DK142144B - Process for the preparation of 7-alpha-aminoacetamido-cephalosporin-4-carboxylic acid derivatives. - Google Patents
Process for the preparation of 7-alpha-aminoacetamido-cephalosporin-4-carboxylic acid derivatives. Download PDFInfo
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- DK142144B DK142144B DK383974AA DK383974A DK142144B DK 142144 B DK142144 B DK 142144B DK 383974A A DK383974A A DK 383974AA DK 383974 A DK383974 A DK 383974A DK 142144 B DK142144 B DK 142144B
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- acid
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- cephalosporin
- carboxylic acid
- aminoacetamido
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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
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
- C07D501/06—Acylation of 7-aminocephalosporanic acid
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- 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
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Description
H2K4H2K4
Den foreliggende opfindelse angår en særlig fremgangsmåde til fremstilling af 7-oi-aminoacetamido-cephalosporin-4-carboxylsyre-derivater.The present invention relates to a particular process for the preparation of 7-α-aminoacetamido-cephalosporin-4-carboxylic acid derivatives.
Der kendes mange cephalosporinantibiotika med en a-aminoacet-05 amidosubstituent, jfr. f.eks. britiske patentskrifter nr. 985.747, I.I74.335, I.265.315, 1.276.314, 1.283.811, I.284.227 og 1.288.282.Many cephalosporin antibiotics are known with an α-aminoacet-05 amido substituent, cf. eg. British Patent Nos. 985,747, I.I74,335, I.265,315, 1,276,314, 1,283,811, I.284,227 and 1,288,282.
De kendte forbindelser, som er omhandlet i disse og mange andre patentbeskrivelser, kan angives ved den almene formel: 10 R-NH·-1-S S\ 0 J (Ky^-CH^R1 COOR2 15 i hvor R betegner hydrogen, hydroxy, acyloxy eller en thiosubsti-tuent, såsom en heterocyklisk thiogruppe, R betegner hydrogen eller en carboxylsyrebeskyttende gruppe, og R betegner gruppen q q 20 R -CH-CO, hvor R er en delvist eller fuldstændigt umættet nh2 cyklisk hydrocarbylgruppe eller heterocyklisk gruppe. De ovennævnte forbindelser kan fremstilles ved at omsætte den tilsvarende forbindelse, 2 hvor R betegner hydrogen, og R betegner en carboxylsyrebeskyt-25 tende gruppe, med en aktiveret form af syren:The known compounds disclosed in these and many other patent disclosures may be indicated by the general formula: R 1 -NH · -1-SS 2 O (Ky 2 -CH 2 R 1 COOR 2 wherein R represents hydrogen, hydroxy, acyloxy or a thiosubstituent such as a heterocyclic thio group, R represents hydrogen or a carboxylic acid protecting group, and R represents the group qq R -CH-CO where R is a partially or completely unsaturated nh2 cyclic hydrocarbyl group or heterocyclic group. may be prepared by reacting the corresponding compound 2 wherein R represents hydrogen and R represents a carboxylic acid protecting group having an activated form of the acid:
R1 2-CH-COOHR1 2-CH-COOH
NHNH
i4 R* 30 4 hvor R har den ovenfor angivne betydning, og R betegner en aminbeskyttende gruppe, og derefter at fjerne den aminbeskyttende gruppe og om ønsket de-esterificere det resulterende produkt tilwherein R is as defined above and R represents an amine protecting group and then removing the amine protecting group and, if desired, deesterifying the resulting product to
OISLAND
35 dannelse af den tilsvarende forbindelse, hvor R betegner hydrogen.To form the corresponding compound wherein R represents hydrogen.
