IE56712B1 - Process for the production of 1-ethoxycarbonyloxyethyl ester of 6-(d-(-)-alpha-amino-alpha-phenylacetamido)penicillanic acid - Google Patents

Process for the production of 1-ethoxycarbonyloxyethyl ester of 6-(d-(-)-alpha-amino-alpha-phenylacetamido)penicillanic acid

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Publication number
IE56712B1
IE56712B1 IE1445/83A IE144583A IE56712B1 IE 56712 B1 IE56712 B1 IE 56712B1 IE 1445/83 A IE1445/83 A IE 1445/83A IE 144583 A IE144583 A IE 144583A IE 56712 B1 IE56712 B1 IE 56712B1
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process according
group
formula
carried out
catalyst
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IE1445/83A
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IE831445L (en
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Astra Laekemedel Ab
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Priority claimed from IT22141/82A external-priority patent/IT1190897B/en
Priority claimed from GB838300331A external-priority patent/GB8300331D0/en
Application filed by Astra Laekemedel Ab filed Critical Astra Laekemedel Ab
Priority to IE1360/91A priority Critical patent/IE56713B1/en
Publication of IE831445L publication Critical patent/IE831445L/en
Publication of IE56712B1 publication Critical patent/IE56712B1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C68/00—Preparation of esters of carbonic or haloformic acids
    • C07C68/02—Preparation of esters of carbonic or haloformic acids from phosgene or haloformates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/96—Esters of carbonic or haloformic acids
    • 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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oncology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Communicable Diseases (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Cephalosporin Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

A compound of formula (IV> wherein R<1> represents a C1-4 alkyl group, a substituted or unsubstituted aryl group or aralkyl group; R<2> represents hydrogen, a C1-4 alkyl group, a substituted or unsubstituted aryl group or an aralkyl group; R<3> represents a C1-4 alkyl group, a substituted or unsubstituted aryl group, an arylkyl group, a C1-4 alkoxy group, an aryloxy group or an amino group; is a useful intermediate in the manufacture of the corresponding unprotected penicillanic acid.

