DK143502B - ANALOGY PROCEDURE FOR PREPARING 7-AMINO-CEPHALOSPORANIC ACID DERIVATIVES - Google Patents
ANALOGY PROCEDURE FOR PREPARING 7-AMINO-CEPHALOSPORANIC ACID DERIVATIVES Download PDFInfo
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- DK143502B DK143502B DK60671A DK60671A DK143502B DK 143502 B DK143502 B DK 143502B DK 60671 A DK60671 A DK 60671A DK 60671 A DK60671 A DK 60671A DK 143502 B DK143502 B DK 143502B
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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
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/36—Methylene radicals, substituted by sulfur atoms
-
- 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
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
-
- 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
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group
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- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Description
(19) DANMARK (®(19) DENMARK (®
É| (12) FREMLÆGGELSESSKRIFT od 11+3502 BÉ | (12) PUBLICATION WRITE OR 11 + 3502 B
DIREKTORATET FOR PATENT- OG VAREMÆRKEVÆSENETDIRECTORATE OF THE PATENT AND TRADEMARKET SYSTEM
(21) Ansøgning nr. 606/71 (51) Int.CI.3 C 07 D 601 /2A(21) Application No. 606/71 (51) Int.CI.3 C 07 D 601 / 2A
(22) Indleveringsdag 10. feb. 1971 (24) Løbedag 10. feb. 1 971 (41) Aim. tilgængelig 12. aug. 1971 (44) Fremlagt 31 · aug. 1981 (86) International ansøgning nr. -(86) International indleveringsdag -(85) Videreførelsesdag -(62) Stamansøgning nr. -(22) Filing day Feb 10 1971 (24) Race day 10 Feb 1 971 (41) Aim. available Aug. 12 1971 (44) Presented 31 Aug. 1981 (86) International Application No. - (86) International Filing Day - (85) Continuation Day - (62) Master Application No. -
(30) Prioritet 11. feb. 1970, 11620/70, JP(30) Priority Feb 11 1970, 11620/70, JP
(71) Ansøger TAKEDA CHEMICAL INDUSTRIES LTD., Osaka, JP.(71) Applicant TAKEDA CHEMICAL INDUSTRIES LTD., Osaka, JP.
(72) Opfinder Toshihiro Ishiguro, JP: Takeshi Fugono, JP: Hiroaki(72) Inventor Toshihiro Ishiguro, JP: Takeshi Fugono, JP: Hiroaki
Noraura, JP.Noraura, JP.
(74) Fuldmægtig ingeniørfirmaet Budde, Schou & Co.(74) The engineering firm Budde, Schou & Co.
(54) Analogifremgangsmåde til fremstil« ling af 7-amlno-cephaloeporansyre« derivater.(54) Analogous procedure for the preparation of 7-amino-cephaloeporanoic acid derivatives.
Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af hidtil ukendte 7-amino-cephalosporansyrederivater, som ]Q er aktive mod grampositive og gramnegative patogene bakterier. Opfin- \1 delsen angår mere specielt fremstillingen af 7-(a-sulfoacylamido)-cep- halosporansyrer.The present invention relates to an analogous process for the preparation of novel 7-amino-cephalosporanoic acid derivatives which are active against Gram-positive and Gram-negative pathogenic bacteria. More particularly, the invention relates to the preparation of 7- (α-sulfoacylamido) -cephalosporanoic acids.
O Der findes mange cephalosporansyrederivater^ som kan anvendes ί mod grampositive og/eller gramnegative mikroorganismer.There are many cephalosporanoic acid derivatives which can be used against Gram-positive and / or Gram-negative microorganisms.
Fra USA-patentskrift nr. 3.278.531 kendes cephalosporinderi-^ vater med den almene formel 2 143502US Patent No. 3,278,531 discloses cephalosporine derivatives of the general formula 2 143502
H\ SH \ S
n-ch—ce nch0 1/ I I I 2n-ch — ce nch0 1 / I I I 2
R /-N\c^C-CH2ZR / -N \ c ^ C-CH 2 Z
0 I0 I
i hvilken substituenterne kan have en lang række betydninger, men hvor i R f.eks. kan betyde aralkenoyl eller en acylgruppe* Z kan betydein which the substituents may have a variety of meanings, but where in R e.g. may mean aralkenoyl or an acyl group * Z may mean
-SO-LAKE
og Y kan betyde COOH.and Y may mean COOH.
Fra beskrivelsen til dansk patentansøgning nr. 3770/71 kendes endvidere cephalosporinforbindelser med formlenFurther, from the specification to Danish patent application No. 3770/71, cephalosporin compounds of the formula are known.
Sv XSv X
R-NH-_f Y.R-NH-f Y
1-N J-CH2S-f |[1-N J-CH 2 S-f | [
- </ Y- </ Y
COOH JCOOH J
hvor R kan betyde en acylgruppe^ og X kan betyde et hydrogenatom eller et halogenatom.wherein R may represent an acyl group, and X may represent a hydrogen atom or a halogen atom.
