HK1000095B - Process for the preparation of 23-(c1-c6 alkyloxime )ll - f28249 compounds - Google Patents
Process for the preparation of 23-(c1-c6 alkyloxime )ll - f28249 compounds Download PDFInfo
- Publication number
- HK1000095B HK1000095B HK97101524.7A HK97101524A HK1000095B HK 1000095 B HK1000095 B HK 1000095B HK 97101524 A HK97101524 A HK 97101524A HK 1000095 B HK1000095 B HK 1000095B
- Authority
- HK
- Hong Kong
- Prior art keywords
- nitrobenzoyl
- compound
- mmole
- yield
- dimethyl sulfoxide
- Prior art date
Links
Description
The present invention relates to a process for the manufacture of 23-(C₁-C₆alkyloxime)-LL-F28249 compounds. The designation of LL-F28249 is used to describe a series of compounds produced by the fermentation broth of Streptomyces cyaneogriseus subspecies noncyanogenus, deposited in the NRRL collection under deposit accession number 15773.
It is an object of this invention to provide a process for the manufacture of 23-(C₁-C₆alkyloxime)-LL-F28249 compounds and more specifically 23-(methyloxime)-LL-F28249α (moxidectin), a potent endectocidal agent.
The present invention relates to a process for the preparation of 23-(C₁-C₆alkyloxime)-LL-F28249 compounds which comprises protecting the 5-hydroxy group of LL-F28249 compounds with p-nitrobenzoyl chloride to give the corresponding 5-O(p-nitrobenzoyl)-LL-F28249 compound; oxidizing said compound to give a 5-O(p-nitrobenzoyl)-23-oxo-LL-F28249 derivative in a crystalline state; reacting said derivative with a C₁-C₆alkoxylamine or salt thereof to give the 23-(C₁-C₆alkyloxime)-5-O(p-nitrobenzoyl)-LL-F28249 intermediate in a crystalline state; and deprotecting said intermediate in the presence of base to give the desired 23-(C₁-C₆alkyloxime)-LL-F28249 compound. Optionally, the crystalline 5-O(p-nitrobenzoyl-23-oxo-LL-F28249 derivatives are deprotected in the presence of base to give the corresponding 23-oxo-LL-F28249 compounds and said compounds are reacted with a C₁-C₆alkoxylamine, or salt thereof, to give the desired 23-(C₁-C₆alkyloxime)-LL-F28249 compound.
The 23-(C₁-C₆alkyloxime)-LL-F28249 compounds and their use as anthelmintic, insecticidal, nematicidal, ectoparasiticidal and acaricidal agents are described in U. S. Patent No. 4,916,154. The antibiotic compounds designated LL-F28249 are described in co-pending U. S. patent application Serial No. 732,252, filed on May 10, 1985.
The invention herein described relates to a process for the manufacture of 23-(C₁-C₆alkyloxime) derivatives of LL-F28249 compounds. The LL-F28249 compounds are represented by the following structural formula
| Component | R₁ | R₂ | R₃ | R₇ |
| LL-F28249α | CH(CH₃)₂ | H | CH₃ | CH₃ |
| LL-F28249β | CH₃ | H | CH₃ | CH₃ |
| LL-F28249c | CH₃ | CH₃ | CH₃ | CH₃ |
| LL-F28249ε | CH(CH₃)₂ | H | H | CH₃ |
| LL-F28249f | CH₂CH₃ | H | CH₃ | CH₃ |
| LL-F28249h | CH(CH₃)₂ | H | CH₃ | CH₂CH₃ |
| LL-F28249i | CH(CH₃)₂ | H | CH₂CH₃ | CH₃ |
| LL-F28249k | CH(CH₃)₂ | CH₃ | CH₃ | CH₃ |
There is provided a process for the manufacture of 23-(C₁-C₆alkyloxime)-LL-F28249 compounds wherein R₂ is hydrogen which comprises protecting the 5-hydroxy group of said LL-F28249 compounds with p-nitrobenzoyl chloride to yield the corresponding 5-O(p-nitrobenzoyl)-LL-F28249 compound; oxidizing said compound to yield the 5-O(p-nitrobenzoyl)-33-oxo-LL-F28249 derivative in a crystalline state; reacting said derivative with a C₁-C₆alkoxyamine or salt thereof to yield the 23-(C₁-C₆alkyloxime)-5-O(p-nitrobenzoyl)-LL-F28249 intermediate in a crystalline state; and deprotecting said intermediate in the presence of base to yield the desired 23-(C₁-C₆alkyloxime)-LL-F28249 compound. There is further provided a process for the manufacture of 23-(C₁-C₆alkyloxime)-LL-F28249 compounds wherein the crystalline 5-O(p-nitrobenzoyl)-23-oxo-LL-F28249 derivatives are deprotected in the presence of base to yield the corresponding 23-oxo-LL-F28249 compounds and said compounds are reacted with a C₁-C₆alkoxylamine or salt thereof to yield the desired 23-(C₁-C₆alkyloxime)-LL-F28249 compound.
