LT3674B - Process for the preparation of 23-(c1-c6 alkyloksime)-llf28249 compounds - Google Patents

Abstract

The described 23-(C<1>-C<6> alkyloxime)-LL-F28249 compound production method of crystal 5-O(p- nitrobenzoyl) oxidation is achieved by oxidation of 5-O-(p- nitrobenzoyl)- -LL-F28249 crystal compounds.

Description

The present invention is directed to the preparation of 23- (C 1 -C 8 alkyloxime) -LL-F28249 compounds. The abbreviation LL-F28249 is used for a series of compounds produced by the enzyme broth of the noncyanogenus subspecies of the species Streptomyces cyaneogriseus, stored in the NRR Collection under number 15773.

It is an object of the present invention to provide a process for the preparation of 23- (C 1 -C 8 alkyloxym) LL-F28249 compounds, more particularly 23- (methyloxime) -LLF28249a (moxidectin), a potent endectocidal agent.

The present invention relates to a process for the preparation of 23- (C 1 -C 8 alkyloxyim) -LLF28249 compounds, which comprises blocking the 5-position hydroxyl group of the LL-F28249 compound with p-nitrobenzoyl chloride to form the corresponding 5-0- (pnitrobenzoyl) -LL-F28249 compound. this compound by oxidation to form 5-0- (p-nitrobenzoyl) -23-oxo-LLF28249 crystalline derivative of this derivative with a C ₁ -C ₆ alkoksilaminu or a salt thereof, forming an crystalline 23- (Οχ-Cgalkiloksim) -5- 0- (p-nitrobenzoyl) LL-F28249, and deprotection of this intermediate in the presence of a base to form the desired compound, 23 (C 1 -C 8 alkyloxime) -LL-F28249. Crystalline 5-O- (p-nitrobenzoyl) -23-oxo-LL-F28249 crystalline compounds can be deprotected to form the corresponding 23-oxo-LL-F28249 compounds, and then treated with C 1 -C 8 alkoxylamine or a salt thereof to give the desired compound 23- (C 1-6 -C 8 alkyloxim) -LL-F28249.

23- (C 1 -C 6 -C 6 alkyloxim) -LL-F28249 compounds and their use as anthelmintic, insecticidal, non-anodic, anti -ectoparasiticidal and acaricidal agents are described in U.S. Pat. No. 4,916,154. Compound antibiotics designated LL-F28249 described in pending US application Serial No. 732252, filed May 1985 May 10

This invention relates to a process for the preparation of (C 1 -C 8 alkyloxy) derivatives of compound LL-F28249 23. The structural formula of LL-F28249 compounds is:

The component Ri r ₂ r ₃ r ₇ LL-F28249 {X CH (CH ₃ ) ₂ H ch ₃ ch ₃ LL-F28249p ch ₃ H ch ₃ ch ₃ LL-F28249c ch ₃ ch ₃ ch ₃ ch ₃ LL-F282498 CH (CH ₃ ) ₂ H H ch ₃ LL-F28249f ch ₂ ch ₃ H ch ₃ ch ₃ LL-F28249h CH (CH ₃ ) ₂ H ch ₃ ch ₂ ch ₃ LL-F28249i CH (CH ₃ ) ₂ H ch ₂ ch ₃ ch ₃ LL-F28249k CH (CH ₃ ) ₂ ch ₃ ch ₃ ch ₃ The following is suggested 23- (Ci-C ₆ alkyloxym) -L1 -F28249 of compounds method of obtaining, in which crystalline 5-0- (p- nitrobenzene

zoyl) -23-oxo-LL-F28249 derivatives are deprotected using a base to give the corresponding 23-oxo-LL-F28249 compounds and then treated with C ₁ -C ₆ alkoxylamine or a salt thereof to give the desired compound, 23 - (C 1 -C 8 alkyloxime) -LL-F28249.