22
En egnet aminbeskyttende gruppe R er enaminen dannet ved om- 142H4 2 sætning med en passende β-dicarbonylforbindelse, men nyttigheden af den beskyttende gruppe kan undertiden forringes på grund af problemer forbundet med isoleringen af det ønskede produkt, som følger efter spaltningen af enaminen. Som følge af reaktiviteten af 05 β-dicarbonyiforbindelsen, der regenereres ved spaltningsreaktionen, kan den således genreagere med a-aminoacetaminoforbindelsen under påfølgende rensnings- og isoleringstrin, hvilket forårsager formindskelse af udbyttet. Dette problem kan løses ved at udføre enamin-spaltningen på en sådan måde, at den frie aminocephalosporinester 10 udfældes fra reaktionsopløsningsmidlet, efterladende den regenererede β-dicarbonylforbindelse i moderluden, og derpå de-esterificeres, renses og isoleres. Medens sidstnævnte fremgangsmåde fjerner det ovennævnte første problem, løser det ikke problemet med formindsket udbytte, da indførelsen af det yderligere trin med isolering af den 15 frie aminoester med formel I i sig selv bevirker et lige så stort, om ikke større tab i udbytte.A suitable amine protecting group R is the enamine formed by reaction with an appropriate β-dicarbonyl compound, but the usefulness of the protecting group can sometimes be impaired due to problems associated with the isolation of the desired product following the cleavage of the enamine. Thus, due to the reactivity of the 05 β-dicarbonyi compound which is regenerated by the cleavage reaction, it can react with the α-aminoacetamino compound during subsequent purification and isolation steps, causing a decrease in the yield. This problem can be solved by carrying out the enamine cleavage in such a way that the free aminocephalosporin ester 10 is precipitated from the reaction solvent, leaving the regenerated β-dicarbonyl compound in the mother liquor, and then deesterified, purified and isolated. While the latter method removes the aforementioned first problem, it does not solve the problem of diminished yield, since the introduction of the additional step of isolating the free amino ester of formula I per se results in an equal, if not greater, loss in yield.
Den foreliggende opfindelse tilvejebringer en forbedret fremgangsmåde til fremstilling af 7-a-aminoacetamido-cephalosporin-4-carbonyl-syrederivater med den almene formel I: 20 nThe present invention provides an improved process for the preparation of 7-α-aminoacetamido-cephalosporin-4-carboxylic acid derivatives of the general formula I: 20 n
Rx-CH-C- nh2 1Rx-CH-C- nh2 1
_N_N
o/island/
COOHCOOH
hvori Rx betegner phenyl eller 1,4-cyclohexadienyI.wherein Rx represents phenyl or 1,4-cyclohexadienyl.
Fremgangsmåden ifølge opfindelsen er ejendommelig ved, at man 30 1) omsætter en 7-aminocephalosporin-4-carboxylsyre-ester med den almene formel:The process of the invention is characterized in that 1) is reacted with a 7-aminocephalosporin-4-carboxylic acid ester of the general formula:
H2NnN_//<SvNH2NnN _ // <SVN
IIII
35 /- C00R2 2 335 / - C00R2 2 3
U21MU21M
hvori R betegner en esterdannende gruppe, eller et syreadditions-salt deraf, med en forbindelse med den almene formel:wherein R represents an ester-forming group, or an acid addition salt thereof, having a compound of the general formula:
Rx —CH—CO„HRx —CH— CO „H
05 | NH 111 I 9 705 | NH 111 I 9 7
C = CH— C — RC = CH - C - R
