WO1992007840A1 - Derive de thioester de thiazole - Google Patents

Derive de thioester de thiazole Download PDF

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Publication number
WO1992007840A1
WO1992007840A1 PCT/JP1991/001482 JP9101482W WO9207840A1 WO 1992007840 A1 WO1992007840 A1 WO 1992007840A1 JP 9101482 W JP9101482 W JP 9101482W WO 9207840 A1 WO9207840 A1 WO 9207840A1
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WO
WIPO (PCT)
Prior art keywords
formula
compound
protecting group
acid
group
Prior art date
Application number
PCT/JP1991/001482
Other languages
English (en)
Japanese (ja)
Inventor
Takeo Kobori
Rumi Yamamoto
Mikako Fujita
Tamejiro Hiyama
Takatoshi Nagate
Original Assignee
Taisho Pharmaceutical Co., Ltd.
Sagami Chemical Research Center
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Taisho Pharmaceutical Co., Ltd., Sagami Chemical Research Center filed Critical Taisho Pharmaceutical Co., Ltd.
Publication of WO1992007840A1 publication Critical patent/WO1992007840A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles 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 in position 2
    • C07D277/70—Sulfur atoms
    • C07D277/74—Sulfur atoms substituted by carbon atoms
    • 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

Definitions

  • the present invention relates to a novel thiazole thioester derivative, and more particularly, to a (Z) 1-2- (2-aminothiazole-14-yl) 1 having excellent antibacterial activity against Gram-positive bacteria and Gram-negative bacteria.
  • a method for producing a cephalosporin derivative having a [1-2-hydroxyiminoacetamide] group is known [R. Bucourt et. Al., Tetrahedron, 1978, 34, 2233; JP-A-56-21600; JP-A-2'-73090]. ,
  • Ph represents a phenyl group
  • the above-mentioned method is not suitable for the production of a cefm compound using a compound of the formula (1), (2) or (3), which is expensive as a condensing agent for 1-hydroxybenzotriazole and dicyclohexylcarbodiyl.
  • This method is not preferable as a production method on an industrial scale in that a medium or the like must be used.
  • the thiazole thioester compound represented by the formula (I) provided by the present invention can be produced at a very low cost, and has excellent antibacterial activity against Gram-positive bacteria and Gram-negative bacteria.
  • (Z) — 2- (2-Aminothiazol-4-yl) cephalosporin derivative having a 2-hydroxyiminoacetamide group at the 7-position (for example, JP-A-58-184036, (See JP-A-62-492 and JP-A-2-22283) are found to be extremely useful as production intermediates.
  • JP-A-58-184036 See JP-A-62-492 and JP-A-2-22283
  • the ⁇ hydroxy protecting group '' which can be represented by is any hydroxy protecting group which can be easily removed by a deprotecting group reaction such as hydrolysis or hydrogenolysis using an acid or a base as a catalyst. it can, for example, trityl, (p-Anishiru) Jifuenirumechiru such as Ariru substituted methylol 0 Le group;.
  • hydroxy protecting groups preferred are (p-anisyl), diphenylmethyl, t-butoxymethyl, tetrahydroviranyl, (1-methyl-1-methoxy) ethyl, and the like. Is preferred o
  • reaction formula A The thiazole thioester compound of the formula (I) of the present invention can be produced, for example, by the method shown in the following reaction formula A. Reaction formula A
  • R 2 represents a carboxy protecting group
  • three Xs each independently represent an aryl group or an alkoxy group
  • three Ys each independently represent an alkyl group. Or two of them, Y, together with the N atom to which they are attached, may further contain a heteroatom such as N, S, O, etc.
  • a 5- or 6-membered nitrogen-containing heterocyclic group Preferably a 5- or 6-membered nitrogen-containing heterocyclic group).
  • a “carboxy protecting group” represented by R 2 is any carboxy protecting group that can be easily removed by a deprotecting reaction such as hydrolysis using an acid or base as a catalyst, for example, methyl, ethyl, propyl And tert-butyl and the like; and substituted or unsubstituted aralkyl groups such as p-ditrophenylmethyl and diphenylmethyl.
