CH626369A5 - Method for the preparation of derivatives of 7-amino-delta(3)-deacetoxycephalosporanic acid - Google Patents
Method for the preparation of derivatives of 7-amino-delta(3)-deacetoxycephalosporanic acid Download PDFInfo
- Publication number
- CH626369A5 CH626369A5 CH663377A CH663377A CH626369A5 CH 626369 A5 CH626369 A5 CH 626369A5 CH 663377 A CH663377 A CH 663377A CH 663377 A CH663377 A CH 663377A CH 626369 A5 CH626369 A5 CH 626369A5
- Authority
- CH
- Switzerland
- Prior art keywords
- formula
- mixture
- group
- added
- derivatives
- Prior art date
Links
Classifications
-
- 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
- C07D501/02—Preparation
- C07D501/08—Preparation by forming the ring or condensed ring systems
- C07D501/10—Preparation by forming the ring or condensed ring systems from compounds containing the penicillin ring system
-
- 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)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Molecular Biology (AREA)
- Cephalosporin Compounds (AREA)
Description
La presente invenzione si riferisce ad un metodo per la preparazione di derivati dell'acido 7-amino-A3-desacetossi-20 cefalosporanico di formula ch3)2 The present invention relates to a method for the preparation of 7-amino-A3-desacethoxy-20 cephalosporanic acid derivatives of formula ch3) 2
(II) (II)
COOR COOR
R-CHo-C0NH R-CHO-C0NH
25 d 25 d
1 1
in cui R ed R! sono quali sopra definiti viene fatto reagire in ambiente anidro, in un solvente aprotico scelto dal gruppo costituito da diossano, toluene, benzene, dimetilacetamide, dimetossietano e loro miscele, ad una temperatura compresa tra +60°C e 130°C e per un periodo tra circa 1 e 9 ore, con un agente sililante costituito da lattami ciclici di formula where R and R! are as defined above is reacted in an anhydrous medium, in an aprotic solvent selected from the group consisting of dioxane, toluene, benzene, dimethylacetamide, dimethoxyethane and their mixtures, at a temperature between + 60 ° C and 130 ° C and for a period between about 1 and 9 hours, with a silylating agent consisting of cyclic lactams of formula
30 30
(I) (THE)
in cui R è un radicale scelto dal gruppo costituito da fenile e fenossi ed Rt è un radicale scelto dal gruppo costituito da -H e da un gruppo protettore del gruppo carbossilico, carat-35 terizzato dal fatto che un solfossido di penicillina di formula wherein R is a radical chosen from the group consisting of phenyl and phenoxy and Rt is a radical chosen from the group consisting of -H and a protecting group of the carboxylic group, characterized by the fact that a penicillin sulfoxide of formula
(CH3)3Si-N (CH3) 3Si-N
(CH2>n (CH2> n
(III) (III)
