IE46478B1 - Chemical process for the preparation of clavulanic acid derivatives - Google Patents

Chemical process for the preparation of clavulanic acid derivatives

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Publication number
IE46478B1
IE46478B1 IE477/78A IE47778A IE46478B1 IE 46478 B1 IE46478 B1 IE 46478B1 IE 477/78 A IE477/78 A IE 477/78A IE 47778 A IE47778 A IE 47778A IE 46478 B1 IE46478 B1 IE 46478B1
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Ireland
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group
formula
methyl
compound
ethyl
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IE477/78A
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IE780477L (en
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Beecham Group Ltd
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Priority claimed from GB10082/77A external-priority patent/GB1582864A/en
Application filed by Beecham Group Ltd filed Critical Beecham Group Ltd
Publication of IE780477L publication Critical patent/IE780477L/en
Publication of IE46478B1 publication Critical patent/IE46478B1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—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, cefaclor, or cephalexine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D503/00—Heterocyclic compounds containing 4-oxa-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxapenicillins, clavulanic acid derivatives; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrane Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

Process for preparing ethers of clavulanic esters of the formula II in which the group -CO2R1 is an esterified carboxylic acid group, R3 and R4 are identical or different and denote hydrogen atoms or alkyl radicals having 1 to 4 carbon atoms and R5 represents such a radical that the group -CR4R4R5 is an inert organic radical having up to 18 carbon atoms, characterised by reaction of a clavulanic ester of the formula III with a halide of the formula IV in which X is an iodine, bromine or chlorine atom, in the presence of a compound providing silver ions. The ethers of clavulanic esters which are produced are useful as intermediates for preparing medicinal active compounds.

