JPS59222500A - Preparation of macrolide antibiotic substance derivative - Google Patents
Preparation of macrolide antibiotic substance derivativeInfo
- Publication number
- JPS59222500A JPS59222500A JP58095758A JP9575883A JPS59222500A JP S59222500 A JPS59222500 A JP S59222500A JP 58095758 A JP58095758 A JP 58095758A JP 9575883 A JP9575883 A JP 9575883A JP S59222500 A JPS59222500 A JP S59222500A
- Authority
- JP
- Japan
- Prior art keywords
- group
- formula
- carbon atoms
- alkyl
- phenyl
- 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.)
- Granted
Links
- 239000003120 macrolide antibiotic agent Substances 0.000 title claims description 6
- 239000000126 substance Substances 0.000 title abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 11
- -1 organic acid halide Chemical class 0.000 claims abstract description 10
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 8
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims abstract description 7
- 125000002252 acyl group Chemical group 0.000 claims abstract description 7
- 239000002904 solvent Substances 0.000 claims abstract description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 5
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims abstract description 5
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims abstract description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims abstract description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims abstract description 4
- 125000005843 halogen group Chemical group 0.000 claims abstract description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 abstract description 57
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 abstract description 9
- 150000001875 compounds Chemical class 0.000 abstract description 4
- 150000003512 tertiary amines Chemical class 0.000 abstract description 4
- 230000003115 biocidal effect Effects 0.000 abstract description 3
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 2
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 238000000034 method Methods 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- 238000001816 cooling Methods 0.000 description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
- 238000005917 acylation reaction Methods 0.000 description 5
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 4
- 239000012346 acetyl chloride Substances 0.000 description 4
- 230000010933 acylation Effects 0.000 description 4
- 239000013058 crude material Substances 0.000 description 4
- 229960002757 midecamycin Drugs 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- DMUAPQTXSSNEDD-QALJCMCCSA-N Midecamycin Chemical compound C1[C@](O)(C)[C@@H](OC(=O)CC)[C@H](C)O[C@H]1O[C@H]1[C@H](N(C)C)[C@@H](O)[C@H](O[C@@H]2[C@H]([C@H](OC(=O)CC)CC(=O)O[C@H](C)C/C=C/C=C/[C@H](O)[C@H](C)C[C@@H]2CC=O)OC)O[C@@H]1C DMUAPQTXSSNEDD-QALJCMCCSA-N 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- OJGMBLNIHDZDGS-UHFFFAOYSA-N N-Ethylaniline Chemical compound CCNC1=CC=CC=C1 OJGMBLNIHDZDGS-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- MXHTZQSKTCCMFG-UHFFFAOYSA-N n,n-dibenzyl-1-phenylmethanamine Chemical compound C=1C=CC=CC=1CN(CC=1C=CC=CC=1)CC1=CC=CC=C1 MXHTZQSKTCCMFG-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 description 1
- LVPZSMIBSMMLPI-UHFFFAOYSA-N 2-(diethylamino)acetonitrile Chemical compound CCN(CC)CC#N LVPZSMIBSMMLPI-UHFFFAOYSA-N 0.000 description 1
- 229930188120 Carbomycin Natural products 0.000 description 1
- IEMDOFXTVAPVLX-YWQHLDGFSA-N Leucomycin A1 Chemical compound CO[C@H]1[C@H](O)CC(=O)O[C@H](C)C\C=C\C=C\[C@H](O)[C@H](C)C[C@H](CC=O)[C@@H]1O[C@H]1[C@H](O)[C@@H](N(C)C)[C@H](O[C@@H]2O[C@@H](C)[C@H](OC(=O)CC(C)C)[C@](C)(O)C2)[C@@H](C)O1 IEMDOFXTVAPVLX-YWQHLDGFSA-N 0.000 description 1