40 R-CH2-C0N. 40 R-CH2-C0N.
in cui n è un numero intero tra 3 e 5 inclusi, per formare nella miscela di reazione un nuovo composto intermedio costituito da un derivato azetidinonico di formula wherein n is an integer between 3 and 5 inclusive, to form in the reaction mixture a new intermediate compound consisting of an azetidinonic derivative of formula
45 45
(CH3)2 (CH3) 2
a« to"
•CÖOR • Coor
1 1
R-CHg-CONff R-CH?-CONff
-N -N
/Wn \ / Wn \
;0 ; 0
//CKz ioOR« ^CH3 // CKz ioOR «^ CH3
V V
TU YOU
(IV) (IV)
in cui R è un radicale scelto dal gruppo costituito da fenile e fenossi ed Rj è un radicale scelto dal gruppo costituito da -H e da un gruppo protettore del gruppo carbossilico, viene 50 fatto reagire in ambiente anidro, in un solvente aprotico scelto dal gruppo costituito da diossano, toluene, benzene, dimetilacetamide, dimetossietano e loro miscele, ad una temperatura compresa tra +60°C e +130°C e per un periodo tra circa 1 e 9 ore, con un agente sililante costituito da lat-55 tami ciclici di formula wherein R is a radical selected from the group consisting of phenyl and phenoxy and Rj is a radical chosen from the group consisting of -H and a protecting group of the carboxylic group, it is made to react in an anhydrous medium, in an aprotic solvent chosen by the group consisting of dioxane, toluene, benzene, dimethylacetamide, dimethoxyethane and their mixtures, at a temperature between + 60 ° C and + 130 ° C and for a period between about 1 and 9 hours, with a silylating agent consisting of lat-55 tami cyclical formula
(CH3)3Si- (CH3) 3Si-
N N
60 60
che, dopo isolamento o nella stessa miscela viene fatto reagire con un agente ciclizzante scelto dal gruppo costituito dall'acido bromidrico e suoi derivati, ed una base scelta dal gruppo costituito da ammoniaca e suoi derivati e da piridina e suoi derivati, si scalda a ricadere, quindi si raffredda sostanzialmente alla temperatura ambiente, si aggiunge acqua, si acidifica ad un pH compreso tra circa 2,5 e 0,5, si raffred di) which, after isolation or in the same mixture, is reacted with a cyclizing agent selected from the group consisting of hydrobromic acid and its derivatives, and a base selected from the group consisting of ammonia and its derivatives and pyridine and its derivatives, is heated to reflux then it is cooled substantially to room temperature, water is added, acidified to a pH between about 2.5 and 0.5, it is cooled)
65 65
in cui n è un numero intero tra 3 e 5 inclusi, per formare nella miscela di reazione un nuovo composto intermedio costituito da un derivato azetidinonico di formula wherein n is an integer between 3 and 5 inclusive, to form in the reaction mixture a new intermediate compound consisting of an azetidinonic derivative of formula
3 3
626369 626369
R-CH2-C0NH R-CH2-C0NH
^l(CVn ^ L (CVn
Nv l \c «so Nv l \ c «know
(IV) (IV)
ÖO OB. ÖO OB.
che dopo isolamento o nella stessa miscela viene fatto reagire con un agente ciclizzante scelto dal gruppo costituito dall'acido bromidrico e suoi derivati, ed una base scelta dal gruppo costituito da ammoniaca e suoi derivati e da piridina e suoi derivati, si scalda a ricadere, quindi si raffredda sostanzialmente alla temperatura ambiente, si aggiunge acqua, si acidifica ad un pH compreso tra circa 2,5 e 0,5, si raffredda ad una temperatura compresa tra 0°C e la temperatura ambiente e si filtra, ottenendosi un precipitato costituito essenzialmente dal composto di formula (I). Il composto di formula (I) è di per sè ben noto ed è, ad esempio, descritto in Chauvette et al, J. Ord. Chem. 36, 1259 (1971). which after isolation or in the same mixture is reacted with a cyclizing agent selected from the group consisting of hydrobromic acid and its derivatives, and a base chosen from the group consisting of ammonia and its derivatives and pyridine and its derivatives, is heated to reflux, then it is substantially cooled to room temperature, water is added, acidified to a pH between about 2.5 and 0.5, cooled to a temperature between 0 ° C and room temperature and filtered, obtaining a precipitate consisting of essentially from the compound of formula (I). The compound of formula (I) is per se well known and is, for example, described in Chauvette et al, J. Ord. Chem. 36, 1259 (1971).
I solfossidi di penicilline di formula (II) sono di per sè ben noti e sono, ad esempio, descritti in Flynn, Cephalosporin and Penicillins, capitolo 16. The penicillin sulphoxides of formula (II) are per se well known and are, for example, described in Flynn, Cephalosporin and Penicillins, chapter 16.
Anche i lattami ciclici di formula (III) sono di per sè ben noti e sono, ad esempio, descritti in Ruhlman et al, Ann. Chem. 686, 226 (1965). Cyclic lactams of formula (III) are also well known per se and are, for example, described in Ruhlman et al, Ann. Chem. 686, 226 (1965).