  • the phosphorus compound represented by X 3 P includes a phosphine compound and a phosphorous acid compound, and specifically includes triarylphosphines such as triphenylphosphine; trimethyl phosphate, triethyl phosphite, and the like. And the like.
  • tertiary amine compounds represented by Y 3 N include, for example, N-alkyl-substituted nitrogen-containing heterocyclic compounds such as N-methylmorpholine, N-methylpyridine and N-methylpyrrolidine; triethylamine, ⁇ , ⁇ — Trialkylamines such as disopropylethylamine, and the like.
  • the protecting group is added to the hydroxyimino group of the compound of the formula ( ⁇ ) as a raw material.
  • reagents for introducing a protecting group include aryl-substituted methyl chlorides such as trityl chloride and (P-anisyl) diphenylmethyl chloride; methoxymethyl chloride, and t-butoxymethyl chloride.
  • the reaction can be carried out in the presence of a base such as pyridine or triethylamine, or an acid such as benzenesulfonic acid or ⁇ -toluenesulfonic acid, if necessary.
  • a base such as pyridine or triethylamine
  • an acid such as benzenesulfonic acid or ⁇ -toluenesulfonic acid
  • a solvent for the reaction for example, a solvent that does not participate in the reaction, such as tetrahydrofuran, ethyl acetate, dichloromethylene, and N, N-dimethylformamide can be used.
  • the reaction temperature is not particularly limited, but usually room temperature is used.
  • the compound of the formula (W) is produced by reacting the compound of the formula (m) obtained in the step (A) with thiourea.
  • the reaction of the compound of formula (m) with thiourea is usually preferably carried out in a mixed solvent of water such as tetrahydrofuran, ethanol, N, N-dimethylformamide and the like. It can range from about 0 to about 70 ° C, preferably from about 10 to about 40 ° C.
  • the amount of thiourea used is not strictly limited, but is generally in the range of 1 to 10 mol, especially 1 to 2 mol, per mol of the compound of the formula (ffl).
  • This step (C) is a step of hydrolyzing the compound of the formula (IV) obtained in the above step (B) to obtain a free carboxylic acid of the formula (V).
  • the hydrolysis reaction of the compound of the formula (IV) can be performed in the presence of a base according to a conventional method. Suitable bases that can be used include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate and the like.
  • the reaction is preferably performed using a solvent.
  • a mixed solvent of tetrahydrofuran, dioxane, ethanol, methanol, or the like and water can be used.
  • the reaction temperature can usually be in the range of about 0 to about 200 ° C, preferably about 80 to about 120 ° C.
  • the amount of dithiobenzothiazole used is not particularly limited.
  • the compound (V) can be used in an amount of 1 to 10 mol, preferably 1 to 1.5 mol, per 1 mol of the compound.
  • the phosphorus compound and the tertiary amine compound are each in an amount of about 1 to about 1.5 mol per 1 mol of the compound of the formula (V).
  • the reaction is generally carried out in a solvent inert to the reaction, such as acetonitrile, acetone, tetrahydrofuran, and dichloromethane, at a temperature in the range of about -20 to about 100 ° C, preferably about 0 to about 60 ° C. Can be.
  • a solvent inert such as acetonitrile, acetone, tetrahydrofuran, and dichloromethane
  • the compound of formula (1-1) thus formed is separated and purified from the reaction mixture after completion of the reaction by a method known in the art, for example, crystallization, filtration, washing, drying, etc. can do.
  • the compound of the formula (I-11) may be further converted to a compound of the formula (I) in which R, is a hydrogen atom by removing the hydroxy protecting group (Rn), if necessary. can do.
