JPH0158189B2 - - Google Patents
Info
- Publication number
- JPH0158189B2 JPH0158189B2 JP56044854A JP4485481A JPH0158189B2 JP H0158189 B2 JPH0158189 B2 JP H0158189B2 JP 56044854 A JP56044854 A JP 56044854A JP 4485481 A JP4485481 A JP 4485481A JP H0158189 B2 JPH0158189 B2 JP H0158189B2
- Authority
- JP
- Japan
- Prior art keywords
- singlet
- group
- ethyl acetate
- carboxylic acid
- general formula
- 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
Links
- -1 benzenesulfonylamino group Chemical group 0.000 claims description 14
- 150000001875 compounds Chemical class 0.000 claims description 12
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- 150000008282 halocarbons Chemical class 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 14
- 238000000034 method Methods 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 125000002252 acyl group Chemical group 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 125000003277 amino group Chemical group 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 3
- 235000002639 sodium chloride Nutrition 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 2
- KIWBPDUYBMNFTB-UHFFFAOYSA-N Ethyl hydrogen sulfate Chemical compound CCOS(O)(=O)=O KIWBPDUYBMNFTB-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 238000006884 silylation reaction Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- XOHZHMUQBFJTNH-UHFFFAOYSA-N 1-methyl-2h-tetrazole-5-thione Chemical compound CN1N=NN=C1S XOHZHMUQBFJTNH-UHFFFAOYSA-N 0.000 description 1
- ALCKLBOCZKLPJN-UHFFFAOYSA-N 3-cyanopropanethioyl chloride Chemical compound ClC(=S)CCC#N ALCKLBOCZKLPJN-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- FQYUMYWMJTYZTK-UHFFFAOYSA-N Phenyl glycidyl ether Chemical compound C1OC1COC1=CC=CC=C1 FQYUMYWMJTYZTK-UHFFFAOYSA-N 0.000 description 1
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 1
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- AWMVMTVKBNGEAK-UHFFFAOYSA-N Styrene oxide Chemical compound C1OC1C1=CC=CC=C1 AWMVMTVKBNGEAK-UHFFFAOYSA-N 0.000 description 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 1
- 229910021536 Zeolite Inorganic materials 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 125000002668 chloroacetyl group Chemical group ClCC(=O)* 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- FEZFGJCSBWYLCC-UHFFFAOYSA-N dicyclohexylazanium;bromide Chemical compound Br.C1CCCCC1NC1CCCCC1 FEZFGJCSBWYLCC-UHFFFAOYSA-N 0.000 description 1
- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical compound O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 125000006575 electron-withdrawing group Chemical group 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- LIGACIXOYTUXAW-UHFFFAOYSA-N phenacyl bromide Chemical compound BrCC(=O)C1=CC=CC=C1 LIGACIXOYTUXAW-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000004055 thiomethyl group Chemical group [H]SC([H])([H])* 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000010457 zeolite Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Landscapes
- Cephalosporin Compounds (AREA)
Description
【発明の詳細な説明】
本発明は微生物の培養によつて得られるセフア
マイシンCすなわち7β―(D―5―アミノ―5
―カルボキシバレルアミド―7α―メトキシ―3
―セフエム―4―カルボン酸の7位側鎖アミノ基
を保護し、3位をS―ヘテロ環に、又カルボキシ
ル基をハロゲン原子を有するか有しないフエナシ
ルエステルに誘導した化合物を原料として、7位
側鎖を目的とするアシル基に変換する方法に関す
るものである。DETAILED DESCRIPTION OF THE INVENTION The present invention provides cefamycin C, i.e., 7β-(D-5-amino-5
-Carboxyvaleramide-7α-methoxy-3
Using a compound in which the amino group at the 7-position side chain of -cefem-4-carboxylic acid is protected, the 3-position is converted into an S-heterocycle, and the carboxyl group is induced into a phenacyl ester with or without a halogen atom as a raw material, 7 The present invention relates to a method for converting a position side chain into a desired acyl group.
