JPH05345786A - Production of hydroxycephamcarboxylic acid ester - Google Patents
Production of hydroxycephamcarboxylic acid esterInfo
- Publication number
- JPH05345786A JPH05345786A JP3936093A JP3936093A JPH05345786A JP H05345786 A JPH05345786 A JP H05345786A JP 3936093 A JP3936093 A JP 3936093A JP 3936093 A JP3936093 A JP 3936093A JP H05345786 A JPH05345786 A JP H05345786A
- Authority
- JP
- Japan
- Prior art keywords
- carboxylic acid
- equivalents
- ester
- water
- parts
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Cephalosporin Compounds (AREA)
Abstract
Description
【０００１】[0001]
【発明の目的】この発明は３−ヒドロキシセフアム−４
−カルボン酸アラルキルエステルから３ーセフエムー４
ーカルボン酸アラルキルエステルを製造する方法の改良
法に関する。OBJECT OF THE INVENTION The present invention is 3-hydroxycepham-4.
-Carboxylic acid aralkyl ester to 3-Scheme 4
-It relates to an improved method for producing a carboxylic acid aralkyl ester.
【０００２】[0002]
【発明の構成】この発明の方法は３−ヒドロキシ基の
脱離、３ーヒドロキシをアシル化する反応、３−ア
シル化物７−アミドの脱アシル化、３−アシルオキシ
基の脱離などとその組合わせからなる。BEST MODE FOR CARRYING OUT THE INVENTION The method of the present invention comprises elimination of 3-hydroxy group, reaction of acylating 3-hydroxy, deacylation of 3-acylated 7-amide, elimination of 3-acyloxy group and combinations thereof. Consists of.
【０００３】Ｉ．ヒドロキシ基の脱離反応 ７−アミド−３ξ−ヒドロキシセフアム−４−カルボン
酸アラルキルエステルは非プロトン性有機溶媒５〜２０
容量部中、１〜３当量の（アルカンまたはアリ−ル）ス
ルホニルハライドとトリアルキルアミン１〜１０当量な
どの脱離反応剤の存在下＋３０℃〜−６０℃で反応させ
ると５時間以内に目的とする３−セフエム化合物を７０
〜９０％の収率で与える。I. Elimination reaction of hydroxy group 7-amido-3ξ-hydroxycepham-4-carboxylic acid aralkyl ester is an aprotic organic solvent 5 to 20.
In a volume part, 1 to 3 equivalents of (alkane or aryl) sulfonyl halide and 1 to 10 equivalents of trialkylamine in the presence of a elimination reaction agent are reacted at + 30 ° C to -60 ° C for 5 hours or less. 3-Chem compound to 70
Giving in ~ 90% yield.
【０００４】ＩＩ．３ーＯーアシル化反応 また、前記ＩＩの反応は原料である７−アミド−３ξ−
ヒドロキシセフアム−４−カルボン酸アラルキルエステ
ルの３ーヒドロキシ基をアシル化した７−アミド−３ξ
−アシルオキシセフアム−４−カルボン酸アラルキルエ
ステルを用いることもできる。この反応は常法により実
施できる。酸捕捉剤にトリアルキルアミンを利用する
と、アシルオキシ基の脱離反応が併発するので、ピリジ
ンなどの芳香族塩基の方が適当である。II. 3-O-acylation reaction Further, the reaction of the above II is 7-amide-3ξ- which is a raw material.
Hydroxycepham-4-carboxylic acid aralkyl ester acylated 7-amide-3ξ of 3-hydroxy group
It is also possible to use -acyloxycephum-4-carboxylic acid aralkyl esters. This reaction can be carried out by a conventional method. When a trialkylamine is used as the acid scavenger, the elimination reaction of the acyloxy group occurs simultaneously, so an aromatic base such as pyridine is more suitable.
【０００５】ＩＩＩ．７ー脱アミド化反応 ７−アミド−３ξ−ヒドロキシセフアム−４−カルボン
酸アラルキルエステルまたは７−アミド−３ξ−アシル
オキシセフアム−４−カルボン酸アラルキルエステルは
五塩化リンー芳香族塩基と反応させてイミノクロリドと
し、これをアルコ−ルと反応させてイミノエ−テルとし
たのち酸と反応させる方法など常法による酸性条件下の
アミドリシスにより新規化合物である７−アミノ−３ξ
−（ヒドロキシまたは保護ヒドロキシ）セフアム−４−
カルボン酸アラルキルエステルとすることもできる。こ
の段階では反応液には３−セフエム−４−カルボキシレ
−トに起因する２６０nmの吸収は認められない。III. 7-Deamidation Reaction 7-amide-3ξ-hydroxycepham-4-carboxylic acid aralkyl ester or 7-amide-3ξ-acyloxycepham-4-carboxylic acid aralkyl ester is reacted with phosphorus pentachloride-aromatic base. A new compound, 7-amino-3ξ, is obtained by amide lysis under acidic conditions according to a conventional method such as imino chloride, which is reacted with alcohol to form imino ether and then reacted with acid.
-(Hydroxy or protected hydroxy) cepham-4-
It can also be a carboxylic acid aralkyl ester. At this stage, no absorption at 260 nm due to 3-CEM-4-carboxylate was observed in the reaction solution.
【０００６】ＩＶ．３ー脱アシルオキシ化反応 ７−アミド−３ξ−アシルオキシセフアム−４−カルボ
ン酸アラルキルエステルは常法によりトリアルキルアミ
ンなどの酸捕捉剤を作用させればアシルオキシ基の脱離
反応が起きる。IV. 3-Deacyloxylation reaction 7-amido-3ξ-acyloxycepham-4-carboxylic acid aralkyl ester undergoes an acyloxy group elimination reaction when an acid scavenger such as trialkylamine is allowed to act by a conventional method.
【０００７】Ｖ．反応条件 各反応は特に指定した場合を除き、通常−８０℃〜＋３
０℃（とくに−５０℃〜−３０℃）の温度で１０分間〜
１０時間かけて反応させることができる。これらは溶媒
中、好ましくは撹拌ないし無水条件下に実施する。その
他の常法は、いずれも適用できる。V. Reaction conditions Unless otherwise specified, each reaction is usually −80 ° C. to +3.
At a temperature of 0 ° C (especially -50 ° C to -30 ° C) for 10 minutes
It is possible to react for 10 hours. These are carried out in a solvent, preferably under stirring or anhydrous conditions. Any other conventional method can be applied.
【０００８】反応用溶媒としては、炭化水素（ペンタ
ン、ヘキサン、オクタン、ベンゼン、トルエン、キシレ
ンなど）、ハロゲン化炭化水素（ジクロロメタン、クロ
ロホルム、四塩化炭素、ジクロロエタン、トリクロロエ
タン、クロロベンゼンなど）、エ−テル（ジエチルエ−
テル、メチルイソブチルエ−テル、アニソ−ル、ジオキ
サン、テトラヒドロフランなど）、エステル（酢酸エチ
ル、酢酸イソブチル、安息香酸メチルなど）、ニトリル
（アセトニトリル、ベンゾニトリルなど）、アミド（ホ
ルムアミド、アセトアミド、ジメチルホルムアミド、ジ
メチルアセトアミド、ヘキサメチルホスホロトリアミド
など）、カルボン酸（ギ酸、酢酸、プロピオン酸な
ど）、有機塩基（ジエチルアミン、トリエチルアミン、
ピリジン、ピコリン、コリジン、キノリンなど）、アル
コ−ル（メタノ−ル、エタノ−ル、プロパノ−ル、ヘキ
サノ−ル、オクタノ−ル、ベンジルアルコ−ルなど）、
その他の系列に属する工業用溶媒またはその混合物を採
用できる。The reaction solvent includes hydrocarbons (pentane, hexane, octane, benzene, toluene, xylene, etc.), halogenated hydrocarbons (dichloromethane, chloroform, carbon tetrachloride, dichloroethane, trichloroethane, chlorobenzene, etc.), ether. (Diethyl ether
Ter, methyl isobutyl ether, anisole, dioxane, tetrahydrofuran, etc.), ester (ethyl acetate, isobutyl acetate, methyl benzoate, etc.), nitrile (acetonitrile, benzonitrile, etc.), amide (formamide, acetamide, dimethylformamide, etc.) Dimethylacetamide, hexamethylphosphorotriamide, etc.), carboxylic acids (formic acid, acetic acid, propionic acid, etc.), organic bases (diethylamine, triethylamine,
Pyridine, picoline, collidine, quinoline, etc.), alcohols (methanol, ethanol, propanol, hexanole, octanole, benzyl alcohol, etc.),
Industrial solvents belonging to other series or mixtures thereof can be adopted.