Forbindelserne fremstillet ved den her omhandlede fremgangsmåde har imidlertid MIC-værdier på 50 Mg/ml eller mindre mod Ps. aeruginosa j mens forbindelserne kendt fra det ovennævnte USA-patentskrift ikke er virksomme herimod^ og de fra beskrivelsen til dansk patentansøgning nr. 3770/71 kendte forbindelser har MIC-værdier på over 100 iiig/ml mod denne mikroorganisme. De foreliggende forbindelser har således en bedre virkning overfor især Pseudomonas end de kendte forbindelser .However, the compounds prepared by the present process have MIC values of 50 Mg / ml or less against Ps. aeruginosa while the compounds known from the aforementioned United States Patent are not effective thereto and the compounds known from the specification for Danish Patent Application No. 3770/71 have MIC values of over 100 µg / ml against this microorganism. Thus, the present compounds have a better effect on Pseudomonas in particular than the known compounds.
De her omhandlede forbindelser har den almene formelThe compounds of this invention have the general formula
SS
R—CHC0NH--Y.R CHC0NH - Y.
I II I
S0,M J-„N ^ 3 / cHg-x GOOM4 5 143502 i hvilken R betyder hydrogen, alkyl med 1-6 carbonatomer eller phenyl, M og M' kan være ens eller forskellige og hver især betyder hydrogen, alkalimetal, jordalkalimetal eller organisk amin, og X betyder ✓S, -OCOCH-j eller -S- ^ J| l oWherein R means hydrogen, alkyl of 1-6 carbon atoms or phenyl, M and M 'may be the same or different and each means hydrogen, alkali metal, alkaline earth metal or organic amine and X means ✓S, -OCOCH-j or -S- ^ J | l o
De her omhandlede forbindelser er hidtil ukendte, da de indeholder a-sulfoacylaminogruppen i 7-stillingen. Typiske forbindelser er repræsenteret ved følgende: (1) R = phenyl, M = M' = Na, X = -OCOCH^ (2) R = Η, M = M' = Na, X = -OCOCH^ (3) R = CH^-, M = M' = Na, X = -OCOCH^ (4) R = CH5(CH2)5-, M = M1 = Na, X = -OCOCHy og Λ *The compounds of this invention are novel as they contain the α-sulfoacylamino group at the 7-position. Typical compounds are represented by the following: (1) R = phenyl, M = M '= Na, X = -OCOCH ^ (2) R = Η, M = M' = Na, X = -OCOCH ^ (3) R = CH2 -, M = M '= Na, X = -OCOCH ^ (4) R = CH5 (CH2) 5-, M = M1 = Na, X = -OCOCHy and Λ *
(5) R = phenyl, M = M1 = Na, X - -S-L JJ(5) R = phenyl, M = M1 = Na, X - -S-L YY
0 R kan betyde ethyl, n-propyl, isopropyl, isobutyl, n-hexyl, og cyclohexyl. M og M’ kan betyde kalium, calcium, magnesium eller andre ugiftige alkali- eller jordalkalimetaller. Desuden kan M og M1 betyde ugiftige organiske aminer såsom triethylamin, pro-cain, dibenzylamin, N-benzyl^-phenethylamin, 1-ephenamin, og N,N1-bisdehydroabiethylethylendiamin. Andre aminer, som har været anvendt til saltdannelse med benzylpenicillin, kan også anvendes.O R may mean ethyl, n-propyl, isopropyl, isobutyl, n-hexyl, and cyclohexyl. M and M 'may mean potassium, calcium, magnesium or other non-toxic alkaline or alkaline earth metals. In addition, M and M1 may represent non-toxic organic amines such as triethylamine, procaine, dibenzylamine, N-benzyl-phenethylamine, 1-ephenamine, and N, N1-bisdehydroabiethylethylenediamine. Other amines which have been used for salt formation with benzylpenicillin may also be used.
De her omhandlede forbindelser har både sulfo- og carboxylgrup-per og kan være enten sure eller neutrale salte afhængigt af ovennævnte sure gruppers surhedsgrad. Der findes ét eller to asymmetriske carbonatomer i molekylet. De her omhandlede forbindelser kan forekomme i to optisk aktive former (D- og L-diastereoisomere), når a-sulfocarb-oxylsyrer, hvor α-carbonatomet er asymmetrisk, anvendes som udgangsmaterialer.The compounds of the present invention have both sulfo and carboxyl groups and may be either acidic or neutral salts depending on the acidity of the above acidic groups. There are one or two asymmetric carbon atoms in the molecule. The compounds of this invention may exist in two optically active forms (D and L diastereoisomers) when α-sulfocarboxylic acids, wherein the α-carbon atom is asymmetric, are used as starting materials.
Forbindelserne er virksomme mod Pseudomonas aeruginosa, Escherichia coli, Proteus vulgaris, Proteus morganii, Proteus mira-billis, Klebsiella pneumoniae, Staphylococcus aureus, .Bacillus subti-lis, Sarcina lutea og lignende. Forbindelserne kan administreres oralt, ved subcutan injektion eller ved intravenøs injektion'.: 'Cos'iéstørrelsen ’λ.' 4 143502 er fra ca. 5 til 500 mg/kg/dag, fortrinsvis ca. 10-200 mg/kg/dag, med 2-k daglige doser mod f.eks. pseudomonasinfektioner.The compounds are effective against Pseudomonas aeruginosa, Escherichia coli, Proteus vulgaris, Proteus morganii, Proteus mira-billis, Klebsiella pneumoniae, Staphylococcus aureus, Bacillus subtilis, Sarcina lutea and the like. The compounds can be administered orally, by subcutaneous injection or by intravenous injection ':' Cos'ié size 'λ.' 4 143502 is from approx. 5 to 500 mg / kg / day, preferably approx. 10-200 mg / kg / day, with 2-k daily doses against e.g. pseudomonas infections.