Description

This ester 1s isolated in the for® of e hydrochloride end is known as bacampicillin hydrochloride.
On the basis of previous known processes (cf. Belgian patent No. 772723), bacampicillin hydrochloride can be synthesized by the two following methods: A) Reaction of potassium benzylpenicillin with o~chlorodiethylearbonate in organic solvents or in an aqueous solution of 70% dioxane in the presence of sodium bicarbonate. The 1-ethoxycarbonyloxyethyl ester of benzylpenicillin which is obtained fs subjected to the reaction of remov 0 ing the phenylacetic chain, via the im1noch1oride~1minoether, in order to obtain the 1’’ethoxycarbonyloxyethyl ester of the 6-aminopenicil lanic acid, which is isolated as the hydrochloride.
By subsequent condensation of the latter intermediate with 0ψ)<· phenylglycine, the compound according to formula 1 is obtained. £5 B) Esterification reaction of the d-tO-l-J-a-asido-a^phenylacetamido)pencillanic acid with α-chlorodiethylcerbonate in a polar solvent.
Subsequently, by catalytic hydrogenation of the 1-ethoxycarbonyloxyethyl ester of the o-(0(o)*a»azido-aophenylaceteraido)penieillanic acid the compound according to formula I is obtained.
As one can see, these methods are rather complex since they involve the use of numerous raw materials and lengthy processing times.
A prime object of this invention is to provide a method of preparing 0 the active substance concerned which is easier to carry out and industrially more advantageous. A more specific object of this invention is 25 to provide a method of preparing bfiempieillin using ampicillin as start ing material, with considerable simplification of the said method and obtaining a high degree of purity of the desired product.
It is possible to achieve the said prirae object of preparing the l-£thOKycarbonyloxy3thyl ester of the 6-(D-(-)"®^amino^phenylacetamido) penicillanic acid having the following formula: /CH3 CH— CO—HH—CH—CH C HH. 1^3 (1) fi* CH-COO—CH™ 0—COOCJb , Π CHAcharacterised by the following stages: a) reacting ampicillin or an alkali metal, alkaline earth metal or organic base salt thereof with a reactive derivative of acetoacetic acid to form the corresponding enamine having the following formula: where: represents an alkyl group containing 1 to 4 carbon atoms, e substituted or unsubstituted aryl group or an aralkyl group; R represents hydrogen, an alkyl group containing 1 to 4 carbon atoms, a substituted or unsubstituted aryl group or an arylkyl group; R3 represents an alkyl group containing 1 to 4 carbon atoms, a substituted or unsubstituted acyl group, an arylkyl group, an alkoxy group containing 1 to 4 carbon atoms, an aryloxy group or an amino group, and x represents hydrogen, an alkali metal, an alkaline-earth metal or an organic base; b) reaction of the resulting intermediate with an halo ^diethylcarbonate having the following formulas g—CH — O—-COOC0Hg (XXX) cb3 wherein £ is Cl or X in the presence of a catalyst to form the corresponding ester having the following formula: 3 where R, R and R have the same significance as above and c) subjecting ester XV to mild hydrolysis in an acid medium, 15 obtaining the compound according to formula (X).
The esterification reaction between the compounds XX and XXI is carried out with an esterification catalyst present.
The addition of a catalyst at this stage considerably shortens the reaction times and provides higher yields of the product with a greater degree of purity.
For this purpose the following substances can be used as catalysts: quaternary «ionium salts0 for example tetrabutylamimonium bromide, the bromides or iodides of alkali Ratals and, cyclic ethers.
The catalyst may be used in an amount which varies from 0.005 to 0.10 5 moles per mole of compound HI to mounts which are equimolar with the compound Hl. In a preferred embodiment tetrabutylammonium bromide is used in an amount of from 0.01 to 0.10 moles per mole of compound 111.
I· 3 Illustrative examples of the radicals R , R and R are: alkyl: CHr C^. n-CjHj. i-CjHp n-C^Hg alfcOKv (R3 only): OCHj, OC^, OCHjCHjCHj, OCHtCHj^, OCCH^jCHj fi Ί The radical X is selected among groups which ere well known in the art, for «xample alkali metal: ^a. K alkaline earth metals: Ca, Hg organic base; orgsnic bases which are known in the synthesis of penicil 11ns» e.g. tertiary οιμοιΗομ groups, triethyloine* ethylpiperidine and methyImorpholIne.
In the preferred embodiment of the invention» the group protecting the isain© group of the ampicillin Is a 1 ethoxy-carbonyl "propsn-2-yl group w ffl 1 «ethoxy-carbonyl«propewZ’yl group for which the preferred inter-* mediate is the sodium or potassium gait of the E1~( 1-mothoxy-carbony1propen-2-yl, penicillanic acid respectively fWWtboxy^arbonylpropent 9 2-yl penicil lani e acid according to formula Π {8 " methyl; ir « methyl; 83 = methoxy or ethoxy and X » Ha or K).