Using LL-F28249α as starting material and methoxylamine hydrochloride as the C₁-C₆alkoxylamine reagent, the processes of the invention can be illustrated as shown in flow diagram I wherein PNB designates the functionality p-nitrobenzoyl.
Protection of the 5-hydroxy group of LL-F28249α is achieved by the reaction of LL-F28249α with p-nitrobenzoyl chloride in the presence of an organic solvent such as toluene, methylene chloride, ethyl acetate, acetonitrile and the like, preferably toluene, and an organic base such as pyridine, triethylamine, N-methylpyrrolidone, and the like, preferably triethylamine.
Surprisingly, it has been found that oxidation of 5-O(p-nitrobenzoyl)-LL-F28249 compounds gives a crystalline product, the corresponding 5-O(p-nitrobenzoyl)-23-oxo-LL-F28249 compound. A crystalline intermediate allows a simplified, efficient purification of said intermediate via recrystallization from a suitable organic solvent and eliminates complex, time consuming purification by procedures such as column chromatography. Oxidation of the 5-O(p-nitrobenzoyl)-LL-F28249 compound is successfully achieved using an oxidizing system selected from the group consisting of pyridinium dichromate and acetic anhydride; pyridinium dichromate and dimethylformamide; aluminum t-butoxide and o-benzoquinone; phosphorous pentoxide and dimethyl sulfoxide; dicyclohexylcarbodiimide and dimethyl sulfoxide; manganese dioxide; and acetic anhydride and dimethyl sulfoxide.
A preferred oxidizing system for the oxidation of 5-O(p-nitrobenzoyl)-LL-F28249 compounds is manganese dioxide in the presence of a solvent such as methylene chloride, acetonitrile, ethyl acetate or the like, preferably ethyl acetate.
A more preferred oxidizing system for the oxidation of 5-O(p-nitrobenzoyl)-LL-F28249 compounds is acetic anhydride and dimethyl sulfoxide in the presence of pyridine and an acid such as acetic acid, trifluoroacetic acid, dichloroacetic acid, monochloroacetic acid and the like, preferably monochloroacetic acid. Surprisingly, it has been found that the use of acetic anhydride and dimethyl sulfoxide in the presence of pyridine and an acid greatly enhances the yield of the 5-O(p-nitrobenzoyl)-23-oxo-LL-F28249 derivatives over the use of acetic anhydride and dimethyl sulfoxide alone. For example, the acetic anhydride and dimethyl sulfoxide oxidation is carried out in the presence of pyridine and monochloroacetic acid, the yield of 5-O(p-nitrobenzoyl)-23-oxo-LL-F28249α is 76%; whereas when the same oxidation is carried out without the presence of pyridine and monochloroacetic acid, the yield is 2-4%.
Optionally, the crystalline 5-O(p-nitrobenzoyl)-23-oxo-LL-F28249 derivative is purified by recrystallization from a suitable solvent (preferably n-propanol) prior to deprotection (removal of the p-nitrobenzoyl group) or reaction with C₁-C₆alkoxylamine hydrochloride.
Preferably, a solution of the crude reaction product, 5-O(p-nitrobenzoyl)-23-oxo-LL-F28249 compound, in an organic solvent, such as toluene, is reacted with an aqueous solution of C₁-C₆alkoxylamine hydrochloride and sodium acetate and stirred until oxime formation is complete. The thus-formed 23-(C₁-C₆alkyloxime)-5-O(p-nitrobenzoyl)-LL-F28249 intermediate is isolated and then purified by recrystallization from a suitable solvent, preferably n-butanol.
The recrystallized 23-(C₁-C₆alkyloxime-5-O(p-nitrobenzoyl)-LL-F28249 compound is deprotected by reaction with sodium hydroxide at 0°-25°C to give the desired 23-(C₁-C₆alkyloxime)-LL-F28249 product. The deprotection is acheived by reacting a solution of a 23-(C₁-C₆alkyloxime)-5-O(p-nitrobenzoyl)-LL-F28249 compound in an organic solvent such as toluene, dioxane, n-butanol or the like, preferably dioxane, with an aqueous solution of sodium hydroxide at 0°-25°C and isolating the product 23-(C₁-C₆alkyloxime)-LL-F28249 compound from the organic phase using standard procedures such as concentration and filtration or removal of the solvent.