Using the starting material using LL-F28249 and methoxylamine hydrochloride as C 1 -C 8 alkoxylamine, the process of the present invention can be illustrated in Scheme 1, wherein PNB is a p-nitrobenzoyl group:

Scheme 1

ch ₃ ohh ₂ -hci

CHjO-N

CHjO-N

OPKB tr <

The 5-position hydroxyl group of LL-F28249 is blocked by treatment with p-nitrobenzoyl chloride of LL-F28249 in an organic solvent such as toluene, methylene chloride, ethyl acetate, acetonitrile, etc., preferably in toluene, and in the presence of an organic base such as, for example, pyridine, triethylamine, N-methylpyrrolidine and the like, preferably triethylamine.

Unexpectedly, oxidation of 5-0- (p-nitrobenzoyl) -LL-F28249 resulted in the crystalline product, the corresponding compound 5-0- (p-nitrobenzoyl) -23-oxo-LL-F28249. This crystalline product can be purified easily and efficiently by recrystallization from a suitable organic solvent, thus avoiding the long and complex purification procedure which requires methods such as column chromatography. The 5-0- (p-nitrobenzoyl) -LL-F28249 compounds can be successfully oxidized using an oxidation system selected from the group consisting of pyridine bichromate and acetic anhydride; pyridine bichromate and dimethylformamide; tert-butoxyaluminum and o-benzoquinone; phosphorus pentoxide and dimethylsulfoxide; manganese dioxide; and acetic anhydride and dimethylsulfoxide.

The preferred oxidation system for the oxidation of 5-0- (p-nitrobenzoyl) -LL-F28249 is manganese dioxide in a solvent such as methylene chloride 3674B, acetonitrile, ethyl acetate and the like, preferably ethyl acetate.

An even better oxidation system for the oxidation of 5-0- (p-nitrobenzoyl) -LL-F28249 is acetic anhydride and dimethylsulfoxide in the presence of pyridine and an acid such as acetic acid, trifluoroacetic acid, dichloroacetic acid, monochloroacetic acid and the like. , preferably monochloroacetic acid. Unexpectedly, it has been found that the use of acetic anhydride and dimethylsulfoxide in the presence of pyridine and acid greatly increases the yield of 5-O- (p-nitrobenzoyl) -23-oxo-LLF28249 derivatives compared to using only acetic anhydride and dimethylsulfoxide. For example, when oxidized with acetic anhydride and dimethylsulfoxide in the presence of pyridine and monochloroacetic acid, the yield of 5-O- (p-nitrobenzoyl) -23-oxo-LL-F28249oc is 76%, whereas in the absence of pyridine and monochloroacetic acid, yield is 2-4%.

The crystalline 5-0- (p-nitrobenzoyl) -23-oxo-LL-F28249 derivative can be purified before deprotection (p-nitrobenzoyl cleavage) or by reaction with C ₁ -C ₆ alkoxylamine hydrochloride by recrystallization from a suitable solvent (preferably n- propanol).

The preferred solution of the crude reaction product, 5-0- (p-nitrobenzoyl) -23-oxo-LL-F28249, in an organic solvent such as toluene is treated with an aqueous solution of C ₁ -C ₆ alkoxylaminohydrochloride and sodium acetate until stirred. oxime. The resulting intermediate, 23- (C ₁ -C ₆ alkyloxyim) -5-0- (p-nitrobenzoyl) -LL-F28249, is isolated and purified by recrystallization from a suitable solvent, preferably n-butanol.

Recrystallization of 23- (C ₁ -C ₈ alkyloxime) -5-0- (p-nitrobenzoyl) -LL-F28249 is deprotected by treatment with sodium hydrocarbon 3674 B at 0-25 ° C to give the desired product 23- (C ₁ -C _6). alkyloxim) -LL-F28249. Deprotection is effected by treatment of a solution of 23 (C 1 -C 8 alkyloxym) -5-0- (p-nitrobenzoyl) -LL-F28249 in an organic solvent such as toluene, dioxane, n-butanol and the like, preferably dioxane, aqueous sodium hydroxide solution at 0-25 ° C and the resultant 23- (C 1 -C 8 alkyloxime) -LL-F28249 is isolated from the organic phase by conventional techniques such as concentration and filtration of the solution or evaporation of the solvent.