Al fine di rendere più chiara la comprensione del metodo secondo la presente invenzione, verranno ora descritti alcuni esempi non limitativi di attuazione del metodo stesso. In order to clarify the understanding of the method according to the present invention, some non-limiting examples of implementation of the method will now be described.
Esempio 1 Example 1
Ad una miscela costituita da 180 g di caprolattame e 250 mi di trietilamina in 800 mi di benzene vengono aggiunti 226 mi di trimetilclorosilano, si riscalda progressivamente sino a ricadere in un'ora e si mantiene quindi a ricadere per ulteriori 4 ore. Si raffredda a temperatura ambiente e si filtra lavando con 400 mi di benzene. To a mixture consisting of 180 g of caprolactam and 250 ml of triethylamine in 800 ml of benzene, 226 ml of trimethylchlorosilane are added, it is heated gradually until it falls again in one hour and is then kept refluxing for a further 4 hours. The mixture is cooled to room temperature and filtered by washing with 400 ml of benzene.
Si evapora il solvente e si distilla a 110-112°C raccogliendo il distillato che passa: si ottengono così 250 g di N-trime-tilsililcaprolattame (di formula generale III). The solvent is evaporated and distilled at 110-112 ° C by collecting the distillate which passes: thus 250 g of N-trime-tylsilyl caprolactam (of general formula III) are obtained.
Alla temperatura ambiente, a 42 g di benzilpenicillina solfossido in 400 mi di diossano anidro si aggiungono graduatamente 155 g di N-trimetilsililcaprolattame. Si scalda a ricadere per 6 ore, si concentra a piccolo volume e si evapora il solvente sotto vuoto. Il residuo viene trattato con una soluzione acquosa acida per acido cloridrico diluito sino a pH 1,5. Si raffredda a 10°C, si filtra ed il prodotto formatosi viene sciolto in acetato di etile e la soluzione lavata con acqua e quindi purificata su colonna di gel di silice. Si anidri-fica su solfato di sodio e si evapora sino a residuo solido che spappolato in etere di petrolio dà 19 g di I-(I-carbossi-2-metil-prop-2-enil)3-fenilacetamido-4-(2-chetoesametilenimmino)-trioazetidin-2-one (avente formula generale IV). At room temperature, 155 g of N-trimethylsilyl caprolactam are gradually added to 42 g of benzylpenicillin sulphoxide in 400 ml of anhydrous dioxane. The mixture is heated under reflux for 6 hours, concentrated to a small volume and the solvent is evaporated under vacuum. The residue is treated with an acid aqueous solution for hydrochloric acid diluted to pH 1.5. The mixture is cooled to 10 ° C, filtered and the product formed is dissolved in ethyl acetate and the solution washed with water and then purified on a silica gel column. The mixture is dried over sodium sulphate and evaporated to a solid residue which, crushed in petroleum ether, gives 19 g of I- (I-carboxy-2-methyl-prop-2-enyl) 3-phenylacetamido-4- (2 ketohexamethylene imino) -trioazetidin-2-one (having general formula IV).
