JPH0227997B2 - 7ARUFUAAMETOKISHISEFUAROSUHORINKAGOBUTSUNOSEIZOHO - Google Patents
7ARUFUAAMETOKISHISEFUAROSUHORINKAGOBUTSUNOSEIZOHOInfo
- Publication number
- JPH0227997B2 JPH0227997B2 JP57060387A JP6038782A JPH0227997B2 JP H0227997 B2 JPH0227997 B2 JP H0227997B2 JP 57060387 A JP57060387 A JP 57060387A JP 6038782 A JP6038782 A JP 6038782A JP H0227997 B2 JPH0227997 B2 JP H0227997B2
- Authority
- JP
- Japan
- Prior art keywords
- formula
- compound
- reaction
- methyl
- group
- 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.)
- Expired - Lifetime
Links
- -1 mercaptomethyl group Chemical group 0.000 claims description 35
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 31
- 150000001875 compounds Chemical class 0.000 claims description 30
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 7
- BOFAIBPJCWFJFT-UHFFFAOYSA-N 4-methoxy-1-oxidopyridin-1-ium Chemical compound COC1=CC=[N+]([O-])C=C1 BOFAIBPJCWFJFT-UHFFFAOYSA-N 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 229910052717 sulfur Chemical group 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 2
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 42
- 238000006243 chemical reaction Methods 0.000 description 35
- 238000000034 method Methods 0.000 description 17
- 150000001805 chlorine compounds Chemical class 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 239000002253 acid Substances 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 239000012300 argon atmosphere Substances 0.000 description 5
- RTEXIPZMMDUXMR-UHFFFAOYSA-N benzene;ethyl acetate Chemical compound CCOC(C)=O.C1=CC=CC=C1 RTEXIPZMMDUXMR-UHFFFAOYSA-N 0.000 description 5
- MDHYEMXUFSJLGV-UHFFFAOYSA-N beta-phenethyl acetate Natural products CC(=O)OCCC1=CC=CC=C1 MDHYEMXUFSJLGV-UHFFFAOYSA-N 0.000 description 5
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 5
- 239000012442 inert solvent Substances 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 150000004702 methyl esters Chemical class 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 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
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-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
- 239000011230 binding agent Substances 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- WBKFWQBXFREOFH-UHFFFAOYSA-N dichloromethane;ethyl acetate Chemical compound ClCCl.CCOC(C)=O WBKFWQBXFREOFH-UHFFFAOYSA-N 0.000 description 2
- YDVNLQGCLLPHAH-UHFFFAOYSA-N dichloromethane;hydrate Chemical compound O.ClCCl YDVNLQGCLLPHAH-UHFFFAOYSA-N 0.000 description 2
- OAMZXMDZZWGPMH-UHFFFAOYSA-N ethyl acetate;toluene Chemical compound CCOC(C)=O.CC1=CC=CC=C1 OAMZXMDZZWGPMH-UHFFFAOYSA-N 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- YGBFLZPYDUKSPT-MRVPVSSYSA-N cephalosporanic acid Chemical compound S1CC(COC(=O)C)=C(C(O)=O)N2C(=O)C[C@H]21 YGBFLZPYDUKSPT-MRVPVSSYSA-N 0.000 description 1
- 125000001271 cephalosporin group Chemical group 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 238000007254 oxidation reaction Methods 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
- 238000001228 spectrum Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cephalosporin Compounds (AREA)
Description
【発明の詳細な説明】
本発明は、セフエム化合物の製造法に関し、更
に詳しくは7α−メトキシセフアロスポリン化合
物の新規な製造法に関するものである。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a cefem compound, and more particularly to a novel method for producing a 7α-methoxycephalosporin compound.
7α−メトキシセフアロスポリン化合物は、β
−ラクタマーゼに対して強い抵抗性を有しおり、
かつ、グラム陽性菌及びグラム陰性菌に対して広
範囲な抗菌スペクトルを示すことが知られ、多く
の誘導体が合成されており、その中のいくつかは
実際の化学療法剤として用いられている。従つ
て、セフアロスポリン骨格の7α−位に、化学的
にメトキシ基を導入する方法は、工業的に極めて
重要となつており、これまでにも多数の方法が報
告されている。これらのメトキシ基導入法は、整
理すると次の二つに大別することができる。 7α-Methoxycephalosporin compounds are
-Has strong resistance to lactamases,
It is also known to exhibit a broad antibacterial spectrum against Gram-positive and Gram-negative bacteria, and many derivatives have been synthesized, some of which are used as actual chemotherapeutic agents. Therefore, the method of chemically introducing a methoxy group into the 7α-position of the cephalosporin skeleton has become extremely important industrially, and many methods have been reported so far. These methoxy group introduction methods can be roughly classified into the following two types.
(1) ７−アミノセフエム化合物を、適当なアミノ
誘導体に導き、酸化反応又は脱離・付加反応に
よつて、７−位にメトキシ基を導入した後、ア
シル化を行なつて、7α−メトキシ−7β−アシ
ルアミノセフアロスポリン化合物を得る方法
〔Tetrahedron Letters，3505（1973）；同前、
273（1973）；J.Org.Chem.，39，2794（1974）；
同前，38，2857（1973）；Tetrahedron
Letters，4653（1973）；同前、2705（1975）；
Chem.Pharm.Bull.，25，1645（1977）；J.Am.
Chem.Soc.，99，5505（1977）等〕及び
(2) ７−アシルアミノセフエム化合物から出発
し、C7−イミノ化合物を経由して、元のアシ
ル基を有する7α−メトキシ−7β−アシルアミ
ノセフアロスポリン化合物を得る方法〔J.Am.
Chem.Soc.，95，2403（1973）；Tetrahedron
Letters，1307（1976）；J.Chem.Soc.Chem.