In order that the invention may be more fully understood, the following are examples, in particular for the purpose of illustration. These examples are not intended to limit the scope of the invention as set forth in the claims.

Unless otherwise stated, all parts indicated are parts by weight; analysis by high pressure liquid chromatography (abbreviated ASSCh) and proton magnetic resonance (abbreviated ¹ H-NMR).

example

Preparation of 5-0- (p-nitrobenzoyl) -LL-F28249cc

A stirred solution of LL-F28249a (6.36 g, 10.4 mol) in methylene chloride was treated with pyridine (1.98 g, 25.0 mol) and p-nitrobenzoyl chloride (2.45 g, 13.2 mol) at 20-25 ° At C. After 4 hours, the reaction mixture was treated with saturated sodium bicarbonate solution and methylene chloride at 20-25 ° C and stirred until completely dissolved. The layers are separated and the organic layer is washed successively with saturated sodium bicarbonate solution, 5% hydrochloric acid and saturated sodium chloride solution, evaporated in vacuo to give 7.9 g (quantitative yield) of the desired product as a solid foam. The product idenLT 3674 B was identified by ASSCh, 1 H-NMR and mass spectroscopy.

example

Preparation of 5-0- (p-nitrobenzoyl) -LL-F28249a

A stirred solution of LL-F28249a (6.13 g, 10.0 mmol) in toluene was treated with triethylamine (2.53 g, 25 mmol), cooled to 15 ° C, and several portions of p-nitrobenzoyl chloride (2) were added at 15-22 ° C. , 60 g, 14 mmol) and stirred for 6 hours at 20-24 ° C. Water was added to the reaction mixture, stirred for 10 minutes and filtered. The filtrate is separated and the organic layer is washed successively with saturated sodium bicarbonate solution, 3N hydrochloric acid and water. Evaporation of the solvent in vacuo afforded 7.55 g of the desired product as a solid foam.

example

Preparation of 5-O- (p-nitrobenzoyl) -23-oxo-LL-F28249a using pyridine bichromate and dimethylformamide in stirring 5-0- (p-nitrobenzoyl) -LL-F28249a (3.12 g.

To a solution of 4.10 mmol) in dimethylformamide was added one portion of pyridine bichromate (18.8 g, 50 mmol), stirred at 20-25 ° C for 6 hours, the reaction mixture was poured into water, stirred for 15 minutes and filtered. The filtered precipitate was washed with water, air dried and dissolved in ethyl acetate. The resulting mixture was refluxed for 15 minutes, treated with diatomaceous earth and filtered. The filtrate was evaporated in vacuo. The remaining red-brown solid is recrystallized from n-propanol. 3.33 g (52% yield of LL-F28249) of the desired product are obtained in the form of white crystals. Lyd. mp: 217-221 ° C. The ProLT 3674 B well was identified by ¹ H-NMR and mass spectroscopy.

example

Preparation of 5-O- (p-nitrobenzoyl) -23-oxo-LL-F28249a Using Pyridine Bichromate and Acetic Anhydride

To a freshly prepared mixture of pyridine bichromate (0.19 g, 0.5 mmol) and acetic anhydride (0.3 g, 3.0 mmol) was added 5-O- (p-nitrobenzoyl) -LL-F28249 (0.38). g,

0.5 mmol) in methylene chloride with vigorous stirring. The reaction mixture was stirred at room temperature for 15 minutes, refluxed for 6-8 hours, cooled to room temperature and treated with water. After thorough mixing, the layers are separated and the organic layer is washed with saturated sodium bicarbonate solution and evaporated in vacuo. The residue was dissolved in ethyl acetate and chromatographed on silica gel using ethyl acetate as eluent. Slightly grayish material is obtained. This solid was mixed with ethyl acetate: hexane (55:45), filtered, and the filtrate concentrated in vacuo. 0.26 g of a slightly yellowish solid are obtained. The material was identified by ¹ H-NMR and ASSCh methods.