Fremgangsmåden ifølge opfindelsen er ejendommelig ved, at 7-aminocephalosporansyre som sådan, i form af et salt eller i form af en let sønderdelefig ester med formlenThe process of the invention is characterized in that 7-aminocephalosporanoic acid as such, in the form of a salt or in the form of a slightly decomposable ester of the formula
SS
YNH--s' η J— 1 2YNH - s' η J— 1 2
C00Z'—RC00Z'-R
'R4 i'hvilken X er defineret som ovenfor, Z betyder silicium eller tin, 23 ii R , r og R er ens eller forskellige carbonhydridgrupper, og en af dem kan være halogen, og de desuden i dette tilfælde kan kombineres med et aktivt hydrogenatom under dannelse af en polymer, og Y betyder et hydrogenatom eller -ZR^R^R4, omsættes med en a-sulfocarboxylsyre med formlen'R4 in which X is defined as above, Z means silicon or tin, 23 in R, R and R are the same or different hydrocarbon groups and one of them may be halogen and in addition in this case they may be combined with an active hydrogen atom to form a polymer and Y is a hydrogen atom or -ZR 1 R 2 R 4, reacted with an alpha-sulfocarboxylic acid of the formula
HH
R-OCOOHR OCOOH
rr
SO^HSO ^ H
hvor R er defineret som ovenfor, eller et funktionelt derivat deraf, hvorpå om ønsket a) når der er anvendt en let sønderdelelig ester, en i kondensationsproduktet tilstedeværende estergruppe spaltes ved behandling med vand eller en lavere alkohol, og/eiler b) en forbindelse, hvor X er -OCOCH^, omsættes med 2-mercaptopyridin-oxid med formlen G-sh 1· 0 5 143502 eller et salt heraf til dannelse af en forbindelse, hvor X betyderwherein R is as defined above, or a functional derivative thereof, wherein, if desired a) when a slightly decomposable ester, an ester group present in the condensation product is cleaved by treatment with water or a lower alcohol, and / or b) a compound; where X is -OCOCH 2, is reacted with 2-mercaptopyridine oxide of the formula G-sh 1 · 0 5 143502 or a salt thereof to form a compound wherein X is
OISLAND
i 0 og/eller c) en forbindelse, hvor M og/eller M1 er hydrogen, på 1 og for sig kendt måde omdannes til en forbindelse, hvor M og/eller M1 er alkalimetal, jordalkalimetal eller en organisk amin.in 0 and / or c) a compound wherein M and / or M1 is hydrogen is converted in a manner known per se to a compound wherein M and / or M1 is alkali metal, alkaline earth metal or an organic amine.
α-Sulfophenyleddikesyre, a-sulfopropionsyre, a- sulf oeddikesyre og andre er kommercielt tilgaangelige og fremstilles ved sulfonering af de tilsvarende carboxylsyrer med svovlsyreanhydrld. Sulfogryppen kan eventuelt beskyttes i form af sulfonamid eller sulfonat under kondensationen med 7-aminocephalosporansyre.α-Sulfophenylacetic acid, α-sulfopropionic acid, α-sulfonic acetic acid and others are commercially available and are prepared by sulfonating the corresponding carboxylic acids with sulfuric anhydride. The sulfogroup may optionally be protected in the form of sulfonamide or sulfonate during the condensation with 7-aminocephalosporanoic acid.
Funktionelle derivater af a-sulfocarboxylsyrerne ar carboxyl-syrehalogenider såsom chlorider eller bromider, blandede anhydrider såsom lavere alkyloxy- eller aralkyloxycarbonsyreanhydrider, a-toluen-sulfonsyreanhydrider, azider eller aktiverede estere, f.eks. med p-nj-trophenol, 2,4-dinitrophenol eller pentachlorphenol eller carboazid. Disse derivater kan fås ud fra α-sulfocarboxylsyren på vilkårlig konven»· tionel måde. Syrehalogenideme fremstilles f.eks. ved at behandle α-sulfocarboxylsyren med et halogeneringsmiddel såsom thionylqhlorid, phosphoroxychlorid eller phosphoroxybromid.Functional derivatives of the α-sulfocarboxylic acids are carboxylic acid halides such as chlorides or bromides, mixed anhydrides such as lower alkyloxy or aralkyloxycarboxylic anhydrides, α-toluene sulfonic anhydrides, azides or activated esters, e.g. with p-nj-trophenol, 2,4-dinitrophenol or pentachlorophenol or carboazide. These derivatives can be obtained from the α-sulfocarboxylic acid in any conventional manner. The acid halides are prepared e.g. by treating the α-sulfocarboxylic acid with a halogenating agent such as thionyl chloride, phosphorus oxychloride or phosphorus oxybromide.