このような方法の従来法としてはゼオライトを
触媒に用いてアシル交換する方法(特開昭50―
105687号)、シリル化を行つた後アシル交換する
方法(特開昭50―85386号)、又このようなシリル
化又は触媒を使用しない方法として特開昭55―
20723号等がある。このような方法でアシル交換
を行い、より有効な抗菌剤又はその中間体を製造
する際、工業的に問題になるのは、その収率であ
る。本発明者等はセフアマイシン誘導体に関して
7位側鎖のアミノ基の保護基の種類、3位の置換
基の種類、4位カルボキシル基の保護基の種類に
より収率が大きく左右される事を基にして、この
組合せについて種々検討した結果、7位側鎖のア
ミノ基の保護基が電子吸引性の基であり、3位が
ヘテロ環S―メチル基であり、7位側鎖のカルボ
ン酸および4位カルボン酸の保護基としてはハロ
ゲン原子を有するか有しないフエナシルエステル
である場合に極めて高収率でアシル交換反応が進
行する事を見出し本発明を完成した。すなわち本
発明は
一般式
式中、R1はベンゼンスルホニルアミノ基を示
し、R2は水素原子またはハロゲン原子を示し、
R3は1―メチル―1H―テトラゾール―5―イル
基を示す。)で表わされる化合物をハロゲン化炭
化水素系溶媒中
式 R4−X ()
(式中、R4はクロロアセチル基またはシアノ
メチルチオアセチル基を示し、Xはハロゲン原子
を示す。)で表わされる化合物と反応させる事を
特徴とする一般式
(式中、R2,R3およびR4は前述したものと同
意義を有する。)で表わされるセフアマイシン誘
導体の製法に関する。 The conventional method for such a method is a method of acyl exchange using zeolite as a catalyst (Japanese Patent Application Laid-Open No. 1989-1999).
105687), a method of acyl exchange after silylation (Japanese Patent Application Laid-open No. 85386, 1983), and a method of silylation or a method that does not use a catalyst, as described in Japanese Patent Application Laid-Open No. 1982-
There are issues such as No. 20723. When producing a more effective antibacterial agent or its intermediate by performing acyl exchange using such a method, the yield becomes an industrial problem. The present inventors based on the fact that the yield of cefamycin derivatives is greatly affected by the type of protecting group for the amino group in the 7-position side chain, the type of substituent at the 3-position, and the type of the protecting group for the carboxyl group at the 4-position. As a result of various studies on this combination, we found that the protecting group for the amino group in the 7-position side chain is an electron-withdrawing group, the 3-position is a heterocyclic S-methyl group, and the carboxylic acid in the 7-position side chain and The inventors have completed the present invention by discovering that the acyl exchange reaction proceeds in an extremely high yield when the protecting group for the position carboxylic acid is a phenacyl ester with or without a halogen atom. That is, the present invention has the general formula In the formula, R 1 represents a benzenesulfonylamino group, R 2 represents a hydrogen atom or a halogen atom,
R 3 represents a 1-methyl-1H-tetrazol-5-yl group. ) in a halogenated hydrocarbon solvent A compound represented by the formula R 4 -X () (wherein R 4 represents a chloroacetyl group or a cyanomethylthioacetyl group, and X represents a halogen atom) General formula characterized by reaction with The present invention relates to a method for producing a cefamycin derivative represented by the formula (wherein R 2 , R 3 and R 4 have the same meanings as described above).
本発明の原料として使用される一般式()を
有する化合物は、セフアマイシンCの7位側鎖の
アミノ基を保護し、3位のカルバモイルオキシメ
チル基をヘテロ環チオメチル基に変換し、7位側
鎖のカルボキシル基及び4位のカルボキシル基を
ハロゲン原子を有するか、有しないフエナシルエ
ステル化する事により得られる。本発明の方法を
用いれば微生物の培養によつて得られるセフアマ
イシンCの3位及び7位を連続して目的とする基
に変換する事ができ、より抗菌力の強い化合物を
製造し得て、工業的に極めて有用な方法を提供す
るものである。 The compound having the general formula () used as a raw material of the present invention protects the amino group of the 7-position side chain of cefamycin C, converts the 3-position carbamoyloxymethyl group to a heterocyclic thiomethyl group, and protects the 7-position side chain amino group of cefamycin C. It is obtained by converting the carboxyl group of the chain and the carboxyl group at the 4-position into a phenacyl ester with or without a halogen atom. By using the method of the present invention, it is possible to successively convert the 3- and 7-positions of cefamycin C obtained by culturing microorganisms into the desired group, and it is possible to produce a compound with stronger antibacterial activity. This provides an industrially extremely useful method.