A 15 g di I-(I-carbossi-2-metilprop-2-enil)3-fenilacetami-do-4-(2-chetoesametilenimmina)tioazetidin-2-one in 200 mi di diossano anidro vengono aggiunti 36, 2 mi di N,0-bis-tri-metilsililacetamide. Si scalda a 60°C per un'ora e si aggiungono 2,4 mi di piridina e quindi 2,3 mi di bromuro di acetil, dopo di che si riscalda a ricadere per 3 ore. Dopo raffreddamento a temperatura ambiente si aggiungono 250 mi di acqua, si acidifica con acido cloridrico a pH 1,5, si raffredda a 10°C, si filtra, si tratta con 30 mi di isobutilmetilchetone e si ottengono 9,8 g di acido 7-fenilacetamido-A3-desacetossi-cefalosporanico. To 15 g of I- (I-carboxy-2-methylprop-2-enyl) 3-phenylacetami-do-4- (2-ketohexamethylenimine) thioazetidin-2-one in 200 ml of anhydrous dioxane, 36, 2 ml of N, 0-bis-tri-metilsililacetamide. The mixture is heated to 60 ° C for one hour and 2.4 ml of pyridine and then 2.3 ml of acetyl bromide are added, after which it is heated under reflux for 3 hours. After cooling to room temperature, 250 ml of water are added, acidified with hydrochloric acid to pH 1.5, cooled to 10 ° C, filtered, treated with 30 ml of isobutylmethylketone and 9.8 g of acid were obtained 7 -fenilacetamido-A3-desacetossi-cephalosporanic.
Esempio 2 Example 2
Ad una miscela costituita da 85 g di 2-pirrolidone e 165 mi di trietilamina in 600 mi di benzene vengono aggiunti sotto agitazione 150 mi di trimetilclorosilano e si scalda a ri-5 cadere per 3 ore e mezza. Si raffredda a temperatura ambiente, si filtra lavando con 200 mi di benzene, si evapora sotto vuoto il filtrato, si distilla il residuo (18 mm Hg) raccogliendo la frazione a 98-100°C e si ottengono 118 g di N-tri-metilsililpirrolidin-2-one (avente formula generale III), io A 31,5 g di benzilpenicillina solfossido in 400 mi di diossano anidro si aggiungono 95 g di N-trimetilsililpirroIidin-2--one e si scalda a ricadere per 5 ore. Si raffredda a temperatura ambiente; si aggiungono 500 mi di acqua e si porta il pH a 1,7 con acido cloridrico diluito. Si filtra e si sospen-15 de il precipitato in 600 mi di acqua e si scioglie a pH 7,2 con trietilamina. Si filtra, si lava con 200 mi di acetato di etile e la fase acquosa è trattata con 400 mi di acetato di etile e portata a pH 2 con acido cloridrico. Si anidrifica la fase organica su solfato di sodio, si evapora a secco, si tratta 20 con etere di petrolio e si ottengono 12 g di I-(I-carbossi-2--metiIprop-2-enil)3-fenilacetamido-4-(N-pirrolidin-2-one)tio-azetidin-2-one (di formula generale IV). To a mixture consisting of 85 g of 2-pyrrolidone and 165 ml of triethylamine in 600 ml of benzene, 150 ml of trimethylchlorosilane are added under stirring and the mixture is heated to drop again for 3 and a half hours. The mixture is cooled to room temperature, filtered by washing with 200 ml of benzene, the filtrate is evaporated under vacuum, the residue is distilled (18 mm Hg) collecting the fraction at 98-100 ° C and 118 g of N-tri- are obtained. methylsilylpyrrolidin-2-one (having general formula III), io At 31.5 g of benzylpenicillin sulphoxide in 400 ml of anhydrous dioxane, 95 g of N-trimethylsilylpyrroIidin-2 - one are added and heated to reflux for 5 hours. It cools down to room temperature; 500 ml of water are added and the pH is brought to 1.7 with dilute hydrochloric acid. The precipitate was filtered and suspended in 600 ml of water and dissolved at pH 7.2 with triethylamine. It is filtered, washed with 200 ml of ethyl acetate and the aqueous phase is treated with 400 ml of ethyl acetate and brought to pH 2 with hydrochloric acid. The organic phase is anhydrified on sodium sulphate, evaporated to dryness, treated with 20 petroleum ether and 12 g of I- (I-carboxy-2 - metiIprop-2-enyl) 3-phenylacetamido-4- are obtained (N-pyrrolidin-2-one) thio-azetidin-2-one (of general formula IV).