i 10 CH3 hvori Rx har den ovenfor anførte betydning, og R^ betegner C-j_^alkyl ell$r C^aikoxy, hvilken forbindelse er en aktiveret form af en a-aminoeddikesyre, hvis aminogruppe er beskyttet ved omsæt-15 ning med en β-dicarbonylforbindelse, 2) spalter den aminobeskyttende gruppe fra den resulterende 7-a-aminoacetamido-cephalosporinforbindelse til frembringelse af en forbindelse med den almene formel: 20 i!in CH 3 wherein R x is as defined above and R 1 represents C 1-6 alkyl or C 1-6 alkoxy, which compound is an activated form of an α-amino acetic acid whose amino group is protected by reaction with a β-dicarbonyl compound, 2) cleaves the amino protecting group from the resulting 7-α-aminoacetamido-cephalosporin compound to produce a compound of the general formula:
Rx-JH—C-NH S S\ nh2 i 25Rx-JH-C-NH S S \ nh2 in 25
25 COOR25 COOR
2 hvori Rx har den ovenfor anførte betydning, og R' betegner hydrogen eller en esterdannende gruppe, 30 3) tilsætter en hydrazin eller semicarbazid i en mængde, som er tilstrækkelig til at modvirke genomsætning af β-dicarbonylforbindeisen dannet ved spaltningen af den aminobeskyttende gruppe, med den under trin 2) dannede 7-of-aminoacetamido-cephaiosporinforbindelse, 35 °9 142144 4 4) om nødvendigt, de-esterificerer en eventuelt dannet cephalosporin-ester til frembringelse af den ønskede 7-a-aminoacetamido-cephalo-spor in -4-carboxy I sy re.2 wherein Rx is as defined above, and R 'is hydrogen or an ester-forming group, 3) adding a hydrazine or semicarbazide in an amount sufficient to counteract the translocation of the β-dicarbonyl compound ice formed by the cleavage of the amino protecting group, with the 7-of-aminoacetamido-cephaiosporin compound, 35 ° 9 formed, if necessary, de-esterifying an optionally formed cephalosporin ester to produce the desired 7-α-aminoacetamido-cephalo trace in 4-carboxy In its re.
I trin 1) beskyttes α-aminosubstituenten ved enamindannelse.In step 1), the α-amino substituent is protected by enamine formation.
05 Fortrinsvis udføres acyleringen i et dipolært aprot opløsningsmiddel såsom dimethylformamid eller acetonitril. Acyleringen udføres normalt ved en temperatur på ca. 0°C eller derunder, og mest fordelagtigt ved en temperatur i intervallet fra -15°C til -50°C.Preferably, the acylation is carried out in a dipolar aprotic solvent such as dimethylformamide or acetonitrile. The acylation is usually performed at a temperature of approx. 0 or less, and most advantageously at a temperature in the range of -15 ° C to -50 ° C.
I den 7-aminocephalosporin-4-carboxylsyreester (II), som acyl-10 eres, kan et syreadditionssalt f.eks. være hydrochlorid- eller tosylat-saltet, og R kan betegne enhver af de grupper, som i almindelighed anvendes til beskyttelse af carboxylsyrefunktionen i et cephalosporin-molekyle. Eksempler på sådanne grupper er benzyl, p-nitrobenzyl, p-methoxybenzyl, 3,5-dimethoxybenzyl, diphenylmethyl, 2,2,2-tri-15 chloroethyl, t-butyl, phenacyl, benzyloxymethyl og tetrahydropyranyl.In the 7-aminocephalosporin-4-carboxylic acid ester (II), which is acylated, an acid addition salt can e.g. may be any hydrochloride or tosylate salt, and R may represent any of the groups commonly used to protect the carboxylic acid function of a cephalosporin molecule. Examples of such groups are benzyl, p-nitrobenzyl, p-methoxybenzyl, 3,5-dimethoxybenzyl, diphenylmethyl, 2,2,2-trichloroethyl, t-butyl, phenacyl, benzyloxymethyl and tetrahydropyranyl.
Mest fordelagtigt er forbindelsen med formel II, p-nitrobenzyl-7--aminodesacetoxycephalosporanat.Most advantageous is the compound of formula II, p-nitrobenzyl-7-aminodesacetoxycephalosporanate.