本発明の方法に於て7位アシル基交換反応は前
記一般式()を有する化合物と前記一般式
()を有する化合物をハロゲン化炭化水素系溶
媒中接触させる事により容易に実施することが出
来る。このようなハロゲン化炭化水素系溶媒とし
てはジクロロメタン,クロロホルム,トリクレン
があげられるが、1,2―ジクロロエタンが最も
好ましい。前記一般式()に於ける×で示され
るハロゲン原子としてはクロルまたはブロムがあ
げられる。カルボン酸ハライド()の使用量は
化合物()に対して1〜10モル比であるが、5
〜10モル比が好ましい。反応温度は通常50〜100
℃である。反応の進行状況は薄層クロマトグラフ
イーによつて追跡する事ができる。反応に要する
時間は数十分乃至10時間である。 In the method of the present invention, the 7-position acyl group exchange reaction can be easily carried out by bringing the compound having the above general formula () into contact with the compound having the above general formula () in a halogenated hydrocarbon solvent. . Examples of such halogenated hydrocarbon solvents include dichloromethane, chloroform, and trichlene, and 1,2-dichloroethane is most preferred. Examples of the halogen atom represented by x in the general formula () include chlorine and bromine. The amount of carboxylic acid halide () used is 1 to 10 molar ratio to the compound (), but 5
~10 molar ratios are preferred. Reaction temperature is usually 50-100℃
It is ℃. The progress of the reaction can be followed by thin layer chromatography. The time required for the reaction is several tens of minutes to 10 hours.
なお、本アシル交換反応は脱酸剤の存在下にお
いて好適に実施することができるが、ここで使用
される脱酸剤としてはプロピレンオキサイド,ブ
チレンオキサイド,スチレンオキサイド,フエニ
ルグリシジルエーテル等があげられる。 Note that this acyl exchange reaction can be suitably carried out in the presence of a deoxidizing agent, and examples of the deoxidizing agent used here include propylene oxide, butylene oxide, styrene oxide, phenyl glycidyl ether, etc. .
本反応によつて得られる前記一般式()を有
する目的化合物は常法により採取する事が出来
る。反応混合物から溶媒を留去し残留物にイソプ
ロピルエーテルを加え、粉末として採取するか、
又はクロマトグラフイーにより精製採取する事が
出来る。 The target compound having the general formula () obtained by this reaction can be collected by a conventional method. Distill the solvent from the reaction mixture and add isopropyl ether to the residue and collect it as a powder, or
Alternatively, it can be purified and collected by chromatography.
本発明の方法によつて得られる前記一般式
()で表わされる化合物は不活性溶媒中、亜鉛
と鉱酸若しくはスルホン酸と反応させることによ
つて一般式
(式中、R3およびR4は前述したものと同意義
を有する。)で表わされるセフアマイシン誘導体
およびその薬理上許容される塩を製造することが
でき、化合物()は優れた抗菌作用を有する医
薬として有用な化合物である。 The compound represented by the general formula () obtained by the method of the present invention can be obtained by reacting zinc with a mineral acid or a sulfonic acid in an inert solvent. (In the formula, R 3 and R 4 have the same meanings as described above.) A cefamycin derivative and its pharmacologically acceptable salt can be produced, and the compound () has excellent antibacterial activity. It is a compound useful as a medicine.
次に実施例および参考例をあげて本発明を更に
具体的に説明する。 Next, the present invention will be explained in more detail with reference to Examples and Reference Examples.