example

Preparation of 5-O- (p-nitrobenzoyl) -23-oxo-LL-F-28249a Using Tert-Butoxyaluminum and o-Benzoquinone

A mixture of 5-O- (p-nitrobenzoyl) -LL-F28249a (0.38 g, 0.50 mmol), tert-butoxyaluminum (0.184 g, 0.74 mmol) and o-benzoquinone (0.216 g, 2 mmol) stirred in toluene and refluxed for 2 hours, cooled to room temperature, treated with toluene and dilute sulfuric acid (16%), mixed with 5 mL of MT74B and filtered. The filtrate is separated off, the organic layer is washed with water and evaporated in vacuo. A glassy residue is obtained. It is dissolved in ethyl acetate and filtered through neutral alumina. Evaporation of the filtrate in vacuo afforded 0.324 g of white material (71% yield, ASSCh).

example

Preparation of 5-O- (p-nitrobenzoyl) -23-oxo-LL-F-28249a Using Phosphorus Pentoxide and Dimethylsulfoxide

To a solution of 5-0- (p-nitrobenzoyl) -LL-F28249a (0.38 g, 0.50 mmol) and dimethylsulfoxide (0.75 g, 9.6 mmol) in methylene chloride was added immediately a powdered phosphorus pentoxide (0.107 g, 0.75 mmol), stirred at 2025 ° C for 19 hours, added triethylamine (0.30 g, 3.0 mmol), stirred for 30 minutes, then added methylene chloride and water and stirred for a further 5 minutes. Separate the layers, wash the organic layer with dilute hydrochloric acid (7%) and evaporate in vacuo. 0.28 g (47% purity, ASSCh) of the desired product is obtained as a white solid.

example

Preparation of 5-O- (p-nitrobenzoyl) -23-oxo-LL-F28249a Using Manganese Dioxide and Methylene Chloride as a Solvent in 5-0- (p-Nitrobenzoyl) -LL-F28249a (0.19 g, 0.25) mole) in methylene chloride was added manganese dioxide (8.0 g, 92 mmol) at 20-25 ° C for 2 hours, methylene chloride was added and filtered. The filtrate was evaporated in vacuo. 0.08 g (51% purity, 51% purity) of the white solid is obtained.

example

Preparation of 5-O- (p-nitrobenzoyl) -23-oxo-LL-F28249a Using Manganese Dioxide and Acetonitrile as Solvent

To a solution of 5-0- (p-nitrobenzoyl) -LL-F28249a (0.19 g, 0.25 mmol) in acetonitrile was added manganese dioxide (8.0 g, 92 mmol), stirred at room temperature for 3 hours, acetonitrile added, stirred another 5 minutes and filtered. The filtered precipitate is suspended in methylene chloride and filtered. The acetonitrile and methylene chloride filtrates are combined, washed with water and evaporated in vacuo. 0.14 g (69% purity, ASSCh) of the title compound is obtained as a white solid.

example

Preparation of 5-O- (p-nitrobenzoyl) -23-oxo-LL-F28249a Using Manganese Dioxide and Ethyl Acetate as Solvent

To a solution of 5-0- (p-nitrobenzoyl) -LL-F28249a (1.0 g, 1.3 mmol) in ethyl acetate was added manganese dioxide (20.0 g, 230 mmol), stirred at 20-25 ° C for 3 hours and filtered. The filtered precipitate was washed with ethyl acetate, the filtrates were mixed, manganese dioxide (8.0 g, 92 mmol) was added, stirred at 20-25 ° C for 3 hours and filtered. The filtered precipitate is washed with ethyl acetate and the filtrates are combined and evaporated in vacuo. 0.8 g (70% purity according to ASSCh) of the title compound is obtained as a white solid. Recrystallization from n-propanol gave white crystals with a melting point of 218-222 ° C.