Grammi 9 di l-(l-carbossi-2-metilprop-2-enil)3-fenil-acetamido-4-(N-pirrolidin-2-one)tioazetidin-2-one sono sospe-25 si in 120 mi di toluene anidro. Alla miscela si aggiungono 12,6 mi di esametildisilossano e 16,5 mi di trimetilclorosilano. 9 grams of l- (l-carboxy-2-methylprop-2-enyl) 3-phenyl-acetamido-4- (N-pyrrolidin-2-one) thioazetidin-2-one are suspended in 25 ml in 120 ml of toluene anhydrous. 12.6 ml of hexamethyldisiloxane and 16.5 ml of trimethylchlorosilane are added to the mixture.
Si scalda a 50° per 1 ora. Poi si aggiungono 3,2 g di bromidrato di piridina e si scalda a ricadere per 2 ore. Si raffredda a temperatura ambiente e si colano nella miscela 35 mi 30 di metanolo. Il prodotto viene portato in fase acquosa per estrazione con due porzioni da 100 mi di una soluzione di ammoniaca al 10%. Agli estratti acquosi riuniti si aggiungono 50 mi di acetone e si acidifica con acido cloridrico 3N fino a pH 0,8. Il precipitato viene filtrato e lavato a dare 35 5,6 g di acido 7-fenilacetamido-A3-desacetossicefaIosporanico. It is heated to 50 ° for 1 hour. Then 3.2 g of pyridine hydrochloride are added and the mixture is heated under reflux for 2 hours. The mixture is cooled to room temperature and 35 ml 30 of methanol are poured into the mixture. The product is brought into the aqueous phase by extraction with two 100 ml portions of a 10% ammonia solution. 50 ml of acetone are added to the combined aqueous extracts and acidified with 3N hydrochloric acid up to pH 0.8. The precipitate is filtered and washed to give 35 5.6 g of 7-phenylacetamido-A3-desacethoxy-alpha-ioporanic acid.
Esempio 3 Example 3
A 105 g di 5-valerolattame e 180 mi di trietilamina posti in 600 mi di toluene, si aggiungono 165 mi di trimetilcloro-40 silano e si scalda a ricadere per 4 ore e mezza. Si raffredda la miscela e si filtra lavando con 200 mi di toluene ed il filtrato è evaporato a secco ed il residuo distillato per dare a 79°-80°C (12 mm Hg) 158 g di N-trimetiIsiIiIpiperidin-2-one. A 35 g di benzilpenicillina solfossido posti in 500 mi di dios-45 sano anidro si aggiungono 120 g di N-trimetiisiIilpiperidin-2--one e si scalda a ricadere per 6 ore. Si raffredda a temperatura ambiente, si aggiungono 600 mi di acqua e si porta il pH a 1,8 con acido cloridrico diluito. Si filtra, si scioglie il precipitato in acetato di etile, si tratta con una soluzione ac-50 quosa diluita di idrossido di potassio e si estrae a pH 7,2. La fase acquosa viene passata su colonna di allumina basica e l'eluito lavato con acetato di etile ed acidificato con acido cloridrico diluito. Dalla fase organica evaporata a secco si ottengono, dopo lavaggio del residuo con etere di petrolio, 55 13,9 g di l-(l-carbossi-2-metilprop-2-enil)3-fenilacetamido--4-(N-piperidin-2-one)tioazetidin-2-one. To 105 g of 5-valerolactam and 180 ml of triethylamine placed in 600 ml of toluene, 165 ml of trimethylchloro-40 silane are added and the mixture is heated under reflux for 4 and a half hours. The mixture is cooled and filtered by washing with 200 ml of toluene and the filtrate is evaporated to dry and the residue distilled to give 158 g of N-trimetiIsiIiIpiperidin-2-one at 79 ° -80 ° C (12 mm Hg). To 35 g of benzylpenicillin sulfoxide placed in 500 ml of anhydrous healthy dios-45, 120 g of N-trimetiisiIilpiperidin-2 - one are added and the mixture is heated under reflux for 6 hours. The mixture is cooled to room temperature, 600 ml of water are added and the pH is brought to 1.8 with dilute hydrochloric acid. It is filtered, the precipitate is dissolved in ethyl acetate, it is treated with a diluted aqueous solution of potassium hydroxide and extracted at pH 7.2. The aqueous phase is passed on a basic alumina column and the eluate washed with ethyl acetate and acidified with dilute hydrochloric acid. From the dry evaporated organic phase, after washing the residue with petroleum ether, 55 13.9 g of l- (1-carboxy-2-methylprop-2-enyl) 3-phenylacetamido - 4- (N-piperidin) are obtained -2-one) tioazetidin-2-one.