- YQLFLCVNXSPEKQ-UHFFFAOYSA-N Mycarose Natural products CC1OC(O)CC(C)(O)C1O YQLFLCVNXSPEKQ-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- FQVHOULQCKDUCY-OGHXVOSASA-N [(2s,3s,4r,6s)-6-[(2r,3s,4r,5r,6s)-6-[[(1s,3r,7r,8s,9s,10r,12r,14e,16s)-7-acetyloxy-8-methoxy-3,12-dimethyl-5,13-dioxo-10-(2-oxoethyl)-4,17-dioxabicyclo[14.1.0]heptadec-14-en-9-yl]oxy]-4-(dimethylamino)-5-hydroxy-2-methyloxan-3-yl]oxy-4-hydroxy-2,4-dimeth Chemical compound O([C@@H]1[C@@H](C)O[C@H]([C@@H]([C@H]1N(C)C)O)O[C@H]1[C@@H](CC=O)C[C@@H](C)C(=O)/C=C/[C@@H]2O[C@H]2C[C@@H](C)OC(=O)C[C@H]([C@@H]1OC)OC(C)=O)[C@H]1C[C@@](C)(O)[C@@H](OC(=O)CC(C)C)[C@H](C)O1 FQVHOULQCKDUCY-OGHXVOSASA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 125000003172 aldehyde group Chemical group 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229950005779 carbomycin Drugs 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- OAIVIYSBZFEOIU-UHFFFAOYSA-N chloroform;propan-2-one Chemical compound CC(C)=O.ClC(Cl)Cl OAIVIYSBZFEOIU-UHFFFAOYSA-N 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 230000020176 deacylation Effects 0.000 description 1
- 238000005947 deacylation reaction Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- ORRQJZMYQQDYDX-UHFFFAOYSA-N ethyl 2-(diethylamino)acetate Chemical compound CCOC(=O)CN(CC)CC ORRQJZMYQQDYDX-UHFFFAOYSA-N 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- GQNZGCARKRHPOH-RQIKCTSVSA-N miocamycin Chemical compound C1[C@](OC(C)=O)(C)[C@@H](OC(=O)CC)[C@H](C)O[C@H]1O[C@H]1[C@H](N(C)C)[C@@H](O)[C@H](O[C@@H]2[C@H]([C@H](OC(=O)CC)CC(=O)O[C@H](C)C/C=C/C=C/[C@H](OC(C)=O)[C@H](C)C[C@@H]2CC=O)OC)O[C@@H]1C GQNZGCARKRHPOH-RQIKCTSVSA-N 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- JYAQWANEOPJVEY-LYFYHCNISA-N mycarose Chemical compound C[C@H](O)[C@H](O)[C@](C)(O)CC=O JYAQWANEOPJVEY-LYFYHCNISA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- OQZFWVNMGTZNKT-UHFFFAOYSA-N propan-2-one;tetrachloromethane Chemical compound CC(C)=O.ClC(Cl)(Cl)Cl OQZFWVNMGTZNKT-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
Landscapes
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
本発明はマク０．フィト抗生物質に含まれる第３級水酸
基のアシル誘導体の新規製造法に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention is based on Mac0. This invention relates to a new method for producing acyl derivatives of tertiary hydroxyl groups contained in phytoantibiotics.
一般に有用なマクロライド抗生物質にはマイカロースを
含むものが多い、例えばロイ、コマイシン、ミデカマイ
シン、アンゴラマイシン、スピンマイシン、カルボマイ
シン、メガロマイシン等がアル。Many commonly useful macrolide antibiotics contain mycarose, such as leucomycin, comycin, midecamycin, angoramycin, spinmycin, carbomycin, and megaromycin.
これらはすべて６“位に第３級の水酸基が含まれ、通常
の水酸基用のアシル化剤ではアシル化されないことが知
られている。All of these contain a tertiary hydroxyl group at the 6'' position, and it is known that they cannot be acylated with ordinary acylating agents for hydroxyl groups.
本発明者等はこの第３級の水酸基のアシル化反応を種々
検討した結果、Ｎ、Ｎ−ジアルキルアニリン、Ｎ、Ｎ−
ジアルキルアミノアセトニトリル及びアルキル Ｎ、Ｎ
−ジアルキルアミノアセテートから選んだ第６級アミン
の存在下に有機溶剤、好ましくはジクロルメタン、酢酸
エチル等の中で有機酸ハライドを反応せしめると容易に
第３級の水酸基がアシル化されることを見出し本発明を
完成させた。As a result of various studies on the acylation reaction of this tertiary hydroxyl group, the present inventors found that N,N-dialkylaniline, N,N-
dialkylaminoacetonitrile and alkyl N,N
- It has been found that tertiary hydroxyl groups can be easily acylated by reacting an organic acid halide in an organic solvent, preferably dichloromethane, ethyl acetate, etc., in the presence of a 6th amine selected from dialkylamino acetates. The present invention has been completed.
