JPS6287599A - Production of oxime derivative of erythromycin - Google Patents
Production of oxime derivative of erythromycinInfo
- Publication number
- JPS6287599A JPS6287599A JP60228170A JP22817085A JPS6287599A JP S6287599 A JPS6287599 A JP S6287599A JP 60228170 A JP60228170 A JP 60228170A JP 22817085 A JP22817085 A JP 22817085A JP S6287599 A JPS6287599 A JP S6287599A
- Authority
- JP
- Japan
- Prior art keywords
- erythromycin
- oxime
- alkali metal
- metal salt
- methanol
- Prior art date
- Legal status (The legal status 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 status listed.)
- Pending
Links
- -1 oxime derivative of erythromycin Chemical class 0.000 title claims abstract description 21
- 238000004519 manufacturing process Methods 0.000 title claims description 8
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 claims abstract description 21
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 9
- 239000002253 acid Substances 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 11
- 150000002923 oximes Chemical class 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 abstract description 36
- 239000002904 solvent Substances 0.000 abstract description 7
- 150000001875 compounds Chemical class 0.000 abstract description 6
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 229960003276 erythromycin Drugs 0.000 abstract description 5
- 150000002443 hydroxylamines Chemical class 0.000 abstract description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 4
- 239000002585 base Substances 0.000 abstract description 4
- 239000006227 byproduct Substances 0.000 abstract description 3
- 239000003242 anti bacterial agent Substances 0.000 abstract 1
- 229940088710 antibiotic agent Drugs 0.000 abstract 1
- 238000006146 oximation reaction Methods 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 23
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 6
- IDRYSCOQVVUBIJ-UHFFFAOYSA-N Erythromycin-B Natural products CC1C(OC2C(C(CC(C)O2)N(C)C)O)C(C)(O)CC(C)C(=O)C(C)C(O)C(C)C(CC)OC(=O)C(C)C1OC1CC(C)(OC)C(O)C(C)O1 IDRYSCOQVVUBIJ-UHFFFAOYSA-N 0.000 description 5
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 5
- 239000001632 sodium acetate Substances 0.000 description 5
- 235000017281 sodium acetate Nutrition 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- KYTWXIARANQMCA-PGYIPVOXSA-N (3r,4s,5s,6r,7r,9r,10z,11s,12r,13s,14r)-6-[(2s,3r,4s,6r)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-14-ethyl-7,12,13-trihydroxy-10-hydroxyimino-4-[(2r,4r,5s,6s)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-3,5,7,9,11,13-hexamethyl-oxacyclotetradec Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=N\O)/[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 KYTWXIARANQMCA-PGYIPVOXSA-N 0.000 description 3
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 3
- 241000486679 Antitype Species 0.000 description 3
- 229930006677 Erythromycin A Natural products 0.000 description 3
- 230000003115 biocidal effect Effects 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 235000011056 potassium acetate Nutrition 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- AYJRCSIUFZENHW-UHFFFAOYSA-L barium carbonate Chemical compound [Ba+2].[O-]C([O-])=O AYJRCSIUFZENHW-UHFFFAOYSA-L 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- SPWVRYZQLGQKGK-UHFFFAOYSA-N dichloromethane;hexane Chemical compound ClCCl.CCCCCC SPWVRYZQLGQKGK-UHFFFAOYSA-N 0.000 description 2
- 150000002084 enol ethers Chemical class 0.000 description 2
- IDRYSCOQVVUBIJ-PPGFLMPOSA-N erythromycin B Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@H]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)C)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 IDRYSCOQVVUBIJ-PPGFLMPOSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- JXKPEJDQGNYQSM-UHFFFAOYSA-M sodium propionate Chemical compound [Na+].CCC([O-])=O JXKPEJDQGNYQSM-UHFFFAOYSA-M 0.000 description 2