In order to facilitate a further understanding of the invention, the following examples are presented primarily for the purpose of illustrating more specific details thereof. The invention is not to be limited thereby except as defined in the claims.
Unless otherwise noted, all parts are by weight, all high pressure liquid chromatographic analyses are designated as HPLC analyses, and all proton nuclear magnetic spectroscopic analyses are designated as ¹HNMR analyses.
A stirred solution of LL-F28249α (6.36 g, 10.4 mmole) in methylene chloride is treated with pyridine (1.98 g, 25.0 mmole) and p-nitrobenzoyl chloride (2.45 g, 13.2 mmole) at 20°-25°C. After 4 hours at 20°-25°, the reaction mixture is treated with saturated sodium bicarbonate and methylene chloride and stirred until solution is complete. The phases are separated, the organic phase in washed sequentially with saturated sodium bicarbonate, 5% hydrochloric acid, and saturated sodium chloride and concentrated in vacuo to give the title compound as a solid foam, 7.9 g (quantitative yield) identified by liquid chromatography, ¹HNMR and mass spectral analyses.
A stirred solution of LL-F28249α (6.13 g, 10.0 mmoles) in toluene is treated with triethylamine (2.53 g, 25 mmole), cooled to 15°C, treated portionwise with p-nitrobenzoyl chloride (2.60 g, 14 mmole) at a temperature range of 15°-22°C, and stirred for 6 hours at 20°-24°C. The reaction mixture is treated with water, stirred for 10 minutes and filtered. The filtrate is separated, the organic phase is washed sequentially with saturated sodium bicarbonate, 3N hydrochloric acid and water, and concentrated in vacuo to give the title product as a solid foam, 7.55 g.
A stirred solution of 5-O(p-nitrobenzoyl)-LL-F28249α (3.12 g, 4.10 mmole) in dimethylformamide is treated with pyridinium dichromate (18.8 g, 50 mmole) in a single portion, stirred at 20°-25°C for 6 hours and poured into water. The reaction mixture is stirred for 15 minutes and filtered. The filter cake is washed with water, air-dried and taken up in ethyl acetate. The resulting mixture is heated at reflux temperature for 15 minutes, treated with diatomaceous earth and filtered. The filtrate is concentrated in vacuo to give a red-brown solid which is recrystallized from n-propanol to give the title product as white crystals, 3.33 g (52% overall yield from LL-F28249α) mp 217-221°C identified by ¹HNMR and mass spectral analyses.
A solution of 5-O(p-nitrobenzoyl)-LL-F28249α (0.38 g, 0.5 mmol) in methylene chloride is added to a freshly prepared mixture of pyridinium dichromate (0.19 g, 0.5 mmol) and acetic anhydride (0.3g, 3.0 mmol) with vigorous stirring. The reaction mixture is stirred at room temperature for 15 minutes, heated at reflux temperature for 6-8 hours, cooled to room temperature, and treated with water. After vigorous stirring, the phases are separated and the organic phase is washed with saturated sodium bicarbonate solution and concentrated in vacuo to give a residue. The residue is taken up in ethyl acetate and chromatographed using silica gel and ethyl acetate as eluent to give a pale yellow/grey solid. This solid is stirred with ethyl acetate; hexanes (55:45 v/v) filtered, and the filtrate is concentrated in vacuo to give the title compound as a pale yellow solid, 0.26 g, identified by ¹HNMR and HPLC analyses.
A stirred mixture of 5-O(p-nitrobenzoyl)-LL-F28249α (0.38 g, 0.50 mmole), aluminum t-butoxide (0.184 g, 0.75 mmole) and o-benzoquinone (0.216 g, 2.0 mmole) in toluene is heated at reflux temperature for 2 hours, cooled to room temperature, treated with toluene and dilute sulfuric acid (16%), stirred for 5 minutes and filtered. The filtrate is separated and the organic phase is washed with water and concentrated in vacuo to give a glassy solid residue. The residue is taken up in ethyl acetate and filtered through neutral alumina. The filtrate is concentrated in vacuo to give the title product as a white solid, 0.324 g, (71% yield by HPLC analyses).
A solution of 5-O(p-nitrobenzoyl)-LL-F28249α (0.38 g, 0.50 mmoles) and dimethyl sulfoxide (0.75 g, 9.6 mmoles) in methylene chloride is treated with powdered phosphorous pentoxide (0.107 g, 0.75 mmole) in one portion, stirred at 20°-25°C for 19 hours, treated dropwise with triethylamine (0.30 g, 3.0 mmole), stirred for 30 minutes, treated further with methylene chloride and water and stirred for 5 minutes. The phases are separated and the organic phase is washed with dilute hydrochloric acid (7%) and concentrated in vacuo to give the title product as a white solid, 0.28 g (47% purity by HPLC analysis).