example

Preparation of 5-O- (p-nitrobenzoyl) -23-oxo-LL-F28249a Using Dicyclohexylcarbodiimide and Dimethylsulfoxide

To a solution of 5-O- (p-nitrobenzoyl) -LL-F28249a (0.38 g, 0.5 mmol) in benzene was added successively dimethylsulfoxide (0.78 g, 10 mmol), pyridine (0.04 g, 0, 5 mmol), trifluoroacetic acid (0.03 g, 0.25 mmol) and dicyclohexylcarbodiimide (0.31 g, 1.5 mmol) were stirred at 20-25 ° C for 21 h, then benzene was added and filtered. The filtered precipitate is washed with benzene. The combined filtrates are washed with water and evaporated in vacuo. 0.34 g of solid is obtained in the form of a slightly orange-brown solid. According to ASSCh data, the yield is 75%.

Example 1

Preparation of 5-O- (p-nitrobenzoyl) -23-oxo-LL-F28249a using acetic anhydride and dimethylsulfoxide in the presence of pyridine trifluoroacetate

A mixture of 5-O- (p-nitrobenzoyl) -LL-F28249a (0.38 g, 0.5 mmol), dimethylsulfoxide (0.78 g, 10 mmol) and pyridine trifluoroacetate (0.97 g, 0.5 mmol) in ethyl acetate acetic anhydride (0.26 g, 2.5 mmol) was added dropwise and the mixture was stirred for 24 hours at 20-25 ° C. Ethyl acetate and water are then added, the layers are separated, the organic layer is washed with water and the solvent is evaporated off under vacuum. A viscous oil is obtained. It is dissolved in methylene chloride, evaporated in vacuo to give 0.3 g of a yellow solid; material identified by ASSCh data.

example

Preparation of 5-O- (p-nitrobenzoyl) -23-oxo-LL-F28249a Using Acetic Anhydride and Dimethylsulfoxide in the presence of Pyridine and Dichloroacetic Acid

To a mixture of 5-O- (p-nitrobenzoyl) -LL-F28249a (7.26 g, 10 mmol) and pyridine (31.6 g, 400 mmol) was added dimethyl sulfoxide (15.5 g, 200 mmol) and dichloroacetic acid (1.29 g, 10 mmol), cool to 2-3 ° C, add acetic anhydride (5.1 g, 50 mmol) at 3-7 ° C and add methylene chloride and water. The reaction mixture is stirred for 15-30 minutes at room temperature and the layers are separated. The organic layer was washed with cold dilute hydrochloric acid (5%) and 5% sodium chloride solution, evaporated in vacuo to give 7.47 g (73% purity by ASSCh) of the desired material as a solid yellow foam.

The yields of the compound obtained by essentially the same method, except for acid conversion, are given in Table 1.

example

Preparation of 5-O- (p-nitrobenzoyl) -23-oxo-LL-F28249a Using Acetic Anhydride and Dimethylsulfoxide in the presence of Pyridine and Monochloroacetic Acid

To a mixture of 5-0- (p-nitrobenzoyl) -LL-F28249a (1.52 g, 2.0 mmol) and pyridine (3.12 g, 40 mmol) in toluene was added dimethyl sulfoxide (3.12 g, 40 mmol) and of monochloroacetic acid (0.19 g, 2.0 mmol) was cooled to 2-3 ° C and acetic anhydride (0.82 g, 8.0 mmol) was added dropwise at 3-5 ° C. The reaction mixture was stirred at 2-3 ° C for 7 hours, toluene and water were added, stirred at 15-20 ° C for 10 minutes, and the layers were separated. The organic layer is washed successively with cold 2.4 N hydrochloric acid and water at 15-20 [deg.] C., and the solvent is evaporated off under vacuum to give 1.4 g of a yellow solid foam. It has a purity of 71% according to ASSCh.

table

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LT) kO ΓDCAR 1,0 Ethyl acetate 20-25

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example

Evaluation of the oxidation of 5-0- (p-nitrobenzoyl) -LL-F28249a to 5-0- (pnitrobenzoyl) -23-oxo-LL-F28249a using various oxidants