Comm.，516（1976）等／である。(1) A 7-aminocephalic compound is converted into a suitable amino derivative, a methoxy group is introduced at the 7-position by an oxidation reaction or an elimination/addition reaction, and then acylation is performed to form a 7α-methoxy- Method for obtaining 7β-acylaminocephalosporin compounds [Tetrahedron Letters, 3505 (1973);
273 (1973); J.Org.Chem., 39 , 2794 (1974);
Ibid., 38 , 2857 (1973); Tetrahedron
Letters, 4653 (1973); Ibid., 2705 (1975);
Chem.Pharm.Bull., 25 , 1645 (1977); J.Am.
Chem.Soc., 99 , 5505 (1977) etc.] and (2) Starting from a 7-acylaminocephalic compound, via a C 7 -imino compound, 7α-methoxy-7β- having the original acyl group is produced. Method for obtaining acylaminocephalosporin compounds [J.Am.
Chem.Soc., 95 , 2403 (1973); Tetrahedron
Letters, 1307 (1976); J.Chem.Soc.Chem.
Comm., 516 (1976) etc./.
これらの法のうち、(1)の方法において、強力な
酸化剤を使用する場合には、酸化されやすい側
鎖、例えば、硫黄含有の側鎖等が酸化されて副産
物を生じるという欠点がある。又、反応経路が長
くて煩雑である等の欠点も存在する。これに対
し、(2)の方法は、反応工程数が少なく、ワンポツ
ト（one−pot）反応であることが期待され、(1)
の方法に比べて工業的であると言える。 Among these methods, when a strong oxidizing agent is used in method (1), there is a drawback that side chains that are easily oxidized, such as sulfur-containing side chains, are oxidized to produce by-products. Further, there are also disadvantages such as the reaction route being long and complicated. On the other hand, method (2) requires fewer reaction steps and is expected to be a one-pot reaction;
It can be said that this method is more industrial than the method of
本発明者らは、セフアロスポリン骨格の7α−
位に、効率よく置換基を導入する新規な反応につ
いて、鋭意研究を重ねた結果、(2)の範疇に属する
が、これらとは異なる新規な方法を見出すことに
成功し、本発明を完成させるに至つた。 The present inventors discovered that the 7α-
As a result of intensive research into a novel reaction that efficiently introduces a substituent into the position, we succeeded in discovering a new method that belongs to the category (2), but is different from these, and completed the present invention. It came to this.
即ち、本発明の、7α−メトキシセフアロスポ
リン化合物の製造法は、次式（）：
〔式中、R1は、アルキル基又は次式：Ａ−Ｂ−
CH2−（式中、Ａは、非置換の、若しくは置換さ
れたアルキル基、又はアリール基を表わし、Ｂ
は、酸素原子若しくは硫黄原子を表わす。）で示
される残基を表わし、R2は、水素原子又はカル
ボキシル基の保護基を表わし、R3は、メチル基
又はヘテロ環残基で置換されたメルカプトメチル
基を表わす。〕
で示される化合物を五塩化リンで処理し、
次式（）：
（式中、R1、R2及びR3は、前記と同義である。）
で示される化合物を得、これを、４−メトキシピ
リジン−Ｎ−オキサイドで処理し、
次式（）：
（式中、R1、R2及びR3は、前記と同義である。）
で示される化合物を得、これを、メタノールで処
理し、
次式（）：
（式中、R1、R2及びR3は、前記と同義である。）
で示される化合物を得ることを特徴とするもので
ある。 That is, the method for producing the 7α-methoxycephalosporin compound of the present invention is carried out by the following formula (): [In the formula, R 1 is an alkyl group or the following formula: AB-
CH 2 - (wherein A represents an unsubstituted or substituted alkyl group or an aryl group, and B
represents an oxygen atom or a sulfur atom. ), R 2 represents a hydrogen atom or a carboxyl group protecting group, and R 3 represents a methyl group or a mercaptomethyl group substituted with a heterocyclic residue. ] The compound represented by is treated with phosphorus pentachloride to form the following formula (): (In the formula, R 1 , R 2 and R 3 have the same meanings as above.) A compound represented by the following formula () is obtained, and this is treated with 4-methoxypyridine-N-oxide, and the following formula (): (In the formula, R 1 , R 2 and R 3 have the same meanings as above.) A compound represented by the following formula () is obtained and treated with methanol: (In the formula, R 1 , R 2 and R 3 have the same meanings as above.)
It is characterized by obtaining a compound represented by:
以下、本発明を更に詳しく説明する。 The present invention will be explained in more detail below.