- 239000004324 sodium propionate Substances 0.000 description 2
- 235000010334 sodium propionate Nutrition 0.000 description 2
- 229960003212 sodium propionate Drugs 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- OHVLMTFVQDZYHP-UHFFFAOYSA-N 1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-2-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound N1N=NC=2CN(CCC=21)C(CN1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)=O OHVLMTFVQDZYHP-UHFFFAOYSA-N 0.000 description 1
- KZEVSDGEBAJOTK-UHFFFAOYSA-N 1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-2-[5-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]ethanone Chemical compound N1N=NC=2CN(CCC=21)C(CC=1OC(=NN=1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)=O KZEVSDGEBAJOTK-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- LDXJRKWFNNFDSA-UHFFFAOYSA-N 2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound C1CN(CC2=NNN=C21)CC(=O)N3CCN(CC3)C4=CN=C(N=C4)NCC5=CC(=CC=C5)OC(F)(F)F LDXJRKWFNNFDSA-UHFFFAOYSA-N 0.000 description 1
- JQMFQLVAJGZSQS-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-N-(2-oxo-3H-1,3-benzoxazol-6-yl)acetamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)NC1=CC2=C(NC(O2)=O)C=C1 JQMFQLVAJGZSQS-UHFFFAOYSA-N 0.000 description 1
- XHRCFGDFESIFRG-UHFFFAOYSA-N 2-chloro-n-ethyl-n-[(2-methylphenyl)methyl]ethanamine Chemical compound ClCCN(CC)CC1=CC=CC=C1C XHRCFGDFESIFRG-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- YDVNLQGCLLPHAH-UHFFFAOYSA-N dichloromethane;hydrate Chemical class O.ClCCl YDVNLQGCLLPHAH-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 239000012156 elution solvent Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- BWILYWWHXDGKQA-UHFFFAOYSA-M potassium propanoate Chemical compound [K+].CCC([O-])=O BWILYWWHXDGKQA-UHFFFAOYSA-M 0.000 description 1
- 239000004331 potassium propionate Substances 0.000 description 1
- 235000010332 potassium propionate Nutrition 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- MFBOGIVSZKQAPD-UHFFFAOYSA-M sodium butyrate Chemical compound [Na+].CCCC([O-])=O MFBOGIVSZKQAPD-UHFFFAOYSA-M 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
Landscapes
- Saccharide Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
産業上の利用分野
本発明は、抗生物質合成の中間体として有用なエリスロ
マイシン類のオキシム゛誘導体の製造法に関する。DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to a method for producing oxime derivatives of erythromycins useful as intermediates in antibiotic synthesis.
従来の技術
エリスロマイシン類のオキシム誘導体は、抗生物質合成
中間体として重要なものである。BACKGROUND OF THE INVENTION Oxime derivatives of erythromycins are important as intermediates in antibiotic synthesis.
エリスロマイシンＡ オキシムの製造に関しては、エリ
スロマイシンＡをメタノール中ヒト［Ｊキシルアミンと
処理することにより比較的低収率で得る方法が公知であ
る（デトラヘドロン レターズ、１９７０．１５７）。Regarding the production of erythromycin A oxime, a method is known in which erythromycin A is obtained in relatively low yields by treatment with human [J xylamine in methanol (Detrahedron Letters, 1970.157).
その他の方法として、ヒドロキシルアミン塩酸塩と、塩
基として炭酸バリウムを用いる方法（英国特許明細書第
１，１１０゜５０４号）、ピリジンを用いる方法（特開
昭５９−１０４３９８号公報）、炭酸ナトリウムを用い
る方法（特開昭６０−３８３９３号公報）などが報告さ
れている。Other methods include a method using hydroxylamine hydrochloride and barium carbonate as a base (British Patent Specification No. 1,110°504), a method using pyridine (Japanese Unexamined Patent Publication No. 104398/1983), and a method using sodium carbonate. A method (Japanese Unexamined Patent Publication No. 60-38393) has been reported.
また、エリスロマイシンＢ オキシムの製造に関しては
、ヒドロキシルアミン塩酸塩とトリエチルアミンととも
に還流する方法が報告されている［ジャーナル オブオ
ーガニック ゲミストリー第３９巻２４９２頁（１９７
４年）コ。Regarding the production of erythromycin B oxime, a method has been reported in which it is refluxed with hydroxylamine hydrochloride and triethylamine [Journal of Organic Gemistry Vol. 39, p. 2492 (197
4th grade) Ko.