従って本発明によると、次の一般式（Ｍ）１
〔式中、Ｒ８は水素原子又は基−ｃ −Ｒ（但しＲは炭
素数１〜６個のアルキル基、フェニル基又は炭素数７〜
１０個のアラルキル基を表わす）を表わし、Ｒ１はアセ
チル基又はプロピオニル基を表わし、ａＳは−Ｃ−ビ（
但しＲ′はメチル基、エチル基、プロピル基、イソゾロ
ピル基 ゛ ０ 又はイソブチル基を表わす
）を表わす〕で示される抗生ｉ質又はその誘導体に対し
て次式（ｍ）Ｂ、ＣＯＸ
（ｍ）（式中、几は炭素数１〜６個のアルキル基、
フェニル基又は炭素数７〜１ｏ個のアラルキル基を表わ
し、Ｘはハロゲン原子を表わす）の有機酸ハライドをＮ
、Ｎ−ジアルキルアニリン％Ｎ、Ｎ−ジアルキルアミノ
アセトニトリル及びアルキル Ｎ。Therefore, according to the present invention, the following general formula (M)1 [wherein R8 is a hydrogen atom or a group -c-R (where R is an alkyl group having 1 to 6 carbon atoms, a phenyl group, or a carbon number 7 to
10 aralkyl groups), R1 represents an acetyl group or a propionyl group, and aS represents -C-bi(
However, R' represents a methyl group, an ethyl group, a propyl group, an isozoropyl group (0 or an isobutyl group)] or its derivatives, the following formula (m) B, COX
(m) (wherein, 几 is an alkyl group having 1 to 6 carbon atoms,
represents a phenyl group or an aralkyl group having 7 to 1 o carbon atoms, and X represents a halogen atom).
, N-dialkylaniline %N, N-dialkylaminoacetonitrile and alkyl N.
Ｎ−）アルキルアミノアセテートから選ばれた第３級ア
ミンの存在下に溶媒中で反応さすで次の一般式（Ｉ）
１
〔式中、Ｂ／、及びＲ４は−Ｃ−Ｒ（但しＲは炭素数１
〜６個のアルキル基、フェニル基又は炭素数７〜１０個
のアラルキル基を表わす）を表わし、ＦＬｔはアセチル
基又はプロピオニル基を表わし、Ｒ３は
１
−Ｃ−Ｒ’
（但しＲ′はメチル基、エチル基、プロピル基、イソプ
ロピル基又はイソブチル基を表わす）を表ゎ１
し、Ｒｓは−ＣＨ，ＣＨＯ又は−ＣＨ＝ＣＨ−０−Ｃ−
ＦＬ （但しＲは炭素数１〜６個のアルキル基、フェニ
ル基又は炭素数７〜１０個のアラルキル基を表わす）を
表わす〕で示されるアシル誘導体を生成し、所望ならば
このアシル誘導体を更に含水アルコール中で部分脱アシ
ル化処理して次の一般式（Ｉっ（式中、ａＦ、Ｒ８、Ｒ
８及び丸は前述の意義を有する）の９，６”−ジアシル
誘導体を得ることを特徴とするマク四ライド抗生物質誘
導体の製造法が提供される。The reaction is carried out in a solvent in the presence of a tertiary amine selected from N-)alkylaminoacetates to form the following general formula (I) 1 [wherein, B/ and R4 are -C-R (however, R is Carbon number 1
~6 alkyl group, phenyl group, or aralkyl group having 7 to 10 carbon atoms), FLt represents an acetyl group or propionyl group, and R3 represents 1 -C-R' (however, R' is a methyl group). , ethyl group, propyl group, isopropyl group or isobutyl group), and Rs is -CH, CHO or -CH=CH-0-C-
FL (where R represents an alkyl group having 1 to 6 carbon atoms, a phenyl group, or an aralkyl group having 7 to 10 carbon atoms)], and if desired, this acyl derivative can be further processed. Partial deacylation treatment is carried out in aqueous alcohol to obtain the following general formula (I (where aF, R8, R
8 and circles have the above-mentioned meanings.