本発明の製造法において、出発物質として用い
られる前記式（）で示される化合物としては、
例えば、
7β−フエノキシアセトアミド−３−メチル−
３−セフエム−４−カルボン酸、
7β−アセトアミド−３−メチル−３−セフエ
ム−４−カルボン酸、
7β−フエノキシアセトアミド−３−（１−メチ
ル−1H−テトラゾール−５−イル）チオメチル
−３−セフエム−４−カルボン酸、
7β−（２−tert−ブトキシカルボニルアミノ−
２−ジフエニルメトキシカルボニル）エチルチオ
アセトアミド−３−メチル−３−セフエム−４−
カルボン酸、
7β−（２−ジフエニルメトキシカルボニル）エ
チルチオアセトアミド−３−（１−メチル−1H−
テトラゾール−５−イル）チオメチル−３−セフ
エム−４−カルボン酸、
7β−シアノメチルチオアセトアミド−３−（１
−メチル−1H−テトラゾール−５−イル）チオ
メチル−３−セフエム−４−カルボン酸、
7β−（Ｄ−２−アミノ−２−カルボキシ）エチ
ルチオアセトアミド−３−（１−メチル−1H−テ
トラゾール−５−イル）チオメチル−３−セフエ
ム−４−カルボン酸、
7β−フエノキシアセトアミドセフアロスポラ
ン酸、
7β−（２−チエニルアセトアミド）セフアロス
ポラン酸、
本発明における第一工程は、前記式（）で示
される化合物を五塩化リンで処理することによ
り、前記式（）で示されるイミドイルクロライ
ド化合物に変換する工程である。この工程を式で
示すと、次の通りである。 In the production method of the present invention, the compound represented by the formula () used as a starting material is:
For example, 7β-phenoxyacetamido-3-methyl-
3-cephem-4-carboxylic acid, 7β-acetamido-3-methyl-3-cephem-4-carboxylic acid, 7β-phenoxyacetamido-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl- 3-cephem-4-carboxylic acid, 7β-(2-tert-butoxycarbonylamino-
2-diphenylmethoxycarbonyl)ethylthioacetamide-3-methyl-3-cephem-4-
Carboxylic acid, 7β-(2-diphenylmethoxycarbonyl)ethylthioacetamide-3-(1-methyl-1H-
7β-cyanomethylthioacetamide-3-(1
-Methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, 7β-(D-2-amino-2-carboxy)ethylthioacetamide-3-(1-methyl-1H-tetrazole- 5-yl)thiomethyl-3-cephem-4-carboxylic acid, 7β-phenoxyacetamidocephalosporanic acid, 7β-(2-thienylacetamido)cephalosporanic acid, the first step in the present invention is This is a step of converting the shown compound into an imidoyl chloride compound shown by the above formula () by treating it with phosphorus pentachloride. This process is expressed as follows.
（式中、R1、R2及びR3は、前記と同義である。）
かかる反応は、不活性溶媒中、前述の出発物質
（）と五塩化リンとを、酸結合剤の存在下、−50
〜40℃の範囲で、0.5〜４時間反応させることに
より行なわれる。本反応に用いられる不活性溶媒
としては、例えば、クロロホルム、ジクロルメタ
ン、ジクロルエタン、ベンゼン等が挙げられる。
酸結合剤としては、例えば、Ｎ，Ｎ−ジメチルア
ニリン、ピリジン、キノリン等の有機第三アミン
が挙げられる。 (In the formula, R 1 , R 2 and R 3 have the same meanings as above.) Such a reaction is carried out by combining the above-mentioned starting material () and phosphorus pentachloride in an inert solvent in the presence of an acid binder, −50
The reaction is carried out at a temperature of -40°C for 0.5 to 4 hours. Examples of the inert solvent used in this reaction include chloroform, dichloromethane, dichloroethane, and benzene.
Examples of acid binders include organic tertiary amines such as N,N-dimethylaniline, pyridine, and quinoline.
前記式（）で示されるイミドイルクロライド
化合物の採取は、生成したイミドイルクロライド
化合物が水分は弱アルカリ水溶液に安定な場合に
は、反応液を水と混和しない有機溶媒で希釈後、
弱アルカリ水溶液又は水で洗浄し、次いで、有機
層を硫酸マグネシウム等の乾燥剤で乾燥した後、
溶媒を留去することにより行なわれる。かかる操
作により、実用上、純品とみなされるイミドイル
クロライド化合物が得られる。一方、前記式
（）で示される化合物が、水に対して不安定な
場合には、反応溶液をそのまま減圧下にて、溶媒
及び揮発成分を充分留去した後、残留物に、テト
ラヒドロフラン（THF）、ベンゼン、又はトルエ
ン等の不活性溶媒を加えて不溶部を除去し、更
に、減圧乾固することにより、イミドイルクロラ
イド化合物を得ることができる。 The imidoyl chloride compound represented by the above formula () can be collected by diluting the reaction solution with an organic solvent that is immiscible with water, if the produced imidoyl chloride compound is stable in a weakly alkaline aqueous solution.
After washing with a weak alkaline aqueous solution or water, and then drying the organic layer with a desiccant such as magnesium sulfate,
This is done by distilling off the solvent. This operation yields an imidoyl chloride compound that is considered to be a pure product in practical terms. On the other hand, if the compound represented by the above formula () is unstable in water, the reaction solution is left under reduced pressure, the solvent and volatile components are sufficiently distilled off, and the residue is mixed with tetrahydrofuran (THF). ), benzene, toluene, or other inert solvent to remove the insoluble portion, and further drying under reduced pressure to obtain an imidoyl chloride compound.
本発明の次の工程は、前述のようにして得られ
た前記式（）で示される化合物を、４−メトキ
シピリジン−Ｎ−オキサイドで処理することによ
り、前記式（）で示されるピリドン化合物に変
換する工程である。この工程を式で示すと、次の
通りである。 In the next step of the present invention, the compound represented by the formula () obtained as described above is treated with 4-methoxypyridine-N-oxide to form a pyridone compound represented by the formula (). This is the process of converting. This process is expressed as follows.
（式中、R1、R2及びR3は、前記と同義である。）
４−メトキシピリジン−Ｎ−オキサイドは、前
記式（）で示される化合物に対して、１〜３当
量加えれば充分であるが、更に増量してもよい。
本反応は、クロロホルム、ジクロルメタン、ジク
ロルエタン、ベンゼン等の不活性溶媒中、室温か
ら80℃の範囲で、0.5〜10時間反応させることに
より行なうことができる。反応終了後、反応液を
水と混和しない有機溶媒で希釈し、水洗後、乾燥
し、溶媒を留去し、必要であれば、通常のカラム
クロマトグラフイー等により精製し、前記式
（）で示される化合物を得ることができる。 (In the formula, R 1 , R 2 and R 3 have the same meanings as above.) It is sufficient to add 1 to 3 equivalents of 4-methoxypyridine-N-oxide to the compound represented by the above formula (). However, the amount may be further increased.