【０００９】目的とする各生成物は反応液から未反応原
料、副生成物、溶媒などの夾雑物を抽出、蒸発、洗浄、
濃縮、沈殿、ロ過、乾燥などの常法により除去したの
ち、吸着、溶離、蒸留、沈殿、析出、クロマトグラフイ
−など、常用の後処理法を組み合わせて処理すれば単離
することができる。Each target product is obtained by extracting, evaporating and washing impurities such as unreacted raw materials, by-products and solvents from the reaction solution.
After removal by a conventional method such as concentration, precipitation, filtration, and drying, it can be isolated by a combination of conventional post-treatment methods such as adsorption, elution, distillation, precipitation, precipitation, and chromatography. ..
【００１０】[0010]
【効果】７−アミノ−３ξ−（ヒドロキシまたは保護ヒ
ドロキシ）セフアム−４−カルボン酸アラルキルエステ
ルにカルボン酸の反応性誘導体、例えば塩化物または無
水物を作用させてアミド化すれば７−アミド−３ξ−
（ヒドロキシまたは保護ヒドロキシ）セフアム−４−カ
ルボン酸アラルキルエステルを得る。これも前記のよう
な脱離反応により二重結合を導入すれば、対応する７−
アミド−３ー非置換ー３−セフエム−４−カルボン酸ア
ラルキルエステルとなる。このようにして製造できる３
ξ−ヒドロキシセフアム−４−カルボン酸エステルは各
種３−非置換セフアロスポリンの合成中間体である。こ
れらの化合物のアラルキルエステルにルイス酸などとカ
チオン捕捉剤を用いる特開昭５２−１０６８９１の方法
などを適用して脱エステル化してカルボン酸とすれば、
すぐれた抗菌性を有するセフアロスポリン剤を製造でき
る。[Effect] 7-amido-3ξ is obtained by reacting 7-amino-3ξ- (hydroxy or protected hydroxy) cepham-4-carboxylic acid aralkyl ester with a reactive derivative of carboxylic acid such as chloride or anhydride to amidate. −
(Hydroxy or protected hydroxy) cepham-4-carboxylic acid aralkyl ester is obtained. If a double bond is introduced by the elimination reaction as described above, the corresponding 7-
It becomes an amide-3-unsubstituted-3-cem-4-carboxylic acid aralkyl ester. Can be manufactured in this way 3
ξ-Hydroxycepham-4-carboxylic acid ester is a synthetic intermediate for various 3-unsubstituted cephalosporins. When the aralkyl ester of these compounds is deesterified to a carboxylic acid by applying the method of JP-A-52-106891 using a Lewis acid and a cation trapping agent,
A cefalosporin agent having excellent antibacterial properties can be produced.
【００１１】[0011]
【実施例】以下に実施例により本発明の態様を説明す
る。試薬の量はベータラクタム原料に対する部（重量
部）と当量（モル当量）で表わす。濃縮は減圧下に行な
い、溶液の乾燥には硫酸ナトリウムを用いる。脱アシル
オキシ化に際しては、反応開始前に反応系を湿ったｐＨ
試験紙によりチェックし、ｐＨ９になるまでトリエチル
アミンを加えた。使用した略号は、以下の通りである。 BOC ＝ｔ−ブトキシカルボニル。 Bz ＝ベンジ
ル。 Bu-t ＝ｔ−ブチル。 Cbz ＝カルボベンゾキシ。
Ph ＝フエニル。EXAMPLES The embodiments of the present invention will be described below with reference to examples. The amount of the reagent is expressed in parts (parts by weight) and equivalents (molar equivalents) relative to the beta-lactam raw material. Concentration is performed under reduced pressure, and sodium sulfate is used to dry the solution. Before deacyloxylation, wet the reaction system before starting the reaction.
Check with test paper and add triethylamine until pH = 9. The abbreviations used are as follows. BOC = t-butoxycarbonyl. Bz = benzyl. Bu-t = t-butyl. Cbz = carbobenzoxy.
Ph = phenyl.
【００１２】実施例１ （３−ヒドロキシの脱離反応）Example 1 (elimination reaction of 3-hydroxy)
【化１】 1) ３ξ−ヒドロキシ−７β−フエニルアセチルアミノ
セフアム−４ξ−カルボン酸ジフエニルメチルエステル
をジクロロメタン１３部に懸濁し、Ｎ2下−１０℃に
冷却してトリエチルアミン４当量を加へ、次いでメタン
スルホン酸クロリド２．０当量を−１０℃で７分間を要
して加える。生成するメタンスルフオン酸エステルを
−１０℃近辺で３０分間反応後塩化メチレン２０部を加
える。反応液を、水、５％硫酸と水で洗い、硫酸ナトリ
ウムで乾燥し、濃縮する。残渣にメタノ−ル４部を加え
て結晶化させると７β−フエニルアセチルアミノ−３−
セフエム−４−カルボン酸ジフエニルエステルを得
る。収率：７５．４％。[Chemical 1] 1) 3ξ-Hydroxy-7β-phenylacetylaminocepham-4ξ-carboxylic acid diphenylmethyl ester was suspended in 13 parts of dichloromethane, cooled to −10 ° C. under N 2 and added with 4 equivalents of triethylamine, and then methane. Add 2.0 equivalents of sulfonic acid chloride over 7 minutes at -10 ° C. After reacting the produced methanesulphonic acid ester at around -10 ° C for 30 minutes, 20 parts of methylene chloride is added. The reaction solution is washed with water, 5% sulfuric acid and water, dried over sodium sulfate and concentrated. When 4 parts of methanol was added to the residue for crystallization, 7β-phenylacetylamino-3-
Cefem-4-carboxylic acid diphenyl ester is obtained. Yield: 75.4%.
【００１３】2) ３ξ−ヒドロキシ−７β−フエニルア
セチルアミノセフアム−４ξ−カルボン酸ジフエニルメ
チルエステルをジメチルホルムアミド（モレキユラ−
シ−ブ乾燥品）９．５部に溶解、Ｎ2下−５０℃に冷却
し、トリエチルアミン４当量を注加、次いでメタンスル
ホン酸クロリド２当量を−５２〜−４５℃で３分間を要
して滴下し、−５５〜−４５℃で２．５時間反応してメ
タンスルホン酸エステルを生成させ、次いで−１５〜
−１２℃で５０分間反応させる。反応液を酢酸エチルで
抽出、水、５％塩酸および水で洗い、硫酸ナトリウムで
乾燥し、濃縮する。残分をメタノ−ル４部から結晶化さ
せると７β−フエニルアセチルアミノ−３−セフエム−
４−カルボン酸ジフエニルメチルエステルを得る。収
率：８１．５３％。mp. １６６℃（分解）。 ＩＲ (Nujol) ν: 3250, 1775, 1710, 1645 1625 cm-1. ＮＭＲ (CDCl3) δ：3.30〜3.43(m, 2H), 3.63(s, 2H),
4.90(d, J=4.5Hz, 1H),5.93(dd, J1=4.5Hz, J2=9Hz, 1
H), 6.45〜6.67(m, 2H). 6.90(s, 1H), 7.30(m,15H), p
pm.2) 3ξ-Hydroxy-7β-phenylacetylaminocepham-4ξ-carboxylic acid diphenylmethyl ester was added to dimethylformamide (Molecular).
(Dry dried sheave) dissolved in 9.5 parts, cooled to -50 ° C under N 2 , added 4 equivalents of triethylamine, and then added 2 equivalents of methanesulfonic acid chloride at -52 to -45 ° C for 3 minutes. And added dropwise, and reacted at −55 to −45 ° C. for 2.5 hours to generate methanesulfonic acid ester, and then −15 to −15.