A solution of 5-O(p-nitrobenzoyl)-LL-F28249α (0.19 g, 0.25 mmole) in methylene chloride is treated with manganese dioxide (8.0 g, 92 mmoles), stirred at 20°-25°C for 2 hours, treated further with methylene chloride, stirred for 5 minutes and filtered. The filtrate is concentrated in vacuo to give the title compound as a white solid, 0.08 g, 51% purity by HPLC analysis.
A solution of 5-O(p-nitrobenzoyl)-LL-F28249α (0.19 g, 0.25 mmole) in acetonitrile is treated with manganese dioxide (8.0 g, 92 mmoles), stirred for 3 hours at room temperature, treated further with acetonitrile, stirred for 5 minutes and filtered. The filter cake is slurried in methylene chloride and filtered. The acetonitrile and methylene chloride filtrates were combined, washed with water and concentrated in vacuo to give the title compound as a white solid, 0.14 g, 69% purity by HPLC analysis.
A solution of 5-O(p-nitrobenzoyl)-LL-F28249α (1.0 g, 1.3 mmole) in ethyl acetate is treated with manganese dioxide (20.0 g, 230 mmole), stirred at 20°-25°C for 3 hours and filtered. The filter cake is washed with ethyl acetate. The filtrates are combined, treated with manganese dioxide (8.0 g, 92 mmole), stirred at 20°-25°C for 2 hours and filtered. The filter cake is washed with ethyl acetate; the filtrates are combined and concentrated in vacuo to give the title product as a white solid, 0,8 g, (70% purity by HPLC analysis). The solid is recrystallized from n-propanol to give white crystals, mp 218-222°C.
A solution of 5-O(p-nitrobenzoyl)-LL-F28249α (0.38 g, 0.50 mmole) in benzene is treated sequentially with dimethyl sulfoxide (0.78 g, 10 mmole), pyridine (0.04 g, 0.5 mmole) trifluoroacetic acid (0.03 g, 0.25 mmole) and dicyclohexylcarbodiimide (0.31 g, 1.5 mmole), stirred at 20°-25°C for 21 hours, treated further with benzene and filtered. The filter cake is washed with benzene. The combined filtrates are washed with water and concentrated in vacuo to give the title compound as a light orange-brown solid, 0.34 g, 75% yield by HPLC analysis.
A mixture of 5-O(p-nitrobenzoyl)-LL-F28249α (0.38 g, 0.5 mmole), dimethyl sulfoxide (0.78 g, 10 mmole) and pyridinium trifluoroacetate (0.97 g, 0.5 mmole) in ethyl acetate is treated dropwise with acetic anhydride (0.26 g, 2.5 mmole), stirred for 24 hours at 20°-25°C and treated with ethyl acetate and water. The phases are separated; the organic phase is washed with water and concentrated in vacuo to give a viscous oil residue. The residue is taken up in methylene chloride and concentrated in vacuo to give the title product as a yellow solid, 0.36 g, identified by HPLC analysis.
A mixture of 5-O(p-nitrobenzoyl)-LL-F28249α (7.26 g, 10 mole) and pyridine (31.6 g, 400 mmole) is treated with dimethyl sulfoxide (15.6 g, 200 mmole) and dichloroacetic acid (1.29 g, 10 mmole), cooled to 2°-3°C, treated dropwise with acetic anhydride (5.1 g, 50 mmole) at 3°-7°C and treated with methylene chloride and water. The reaction mixture is stirred at ambient temperatures for 15-30 minutes and the phases are separated. The organic phase is washed with cold dilute hydrochloric acid (5%), and 5% sodium chloride solution and concentrated in vacuo to give the title product as a yellow solid foam, 7.47 g, 73% purity by HPLC analysis.
Using essentially the same procedure, but varying the acid reagent used, the following yields are obtained and reported in Table I.
A mixture of 5-O(p-nitrobenzoyl)-LL-F28249α (1.52 g, 2.0 mmole) and pyridine (3.16 g, 40 mmole) in toluene is treated with dimethyl sulfoxide (3.12 g, 40 mmole) and monochloroacetic acid (0.19 g, 2.0 mmole), cooled to 2°-3°C, treated dropwise with acetic anhydride (0.82 g, 8.0 mmole) at 3°-5°C, stirred at 2-3°C for 7 hours and treated further with toluene and water. After stirring the reaction mixture at 15°-20°C for 10 minutes, the phases are separated. The organic phase is washed sequentially with cold 2.4N hydrochloric acid and water at 15-20°C and concentrated in vacuo to give the title product as a yellow solid foam, 1.4 g, 71% purity by HPLC analysis.
