JPS6155905B2 - - Google Patents
Info
- Publication number
- JPS6155905B2 JPS6155905B2 JP58012560A JP1256083A JPS6155905B2 JP S6155905 B2 JPS6155905 B2 JP S6155905B2 JP 58012560 A JP58012560 A JP 58012560A JP 1256083 A JP1256083 A JP 1256083A JP S6155905 B2 JPS6155905 B2 JP S6155905B2
- Authority
- JP
- Japan
- Prior art keywords
- formula
- group
- ester
- ethyl
- hydrogen
- 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
- 150000001875 compounds Chemical class 0.000 claims description 14
- 150000002148 esters Chemical class 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 230000002140 halogenating effect Effects 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- -1 tertiary-butyl Chemical group 0.000 description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 229910052739 hydrogen Inorganic materials 0.000 description 8
- 239000001257 hydrogen Substances 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 238000001816 cooling Methods 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 125000005646 oximino group Chemical group 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- WDJHALXBUFZDSR-UHFFFAOYSA-N acetoacetic acid Chemical compound CC(=O)CC(O)=O WDJHALXBUFZDSR-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- YJEYUQKGTNBYRH-UHFFFAOYSA-N ethyl 2-ethoxyimino-3-oxobutanoate Chemical compound CCON=C(C(C)=O)C(=O)OCC YJEYUQKGTNBYRH-UHFFFAOYSA-N 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- NYBWUHOMYZZKOR-UHFFFAOYSA-N tes-adt Chemical class C1=C2C(C#C[Si](CC)(CC)CC)=C(C=C3C(SC=C3)=C3)C3=C(C#C[Si](CC)(CC)CC)C2=CC2=C1SC=C2 NYBWUHOMYZZKOR-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 125000006000 trichloroethyl group Chemical group 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/34—Oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/40—Unsubstituted amino or imino radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/44—Acylated amino or imino radicals
- C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
-
- 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
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Communicable Diseases (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Cephalosporin Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
【発明の詳細な説明】
本発明は、式
［式中、Ｘはハロゲン原子を、R5は保護された水
酸基を示す。］で表わされる化合物のエステル及
びその製造法に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the formula [In the formula, X represents a halogen atom and R 5 represents a protected hydroxyl group. This invention relates to an ester of a compound represented by the following formula and a method for producing the same.
本発明の化合物［XII］のエステルは、式
〔式中、R12は低級アルコキシ基または保護されて
いてもよいアミノ基を示す。〕で表わされる化合
物と反応させ、要すれば保護基を除去することに
より、式
〔式中、R13は水酸基または保護されていてもよい
アミノ基を、他は前記と同意義。〕で表わされる
化合物を製造するための有用な合成中間体であつ
て、得られる化合物〔XI〕は、たとえば式
〔式中、R3は水素またはメトキシ基を、R4は水素
または求核性化合物残基を示す。〕で表わされる
化合物と反応させ、要すれば保護基を除去して、
広くグラム陽性菌、陰性菌に対し高い抗菌力を示
す式
〔式中の記号は前記と同意義。〕で表わされる化合
物などを製造するのに有用である。 The ester of the compound [XII] of the present invention has the formula [In the formula, R 12 represents a lower alkoxy group or an optionally protected amino group. ] By reacting with a compound represented by the formula and removing the protecting group if necessary, the formula [In the formula, R 13 is a hydroxyl group or an optionally protected amino group, and the others are as defined above. ] is a useful synthetic intermediate for producing the compound represented by the formula, and the obtained compound [XI] is, for example, [In the formula, R 3 represents hydrogen or a methoxy group, and R 4 represents hydrogen or a nucleophilic compound residue. ], removing the protecting group if necessary,
A formula that shows high antibacterial activity against a wide range of Gram-positive and Gram-negative bacteria. [Symbols in the formula have the same meanings as above. It is useful for producing compounds represented by the following.