実施例 1
(a) 7β―(D―5―ベンゼンスルホニルアミノ
―5―カルボキシバレルアミド)―7―α―メ
トキシ―3―カルバモイルオキシメチル―3―
セフエム―4―カルボン酸70g(純度85%)に
1―メチル―5―メルカプトテトラゾール175
g、水12ml及びアセトン3mlを加え、内温65〜
75℃で20分間加熱撹拌する。この際時々減圧に
して、水、アセトンを少量ずつ留去する。つい
で水200ml及び酢酸エチル500mlを加え、塩酸で
水層のPHを1.5とする、食塩50gを加えよくか
きまぜ、酢酸エチル層を分離し、水層を100ml
の酢酸エチルで2回抽出し、先の酢酸エチル層
と合し減圧濃縮乾固する。これにイソプロピル
エーテル1.6を加え、よくかきまぜるとアメ
状物が粉末化するので、これを集しイソプロ
ピルエーテルで洗浄する。これを500mlのエタ
ノールに溶解し、ジシクロヘキシルアミン43.2
gを加え、氷水浴中1時間放置すると白色結晶
が析出する。これを集しエタノール洗浄、乾
燥すると、76.4gの7β―(D―5―ベンゼンス
ルホニルアミノ―5―カルボキシバレルアミ
ド)―7α―メトキシ―3―(1―メチルテト
ラゾール―5―イル)チオメチル―3―セフエ
ム―4―カルボン酸・ジージシクロヘキシルア
ミン塩が得られた。この母液を更に濃縮乾固
し、少量のエタノールを加え数日(約6日)放
置すると更に結晶が析出するので同様に集乾
燥すると、8.2gの同結晶が得られた。合計収
量84.6g、収率83.0%このようにして得られた
結晶1gをとり5mlのメタノールに溶解し、シ
ロツプ状になるまで減圧濃縮し、5mlのエタノ
ールを加え、放置すると純品が得られた。Example 1 (a) 7β-(D-5-benzenesulfonylamino-5-carboxyvaleramide)-7-α-methoxy-3-carbamoyloxymethyl-3-
Cefem-4-carboxylic acid 70g (purity 85%) to 1-methyl-5-mercaptotetrazole 175
g, add 12 ml of water and 3 ml of acetone, and bring the internal temperature to 65~
Heat and stir at 75°C for 20 minutes. At this time, water and acetone are distilled off little by little by reducing the pressure from time to time. Next, add 200 ml of water and 500 ml of ethyl acetate, adjust the pH of the aqueous layer to 1.5 with hydrochloric acid, add 50 g of common salt, stir well, separate the ethyl acetate layer, and remove 100 ml of the aqueous layer.
Extract twice with ethyl acetate, combine with the previous ethyl acetate layer, and concentrate to dryness under reduced pressure. Add 1.6 liters of isopropyl ether to this and stir well. The candy-like substance will turn into powder, which will be collected and washed with isopropyl ether. Dissolve this in 500ml of ethanol and dicyclohexylamine 43.2
g and left in an ice water bath for 1 hour to precipitate white crystals. After collecting, washing with ethanol, and drying, 76.4 g of 7β-(D-5-benzenesulfonylamino-5-carboxyvaleramide)-7α-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-3 -Cefem-4-carboxylic acid didicyclohexylamine salt was obtained. This mother liquor was further concentrated to dryness, a small amount of ethanol was added, and when it was left to stand for several days (about 6 days), more crystals were precipitated, so it was collected and dried in the same manner to obtain 8.2 g of the same crystals. Total yield: 84.6 g, yield: 83.0% 1 g of the crystals thus obtained was dissolved in 5 ml of methanol, concentrated under reduced pressure until it became syrupy, added with 5 ml of ethanol, and left to stand, yielding a pure product. .