Den i trin 1) anvendte forbindelse med den almene formel III fremstilles let ved at man omsætter en syre med formlenThe compound of general formula III used in step 1) is readily prepared by reacting an acid of the formula
20 Rx-CH-COOHRx-CH-COOH
NH2 eller et salt deraf med en β-dicarbonylforbindelse med formlen CHg-CO-CF^-CO-R^. Da of-carbonatomet i syren med formel III er et 25 asymmetrisk carbonatom, kan syren eksistere i to optisk aktive isomere former, D- og L-former, såvel som i form af en racemisk blanding.NH 2 or a salt thereof with a β-dicarbonyl compound of the formula CH 2 -CO-CF 2 -CO-R 2. Since the off-carbon atom of the acid of formula III is an asymmetric carbon atom, the acid may exist in two optically active isomeric forms, D and L forms, as well as in the form of a racemic mixture.
Som det vil kunne forstis, bibeholdes konfigurationen af a-carbonatomet i syren med formel III uforandret under acyleringsreaktionen, og da D-formen af cephalosporinslutproduktet foretrækkes, foretrækkes 30 det også at anvende en syre med formel III, som befinder sig på D-formen. Mest fordelagtigt anvendes D-formen af en syre med formel III, hvor R^ betegner methoxy.As will be appreciated, the configuration of the α-carbon atom in the acid of Formula III is maintained unchanged during the acylation reaction, and since the D-form of the cephalosporin end product is preferred, it is also preferred to use an acid of Formula III which is in the D-form. Most advantageously, the D-form of an acid of formula III is used, wherein R 2 represents methoxy.
Som angivet ovenfor er forbindelsen III en aktiveret form af en oi-aminoeddikesyre. Denne aktiverede form kan være syrechloridet 35 eller anhydridet, men er fortrinsvis et blandet anhydrid, f.eks. dannet ved omsætning af et C-|_^ alkylchlorformiat, især methylchlorformiat med et salt af den særlige syre.As indicated above, Compound III is an activated form of an o-aminoacetic acid. This activated form may be the acid chloride or anhydride, but is preferably a mixed anhydride, e.g. formed by reaction of a C 1-6 alkyl chloroformate, especially methyl chloroformate with a salt of the particular acid.
142144 5 I trin 2) fjernes den aminobeskyttende gruppe pi i og for sig kendt måde, f.eks. ved syrehydrolyse under anvendelse af fortyndet eddikesyre eller saltsyre. Efter hydrolysen opnås den frie 7-a-amino-acetamidocephalosporin sammen med den regenererede β-dicarbonyl-05 forbindelse, der oprindeligt anvendtes til beskyttelse af a-aminoeddike-syren. Herefter tilsættes i trin 3) tilstrækkeligt hydrazin eller semi-carbazid til at modvirke genomsætning af β-dicarbonylforbindeisen med oi-aminogruppen i 7-acetaminocephalosporinen. Hydrazinen vil normalt blive anvendt i ækvimolære forhold med hensyn til β-di-10 carbonylforbindelsen, men om ønsket kan der anvendes et overskud deraf.In step 2), the amino protecting group p1 is removed in a manner known per se, e.g. by acid hydrolysis using dilute acetic or hydrochloric acid. Following the hydrolysis, the free 7-α-amino-acetamidocephalosporin is obtained together with the regenerated β-dicarbonyl-05 compound originally used to protect the α-amino-acetic acid. Then, in step 3), sufficient hydrazine or semi-carbazide is added to counteract the transposition of the β-dicarbonyl compound ice with the o-amino group of the 7-acetaminocephalosporin. The hydrazine will normally be used in equimolar conditions with respect to the β-di-carbonyl compound, but if desired, an excess thereof may be used.
Efter dette trin de-esterificeres i trin 4) om nødvendigt den resulterende cephalosporinester på sædvanlig mide, f.eks. ved behandling med vandig eddikesyre og zinkstøv, behandling med vand-15 fri trifluoreddikesyre, behandling med zink og vandig mineralsyre, såsom saltsyre eller ved hjælp af enhver anden mild hydrolyse- eller hydrogenolysereaktion, afhængende af estergruppen, som skal fjernes.After this step, in step 4), if necessary, the resulting cephalosporin ester is de-esterified in the usual manner, e.g. by treatment with aqueous acetic acid and zinc dust, treatment with anhydrous trifluoroacetic acid, treatment with zinc and aqueous mineral acid such as hydrochloric acid or by any other mild hydrolysis or hydrogenolysis reaction, depending on the ester group to be removed.