A variety of oxidizing systems are evaluated for the conversion of 5-O(p-nitrobenzoyl)-LL-F28249α to 5-O(p-nitrobenzoyl)-23-oxo-LL-28249α. The reagents, reaction conditions and percent 5-O(p-nitrobenzoyl)-23-oxo-LL-28249α obtained as determined by HPLC analysis are reported in Table II.
A solution of 5-O(p-nitrobenzoyl)-23-oxo-LL-F28249α (10.67 g, 14.0 mmole) in n-butanol is treated with a solution of methoxylamine hydrochloride (2.34 g, 28.1 mmole) and anhydrous sodium acetate (2.30 g, 28.1 mmole) in water at 20°-22°C, stirred for 2 hours at 20°-22°C and filtered. The filter cake is air-dried and recrystallized from n-butanol (filtered hot) to give the title compound as a colorless solid, 3.6 g, 91% purity by HPLC analysis.
A solution of 5-O(p-nitrobenzoyl)-23-oxo-LL-F28249α (1.5 g, 2.0 mmole) in toluene is treated with a solution of methoxylamine hydrochloride (0.25 g, 3.0 mmol) and anhydrous sodium acetate (0.25 g, 3.0 mmol) in water and stirred at 20°-25°C for 10 hours. The toluene phase is separated, washed with water and concentrated in vacuo to give a solid residue. The solid is recrystallized from n-butanol to give the title product, 0.65 g, identified by HPLC analysis.
A solution of 5-O(p-nitrobenzoyl)-23-(methyloxime)-LL-F28249α (1.58 g, 2.0 mmole) in dioxane is treated dropwise with 4% sodium hydroxide (3.0 g, 3.0 mmole NaOH) at 8°-12°C, stirred for 3 hours at 8°-12°C, treated with toluene and water, and stirred for 5 minutes at ambient temperatures. The phases are separated and the organic phase is washed with 10% sodium chloride and concentrated in vacuo to give the title compound as a white solid foam, 1.15 g, 89% purity by HPLC analysis.
A mixture of 5-O(p-nitrobenzoyl)-23-oxo-LL-F28249α (1.52 g, 2.0 mmole) and 4% sodium hydroxide (3.3 g, 3.3 mmole NaOH) in dioxane is stirred at 23°C for 2 hours, treated with toluene and water and shaken. The phases are separated and the organic phase is washed with water and concentrated in vacuo to give the title compound as a solid foam, 0.90 g identified by ¹HNMR.
A mixture of 23-oxo-LL-F28249α (0.90 g, 1.5 mmole), methoxylamine hydrochloride (0.42 g, 5.0 mmole), anhydrous sodium acetate (0.41 g, 5.0 mmole), acetic acid and dioxane is stirred at 20°-25°C for 22 hours, treated with toluene and water and stirred for 5 minutes. The phases are separated, and the organic phase is washed with water and concentrated in vacuo to give the title compound as a solid foam, 0.84 g, 71% purity by HPLC analysis.
Claims (10)
- A process for the preparation of a 23-(C₁-C₆alkyloxime)-LL-F28249 compound characterized by protecting the 5-hydroxy group of a LL-F28249 compound with p-nitrobenzoyl chloride to yield a 5-O(p-nitrobenzoyl)-LL-F28249 compound; oxidizing said compound to yield a 5-O(p-nitrobenzoyl)-23-oxo-LL-F28249 derivative in a crystalline state; reacting said derivative with a C₁-C₆alkoxylamine or salt thereof to yield a 23-(C₁-C₆alkyloxime)-5-O(p-nitrobenzoyl)-LL-F28249 intermediate; and deprotecting said intermediate in the presence of base to yield the product 23-(C₁-C₆alkyloxime)-LL-F28249 compound.
- A process for the preparation of a 23-(C₁-C₆alkyloxime)-LL-F28249 compound characterized by protecting the 5-hydroxy group of a LL-F28249 compound with p-nitrobenzoyl chloride to yield a 5-O(p-nitrobenzoyl)-LL-F28249 compound; oxidizing said compound to yield a 5-O(p-nitrobenzoyl-23-oxo-LL-F28249 derivative in a crystalline state; deprotecting said derivative in the presence of base to yield a 23-oxo-LL-F28249 compound; and reacting said compound with a C₁-C₆alkoxylamine or salt thereof to yield the product 23-(C₁-C₆alkyloxime)-LL-F28249 compound.