融点 143〜145℃(分解)
元素分析 C23H27N7O9S3・2C12H23N
実験値C;55.94,H;7.45,N;12.39,
S;9.33
計算値C;56.21,H;7.33,N;12.56,
S;9.58
(b) 7β―(D―5―ベンゼンスルホニルアミノ
―5―カルボキシバレルアミド)―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・ジ―ジシクロヘキシルアミン塩
〔純度96%(HPLCによる)〕10gを、ジメチル
ホルムアミド50ml中にフエナシルブロマイド
4.4gをとかした溶液中に0〜5℃で少量ずつ
加える、(10分)その後室温で30分撹拌し、酢
酸エチル200mlを加え不溶物(ジ―シクロヘキ
シルアミン・臭化水素酸塩)を去し、少量の
酢酸エチルで洗浄し、酢酸エチル層を50mlの水
で2回洗浄する。酢酸エチル層を減圧で濃縮す
ると、泡状固形物として相当するジフエナシル
エステル9.2gが得られた。Melting point 143-145℃ (decomposition) Elemental analysis C 23 H 27 N 7 O 9 S 3・2C 12 H 23 N Experimental value C; 55.94, H; 7.45, N; 12.39, S; 9.33 Calculated value C; 56.21, H ;7.33, N; 12.56, S; 9.58 (b) 7β-(D-5-benzenesulfonylamino-5-carboxyvaleramide)-7α-methoxy-3-(1-methyl-1H-tetrazol-5-yl) Thiomethyl-3-cephem-4-
10 g of carboxylic acid di-dicyclohexylamine salt [96% purity (by HPLC)] was added to phenacyl bromide in 50 ml of dimethylformamide.
Add 4.4g little by little to the dissolved solution at 0-5℃ (10 minutes), then stir at room temperature for 30 minutes, add 200ml of ethyl acetate to remove insoluble matter (di-cyclohexylamine hydrobromide). Wash with a small amount of ethyl acetate, and wash the ethyl acetate layer twice with 50 ml of water. The ethyl acetate layer was concentrated under reduced pressure to yield 9.2 g of the corresponding diphenacyl ester as a foamy solid.
nmr δ ppm(CDCl3)
1.50〜2.95(多重線 7H)
3.43 (一重線 3H)
3.58 (ブロード一重線 2H)
3.78 (一重線 3H)
4.38 (一重線 2H)
5.00 (一重線 1H)
5.07 (一重線 2H)
5.45 (ブロード一重線 2H)
6.0 〜6.15(二重線 1H)
7.22〜8.02(多重線 15H)
これに1,2―ジクロロエタン200ml及びモノ
クロロアセチルクロライド10.0mlを加え撹拌しな
がら4時間還流する。ついで溶媒を減圧留去し、
残留物にイソプロピルエーテル100mlを加えよく
かきまぜ得られた粉末状物質を集すると、
11.04gの7β―モノクロロアセタミド―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
ボン酸フエナシルエステルの粗製物が得られた。
純度44.7%、純度換算収率93%これをシリカゲル
カラムクロマトに付しベンゼン:酢酸エチル3:
1で展開、分離精製すると純品が得られた。 nmr δ ppm (CDCl 3 ) 1.50 to 2.95 (multiplet 7H) 3.43 (singlet 3H) 3.58 (broad singlet 2H) 3.78 (singlet 3H) 4.38 (singlet 2H) 5.00 (singlet 1H) 5.07 (singlet 2H) 5.45 (Broad singlet 2H) 6.0 - 6.15 (Double line 1H) 7.22 - 8.02 (Multiple line 15H) 200 ml of 1,2-dichloroethane and 10.0 ml of monochloroacetyl chloride were added to this and refluxed for 4 hours with stirring. Then, the solvent was distilled off under reduced pressure,
Add 100ml of isopropyl ether to the residue, stir well, and collect the resulting powdery substance.
11.04g of 7β-monochloroacetamide-7α-methoxy-3-(1-methyl-1H-tetrazole-
A crude product of 5-ylthiomethyl)-3-cephem-4-carboxylic acid phenacyl ester was obtained.