化合物〔XII〕において、R5は保護された水酸
基を示す。このような水酸基の保護基としては本
発明における各反応を阻害しない限りいかなるも
のでもよく通常メチル、エチルのような低級アル
キル基、フエニル、チエニルのようなアリール
基、アセチル、ベンゾイルのようなアシル基が用
いられる。化合物〔XII〕中、は塩素、臭素、ヨ
ウ素、フツ素などのハロゲンを示す。また、カル
ボキシル基は保護されている。このような保護基
としては、酸性条件、アルカリ性条件、還元条件
等の緩和な条件で除去しうるものなら何でもよ
く、たとえば一般にペプチド合成においてカルボ
キシル基の保護基として用いられるものから選択
され、たとえばメチル、エチル、プロピル、イソ
プロピル、ブチル、第２ブチル、イソブチル、第
３ブチルなどのアルキル基、β−メチルスルホニ
ルエチル、トリクロルエチル、ジフエニルメチル
などの置換アルキル基、フエニル、トリルなどの
アリール基、ｐ−第３ブチルフエニル、ｐ−ニト
ロフエニルなどの置換アリール基、ベンジル、フ
エネチル、トルベンジルなどのアラルキル基、ｐ
−メトキシベンジル、ｐ−ニトロベンジルなどの
置換アラルキル基などが用いられる。この化合物
〔XII〕は保護されたオキシイミノ基に関して理論
的にsyn−およびanti−の両異性体が存在し、両
者とも同様に有用な合成中間体として用いられ
る。 In compound [XII], R 5 represents a protected hydroxyl group. Any type of protecting group for the hydroxyl group may be used as long as it does not inhibit each reaction in the present invention. Usually, lower alkyl groups such as methyl and ethyl, aryl groups such as phenyl and thienyl, and acyl groups such as acetyl and benzoyl are used. is used. In compound [XII], represents a halogen such as chlorine, bromine, iodine, or fluorine. Furthermore, the carboxyl group is protected. Any protecting group may be used as long as it can be removed under mild conditions such as acidic conditions, alkaline conditions, and reducing conditions. , alkyl groups such as ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tertiary-butyl, substituted alkyl groups such as β-methylsulfonylethyl, trichloroethyl, diphenylmethyl, aryl groups such as phenyl, tolyl, Substituted aryl groups such as 3-butylphenyl and p-nitrophenyl, aralkyl groups such as benzyl, phenethyl, and tolbenzyl, p
Substituted aralkyl groups such as -methoxybenzyl and p-nitrobenzyl are used. This compound [XII] theoretically exists in both syn- and anti-isomers with respect to the protected oximino group, and both are equally useful as synthetic intermediates.
化合物〔XII〕のエステルは、対応するα位に保
護されたオキシイミノ基を有するβ−ケト酪酸の
エステルを常法に従つてハロゲン化することによ
つて得られる。 The ester of compound [XII] can be obtained by halogenating the corresponding ester of β-ketobutyric acid having a protected oximino group at the α-position according to a conventional method.
実施例 １
α−エトキシイミノ−β−ケト酪酸エチルエス
テル18.7ｇをクロロホルム100mlに溶解し、氷冷
下に臭素15.9ｇをクロロホルム20mlに溶解した液
を徐々に滴下する。30分間撹拌したのち、室温に
もどしてさらに1.5時間撹拌する。反応混合物を
水洗し、炭酸水素ナトリウム水溶液にて洗浄した
のち、さらに水洗し硫酸マグネシウムで乾燥す
る。で乾燥し、溶媒を留去してα−エトキシイミ
ノ−β−ケト−γ−ブロム酪酸エチルを得る。Example 1 18.7 g of α-ethoxyimino-β-ketobutyric acid ethyl ester is dissolved in 100 ml of chloroform, and a solution of 15.9 g of bromine dissolved in 20 ml of chloroform is gradually added dropwise under ice cooling. After stirring for 30 minutes, return to room temperature and stir for an additional 1.5 hours. The reaction mixture is washed with water, an aqueous sodium bicarbonate solution, further washed with water, and dried over magnesium sulfate. and evaporate the solvent to obtain ethyl α-ethoxyimino-β-keto-γ-bromobutyrate.