Grammi 11 di l-(l-carbossi-2-metilprop-2-enil)3-fenilacet-amido-4-(N-piperidin-2-one)tioazetidin-2-one e 22,9 g di N-trimetilsililpirrolidin-2-one in 200 mi di diossano anidro 60 vengono scaldati a 60°C per 45 minuti, si aggiungono 1,55 mi di piridina e 1,5 mi di bromuro di acetile e si scalda a ricadere per 2 ore. Si raffredda quindi a temperatura ambiente, si aggiungono 300 mi di acqua, si porta il pH a 1,7 con acido cloridrico diluito, quindi si scioglie il precipitato con una 65 soluzione diluita di idrossido di sodio a pH 7,2, si lava con acetato di etile. La soluzione organica viene trattata con 2-etilesanoato potassico e si ottengono 5,6 g di sale potassico dell'acido 7-fenilacetamido-A3-desacetossicefalosporanico. 11 grams of l- (l-carboxy-2-methylprop-2-enyl) 3-phenylacet-starch-4- (N-piperidin-2-one) thioazetidin-2-one and 22.9 g of N-trimethylsilylpyrrolidin- 2-one in 200 ml of anhydrous dioxane 60 are heated to 60 ° C for 45 minutes, 1.55 ml of pyridine and 1.5 ml of acetyl bromide are added and the mixture is heated under reflux for 2 hours. The mixture is then cooled to room temperature, 300 ml of water are added, the pH is brought to 1.7 with dilute hydrochloric acid, then the precipitate is dissolved with a 65 dilute solution of sodium hydroxide at pH 7.2, washed with ethyl acetate. The organic solution is treated with potassium 2-ethylhexanoate and 5.6 g of potassium salt of 7-phenylacetamido-A3-desacethoxy-cephalosporanic acid are obtained.
626369 626369
4 4
Esempio 4 Example 4
Grammi 35 di benzilpenicillina solfossido vengono trattati in 350 mi di diossano anidro con 120 g di trimetilsililcapro-lattame. Si scalda a 55°C per un'ora, quindi si caricano 1,8 mi di piridina e 4,5 di bromuro di acetile e si scalda a ricadere per 6 ore. Si raffredda la miscela a temperatura ambiente e si aggiungono 450 mi di acqua, si porta il pH della miscela a 1,7 con acido solforico diluito, si raffredda a 10°C e si filtra. Il prodotto ottenuto viene spappolato in 50 mi di isobu-tilmetilchetone e rifiltrato dà 25,8 g di acido 7-fenilacetami-do-A3-desacetossicefalosporanico. 35 grams of benzylpenicillin sulfoxide are treated in 350 ml of anhydrous dioxane with 120 g of trimethylsilyl capro-lactam. The mixture is heated to 55 ° C for one hour, then 1.8 ml of pyridine and 4.5 of acetyl bromide are added and the mixture is heated under reflux for 6 hours. The mixture is cooled to room temperature and 450 ml of water are added, the pH of the mixture is brought to 1.7 with dilute sulfuric acid, it is cooled to 10 ° C and filtered. The obtained product is pulped in 50 ml of isobu-tylmethylketone and refiltered gives 25.8 g of 7-phenylacetami-do-A3-desacethoxy-cephalosporanic acid.