Det vil derfor ses, at den til spaltning af den enaminbeskyttende gruppe i trin 2) anvendte syrehydrolyse eller hydrogenolyse i mange 20 tilfælde også vil fremkalde den ønskede de-esterificering, og det er et foretrukket træk ved fremgangsmåden ifølge opfindelsen, at ester-og enamingrupperne, som anvendes til beskyttelse af reaktanterne med hhv. formel II og III, bør være udvalgt således, at en sådan 2 samtidig fjernelse tillades. Hvis R f.eks. betegner p-nitrobenzyl, 25 og betegner methoxy, vil anvendelsen af zink og saltsyre i trin 2) samtidig afblokere amino- og carboxyfunktionerne til direkte dannelse af den ønskede 7-a-aminoacetamidocephalosporin-4-carboxylsyre, som efter tilsætning af hydrazinforbindelsen til reaktionsblandingen kan renses og isoleres på konventionel måde.Therefore, it will be seen that the acid hydrolysis or hydrogenolysis used in cleavage of the enamine protecting group in step 2) will in many cases also produce the desired deesterification, and it is a preferred feature of the process of the invention that the ester and enamine groups which is used to protect the reactants with respectively. formulas II and III, should be selected such that such 2 simultaneous removal is permitted. For example, if R represents p-nitrobenzyl, and represents methoxy, the use of zinc and hydrochloric acid in step 2) simultaneously blocks the amino and carboxy functions to directly form the desired 7-α-aminoacetamidocephalosporin-4-carboxylic acid, which after addition of the hydrazine compound to the reaction mixture can is purified and isolated by conventional means.
30 Som en foretrukket anvendelse af fremgangsmåden ifølge opfind elsen kan nævnes fremstillingen af den antibiotiske cephalosporin kendt som cephalexin, dvs. forbindelsen med formlen: 35 6 142U4 ^-CH-CO-NH —i-|^δΧν 05 V=l/NH2 I-N CH„ q/ ^As a preferred use of the method of the invention may be mentioned the preparation of the antibiotic cephalosporin known as cephalexin, i.e. compound of formula: 6 6 142U4 ^ -CH-CO-NH-i | ^ δΧν 05 V = 1 / NH2 I-N CH2 q / ^
COOHCOOH
10 Ved fremstilling af cephalexin ved fremgangsmåden ifølge op findelsen omsættes fortrinsvis p-nitrobenzylesteren af 7-aminodes-acetoxycephalosporansyre med et blandet anhydrid af N-(2-methoxy-carbonyl-1-methylvinyl)-D-a-phenylglycin i dimethylformamid, idet den resulterende p-nitrobenzylester af 7-[N-(2-methoxycarbonyl-1-15 -methylvinyl)-D-ci-aminophenylacetamido]desacetoxycephalosporansyre reduceres i et surt medium til fjernelse af diamino- og car boxy beskyttende grupper, hvorefter en hydrazinforbindelse tilsættes i tilstrækkelig mængde til at modvirke genomsætning af methylacetoacetatet med den således fremstillede cephalexin, og sidstnævnte forbindelse iso-20 leres så på konventionel måde til dannelse af cephalexin med en høj grad af renhed. Især er den resulterende cephalexin i alt væsentligt fri for de aromatiske aminurenheder, som kan være til stede i cephalexin fremstillet ved hjælp af kendte fremgangsmåder, som indebærer en aminbeskyttet phenylglycinacylering af p-nitrobenzylesteren af 25 7-aminodesacetoxycephalosporansyre. Skønt sådanne fra teknikken kendte fremgangsmåder kan give cephalexin i højt udbytte, gør nærværelsen af de førnævnte aromatiske aminurenheder cephalexinen uanvendelig uden omfattende yderligere rensningstrin, som bevirker et hurtigt generelt udbyttetab og væsentlige yderligere