発明が解決しようとするＩＬ’ｌ Ｌαしかし、上記従
来方法では収率が未だ充分でなく、また、たとえば式Ｉ
、
（式中、Ｃｂｚはベンジルオキシカルボニル基を示す。IL'l Lα to be solved by the invention However, the yield is still insufficient in the above conventional method, and for example,
, (wherein, Cbz represents a benzyloxycarbonyl group.
）にて表わされるエリスロマイシン誘導体に上記従来方
法を適用したところ、炭酸ノくリウムとヒドロキシルア
ミン塩酸塩を用いた製造法では、式■、
（式中、Ｃｂｚは前記と同意義。）で表わされる脱水生
成物、通称エノールエーテル体が多量に生成し、目的と
するオキシム体の生成は極く僅かであった。また、トリ
エチルアミンとヒドロキシルアミン塩酸塩を用いた製造
法では、反応が非常に遅く、長時間の還流にもかかわら
ず、目的物の収率は非常に低いものであった。) When the above-mentioned conventional method was applied to the erythromycin derivative represented by formula (2), the production method using notrium carbonate and hydroxylamine hydrochloride resulted in the following formula (where Cbz has the same meaning as above): A large amount of a dehydrated product, commonly known as an enol ether, was produced, and only a small amount of the desired oxime was produced. Furthermore, in the production method using triethylamine and hydroxylamine hydrochloride, the reaction was very slow and the yield of the target product was very low despite long reflux.
さらに、トリエチルアミンの代わりに他の塩基、たとえ
ばピリジン、２，６−シメチルビリジン、Ｎ、Ｎ−ジメ
チルアニリンなどとヒドロキシルアミン塩酸塩を用いて
も、エノールエーテル体の増加を防ぐことができなかっ
た。Furthermore, the use of other bases such as pyridine, 2,6-dimethylpyridine, N,N-dimethylaniline, etc. and hydroxylamine hydrochloride instead of triethylamine did not prevent the increase in enol ether forms. .
問題点を解決するためｑ壬週
本発明者らは、上記従来法の欠点を解決すべく種々検討
した結果、低級アルキルカルボン酸のアルカリ金属塩と
ヒドロキシルアミン塩類の組み合わせが、副生物示少な
く、したがって高収率しかも高純度でエリスロマイシン
類のオキシム誘導体を製造できることを見い出し、本発
明を完成した。すなわち、本発明は、エリスロマイシン
類を適当な溶媒中、低級アルキルカルボン酸のアルカリ
金属塩を塩基として用いてヒドロキシルアミン塩類を反
応させ、エリスロマイシン類のオキシム誘導体を得る方
法である。In order to solve the problems, the present inventors have conducted various studies to solve the drawbacks of the conventional methods described above. As a result, the present inventors have found that the combination of an alkali metal salt of a lower alkyl carboxylic acid and a hydroxylamine salt produces fewer by-products. Therefore, the inventors have discovered that oxime derivatives of erythromycins can be produced with high yield and high purity, and have completed the present invention. That is, the present invention is a method for obtaining oxime derivatives of erythromycins by reacting erythromycins with hydroxylamine salts in a suitable solvent using an alkali metal salt of a lower alkyl carboxylic acid as a base.
本発明におけるエリスロマイシン類とは、エリスロマイ
シンＡ、エリスロマイシンＢおよびこれらの誘導体を意
味し、エリスロマイシン類のオキシム誘導体とは、上記
エリスロマイシン類の９位才キシム誘導体を意味する。In the present invention, erythromycins refer to erythromycin A, erythromycin B, and derivatives thereof, and oxime derivatives of erythromycins refer to 9-position xime derivatives of the above-mentioned erythromycins.
以下、本発明の好ましい実施態様について説明する。Preferred embodiments of the present invention will be described below.
反応溶媒については、アルコール系溶媒が望ましく、特
にメタノール、エタノールが望ましい。As for the reaction solvent, alcoholic solvents are preferable, and methanol and ethanol are particularly preferable.