NMR（CDCl3）：δ1.20〜1.60（ｍ、6H、CH3
×２）、4.10〜4.60（ｍ、4H、CH2×２）、4.32
（ｓ、2H、BrCH2）
得られたものにエタノール250mlを加え、チオ
尿素15.2ｇを加えて２時間還流する。冷却したの
ち溶媒を減圧留去し、残留物に水250mlを加える
と固体が析出する。これを取し、水洗したのち
乾燥するとα−エトキシイミノ−２−アミノチア
ゾール−４−イル酢酸エチルエステル臭化水素酸
塩17.9ｇが得られる。収率55％。 NMR ( CDCl3 ): δ1.20-1.60 (m, 6H, CH3
×2), 4.10 to 4.60 (m, 4H, CH 2 ×2), 4.32
(s, 2H, BrCH 2 ) Add 250 ml of ethanol to the obtained mixture, add 15.2 g of thiourea, and reflux for 2 hours. After cooling, the solvent was distilled off under reduced pressure, and 250 ml of water was added to the residue to precipitate a solid. This is taken, washed with water, and then dried to obtain 17.9 g of α-ethoxyimino-2-aminothiazol-4-yl acetic acid ethyl ester hydrobromide. Yield 55%.
元素分析値 C9H14N3O3SBr
計算値：Ｃ 33.34；Ｈ 4.35；Ｎ 12.96
実測値：Ｃ 32.52；Ｈ 3.98；Ｎ 12.92
本品の核磁気共鳴スペクトル（100MHz、d6−
DMSO中）は1.30および1.32ppmに２種類のエチ
ル基メチル水素の三重線、4.28および4.37ppmに
２種類のエチル基メチレン水素の四重線、
7.63ppmにチアゾール５位水素の単線、9.12ppm
にアミノ基水素の巾広い単線共鳴線を示す。Elemental analysis value C 9 H 14 N 3 O 3 SBr Calculated value: C 33.34; H 4.35; N 12.96 Actual value: C 32.52; H 3.98; N 12.92 Nuclear magnetic resonance spectrum of this product (100MHz, d 6 -
(in DMSO) has two types of ethyl group methyl hydrogen triplet at 1.30 and 1.32 ppm, two types of ethyl group methylene hydrogen quartet at 4.28 and 4.37 ppm,
Single line of thiazole 5-position hydrogen at 7.63ppm, 9.12ppm
shows a broad single-line resonance line of amino group hydrogen.
実施例 ２
(1) α−メトキシイミノ−β−ケト酪酸エチル
27.3ｇをクロロホルム120mlに溶かし、これに
氷冷下臭素25.3ｇをクロロホルム30mlに溶かし
た液を30分間で滴下する。その後室温で１時間
撹拌し反応させる。反応物を希炭酸水素ナトリ
ウム水溶液、水で洗浄した後有機層を乾燥す
る。溶剤を留去して粗製のα−メトキシイミノ
−β−ケト−γ−ブロム酪酸エチルを油状物と
して得る。Example 2 (1) Ethyl α-methoxyimino-β-ketobutyrate
27.3 g was dissolved in 120 ml of chloroform, and a solution of 25.3 g of bromine dissolved in 30 ml of chloroform was added dropwise to this solution over 30 minutes under ice cooling. Thereafter, the mixture is stirred at room temperature for 1 hour to react. After washing the reaction product with a dilute aqueous sodium hydrogen carbonate solution and water, the organic layer is dried. The solvent is distilled off to obtain crude ethyl α-methoxyimino-β-keto-γ-bromobutyrate as an oil.