This reaction can be carried out in an inert solvent such as chloroform, dichloromethane, dichloroethane, or benzene at a temperature ranging from room temperature to 80°C for 0.5 to 10 hours. After the reaction is completed, the reaction solution is diluted with an organic solvent that is immiscible with water, washed with water, dried, the solvent is distilled off, and if necessary, purified by ordinary column chromatography, etc. The compounds shown can be obtained.
本発明の最後の工程は、前述のようにして得ら
れた前記式（）で示されるピリドン化合物を、
メタノールで処理することにより、前記式（）
で示される目的化合物を得る工程である。この工
程を式で示すと、次の通りである。 In the final step of the present invention, the pyridone compound represented by the formula () obtained as described above is
By treatment with methanol, the formula ()
This is a step to obtain the target compound represented by. This process is expressed as follows.
（式中、R1、R2及びR3は、前記と同義である。）
本反応は、メタノール中、又は前記式（）で
示される化合物に対して、１〜100当量のメタノ
ールを含有するベンセン、クロロホルム、ジクロ
ルメタン、ジクロルエタン等の不活性溶媒中にお
いて行なうことができる。反応温度は、室温〜
130℃の範囲であることが好ましく、又、溶媒の
沸点以上に温度を高める時には、封管中で行なう
ことが好ましい。以上の条件下において、0.5〜
24時間反応させることにより、容易に反応は終了
する。反応終了後、減圧下にて溶媒を留去し、残
渣を水と混和しない有機溶媒に溶解し、水洗後、
乾燥し、溶媒を留去し、必要であれば、通常の精
製手段により精製し、前記式（）で示される目
的とする7α−メトキシセフアロスポリン化合物
を得ることができる。本反応において、副産物と
してΔ2−異性体が存在する場合には、通常のカ
ラムクロマトグラフイー等により、分離、精製
し、目的物を得ることができる。 (In the formula, R 1 , R 2 and R 3 have the same meanings as above.) This reaction is carried out in methanol or in an amount containing 1 to 100 equivalents of methanol relative to the compound represented by the above formula (). This can be carried out in an inert solvent such as benzene, chloroform, dichloromethane, dichloroethane or the like. The reaction temperature is room temperature ~
The temperature is preferably in the range of 130°C, and when the temperature is raised above the boiling point of the solvent, it is preferably carried out in a sealed tube. Under the above conditions, 0.5~
The reaction is easily completed by reacting for 24 hours. After the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in an organic solvent that is immiscible with water, and after washing with water,
The product is dried, the solvent is distilled off, and if necessary, it is purified by a conventional purification method to obtain the desired 7α-methoxycephalosporin compound represented by the above formula (). In this reaction, if a Δ 2 -isomer is present as a byproduct, it can be separated and purified by conventional column chromatography or the like to obtain the desired product.
以下、実施例により本発明を更に詳しく説明す
るが、これらの実施例は、何ら本発明を限定する
ものではない。 EXAMPLES Hereinafter, the present invention will be explained in more detail with reference to Examples, but these Examples are not intended to limit the present invention in any way.
実施例 １
7β−フエノキシアセトアミド−7α−メトキシ
−３−メチル−３−セフエム−４−カルボン酸
メチルエステル
(1) イミドイルクロライド化合物
五塩化リン1.3gを乾燥ジクロルメタン60mlに
溶解し、氷冷下、ピリジン0.75ml及び7β−フエ
ノキシアセトアミド−３−メチル−３−セフエ
ム−４−カルボン酸メチルエステル1.8gを加
え、２時間反応させる。反応終了後、反応液を
冷５％炭酸ナトリウム水溶液150ml中に注ぎ、
ジクロルメタン100〜150mlを加え抽出し、有機
層を飽和食塩水で洗浄後、無水硫酸マグネシウ
ムで乾燥し、溶媒留去する。残渣を少量のジク
ロルメタンに溶解し、ｎ−ヘキサンを加え、生
成する不溶部をジクロルメタンに溶解し、減圧
下、濃縮・乾固して、イミドイルクロライド化
合物を得る。Example 1 7β-phenoxyacetamide-7α-methoxy-3-methyl-3-cephem-4-carboxylic acid methyl ester (1) imidoyl chloride compound Dissolve 1.3 g of phosphorus pentachloride in 60 ml of dry dichloromethane, add 0.75 ml of pyridine and 1.8 g of 7β-phenoxyacetamide-3-methyl-3-cephem-4-carboxylic acid methyl ester under ice cooling, and react for 2 hours. let After the reaction was completed, the reaction solution was poured into 150 ml of cold 5% sodium carbonate aqueous solution.
Extract by adding 100 to 150 ml of dichloromethane, wash the organic layer with saturated brine, dry over anhydrous magnesium sulfate, and evaporate the solvent. The residue is dissolved in a small amount of dichloromethane, n-hexane is added, and the resulting insoluble portion is dissolved in dichloromethane and concentrated to dryness under reduced pressure to obtain an imidoyl chloride compound.