従来第３級アルコールは不活性のためアシル化すること
は困難であシ、これまでに例えば第３級アルコールのア
シル化法としては４−ジメチルアミノピリジン法（アン
ゲバンテ ヘミ−８１巻１００１頁（’１９６９年）
Ｗ、３ｔｅｇｌｉｃｈ。Conventionally, it has been difficult to acylate tertiary alcohols due to their inertness, and for example, the 4-dimethylaminopyridine method (Angevant Hemi Vol. 81, p. 1001) has been used to acylate tertiary alcohols. (1969)
W, 3teglich.
Ｇ、Ｈｏｆｌｅ）や１−メチル−２−ハロピリジニウム
塩法（ケミストリー レター １０４５頁（１９７５年
） Ｔ、 Ｍｕｋａｉｙａｍａ、 Ｍ、 Ｕｓｕｉ、
Ｅ、 ８ｈｉｍａｄａ ）等が知られているが、高価な
試薬を使用しなければ収率よく達成できなかった。また
トリベンジルアミンを用いる方法（ザ ジャーナル オ
ブ アンチバイオティクス ３４巻 １００１頁（１９
８１年））では上記一般式（ｎ）において石が本発明の
場合のととくアシル基である場合にはそのアシル基がカ
ルボン酸として脱離することによって次式のととき６，
４−二重結合体が副生ずるととが知られている。G, Hofle) and 1-methyl-2-halopyridinium salt method (Chemistry Letters, p. 1045 (1975) T, Mukaiyama, M, Usui,
E, 8himada), etc. are known, but they could not be achieved in good yields without using expensive reagents. Also, a method using tribenzylamine (The Journal of Antibiotics, Vol. 34, p. 1001 (19
1981)), when the stone in the above general formula (n) is an acyl group, especially in the case of the present invention, the acyl group is eliminated as a carboxylic acid, so that the following formula 6,
It is known that a 4-double bond is produced as a by-product.
〔式中、Ｒ８、Ｂ、及びＲ４は前記の意義を有する〕本
発明者等は、特にマクロライド抗生物質のアシル化の場
合、酸で容易に分解するし、精製も困難であるため単純
な系での反応が必要であるとの観点から工業的実施に適
する安価なアシル化法を開発する目的で種々検討し、す
でに上記式（Ｉｔ）のマクミライド抗生物質又はその誘
導体と式（ＩＩＩ）の有機酸ハライドとをモレキュ２−
シーブの存在下に溶媒中で反応させる方法を提案した（
４？開昭５４− ′５２４９５号公報）。本発明の方法
は上記モレキュシーシーブ法をより簡便にしたものであ
る。[In the formula, R8, B, and R4 have the above-mentioned meanings] In particular, in the case of acylation of macrolide antibiotics, the present inventors have determined that the acylation of macrolide antibiotics is easy to decompose with acids and that purification is difficult. From the viewpoint of the need for a reaction in a system, various studies have been conducted for the purpose of developing an inexpensive acylation method suitable for industrial implementation, and the makmilide antibiotic of the above formula (It) or a derivative thereof and the formula (III) have already been investigated. Molecule 2- with organic acid halide
We proposed a method of reacting in a solvent in the presence of sieves (
4? Publication No. 54-'52495). The method of the present invention is a simpler version of the molecular sieve method described above.
本発明の方法、を実施するに当っては、前記式（ＴＩ）
の試料を不活性な溶媒例えばジクロルメタン、酢酸エチ
ル等に溶解する、溶媒量は試料（重量）の２〜１０倍量
が好ましい。つぎに第３級アミン塩基（Ｎ、Ｎ−ジアル
キルアニリン、Ｎ−Ｎ−ジアルキルアミノアセトニトリ
ル又はアルキル Ｎ、Ｎ−ジアルキルアミノアセテート
）を試料モル数の２〜２０倍量加え、Ｏ℃〜５℃に冷却
する。無水の反応条件で酸ハライドを試料モル数の５〜
２０倍量添加して攪拌する。反応混合物を徐々に加温し
、４０℃〜９０℃で１０〜１００時間反応せしめる。用
いた溶剤によっては速答冷却器が必要であるが、反応は
密閉条件で行なってもよい。反応終了後、アミンの塩を
枦去し、通常の処理を行なえば容易に前記式（Ｉ）の化
合物が副生成物をほとんど含むことなしに得られる。特
に本発明の方法によれば前記トリベンジルアミンを使用
する既知の方法において副生ずる６、４−二重結合体の
副生がない点が特筆される。In carrying out the method of the present invention, the formula (TI)
The sample is dissolved in an inert solvent such as dichloromethane, ethyl acetate, etc. The amount of solvent is preferably 2 to 10 times the sample (weight). Next, add a tertiary amine base (N,N-dialkylaniline, N-N-dialkylaminoacetonitrile, or alkyl N,N-dialkylaminoacetate) in an amount of 2 to 20 times the number of moles of the sample, and heat to 0°C to 5°C. Cooling. Under anhydrous reaction conditions, acid halide is added to 5 to 5 moles of sample.