NMR（CDCl3）：δ1.30（ｔ、3H、CH3）、
4.12（ｓ、3H、OCH3）、4.32（ｓ、2H、
BrCH2）、4.33（ｑ、2H、CH2）
(2) 本品全量をエタノール250mlに溶かし、これ
にチオ尿素24ｇを加えて３時間加熱還流させ
る。冷後析出物を取しエタノールで洗浄す
る。得られた結晶状物質を酢酸エチル：テトラ
ヒドロフラン（１：１）混合物300mlに懸濁し
10％炭酸水素ナトリウム水溶液を200ml加えて
よくふり有機層を分取する。乾燥後溶剤を留去
して得られた結晶をエーテルで洗浄しα−メト
キシイミノ−α−（２−アミノチアゾール−４
−イル）酢酸エチルを得る。16.86ｇ。融点112
〜113℃。 NMR (CDCl 3 ): δ1.30 (t, 3H, CH 3 ),
4.12 (s, 3H, OCH 3 ), 4.32 (s, 2H,
BrCH 2 ), 4.33 (q, 2H, CH 2 ) (2) Dissolve the entire amount of this product in 250 ml of ethanol, add 24 g of thiourea, and heat under reflux for 3 hours. After cooling, remove the precipitate and wash with ethanol. The obtained crystalline material was suspended in 300 ml of a mixture of ethyl acetate and tetrahydrofuran (1:1).
Add 200 ml of 10% sodium bicarbonate aqueous solution, shake well, and separate the organic layer. After drying, the solvent was distilled off and the resulting crystals were washed with ether to give α-methoxyimino-α-(2-aminothiazole-4
-yl) ethyl acetate is obtained. 16.86g. Melting point 112
~113℃.
元素分析値 C8H11N3O3S
計算値：Ｃ 41.91；Ｈ 4.84
実測値：Ｃ 41.20；Ｈ 4.70
核磁気共鳴スペクトル（60MHz、CDCl3中）
は4.04ppmにメトキシ水素の単線、7.44ppmにチ
アゾール環５位水素の単線共鳴線を示す。Elemental analysis value C 8 H 11 N 3 O 3 S Calculated value: C 41.91; H 4.84 Actual value: C 41.20; H 4.70 Nuclear magnetic resonance spectrum (60 MHz, in CDCl 3 )
shows a single line of methoxy hydrogen at 4.04 ppm and a single line resonance line of hydrogen at the 5-position of the thiazole ring at 7.44 ppm.
Claims (1)
酸基を示す］で表わされる化合物のエステル。 ２ 式 ［式中、R5は保護された水酸基を示す］で表わさ
れる化合物のエステルをハロゲン化することを特
徴とする式 ［式中、Ｘはハロゲン原子を、R5は前記と同意義
を示す］で表わされる化合物のエステルの製造
法。[Claims] 1 formula An ester of a compound represented by the formula [wherein, X represents a halogen atom and R 5 represents a protected hydroxyl group]. 2 formulas A formula characterized by halogenating an ester of a compound represented by [wherein R 5 represents a protected hydroxyl group] A method for producing an ester of a compound represented by the formula [wherein, X represents a halogen atom and R 5 has the same meaning as defined above].