Various systems oxidizing 5-0 (p-nitrobenzoyl) -LL-F28249a to 5-0- (p-nitrobenzoyl) -23oxo-LL-F28249a were evaluated. Reagents, Reaction Conditions, and Reactions

The percentages of 5-0- (p-nitrobenzoyl) -23-oxo-LL-F28249a as determined from ASSCh data are given in Table 2.

table a

σι m

d oo d

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P

P

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Product% (% area, ASSCh) Γ Time or. kO 2 ° ^υ | 2 m ε a φ CO ♦ H i-1 a; • H a M • H E •> Mol kvi m Φ oh P • H P O P p CM n H 01 a: o n C P P 2 <—1 m

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O

o • k 00 • k o * k d »K r - t k. d * k o d * k o d »K d * k o o rH 1 "1 o o kO o t-1 5-1 , —1

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d ud rLT 3674 B

f 03 03 03 03 03 03 -P -P -P • P pi 4-> 4-1 03 03 03 03 03 03 03 she she She She She She She She j J J > 1 J > J J J J > J Φ Φ Φ Φ Φ Φ Φ C C C C C C C O 03 O 03 03 05 03 03 03 T) • o • 1 to 1 • n • m • 1-1 -n -H 'H Ή H • P • H -P o u U υ U O u She She She j: She she 03 (i.e. 03 05 03 f o3 φ Φ Φ Φ Φ Φ Φ P P P P P M P LO LO Ό LO rp CM CM LO LO f 03 LT) LO ε (U C LO LO LO LO LO ε 03 C CM 1 CM I CM I CM I CM I CM I CM 1 i O 1 O • H (j 1 O 1 o 1 O 1 o 1 o • P t 1 CM CM M  Ή CM CM CM CM CM > 4 -H J 03 0) 03 > 03 03 03 03 Ό Φ Ό Ό • P Ό • P • P P -H P P o M o o i-1 0 <—1 (—L £ 3 r— | £ 3 £ 3 U Λ U O

03 03 O 03 03 C C O CM c-1 C Φ CM i— | Φ 1-1 4-1 O P O • P Φ CM i-1 CM 4-1 O Ή o Ή Φ 03 O 4-1 O ε

O c Φ • —I • rl

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table (continued)

03 • H 03 4-1 03 > 03 03 Ό Cn 0) 03 • P 03 O 03 Ό o3 03 03 P 03 -P 4-1 She -P C 03 • P O H o O She Mr. Sec U-l 4-1 c O <—1 i-1 Γ— | U -P O P P p 03 03 £ 3 o f — i 03 03 03 Φ P O • P m o m c I-1 G C O O c 4J • P • P • H H b μ N -P • T 'S' o o W o t 4-> Ό i-1 ώ C ε o O O c C 'Z C3 • P Φ -H ♦ H Mr. Z Φ b C c C0 2 2 r> 2 P ε P M • P r \ £} • P 2 2 3 03 03 Ή o3 • P • P • H • H P o CM 2 1 rp 3 * 3 O ffl m O m Ό 4-1 XJ 04 03

00 03 O rH CM co LO kO t-1 c-1 <—1 c-1 t-1 T ^- 1 i-1

example

Preparation of 5-0- (p-nitrobenzoyl) -23- (methyloxime) -LL-F28249a

To a solution of 5-0- (p-nitrobenzoyl) -23-oxo-LL-F28249a (10.67 g, mmol) in n-butanol was added methoxylamine hydrochloride (2.34 g, 28.1 mmol) and anhydrous sodium acetate (2 (30 g, 28.1 mmol) in water at 20-22 ° C, stirred for 2 hours at this temperature and filtered. The filtered precipitate was air dried and recrystallized from n-butanol (hot filtration). 3.6 g of a colorless solid are obtained with a purity of 91% according to ASSCh.