Salte af 7-aminocephalosporansyre er sådanne, som dannet med aminogruppen, såsom hydrochlorider, sulfater eller acetater, eller sådanne, som er dannet med carboxylsyregruppen, såsom natri kalium- eller triethylaminsalte.Salts of 7-aminocephalosporanoic acid are those formed with the amino group such as hydrochlorides, sulfates or acetates, or those formed with the carboxylic acid group such as sodium potassium or triethylamine salts.
De letspaltelige estere af 7-aminocephalosporansyre kan fås på vilkårlig konventionel måde ud fra 7-aminocephalosporansyre, Den forbindelse, i hvilken Y betyder et hydrogenatom, Z betyder et tina-2 3 4 tom, og R , R og R alle betyder n-butylgrupper, fremstille? f.ek?. ved at koge en blanding af 7-aminocephalosporansyre og 0,5 mol ækvivalenter bis(tributyltin)oxid i tør benzen i kort tid.The readily cleavable esters of 7-aminocephalosporanoic acid can be obtained in any conventional manner from 7-aminocephalosporanoic acid, The compound in which Y represents a hydrogen atom, Z represents a tina-2 3 4 empty, and R, R and R , manufacture? stom ?. by boiling a mixture of 7-aminocephalosporanoic acid and 0.5 mole equivalents of bis (tributyltin) oxide in dry benzene for a short time.
6 1435026 143502
Ved den foreliggende fremgangsmåde kondenseres aminogruppen i 7-aminoeephalosporansyren med carboxylgruppen i a-sulfocarboxyl-syren. Sådanne metoder svarer til de i teknikken kendte metoder.In the present process, the amino group of the 7-amino epephalosporanoic acid is condensed with the carboxyl group of the α-sulfocarboxylic acid. Such methods are similar to those known in the art.
I det følgende anføres nogle foretrukne metoder.The following are some preferred methods.
1. 7-aminocephalosporansyre eller salte deraf kondenseres med α-sulfocarboxylsyre i nærværelse af et dehydratiseringsmiddel. Dehy-dratiseringsmidlet er f.eks. Ν,Ν'-dicyclQhexylcarbodiimid, Ν,Ν'-diiso-propylcarbodiimid eller Ν,Ν'-carbonyltriazol.1. 7-Aminocephalosporanoic acid or its salts are condensed with α-sulfocarboxylic acid in the presence of a dehydrating agent. The dehydrating agent is e.g. Ν, Ν'-dicyclhexylcarbodiimide, Ν, Ν'-diisopropylcarbodiimide or Ν, Ν'-carbonyl triazole.
2. De funktionelle derivater af a-sulfocarboxylsyren kondenseres med 7-aminocephalosporansyre eller salte deraf, og 3· de let spaltelige estere af 7-aminocephalosporansyre kondenseres med de funktionelle a-sulfooarboxylsyrederivater.2. The functional derivatives of the alpha-sulfocarboxylic acid are condensed with 7-aminocephalosporanoic acid or salts thereof, and the easily cleavable esters of 7-aminocephalosporanoic acid are condensed with the functional alpha-sulfooarboxylic acid derivatives.
Den lier omhandlede kondensation kan udføres i nærværelse af opløsningsmidler. Opløsningsmidlerne er vand, dioxan, acetone, dime-thylformamid, tetrahydrofuran, dichlormethan, chloroform, ethylendi-chlorid, toluen, benzen eller en vilkårlig blanding af to eller flere af disse.: Ved de ovenfor anførte metoder 1 og 3 er vand ikke ønskelig. Ved metode 2 og 3 ovenfor foretrækkes nærværelse af baser. Baserne er organiske baser såsom triethylamin, tributylamin, dimethylanilin, pyridin, picolin eller quinolin. Eventuelt er baserne uorganiske baser såsom natriumcarbonat, kaliumcarbonat, natriumhydrogencarbonat, kali-umhydrogencarbonat, natriumhydroxid, kaliumhydroxid eller calciumhydroxid.The above-mentioned condensation can be carried out in the presence of solvents. The solvents are water, dioxane, acetone, dimethylformamide, tetrahydrofuran, dichloromethane, chloroform, ethylene dichloride, toluene, benzene or any mixture of two or more of them: In the above methods 1 and 3, water is not desirable. In methods 2 and 3 above, presence of bases is preferred. The bases are organic bases such as triethylamine, tributylamine, dimethylaniline, pyridine, picoline or quinoline. Optionally, the bases are inorganic bases such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide or calcium hydroxide.
Kondensationen gennemføres ved en temperatur i området -5 - 40°C. fortrinsvis -2 - 10°C. Den øvre grænse er 50°C, da eephalosporansyre-derivateme ellers let spaltes.The condensation is carried out at a temperature in the range -5 - 40 ° C. preferably -2-10 ° C. The upper limit is 50 ° C, as the eephalosporanoic acid derivatives are otherwise easily cleaved.
Ved ovennævnte metode 3 behandles det ved fremstillingen fremkomne produkt med vand eller en lavere aliphatisk alkohol til sønderdeling og fraspaltning af estergruppen.In the above method 3, the product obtained in the preparation is treated with water or a lower aliphatic alcohol to decompose and decompose the ester group.