Add 20 times the amount and stir. The reaction mixture is gradually heated and allowed to react at 40°C to 90°C for 10 to 100 hours. Depending on the solvent used, a rapid response cooler may be required, but the reaction may be conducted under closed conditions. After the reaction is completed, the amine salt is removed and the compound of the formula (I) can be easily obtained with almost no by-products by conventional treatment. Particularly noteworthy is that the method of the present invention does not produce a 6,4-double bond as a by-product in the known methods using tribenzylamine.
以上のごとく本法は簡単な反応系、反応条件で安価に第
３級水酸基をアシル化できる方法であり、種々のマクロ
ライド抗生物質の６“位アシル誘導体が得られる。又単
にマクロ２イド抗生物質ばがシでなく一般の第６級アル
コール基をもつ化合物のアシル化にも応用できる方法で
ある。As described above, this method is a method that can inexpensively acylate a tertiary hydroxyl group using a simple reaction system and reaction conditions, and it is possible to obtain 6'-position acyl derivatives of various macrolide antibiotics. This method can also be applied to the acylation of compounds having a general 6th-class alcohol group, not just basic substances.
本法で得たトリアジル誘導体（島＝−ＣＨ，・ＣＨＯ）
とテトラアシル誘導体（Ｒ，＝ −ＣＨ＝ ＣＨ−ＯＣ
ＯＩ’Ｌ ）は通常の含水アルコールで加熱し部分脱ア
シル化を行う゛と有用な９，６”ジアシル誘導体が収率
よく得られる。Triazyl derivatives obtained by this method (island = -CH, CHO)
and tetraacyl derivatives (R,= -CH= CH-OC
When OI'L) is partially deacylated by heating with a conventional aqueous alcohol, a useful 9,6'' diacyl derivative can be obtained in good yield.
以下本発明を実施例によシさらに説明する。The present invention will be further explained below using examples.
実施例１
９．２′−ジアセチルーミデカマイシン（前記式１式％
Ｒ３二ＣＯＣＨ２ＣＨ３） ２２ ｇを酢酸エチル７０
１に溶解し、Ｎ 、 Ｎ−”）エチルアニリン１５ｍＪ
を加え、冷却下に塩化アセチル１５−を加えて５０〜５
５℃で６９時間加熱反応させる。薄層クロマトグラフィ
ー、すなわちＴＬＣ（メルク社シリカゲルプレート、展
開剤四塩化炭素−アセトン（４：１）、発色硫酸）によ
ジアシル化反応生成物の主成分は９ 、２’、 ５“−
トリアセチル体であシ、９ 、１８ 、２’、 ３”−
テトラアセチル体も認められ、原料のスポットのないこ
とを確認する。反応混合物を濃縮乾固の後、酢酸エチル
１４０１１ＬＩ３を加えて濾過し、その酢酸エチル溶液
を水洗し、酢酸エチル層を濃縮乾固して粗製物粉末２３
ｇを得た。Example 1 22 g of 9.2'-diacetylumidecamycin (formula 1% R32COCH2CH3) was dissolved in 70 g of ethyl acetate.
15 mJ of ethylaniline dissolved in
and then add acetyl chloride 15-5 while cooling to 50-5
A heating reaction is carried out at 5° C. for 69 hours. Thin layer chromatography, TLC (Merck silica gel plate, eluent carbon tetrachloride-acetone (4:1), color developing sulfuric acid) reveals that the main components of the diacylation reaction product are 9, 2', 5"-
Triacetyl body, 9, 18, 2', 3"-
Tetraacetyl compounds were also observed, and it was confirmed that there were no spots of the raw material. After the reaction mixture was concentrated to dryness, ethyl acetate 14011LI3 was added and filtered, the ethyl acetate solution was washed with water, and the ethyl acetate layer was concentrated to dryness to obtain crude powder 23.