低級アルキルカルボン酸のアルカリ金属塩としては、た
とえば酢酸ナトリウム、酢酸カリウム、プロピオン酸ナ
トリウム、プロピオン酸カリウム、醋酸ナトリウム、醋
酸カリウムなどである。Examples of the alkali metal salts of lower alkylcarboxylic acids include sodium acetate, potassium acetate, sodium propionate, potassium propionate, sodium acetate, and potassium acetate.
低級アルキルカルボン酸のアルカリ金属塩の使用量は、
反応原料に対して１．２〜１０モル当量用いるが、副生
物の生成を抑えるという点で５〜１０モル当量程当量−
るのが望ましい。The amount of alkali metal salt of lower alkyl carboxylic acid to be used is
It is used in an amount of 1.2 to 10 molar equivalents based on the reaction raw material, but in order to suppress the formation of by-products, it is necessary to use an equivalent amount of 5 to 10 molar equivalents.
It is desirable to
ヒドロキシルアミン塩類としては、通常、塩酸塩を用い
る。ヒドロキシルアミン塩類の使用量は、低級アルキル
カルボン酸のアルカリ金属塩と同様１．２〜１０モル当
量用い、望ましくは５〜７モル当量程度である。Hydrochloride is usually used as the hydroxylamine salt. The amount of hydroxylamine salts to be used is 1.2 to 10 molar equivalents, preferably about 5 to 7 molar equivalents, similar to the alkali metal salts of lower alkyl carboxylic acids.
反応温度としては、０°Ｃ〜溶媒の還流温度の条件の中
から適宜決定すれば良い。The reaction temperature may be appropriately determined from 0°C to the reflux temperature of the solvent.
本発明におけるエリスロマイシン類のオキシム誘導体に
は、２個の異性体（シン型およびアンチ型）が存在する
が、本発明ではシン型でもアンチ型でもよく、またシン
型とアンチ型との混合物であってもよい。The oxime derivative of erythromycin in the present invention has two isomers (syn type and anti type), but in the present invention, it may be either the syn type or the anti type, or it may be a mixture of the syn type and the anti type. It's okay.
発明の効果
本発明方法を用いることにより、従来低収率でしか得ら
れなかったエリスロマイシンＡ オキシムを高収率で得
ることが可能となった。Effects of the Invention By using the method of the present invention, it has become possible to obtain erythromycin A oxime in a high yield, which was conventionally obtained only in a low yield.
また、エリスロマイシンＢ オキシムの製造では、反応
時間を著しく短縮できる。Furthermore, in the production of erythromycin B oxime, the reaction time can be significantly shortened.
さらに、本反応は非常に緩和な条件の為、比較的不安定
なエリスロマイシン類、たとえば式■で表わされるエリ
スロマイシン類にも適用でき、目的物を高収率で得るこ
とができる。Furthermore, since this reaction requires very mild conditions, it can be applied to relatively unstable erythromycins, such as erythromycins represented by formula (2), and the desired product can be obtained in high yield.
この様にして得られるエリスロマイシン類のオキシム誘
導体は、抗生物質合成の中間体として有用である。The oxime derivatives of erythromycins thus obtained are useful as intermediates for antibiotic synthesis.
実施例
次に 実施例により本発明のオキシム化方法をより具体
的に説明する。EXAMPLES Next, the oxime-forming method of the present invention will be explained more specifically using examples.
実施例１
エリスロマイシンＡ １００ｇ、酢酸ナトリウム７８．
２ｇ１ ヒドロキシルアミン塩酸塩４７．３ｇをメタ
ノール４００ｍ１に加え、５０℃で１３時間攪拌した。Example 1 Erythromycin A 100g, sodium acetate 78.
2g1 47.3g of hydroxylamine hydrochloride was added to 400ml of methanol and stirred at 50°C for 13 hours.