(2) ４−ピリドン化合物
(1)で得られたイミドイルクロライド化合物全
量を１，２−ジクロルエタン50mlに溶解し、４
−メトキシピリジン−Ｎ−オキサイド1.4gを加
え、アルゴン雰囲気下、70℃で７時間反応させ
る。反応終了後、ジクロルメタン150mlを加え、
冷水、希炭酸水素ナトリウム水溶液、冷水で順
次洗浄後、無水硫酸マグネシウムで乾燥し、溶
媒を減圧留去して、４−ピリドン化合物の粗粉
末1.9gを得る。これをシリカゲルカラムクロマ
トグラフイー〔ジクロルメタン−メタノール
（25：１）〕にて精製し、薄層クロマトグラフイ
ー（T.L.C.）で単一のスポツトを示す淡黄色の
粉末700mgを得る。(2) 4-pyridone compound Dissolve the entire amount of imidoyl chloride compound obtained in (1) in 50 ml of 1,2-dichloroethane,
-Methoxypyridine-N-oxide (1.4 g) is added, and the mixture is reacted at 70° C. for 7 hours under an argon atmosphere. After the reaction is complete, add 150ml of dichloromethane,
After successively washing with cold water, dilute aqueous sodium bicarbonate solution, and cold water, drying over anhydrous magnesium sulfate, and distilling off the solvent under reduced pressure, 1.9 g of a crude powder of 4-pyridone compound was obtained. This was purified by silica gel column chromatography [dichloromethane-methanol (25:1)] to obtain 700 mg of a pale yellow powder showing a single spot by thin layer chromatography (TLC).
(3) 7β−フエノキシアセトアミド−7α−メトキ
シ−３−メチル−３−セフエム−４−カルボン
酸メチルエステル
(2)で得られた４−ピリドン化合物600mgを乾
燥メタノール60mlに溶解し、封管中、125℃で
30分反応させる。反応終了後、反応液を濃縮
し、残渣をジクロルメタン−水に溶解し、ジク
ロルメタン層を希塩酸、希炭酸水素ナトリウム
水溶液及び水で順次洗浄し、無水硫酸マグネシ
ウムで乾燥後、溶媒を減圧留去して、粗粉末
540mgを得る。これをシリカゲルカラムクロマ
トグラフイー〔ベンゼン−酢酸エチル（５：
１）〕にて精製し、標記目的化合物260mgを得
る。(3) 7β-phenoxyacetamide-7α-methoxy-3-methyl-3-cephem-4-carboxylic acid methyl ester 600 mg of the 4-pyridone compound obtained in (2) was dissolved in 60 ml of dry methanol, and heated at 125℃ in a sealed tube.
Incubate for 30 minutes. After the reaction was completed, the reaction solution was concentrated, the residue was dissolved in dichloromethane-water, the dichloromethane layer was washed successively with dilute hydrochloric acid, dilute aqueous sodium bicarbonate solution, and water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. , coarse powder
Get 540mg. This was subjected to silica gel column chromatography [benzene-ethyl acetate (5:
1)] to obtain 260 mg of the title target compound.
Rf値〔シリカゲル；トルエン−酢酸エチル
（２：１）〕：0.46
NMR（CDCl3）δppm：2.19（ｓ，3H，３−位
のCH3），3.18（ｓ，2H，Ｈ−２），3.58（ｓ，
3H，OCH3），3.86（ｓ，3H，COOCH3），
4.60（ｓ，2H，OCH2CO），5.08（ｓ，1H，Ｈ
−６），6.9〜7.5（ｍ，6H，C6H5O，
CONH）．
IR（KBr）cm-1：1775，1720，1685，1230
実施例 ２
7β−フエノキシアセトアミド−7α−メトキシ
−３−メチル−３−セフエム−４−カルボン酸
ベンズヒドリルエステル
実施例１(1)と同様に処理することにより、7β
−フエノキシアセトアミド−３−メチル−３−セ
フエム−４−カルボン酸ベンズヒドリルエステル
より得られるイミドイルクロライド化合物1gを、
１，２−ジクロルエタン50mlに溶解し、４−メト
キシピリジン−Ｎ−オキサイド1.3gを加え、アル
ゴン雰囲気下、70℃で９時間反応させる。反応終
了後、実施例１(2)と同様に処理し、４−ピリドン
化合物250mgを得る。 Rf value [silica gel; toluene-ethyl acetate (2:1)]: 0.46 NMR (CDCl 3 ) δppm: 2.19 (s, 3H, CH 3 at 3-position), 3.18 (s, 2H, H-2), 3.58 (s,
3H, OCH 3 ), 3.86 (s, 3H, COOCH 3 ),
4.60 (s, 2H, OCH 2 CO), 5.08 (s, 1H, H
−6), 6.9 to 7.5 (m, 6H, C 6 H 5 O,
CONH). IR (KBr) cm -1 : 1775, 1720, 1685, 1230 Example 2 7β-phenoxyacetamide-7α-methoxy-3-methyl-3-cephem-4-carboxylic acid benzhydryl ester By treating in the same manner as in Example 1 (1), 7β
-1 g of imidoyl chloride compound obtained from phenoxyacetamide-3-methyl-3-cephem-4-carboxylic acid benzhydryl ester,
Dissolve in 50 ml of 1,2-dichloroethane, add 1.3 g of 4-methoxypyridine-N-oxide, and react at 70° C. for 9 hours under an argon atmosphere. After the reaction is completed, the same treatment as in Example 1 (2) is carried out to obtain 250 mg of 4-pyridone compound.
得られた４−ピリドン化合物200mgを乾燥メタ
ノール20mlに溶解し、封管中、125℃で40分反応
させる。反応終了後、反応液を濃縮し、残渣をジ
クロルメタンに溶解し、水洗後、無水硫酸マグネ
シウムで乾燥し、溶媒を減圧留去して、粗粉末
150mgを得る。これをシリカゲルカラムクロマト
グラフイー〔ベンゼン−酢酸エチル（９：１）〕
にて精製し、淡黄色粉末の標記目的化合物57mgを
得る。 200 mg of the obtained 4-pyridone compound is dissolved in 20 ml of dry methanol and reacted in a sealed tube at 125°C for 40 minutes. After the reaction, the reaction solution was concentrated, the residue was dissolved in dichloromethane, washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude powder.
Get 150mg. This was subjected to silica gel column chromatography [benzene-ethyl acetate (9:1)].
Purification was performed to obtain 57 mg of the title compound as a pale yellow powder.