Når kondensationen er færdig, kan produktet renses på vilkårlig kendt måde. Sådanne rensemetoder er opløsningsmiddelekstraktion, koncentration, chromatografi, krystallisation eller omkrystallisation. Produktet kan således fås i form af fri baser eller salte. Saltene kan, om ønsket, omdannes til andre ugiftige salte på vilkårlig kendt måde.When the condensation is complete, the product can be purified in any known manner. Such purification methods are solvent extraction, concentration, chromatography, crystallization or recrystallization. The product can thus be obtained in the form of free bases or salts. The salts can, if desired, be converted to other non-toxic salts in any known manner.
Fremgangsmåden ifølge opfindelsen forklares nærmere i de følgende eksempler.The process according to the invention is explained in more detail in the following examples.
7 1435027 143502
Eksempel 1Example 1
Fremstilling af 7-(a-sulfophenylacetamido)-cephalosporansyrePreparation of 7- (α-sulfophenylacetamido) -cephalosporanoic acid
Til en kolbe forsynet med en omrører sættes 2,5 ml IN natriumhydroxidopløsning og 5 ml vand. Blandingen afkøles til 0~5°C i et isvandbad, og under mekanisk omrøring tilsættes 680 mg 7-aminoeephalo-sporansyre. Derpå tilsættes en opløsning, som er fremstillet for sig ved at opløse 5^5 mg α-sulfophenylacetylchlorid i 7 ml diethylether, dråbevis til blandingen i løbet af 15 minutter. Blandingen omrøres i 15 minutter, hvorpå vandlaget isoleres fra reaktionsblandingen, og nævnte lag indstilles på pH-værdien 1,5 med 1 N saltsyre. Derpå ekstra-heres laget to gange med 15 ml pr. g n-butanol, ekstrakterne vaskes to gange med 5 ml vand pr. gang, hvorefter der yderligere ekstraheres med en mættet vandig natriumhydrogencarbonatopløsning. Ekstrakten indstilles på en pH-værdi på 6,5· Efter rensning ved chromatografi på en søjle pakket med polystyrenpulver lyofiliseres eluatfraktionerne indeholdende det pågældende stof, hvorved fås et hvidt pulver i form af natriumsalt. Produktet tørres, og ved analyse fås følgende resultater:To a flask equipped with a stirrer is added 2.5 ml of 1 N sodium hydroxide solution and 5 ml of water. The mixture is cooled to 0 ~ 5 ° C in an ice-water bath and, with mechanical stirring, 680 mg of 7-aminoeephalo-sporanoic acid is added. Then, a solution prepared by dissolving 5 to 5 mg of α-sulfophenylacetyl chloride in 7 ml of diethyl ether is added dropwise to the mixture over 15 minutes. The mixture is stirred for 15 minutes, then the water layer is isolated from the reaction mixture and said layer is adjusted to pH 1.5 with 1N hydrochloric acid. Then the layer is extracted twice with 15 ml per ml. g of n-butanol, the extracts are washed twice with 5 ml of water per ml. and then extracted with a saturated aqueous sodium hydrogen carbonate solution. The extract is adjusted to a pH of 6.5 · After purification by chromatography on a column packed with polystyrene powder, the eluate fractions containing the substance are lyophilized to give a white powder in the form of sodium salt. The product is dried and the following results are obtained by analysis:
Udbytte = 585 mg IR s) max t0111"1)1 1755(lactam, acetat), l6l2(-C00-), 1680(-C0NB), 1225(-S02-), 1046(-S0^Na) NMR(D20) ppm: 2,09(3H,singlet), 3,42 (2H quartet ^=18,0 c/s, J£=l8,0 c/s), Ca 4,75(2H), 5,09(1H, singlet), 5,10(1H, doublet, J=4,5 c/s), 5,70(IH, a, J=4,5 c/s), 7,52(5H, multiplet) UV^H2° : 259 mu(7,l x 105) maxYield = 585 mg IR s) max t0111 "1) 1 1755 (lactam, acetate), 162 (-C00-), 1680 (-CONB), 1225 (-SO2-), 1046 (-SO2 Na) NMR (D20 ) ppm: 2.09 (3H, singlet), 3.42 (2H quartet ^ = 18.0 c / s, J = = 8.0 c / s), Ca 4.75 (2H), 5.09 ( 1H, singlet), 5.10 (1H, doublet, J = 4.5 c / s), 5.70 (1H, a, J = 4.5 c / s), 7.52 (5H, multiplet) UV ^ H2 °: 259 mu (7, lx 105) max
Eksempel 2Example 2