  • the removal of the hydroxy protecting group can be performed by selecting deprotection reaction conditions known per se according to the type of the protecting group. For example, when the hydroxy protecting group is trityl, tetrahydroviranyl, (p-disyl) diphenylmethyl, 2,4-dimethoxybenzyl, etc., for example, hydrochloric acid, sulfuric acid, phosphoric acid, etc.
  • the acid can be used usually in a catalytic amount or a large excess, and the reaction temperature is in the range of about 120 ° C to about 80 ° C, especially about 0 ° C to about 60 ° C. can do.
  • the thiazole thioester compound of the formula (1-1) provided by the present invention is useful as an intermediate for producing a cephalosporin derivative having antibacterial activity.
  • the compound of the formula (I-11) of the present invention is
  • R 3 represents a hydrogen atom or a carboxy protecting group
  • R 4 represents a hydrogen atom or a 3-position substituent commonly found in cephalosporin compounds, and reacted with a 7-aminocephem compound represented by the following formula:
  • R 3 and R 4 are as defined above,
  • the reaction between the compound of the formula (I-11) and the compound of the formula (VI) according to the present invention is inactive in the reaction of, for example, acetone, tetrahydrofuran, ethyl acetate, dichloromethylene, N, N-dimethylformamide and the like.
  • a suitable solvent it can be carried out usually at a temperature in the range of about 150 to about 100 ° C, especially about 15 to about 60 ° C.
  • the removal of the hydroxy protecting group (R u) from the resulting compound of the formula ( ⁇ ) can be carried out by selecting the deprotecting group reaction conditions known per se according to the type of the protecting group. For example, when the hydroxy protecting group is trityl, tetrahydroviranyl, (p-anisyl) diphenylmethyl, 2,4-dimethylbenzyl, etc., these protecting groups can be removed by hydrolysis using an acid. it can.
  • Suitable acids that can be used for this hydrolysis include, for example, inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid; trifluoroacetic acid, formic acid, acetic acid, propionic acid, benzenesulfonic acid, P-toluenesulfonic acid, methanesulfonic acid Organic acids such as acids can be mentioned. Usually, the acid It can be used in a medium amount or a large excess amount.
  • the reaction temperature is usually preferably in the range of about 120 ° C. to about 8 ° C., especially about 0 ° C. to about 60 ° C.
  • the reaction time can be generally about 0.5 to 24 hours.
  • alcohols such as methanol and ethanol; ethers such as dioxane and tetrahydrofuran; ketones such as acetone; nitriles such as acetonitrile; or a mixed solvent of these solvents and water can be used.
  • ethers such as dioxane and tetrahydrofuran
  • ketones such as acetone
  • nitriles such as acetonitrile
  • a mixed solvent of these solvents and water can be used.
  • a large excess of acid may be used as a solvent.
  • the resulting cephalosporin derivative is obtained by removing unreacted raw materials, by-products, solvents, etc. from the reaction mixture by a conventional method (extraction, evaporation, washing, concentration, precipitation, filtration, drying, etc.) It can be isolated by treating it by a processing method (adsorption, elution, distillation, precipitation, precipitation, chromatography, etc.).
  • the reaction proceeds under neutral conditions, and as a result, the desired cephalosporin derivative can be obtained with high purity and high yield.
  • IR (KB r, dis c., Cm " 1 ) 3450, 3250, 3100, 2980, 1730, 1610, 1530, 1440, 1370, 1260, 1230, 1170, 1030, 960, 765,
  • I R (KB r, d i s c., Cm-ri 3450, 3060, 1710, 1610, 1540, 1440, 1370, 1310, 1205, 1050, 980, 915, 900, 860, 760, 700
  • I R (KB r, d i s c., Cm-3330, 2980, 1870, 1750, 1710, 1660, 1520, 1360, 1220, 1120, 980, 800
  • the compound provided by the present invention exhibits excellent antibacterial activity against Gram-positive bacteria and Gram-negative bacteria.
  • the desired cephalosporin derivative can be obtained with high purity and high yield.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Cephalosporin Compounds (AREA)