Rf値〔シリカゲル；トルエン−酢酸エチル
（４：１）〕：0.44
NMR（CDCl3）δppm：2.20（ｓ，3H，３−位の
CH3），3.15（ABq，2H，Ｈ−２），3.58（ｓ，
3H，OCH3），4.60（ｓ，2H，OCH2CO），5.07
（ｓ，1H，Ｈ−６），6.9〜7.5（ｍ，16H，
C6H5O，（C6 H5 ）2CH，CONH），6.88（ｓ，
1H，（C6H5）2CＨ）．
IR（KBr）cm-1：1765，1720，1680，1230
実施例 ３
7β−アセトアミド−7α−メトキシ−３−メチ
ル−３−セフエム−４−カルボン酸メチルエス
テル
(1) イミドイルクロライド化合物
五塩化リン1.44gを乾燥ジクロルメタン60ml
に溶解し、冷却下、ピリジン0.9ml及び7β−ア
セトアミド−３−メチル−３−セフエム−４−
カルボン酸メチルエステル1.62gを加え、０℃
で２時間反応させる。反応終了後、反応液を減
圧下、濃縮・乾固して、イミドイルクロライド
化合物を得る。Rf value [silica gel; toluene-ethyl acetate (4:1)]: 0.44 NMR (CDCl 3 ) δppm: 2.20 (s, 3H, 3-position
CH 3 ), 3.15 (ABq, 2H, H-2), 3.58 (s,
3H, OCH 3 ), 4.60 (s, 2H, OCH 2 CO), 5.07
(s, 1H, H-6), 6.9-7.5 (m, 16H,
C 6 H 5 O, (C 6 H 5 ) 2 CH, CONH), 6.88 (s,
1H, (C 6 H 5 ) 2 C H ). IR (KBr) cm -1 : 1765, 1720, 1680, 1230 Example 3 7β-acetamido-7α-methoxy-3-methyl-3-cephem-4-carboxylic acid methyl ester (1) imidoyl chloride compound 1.44 g of phosphorus pentachloride in 60 ml of dichloromethane
0.9 ml of pyridine and 7β-acetamido-3-methyl-3-cephem-4- under cooling.
Add 1.62g of carboxylic acid methyl ester and heat to 0°C.
Let it react for 2 hours. After the reaction is completed, the reaction solution is concentrated to dryness under reduced pressure to obtain an imidoyl chloride compound.
(2) ４−ピリドン化合物
(1)で得られたイミドイルクロライド化合物全
量を１，２−ジクロルエタン50mlに溶解し、４
−メトキシピリジン−Ｎ−オキサイド2.1gを加
え、室温で30分反応させ、更にアルゴン雰囲気
下、70℃で２時間反応させる。反応終了後、ジ
クロルメタン250mlを加え、冷水、希炭酸水素
ナトリウム水溶液及び水で順次洗浄後、無水硫
酸マグネシウムで乾燥し、溶媒を減圧留去し
て、４−ピリドン化合物の粗粉末880mgを得る。
これをシリカゲルカラムクロマトグラフイー
〔クロロホルム−メタノール（30：１）〕にて精
製し、無色結晶の４−ピリドン化合物350mgを
得る。(2) 4-pyridone compound Dissolve the entire amount of imidoyl chloride compound obtained in (1) in 50 ml of 1,2-dichloroethane,
-Methoxypyridine-N-oxide (2.1 g) is added, and the mixture is reacted for 30 minutes at room temperature, and further reacted for 2 hours at 70°C under an argon atmosphere. After the reaction is complete, 250 ml of dichloromethane is added, and the mixture is washed successively with cold water, a dilute aqueous sodium bicarbonate solution, and water, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure to obtain 880 mg of a crude powder of 4-pyridone compound.
This was purified by silica gel column chromatography [chloroform-methanol (30:1)] to obtain 350 mg of the 4-pyridone compound as colorless crystals.
(3) 7β−アセトアミド−7α−メトキシ−３−セ
フエム−４−カルボン酸メチルエステル
(2)で得られた４−ピリドン化合物300mgを乾
燥メタノール30mlに溶解し、封管中、65℃で
1.5時間反応させる。反応終了後、反応液を減
圧濃縮し、得られる残渣を、シリカゲルカラム
クロマトグラフイー〔ジクロルメタン−酢酸エ
チル（５：２）〕にて精製し、無色粉末の標記
目的化合物117mgを得る。(3) 7β-acetamido-7α-methoxy-3-cephem-4-carboxylic acid methyl ester 300 mg of the 4-pyridone compound obtained in (2) was dissolved in 30 ml of dry methanol, and the mixture was heated at 65°C in a sealed tube.
Incubate for 1.5 hours. After the reaction is completed, the reaction solution is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography [dichloromethane-ethyl acetate (5:2)] to obtain 117 mg of the title compound as a colorless powder.