Purity: 44.7%, purity conversion yield: 93% This was subjected to silica gel column chromatography to yield benzene: ethyl acetate 3:
A pure product was obtained by developing and separating and purifying the product in step 1.
nmr δppm(CDCl3)
3.57 (3H)一重線
3.68 (2H) 〃
3.92 (3H) 〃
4.13 (2H) 〃
4.50 (2H) 〃 (ブロート)
5.08 (1H) 〃
5.55 (2H) 〃
7.25〜8.07(5H)多重線
実施例 2
実施例1と同様に7β―(D―5―ベンゼンス
ルホニルアミノ―5―カルボキシバレルアミド)
―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―カルボン酸ジ―ジシクロヘキシルアミン
塩10gよりそのジフエナシルエステルを合成し、
モノクロロアセチルクロライドの代りにシアノメ
チルチオアセチルクロライド8.5gを使用し6時
間撹拌しつゝ還流せしめ、同様に操作すると、
12.1gの7β―シアノメチルチオアセタミド―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―
カルボン酸フエナシルエステルの粗製物が得られ
た。純度38.0%純度換算収率78.0%これをシリカ
ゲルカラムクロマトに附し、クロロホルム:酢酸
エチル2:1で展開分離精製すると純品が得られ
た。 nmr δppm (CDCl 3 ) 3.57 (3H) Singlet 3.68 (2H) 〃 3.92 (3H) 〃 4.13 (2H) 〃 4.50 (2H) 〃 (Bloat) 5.08 (1H) 〃 5.55 (2H) 〃 7.25~8.07 (5H) ) Multiplet Example 2 Same as Example 1, 7β-(D-5-benzenesulfonylamino-5-carboxyvaleramide)
-7α-methoxy-3-(1-methyl-1H-tetrazol)-5-yl)thiomethyl-3-cephem-4-carboxylic acid di-dicyclohexylamine salt was synthesized from 10 g of its diphenacyl ester,
Using 8.5 g of cyanomethylthioacetyl chloride instead of monochloroacetyl chloride and refluxing with stirring for 6 hours, the same procedure was performed.
12.1g of 7β-cyanomethylthioacetamide-7α-
Methoxy-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-
A crude product of carboxylic acid phenacyl ester was obtained. Purity: 38.0% Purity conversion yield: 78.0% This was applied to silica gel column chromatography and developed and separated and purified with chloroform:ethyl acetate 2:1 to obtain a pure product.
nmr δppm(重アセトン)
3.53 (3H) 一重線
3.60 (2H) 一重線
3.73 (4H) 多重線
3.96 (3H) 一重線
4.50 (2H) ブロード 一重線
5.15 (1H) 一重線
5.63 (2H) 一重線
7.46〜8.2(5H) 多重線
8.58 (1H) ブロード 一重線
参考例 1
7β―シアノメチルチオアセタミド―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
ボン酸フエナシルエステル(HPLCによる純度
88.7%)1.0gにアセトン20mlおよび水2mlを加
えて溶解せしめ、−30℃に冷却する。これにモノ
エチル硫酸5.0mlおよび亜鉛末1.0gを加え−30゜〜
−25℃で2.5時間撹拌する。ついで水50mlおよび
酢酸エチル50mlを加え、よく振盪し酢酸エチル層
を分液する。水層を酢酸エチル30mlで2回抽出
し、先の酢酸エチル層と合し、飽和食塩水で洗浄
後、溶媒を減圧で留去すると、0.847gの7β―シ
アノメチルチオアセタミド―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―カルボン酸が得
られた。(HPLCによる純度73.7%)純度換算収
率88.0%
nmrスペクトルδppm(重アセトン)
3.50 (一重線、3H)
3.60 (一重線、2H)
3.5 〜3.7 (四重線、2H)
3.70 (一重線、2H)
3.90 (一重線、3H)
4.3 〜4.6 (四重線、2H)
5.10 (一重線、1H)
参考例 2
7β―クロルアセタミド―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―カルボン酸フエナ
シルエステル(HPLCによる純度90.1%)1.0gを
アセトン20mlおよび水1mlを加えてとかし、参考
例1の如くモノエチル硫酸および亜鉛末を用いて
反応させ同様に処理すると、0.857gの7β―クロ
ルアセタミド―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―カルボン酸が得られた。
(HPLCによる純度70.3%)純度換算収率85%
nmrスペクトル δppm(重アセトン)