Incubate at -12 ° C for 50 minutes. The reaction solution is extracted with ethyl acetate, washed with water, 5% hydrochloric acid and water, dried over sodium sulfate, and concentrated. The residue was crystallized from 4 parts of methanol to give 7β-phenylacetylamino-3-cephem-.
4-Carboxylic acid diphenylmethyl ester is obtained. Yield: 81.53%. mp. 166 ° C (decomposition). IR (Nujol) ν: 3250, 1775, 1710, 1645 1625 cm -1 .NMR (CDCl 3 ) δ: 3.30 to 3.43 (m, 2H), 3.63 (s, 2H),
4.90 (d, J = 4.5Hz, 1H), 5.93 (dd, J 1 = 4.5Hz, J 2 = 9Hz, 1
H), 6.45 ~ 6.67 (m, 2H). 6.90 (s, 1H), 7.30 (m, 15H), p
pm.
【００１４】実施例２ （３−Ｏ−アシル化反応）Example 2 (3-O-acylation reaction)
【化２】 a: R1=CH3CO- b: R1=PCl4- c: R1=CH3SO2- d:
R1＝p-CH3C6H4SO2-[Chemical 2] a: R 1 = CH 3 CO- b: R 1 = PCl 4 -c: R 1 = CH 3 SO 2 -d:
R 1 = p-CH 3 C 6 H 4 SO 2-
【００１５】Ａ．Ｒ1＝CH3COー ３ξ−ヒドロキシ−７β−フエニルアセチルアミノセフ
アム−４ξ−カルボン酸ジフエニルメチルエステルを
ジクロロメタン１３部にけんだくし、氷冷下ピリジン６
当量と無水酢酸６当量を加え、０〜５℃に１４時間保
つ。反応液を氷水でうすめ、有機層をとり、塩酸、炭酸
水素ナトリウム水と水で洗い、乾燥し、濃縮する。残留
物をジクロロメタン−ヘキサン混液から結晶化すれば３
ξーアセトキシ−７β−フエニルアセチルアミノセフア
ム−４ξ−カルボン酸ジフエニルメチルエステル(3a)を
得る。収率：98.1％。mp.１８７〜１８８℃(分解)。 ＩＲ(Nujol) ν: 3350, 1780, 1740, 1738, 1665 cm-1. ＮＭＲ (CDCl3) δ： 1.63(s, 3H), 2.61(m, 1H), 3.20
(m, 1H), 3.60(s, 2H),4.95(m, 2H), 5.20(d, J=5Hz, 1
H), 5.55(dd, J1=5Hz, J2=9Hz,1H), 6.50(d, J=9Hz, 1
H), 6.83(s, 1H), 7.27(m, 15H) ppm.A. R 1 = CH 3 CO- 3 ξ-hydroxy-7β-phenylacetylaminocepham-4ξ-carboxylic acid diphenylmethyl ester was suspended in 13 parts of dichloromethane, and pyridine 6 was added under ice cooling.
Add equivalents and 6 equivalents of acetic anhydride and keep at 0-5 ° C. for 14 hours. The reaction mixture is diluted with ice water, the organic layer is taken, washed with hydrochloric acid, aqueous sodium hydrogen carbonate and water, dried and concentrated. 3 if the residue was crystallized from a dichloromethane-hexane mixture
ξ-acetoxy-7β-phenylacetylaminocepham-4ξ-carboxylic acid diphenylmethyl ester (3a) is obtained. Yield: 98.1%. mp.187-188 ° C (decomposition). IR (Nujol) ν: 3350, 1780, 1740, 1738, 1665 cm -1 .NMR (CDCl 3 ) δ: 1.63 (s, 3H), 2.61 (m, 1H), 3.20
(m, 1H), 3.60 (s, 2H), 4.95 (m, 2H), 5.20 (d, J = 5Hz, 1
H), 5.55 (dd, J 1 = 5Hz, J 2 = 9Hz, 1H), 6.50 (d, J = 9Hz, 1
H), 6.83 (s, 1H), 7.27 (m, 15H) ppm.
【００１６】Ｂ．Ｒ1＝PCl4 ３ξ−ヒドロキシ−７β−フエニルアセチルアミノセフ
アム−４ξ−カルボン酸ジフエニルメチルエステルを
ジクロロメタン１３部にけんだくし、窒素気体中、０〜
−５℃でピリジン３当量を加える。これを−２０〜−２
５℃に冷却した後、五塩化リン２．７当量を加え、−１
０〜−１５℃に４時間かきまぜれば７−（２−フエニル
−２−クロロメチリデンアミノ−３−テトラクロロホス
ホニルオキシセフアム−４ξ−カルボン酸ジフエニルメ
チルエステル(3b)の溶液を得る。B. R 1 = PCl 4 3 ξ-hydroxy-7β-phenylacetylaminocepham-4ξ-carboxylic acid diphenylmethyl ester was added to 13 parts of dichloromethane, and the mixture was mixed with 0 to 0 in a nitrogen gas.
Add 3 equivalents of pyridine at -5 ° C. This is -20 to -2
After cooling to 5 ° C, 2.7 equivalents of phosphorus pentachloride was added, -1
A solution of 7- (2-phenyl-2-chloromethylideneamino-3-tetrachlorophosphonyloxycepham-4ξ-carboxylic acid diphenylmethyl ester (3b) is obtained by stirring at 0 to -15 ° C for 4 hours. ..
【００１７】Ｃ．Ｒ1＝CH3SO2- ３ξ−ヒドロキシ−７β−フエニルアセチルアミノセフ
アム−４ξ−カルボン酸ジフエニルメチルエステルを
ジクロロメタン１８部にけんだくし、−３０℃に冷却
し、塩化メタンスルホニル６当量を加え、ピリジン６当
量を滴下する。これに混合物を０〜５℃で１７時間反応
させる。反応液を氷水でうすめ、有機層をとり、塩酸と
水で洗い、乾燥し、濃縮する。残留物を酢酸エチル−ヘ
キサンから結晶化すれば３ξーメシルオキシ−７β−フ
エニルアセチルアミノセフアム−４ξ−カルボン酸ジフ
エニルメチルエステル(3c)を得る。収率：96.5％。mp.
１５１〜１５２℃（分解）。 ＩＲ(Nujol) ν: 3300, 1765, 1720, 1660, 1350, 1180
cm-1. ＮＭＲ (CDCl3) δ： 2.65(s, 3H), 2.83(m, 1H), 3.40
(m, 1H), 3.57(s, 2H),4.9〜5.1(m, 2H), 5.20(d, J=5H
z, 1H), 5.50(dd, J1=5Hz, J2=9Hz, 1H), 6.43(d, J=9H
z, 1H),6.87(s, 1H), 7.32(s, 15H) ppm.C. R 1 = CH 3 SO 2 -3 ξ-hydroxy-7β-phenylacetylaminocepham-4 ξ-carboxylic acid diphenylmethyl ester was suspended in 18 parts of dichloromethane, cooled to -30 ° C., and 6 equivalents of methanesulfonyl chloride were added. And 6 equivalents of pyridine are added dropwise. The mixture is reacted with this at 0-5 ° C. for 17 hours. The reaction solution is diluted with ice water, the organic layer is taken, washed with hydrochloric acid and water, dried and concentrated. The residue was crystallized from ethyl acetate-hexane to give 3ξ-mesyloxy-7β-phenylacetylaminocepham-4ξ-carboxylic acid diphenylmethyl ester (3c). Yield: 96.5%. mp.
151-152 ° C (decomposition). IR (Nujol) ν: 3300, 1765, 1720, 1660, 1350, 1180
cm -1 .NMR (CDCl 3 ) δ: 2.65 (s, 3H), 2.83 (m, 1H), 3.40
(m, 1H), 3.57 (s, 2H), 4.9 ~ 5.1 (m, 2H), 5.20 (d, J = 5H
z, 1H), 5.50 (dd, J 1 = 5Hz, J 2 = 9Hz, 1H), 6.43 (d, J = 9H
z, 1H), 6.87 (s, 1H), 7.32 (s, 15H) ppm.