Rf値〔シリカゲル；ベンゼン−酢酸エチル
（５：４）〕：0.48
NMR（CDCl3）δppm：2.13（ｓ，3H，
CH3CO），2.15（ｓ，3H，３−位のCH3），
3.27（ABq，2H，Ｈ−２），3.56（ｓ，3H，
OCH3），3.85（ｓ，3H，COOCH3），5.06
（ｓ，1H，Ｈ−６），6.71（broad，ｓ，1H，
CONH）．
実施例 ４
7β−（２−tert−ブトキシカルボニルアミノ−
２−ジフエニルメトキシカルボニル）エチルチ
オアセトアミド−7α−メトキシ−３−メチル
−３−セフエム−４−カルボン酸ベンズヒドリ
ルエステル
(1) イミドイルクロライド化合物
五塩化リン600mgを乾燥ジクロルメタン50ml
に溶解し、冷却下、ピリジン0.36ml及び7β−
（２−tert−ブトキシカルボニルアミノ−２−
ジフエニルメトキシカルボニル）エチルチオア
セトアミド−３−メチル−３−セフエム−４−
カルボン酸ベンズヒドリルエステル1.6gを加
え、０℃で３時間反応させる。反応終了後、実
施例１(1)と同様に処理し、イミドイルクロライ
ド化合物1.58gを得る。 Rf value [silica gel; benzene-ethyl acetate (5:4)]: 0.48 NMR (CDCl 3 ) δppm: 2.13 (s, 3H,
CH 3 CO), 2.15 (s, 3H, 3-position CH 3 ),
3.27 (ABq, 2H, H-2), 3.56 (s, 3H,
OCH 3 ), 3.85 (s, 3H, COOCH 3 ), 5.06
(s, 1H, H-6), 6.71 (broad, s, 1H,
CONH). Example 4 7β-(2-tert-butoxycarbonylamino-
2-diphenylmethoxycarbonyl)ethylthioacetamide-7α-methoxy-3-methyl-3-cephem-4-carboxylic acid benzhydryl ester (1) imidoyl chloride compound Phosphorus pentachloride 600mg dried dichloromethane 50ml
0.36 ml of pyridine and 7β-
(2-tert-butoxycarbonylamino-2-
diphenylmethoxycarbonyl)ethylthioacetamide-3-methyl-3-cephem-4-
Add 1.6 g of carboxylic acid benzhydryl ester and react at 0°C for 3 hours. After the reaction is completed, the same treatment as in Example 1(1) is carried out to obtain 1.58 g of imidoyl chloride compound.
(2) ４−ピリドン化合物
(1)で得られたイミドイルクロライド化合物全
量を１，２−ジクロルエタン30mlに溶解し、４
−メトキシピリジン−Ｎ−オキサイド700mgを
加え、アルゴン雰囲気下、70℃で1.5時間反応
させる。反応終了後、実施例１(2)と同様に処理
し、４−ピリドン化合物265mgを得る。(2) 4-pyridone compound Dissolve the entire amount of imidoyl chloride compound obtained in (1) in 30 ml of 1,2-dichloroethane,
-Methoxypyridine-N-oxide (700 mg) is added, and the mixture is reacted at 70°C for 1.5 hours under an argon atmosphere. After the reaction is completed, the same treatment as in Example 1 (2) is carried out to obtain 265 mg of 4-pyridone compound.
(3) 7β−（２−tert−ブトキシカルボニルアミノ
−２−ジフエニルメトキシカルボニル）エチル
チオアセトアミド−7α−メトキシ−３−メチ
ル−３−セフエム−４−カルボン酸ベンズヒド
リルエステル
(2)で得られた４−ピリドン化合物250mgを乾
燥メタノール25mlに溶解し、封管中、70℃で１
時間反応させる。反応終了後、実施例３(3)と同
様に処理し、標記目的化合物72mgを得る。(3) 7β-(2-tert-butoxycarbonylamino-2-diphenylmethoxycarbonyl)ethylthioacetamide-7α-methoxy-3-methyl-3-cephem-4-carboxylic acid benzhydryl ester 250 mg of the 4-pyridone compound obtained in (2) was dissolved in 25 ml of dry methanol, and the mixture was heated to 70°C in a sealed tube.
Allow time to react. After the reaction was completed, the same procedure as in Example 3(3) was carried out to obtain 72 mg of the desired title compound.
Rf値〔シリカゲル；ジクロルメタン−酢酸エ
チル（９：１）〕：0.3
NMR（CDCl3）δppm：1.42（ｓ，9H，
（CH3）3C），2.16（ｓ，3H，３−位のCH3），
3.10（ｄ，2H，CHCH2 Ｓ），3.22（ｓ，2H，
SCH2CO），3.25（dd，2H，Ｈ−２），4.63
（ｍ，1H，ＣＨCH2S），5.04（ｓ，1H，Ｈ−
６），6.90（broad ｓ，2H，（C6H5）2CＨ×
２），7.0〜7.5（ｍ，22H，（C6 H5 ）2CH×２，
CONH×２）．
実施例 ５
7β−フエノキシアセトアミド−7α−メトキシ
−３−（１−メチル−1H−テトラゾール−５−
イル）チオメチル−３−セフエム−４−カルボ
ン酸メチルエステル
実施例１(1)と同様に処理することにより、7β
−フエノキシアセトアミド−３−（１−メチル−
1H−テトラゾール−５−イル）チオメチル−３
−セフエム−４−カルボン酸メチルエステルより
得られるイミドイルクロライド化合物1.7gを、
１，２−ジクロルエタン50mlに溶解し、４−メト
キシピリジン−Ｎ−オキサイド1.3gを加え、アル
ゴン雰囲気下、70℃で３時間反応させる。反応終
了後、実施例１(2)と同様に処理し、４−ピリドン
化合物280mgを得る。 Rf value [silica gel; dichloromethane-ethyl acetate (9:1)]: 0.3 NMR (CDCl 3 ) δppm: 1.42 (s, 9H,
(CH 3 ) 3 C), 2.16 (s, 3H, 3-position CH 3 ),
3.10 (d, 2H, CHC H 2 S), 3.22 (s, 2H,
SCH 2 CO), 3.25 (dd, 2H, H-2), 4.63
(m, 1H, C H CH 2 S), 5.04 (s, 1H, H-
6), 6.90 (broad s, 2H, (C 6 H 5 ) 2 C H ×
2), 7.0~7.5 (m, 22H, (C 6 H 5 ) 2 CH x 2,
CONH×2). Example 5 7β-Phenoxyacetamide-7α-methoxy-3-(1-methyl-1H-tetrazole-5-
yl)thiomethyl-3-cephem-4-carboxylic acid methyl ester By treating in the same manner as in Example 1 (1), 7β
-Phenoxyacetamide-3-(1-methyl-
1H-tetrazol-5-yl)thiomethyl-3
- 1.7 g of imidoyl chloride compound obtained from cefem-4-carboxylic acid methyl ester,
Dissolve in 50 ml of 1,2-dichloroethane, add 1.3 g of 4-methoxypyridine-N-oxide, and react at 70° C. for 3 hours under an argon atmosphere. After the reaction is completed, the same treatment as in Example 1 (2) is carried out to obtain 280 mg of 4-pyridone compound.