3.5 (一重線、3H)
3.67 (一重線、2H)
3.98 (一重線、3H)
4.42 (ブロード一重線、2H)
5.08 (一重線、1H) nmr δppm (heavy acetone) 3.53 (3H) Singlet 3.60 (2H) Singlet 3.73 (4H) Multiplet 3.96 (3H) Singlet 4.50 (2H) Broad Singlet 5.15 (1H) Singlet 5.63 (2H) Singlet 7.46 ~8.2 (5H) Multiplet 8.58 (1H) Broad Singlet reference example 1 7β-cyanomethylthioacetamide-7α-methoxy-3-(1-methyl-1H-tetrazole-
5-yl)thiomethyl-3-cephem-4-carboxylic acid phenacyl ester (purity by HPLC)
Add 20 ml of acetone and 2 ml of water to 1.0 g of 88.7%) to dissolve, and cool to -30°C. Add 5.0ml of monoethyl sulfate and 1.0g of zinc powder to this and bring to -30°~
Stir at −25°C for 2.5 hours. Next, add 50 ml of water and 50 ml of ethyl acetate, shake well, and separate the ethyl acetate layer. The aqueous layer was extracted twice with 30 ml of ethyl acetate, combined with the previous ethyl acetate layer, washed with saturated brine, and the solvent was distilled off under reduced pressure, yielding 0.847 g of 7β-cyanomethylthioacetamide-7α-methoxy. -3
-(1-methyl-1H-tetrazol-5-yl)
Thiomethyl-3-cephem-4-carboxylic acid was obtained. (Purity by HPLC 73.7%) Purity conversion yield 88.0% nmr spectrum δppm (heavy acetone) 3.50 (singlet, 3H) 3.60 (singlet, 2H) 3.5 - 3.7 (quartet, 2H) 3.70 (singlet, 2H) ) 3.90 (singlet, 3H) 4.3 to 4.6 (quartet, 2H) 5.10 (singlet, 1H) Reference example 2 7β-Chloracetamide-7α-methoxy-3-
(1-Methyl-1H-tetrazol-5-yl)thiomethyl-3-cepheme-4-carboxylic acid phenacyl ester (purity 90.1% by HPLC) 1.0 g was dissolved with 20 ml of acetone and 1 ml of water. By reacting with monoethyl sulfuric acid and zinc powder and treating in the same manner as above, 0.857 g of 7β-chloroacetamide-7α-methoxy-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4- A carboxylic acid was obtained.
(Purity by HPLC 70.3%) Purity equivalent yield 85% nmr spectrum δppm (heavy acetone) 3.5 (singlet, 3H) 3.67 (singlet, 2H) 3.98 (singlet, 3H) 4.42 (broad singlet, 2H) 5.08 (single line, 1H)
Claims (1)
示し、R2は水素原子またはハロゲン原子を示し、
R3は1―メチル―1H―テトラゾール―5―イル
基を示す。)で表わされる化合物をハロゲン化炭
化水素溶媒中 一般式 R4X (式中、R4はクロロアセチル基またはシアノ
メチルチオアセチル基を示し、Xはハロゲン原子
を示す。)で表わされる化合物とを反応させるこ
とを特徴とする 一般式 (式中、R2,R3およびR4は前述したものと同
意義を有する。)で表わされるセフアマイシン誘
導体の製法。[Claims] 1. General formula (In the formula, R 1 represents a benzenesulfonylamino group, R 2 represents a hydrogen atom or a halogen atom,
R 3 represents a 1-methyl-1H-tetrazol-5-yl group. ) in a halogenated hydrocarbon solvent with a compound represented by the general formula R 4 A general formula characterized by A method for producing a cefamycin derivative represented by the formula (wherein R 2 , R 3 and R 4 have the same meanings as defined above).
Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP4485481A JPS57159789A (en) | 1981-03-27 | 1981-03-27 | Preparation of cephamycin derivative |
DK075582A DK162603C (en) | 1981-02-23 | 1982-02-22 | PROCEDURE FOR PREPARING BETA-LACTAM ANTIBIOTICA |
CH108282A CH646977A5 (en) | 1981-02-23 | 1982-02-22 | Process for the preparation of derivatives of beta-lactam antibiotics |
SE8201087A SE452620B (en) | 1981-02-23 | 1982-02-22 | PROCEDURE FOR THE PREPARATION OF BETA-LACTIC ANTIBIOTICS DERIVATIVES |
NL8200708A NL8200708A (en) | 1981-02-23 | 1982-02-23 | PROCESS FOR THE PREPARATION OF BETA-LACTAMANTIBIOTIC COMPOUNDS. |
ES509837A ES509837A0 (en) | 1981-02-23 | 1982-02-23 | A PROCEDURE TO PREPARE ANTIBIOTIC-LACTAMIC DERIVATIVES. |
CA000396796A CA1194470A (en) | 1981-02-23 | 1982-02-23 | PROCESS FOR PREPARING DERIVATIVES OF .beta.-LACTAM ANTI- BIOTICS |
IT67194/82A IT1157951B (en) | 1981-02-23 | 1982-02-23 | PROCEDURE FOR THE PREPARATION OF BETALACTAMIC ANTIBIOTICS |
FI820582A FI72521C (en) | 1981-02-23 | 1982-02-23 | Process for the preparation of cephalosporin derivatives. |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP4485481A JPS57159789A (en) | 1981-03-27 | 1981-03-27 | Preparation of cephamycin derivative |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS57159789A JPS57159789A (en) | 1982-10-01 |
JPH0158189B2 true JPH0158189B2 (en) | 1989-12-11 |
Family
ID=12703064
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP4485481A Granted JPS57159789A (en) | 1981-02-23 | 1981-03-27 | Preparation of cephamycin derivative |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS57159789A (en) |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5520723A (en) * | 1978-08-02 | 1980-02-14 | Nippon Kayaku Co Ltd | Preparation of cephalosporin compound |
-
1981
- 1981-03-27 JP JP4485481A patent/JPS57159789A/en active Granted
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5520723A (en) * | 1978-08-02 | 1980-02-14 | Nippon Kayaku Co Ltd | Preparation of cephalosporin compound |
Also Published As
Publication number | Publication date |
---|---|
JPS57159789A (en) | 1982-10-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP2005526049A (en) | Preparation of benzisoxazole methanesulfonyl chloride and its method of amidation to form zonisamide | |
JP2973143B2 (en) | Process for producing 3-acylamino-6-phenyloxy-7-alkylsulfonylamino-4H-1-benzopyran-4-one or a salt thereof | |
JPH0141152B2 (en) | ||
JPH0158189B2 (en) | ||
JP2826646B2 (en) | 3-substituted-5-halogenopyridine derivatives | |
JPH058200B2 (en) | ||
JPS6310707B2 (en) | ||
JP2957699B2 (en) | Method for producing 7α-alkoxycephem derivative | |
JPS6053039B2 (en) | N-Acetyl/Iramic acid derivative and method for producing the same | |
JP3059007B2 (en) | Method for producing 1- (2-carboxyphenyl) indazole derivative | |
JP2763214B2 (en) | Method for producing L-proline derivative | |
JPS6121638B2 (en) | ||
KR100241089B1 (en) | Novel process for preparation of 2-mercapto-4-methyl-1,3-thiazole-5-acetic acid | |
KR900003882B1 (en) | Process for the preparation of compounds with h2 antihistamine activity | |
EP0060301A1 (en) | Process for preparing cephalosporin compounds | |
JPH0812658A (en) | Production of sydnones | |
JPS6145639B2 (en) | ||
JPS6287599A (en) | Production of oxime derivative of erythromycin | |
KR820000785B1 (en) | Process for preparing 1-(tetrahydro-2-furanyl)-5-fluorouracil | |
JPH10287657A (en) | Production of radiosensitizer | |
JPS6213936B2 (en) | ||
JPS61172846A (en) | Method of optical resolution of (+-)-2-chloroprorionic acid | |
KR100238645B1 (en) | Novel esterification for cephalosporin derivative | |
CH617704A5 (en) | ||
JPH02233692A (en) | Novel n6,2'-o-disubstituted-adenosine-3',5'-cyclic phosphate and production thereof |