【００１８】Ｄ．Ｒ1＝p-CH3C6H4SO2- ３ξ−ヒドロキシ−７β−フエニルアセチルアミノセフ
アム−４−カルボン酸ジフエニルメチルエステルをジ
クロロメタン９部にけんだくし、これに氷冷下にピリジ
ン６当量と塩化トルエンスルホニルを加え、０〜５℃で
１０５時間反応させる。反応液を氷水でうすめ、有機層
をとり、塩酸と水で洗い、乾燥し、濃縮する。残留物を
酢酸エチル−ヘキサンから結晶化すれば３ξ−ｐ−トル
エンスルホニルオキシ−７β−フエニルアセチルアミノ
セフアム−４ξ−カルボン酸ジフエニルメチルエステル
(3d)を得る。収率：８４．７％。mp.１３３〜１３６℃
（分解）。 ＩＲ(Nujol)ν: 3300, 1760, 1730, 1640, 1310,1180 c
m-1. ＮＭＲ(CDCl3)δ: 2.43(s, 3H), 2.70(m, 1H), 3.33(m,
1H), 3.60(s, 2H), 4.53〜4.90(m, 2H), 5.20(d, J=4.
5Hz, 1H), 5.53(dd, J1=4.5Hz, J2=9Hz, 1H), 6.16(d,
J=9Hz, 1H), 6.83(s, 1H), 7.32(m, 17H), 7.63(d, J=8
Hz, 2H) ppm.D. R 1 = p-CH 3 C 6 H 4 SO 2 -3 ξ-Hydroxy-7β-phenylacetylaminocepham-4-carboxylic acid diphenylmethyl ester was added to 9 parts of dichloromethane under ice cooling. 6 equivalents of pyridine and toluenesulfonyl chloride are added and reacted at 0 to 5 ° C for 105 hours. The reaction solution is diluted with ice water, the organic layer is taken, washed with hydrochloric acid and water, dried and concentrated. The residue was crystallized from ethyl acetate-hexane to give 3ξ-p-toluenesulfonyloxy-7β-phenylacetylaminocepham-4ξ-carboxylic acid diphenylmethyl ester.
Get (3d). Yield: 84.7%. mp.133-136 ℃
(Disassembly). IR (Nujol) ν: 3300, 1760, 1730, 1640, 1310, 1180 c
m -1 .NMR (CDCl 3 ) δ: 2.43 (s, 3H), 2.70 (m, 1H), 3.33 (m,
1H), 3.60 (s, 2H), 4.53 ~ 4.90 (m, 2H), 5.20 (d, J = 4.
5Hz, 1H), 5.53 (dd, J 1 = 4.5Hz, J 2 = 9Hz, 1H), 6.16 (d,
J = 9Hz, 1H), 6.83 (s, 1H), 7.32 (m, 17H), 7.63 (d, J = 8
Hz, 2H) ppm.
【００１９】実施例３ （７−脱アミド化反応）Example 3 (7-deamidation reaction)
【化３】 a: R1=CH3CO- b: R1=PCl4- c: R1=CH3SO2- d:
R1=p-CH3C6H4SO2-[Chemical 3] a: R 1 = CH 3 CO- b: R 1 = PCl 4 -c: R 1 = CH 3 SO 2 -d:
R 1 = p-CH 3 C 6 H 4 SO 2-
【００２０】Ａ．Ｒ1＝CH3COー ３ξーアセトキシ−７β−フエニルアセチルアミノセフ
アム−４ξ−カルボン酸ジフエニルメチルエステル(3a)
をジクロロメタン７部にとかし、−２０〜２５℃に冷却
し、窒素気中ピリジン２当量と五塩化リン１．７当量を
加え、ー１０〜ー１５℃で４時間かきまぜる。反応液に
ー３０℃のメタノール１２部を加え、−３０℃で３．５
時間と０〜５℃で２時間かきまぜる。反応液を濃縮し、
ジクロロメタン−水でうすめ、０〜５℃で２０分間かき
まぜたのち有機層をとり、炭酸水素ナトリウム水と水で
洗い、乾燥し、濃縮する。残渣を少量のジクロロメタン
で溶解し、エ−テルを加えて晶析する。結晶を濾取し、
メタノ−ル−水にとかし、炭酸水素ナトリウム水で中和
し、水を加えて結晶化すれば３ξーアセトキシ−７β−
アミノセフアム−４ξ−カルボン酸ジフエニルメチルエ
ステル(4a)を得る。収率：８０．２％。mp. １５５〜１
５６℃（分解）。 ＩＲ（Nujol）ν： 3350, 3300, 1760, 1750, 1735 cm
-1. ＮＭＲ (CDCl3) δ： 1.60(s, 3H), 1.77(m, 2H), 2.70
(m, 1H), 3.27(m, 1H),4.40(m, 1H), 5.13(m, 3H), 6.9
0(s, 1H), 7.23(s, 10H) ppm.A. R 1 = CH 3 CO- 3 ξ-acetoxy-7β-phenylacetylaminocepham-4ξ-carboxylic acid diphenylmethyl ester (3a)
Is dissolved in 7 parts of dichloromethane, cooled to -20 to 25 ° C, 2 equivalents of pyridine and 1.7 equivalents of phosphorus pentachloride are added in a nitrogen atmosphere, and the mixture is stirred at -10 to -15 ° C for 4 hours. 12 parts of methanol at -30 ° C was added to the reaction solution, and 3.5 at -30 ° C.
Stir for 2 hours at 0-5 ° C for 2 hours. The reaction solution is concentrated,
After diluting with dichloromethane-water and stirring for 20 minutes at 0-5 ° C, the organic layer is taken, washed with aqueous sodium hydrogencarbonate and water, dried and concentrated. The residue is dissolved with a small amount of dichloromethane, and ether is added for crystallization. The crystals are filtered off,
When dissolved in methanol-water, neutralized with sodium hydrogencarbonate water, and crystallized by adding water, 3ξ-acetoxy-7β-
Aminocepham-4ξ-carboxylic acid diphenylmethyl ester (4a) is obtained. Yield: 80.2%. mp.155-1
56 ° C (decomposition). IR (Nujol) ν: 3350, 3300, 1760, 1750, 1735 cm
-1 . NMR (CDCl 3 ) δ: 1.60 (s, 3H), 1.77 (m, 2H), 2.70
(m, 1H), 3.27 (m, 1H), 4.40 (m, 1H), 5.13 (m, 3H), 6.9
0 (s, 1H), 7.23 (s, 10H) ppm.
【００２１】Ｂ．Ｒ1＝PCl4 実施例２のＢで得られる７−（２−フエニル−２−クロ
ロメチリデンアミノ−３−テトラクロロホスホニルオキ
シセフアム−４ξ−カルボン酸ジフエニルメチルエステ
ルの溶液にメタノール２０部またはイソブタノ−ル１０
部を加え、０〜５℃で２〜３時間かきまぜる。反応液を
ー２０〜−２５℃に冷却し、トリエチルアミン１４当量
を滴下し、０〜５℃で１５時間かきまぜる。これに−５
〜−１０℃で水２０部を加え、１０分間かきまぜたの
ち、ジクロロメタンで抽出する。抽出液を塩酸、水、５
％炭酸水素ナトリウム水と水で洗い、乾燥し、濃縮す
る。残渣を酢酸エチルから結晶化すれば７−アミノー３
ーセフエム−４−カルボン酸ジフエニルメチルエステル
を得る。 収率：４７．３％（メタノ−ルから）；３７．２％（イ
ソブタノ−ルから）。mp. １５９〜１６０℃（分解）。B. R 1 = PCl 4 To a solution of 7- (2-phenyl-2-chloromethylideneamino-3-tetrachlorophosphonyloxycepham-4ξ-carboxylic acid diphenylmethyl ester obtained in Example 2, B, methanol 20 Parts or isobutanol 10
Parts, and stir at 0-5 ° C for 2-3 hours. The reaction solution is cooled to -20 to -25 ° C, 14 equivalents of triethylamine is added dropwise, and the mixture is stirred at 0 to 5 ° C for 15 hours. -5 to this
Add 20 parts of water at ~ -10 ° C, stir for 10 minutes, and then extract with dichloromethane. The extract is hydrochloric acid, water, 5
Wash with% sodium bicarbonate water and water, dry and concentrate. The residue was crystallized from ethyl acetate to give 7-amino-3.