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB24611/75 | 1975-06-09 | ||
| GB24611/75A GB1536281A (en) | 1975-06-09 | 1975-06-09 | Cephem compounds |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP56087403A Division JPS5858353B2 (en) | 1975-06-09 | 1981-06-05 | Cefem or penam compound and its production method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS58185553A JPS58185553A (en) | 1983-10-29 |
| JPS6155905B2 true JPS6155905B2 (en) | 1986-11-29 |
Family
ID=10214399
Family Applications (5)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP51067524A Expired JPS5822039B2 (en) | 1975-06-09 | 1976-06-08 | Thiazole compound and its manufacturing method |
| JP56087403A Expired JPS5858353B2 (en) | 1975-06-09 | 1981-06-05 | Cefem or penam compound and its production method |
| JP58012560A Granted JPS58185553A (en) | 1975-06-09 | 1983-01-27 | Alpha-protected oxyimino-beta-keto-gamma-halogenobutyric acid |
| JP58178160A Pending JPS5989686A (en) | 1975-06-09 | 1983-09-28 | Cephem or penam compound |
| JP60232072A Granted JPS61143388A (en) | 1975-06-09 | 1985-10-16 | Cephem compound |
Family Applications Before (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP51067524A Expired JPS5822039B2 (en) | 1975-06-09 | 1976-06-08 | Thiazole compound and its manufacturing method |
| JP56087403A Expired JPS5858353B2 (en) | 1975-06-09 | 1981-06-05 | Cefem or penam compound and its production method |
Family Applications After (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP58178160A Pending JPS5989686A (en) | 1975-06-09 | 1983-09-28 | Cephem or penam compound |
| JP60232072A Granted JPS61143388A (en) | 1975-06-09 | 1985-10-16 | Cephem compound |
Country Status (7)
| Country | Link |
|---|---|
| JP (5) | JPS5822039B2 (en) |
| AT (2) | AT344894B (en) |
| GB (1) | GB1536281A (en) |
| HK (1) | HK2282A (en) |
| HU (1) | HU172304B (en) |
| MY (1) | MY8200219A (en) |
| SE (1) | SE444809B (en) |
Families Citing this family (37)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1536281A (en) * | 1975-06-09 | 1978-12-20 | Takeda Chemical Industries Ltd | Cephem compounds |
| DK154939C (en) * | 1974-12-19 | 1989-06-12 | Takeda Chemical Industries Ltd | METHOD OF ANALOGUE FOR THE PREPARATION OF THIAZOLYLACETAMIDO-CEPHEM COMPOUNDS OR PHARMACEUTICAL ACCEPTABLE SALTS OR ESTERS THEREOF |
| FR2346014A1 (en) * | 1976-01-23 | 1977-10-28 | Roussel Uclaf | Amino-thiazolyl-hydroxyimino-acetamido-cephalosporanic acids - with antibacterial activity |
| SE440655B (en) * | 1976-01-23 | 1985-08-12 | Roussel Uclaf | SET TO MAKE NEW OXIME DERIVATIVES OF 7-AMINO-THIAZOLYL-ACETAMIDO-CEPHALOSPORANIC ACID |
| GB1576625A (en) * | 1976-04-12 | 1980-10-08 | Fujisawa Pharmaceutical Co | Syn isomer 3,7 disubstituted 3 cephem 4 carboxylic acid compounds and processes for the preparation thereof |
| FI771866A (en) * | 1976-06-28 | 1977-12-29 | Fujisawa Pharmaceutical Co | |
| AU520269B2 (en) * | 1977-03-14 | 1982-01-21 | Fujisawa Pharmaceutical Co., Ltd. | Cephem and cepham compounds |