Fremstilling af 7-(q-sulfophenylacetamido)-cephalosporansyre 3,78 g 7-aminocephalosporansyre suspenderes i J>0 ml chloroform, og der tilsættes 2,3 g hexamethyldisilazan. Blandingen opvarmes til 65°C i 1,5 timer i et varmt vandbad. Den fremkomne klare opløsning underkastes destillation ved formindsket tryk ved 40°C. Det tilbageblevne stof genopløses i 50 ml chloroform, og der tilsættes 1,9^ S triethylamin. Derpå afkøles denne opløsning, og der tildryppes en 30 ml chloroformopløsning indeholdende 4,3 g a-sulfophenylaceteddike-syrechlorid. Blandingen omrøres ved 15°C i 15 minutter. Efter endt omsætning koncentreres reaktionsblandingen ved stuetemperatur under for 8 143502 mindsket tryk. Derpå opløses produktet i 50 ml vand. Den vandige opløsning indstilles på pH-værdien 1,5 og ekstraheres to gange med 35 nil n-butanol pr. gang. Butanollaget vaskes med en lille mængde vand, hvorefter det atter ekstraheres med en vandig natriumhydrogenearbonatopløsning. Efter indstilling af opløsningens pH-værdi på 6 udkrystalliserer det pågældende stof fra opløsningen og tørres. Der fås 4,3 g natriumsalt af den pågældende forbindelse. IR-analysen gav samme resultat som den i eksempel 1 udførte.Preparation of 7- (q-sulfophenylacetamido) -cephalosporanoic acid 3.78 g of 7-aminocephalosporanoic acid are suspended in J> 0 ml of chloroform and 2.3 g of hexamethyldisilazane are added. The mixture is heated to 65 ° C for 1.5 hours in a hot water bath. The resulting clear solution is subjected to distillation at reduced pressure at 40 ° C. The residue is redissolved in 50 ml of chloroform and 1.9 µS of triethylamine is added. This solution is then cooled and a 30 ml chloroform solution containing 4.3 g of alpha-sulfophenylacetic acetic acid chloride is added dropwise. The mixture is stirred at 15 ° C for 15 minutes. After completion of the reaction, the reaction mixture is concentrated at room temperature under reduced pressure. The product is then dissolved in 50 ml of water. The aqueous solution is adjusted to pH 1.5 and extracted twice with 35 nil of n-butanol per ml. walk. The butanol layer is washed with a small amount of water and then extracted again with an aqueous sodium bicarbonate solution. After setting the pH of the solution to 6, the substance in question crystallizes from the solution and is dried. 4.3 g of sodium salt of the compound are obtained. The IR analysis gave the same result as the one in Example 1.
Eksempel 3Example 3
Fremstilling af 7-(a-sulfoacetamido)-cephalosporansyrePreparation of 7- (α-sulfoacetamido) -cephalosporanoic acid
Efter suspendering af 0,212 g 7-aminocephalosporansyre i 700 ml vand sættes 0,78 ml 1 F natriumhydroxidopløsning og 0,153 g natrium-hydrogene arbonat dertil. Blandingen omrøres omhyggeligt og afkøles på et isvandbad. Derpå tildryppes 3 ml chloroform indeholdende 0,142 g α-sulfpeddikesyrechlorid. Efter endt tilsætning fortsættes omsætningen under omrøring i 20 minutter under afkøling. Efter indstilling af reaktionsblandingens pH-værdi på 2 ekstraheres reaktionsblandingen med 15 ml butanol. Reaktionen gentages to gange. Butanolekstrakteme kombineres og vaskes derpå med en lille mængde vand. Til den således behandlede butanolopløsning sættes forsigtigt en fortyndet vandig natriumhydroxidopløsning, idet pH-værdien holdes på 6, hvorved den ønskede forbindelse ekstraheres til det vandige lag. Det vandige lag vaskes med ether og frysetørres derefter. Udbytte: 0,15 g· IR-spektrerne giver følgende resultater: IR analyse\) ^ (cm-1): 3420(0H), 2950 - 3100(CH), * max 1760(bred C=0), l670(skarp -C0NH-), l6l0(bred -C00-), 1408-1393 (bred) , 1230,1050(-S0^-)After suspending 0.212 g of 7-aminocephalosporanoic acid in 700 ml of water, 0.78 ml of 1 F sodium hydroxide solution and 0.153 g of sodium hydrogen arbonate are added thereto. The mixture is stirred carefully and cooled on an ice-water bath. Then, 3 ml of chloroform containing 0.142 g of α-sulfoacetic acid chloride is added dropwise. After the addition is complete, the reaction is continued with stirring for 20 minutes under cooling. After adjusting the pH of the reaction mixture to 2, the reaction mixture is extracted with 15 ml of butanol. The reaction is repeated twice. The butanol extracts are combined and then washed with a small amount of water. To the butanol solution thus treated is gently added a dilute aqueous sodium hydroxide solution, maintaining the pH of 6, thereby extracting the desired compound to the aqueous layer. The aqueous layer is washed with ether and then lyophilized. Yield: 0.15 g · The IR spectra give the following results: IR analysis (cm -1): 3420 (0H), 2950 - 3100 (CH), * max 1760 (wide C = 0), 1670 (sharp) -C0NH-), 1610 (wide -C00-), 1408-1393 (wide), 1230.1050 (-S0 ^ -)