反応終了後メタノールを減圧上留去し、飽和重曹水ＩＱ
を加えジクロロメタン５００社で２回抽出した。有機層
を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し
た。溶媒を留去して得られた残渣をジクロロメタン−ｎ
−ヘキサンより再結晶し、エリスロマイシンＡ オキシ
ム８６．６ｇを得た。After the reaction, methanol was distilled off under reduced pressure and saturated sodium bicarbonate solution IQ
was added and extracted twice with dichloromethane 500. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent was dichloromethane-n
- Recrystallization from hexane gave 86.6 g of erythromycin A oxime.
収率８４．９ り６
ｍ、ｐ、１５６〜１５９℃
実施例２
エリスロマイシンＢ ５０ｇ、酢酸カリウム４７．８ｇ
。Yield: 84.9 m, p, 156-159°C Example 2 Erythromycin B 50 g, potassium acetate 47.8 g
.
ヒドロキシルアミン塩酸塩２４． ｔｇをメタノール２
００−に加え、室温で５日間攪拌した。反応抜水８００
ｍ１に注ぎ込み、析出した結晶を濾取し、飽和１Ｆ曹水
３００ｍ１、水１００域で順次洗浄した。乾燥後、ジク
ロロメタン−ｎ−ヘキサンより再結晶し、エリスロマイ
シンＢ オキシム４３ｇを得た。Hydroxylamine hydrochloride 24. tg to methanol 2
00- and stirred at room temperature for 5 days. Reaction water removal 800
The precipitated crystals were collected by filtration and washed successively with 300 ml of saturated 1F carbon dioxide solution and 100 ml of water. After drying, it was recrystallized from dichloromethane-n-hexane to obtain 43 g of erythromycin B oxime.
収率８４．２％
ｍ、ｐ、１６７〜１９６℃
実施例３
２’−０，３’−Ｎ−ビス（ベンジルオキシカルボニル
）−Ｎ−デメチルエリスロマイシンＡ１００ｇ、酢酸ナ
トリウム５８．１ｇ、ヒドロキシルアミン塩酸塩３５．
２ｇをメタノール１．２５１に加え、４５℃で１４時間
攪拌した。反応後メタノール約２００ｍ１を留去し、母
液を飽和重曹水ＩＱに注ぎ込み、析出した結晶を濾取し
、ジクロロメタン−ｎ−ヘキサンより再結晶し、２’−
０，３′−Ｎ−ビス（ベンジルオキシカルボニル
ロマイシンＡオキシム８６． ８ｇを得た。Yield 84.2% m, p, 167-196°C Example 3 2'-0,3'-N-bis(benzyloxycarbonyl)-N-demethylerythromycin A 100g, sodium acetate 58.1g, hydroxylamine hydrochloride Salt 35.
2g was added to 1.25ml of methanol and stirred at 45°C for 14 hours. After the reaction, about 200 ml of methanol was distilled off, the mother liquor was poured into saturated sodium bicarbonate solution IQ, the precipitated crystals were collected by filtration, and recrystallized from dichloromethane-n-hexane to give 2'-
86.8 g of 0,3'-N-bis(benzyloxycarbonylromycin A oxime) was obtained.
収率８５．５ ％ ｍ．ｐ．１５２〜１５４℃ ＫＢｒ −ｒ ＩＲ ｖＩｎａｘｃｍ ： ３４２０、１７４７．１７００ 。Yield 85.5% m. p. 152-154℃ KBr -r IR vInaxcm: 3420, 1747.1700.