I got g.
この粗製物のうち１００ｍ９を構造確認のだめＴＬＣで
分離させ、各分画を酢酸エチルで溶出し、Ｒｆ Ｏ，７
の分画よシ９，２’、３“−トリアセチルミデカマイシ
ン粉末５２〜を得た（収率５２チ）。100m9 of this crude product was separated by TLC for structure confirmation, each fraction was eluted with ethyl acetate, and Rf O,7
From the fractionation, 52~9,2',3''-triacetylmidecamycin powder was obtained (yield: 52).
分子量 ９′５９（質量分析による）
ＮＭＦＬ（ＣＤＣＩｓ ） ９．６５ ｐｐｍ （Ｃ
Ｈｏ、 ＩＨ）２．００ ｐｐｍ （アセチル基、９
Ｈ）ＴＬＣにおいて、既知の９ 、２’、 ３“−トリ
アセチルミデカマイシンと一致。Molecular weight 9'59 (by mass spectrometry) NMFL (CDCIs) 9.65 ppm (C
Ho, IH) 2.00 ppm (acetyl group, 9
H) TLC match with known 9,2',3''-triacetyrmidecamycin.
先に得た粗製物２３ｐを７０チ含水メタノール２００ｄ
に溶解し、６５℃で９時間加熱する。反応液を濃縮乾固
し、酢酸エチルで抽出し、水洗し、酢酸エチル層を濃縮
乾固して粗９，３“−ジアセチルミデカマイシン２０９
を得た。本物質は９０％含水プロパツールで容易に再結
でき、１１．９１７ （４９チ）の９，６“−ジアセチ
ルミデヵマイシンを得た。70 g of the previously obtained crude product 200 d of water-containing methanol
and heat at 65°C for 9 hours. The reaction solution was concentrated to dryness, extracted with ethyl acetate, washed with water, and the ethyl acetate layer was concentrated to dryness to give crude 9,3"-diacetylmidecamycin 209.
I got it. This material could be easily reconstituted with 90% aqueous propatool to yield 11.917 (49 units) of 9,6''-diacetylmidecamycin.
、本物質は特開昭５１−２６８８７号公報記載の９，３
“−ジアセチルミデカマイシンに物理化学的性状が完全
に一致した。, this substance is described in JP-A No. 51-26887, 9,3
"The physicochemical properties completely matched those of diacetylmidecamycin.
分子量 ８９７（質量分析による）
ＮＭＲ９，６９（アルデヒド基、１Ｈ）２．０１ （
アセチル基、６Ｈ）
実施例２
ミデカマイシン２０Ｊ７を酢酸エチル７０ｍＪに溶解し
％Ｎ、Ｎ−ジエチルアニリン３０ｍを加えた後、水冷下
にアセチルクロリド２ｏ―を加え、水冷下で６時間撹拌
後、５５−５６℃で６５時間加熱する。この反応液を濃
縮後、酢酸エチルを加えて涙過し、水洗し、酢酸エチル
層を濃縮乾固して２４９の粗物質を得た。これを７０％
含水メタノールで６５℃で１１時間処理し、濃縮乾固し
て粗物質を得た。この物質を９０％含水プロパノールで
再結して１２ｇ（収率５４．５％）の９，６“−ジアセ
チルミデカマイシンの結晶を得た。Molecular weight 897 (by mass spectrometry) NMR 9,69 (aldehyde group, 1H) 2.01 (
Acetyl group, 6H) Example 2 Midecamycin 20J7 was dissolved in 70 mJ of ethyl acetate and 30 m of %N,N-diethylaniline was added thereto. Acetyl chloride 2o- was added under water cooling, and after stirring for 6 hours under water cooling, 55- Heat at 56°C for 65 hours. After concentrating this reaction solution, ethyl acetate was added thereto, the mixture was filtered, washed with water, and the ethyl acetate layer was concentrated to dryness to obtain crude substance 249. 70% of this
The mixture was treated with aqueous methanol at 65° C. for 11 hours and concentrated to dryness to obtain a crude material. This material was recrystallized with 90% aqueous propanol to obtain 12 g (yield 54.5%) of crystals of 9,6''-diacetylmidecamycin.