The Intermediate IV is stable in a neutral or alkaline medium, whereas In an acid medium it is possible to remove the group protecting the Caine group simply, quickly and selectively.
The group protecting the amino group of the ampicillin can be selected g.g. from the groups mentioned in the British patent specification 2o 8Sl§86fl and from other groups which are known in the art.
More specifically, therefore, the process method according to a preferred embodiment of this invention,, comprises the following stages: - transformation of ampicillin trihydrate in a polar solvent, for example H„ Λ-di methyl formamide, into a gait thereof, for example potassium, and subsequent formation of the corresponding enamine (ΙΪ) by reaction with © derivative of acetoaeetie acid, for example methyl acetoacetate. - addition of an esterification catalyst, preferably tetrsbutyl «ionium bromide ** addition of a-chloro or a-iodo-diethylc&rhonate to the reaction mixture to form the l-ethoxycarbonyl oxye thyl ester of the aa^icill in in the form of the enamine (IV)i « hydrolysis of the protective group with HCl diluted in an organic solvent, for example n-butyl acetate/water. « recovery of the bacarapic1ll1n hydrochloride by saturation In the aqueous phase, for example with sodium chloride and extraction with a suitable solvent, for example n-butyl acetate. - concentration of the solution at low pressure in n-butyl acetate ia order to crystallize the product to a high level of purity, the product then being Isolated by filtration.
Among the main advantages of the process according to the Invention, the principal one 1s that, by this process, it is possible to obtain bacampicillin hydrochloride practically in one operation and with a high degree of purity.
In fact the impurities which are present 1n the product obtained by the process according to the present Invention are negligible as compared with the known processes of the previous state of the art.
Another equally Important advantage 1s that ampicillin tri hydrate is used as the starting material, this being a known antibiotic which is easily obtainable 1n pure form and at low cost.
The Intermediate (SI) can be easily prepared as described for example In British patent specification @91536 with a yield of over 95X by reaction of ampicillin trihydrate with methyl or ethyl acetoaeetate. ta §©£ thaw the stoichiometric rat1oQ in the presence of an organic has© ©r an alkali gM©1 carbonate» for example potaggluta carbonait©» The intermediate (IS) can be isolated and added to the esterification reaction in solid form. 0rB without isolation of the intermediate (Π), the esterification reaction can be effected in the same solvent in which V* the reaction for the formation of enamine (XX) took place.
J The reaction for the formation of ampicillin enamine (Π) is conducted in an aprotic polar solvent, such as NJM1mathylacetairidep K.IM1· R&thy1foruom1 To complete the reaction, it is sufficient to leave the components of the mixture in contact at a temperature between gec and 60eCe preferably between 20°C and 30eC, for 2 to 0 hours, preferably 3 hours.
Ths compound ΪΙ can be prepared via acylation of S-eirinopenicillanic acid with a corresponding marine derivative of phenylglycine to the formation of the compound U which thereafter can be esterified directly and converted to baeainpicilbn with isolation of the compound Π.
The esterification reaction after the addition of the a-halodiethylcar 2o bonate to the said mixture, takes place at a temperature between 1S°C ©nd gO’C, preferably between 450C and §§·£□ for a period of time from 1 hour to g4 hourse preferably froa 5 to 10 hours.
The esterification reaction is suitably carried out in an organic solvent such as methylene chloride or acetone, dimethylaeetamide, dl25 wsgthyl formamide and dimethylsulfoxide, or in a mixture of organic solvents. It is possible to use also organic solvent containing water. hi the easiest and most suitable conditions for Industrial purposes, the esterified ©naming (XV) is isolated by dilution of the reaction mixtur© with water and subsequent extraction with a suitable solvent which 1s Inmiscible with water, for example n-butyl acetate.
The acetate phase is agitated with a dilute solution (0.2 - 0.3N, of HCl until the protective group is completely hydrolysed* which requires a contact time of 2 to @ hours, preferably 4-5 hours, at ordinary temperatures. ί Oy addition of sodium chloride, compound (ϊ) separates out from the aqueous phase in the form of the hydrochloride, wbieh is extracted with a suitable solvent, for example n-butyl acetate.
Sy concentrating the organic phase at low pressure et a temperature of 40°C until a small volume remains, crystallization of the product according to formula (I) takes place.
The crystalline product is isolated by filtration, washing and vacuum drying.
The following examples illustrate the present aspects of the invention without limiting it in my way.