| PH17188A (en) * | 1977-03-14 | 1984-06-14 | Fujisawa Pharmaceutical Co | New cephem and cepham compounds and their pharmaceutical compositions and method of use |
| US4370326A (en) * | 1977-09-13 | 1983-01-25 | Fujisawa Pharmaceutical Co., Ltd. | Cephem compounds and composition |
| JPS5444695A (en) * | 1977-09-13 | 1979-04-09 | Fujisawa Pharmaceut Co Ltd | 3,7-disubstituted-3-cephem-4-carboxylic acid and its salt and their preparation |
| FR2410655A1 (en) * | 1977-12-05 | 1979-06-29 | Roussel Uclaf | NEW OXIMES DERIVED FROM 3-SUBSTITUTE 7-AMINO THIAZOLYL ACETAMIDO CEPHALOSPORANIC, THEIR METHOD OF PREPARATION AND THEIR APPLICATION AS MEDICINAL PRODUCTS |
| DE2758001A1 (en) * | 1977-12-24 | 1979-07-12 | Hoechst Ag | CEPHALOSPORINE DERIVATIVES AND METHOD FOR THEIR PRODUCTION |
| FR2387235A1 (en) * | 1978-01-23 | 1978-11-10 | Fujisawa Pharmaceutical Co | PROCESS FOR THE PREPARATION OF COMPOUNDS OF 3,7-DISUBSTITUE-3-CEPHEM-4-CARBOXYLIC ACID AND NEW PRODUCTS THUS OBTAINED, HAVING A STRONG ANTIBACTERIAL ACTIVITY |
| JPS54106495A (en) * | 1978-02-09 | 1979-08-21 | Dai Ichi Seiyaku Co Ltd | Cephem derivative |
| JPS54128594A (en) * | 1978-03-27 | 1979-10-05 | Fujisawa Pharmaceut Co Ltd | 3,7-disubstituted-3-cephem-4-carboxylic acid derivative |
| FR2432521A1 (en) * | 1978-03-31 | 1980-02-29 | Roussel Uclaf | NOVEL O-SUBSTITUTED OXIMES DERIVED FROM 7-AMINO THIAZOLYL ACETAMIDO CEPHALOSPORANIC ACID, THEIR PREPARATION PROCESS AND THEIR USE AS MEDICAMENTS |
| DE2818263A1 (en) * | 1978-04-26 | 1979-11-08 | Bayer Ag | BETA LACTAMANTIBIOTICS |
| US4703046A (en) * | 1978-09-08 | 1987-10-27 | Fujisawa Pharmaceutical Co., Ltd. | Cephem compounds and processes for preparation thereof |
| BE878637A (en) * | 1978-09-11 | 1980-03-06 | Fujisawa Pharmaceutical Co | PROCESS FOR THE PREPARATION OF 3,7-DISUBSTITUTED 3-CEPHEM-4-CARBOXYLIC ACID COMPOUNDS AND THEIR PHARMACEUTICALLY ACCEPTABLE SALTS, NOVEL PRODUCTS THUS OBTAINED AND THEIR USE FOR THEIR ANTIMICROBIAL ACTIVITIES |
| JPS5594354A (en) * | 1979-01-12 | 1980-07-17 | Fujisawa Pharmaceut Co Ltd | Syn-isomer of 2-substituted imino-3-oxo-4-halobutyric acid, its salt, and their preparation |
| JPS5543089A (en) * | 1978-09-12 | 1980-03-26 | Fujisawa Pharmaceut Co Ltd | Preparation of 3-cephem compound |
| US4409215A (en) * | 1979-11-19 | 1983-10-11 | Fujisawa Pharmaceutical Co., Ltd. | 7-Acylamino-3-substituted cephalosporanic acid derivatives and processes for the preparation thereof |
| JPS56125392A (en) * | 1980-03-06 | 1981-10-01 | Fujisawa Pharmaceut Co Ltd | Cepham and cephem compound and preparation thereof |
| JPS57154175A (en) * | 1981-03-16 | 1982-09-22 | Mitsui Toatsu Chem Inc | 2-thiazoleamine derivative, its preparation, and drug composition comprising it |
| US4457929A (en) * | 1982-03-29 | 1984-07-03 | Bristol-Myers Company | 3-Quaternary ammonium methyl)-substituted cephalosporin derivatives |
| JPS5910593A (en) | 1982-06-28 | 1984-01-20 | Bristol Mayers Kenkyusho Kk | Cephalosporin derivative |
| IE55406B1 (en) * | 1982-08-07 | 1990-09-12 | Tanabe Seiyaku Co | Novel cephalosporin compounds and preparation thereof |