得られた４−ピリドン化合物200mgを乾燥メタ
ノール15mlに溶解し、封管中、120℃で40分間反
応させる。反応終了後、反応液を減圧下、濃縮
し、残渣をジクロルメタン−水に溶解し、ジクロ
ルメタン層を希塩酸、希炭酸水素ナトリウム水溶
液及び水で順次洗浄し、無水硫酸マグネシウムで
乾燥後、溶媒を減圧留去して、粗粉末203mgを得
る。これをシリカゲルカラムクロマトグラフイー
〔ベンゼン−酢酸エチル（２：１）〕にて精製し、
標記目的化合物40mgを得る。 200 mg of the obtained 4-pyridone compound is dissolved in 15 ml of dry methanol and reacted in a sealed tube at 120°C for 40 minutes. After the reaction, the reaction solution was concentrated under reduced pressure, the residue was dissolved in dichloromethane-water, the dichloromethane layer was washed successively with dilute hydrochloric acid, dilute aqueous sodium bicarbonate solution, and water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. 203 mg of crude powder was obtained. This was purified by silica gel column chromatography [benzene-ethyl acetate (2:1)],
40 mg of the title target compound is obtained.
Rf値〔シリカゲル；ベンゼン−酢酸エチル
（３：２）〕：0.3
MR（CDCl3）δppm：3.51（ABq，2H，Ｈ−２），
3.55（ｓ，3H，OCH3），3.91（ｓ，6H，Ｎ−
CH3，COOCH3），4.42（ABq，2H，３−位の
CH2S），4.58（ｓ，2H，OCH2CO），5.07（ｓ，
1H，Ｈ−６），6.9〜7.5（ｍ，6H，C6H5O，
CONH）．
IR（KBr）cm-1：1775，1720，1690，1240Rf value [silica gel; benzene-ethyl acetate (3:2)]: 0.3 MR (CDCl 3 ) δppm: 3.51 (ABq, 2H, H-2),
3.55 (s, 3H, OCH 3 ), 3.91 (s, 6H, N-
CH 3 , COOCH 3 ), 4.42 (ABq, 2H, 3-position
CH 2 S), 4.58 (s, 2H, OCH 2 CO), 5.07 (s,
1H, H-6), 6.9-7.5 (m, 6H, C 6 H 5 O,
CONH). IR (KBr) cm -1 : 1775, 1720, 1690, 1240
Claims (1)
しくは置換されたアルキル基又はアリール基を表
し、Ｂは、酸素原子若しくは硫黄原子を表す）で
示される残基を表し、R2は、水素原子又はカル
ボキシル基の保護基を表し、R3は、メチル基又
はヘテロ環残基で置換されたメルカプトメチル基
を表す〕示される化合物を五塩化リンで処理し、 次式： （式中、R1、R2及びR3は、前記と同義である）
で示される化合物を得、これを４−メトキシピリ
ジン−Ｎ−オキサイドで処理し、 次式： （式中、R1、R2及びR3は、前記と同義である）
で示される化合物を得、これを、メタノールで処
理し、 次式： （式中、R1、R2及びR3は、前記と同義である）
で示される化合物を得ることを特徴とする7α−
メトキシセフアロスポリン化合物の製造法。[Claims] Primary formula: [In the formula, R 1 is an alkyl group or the following formula: AB-CH 2 - (wherein, A represents an unsubstituted or substituted alkyl group or an aryl group, and B is an oxygen atom or a sulfur atom. ), R 2 represents a hydrogen atom or a protecting group for a carboxyl group, and R 3 represents a methyl group or a mercaptomethyl group substituted with a heterocyclic residue] is treated with phosphorus pentachloride, and the following formula: (In the formula, R 1 , R 2 and R 3 have the same meanings as above)
A compound represented by is obtained, which is treated with 4-methoxypyridine-N-oxide to form the following formula: (In the formula, R 1 , R 2 and R 3 have the same meanings as above)
A compound represented by is obtained, which is treated with methanol and has the following formula: (In the formula, R 1 , R 2 and R 3 have the same meanings as above)
7α- characterized by obtaining a compound represented by
A method for producing a methoxycephalosporin compound.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP57060387A JPH0227997B2 (en) | 1982-04-13 | 1982-04-13 | 7ARUFUAAMETOKISHISEFUAROSUHORINKAGOBUTSUNOSEIZOHO |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP57060387A JPH0227997B2 (en) | 1982-04-13 | 1982-04-13 | 7ARUFUAAMETOKISHISEFUAROSUHORINKAGOBUTSUNOSEIZOHO |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS58177996A JPS58177996A (en) | 1983-10-18 |
| JPH0227997B2 true JPH0227997B2 (en) | 1990-06-20 |
Family
ID=13140678
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP57060387A Expired - Lifetime JPH0227997B2 (en) | 1982-04-13 | 1982-04-13 | 7ARUFUAAMETOKISHISEFUAROSUHORINKAGOBUTSUNOSEIZOHO |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0227997B2 (en) |
-
1982
- 1982-04-13 JP JP57060387A patent/JPH0227997B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPS58177996A (en) | 1983-10-18 |
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