-Chem-4-carboxylic acid diphenyl methyl ester is obtained. Yield: 47.3% (from methanol); 37.2% (from isobutanol). mp. 159-160 ° C (decomposition).
【００２２】Ｃ．Ｒ1＝CH3SO2- ３ξーメシルオキシ−７β−フエニルアセチルアミノセ
フアム−４ξ−カルボン酸ジフエニルメチルエステル(3
c)をジクロロメタン７部にとかし、−２０〜−２５℃に
冷却し、窒素気中ピリジン２当量と五塩化リン１．７当
量を加え、−１０〜−１５℃で４時間かきまぜる。反応
液に−２５〜−３０℃のメタノ−ル１１部を加え、ー３
０℃で３０分および−５〜０℃で２．５時間かきまぜ
る。反応液をジクロロメタン−氷水でうすめ、０〜５℃
で２０分かきまぜたのち、有機層をとり、水で洗い、乾
燥し、濃縮する。残渣を少量のジクロロメタンで溶解
し、エ−テルを加えて晶析する。結晶を濾取し、メタノ
−ル−水にとかし、炭酸水素ナトリウム水で中和し、水
を加えて結晶化すれば３ξーメシルオキシ−７β−アミ
ノセフアム−４ξ−カルボン酸ジフエニルメチルエステ
ル(4c)を得る。収率：５５．７％。mp. １４５〜１４７
℃（分解）。 ＩＲ（Nujol）ν： 3350, 3300, 1760, 1735, 1340, 11
70 cm-1. ＮＭＲ (CDCl3) δ： 1.77(s, 2H), 2.67(s, 3H), 2.87
(m, 1H), 3.50(m, 1H),4.46(d, J=4Hz, 1H), 5.13(m, 2
H), 5.20(d, J=4Hz, 1H), 6.90(s, 1H), 7.33(s, 10H)
ppm.C. R 1 = CH 3 SO 2 -3 ξ-mesyloxy-7β-phenylacetylaminocepham-4 ξ-carboxylic acid diphenylmethyl ester (3
c) is dissolved in 7 parts of dichloromethane, cooled to -20 to -25 ° C, 2 equivalents of pyridine and 1.7 equivalents of phosphorus pentachloride are added in a nitrogen atmosphere, and the mixture is stirred at -10 to -15 ° C for 4 hours. To the reaction solution was added 11 parts of methanol at -25 to -30 ° C, and -3
Stir at 0 ° C for 30 minutes and at -5 to 0 ° C for 2.5 hours. Dilute the reaction mixture with dichloromethane-ice water, 0-5 ° C.
After stirring for 20 minutes, the organic layer is taken, washed with water, dried and concentrated. The residue is dissolved with a small amount of dichloromethane, and ether is added for crystallization. The crystals were collected by filtration, dissolved in methanol-water, neutralized with aqueous sodium hydrogen carbonate, and crystallized by adding water to give 3ξ-mesyloxy-7β-aminocepham-4ξ-carboxylic acid diphenylmethyl ester (4c). obtain. Yield: 55.7%. mp.145-147
° C (decomposition). IR (Nujol) ν: 3350, 3300, 1760, 1735, 1340, 11
70 cm -1 NMR (CDCl 3 ) δ: 1.77 (s, 2H), 2.67 (s, 3H), 2.87
(m, 1H), 3.50 (m, 1H), 4.46 (d, J = 4Hz, 1H), 5.13 (m, 2
H), 5.20 (d, J = 4Hz, 1H), 6.90 (s, 1H), 7.33 (s, 10H)
ppm.
【００２３】Ｄ．Ｒ1＝p-CH3C6H4SO2- ３ξーｐ−トルエンスルホニルオキシ−７β−フエニル
アセチルアミノセフアム−４ξ−カルボン酸ジフエニル
メチルエステル(3d)をジクロロメタン７部にとかし、−
２０〜−２５℃に冷却し窒素気中ピリジン２当量と五塩
化リン１．７当量を加え、ー１０〜ー１５℃で４時間か
きまぜる。反応液に−３０℃のメタノール１２部を加え
ー２５〜−３０℃で３０分間および０〜５℃で２時間か
きまぜる。反応液を氷水とジクロロメタンでうすめ、０
〜５℃で２０分間かきまぜたのち、有機層をとり、水で
洗い、乾燥し、濃縮する。残渣をジクロロメタン−エ−
テルから結晶化すれば３ξーｐ−トルエンスルホニルオ
キシ−７β−アミノセフアム−４ξ−カルボン酸ジフエ
ニルメチルエステル(4d)トシレ−トを得る。 mp. 190〜194℃（分解）． ＩＲ（Nujol）ν： 1780, 1750, 1360, 1180 cm-1． 元素分析：Ｃ34Ｈ34Ｎ2Ｏ9Ｓ3・Ｈ2Ｏとして 計算値(%):C, 56.73; H, 4.90; N, 3.89; S, 13.36. 実験値(%):C, 56.90; H, 4.78; N, 3.97; S, 13.20.D. R 1 = p-CH 3 C 6 H 4 SO 2 -3ξ-p-toluenesulfonyloxy-7β-phenylacetylaminocepham-4ξ-carboxylic acid diphenylmethyl ester (3d) was dissolved in 7 parts of dichloromethane, and −
The mixture is cooled to 20 to -25 ° C, 2 equivalents of pyridine and 1.7 equivalents of phosphorus pentachloride are added in nitrogen gas, and the mixture is stirred at -10 to -15 ° C for 4 hours. 12 parts of methanol at -30 ° C is added to the reaction solution, and the mixture is stirred at -25 to -30 ° C for 30 minutes and at 0 to 5 ° C for 2 hours. Dilute the reaction mixture with ice water and dichloromethane, and
After stirring at -5 ° C for 20 minutes, the organic layer is taken, washed with water, dried and concentrated. The residue is dichloromethane-
Crystallization from tellurium gives 3ξ-p-toluenesulfonyloxy-7β-aminocepham-4ξ-carboxylic acid diphenylmethyl ester (4d) tosylate. mp. 190-194 ° C (decomposition). IR (Nujol) ν: 1780, 1750, 1360, 1180 cm -1 . Elemental analysis: Calculated as C 34 H 34 N 2 O 9 S 3 · H 2 O (%): C, 56.73; H, 4.90; N, 3.89; S, 13.36. Experimental value (%): C, 56.90; H, 4.78; N, 3.97; S, 13.20.
【００２４】実施例４ （脱アシルオキシ化反応）Example 4 (Deacyloxylation reaction)
【化４】 a: R1=CH3CO- b: R1=PCl4- c: R1=CH3SO2- d:
R1=p-CH3C6H4SO2-[Chemical 4] a: R 1 = CH 3 CO- b: R 1 = PCl 4 -c: R 1 = CH 3 SO 2 -d:
R 1 = p-CH 3 C 6 H 4 SO 2-
【００２５】Ａ．Ｒ1＝CH3COー ３ξーアセトキシ−７β−アミノセフアム−４ξ−カル
ボン酸ジフエニルメチルエステル(4a)をジクロロメタン
にとかし、ー２０〜−２５℃でトリエチルアミン１〜３
当量を加え、徐々に０〜５℃まで昇温し、一夜放置す
る。これに氷水２０部を加え、２０分間かきまぜたの
ち、ジクロロメタンで抽出する。抽出液を塩酸、水、７
％炭酸水素ナトリウム水と５％食塩水で洗い、乾燥し、
濃縮する。残渣を酢酸エチルから結晶化すれば７β−ア
ミノー３ーセフエム−４−カルボン酸ジフエニルメチル
エステルを得る。収率：(1) から ６１．０％。mp. １５９〜１６０℃（分解）． ＩＲ (Nujol)ν：3350, 3300, 1770, 1720, 1630 cm-1. ＮＭＲ (CDCl3)δ：2.76(s, 2H), 3.43(m, 2H), 4.83
(m, 2H), 6.57(m, 1H), 6.90(s, 1H), 7.30(s, 10H) pp
m.A. R 1 = CH 3 CO- 3 ξ-acetoxy-7β-aminocepham-4ξ-carboxylic acid diphenylmethyl ester (4a) was dissolved in dichloromethane, and triethylamine 1 to 3 was added at -20 to -25 ° C.