Abstract

L'invention se rapporte à un composé représenté par la formule générale (I), qui sert d'intermédiaire dans la production de dérivés de céphalosporine à substitution (Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacétamide, qui possèdent une excellente action anti-bactérienne. Dans la formule (I), R1 représente hydrogène ou un groupe protecteur hydroxyle.
PCT/JP1991/001482 1990-11-02 1991-10-30 Derive de thioester de thiazole WO1992007840A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2/298661 1990-11-02
JP29866190 1990-11-02

Publications (1)

Publication Number Publication Date
WO1992007840A1 true WO1992007840A1 (fr) 1992-05-14

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0555769A2 (fr) * 1992-02-14 1993-08-18 Hoechst Aktiengesellschaft Procédé pour la préparation d'esters de céphem, utilisés comme Prodrug
WO1996020198A1 (fr) * 1994-12-23 1996-07-04 Biochemie Gesellschaft Mbh Production de cefotaxime et de nouveaux sels de sodium
WO2003040116A1 (fr) * 2001-11-09 2003-05-15 Antibioticos S.P.A. Procede de preparation de chaines laterales de cephalosporines
JP2006511561A (ja) * 2002-12-20 2006-04-06 アンティビオーティコス エッセ．ピ．ア． 結晶性セフジニル塩
JP2012246291A (ja) * 2011-05-30 2012-12-13 Bcworld Pharm Co Ltd イマチニブ塩基を調製する新規な方法
CN106749333A (zh) * 2016-12-29 2017-05-31 江苏豪森药业集团有限公司 头孢地尼的制备方法
CN108546270A (zh) * 2017-05-31 2018-09-18 郑州大学第附属医院 制备头孢地尼的方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0075095A2 (fr) * 1981-09-23 1983-03-30 F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft Dérivés de céphalosporine, procédé pour leur préparation, compositions pharmaceutiques les contenant et intermédiaires
EP0075104A2 (fr) * 1981-09-23 1983-03-30 F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft Dérivés de céphalosporine, procédé pour leur préparation, compositions pharmaceutiques et intermédiaires
EP0096297A2 (fr) * 1982-06-03 1983-12-21 F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft Procédé de préparation de dérivés de 1-sulfo-2-oxoazétidine
EP0185220A2 (fr) * 1984-12-19 1986-06-25 F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft Intermédiaires pour la préparation de céphalosporines
EP0185221A2 (fr) * 1984-12-19 1986-06-25 F. Hoffmann-La Roche Ag Procédé pour la préparation de dérivés d'aminothiazolylacide acétique

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0075095A2 (fr) * 1981-09-23 1983-03-30 F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft Dérivés de céphalosporine, procédé pour leur préparation, compositions pharmaceutiques les contenant et intermédiaires
EP0075104A2 (fr) * 1981-09-23 1983-03-30 F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft Dérivés de céphalosporine, procédé pour leur préparation, compositions pharmaceutiques et intermédiaires
EP0096297A2 (fr) * 1982-06-03 1983-12-21 F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft Procédé de préparation de dérivés de 1-sulfo-2-oxoazétidine
EP0185220A2 (fr) * 1984-12-19 1986-06-25 F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft Intermédiaires pour la préparation de céphalosporines
EP0185221A2 (fr) * 1984-12-19 1986-06-25 F. Hoffmann-La Roche Ag Procédé pour la préparation de dérivés d'aminothiazolylacide acétique

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5637721A (en) * 1992-02-14 1997-06-10 Hoechst Aktiengesellschaft Process for the preparation of cephem prodrug esters
EP0555769A3 (en) * 1992-02-14 1993-11-24 Hoechst Ag Process for the preparation of cephem-prodrug-esters
EP0555769A2 (fr) * 1992-02-14 1993-08-18 Hoechst Aktiengesellschaft Procédé pour la préparation d'esters de céphem, utilisés comme Prodrug
US5589594A (en) * 1992-02-14 1996-12-31 Hoechst Aktiengesellschaft Process for the preparation of cephem prodrug esters
AU711228B2 (en) * 1994-12-23 1999-10-07 Biochemie Gesellschaft Mbh Production of cefotaxime and new sodium salts
US5831086A (en) * 1994-12-23 1998-11-03 Biochemie Gesellschaft M.B.H. Production of cefotaxime and new sodium salts
WO1996020198A1 (fr) * 1994-12-23 1996-07-04 Biochemie Gesellschaft Mbh Production de cefotaxime et de nouveaux sels de sodium
WO2003040116A1 (fr) * 2001-11-09 2003-05-15 Antibioticos S.P.A. Procede de preparation de chaines laterales de cephalosporines
CN1309713C (zh) * 2001-11-09 2007-04-11 安蒂比奥蒂科斯有限公司 制备头孢菌素侧链的方法
JP2006511561A (ja) * 2002-12-20 2006-04-06 アンティビオーティコス エッセ．ピ．ア． 結晶性セフジニル塩
JP2012246291A (ja) * 2011-05-30 2012-12-13 Bcworld Pharm Co Ltd イマチニブ塩基を調製する新規な方法
CN106749333A (zh) * 2016-12-29 2017-05-31 江苏豪森药业集团有限公司 头孢地尼的制备方法
CN106749333B (zh) * 2016-12-29 2019-05-14 江苏豪森药业集团有限公司 头孢地尼的制备方法
CN108546270A (zh) * 2017-05-31 2018-09-18 郑州大学第附属医院 制备头孢地尼的方法

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