- The process according to claim 1 wherein the oxidation is carried out using an oxidizing system selected from the group consisting of acetic anhydride and dimethyl sulfoxide; manganese dioxide; pyridinium dichromate and acetic anhydride; aluminum t-butoxide and o-benzoquinone; phosphorous pentoxide and dimethyl sulfoxide; and dicyclohexylcarbodiimide and dimethyl sulfoxide.
- The process according to claim 2, wherein the oxidation is carried out using an oxidizing system selected from the group consisting of acetic anhydride and dimethyl sulfoxide; manganese dioxide; pyridinium dichromate and acetic anhydride; aluminum t-butoxide and o-benzoquinone; phosphorous pentoxide and dimethyl sulfoxide; and dicyclohexylcarbodiimide and dimethyl sulfoxide.
- The process according to claims 3 or 4, wherein the oxidizing system is acetic anhydride and dimethyl sulfoxide and the oxidation is carried out in the presence of pyridine and an acid.
- The process according to claims 3 or 4, wherein the oxidizing system is manganese dioxide and the oxidation is carried out in the presence of ethyl acetate.
- The process according to claims 3 or 4, wherein the oxidizing system is pyridinium dichromate and acetic anhydride.
- The process according to claims 1 or 2, wherein the 5-O(p-nitrobenzoyl)-23-oxo-LL-F28249 derivative is purified by recrystallization from a suitable solvent.
- The process according to claim 1, wherein the 23-(C₁-C₆alkyloxime)-5-O(p-nitrobenzoyl)-LL-F28249 intermediate is purified by recrystallization from a suitable solvent.
- The process according to claims 1 or 2, wherein the product compound is 23-(methyloxime)-LL-F28249α.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US405793 | 1989-09-11 | ||
| US07/405,793 US4988824A (en) | 1989-09-11 | 1989-09-11 | Process for the preparation of 23-(C1-C6 alkyloxime)-LL-F28249 compounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1000095B true HK1000095B (en) | 1997-11-21 |
| HK1000095A1 HK1000095A1 (en) | 1997-11-21 |
Family
ID=23605260
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HK97101524A HK1000095A1 (en) | 1989-09-11 | 1997-07-09 | Process for the preparation of 23-(c1-c6 alkyloxime )ll - f28249 compounds |
Country Status (28)
| Country | Link |
|---|---|
| US (1) | US4988824A (en) |
| EP (1) | EP0421081B1 (en) |
| JP (1) | JP2939312B2 (en) |
| KR (1) | KR0160977B1 (en) |
| CN (1) | CN1028428C (en) |
| AT (1) | ATE107650T1 (en) |
| AU (1) | AU634579B2 (en) |
| BG (1) | BG60620B1 (en) |
| BR (1) | BR9004493A (en) |
| CA (1) | CA2024919C (en) |
| DE (1) | DE69010129T2 (en) |
| DK (1) | DK0421081T3 (en) |
| ES (1) | ES2057291T3 (en) |
| GE (1) | GEP19981003B (en) |
| HK (1) | HK1000095A1 (en) |
| HU (1) | HU206721B (en) |
| IE (1) | IE66030B1 (en) |
| IL (1) | IL95303A (en) |
| LV (1) | LV10503B (en) |
| MD (1) | MD425C2 (en) |
| NZ (1) | NZ235151A (en) |
| PL (1) | PL165332B1 (en) |
| PT (1) | PT95242B (en) |
| RU (1) | RU2030416C1 (en) |
| SI (1) | SI9011711A (en) |
| UA (1) | UA26907C2 (en) |
| YU (1) | YU47520B (en) |
| ZA (1) | ZA907186B (en) |
Families Citing this family (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU660205B2 (en) | 1991-12-23 | 1995-06-15 | Virbac, Inc | Systemic control of parasites |
| US5439924A (en) * | 1991-12-23 | 1995-08-08 | Virbac, Inc. | Systemic control of parasites |
| US5478951A (en) | 1994-06-22 | 1995-12-26 | American Cyanamid Company | Method for the purification of 23-E isomers of 23-imino derivatives of LL-F28249 compounds |
| ATE199628T1 (en) | 1995-02-24 | 2001-03-15 | Novartis Erfind Verwalt Gmbh | COMPOSITION FOR FIGHTING PARASITES |
| ES2174027T3 (en) * | 1995-06-30 | 2002-11-01 | American Cyanamid Co | STABLE COMPOSITIONS CONTAINING MACROLIDES AND MACROLIDES COMBINED WITH VACCINES. |