omkostninger.In the preparation of cephalexin by the process of the invention, preferably the p-nitrobenzyl ester of 7-aminodes-acetoxycephalosporanoic acid is reacted with a mixed anhydride of N- (2-methoxy-carbonyl-1-methylvinyl) -Da-phenylglycine in dimethylformamide, the resulting p -nitrobenzyl ester of 7- [N- (2-methoxycarbonyl-1-15-methylvinyl) -D-ci-aminophenylacetamido] desacetoxycephalosporanoic acid is reduced in an acidic medium to remove diamino and carboxy protecting groups, after which a hydrazine compound is added in sufficient quantity to counteract reaction of the methyl acetoacetate with the cephalexin thus produced, and the latter compound is then isolated in conventional manner to form cephalexin with a high degree of purity. In particular, the resulting cephalexin is substantially free of the aromatic amino acid units which may be present in cephalexin prepared by known methods which involve an amine protected phenylglycine acylation of the p-nitrobenzyl ester of 25-aminodesacetoxycephalosporanoic acid. Although such methods known in the art can provide high yield cephalexin, the presence of the aforementioned aromatic amino acid units makes the cephalexin useless without extensive additional purification steps which cause a rapid overall loss of yield and significant additional costs.
30 Fremgangsmåden ifølge opfindelsen belyses i det følgende nærmere ved eksempler.The process according to the invention is illustrated in the following by way of example.
Eksempel 1Example 1
Til en 1-liter kolbe indeholdende dimethylformamid ved 0°C 35 sattes 24,8 g natrium N-(2-methoxycarbony!-1-methylviny!)-D-oi- -phenylglycin (fremstillet ud fra natrium D-a-phenylglycin og methylacetoacetat. Blandingen afkøledes til -40°C, og methylchlor-To a 1-liter flask containing dimethylformamide at 0 ° C was added 24.8 g of sodium N- (2-methoxycarbonyl-1-methylvinyl) -D-o-phenylglycine (prepared from sodium Da-phenylglycine and methylacetoacetate. The mixture was cooled to -40 ° C and methyl chloro-
U2UAU2UA
7 formiat (7,5 ml) og dimethylbenzylamin (0,26 ml) tilsattes. Efter omrøring i 25 minutter tilsattes p-nitrobenzyl 7-aminodesacetoxycephalo-sporanat (32,8 g) i form af hydrochloridsaltet deraf efterfulgt af triethylamin (12,1 ml) og dimethylformamid (140 ml) i løbet af et 05 tidsrum på 20 minutter. Reaktionsblandingen omrørtes i 2 timer ved -25 til -35°C og opvarmedes derpå til 0°C, og vand (32 ml) tilsattes.7 formate (7.5 ml) and dimethylbenzylamine (0.26 ml) were added. After stirring for 25 minutes, p-nitrobenzyl 7-aminodesacetoxycephalo-sporanate (32.8 g) was added in the form of its hydrochloride salt, followed by triethylamine (12.1 ml) and dimethylformamide (140 ml) over a period of 20 minutes. The reaction mixture was stirred for 2 hours at -25 to -35 ° C and then heated to 0 ° C and water (32 ml) was added.
Til den resulterende opløsning sattes saltsyre (54 ml) efterfulgt af zink (21,8 g) i portioner i løbet af et tidsrum på 5 minutter, idet temperaturen holdtes ved 5-10°C. Yderligere saltsyre (35 ml) tilsattes, 10 og opløsningen omrørtes ved 15-20°C i 7 timer.To the resulting solution was added hydrochloric acid (54 ml) followed by zinc (21.8 g) in portions over a period of 5 minutes, keeping the temperature at 5-10 ° C. Additional hydrochloric acid (35 ml) was added, and the solution was stirred at 15-20 ° C for 7 hours.