実施例３
ミデカマイシン１０ｇを酢酸エチル５５１１１に溶解し
、Ｎ、Ｎ−ジエチルアミノアセトニトリル２５１を加え
た後、水冷下に塩化アセチル１０１を加え、水冷下５時
間攪拌後、５０−５３℃で８０時間加熱する。この反応
液を濃縮後、酢酸エチルを加えて濾過し、水洗し、酢酸
エチル層を濃縮乾固して１３．１１７ の粗物質を得た
。これを７０チ含水メタノールで６５℃で１０時間処理
し、濃縮乾固して粗物質を得た。この物質を９０チ含水
プロパツールで再結して４．８９（収率４６．５チ）の
９，３“−ジアセチルミデカマイシンの結晶を得た。Example 3 10 g of midecamycin was dissolved in 55111 ethyl acetate, 251 N,N-diethylaminoacetonitrile was added, and then 101 acetyl chloride was added under water cooling, stirred for 5 hours under water cooling, and then heated at 50-53°C for 80 hours. . After concentrating this reaction solution, ethyl acetate was added thereto, filtered, washed with water, and the ethyl acetate layer was concentrated to dryness to obtain a crude substance of 13.117. This was treated with 70% aqueous methanol at 65° C. for 10 hours, and concentrated to dryness to obtain a crude material. This material was recrystallized with 90% water-containing propatool to obtain 4.89 (yield: 46.5%) crystals of 9,3''-diacetylmidecamycin.
実施例４
一ミデカマイシン２０９を酢酸エチル７０ｍに溶解し、
エチル Ｎ、Ｎ−ジエチルアミノアセテ−）４５ｍ／を
加えた後、水冷下に塩化アセチル２５ｍ１を加え、水冷
下１８時間攪拌後、５０−５３℃で７８時間加熱する。Example 4 -Midecamycin 209 was dissolved in 70m ethyl acetate,
After adding 45 ml of ethyl N,N-diethylaminoacetate, 25 ml of acetyl chloride was added under water cooling, and after stirring for 18 hours under water cooling, the mixture was heated at 50-53°C for 78 hours.
この反応液を濃縮後、酢酸エチルを加え、不溶物を漣過
し、水洗し、酢酸エチル層を濃縮乾固して２２９の粗物
質を得た。これを７０チ含水メタノールで６５℃で９時
間処理し、濃縮乾固して粗物質２５．５９を得た。After concentrating this reaction solution, ethyl acetate was added, insoluble materials were filtered off and washed with water, and the ethyl acetate layer was concentrated to dryness to obtain crude material 229. This was treated with 70% aqueous methanol at 65° C. for 9 hours and concentrated to dryness to obtain 25.59 g of crude material.
とノ粗粉末ヲクロロホルムーアセトン（１ｏ：１）で溶
出するシリカゲルカラムクロマトグラフィーによシ９，
３“−ジアセルミデヵシンの標準サンプルと同一のＲｆ
値の溶出区分を減圧濃縮して目的物９．３“−ジアセチ
ルミデヵマイシンを得る。The coarse powder was purified by silica gel column chromatography eluting with chloroform acetone (1:1)9.
3"-The same Rf as the standard sample of diacermidecascine.
The eluted fraction of the value is concentrated under reduced pressure to obtain the target product 9.3"-diacetylmidecamycin.
収量５．６ ｆ／ （２５チ）。Yield 5.6 f/(25 chi).