Example 1 36.4 g (0.075 m, of potassium N"(1-raethoxycarbony1-propen-2-yl,-6-( Oi-J-^n-amino^e-phenylacetismldo, penicil late are added to a solution of 17.8 g (0.116 m) of o-chlorod1©thylcarbonate and 3 g (0.01 m) of £&£r«butyl«floniura bromide in 150 ml of tt.N-'dimgtbylfonamaide. Under agitation the temperature is raised to 45°C and maintained at 45°C e 50eC for 5 hours.
When heating 1s completed, the reaction mixture is poured into a mixture comprising 300 ml of a 14% aqueous sodium chloride solution and 600 ml of n-butyl Acetate. Tl»e mixture is agitated for 10 minutes, then the ί organic phase is separated and the aqueous phase is extracted with 100 ol of n-butyl acetate. The reunited organic phases0 after two washings with zS ol of H% sodium chloride aqueous solution,, are concentrated at low pressure until an oil Is obtained, The oil is raised with £00 ral of tetrahydrofuran and 100 ral of water; the· solution obtained (pH 4.8) is brought under agitation to pH 1.5 by *> adding, in all, 12 ral of ON HCl in 1 hour.
After leaving the solution to stand for another hour at ordinary temperature, th® tetrahydrofuran is reviewed at low prsssur» at 4G®C, 150 al of n-butyl acetate are added to the remaining aqueous phase (150 ral) and then 15 g of sodium chloride are added.
The organic phase is separated and the aqueous phase is extracted with 100 ral oi‘ n-butyl acetate.
The reunited organic phases ere concentrated under vacuum at 40eC to a volume of 120 nl.
The product is left to crystallise for 15 hours at 5eC. 'it is then filtered, washed with n-butyl acetate (50 ral) and ethyl acetata (50 ral).
It is vacuum dried at 40eC. 2o The following is obtained: 25.2 g (5S.92, of the Wthojcyeartxxiyloxyetbyl ester of the 6-(0=(-)"e-araino"e-pheHy1aeetaraido, penicillanic oeid hydrochloride with s.p. 160-2’C.
Analytical determinations: Titre: 97.822 Rotatory power: *1S&.3* (c«lt Et0H95e) pH: 4.05 (22 aqueous solution) Moisture content: 8.822 Λ tteidual solvents: ethyl acetate 0.45; n-butyl acetate 8.982 IR ©nd IfSKEt spectra standard Residual amicillin; 0.0S2 Ex«ap1e_2 16.2 tai (0.15 m) of methyl ac&toacetate and 30.2 g (0.075 ra) of ampicillin trihydrate are added to a suspension of 12.S& g (0.0907 ra) of finely pulverized anhydrous potassium carbonate 1a 100 ml of N,H-d1ixethy 1 f ormami dc.
It 1s maintained with agitation ot 22*C-23®C for 3 hours and after this time considerable fluidisation of the mass can be observed. h> 17.0 g (0.117 m) of c-chloro-diethylcarbonate, 3 g (0.01 ra) of tetrabutylaiwniurabrcraide and 50 ml of HnH-diraathylfonnaraide are now added in that order.
The mixture Is heated under agitation for 5 hours at 45*C - 50°C, then left to stand at +5*C for 15 hours.
The reaction mass is poured Into a mixture consisting of 500 ml of water and 200 ml of n-butyl acetate and it is agitated until a complete solution Is obtained, the aqueous phase is collected and extracted with another 50 ml of n-butyl acetate.
The reunited organic phases are washed twice with 50 al of water each time. 75 ml of h HCl and 185 ml of water are added to the organic phase subjected to agitation; it Is left under agitation at 2Z®C -23°C for hours.
The aqueous phase is collected and the organic phase is extracted with ml of water. The reunited aqueous phases are brought to pH4 with a ® aqueous solution of Na^CO^ then bleaching carbon Is added to them and they are filtered. 150 ml of n-butyl acetate and 40 g sodium chloride are added to the aqueous filtrate.
The organic phase 1$ separated and the aqueous phase is extracted with 1 100 ral of n-butyl acetate.
The reunited phases 1« butyl ocetete are concentrated at low pressure «it 40*e to © volume of approximately IS© ml.
The product Is left to crystalline for 15 hours at *§0C.
It 1s filtrated, washed with «-butyl acetate (§0 ml) and ethyl acetat® (5© ml).
It is dried under a vacuum of 10 emj Hg 1« the presence of moisture at 25®£ for 24 hours. field: 20.0 g (55S, of the 1 "ethoxycarbonyloxyethyl ester of the 5*(0(«)-ft«*fim1no-o»pheflylacetami i Example 3 The procedure of Example 2 was repeated but using ethyl acetoac^tat® and ampicillin dane salt. 16.1 g of a white crystalline product was obtained of m.p.
X44-148°C (Tottoli apparatus). The SR and TLC analysis conformed to that of a genuine sample,and the product had t RF of 0.35$, a pH of 3.55 (2$ aqueous solution), an assay TQ of 95.2$ and 3.5$ total residue solvents. & The procedure was repeated again but with 9 g of aIpha-chlorodi®thyl carbonate added immediately and the balance added after 2 hours. The reaction mixture was heated for 3 hours at 45°C. 13.7 g. of a crystalline beige product was obtained, m.p. 143-146°C (Tottoli apparatus). The IR and TLC analysis conformed to that of a genuine sample and the product had a SF of 0.2$, a pH of 3.43 (2$ aqueous solution), an assay to 54.8$ and 2.5$ residual solvents.