Esempio 5 Example 5
Grammi 50 di benzilpenicillina solfossido vengono sospesi in 400 mi di toluene anidro. Alla miscela sono aggiunti a temperatura ambiente 171,5 g di trimetilsililcaprolattame. Si 5 scalda a 60°C per 45 minuti fino a dissoluzione. Indi si caricano 9 g di piridina bromidrato e si porta a ricadere la miscela. Si mantiene la temperatura a 110°C per 2 ore. Si raffredda fino a 65°C e si aggiungono 65 mi di metilisobutil-chetone. Indi si colano nella soluzione 375 mi di acqua pre-io riscaldata a 60°C. Si raffredda la miscela a 30°C e si aggiunge acido solforico diluito al 20% fino a pH 1,2, Si agita per 50 grams of benzylpenicillin sulfoxide are suspended in 400 ml of anhydrous toluene. 171.5 g of trimethylsilyl caprolactam are added to the mixture at room temperature. The mixture is heated to 60 ° C for 45 minutes until dissolved. Then 9 g of pyridine hydrochloride are added and the mixture is brought to reflux. The temperature is maintained at 110 ° C for 2 hours. The mixture is cooled to 65 ° C and 65 ml of methylisobutyl ketone are added. Then 375 ml of pre-io water heated to 60 ° C are poured into the solution. The mixture is cooled to 30 ° C and sulfuric acid diluted 20% to pH 1.2 is added, stirring for
I ora a temperatura ambiente e si filtra lavando con 200 mi di acqua, 150 mi di toluene e 75 mi di metilisobutilchetone. I now at room temperature and is filtered by washing with 200 ml of water, 150 ml of toluene and 75 ml of methylisobutylketone.
II prodotto viene seccato in stufa da vuoto a 50°C. Si otten-15 gono 34,7 g di acido 7-fenilacetamido desacetossicefalospo- The product is dried in a vacuum oven at 50 ° C. 15.7 g of 7-phenylacetamide desacethoxy-cephalosphate were obtained.
ranico. ranico.
v v
Claims (4)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT23825/76A IT1063088B (en) | 1976-06-01 | 1976-06-01 | AZETIDINONIC DERIVATIVES AND PROCEDURE FOR THE PREPARATION OF CEPHALOSPORINE |
KR7701295A KR810000859B1 (en) | 1976-06-01 | 1977-06-01 | Method for preparing derivatives of 7-amino- 3-desacetoxy cephalosporanic acid |
Publications (1)
Publication Number | Publication Date |
---|---|
CH626369A5 true CH626369A5 (en) | 1981-11-13 |
Family
ID=26328424
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CH663377A CH626369A5 (en) | 1976-06-01 | 1977-05-31 | Method for the preparation of derivatives of 7-amino-delta(3)-deacetoxycephalosporanic acid |
Country Status (8)
Country | Link |
---|---|
JP (1) | JPS5323989A (en) |
KR (1) | KR810000859B1 (en) |
CH (1) | CH626369A5 (en) |
DE (1) | DE2724286A1 (en) |
FR (1) | FR2353558A1 (en) |
GB (1) | GB1542049A (en) |
IT (1) | IT1063088B (en) |
YU (1) | YU136477A (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102617602A (en) * | 2012-03-15 | 2012-08-01 | 江苏九九久科技股份有限公司 | Method for synthesizing 7-phenylacetylaminodeacetoxycephalo G acid |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ZA695612B (en) * | 1968-08-23 | 1971-03-31 | Lilly Co Eli | Preparation of cephalosporin compounds |
FR2037858A5 (en) * | 1969-03-11 | 1970-12-31 | Glaxo Lab Ltd | |
BE787618A (en) * | 1971-08-17 | 1973-02-16 | Gist Brocades Nv | PROCESS FOR PREPARING HETEROCYCLIC COMPOUNDS |