Claims (1)
数１〜６個のアルキル基、フェニル基又は炭素数７〜１
０個のアラルキル基を表わす）を表わし、Ｒ７はアセチ
ル基又はプロピオニル基を表わし、Ｒｓは−Ｃ−Ｂ、’
（但しＲ′はメチル基、エチル基、プロピル基、イソプ
ロピル基又はイソブチル基を表わす）を表わす〕で示さ
れる抗生物質又はその誘導体に対して次式（Ｉ［［） ％式％（） （式中、Ｒは炭素数１〜６個のアルキル基、フェニル基
又は炭素数７〜１０個のアラルキル基を表わし、Ｘはハ
ロゲン原子を表わす）の有機酸ハライドをＮ、Ｎ−ジア
ルキルアニリン、Ｎ、Ｎ−ジアルキルアミノアセトニト
リル及びアルキル Ｎ。 Ｎ−ジアルキルアミノアセテートから選ばれた第６級ア
ミンの存在下に溶媒中で反応させて次の一般式（Ｉ） Ｒ− Ｏ １ 〔式中、ｎｆ、及びＲ４は一〇 −Ｒ（但し几は炭素数
１〜６個のアルキル基、フェニル基又は炭素数７〜１０
個のアラルキル基を表わす）を表わし、ＦＬｔはアセチ
ル基又はプロピオニル基を表わし、Ｒ３は１ − Ｃ−Ｒ’ （但しＩ（、′はメチル基、エチル基、プロピル基、イ
ソプロピル基又はイソブチル基を表わす）を表わ１ し、Ｒ，は−ＣＨ，ＣＨＯ又は−ＣＨ＝ＣＨ−０−Ｃ−
Ｒ（但しＲは炭素数１〜６個のアルキル基、フェニル基
又ハ炭素数７〜１０個のアラルキル基を表わす）を表わ
す〕で示されるアシル誘導体を主威し、所望ならばこの
アシル誘導体を更に含水アルコール中で部分脱アシル化
処理して次の一般式（Ｉ′）（式中、Ｒ１、ＦＬ、、ｎ
ｓ及び恥は前述の意義を有する）の９，３“−ジアシル
誘導体を得ることを特徴とするマクロライド抗生物質誘
導体の製造法。[Scope of Claims] The following general formula (It) 1 [In the formula, R is a hydrogen atom or a group -C-R (wherein R is an alkyl group having 1 to 6 carbon atoms, a phenyl group, or a phenyl group having 7 to 7 carbon atoms. 1
0 aralkyl group), R7 represents an acetyl group or a propionyl group, and Rs is -C-B,'
(wherein R' represents a methyl group, ethyl group, propyl group, isopropyl group or isobutyl group)] or its derivatives shown by the following formula (I [[) % formula % () (formula (wherein, R represents an alkyl group having 1 to 6 carbon atoms, a phenyl group, or an aralkyl group having 7 to 10 carbon atoms, and X represents a halogen atom), N, N-dialkylaniline, N, N-dialkylaminoacetonitrile and alkyl N. It is reacted in a solvent in the presence of a 6th class amine selected from N-dialkylaminoacetate to form the following general formula (I) R-O1 [where nf and R4 are 10-R (however, is an alkyl group having 1 to 6 carbon atoms, a phenyl group or 7 to 10 carbon atoms
FLt represents an acetyl group or a propionyl group, and R3 represents 1-C-R' (where I(,' represents a methyl group, ethyl group, propyl group, isopropyl group, or isobutyl group); 1 and R is -CH, CHO or -CH=CH-0-C-
R (wherein R represents an alkyl group having 1 to 6 carbon atoms, a phenyl group, or an aralkyl group having 7 to 10 carbon atoms) is mainly used, and if desired, this acyl derivative can be used. is further partially deacylated in a hydrous alcohol to obtain the following general formula (I') (wherein R1, FL, , n
A method for producing a macrolide antibiotic derivative, characterized in that a 9,3"-diacyl derivative is obtained (S and s have the above-mentioned meanings).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP58095758A JPS59222500A (en) | 1983-06-01 | 1983-06-01 | Preparation of macrolide antibiotic substance derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP58095758A JPS59222500A (en) | 1983-06-01 | 1983-06-01 | Preparation of macrolide antibiotic substance derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS59222500A true JPS59222500A (en) | 1984-12-14 |
| JPH0312079B2 JPH0312079B2 (en) | 1991-02-19 |
Family
ID=14146382
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP58095758A Granted JPS59222500A (en) | 1983-06-01 | 1983-06-01 | Preparation of macrolide antibiotic substance derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS59222500A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102775456A (en) * | 2011-05-13 | 2012-11-14 | 北大方正集团有限公司 | Preparation method of midecamycin acetate |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5511505A (en) * | 1978-06-07 | 1980-01-26 | Toyo Jozo Co Ltd | Novel 9,3"-acylleucomycin and its preparation |
-
1983
- 1983-06-01 JP JP58095758A patent/JPS59222500A/en active Granted
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5511505A (en) * | 1978-06-07 | 1980-01-26 | Toyo Jozo Co Ltd | Novel 9,3"-acylleucomycin and its preparation |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102775456A (en) * | 2011-05-13 | 2012-11-14 | 北大方正集团有限公司 | Preparation method of midecamycin acetate |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0312079B2 (en) | 1991-02-19 |
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