pH-værdien indstilledes til 3,3 med triethylamin, og semicarbazid-hydrochloridet (9,5 g) tilsattes. Blandingens pH-vaerdi indstilledes tilbage til pH 3 med yderligere triethylamin og omrørtes i 30 minutter ved pH 3. Den resulterende blanding indstilledes langsomt i løbet af 15 4 timer til pH 6,8 ved tilsætning af triethylamin, idet der udførtes en podning, nlr en pH-værdi på 4,5 nåedes. Det udfældede cephalexin frafiltreredes, vaskedes med dimethylformamid (200 ml), og den udvundne cephalexin udgør 75%.The pH was adjusted to 3.3 with triethylamine and the semicarbazide hydrochloride (9.5 g) was added. The pH of the mixture was adjusted back to pH 3 with additional triethylamine and stirred for 30 minutes at pH 3. The resulting mixture was slowly adjusted over 15 hours to pH 6.8 by the addition of triethylamine, taking a grafting operation. pH of 4.5 was reached. The precipitated cephalexin was filtered off, washed with dimethylformamide (200 ml) and the recovered cephalexin was 75%.
20 Eksempel 2Example 2
Den ovenstående fremgangsmåde gentoges, bortset fra, at trinnet med tilsætning af semicarbazidhydrochlorid udelodes. Udbyttet af cephalexin faldt til 48-52%, hvilket viser værdien af fremgangsmåden ifølge opfindelsen.The above procedure was repeated except that the step of adding semicarbazide hydrochloride is omitted. The yield of cephalexin decreased to 48-52%, showing the value of the process according to the invention.
2525
Eksempel 3Example 3
Den i krav 1 omhandlede fremgangsmåde gentoges, bortset fra at hydrazinhydratet (4,26 g) tilsattes i stedet for semicarbazidhydro-chloridet. Efter tilsætningen steg pH-værdien til 4,5-5,0, og reaktions-30 blandingen podedes og omrørtes i 30 minutter. pH-værdien hævedes derefter langsomt til 6,8 som beskrevet i eksempel 1, idet det udfældede cephalexin frafiltreredes, vaskedes med dimethylformamid og genvandtes i et udbytte på 70-75%.The process of claim 1 was repeated except that the hydrazine hydrate (4.26 g) was added in place of the semicarbazide hydrochloride. After the addition, the pH rose to 4.5-5.0 and the reaction mixture was seeded and stirred for 30 minutes. The pH was then slowly raised to 6.8 as described in Example 1, filtered off the precipitated cephalexin, washed with dimethylformamide and recovered in a 70-75% yield.
35 Eksempel 4Example 4
Den i eksempel 1 omhandlede fremgangsmåde gentoges, bortset fra at natrium N-(2-methoxycarbonyl-1-methy!vinyl)-D-or-phenylglycin 142144 8 erstattedes med natrium N-(2-methoxycarbonyl-1-methylvinyl)-D-ci--cyclohex-1,4-dienylglycin. Et forbedret udbytte af cephradin opnåedes i sammenligning med det udbytte, som kan opnås, når fremgangsmåden udføres i fraværelse af semicarbazid.The procedure of Example 1 was repeated except that sodium N- (2-methoxycarbonyl-1-methylvinyl) -D-or-phenylglycine was replaced by sodium N- (2-methoxycarbonyl-1-methylvinyl) -D- ci - cyclohex-1,4-dienylglycin. An improved yield of cephradine was obtained in comparison with the yield which can be obtained when the method is carried out in the absence of semicarbazide.