example

Preparation of 5-0- (p-nitrobenzoyl) -23- (methyloxime) -LL-F28249a

To 5-0- (p-nitrobenzoyl) -23-oxo-LL-F28249a (1.5 g,

A solution of 2.0 mmol) in toluene was added to a solution of methoxylamine hydrochloride (0.25 g, 3.0 mmol) and anhydrous sodium acetate (0.25 g, 3 mmol) in water and stirred at 20-25 ° C for 10 hours. The toluene layer is separated, washed with water and evaporated in vacuo. The resulting solid precipitate is recrystallized from n-butanol. 0.65 g of the expected product is obtained. It is identified by the ASSCh method.

example

Preparation of 23- (methyloxyim) -LL-F28249a

To a solution of 5-0- (p-nitrobenzoyl) -23- (methyloxime) -LL-F28249a (1.58 g, 2.0 mmol) in dioxane is added a 4% sodium hydroxide solution (3.0 g, 3.0 g). mmol NaOH) at 8-12 ° C, stirred at this temperature for 3 hours, added toluene and water and stirred at room temperature for 5 minutes. The layers are separated, the organic layer is washed with 10% sodium chloride solution and evaporated in vacuo. 1.15 g of the desired product are obtained in the form of a solid, white foam having a purity of 89% according to ASSCh.

example

Preparation of 23-oxo-LL-F28249a

A mixture of 5-O- (p-nitrobenzoyl) -23-oxo-LL-F28249a (1.52 g, 2.0 mmol) and 4% sodium hydroxide (3.3 g, 3.3 mmol NaOH) in dioxane was stirred at 23 ° C. At C for 2 hours, toluene and water were added and shaken. Separate the layers, wash the organic layer with water, evaporate the solvents in vacuo to give 0.90 g of the desired material as a solid foam. The material was identified by ¹ H-NMR.

example

Preparation of 23- (methyloxyim) -LL-F28249a

23-oxo-LL-F28249a (0.90 g, 1.5 mmol), methoxylamine hydrochloride (0.42 g, 5.0 mmol), anhydrous sodium acetate (0.41 g, 5.0 mmol), acetic acid, and the dioxane mixture was stirred at 20-25 ° C for 22 hours, toluene and water were added and stirred for 5 minutes. Separate the layers, wash the organic layer with water, evaporate in vacuo to give 0.84 g of the desired product in the form of a solid foam, with a purity of 71% by ASSCh.

Claims (7)

DEFINITION OF INVENTION 1. A process for the preparation of 23- (C 1 -C 8 alkyloxym) -LL-F28249 wherein the 5-position hydroxyl group of the compound LL-F28249 is blocked with p-nitrobenzoyl chloride, which is oxidized to give 5-0- (p-nitrobenzoyl) -LL-F28249. crystalline 5-O- (p-nitrobenzoyl) -23-oxo-LL-F28249, followed by reaction of the resulting intermediate with C 1 -C 8 alkoxylamine or a salt thereof, and deprotection, or the reverse reaction. 2. The process of claim 1, wherein the oxidation system is selected from the group consisting of: acetic anhydride and dimethylsulfoxide; manganese dioxide; pyridine bichromate and acetic anhydride; tert-butoxyaluminum and o-benzoquinone; phosphorus pentoxide and dimethylsulfoxide; dicyclohexylcarbodiimide and dimethylsulfoxide. 3. A process according to claim 2, wherein acetic anhydride and dimethylsulfoxide are used as the oxidation system and the oxidation is carried out in the presence of pyridine and acid. 4. A process according to claim 2 wherein the oxidation system is manganese dioxide and the oxidation is carried out in the presence of ethyl acetate. 5. A process according to claim 2, wherein pyridine bichromate and acetic anhydride are used as the oxidation system. 6. A process according to claim 1 wherein the 5-O- (p-nitrobenzoyl) -23-oxo-LL-F28249 derivative is purified by recrystallization from a suitable solvent. 7. A process according to claim 1, wherein the intermediate product of the reaction with C 1 -C 8 alkoxylamine or a salt thereof is purified by recrystallization from a suitable solvent.