Claims (1)

1. - Process for the preparation of the l-ethcmyeerboitylosyethyl ester ef the 6»(0“(»,-e-emiflO e Q°ph©nylecetafiiido) penicillanic acid with the formula: /\ Λ CO - HH - CH “ CH C I X CH, (I) CO CH - COO - CH - 0 - COOC 2 h 5 ch 3 comprising a) reacting ampicillin, or an alkali metal, alkaline earth metal or organic base salt thereof, with a reactive derivative of acetoacetic acid to form the corresponding enamine with the formula: / S \ /^3 - CH C. I | C»3 - ft - CH - coox (It) wherein Fp represents an alkyl group containing l-β carbon stews, a substituted or non-substituted aryl group or an aralkyl group; 8 represents hydrogen, an alkyl group containing 1-4 carbon atoms, a substituted or non-substituted aryl group or an aralkyl group; 15 8 3 represents on alkyl group containing 1-4 carbon atoms, o substituted or non-substituted aryl group, on aralkyl group, on alkoxy group containing 1-4 carbon atoiiks, on aryloay group or an amine group, and K represents hydrogen or tin alkfeli metal, on &Xfc&XX»& *?iagxh stet©X or ©n organic ba^e: b) reacting an alkali metal# alkaline earth metal or an organic base salt of formula IX with a compound of formula: S-CH-O-COO-C^Hg (HI) £h 3 k wherein z is Cl or X in the presence of a catalyst to form the corresponding ester with the formula: Ιϊ (IV) wherein 3 2 and R 3 have the meanings specified above, and e) subjecting -ester XV to mild hydrolysis in an ecid medium· 10 Process according to claim 1, therein the ampicillin salt is sn ©Ikali metal or alkaline earth metal salt obtained by transforming ampicillin trihydrate by e oer se known method in © polar solvent * 3» Process according to claim 1 or 2# wherein the 15 formation of the enamine (XX) is carried out by reacting the salt of ©mpicillin with an alkyl acetoacetate in an aprotic polar solvent at a temperature of 0°C to 60 P C and for 2 to S hours· 4. Process according to clcims 3, wherein the alkyl acetoacetate is methyl oc ethyl acetoacetate and Is used in an amount 10-50¾ more than the stoichiometric ratio. 5. Process according to claim 3 or 4, wherein the > 5 aprotic polar solvent Is selected from ft,ft-dimethyl. acetamide, ft,ft u dimethy1formamide, dimethoxyethane, <3imethyIsulpoxide P tetrahydrofuran and dioxane. I 5« Process according to claim 5 in which the polar solvent is ft,ft“diraethylfor©araide. 10 7· Process according to any one of claims 3 to 6, wherein the enamine formation is carried out at a temperature of 20°c to 30°c. 8, Process according to any one of claims 3 to 7, wherein enamine formation is carried out in a time of 3 15 hours· 9. process according to any one of the preceding claims, wherein enamine formation is carried out in the presence of an organic base or an alkali metal carbonate or alkaline earth metal carbonate^ 2. O io 3 Process according to any one of the preceding claims wherein the catalyst is selected from quaternary ammonium salts, alkali metal bromides, alkali metal iodides and cyclic ethers. 11. Process according to claim 10, wherein the catalyst 25 is tetrabutylammonium bromide. 13. Process according to any one of the preceding claims, wherein the catalyst is present in an amount of from 0.005 L8 to 0®10 moles, per mole of the compound XIX „ 13. Processs according to claim 11 wherein the amount of catalyst present is from 0.01 to 0.1 moles per mole of 3. 5 compound ΪΪΧ Λ 14« Process according to any one of the preceding claims, wherein the esterification reaction temperature is 45°c fo 55°c. 15o Process according to any one of the preceding claims, wherein the esterification reaction is carried out in 5-10 hours. 16. Process according to any one of the preceding claims, wherein the hydrolysis is carried out with dilute hydrochloric acid after isolating ester (IV). 17. A process according to claim 1 substantially as hereinbefore described with reference to any one of the Examples.
IE1445/83A 1982-06-29 1983-06-20 Process for the production of 1-ethoxycarbonyloxyethyl ester of 6-(d-(-)-alpha-amino-alpha-phenylacetamido)penicillanic acid IE56712B1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
IE1360/91A IE56713B1 (en) 1982-06-29 1983-06-20 Alpha-bromodiethylcarbonate and its use in the preparation of antibiotics