An equivalent amount is added, the temperature is gradually raised to 0 to 5 ° C., and left overnight. 20 parts of ice water is added to this, and the mixture is stirred for 20 minutes and then extracted with dichloromethane. The extract is hydrochloric acid, water, 7
Washed with 5% aqueous sodium hydrogen carbonate solution and 5% saline solution, dried,
Concentrate. The residue is crystallized from ethyl acetate to give 7β-amino-3-cephem-4-carboxylic acid diphenylmethyl ester. Yield: (1) to 61.0%. mp. 159-160 ° C (decomposition). IR (Nujol) ν: 3350, 3300, 1770, 1720, 1630 cm -1 .NMR (CDCl 3 ) δ: 2.76 (s, 2H), 3.43 (m, 2H), 4.83
(m, 2H), 6.57 (m, 1H), 6.90 (s, 1H), 7.30 (s, 10H) pp
m.
【００２６】同様にして実施例３Ａ〜４Ｄの生成物にジ
クロロメタン中、０〜５℃でトリエチルアミン１〜３当
量を２〜１５時間作用させれば同一の生成物を得る。Similarly, the products of Examples 3A to 4D are treated with 1 to 3 equivalents of triethylamine in dichloromethane at 0 to 5 ° C. for 2 to 15 hours to obtain the same products.
【００２７】実施例５Example 5
【化５】 実施例４と同様の条件下、対応する３ξ−メシルオキシ
−７−アシルアミノセフエム−４ξ−カルボン酸ジフエ
ニルメチルエステルにジクロロメタン中、トリエチル
アミン１〜３当量を室温で１〜６時間作用させれば、第
二表の化合物を得る。[Chemical 5] Under the same conditions as in Example 4, the corresponding 3ξ-mesyloxy-7-acylaminocephem-4ξ-carboxylic acid diphenylmethyl ester was reacted with 1 to 3 equivalents of triethylamine in dichloromethane at room temperature for 1 to 6 hours. , The compounds of Table 2 are obtained.
【００２８】実施例６ (７−アミノのアシル化）Example 6 (Acylation of 7-amino)
【化６】 ７−アミノ−３−アセトキシセフアム−４−カルボン酸
ジフエニルメチルエステルをジクロロメタン７部にと
かし、−３０〜−１０℃に冷却し、これにとピリジン
１．７当量とフエニル酢酸塩化物１．１当量を加え、３
０分間かきまぜる。反応液にトリエチルアミン１〜９当
量を加えて０〜５℃で２４時間かきまぜたのち、氷水で
うすめ、有機層をとり、塩酸と水で洗い、乾燥し、濃縮
する。残留物を酢酸エチル−エ−テルから結晶化すれば
７β−フエニルアセチルアミノ−３−セフエム−４−カ
ルボン酸ジフエニルメチルエステルを得る。収率：７
０．０％。mp. １７０−１７１℃（分解）。[Chemical 6] 7-Amino-3-acetoxycepham-4-carboxylic acid diphenylmethyl ester was dissolved in 7 parts of dichloromethane and cooled to -30 to -10 ° C, and 1.7 equivalents of pyridine and phenylacetic acid chloride were added thereto. Add 1 equivalent 3
Stir for 0 minutes. 1 to 9 equivalents of triethylamine is added to the reaction solution, and the mixture is stirred at 0 to 5 ° C for 24 hours, diluted with ice water, the organic layer is taken, washed with hydrochloric acid and water, dried, and concentrated. The residue is crystallized from ethyl acetate-ether to give 7β-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester. Yield: 7
0.0%. mp. 170-171 ° C (decomposition).
【００２９】前記と同様の条件下、７−アミノ−３−ア
シルオキシセフアム−４−カルボン酸ジフエニルメチル
エステルをジクロロメタン３〜１０部にとかし、−４
０〜−５℃に冷却し、これにピリジン１〜２当量と各７
位側鎖に対応するカルボン酸の塩化物１〜２当量を加
え、１〜２４時間かきまぜる。反応液を塩酸と水で洗
い、乾燥し、濃縮する。残渣を酢酸エチル−エ−テルか
ら結晶化すれば第一表の化合物を合成できる。Under the same conditions as above, 7-amino-3-acyloxycepham-4-carboxylic acid diphenylmethyl ester was dissolved in 3 to 10 parts of dichloromethane to give -4.
Cool to 0-5 ° C and add 1-2 equivalents of pyridine and 7 each.
Add 1-2 equivalents of carboxylic acid chloride corresponding to the side chain and stir for 1 to 24 hours. The reaction solution is washed with hydrochloric acid and water, dried and concentrated. The compounds in Table 1 can be synthesized by crystallizing the residue from ethyl acetate-ether.
【００３０】実施例７ （３−アシルオキシと３−アシ
ルの脱離）Example 7 (elimination of 3-acyloxy and 3-acyl)
【化７】 a: R1=CH3CO- c: R1=CH3SO2- d: R1=p-CH3C6H4SO
2- e: R1=H[Chemical 7] a: R 1 = CH 3 CO- c: R 1 = CH 3 SO 2 -d: R 1 = p-CH 3 C 6 H 4 SO
2 -e: R 1 = H
【００３１】Ａ．Ｒ1＝CH3COー 1) ３ξ−アセトキシ−７β−フエニルアセチルアミノ
セフアム−４ξ−カルボン酸ジフエニルメチルエステル
(3a)をジクロロメタン１３部にとかし、窒素気中、−５
〜０℃に冷却し、ピリジン２当量を加え、−２０〜−２
５℃に冷却し、五塩化リン１．７当量を加えた後、−１
５〜−１０℃で４時間かきまぜる。反応液に−４０〜−
３０℃のメタノ−ル２０部とジクロロメタン５部を加
え、−２５〜−３０℃で３．５時間かきまぜる。反応液
を−２０〜−２５℃とし、これにトリエチルアミン１
０．９当量を滴下し、０〜５℃で一夜放置する。反応液
を氷水２０部でうすめ、２０分間かきまぜたのち、有機
層をとり、塩酸、水、炭酸水素ナトリウム水と水で洗
い、乾燥、濃縮する。残留物を酢酸エチルから結晶化さ
せれば７β−アミノ−３−セフエム−４−カルボン酸ジ
フエニルメチルエステルを得る。収率：６０．２％。A. R 1 = CH 3 CO-1) 3ξ-acetoxy-7β-phenylacetylaminocepham-4ξ-carboxylic acid diphenylmethyl ester
Dissolve (3a) in 13 parts of dichloromethane, and in a nitrogen atmosphere, -5
Cool to ~ 0 ° C, add 2 equivalents of pyridine, and add -20 to -2.
After cooling to 5 ° C. and adding 1.7 equivalents of phosphorus pentachloride, -1
Stir at 5-10 ° C for 4 hours. -40 to-in the reaction solution
Add 20 parts of methanol at 30 ° C. and 5 parts of dichloromethane and stir at −25 to −30 ° C. for 3.5 hours. The reaction solution was brought to -20 to -25 ° C, and triethylamine 1 was added to it.
0.9 eq is added dropwise and left overnight at 0-5 ° C. The reaction solution is diluted with 20 parts of ice water and stirred for 20 minutes, then the organic layer is taken, washed with hydrochloric acid, water, aqueous sodium hydrogencarbonate and water, dried and concentrated. The residue is crystallized from ethyl acetate to give 7β-amino-3-cephem-4-carboxylic acid diphenylmethyl ester. Yield: 60.2%.
【００３２】2) 前記原料物質(3a)をジクロロメタン１
３部にとかし、窒素気中、−５〜０℃に冷却し、ピリジ
ン２当量を加え、−３０〜−２５℃に冷却し、五塩化リ
ン１．７当量を加えた後、−１５〜−１０℃で４時間か
きまぜる。反応液を−２５〜−３０℃に冷却し、これに
窒素気中−３０〜−２０℃のイソブタノ−ル１０部を加
え、０〜５℃で一夜放置する。反応液を−２０〜−２５
℃とし、これにトリエチルアミン１０．９当量を滴下
し、０〜５℃で一夜放置する。反応液をジクロロメタン
２０部と氷水２０部でうすめ、２０分間かきまぜたの
ち、有機層をとり、塩酸、水、炭酸水素ナトリウム水と
水で洗い、乾燥し、濃縮する。残留物を酢酸エチルから
結晶化させれば７β−アミノ−３−セフエム−４−カル
ボン酸ジフエニルメチルエステルを得る。収率：６
０．８％。2) Dichloromethane 1 was used as the starting material (3a).