Description

The present invention relates to a process for the preparation of ethers.
Patent Application Wo: 44295 (which corresponds to Belgian Patent No: 847045) discloses inter alia ethers of clavulanic acid of the formula (I): wherein R^ is a group such that COgR^ is an esterified carboxyl group and Rj is an organic group of up to 18 carbon atcms.
This invention provides a process for the preparation of a compound of the formula (II): tO2R1 wherein R^ is as defined in relation to formula (I), R^ is a hydrogen atom or an alkyl group of 1-4 carbon atoms, R^ is a hydrogen atom or an alkyl group of 1-4 carbon atoms and R^ is a group such that the CR^R^R^ moiety is an inert organic group of up to 18 carbon atoms; which process comprises the reaction of a compound of the formula (III): H, (III) - 2 464 7g wherein R^ is as defined in relation to formula (II) with a compound of the formula (IV): wherein X is I, Br, or Cl and R^, and R^ are defined in relation to formula (II); in the presence of a source of silver ions. When used herein the term inert has the normal meaning of inert under the reaction conditions of the process.
Optionally, an alkaline earth metal oxide may also be present. Prefer ably, the oxide is calcium oxide. Preferably the oxide is powdered.
The preferred source of silver ions is silver oxide. Generally 1-2 equivalents of silver ions are anployed per equivalent of compound of the formula (ill).
When calcium oxide is also present it is generally employed in the proportion of 1-2 equivalents per equivalent of compound of the formula (III).
Suitable values for R^ include the hydrogen atom and the methyl, ethyl, n-propyl and n-butyl groups.
Suitable values for include the hydrogen atom and the methyl, ethyl, n-propyl and n-butyl groups.
A preferred value for is the hydrogen atom and a preferred value for is the hydrogen atom so that it will be appreciated that certain preferred processes of this invention are adapted to provide compounds of the formula Λ (II) wherein the CR^R^R^ moiety is a CH2~R group where CHgR1 is an inert organic group of up to 18 carhon atoms. - 3 46478 Suitable value for include the hydrogen atom and the methyl, ethyl, n-propyl, n-butyl, n-pentyl, iso-propyl, vinyl, phenyl. and p-methoxy benzyl groups.
Particularly suitable values for include the hydrogen atom and the methyl, ethyl, phenyl and vinyl groups.
Favoured values for R^ include the hydrogen atom and the methyl and ethyl groups.
A preferred value for R^ is the hydrogen atom.
A further preferred value for R^ is the methyl group.
Highly favoured processes of this invention are those adapted to the preparation of the compounds of the formula (II) wherein CR^R^R^ is a methyl group or wherein CR^R^R^ is an ethyl group. Hence a preferred ccmpound of the formula (IV) is methyl iodide and a further-preferred conpound of the formula (IV) is ethyl iodide.
Suitable esters of the formula (H) include those wherein is a group 12 3 1 A or CHA A wherein A is an alkyl group of 1-8 carbon atcms, optionally sub4 4 4 4 stituted by halogen or by a group of the formula QA ,OCOA , SA or SO^ -2 wherein A is a hydrocarbon group of up to 6 carbon atoms; A is a hydrogen atom, an alkyl group of up to 4 carbon atoms or a phenyl group optionally substituted by halogen or by a group 5 5 5 A or OA where A is an alkyl group of up to 6 carbon atoms; and A3 is a phenyl group optionally substituted by halogen or 5 5 5 by a group A or OA where A is an alkyl group.
Other suitahie esters are those of the formula (II) wherein is an alkenyl group of up to 8 carbon atoms.
Examples of such esters are the allyl esters.
Esters of this invention are preferably in-vivo hydrolysable. Suitable esters include those described in Belgian Patent No: 827926 as being in-vivo hydrolyaablo esters of clavulanic acid. Particularly suitable in-vivo hydrolysable esters include acetoxymethyl, a-acetoxyethyl, pivaloyloxymethyl, phthalidyl, ethoxycarbonyloxymethyl, and ethoxycarbonyloxyethyl esters.
Most suitably the ester group is one readily convertible to a salt corresponding to the compound of the formula (II) by mild hydrolysis or hydrogenolysis as described in the said Belgian patent specification.
Particularly suitable esters include benzyl, £-methoxybenzyl, methyl and methoxymethyl esters. Nitrobenzyl esters, for example, £-nitrobenzyl esters are also suitable.
The etherification reaction is generally carried out in an inert medium at non extreme temperatures.
Suitable media for the reaction include hydrocarbon solvents such as benzene and toluene and other conventional solvents such as ethyl acetate, tetrahydrofuran, or acetone.
The reaction may be best effected at a temperature of from 10° to 100°C, for example 30° - 80°C.
It is desirable that the reaction mixture is maintained under anhydrous conditions.
Once the reaction is over (for example as judged by tic) the mixture is allowed to cool, filtered to remove suspended solids and then evaporated. If desired the resulting material can be purified by such conventional procedures as column chromatography. -5 46478 In those cases where the product of the reaction is a compound of the formula (II) wherein R^ is a group CR-^R^R^, the starting material may he a salt of clavulanic acid, when the reaction may be regarded as proceeding via the formation of an ester of clavulanic acid followed by in situ etherification.
Normally, such a reaction will be carried out in the presence of a crown ether to solubilise the salt of clavulanic acid.
This is a less preferred aspect of the invention.