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
IT22141/82A IT1190897B (en) 1982-06-29 1982-06-29 PROCEDURE FOR THE PREPARATION OF THE 1-ETHOXYCARBONYLOXYETHYL ACID ACID 6- (D (-) - ALPHA AMINOALPHA-PHENYLACETAMIDE) -PENICILLANIC
GB8226751 1982-09-20
GB8228622 1982-10-06
GB8232629 1982-11-16
GB838300331A GB8300331D0 (en) 1983-01-07 1983-01-07 Preparation of bromo carbonates

Publications (2)

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IE831445L IE831445L (en) 1983-12-29
IE56712B1 true IE56712B1 (en) 1991-11-20

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AU (1) AU566803B2 (en)
BG (3) BG37527A3 (en)
CH (2) CH657620B (en)
CY (2) CY1520A (en)
DD (1) DD211561A5 (en)
DE (2) DE3322783A1 (en)
DK (3) DK160039C (en)
FI (1) FI79115C (en)
FR (1) FR2543957B1 (en)
GB (3) GB2168050A (en)
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HU (1) HU191534B (en)
IE (1) IE56712B1 (en)
IL (1) IL68992A (en)
IS (1) IS1361B6 (en)
NL (1) NL194081C (en)
NO (3) NO157696C (en)
NZ (1) NZ204736A (en)
PT (1) PT76944B (en)
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FR2573756B1 (en) * 1984-11-23 1987-01-16 Poudres & Explosifs Ste Nale PROCESS FOR THE PREPARATION OF BROMO-1 ETHYL AND HYDROCARBYL CARBONATES AND NOVEL BROMO-1 ETHYL AND HYDROCARBYL CARBONATES

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CH516593A (en) * 1967-09-29 1971-12-15 Leo Pharm Prod Ltd Alpha amino-benzyl penicillins - useful as oral antibiotics
US3873521A (en) * 1970-09-17 1975-03-25 Astra Laekemedel Ab Esters of {60 -amino penicillins
IE35648B1 (en) * 1970-09-25 1976-04-14 Beecham Group Ltd Penicillins
DE2161420A1 (en) * 1970-12-30 1972-07-27 Toyama Chemical Co. Ltd., Tokio Penicillin derivatives and processes for their preparation
BE784800A (en) * 1971-06-15 1972-10-02 Yamanouchi Pharma Co Ltd PROCESS FOR PREPARING NEW OXYMETHYL ESTERS OF PENICILLIN AND CEPHALOSPORIN
IL41313A (en) * 1972-02-15 1976-08-31 Harrison Ltd Preparation of the lh-and fsh-releasing hormone and compositions containing it
GB1425571A (en) * 1972-03-13 1976-02-18 Astra Laekemedel Ab Penicillins and cephaosporins
GB1426869A (en) * 1972-03-13 1976-03-03 Astra Laekemedel Ab Penicillins
GB1426717A (en) * 1972-03-13 1976-03-03 Astra Laekemedel Ab Penicillins
SE397981B (en) * 1973-02-19 1977-11-28 Astra Laekemedel Ab NEW TETRAALKYLAMMONIUM SALTS OF 6-AMINOPENICILLANIC ACID AND OF BENZYLPENICILLIN INTENDED TO BE USED AS INTERMEDIATE PRODUCTS IN THE PREPARATION OF CERTAIN ESTERS OF 6-AMINOPENICILLANIC ACID AND OF BENZYLPENIC
GB1565656A (en) * 1975-12-13 1980-04-23 Beecham Group Ltd Preparation of substituted penicillin acid esters
GB1598568A (en) * 1977-04-19 1981-09-23 Glaxo Lab Ltd Esters of(6r,7r)-3-carbamoyloxymethyl-7-((z)-2-(fur-2-yl)-2-methoxyiminoacetamido)-ceph-3-em-4-carboxylic acid
JPS5444694A (en) * 1977-09-06 1979-04-09 Kou Kamata Aminobenzylpenicillin derivative
DE3323462A1 (en) * 1982-06-30 1984-01-12 Glaxo Group Ltd., London CEPHALOSPORINE ANTIBIOTICS
DE3380024D1 (en) * 1982-11-04 1989-07-13 Astra Laekemedel Ab Process for the preparation of the 1'-ethoxycarbonyloxyethyl ester of benzylpenicillin