’Ｈ−ＮＭＲ （ＣＤＣｕ３ ） ｌ； （ｐｐｍ）
；２、８２．２．８６（ ３Ｈ 、 Ｎ Ｃ Ｈ ｓ
）３、０２．３．３８（ ３Ｈ 、 ３”−Ｏ Ｃ Ｈ
） ）５、 ００−５． ３０ （ ４Ｈ ）７、
２０−７． ５０ （ ＩＯＨ ’）８、３２（ １）
（、 Ｎ Ｏ Ｈ ）元素分析値（ ＣａｔＨｙ−Ｎ−
０＋ｙとして）理論値（％） Ｃ：６２．２６．Ｈニ
ア、８４。１２．７９実測値（％） Ｃ：６２．０５
．Ｈニア、６１，Ｎ：２．６７実施例４
２’−０．３’−Ｎ−ビス（ベンジルオキシカルボニル
）−Ｎ−デメチルエリスロマイシンＡ５ｇ１プロピオン
酸ナトリウム３． ４０ｇ， ヒドロキシルアミン塩
酸塩１．７６ｇをメタノール２０ｍＱに加え、４５°Ｃ
で１４時間攪拌した後、さらに１時間加熱還流した。溶
媒を留去し、ジクロロメタンで抽出し、飽和重仔水５０
ｍｌ、飽和食塩水５０ｍｌで順次洗浄し、無水硫酸マグ
ネシウムで乾燥した。溶媒を留去して得られた残渣をシ
リカゲルカラムクロマトグラフィー（溶出溶媒；クロロ
ホルム：メタノール＝ＬＱＯ：２〜１００：１０）で精
製し、２’−０。'H-NMR (CDCu3) l; (ppm)
;2, 82.2.86 ( 3H , N C H s
) 3, 02.3.38 ( 3H , 3”-OC H
))5, 00-5. 30 (4H)7,
20-7. 50 (IOH') 8, 32 (1)
(,NOH) elemental analysis value (CatHy-N-
0+y) Theoretical value (%) C: 62.26. H near, 84.12.79 Actual value (%) C: 62.05
．． Hnia, 61, N: 2.67 Example 4 2'-0.3'-N-bis(benzyloxycarbonyl)-N-demethylerythromycin A5g1 Sodium propionate 3. Add 40g of hydroxylamine hydrochloride and 1.76g of hydroxylamine hydrochloride to 20mQ of methanol and heat at 45°C.
After stirring for 14 hours, the mixture was further heated under reflux for 1 hour. The solvent was distilled off, extracted with dichloromethane, and diluted with 50% saturated dichloromethane water.
ml and 50 ml of saturated saline solution, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (elution solvent: chloroform:methanol=LQO: 2 to 100:10) to obtain 2'-0.
３′−Ｎ−ビス（ベンジルオキシカルボニルＮ−デメチ
ルエリスロマイシンＡ オキシム４． ｏｓｇを得た。3'-N-bis(benzyloxycarbonyl N-demethylerythromycin A oxime 4.osg was obtained.
収率８０．３％
本化合物は、実施例３で得られた化合物と物理重性状が
一致した。Yield: 80.3% This compound had the same physical properties as the compound obtained in Example 3.
実施例５
２°−０，３’−Ｎ−ビス（ベンジルオキシカルボニル
）−Ｎ−デメチルエリスロマイシンＡ５ｇ、ｎ−酪酸ナ
トリウム３．９０ｇ、 ヒドロキシルアミン塩酸塩１
９６ｇをメタノール２０ｍ１に加え、以下実施例４と同
様の反応および後処理を行ない２′−０，３’−Ｎ−ビ
ス（ベンジルオキシカルボニル）−Ｎ−デメチルエリス
ロマイシンＡオキシム４，３ｇを得た。Example 5 2°-0,3'-N-bis(benzyloxycarbonyl)-N-demethylerythromycin A 5 g, sodium n-butyrate 3.90 g, hydroxylamine hydrochloride 1
96 g was added to 20 ml of methanol, and the same reaction and post-treatment as in Example 4 were carried out to obtain 4.3 g of 2'-0,3'-N-bis(benzyloxycarbonyl)-N-demethylerythromycin A oxime. .
収率８４，６％
本化合物は、実施例３で得られた化合物と物理的性状が
一致した。Yield: 84.6% This compound had the same physical properties as the compound obtained in Example 3.