Eksempel 4Example 4
Fremstilling af 7-(a-sulfopropionamido)-cephalosporansyre 0,272 g 7-arainocephalosporansyre (1,0 x 10-¾) opløses i en vandig natriumhydroxidopløsning indeholdende 1,0 x 10 ^ mol NaOH, og derpå tilsættes 0,234 g (2,8 x 10"·^ mol) natriumhydrogencarbonat. Blandingen afkøles til 0-2°C, og der tilsættes 2 ml etheropløsning indeholdende 0,2 g a-sulfopropionylchlorid (1,16 x ΙΟ-·'5 M). Reaktionen fortsættes ved 0-2°C i 15 minutter under omrøring. Efter endt reaktion indstilles pH-værdien på 1,5, og først vaskes opløsningen med 9 143502 ether, hvorpå den ekstraheres to gange med 10 ml n-butanol. Ekstrakten ekstraheres igen med en vandig natriumhydrogencarbonatopløsning· Efter indstilling af vandlaget på pH-værdien 6,0 underkastes det frysetørring. Der fås 0,2 g farveløst krystallinsk pulver af den ønskede forbindelse. IR-spektrer af forbindelsen, fremstillet ved KBr-metoden, har maksimumstoppe ved følgende frekvenser: 3400( OH), 2950(CH), 1760(lactam), l860(CONH), l620(-C00Na), 1410, 12^0, 1045(-S0yJa).Preparation of 7- (α-sulfopropionamido) -cephalosporanoic acid 0.272 g of 7-araocephalosporanoic acid (1.0 x 10-) are dissolved in an aqueous sodium hydroxide solution containing 1.0 x 10 The mixture is cooled to 0-2 ° C and 2 ml of ether solution containing 0.2 g of α-sulfopropionyl chloride (1.16 x ΙΟ- · 5 M) is added. The reaction is continued at 0-2 ° C. After stirring, the pH is adjusted to 1.5 and the solution is first washed with ether (9 143502) and then extracted twice with 10 ml of n-butanol. The extract is extracted again with an aqueous sodium hydrogen carbonate solution. setting the water layer to pH 6.0 is subjected to freeze drying 0.2 g of colorless crystalline powder of the desired compound is obtained. IR spectra of the compound prepared by the KBr method have maximum peaks at the following frequencies: 3400 (OH) , 2950 (CH), 1760 (lactam), 1860 (CONH), 1620 (-C00Na), 1410, 12 45 (-S0yJa).
Eksempel 5Example 5
Fremstilling af 7-(a-sulfocapronamido)-cephalosporansyre 0,2 g 7-aminocephalosporansyre (7,35 x 10’^M) opløses i et blandet opløsningsmiddel indeholdende 0,75 ral IN natriumhydroftidopløs-ning og 7>5 ral vand, hvorpå der tilsættes 0,17 g natriumhydrogencar-bonat. Blandingen afkøles til 0-3°C, og der tilsættes 2 ml etheropløs-ning indeholdende 0,15 g (7>65 x lO^M) a-sulfo-n-eaproylchlorid.Preparation of 7- (α-sulfocapronamido) -cephalosporanoic acid 0.2 g of 7-aminocephalosporanoic acid (7.35 x 10 '^ M) is dissolved in a mixed solvent containing 0.75 ral IN sodium hydrophide solution and 7> 5 ral water, 0.17 g of sodium hydrogen carbonate is added. The mixture is cooled to 0-3 ° C and 2 ml of ethereal solution containing 0.15 g (7> 65 x 10 µM) of α-sulfo-n-eaproyl chloride is added.
Efter at reaktionen fortsættes ved 0-3°C i 15 minutter underkastes reaktionsblandingen samme behandling som beskrevet i eksempel 4. Forbindelsen fås i et udbytte på 0,25 g· De rå krystaller renses ved hjælp af søjlechromatografi under anvendelse af granulært polystyren (100-400 mesh) som fyldstof og vand som fremkalder, hvorved fås 0,1 g rene krystaller. IR-analyse giver følgende resultater: IR^ ^ (cm"1): 3450(0H, bred), 2950(CH), 1760(lactftm), 1675(-C0NH-), 1605(-000-), 1530, 1410, 1380, 1225(-S0g-), ll80(skarp), 1043 (-SO^Na), 952, 815, 791j 755, 725.After the reaction is continued at 0-3 ° C for 15 minutes, the reaction mixture is subjected to the same treatment as described in Example 4. The compound is obtained in a yield of 0.25 g. The crude crystals are purified by column chromatography using granular polystyrene (100 g). 400 mesh) as a filler and water as a developer to give 0.1 g of pure crystals. IR analysis yields the following results: IR + (cm , 1380, 1225 (-SO 2 -), 1180 (sharp), 1043 (-SO 2 Na), 952, 815, 791j 755, 725.
Eksempel 6Example 6
Fremstilling af 7-(a-sulfophenylacetamido)-3-/§-(l-oxido--2 * pyrldyl) thiomethyl7-A -cephem-4-earboxylsyre- dinatriumsalt.Preparation of 7- (α-sulfophenylacetamido) -3- [β- (1-oxido-2 * pyridyl) thiomethyl7-A-cephem-4-earboxylic acid disodium salt.