Claims (2)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB3433773 | 1973-07-19 | ||
| GB3433773A GB1473090A (en) | 1973-07-19 | 1973-07-19 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK383974A DK383974A (en) | 1975-03-17 |
| DK142144B true DK142144B (en) | 1980-09-08 |
| DK142144C DK142144C (en) | 1981-02-09 |
Family
ID=10364389
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK383974AA DK142144B (en) | 1973-07-19 | 1974-07-17 | Process for the preparation of 7-alpha-aminoacetamido-cephalosporin-4-carboxylic acid derivatives. |
Country Status (25)
| Country | Link |
|---|---|
| JP (1) | JPS6113478B2 (en) |
| AR (1) | AR211686A1 (en) |
| AT (1) | AT338972B (en) |
| BE (1) | BE817790A (en) |
| BG (1) | BG25799A3 (en) |
| CA (1) | CA1024508A (en) |
| CH (1) | CH582189A5 (en) |
| CS (1) | CS188188B2 (en) |
| DD (1) | DD112134A5 (en) |
| DE (1) | DE2434017C3 (en) |
| DK (1) | DK142144B (en) |
| ES (1) | ES428386A1 (en) |
| FR (1) | FR2237635B1 (en) |
| GB (1) | GB1473090A (en) |
| HU (1) | HU168065B (en) |
| IE (1) | IE39506B1 (en) |
| IL (1) | IL45101A (en) |
| NL (1) | NL187811C (en) |
| PH (1) | PH11147A (en) |
| PL (1) | PL91364B1 (en) |
| RO (1) | RO64483A (en) |
| SE (1) | SE415765B (en) |
| SU (1) | SU622409A3 (en) |
| YU (1) | YU182574A (en) |
| ZA (1) | ZA743890B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1126544B (en) * | 1979-12-07 | 1986-05-21 | Dobfar Spa | PROCEDURE FOR THE PREPARATION OF 7-AMINO-DESACETOXY CEPHALOSPORANIC ACID DERIVATIVES |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR1602620A (en) * | 1965-03-08 | 1971-01-04 | Antibacterial cephalosporin cpds |
-
1973
- 1973-07-19 GB GB3433773A patent/GB1473090A/en not_active Expired
-
1974
- 1974-06-17 IE IE1263/74A patent/IE39506B1/en unknown
- 1974-06-18 CA CA202,732A patent/CA1024508A/en not_active Expired
- 1974-06-18 ZA ZA00743890A patent/ZA743890B/en unknown
- 1974-06-21 IL IL45101A patent/IL45101A/en unknown
- 1974-06-28 YU YU01825/74A patent/YU182574A/en unknown
- 1974-07-05 PH PH16018A patent/PH11147A/en unknown
- 1974-07-10 CH CH948774A patent/CH582189A5/xx not_active IP Right Cessation
- 1974-07-10 JP JP49079044A patent/JPS6113478B2/ja not_active Expired
- 1974-07-10 NL NLAANVRAGE7409299,A patent/NL187811C/en not_active IP Right Cessation
- 1974-07-10 CS CS744896A patent/CS188188B2/en unknown
- 1974-07-16 DE DE2434017A patent/DE2434017C3/en not_active Expired
- 1974-07-17 DD DD179967A patent/DD112134A5/xx unknown
- 1974-07-17 FR FR7424795A patent/FR2237635B1/fr not_active Expired
- 1974-07-17 DK DK383974AA patent/DK142144B/en not_active IP Right Cessation
- 1974-07-17 ES ES428386A patent/ES428386A1/en not_active Expired
- 1974-07-18 BE BE146673A patent/BE817790A/en not_active IP Right Cessation
- 1974-07-18 HU HULI261A patent/HU168065B/hu unknown
- 1974-07-18 AR AR254755A patent/AR211686A1/en active
- 1974-07-18 SE SE7409415A patent/SE415765B/en not_active IP Right Cessation
- 1974-07-18 SU SU742045556A patent/SU622409A3/en active
- 1974-07-18 PL PL1974172840A patent/PL91364B1/pl unknown
- 1974-07-19 BG BG7400027304A patent/BG25799A3/en unknown
- 1974-07-19 AT AT597874A patent/AT338972B/en active
- 1974-07-19 RO RO7479536A patent/RO64483A/en unknown
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PUP | Patent expired |