 2 2 1 8 4 0

(Tetrafu, 'Chill Ammonium) 50

1 7 Bis succinate says 1 6 2 5 3 3

(Tetrafu Chillammonium)

1 8 D-bis tartrate 〃 room temperature ~ 3 7 1 6 8 0

(Tetrafu Chill Ammonium) 50

1 9 L-bis-tartrate "" 1 1 6 9

(Tetrahu, 'Chilan Moyuum)

2 0 4 2 0 0 Temperature

2 1 Lid / bis oleate! F Room temperature to 2 2 1 1 4 7

(Tetrafu, 'Chill Ammonium) 50

Example 22

Under an argon atmosphere, 5, 4 '- bis (O-t-butyldimethylsilyl) Eipame cutin B _la [Compound (II): R ² and R ³ = t-butyldimethylsilyl, R ⁴ = Echiru] (15.3 mg, 0.014 mmol) was dissolved in acetonitrile (0.3 mL), pyridine (0.14 mL) and pyridine hydrofluoride (0.14 mL) were added under ice-cooling, and the mixture was stirred at room temperature for 14 hours. The mixture was extracted with ether, and the obtained organic layer was washed with 3% hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated saline in that order, and dried over anhydrous sodium sulfate. by preparative thin layer silica gel chromatography (hexane: acetic acid Echiru = 1: 1) to obtain Eibamekuchin B _la [compound (V ia)] a (8.4 mg, 69%) as a colorless Amorufa scan solid obtained. ¹ H-NMR of the purified product (400 MHz, CDC1 ₃₎ is Abamectin

It was identical to that of B and _a . Industrial applicability

INDUSTRIAL APPLICABILITY 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.

Claims

Scope of claim General formula (I)

(In the formula, 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 methyl or ethyl). A general formula (II) characterized by subjecting a 23-O-sulfonylaivamectin B ₂ derivative represented by the general formula (II) to a desulfonate reaction in the presence of diammonium dibasic acid.

(Wherein, R ² , R ³ and R ⁴ have the same meanings as described above).

2. General formula (I)

(Wherein, RR ² , R ³ and R ⁴ have the same meanings as described above). 23-O-sulfonyl eibamectin B ₂ derivative

3. General formula (I I I)

(Wherein R ² , R ³ and R ⁴ have the same meanings as described above), wherein a substituted or unsubstituted sulfonyl is introduced into the hydroxyl group at position C 23 of the aivamectin B ₂ derivative represented by the general formula (I)

The presence of (wherein, R ¹ R ² R ³ Beauty R ⁴ has the same meaning as defined above) to give a 23-0- sul ho sulfonyl Able fit cutin B ₂ derivatives represented by further this dibasic acid Jianmoniumu A general formula (II) characterized by a desulfonate reaction

(Wherein, R ² R ³ and R ⁴ are as defined above)

A method for producing a _Bt derivative.

4. General formula (IV)

OMe

M e: Meter (Wherein, R ⁴ has the same meaning as described above).

(Wherein, RR ^2, R ³ and R ⁴ are the same as defined above) in the presence of a dibasic acid Jianmoniumu the 23- O over sulfonyl Rays fit cutin B ₂ derivative represented by is reacted desulfonation acid General formula (II)

(Wherein R ² , R ³ and R ⁴ have the same meanings as described above).

5. Diammonium dibasic acid has the general formula (V)

(V) (Wherein, R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are the same or different and are alkyl, cycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted Represents an unsubstituted aryl or a substituted or unsubstituted heterocyclic group; X represents a single bond, methylene, alkylidene, hydroxyl-substituted or unsubstituted alkylene, cycloalkylene, substituted or unsubstituted anolekenylene, substituted or unsubstituted alkynylene Or a substituted or unsubstituted arylene)

The production method according to claim 1, 3 or 4, which is (quaternary ammonium).

6. The process according to any one of claims 1, 3, 4, or 5, wherein the hydroxyl-protecting group defined as R ² and R ^{3 in} the general formula (I) is silyl substituted with lower alkyl or aryl. Method.