^N-CH-C0NH-^ ^ \ S03Na0J—NN^-CH2s-kNJ* « J,^ N-CH-CONH- ^ ^ \ SO3NaOJ-NN ^ -CH2s-kNJ * «J,
COONa JCOONa J
0,217 g 7-(ct-sulfophenylacetamido)-cephalosporansyre og 0,164 g 2-mercaptopyridinoxid opløses i 15 ml vand, og væskens pH-værdi indstilles på 6,4. Blandingen opvarmes ved 40°C i 18 timer. Efter endt reaktion underkastes reaktionsproduktet frysetørring, hvorved 10 143502 fås 0,35ο g pulver. Det pågældende produkt isoleres derfra ved hjælp af søjle ehromat ografi under anvendelse af cellulosepulver som fyldstof og et blandet opløsningsmiddel af n-propanol, vand og triehlor-eddikesyre (75:24:1) som fremkalder. Fraktionatet underkastes derpå destillation under formindsket tryk og vask med hexan. Uopløseligt produkt kombineres og opløses i vand. Når den vandige opløsnings pH-værdi er indstillet på 6,4, lyofiliseres det rensede produkt. Udbyttet af den fremkomne forbindelse er Ο,ΟδΟ g. IR-spektrer giver følgende resultater: iRÆ C™"1)1 5^50(OH), 1765(lactam), l680(-C0NH-), 1615(-000-), i48o, 1360, 1215, 1050(-so^-), 840, 750, 705.Dissolve 0.217 g of 7- (ct-sulfophenylacetamido) -cephalosporanoic acid and 0.164 g of 2-mercaptopyridine oxide in 15 ml of water and adjust the pH of the liquid to 6.4. The mixture is heated at 40 ° C for 18 hours. Upon completion of the reaction, the reaction product is subjected to freeze-drying to give 0.35ο g of powder. The product in question is isolated therefrom by column ehromatography and graphite using cellulose powder as filler and a mixed solvent of n-propanol, water and triehloroacetic acid (75: 24: 1) as the developer. The fraction is then subjected to distillation under reduced pressure and washing with hexane. Insoluble product is combined and dissolved in water. When the pH of the aqueous solution is set to 6.4, the purified product is lyophilized. The yield of the resultant compound is Ο, ΟδΟ g. IR spectra give the following results: iRÆ C ™ 1) 1 5 ^ 50 (OH), 1765 (lactam), l680 (-CONH-), 1615 (-000-) , i48o, 1360, 1215, 1050 (-so ^ -), 840, 750, 705.
Claims (1)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1162070 | 1970-02-11 | ||
| JP1162070A JPS4945877B1 (en) | 1970-02-11 | 1970-02-11 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DK143502B true DK143502B (en) | 1981-08-31 |
| DK143502C DK143502C (en) | 1982-02-15 |
Family
ID=11782950
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK60671A DK143502C (en) | 1970-02-11 | 1971-02-10 | ANALOGY PROCEDURE FOR PREPARING 7-AMINO-CEPHALOSPORANIC ACID DERIVATIVES |
Country Status (10)
| Country | Link |
|---|---|
| JP (1) | JPS4945877B1 (en) |
| BE (1) | BE762725A (en) |
| CA (1) | CA955247A (en) |
| CH (1) | CH599962A5 (en) |
| DE (1) | DE2106500C3 (en) |
| DK (1) | DK143502C (en) |
| FR (1) | FR2081504A1 (en) |
| NL (1) | NL168228C (en) |
| NO (1) | NO142912C (en) |
| SE (1) | SE385899B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6088513A (en) * | 1983-10-21 | 1985-05-18 | 石井 育子 | Dish for tablewear |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AT290728B (en) * | 1968-09-28 | 1971-05-15 | Takeda Chemical Industries Ltd | METHOD FOR MANUFACTURING NEW PENICILLIN |
-
1970
- 1970-02-11 JP JP1162070A patent/JPS4945877B1/ja active Pending
-
1971
- 1971-02-04 CA CA104,465A patent/CA955247A/en not_active Expired
- 1971-02-09 NO NO47171A patent/NO142912C/en unknown
- 1971-02-09 NL NL7101710A patent/NL168228C/en not_active IP Right Cessation
- 1971-02-10 DK DK60671A patent/DK143502C/en not_active IP Right Cessation
- 1971-02-10 CH CH194671A patent/CH599962A5/xx not_active IP Right Cessation
- 1971-02-10 BE BE762725A patent/BE762725A/en not_active IP Right Cessation
- 1971-02-10 SE SE164771A patent/SE385899B/en unknown
- 1971-02-11 FR FR7104628A patent/FR2081504A1/en active Granted
- 1971-02-11 DE DE19712106500 patent/DE2106500C3/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| DK143502C (en) | 1982-02-15 |
| CH599962A5 (en) | 1978-06-15 |
| NL168228B (en) | 1981-10-16 |
| NO142912B (en) | 1980-08-04 |
| DE2106500A1 (en) | 1971-08-26 |
| JPS4945877B1 (en) | 1974-12-06 |
| NL7101710A (en) | 1971-08-13 |
| FR2081504A1 (en) | 1971-12-03 |
| CA955247A (en) | 1974-09-24 |
| DE2106500B2 (en) | 1979-10-04 |
| NL168228C (en) | 1982-03-16 |
| FR2081504B1 (en) | 1975-06-06 |
| DE2106500C3 (en) | 1980-06-19 |
| SE385899B (en) | 1976-07-26 |
| NO142912C (en) | 1980-11-12 |
| BE762725A (en) | 1971-08-10 |
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