| WO1999017760A2 (en) | 1997-10-02 | 1999-04-15 | Microcide Pharmaceuticals, Inc. | Fungal or mammalian cell efflux pump inhibitors for enhancing susceptibility of the cell to a drug |
| US6762327B2 (en) * | 2002-04-29 | 2004-07-13 | Wyeth | Selective oxidation process with enhanced safety |
| US7348417B2 (en) * | 2003-08-07 | 2008-03-25 | Wyeth | Method of purifying moxidectin through crystallization |
| NZ548934A (en) * | 2006-05-08 | 2007-01-26 | Wyeth Corp | Process for preparing moxidectin |
| AU2006203459B2 (en) * | 2006-05-08 | 2010-02-25 | Wyeth | Intermediates and processes using them |
| NZ548936A (en) * | 2006-06-22 | 2007-02-23 | Wyeth Corp | Selective oxidation of LL-F28249-alpha using o-iodoxybenzoic acid |
| PL3351546T3 (en) | 2011-12-02 | 2024-09-09 | Boehringer Ingelheim Vetmedica Gmbh | Long-acting injectable moxidectin formulations |
| CN104277050B (en) * | 2013-07-04 | 2016-05-04 | 北大方正集团有限公司 | A kind of method of preparing moxidectin |
| CN104017001B (en) * | 2014-06-18 | 2016-01-13 | 大连九信生物化工科技有限公司 | A kind of method of chemosynthesis mosictin |
| CN104292239A (en) * | 2014-09-30 | 2015-01-21 | 大连九信生物化工科技有限公司 | Method for removing by-product dimethyl sulfide in moxidectin production process |
| CN104628740B (en) * | 2015-02-13 | 2017-06-16 | 河北圣雪大成制药有限责任公司 | A kind of chemical synthesis and the method for purifying moxidectin |
| CN104860961B (en) * | 2015-04-10 | 2017-08-04 | 新宇药业股份有限公司 | One kind prepares 5 oxygen（P-nitrophenyl formyl）The method of nimoctin |
| CN106831811B (en) * | 2015-08-12 | 2018-10-26 | 内蒙古佳瑞米精细化工有限公司 | A method of preparing high-content nimoctin |
| CN114591347B (en) * | 2022-03-29 | 2023-03-24 | 河北美荷药业有限公司 | Moxidectin intermediate and preparation method thereof, and preparation method of moxidectin |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4201861A (en) * | 1977-10-03 | 1980-05-06 | Merck & Co., Inc. | Acyl derivatives of C-076 compounds |
| IL78621A (en) * | 1985-04-30 | 1991-06-30 | American Cyanamid Co | Mylbemycin analogs,their preparation and pesticidal compositions containing them |
| CA1296329C (en) * | 1986-06-06 | 1992-02-25 | Derek R. Sutherland | Macrolide compounds |
| ES2058082T3 (en) * | 1986-09-12 | 1994-11-01 | American Cyanamid Co | DERIVATIVES 23-OXO (CETO) AND 23-IMINO OF COMPOUNDS LL-F28249. |
| US4916154A (en) * | 1986-09-12 | 1990-04-10 | American Cyanamid Company | 23-Imino derivatives of LL-F28249 compounds |
| US4855317A (en) * | 1987-03-06 | 1989-08-08 | Ciba-Geigy Corporation | Insecticides and parasiticides |
| GB8721377D0 (en) * | 1987-09-11 | 1987-10-21 | Glaxo Group Ltd | Chemical compounds |
| GB8721376D0 (en) * | 1987-09-11 | 1987-10-21 | Glaxo Group Ltd | Chemical compounds |
| EP0341974B1 (en) * | 1988-05-10 | 1996-01-24 | American Cyanamid Company | Macrolide compounds |
| GB8813150D0 (en) * | 1988-06-03 | 1988-07-06 | American Cyanamid Co | Chemical compounds |
| US4900758A (en) * | 1989-05-11 | 1990-02-13 | Ici Americas Inc. | Novel insecticides |
| EP0423445B1 (en) * | 1989-09-11 | 1995-11-08 | American Cyanamid Company | 13-alkyl-23-imino and 13-halo-23-imino derivatives of LL-F28249 compounds and their use as endo- and ectoparasiticidal insecticidal, acaricidal and nematocidal agents |
-
1989
- 1989-09-11 US US07/405,793 patent/US4988824A/en not_active Expired - Lifetime
-
1990
- 1990-08-03 DK DK90114919.5T patent/DK0421081T3/en active
- 1990-08-03 EP EP90114919A patent/EP0421081B1/en not_active Expired - Lifetime
- 1990-08-03 AT AT90114919T patent/ATE107650T1/en not_active IP Right Cessation
- 1990-08-03 ES ES90114919T patent/ES2057291T3/en not_active Expired - Lifetime
- 1990-08-03 DE DE69010129T patent/DE69010129T2/en not_active Expired - Lifetime
- 1990-08-06 IL IL9530390A patent/IL95303A/en unknown