| JPS6150973A (en) * | 1983-11-16 | 1986-03-13 | Fujisawa Pharmaceut Co Ltd | Substituted iminoacetic acid derivative and salt and preparation thereof |
| IT1180207B (en) * | 1984-07-30 | 1987-09-23 | Istituto Biochimico Italiano | PROCEDURE FOR THE PREPARATION, WITH HIGH YIELD AND PURITY, OF BETA-LACTAMIC ANTIBIOTICS |
| JPS60155167A (en) * | 1984-07-31 | 1985-08-15 | Fujisawa Pharmaceut Co Ltd | Substituted iminoacetic acid derivative and its salt |
| JPS61121746U (en) * | 1985-01-16 | 1986-07-31 | ||
| EP0210815A3 (en) * | 1985-07-25 | 1988-04-20 | Beecham Group Plc | 6-beta-(alpha-etherified oxyimino)-acylamino penicillanic-acid derivatives, their preparation and use |
| GB8519606D0 (en) * | 1985-08-05 | 1985-09-11 | Fujisawa Pharmaceutical Co | 3 7-d substituted-3-cephem compounds |
| EP0373216A4 (en) * | 1987-02-02 | 1992-08-12 | Teijin Limited | Cephalosporin compounds or their salts, process for their preparation, and parmaceutical compositions |
| EP0347459A4 (en) * | 1987-02-03 | 1990-04-10 | Teijin Ltd | Cephalosporin compounds or their salts, process for their preparation, and pharmaceutical compositions. |
| JPH02281051A (en) * | 1989-04-21 | 1990-11-16 | Toyo Tire & Rubber Co Ltd | Tread rubber composition for tire |
| JPH09110877A (en) | 1995-10-17 | 1997-04-28 | Katayama Seiyakushiyo:Kk | Cephem compound, its production and antibacterial agent containing the compound |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1536281A (en) * | 1975-06-09 | 1978-12-20 | Takeda Chemical Industries Ltd | Cephem compounds |
-
1975
- 1975-06-09 GB GB24611/75A patent/GB1536281A/en not_active Expired
- 1975-12-17 HU HU75TA00001381A patent/HU172304B/en unknown
- 1975-12-19 AT AT967775A patent/AT344894B/en not_active IP Right Cessation
-
1976
- 1976-06-08 JP JP51067524A patent/JPS5822039B2/en not_active Expired
-
1977
- 1977-07-18 AT AT517177A patent/AT347587B/en not_active IP Right Cessation
- 1977-11-23 SE SE7713233A patent/SE444809B/en not_active IP Right Cessation
-
1981
- 1981-06-05 JP JP56087403A patent/JPS5858353B2/en not_active Expired
-
1982
- 1982-01-14 HK HK22/82A patent/HK2282A/en unknown
- 1982-12-30 MY MY219/82A patent/MY8200219A/en unknown
-
1983
- 1983-01-27 JP JP58012560A patent/JPS58185553A/en active Granted
- 1983-09-28 JP JP58178160A patent/JPS5989686A/en active Pending
-
1985
- 1985-10-16 JP JP60232072A patent/JPS61143388A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| SE7713233L (en) | 1977-11-23 |
| JPS51149296A (en) | 1976-12-22 |
| HK2282A (en) | 1982-01-22 |
| ATA967775A (en) | 1977-12-15 |
| HU172304B (en) | 1978-07-28 |
| JPS5858353B2 (en) | 1983-12-24 |
| MY8200219A (en) | 1982-12-31 |
| AT344894B (en) | 1978-08-10 |
| JPH0346474B2 (en) | 1991-07-16 |
| GB1536281A (en) | 1978-12-20 |
| JPS5822039B2 (en) | 1983-05-06 |
| JPS5756485A (en) | 1982-04-05 |
| ATA517177A (en) | 1978-05-15 |
| JPS58185553A (en) | 1983-10-29 |
| AT347587B (en) | 1979-01-10 |
| JPS5989686A (en) | 1984-05-23 |
| JPS61143388A (en) | 1986-07-01 |
| SE444809B (en) | 1986-05-12 |
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