Melt in 3 parts, cool to −5 to 0 ° C. in a nitrogen atmosphere, add 2 equivalents of pyridine, cool to −30 to −25 ° C., add 1.7 equivalents of phosphorus pentachloride, and then −15 to − Stir at 10 ° C for 4 hours. The reaction solution is cooled to -25 to -30 ° C, 10 parts of isobutanol at -30 to -20 ° C in nitrogen gas is added thereto, and the mixture is left to stand at 0 to 5 ° C overnight. The reaction solution is -20 to -25
The temperature is adjusted to 0 ° C, 10.9 equivalents of triethylamine is added dropwise thereto, and the mixture is left standing at 0 to 5 ° C overnight. The reaction solution is diluted with 20 parts of dichloromethane and 20 parts of ice water and stirred for 20 minutes. The organic layer is collected, washed with hydrochloric acid, water, sodium hydrogen carbonate solution and water, dried and concentrated. The residue is crystallized from ethyl acetate to give 7β-amino-3-cephem-4-carboxylic acid diphenylmethyl ester. Yield: 6
0.8%.
【００３３】Ｃ．Ｒ1＝CH3SO2- ３ξ−メシルオキシ−７β−フエニルアセチルアミノセ
フアム−４ξ−カルボン酸ジフエニルメチルエステル(3
c)をジクロロメタン７部にとかし、窒素気中、−２０〜
−２５℃に冷却し、ピリジン２当量と五塩化リン１．７
当量を加えた後、−１５〜−１０℃で４時間かきまぜ
る。反応液に−４０〜−３０℃のメタノ−ル１２部を加
え、−３０℃で３０分間と０〜５℃で２．５時間かきま
ぜる。反応液を−３０℃とし、これにトリエチルアミン
８．１当量を滴下し、０〜５℃で一夜放置する。反応液
を氷水とジクロロメタンでうすめ、０〜５℃で２０分間
かきまぜたのち、有機層をとり、塩酸、水、炭酸水素ナ
トリウム水と水で洗い、乾燥し、濃縮する。残留物を酢
酸エチルから結晶化させれば７β−アミノ−３−セフエ
ム−４−カルボン酸ジフエニルメチルエステルを得
る。収率：５５．７％。C. R 1 = CH 3 SO 2 -3 ξ-mesyloxy-7β-phenylacetylaminocepham-4 ξ-carboxylic acid diphenylmethyl ester (3
c) is dissolved in 7 parts of dichloromethane, and in a nitrogen atmosphere, -20 to
Cool to −25 ° C., 2 equivalents of pyridine and 1.7 of phosphorus pentachloride.
After adding the equivalent amount, stir at -15 to -10 ° C for 4 hours. To the reaction solution, 12 parts of methanol at -40 to -30 ° C is added, and the mixture is stirred at -30 ° C for 30 minutes and at 0-5 ° C for 2.5 hours. The reaction solution is brought to -30 ° C, 8.1 equivalent of triethylamine is added dropwise thereto, and the mixture is left standing at 0-5 ° C overnight. The reaction solution is diluted with ice water and dichloromethane and stirred at 0 to 5 ° C for 20 minutes. The organic layer is collected, washed with hydrochloric acid, water, aqueous sodium hydrogen carbonate solution and water, dried and concentrated. The residue is crystallized from ethyl acetate to give 7β-amino-3-cephem-4-carboxylic acid diphenylmethyl ester. Yield: 55.7%.
【００３４】Ｄ．Ｒ1＝p-CH3C6H4SO2- ３ξ−ｐ−トシルオキシ−７β−フエニルアセチルアミ
ノセフアム−４ξ−カルボン酸ジフエニルメチルエステ
ル(3d)をジクロロメタン７部にとかし、−１０〜−１５
℃に冷却し、ピリジン２当量と五塩化リン１．７当量を
加えた後、−１５〜−１０℃で４時間かきまぜる。反応
液に−４０〜−３０℃のメタノ−ル１２部を加え、−３
０℃で３０分間と０〜５℃で２．５時間かきまぜる。反
応液を−３０〜−４０℃とし、これにトリエチルアミン
８当量を滴下し、０〜５℃で２時間かきまぜたのち一夜
放置する。反応液を氷水とジクロロメタンでうすめ、０
〜５℃で２０分間かきまぜたのち、有機層をとり、塩
酸、水、炭酸水素ナトリウム水と水で洗い、乾燥し、濃
縮する。残留物を酢酸エチルから結晶化させれば７β−
アミノ−３−セフエム−４−カルボン酸ジフエニルメチ
ルエステルを得る。収率：５７．９％。D. R 1 = p-CH 3 C 6 H 4 SO 2 -3ξ-p-tosyloxy-7β-phenylacetylaminocepham-4ξ-carboxylic acid diphenylmethyl ester (3d) was dissolved in 7 parts of dichloromethane to give -10. -15
After cooling to ℃, 2 equivalents of pyridine and 1.7 equivalents of phosphorus pentachloride are added, and then stirred at -15 to -10 ° C for 4 hours. To the reaction solution was added 12 parts of methanol at -40 to -30 ° C, and -3
Stir at 0 ° C for 30 minutes and 0-5 ° C for 2.5 hours. The reaction solution is brought to -30 to -40 ° C, 8 equivalents of triethylamine is added dropwise thereto, and the mixture is stirred at 0 to 5 ° C for 2 hours and then left overnight. Dilute the reaction mixture with ice water and dichloromethane, and
After stirring for 20 minutes at -5 ° C, the organic layer is taken, washed with hydrochloric acid, water, and aqueous sodium hydrogencarbonate and water, dried and concentrated. If the residue was crystallized from ethyl acetate, 7β-
Amino-3-cephem-4-carboxylic acid diphenylmethyl ester is obtained. Yield: 57.9%.
【００３５】Ｅ．Ｒ1＝H 1) ３ξ−ヒドロキシ−７β−フエニルアセチル アミノセフアム−４ξ−カルボン酸ジフエニルメチルエ
ステル(3e)をジクロロメタン１３部にけんだくし、窒素
気中、−５〜０℃に冷却し、ピリジン３当量を加え、−
２０〜−２５℃に冷却し、五塩化リン２．７当量を加え
た後、−１５〜−１０℃で４時間かきまぜる。反応液に
−４０〜−３０℃のメタノ−ル２０部を加え、−１０〜
−１５℃で３時間かきまぜる。反応液を−２０〜−２５
℃とし、これにトリエチルアミン１２当量を滴下、０〜
５℃で一夜放置する。反応液を氷水２０部でうすめ、０
〜５℃で２０分間かきまぜたのち、有機層をとり、塩
酸、水、炭酸水素ナトリウム水と水で洗い、乾燥し、濃
縮する。残留物を酢酸エチルから結晶化させれば７β−
アミノ−３−セフエム−４−カルボン酸ジフエニルメチ
ルエステルを得る。収率：４７．３％。E. R 1 = H 1) 3ξ-hydroxy-7β-phenylacetylaminocepham-4ξ-carboxylic acid diphenylmethyl ester (3e) was suspended in 13 parts of dichloromethane and cooled to −5 to 0 ° C. in a nitrogen atmosphere, Add 3 equivalents of pyridine,
After cooling to 20 to -25 ° C and adding 2.7 equivalents of phosphorus pentachloride, the mixture is stirred at -15 to -10 ° C for 4 hours. 20 parts of methanol at -40 to -30 ° C was added to the reaction solution, and -10 to
Stir at -15 ° C for 3 hours. The reaction solution is -20 to -25
12 ° C of triethylamine was added dropwise to 0 ° C,
Leave overnight at 5 ° C. The reaction solution was diluted with 20 parts of ice water, and 0
After stirring for 20 minutes at -5 ° C, the organic layer is taken, washed with hydrochloric acid, water, and aqueous sodium hydrogencarbonate and water, dried and concentrated. If the residue was crystallized from ethyl acetate, 7β-
Amino-3-cephem-4-carboxylic acid diphenylmethyl ester is obtained. Yield: 47.3%.