GB1465893A (en) * | 1973-02-09 | 1977-03-02 | Gist Brocades Nv | I-carboxypropenyl-4-iminothio-azetidine-2-one derivatives methods for their preparation and use |
-
1976
- 1976-06-01 IT IT23825/76A patent/IT1063088B/en active
-
1977
- 1977-05-28 DE DE19772724286 patent/DE2724286A1/en not_active Ceased
- 1977-05-30 JP JP6390077A patent/JPS5323989A/en active Granted
- 1977-05-30 GB GB7722686A patent/GB1542049A/en not_active Expired
- 1977-05-31 CH CH663377A patent/CH626369A5/en not_active IP Right Cessation
- 1977-06-01 KR KR7701295A patent/KR810000859B1/en active
- 1977-06-01 YU YU01364/77A patent/YU136477A/en unknown
- 1977-06-01 FR FR7717607A patent/FR2353558A1/en active Granted
Also Published As
Publication number | Publication date |
---|---|
JPS5323989A (en) | 1978-03-06 |
IT1063088B (en) | 1985-02-11 |
JPS6153358B2 (en) | 1986-11-17 |
DE2724286A1 (en) | 1977-12-15 |
KR810000859B1 (en) | 1981-08-10 |
GB1542049A (en) | 1979-03-14 |
FR2353558A1 (en) | 1977-12-30 |
YU136477A (en) | 1982-10-31 |
FR2353558B1 (en) | 1983-12-16 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP0022219B1 (en) | 5-oxo- and 5-thioxoproline derivatives, process for their production and pharmaceutical compositions containing them | |
CA1126260A (en) | Penicillins and cephalosporins | |
Peet et al. | Mechanistic observations in the gewald syntheses of 2‐aminothiophenes | |
US5401841A (en) | Process for the production of cephalosporines | |
Applegate et al. | Synthesis of 2-, 4-, and 7-methylthio-substituted cephalosporins | |
SU1282818A3 (en) | Method of producing orthocondensed derivatives of pyrrole | |
US3714156A (en) | Lactam process | |
EP0000645B1 (en) | Isopenicillins, processes for their preparation, and compositions containing them | |
Bose et al. | A 5‐methylthiopenicillin analog and its transformation to novel bicyclic β‐lactams | |
CH626369A5 (en) | Method for the preparation of derivatives of 7-amino-delta(3)-deacetoxycephalosporanic acid | |
FI75165B (en) | FOERBAETTRAT FOERFARANDE FOER FRAMSTAELLNING AV PENICILLANSYRAKLORMETYLESTRAR. | |
GB2048857A (en) | -lactamase inhibitors | |
DE2323395A1 (en) | PROCESS FOR THE MANUFACTURING OF DESACETOXYCEPHALOSPORINES AND NEW INTERMEDIATE PRODUCTS | |
FI64940C (en) | FREQUENCY REFRIGERATION FOR NYA 6-METHOXY-ALPHA-CARBOXIPENICILLINER | |
US4064137A (en) | Penicillin and cephalosporin derivatives and process for preparing the same | |
US4278792A (en) | Method of producing derivatives of 6-β-amidinopenicillanic acid | |
US4424356A (en) | Process for the preparation of 5,6,7,7a-tetrahydro-4H-thieno- 3,2,-c!pyridin-2-one | |
US4091026A (en) | Thiazoleneazetidinones from dithiazeneazetidinones | |
US4304779A (en) | 6-(Nitrogen-containing heterocyclic)hydroxymethylpenicillanic acids, compounds related thereto and processes for their preparation | |
US3971780A (en) | Thio-β-lactam cephalosporins | |
KR910005230B1 (en) | Process for producing azetidinones | |
US3935198A (en) | Process for the preparation of the cephalosporanic acid derivative | |
CA1072544A (en) | Process for preparing penicillins | |
US3781283A (en) | Process for preparing cephem-4-carboxylic acid esters | |
US5066799A (en) | Intermediates for the preparation of aminothiazoloximino cephalosporins |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PL | Patent ceased |