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YU43693B (en) 1989-10-31
IS2825A7 (en) 1984-07-08
DK296683D0 (en) 1983-06-28
BG38336A3 (en) 1985-11-15
GB8522827D0 (en) 1985-10-23
DK105990D0 (en) 1990-04-30
NZ204736A (en) 1986-11-12
DE3348299C2 (en) 1990-12-20
FR2543957A1 (en) 1984-10-12
FI79115C (en) 1989-11-10
NL194081B (en) 2001-02-01
DK106090A (en) 1990-04-30
NL8302286A (en) 1984-01-16
GB2169287A (en) 1986-07-09
CH657620B (en) 1986-09-15
NO851255L (en) 1983-12-30
JPH0730082B2 (en) 1995-04-05
PT76944A (en) 1983-07-01
BG37527A3 (en) 1985-06-14
FR2543957B1 (en) 1986-10-24
JPH0543583A (en) 1993-02-23
DK159821B (en) 1990-12-10
IS1361B6 (en) 1989-05-25
SE8303414L (en) 1983-12-30
FI832363L (en) 1983-12-30
NO832351L (en) 1983-12-30
GR78585B (en) 1984-09-27
GB8528958D0 (en) 1986-01-02
JPH0819052B2 (en) 1996-02-28
DK106090D0 (en) 1990-04-30
GB2168699B (en) 1987-04-15
DE3322783C2 (en) 1991-01-31
GB8522826D0 (en) 1985-10-23
BG38335A3 (en) 1985-11-15
NL194081C (en) 2001-06-05
DK160039B (en) 1991-01-21
GB2168699A (en) 1986-06-25
DK296683A (en) 1983-12-30
SE454879B (en) 1988-06-06
DK167807B1 (en) 1993-12-20
IE831445L (en) 1983-12-29
FI79115B (en) 1989-07-31
AU1632883A (en) 1984-01-05
DD211561A5 (en) 1984-07-18
PT76944B (en) 1986-04-09
NO157696B (en) 1988-01-25
YU141583A (en) 1986-06-30
SE9100548L (en) 1991-02-26
CY1519A (en) 1990-11-16
IL68992A (en) 1991-06-10
SE8303414D0 (en) 1983-06-15
AU566803B2 (en) 1987-10-29
CH656377A5 (en) 1986-06-30
NO851254L (en) 1983-12-30
JPH0717918A (en) 1995-01-20
DK159821C (en) 1991-04-29
NO157696C (en) 1988-05-04
GB2168050A (en) 1986-06-11
YU43926B (en) 1989-12-31
FI832363A0 (en) 1983-06-28
CY1520A (en) 1990-11-16
DE3322783A1 (en) 1984-02-09
SE503843C2 (en) 1996-09-16
YU21886A (en) 1987-10-31
DK160039C (en) 1991-06-10
HU191534B (en) 1987-03-30
SE9100548D0 (en) 1991-02-26
DK105990A (en) 1990-04-30
ATA238483A (en) 1986-10-15
AT383128B (en) 1987-05-25
GB2169287B (en) 1987-04-08

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