- 1990-09-03 NZ NZ235151A patent/NZ235151A/en unknown
- 1990-09-07 CA CA002024919A patent/CA2024919C/en not_active Expired - Lifetime
- 1990-09-07 JP JP2235958A patent/JP2939312B2/en not_active Expired - Lifetime
- 1990-09-07 PT PT95242A patent/PT95242B/en not_active IP Right Cessation
- 1990-09-10 BR BR909004493A patent/BR9004493A/en not_active IP Right Cessation
- 1990-09-10 ZA ZA907186A patent/ZA907186B/en unknown
- 1990-09-10 YU YU171190A patent/YU47520B/en unknown
- 1990-09-10 HU HU905842A patent/HU206721B/en unknown
- 1990-09-10 UA UA4831093A patent/UA26907C2/en unknown
- 1990-09-10 BG BG92810A patent/BG60620B1/en unknown
- 1990-09-10 KR KR1019900014281A patent/KR0160977B1/en not_active Expired - Lifetime
- 1990-09-10 RU SU904831093A patent/RU2030416C1/en active
- 1990-09-10 SI SI9011711A patent/SI9011711A/en unknown
- 1990-09-10 CN CN90107676A patent/CN1028428C/en not_active Expired - Lifetime
- 1990-09-10 IE IE327390A patent/IE66030B1/en not_active IP Right Cessation
- 1990-09-10 AU AU62362/90A patent/AU634579B2/en not_active Expired
- 1990-09-10 PL PL90286824A patent/PL165332B1/en unknown
-
1993
- 1993-06-28 LV LVP-93-697A patent/LV10503B/en unknown
- 1993-07-31 GE GEAP19931302A patent/GEP19981003B/en unknown
-
1994
- 1994-07-12 MD MD95-0307A patent/MD425C2/en unknown
-
1997
- 1997-07-09 HK HK97101524A patent/HK1000095A1/en not_active IP Right Cessation
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0421081B1 (en) | Process for the preparation of 23-(C1-C6 alkyloxime)LL-F28249 compounds | |
| HK1000095B (en) | Process for the preparation of 23-(c1-c6 alkyloxime )ll - f28249 compounds | |
| CA1215708A (en) | New process for the synthesis of pyrido-imidazo- rifamycins | |
| US4427587A (en) | Total synthesis of antitumor antibiotics BBM-2040A and BBM-2040B | |
| EP0354583B1 (en) | DC-88A derivatives | |
| US4564675A (en) | Process for producing 4'-demethyl-epipodophyllotoxin-β-D-ethylidene-glucoside and acyl-derivative thereof | |
| EP0180415B1 (en) | A 6-0-methylerythromycin A derivative | |
| US4395558A (en) | 9-Epi-mitomycin B and D compounds | |
| US4365058A (en) | Method of preparation of esters of antibiotics selected from the group consisting of polyene macrolides and of N-substituted derivatives thereof | |
| HUP0003399A2 (en) | An improved process for the production of an antiparasitic substance | |
| CA1295612C (en) | Nitrogen containing derivatives of epipodophyllotoxin glucosides | |
| CA2196932C (en) | Process for the glycosidation of colchicine derivatives and products o btained | |
| CA1248944A (en) | Anthracycline glycosides | |
| OHTSUKA et al. | Studies on tRNA and Related Compounds. XXXVII. Synthesis and Physical Properties of 2'-or 3'-O-(o-Nitrobenzyl) nucleosides: the Use of o-Nitrophenyldiazomethane as a Synthetic Reagent | |
| EP4389732A1 (en) | Method for synthesizing 5,8-diamino-3,4-dihydro-2h-1-naphthalenone and intermediate compound used therein | |
| EP0000656B1 (en) | 4"-ureido-oleandomycin derivatives, process for their preparation and their use in pharmaceutical compositions | |
| Morimoto et al. | Chemical modification of erythromycins IV. Synthesis and biological properties of 6-O-methylerythromycin B | |
| GB1585316A (en) | Erythromycin a intermediates | |
| US4661588A (en) | 23-O-substituted carbamoyl-23-demycinosyldesmycosin | |
| CA2059999C (en) | Process for preparing 2'-(diethylamino)rifamycin p (p/dea) | |
| US5637680A (en) | Process for the preparation of etoposide phosphate and intermediate thereof | |
| JPS6144868A (en) | Novel frediricamycin a derivative | |
| JPH031317B2 (en) | ||
| Paris et al. | Unusual transformation of the 3-hydroxy-picolinoyl residue of pristinamycin IA | |
| CS158992A3 (en) | Process for preparing 6-0-acylelasmycin a derivatives |