実施例６
２’−０，３’−Ｎ−ビス（ベンジルオキシカルボニル
）−Ｎ−デメチルエリスロマイシンＢ３ｇ１酢酸ナトリ
ウム２．４ｇ、 ヒドロキシルアミン塩酸塩１．４５
ｇをメタノール１２ｍ１に加え、室温で５日間攪拌した
。以下、実施例４と同様に処理して、シリカゲルカラム
クロマトグラフィー（溶出溶媒；酢酸エチル：ヘキサン
−１：１）で精製し、２°−０，３’−Ｎ−ビス（ベン
ジルオキシカルボニル）−Ｎ−デメチルエリスロマイシ
ンＡオキシム２．４５ｇを得た。Example 6 2'-0,3'-N-bis(benzyloxycarbonyl)-N-demethylerythromycin B3g1 Sodium acetate 2.4g, Hydroxylamine hydrochloride 1.45
g was added to 12 ml of methanol, and the mixture was stirred at room temperature for 5 days. Thereafter, the treatment was carried out in the same manner as in Example 4, and the 2°-0,3'-N-bis(benzyloxycarbonyl)- 2.45 g of N-demethylerythromycin A oxime was obtained.
収率８０．３ ％
ｍ、ｐ、１４６〜１４８℃
（酢酸エチル−石油エーテルより再結晶）工ＲｖＫ Ｂ
ｒ −・
ｍａｘＣｍ’
３４６０ 、１７５０ 、１７１０
’ Ｈ−Ｎ Ｍ Ｒ（ＣＤＣｆ１３）δ（ｐｐｍ）；２
．８２．２．８６（３Ｈ、Ｎ ＣＲ３）３．０２，３．
３８（３Ｈ、３“−０ＣＲ，）５、０４−５．２０ （
４Ｈ）
７、２０−７．４６ （ＩＯＨ）
８．０６（ＩＨ，Ｎ ＯＨ）Yield 80.3% m, p, 146-148°C (recrystallized from ethyl acetate-petroleum ether) Engineering RvK B
r - maxCm' 3460, 1750, 1710' H-N M R (CDCf13) δ (ppm); 2
．． 82.2.86 (3H, N CR3) 3.02,3.
38 (3H, 3"-0CR,) 5, 04-5.20 (
4H) 7, 20-7.46 (IOH) 8.06 (IH, N OH)
Claims (1)
において、低級アルキルカルボン酸のアルカリ金属塩を
用いることを特徴とするエリスロマイシン類のオキシム
誘導体の製造方法。(1) A method for producing oxime derivatives of erythromycins, which comprises using an alkali metal salt of a lower alkylcarboxylic acid in the method of converting the 9-position of erythromycins into oxime.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP60228170A JPS6287599A (en) | 1985-10-14 | 1985-10-14 | Production of oxime derivative of erythromycin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP60228170A JPS6287599A (en) | 1985-10-14 | 1985-10-14 | Production of oxime derivative of erythromycin |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS6287599A true JPS6287599A (en) | 1987-04-22 |
Family
ID=16872319
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP60228170A Pending JPS6287599A (en) | 1985-10-14 | 1985-10-14 | Production of oxime derivative of erythromycin |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS6287599A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5274085A (en) * | 1988-05-19 | 1993-12-28 | Taisho Pharmaceutical Co., Ltd. | Process for preparing erythromycin A oxime or a salt thereof |
| WO2000039142A1 (en) * | 1998-12-29 | 2000-07-06 | Hanmi Pharmaceutical Co., Ltd. | Erythromycin a compounds and process for preparing the same |
| US7414114B2 (en) | 2000-08-23 | 2008-08-19 | Wockhardt Limited | Process for preparation of anhydrous azithromycin |
-
1985
- 1985-10-14 JP JP60228170A patent/JPS6287599A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5274085A (en) * | 1988-05-19 | 1993-12-28 | Taisho Pharmaceutical Co., Ltd. | Process for preparing erythromycin A oxime or a salt thereof |
| WO2000039142A1 (en) * | 1998-12-29 | 2000-07-06 | Hanmi Pharmaceutical Co., Ltd. | Erythromycin a compounds and process for preparing the same |
| US6528628B1 (en) | 1998-12-29 | 2003-03-04 | Hanmi Pharmaceutical Co., Ltd. | Erythromycin a compounds and process for preparing the same |
| US7414114B2 (en) | 2000-08-23 | 2008-08-19 | Wockhardt Limited | Process for preparation of anhydrous azithromycin |
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