【００３６】2) 前記原料物質(3e)をジクロロメタン１
３部にとかし、窒素気中、−５〜０℃に冷却し、ピリジ
ン３当量を加え、−２０〜−２５℃に冷却し、五塩化リ
ン２．７当量を加えた後、−１５〜−１０℃で４時間か
きまぜる。反応液に−４０〜−３０℃のイソブタノ−ル
１１部を加え、０〜５℃で２時間かきまぜたのち、０〜
５℃で一夜放置する。反応液を−２０〜−２５℃とし、
これにトリエチルアミン１４当量を滴下し、０〜５℃で
一夜放置する。反応液を氷水とジクロロメタンでうす
め、２０分間かきまぜたのち、有機層をとり、塩酸、
水、炭酸水素ナトリウム水と水で洗い、乾燥し、濃縮す
る。残留物を酢酸エチルから結晶化させれば、７β−ア
ミノ−３−セフエム−４−カルボン酸ジフエニルメチル
エステルを得る。収率：３７．２％。2) The starting material (3e) was added to dichloromethane 1
Melt in 3 parts, cool to −5 to 0 ° C. in a nitrogen atmosphere, add 3 equivalents of pyridine, cool to −20 to −25 ° C., add 2.7 equivalents of phosphorus pentachloride and then −15 to −−. Stir at 10 ° C for 4 hours. To the reaction solution was added 11 parts of isobutanol at -40 to -30 ° C, and the mixture was stirred at 0 to 5 ° C for 2 hours, then 0 to
Leave overnight at 5 ° C. The reaction solution was set at -20 to -25 ° C,
To this, 14 equivalents of triethylamine was added dropwise, and the mixture was left at 0 to 5 ° C overnight. The reaction solution was diluted with ice water and dichloromethane, and the mixture was stirred for 20 minutes, then the organic layer was collected, hydrochloric acid,
Wash with water, aqueous sodium hydrogen carbonate and water, dry and concentrate. The residue is crystallized from ethyl acetate to give 7β-amino-3-cephem-4-carboxylic acid diphenylmethyl ester. Yield: 37.2%.
【００３７】[0037]
【参考例】第一表の７−アミノ−３−セフエム−４−カ
ルボン酸ジフエニルメチルエステル（Ｒ＝Ｈ）をジク
ロロメタン７部にとかし、０℃でこれに各７位側鎖に対
応するカルボン酸の塩化物１〜２当量とピリジン１〜２
当量を加え、１〜５時間かきまぜる。反応液を塩酸と水
で洗い、乾燥し、濃縮する。残留物を酢酸エチル−エ−
テルから結晶化すれば第一表の化合物（Ｒ＝所定アシ
ル）を合成できる。[Reference Example] 7-Amino-3-cephem-4-carboxylic acid diphenylmethyl ester (R = H) in Table 1 was dissolved in 7 parts of dichloromethane and the carboxylic acid corresponding to each 7-position side chain was added at 0 ° C. 1-2 equivalents of chloride of acid and 1-2 of pyridine
Add equivalent amount and stir for 1-5 hours. The reaction solution is washed with hydrochloric acid and water, dried and concentrated. The residue was washed with ethyl acetate
The compound shown in Table 1 (R = predetermined acyl) can be synthesized by crystallization from tellurium.
【００３８】第一表Table 1
【化８】 [Chemical 8]
【表１】 [Table 1]
【表２】 [Table 2]
Claims (2)
−４−カルボン酸アラルキルエステル。1. A 7-amino-3-acyloxycepham-4-carboxylic acid aralkyl ester.
セフアム−４ξ−カルボン酸エステルに酸捕捉剤として
の芳香族塩基の存在下に、カルボン酸またはスルホン酸
の塩化物または無水物を作用させて３−（カルボン酸ア
シルまたはスルホン酸アシル）オキシ−７β−アシルア
ミノセフアム−４ξ−カルボン酸エステルを製造する方
法。2. A chloride or an anhydride of a carboxylic acid or a sulfonic acid is allowed to act on a 3ξ-hydroxy-7β-acylaminocepham-4ξ-carboxylic acid ester in the presence of an aromatic base as an acid scavenger. A method for producing a 3- (carboxylic acid acyl or sulfonic acid acyl) oxy-7β-acylaminocepham-4ξ-carboxylic acid ester.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3936093A JPH0826038B2 (en) | 1993-02-02 | 1993-02-02 | Process for producing hydroxycepham carboxylic acid ester |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3936093A JPH0826038B2 (en) | 1993-02-02 | 1993-02-02 | Process for producing hydroxycepham carboxylic acid ester |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP59275709A Division JPH0645625B2 (en) | 1984-06-08 | 1984-12-28 | Process for producing hydroxycepham carboxylic acid ester |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP6101844A Division JP2554990B2 (en) | 1994-04-15 | 1994-04-15 | 3-Acyloxy-7β-aminocepham-4-carboxylic acid diphenylmethyl ester and process for producing the same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH05345786A true JPH05345786A (en) | 1993-12-27 |
| JPH0826038B2 JPH0826038B2 (en) | 1996-03-13 |
Family
ID=12550908
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP3936093A Expired - Lifetime JPH0826038B2 (en) | 1993-02-02 | 1993-02-02 | Process for producing hydroxycepham carboxylic acid ester |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0826038B2 (en) |
-
1993
- 1993-02-02 JP JP3936093A patent/JPH0826038B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0826038B2 (en) | 1996-03-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR920005830B1 (en) | Process for preparing amino-hydroxy cepham carboxylates | |
| JP2554990B2 (en) | 3-Acyloxy-7β-aminocepham-4-carboxylic acid diphenylmethyl ester and process for producing the same | |
| SU546282A3 (en) | The method of obtaining 7-α-amino-7 methoxy-cephalosporin esters | |
| US6005101A (en) | Glutaryl 7-ACA derivatives and processes for obtaining them | |
| FI73968C (en) | Process for the preparation of phenylglycyl chloride hydrochlorides | |
| JPH05345786A (en) | Production of hydroxycephamcarboxylic acid ester | |
| JPH0454674B2 (en) | ||
| US4584371A (en) | Catalytic process for preparing 3-ester-methyl cephalosporins from desacetyl-7-aminocephalosporanic acid | |
| HU191696B (en) | Process for producing 3-exomethylene-cephame derivatives | |
| US4252973A (en) | Process for chemically removing the acyl sidechain from cephalosporins and penicillins | |
| JPS6135199B2 (en) | ||
| JPS61155388A (en) | Production of hydroxycephamcarboxylic acid ester | |
| JPS6123198B2 (en) | ||
| NO160660B (en) | PROCEDURE FOR THE PREPARATION OF PENICILLIN OR CEPHALOSPORINIMINOHALOGENIDES. | |
| US4334065A (en) | Cephalosporin intermediates | |
| FI89925B (en) | FRAMEWORK FOR FOUNDATION WITHOUT FUEL | |
| JPS63115887A (en) | Production of 7-amino-3-alkoxymethylcephalosporins | |
| Aratani et al. | Synthesis of 1-oxa-2-oxocephalosporins | |
| JPS6190A (en) | Preparation of hydroxycepham carboxylic acid ester | |
| Alpegiani et al. | Expeditious Synthesis of 4-(tert-Butylcarbonyl)-7α-methoxy-3-methyl-Δ3-cephem 1, 1-Dioxide. Convenient Access to 7-Substituted Analogues | |
| US5663330A (en) | Process for the selective sulfoxide reduction of 3-hydroxy cephem and 3-methylene cepham compounds | |
| US4001239A (en) | Cephalosporin cleavage process | |
| SU703023A3 (en) | Method of preparing 3-acyloxymethyl-delta-2-cephems | |
| KR810000636B1 (en) | Process for preparing cephalosporin compound | |
| JPS6135198B2 (en) |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EXPY | Cancellation because of completion of term |