The following examples illustrate the invention. - 6 46478 Example 1 p-Methoxybenzyl O-Ethylclavulanate A mixture of p-methoxybenzyl clavulanate (3.19 g), powdered calcium oxide (4.0 g), silver oxide (4.0 g), and ethyl iodide (6 ml) in benzene (50 ml) was boiled under reflux for 2 h. The cooled reaction mixture was filtered and the filtrate evaporated to give an oil which was chromatographed over silica gel (30 g). Elution of the column with ethyl acetate-cyclohexane (ls4) afforded the title compound (0.74 g) in pure form identical to an authentic sample (ir. and n.m.r. comparisons) A similar result may be obtained by replacing the ethyl iodide with ethyl bromide and carrying out the reaction at 40°C for a longer period.
The corresponding methyl ether can also be prepared by substituting methyl iodide for the above ethyl iodide. -7 46478 p-Methoxybenzyl O-Benzylclavulanate Example 2 H * CH20H -> 'CO2CH2^-OCH3 λ mixture of p-methoxybenzyl clavulanate (3.19 g), powdered calcium oxide (4.0 g), silver oxide (4.0 g) and benzyl bromide (5 ml) in benzene (50 ml) was boiled under reflux for 2 h. The cooled reaction mixture was filtered and the filtrate evaporated to give an oil which was chromatographed over silica gel (30 g). Elution of the column with ethyl acetate-cyclohexane (ls4) afforded the title compound (l.O (liquid film) 1810, 1750, 1700, 1310, 1250, 1180 and 1040 cm1, & (CDCLj) 7.22 (5H, s, ArH), 7.19 (2H, d, J = ArH), 6.76 (2H, d, J = 9Hz, ArH), .58 (IH, d, J = 2.5Hz, 5-CH), 5.08 (2H, s, -CHgAr), 5.00 (IH, broad s, 3-CH), 4.80 (IH, broad t, J = 8Hz, 8-CH), 4.38 (2H, s, -CH^r), 4.05 (2H, broad d, J = 8Hz, 9-CH|, 3.70 (3H, s, OCH^), 3.40 (lH, dd, J = 17Hz, J' x 2.5Hz, 6a-CH), and 2.96 (IH, d, J = 17Hz, 6β-0Η). - 8 46478 Example 3 ^^lethox^bonz^l^O^AlVjOclajniljttnat^ A mixture of p-methoxybenzyl clavulanate (3.19 g), powdered calcium oxide (4.0g), silver oxide (4.0g), and allyl bromide (4 ml) in benzene (30 ml) was stirred at room temperature for 66 h. The mixture was filtered and the filtrate evaporated to give an oil which was chromatographed over silica gel (20 g). Elution of the column with cyclohexaneethyl acetate (4:l) afforded the title compound (0.65 g),)/^* (liquid film) 3020, 1810, 1750, 1700, 1310, 1255, 1080 and 1040 cm-1, & (CDClj) 7.30 (2H, d, J = 9Hz, ArH), 6.86 (2H, d, J - 9Hz, ArH), 5.95 (IH, m, C=CH), 5.67 (IH, d, J = 2.5Hz, 5-CH), 5.32 (2H, ra, C=CH), 5.13 (2H, s, —CH^Ar), 5.06 (IH, s, 3-CH), 4.83 (IH, broad t, J = 8Hz, 8-CH), 4.06 (2H, broad d, J = 8Hz, 9-CH2), 3.92 (2H, m, -OCH2-CH=CH2), 3.80 (3H, s, OCH3), 3.50 (IH, dd, J - 17Hz, J' = 2.5Hz, 6a-CH), and 3.00 (IH, d, J = 17 Hz, 6P-CH). _ 9 46478 Benzyl O-methylclavulanate Example 4 V O t 'COCHCH 1COCHC.H 2265 2265 mixture of benzyl clavulanate (8.67g), calcium oxide (I2g), oxide (I2g) and methyl iodide (15ml) in benzene (50ml) was under reflux for 2 hours. The mixture was allowed to cool, was A silver heated filtered and the filtrate evaporated to give an oil which was chromatographed over silica gel (50g), eluting with ethyl acetate/cyclohexane - l/4 to give the title compound (2.81g). -10 46478 Example 5 Benzyl O-Nonylclavulanate H j/ CH OH xco2ch2c6h5 Benzyl clavulanate (2.89g) in ethyl acetate (10ml) and iodononane (12.7k) were heated under reflux with stirring in presence of silver oxide (4g) and calcium oxide (4g) for 3 hours. Tic showed a fastrunning zone and a much diminished Zone due to starting mater id. 1. The mixture was filtered, the insolubles washed with ethyl acetate (50ml) and the filtrate evaporated under reduced pressure to a dark oil.
This was subjected to column chromatography on silica gel, using ethyl acetate and cyclohexane graded from lslO to ls2 as eluents.
Fractions after the nonyl iodide had been eluted contained the product, which was isolated as a pale yellow oil by evaporation of the solvents; yield 0.64g. Tr. (l/fb 1805, 1750, 1695cm1. n.m.r. (CDC^) διθ,86 (3H, t, J 7Hz, CH3), 1.25 (14H, m, 0-CHo(CHo) C^), 2.98 (IH, d, J 17Hz, 6-3-CH), 3.31 (2H, t, J 7Hz, OCH^CHj ), 3.43 (IH, dd, J 17Hz and 3Hz, 6-a-CH), 3.98 (2H, d, J 7Hz, CH2CH=), 4.78 (IH, t, J 7Hz, CH=), 5.02 (IH, s, 3-CH), 5.12 (2H, s, FhCH.), 5.61 (IH, d, J 3Hz, 5-CH) and 7.27 (5H, s, CJL).
(FT) Example 6 Benzyl (B^-O-g-butylclavulanate CH, ^•0, CH-O-CH-CH 2 25 N-~Y co2ch2c6h5 Benzyl clavulanate (2.89g) in ethyl acetate (7ml) and 2-iodobutane (9g) were refluxed with stirring in the presence of silver oxide (4g) and calcium oxide (4g) for 2| hr. The insoluble materials were filtered off, and the filtrate concentrated in vacuo to a yellow oil, which was subjected to column chromatography on silica gel using ethyl acetate and cyclohexane graded from lilO to 1:2 ratio. The ether was eluted after the 2-iodobutane. Fractions containing the ether (by tic) were evaporated in vacuo to yield the compound (O,57g) as a pale yellow oil. I.r. (2/f) 1808, 1753, 1698 cm-1.
Nmr (CDCip&0.84 (3H, t, J 7Hz, CH2CH3), 1.07 (3H, d, J 7Hz, CH-CH^, I. 26 - 1.63 (2H, nf, CH^), 2.96 (IH, d, J 17Hz, 6-6-CH), 3.26 (IH, qt, J, 7Hz OCH), 3.41 (OH, dd, I7Hz, 3Hz, 6-a-CO), 3.8 - 4.25 (IH, m, 9-01^), 4.77 (IH, t, J 8Hz 8-Ctt), 5.20 (IH, s, 3-CH), 5.12 (2H, s, CH2Fh), .90 (IH, d, J 3Hz, 5-CH) 7.28 (5H, s, C^). - 12 46478 Example 7 Benzyl O-t-Amyl clavulanate Benzyl clavulanate(2.89g) in ethyl acetate (20ml) and 2-iodo-2meth.vlbutane (6.5ml, 9.9g)were stirred at room temperature in the presence of silver oxide (4g) and calcium oxide (4g) for 3 hr. The insoluble material was filtered off, washed with ethyl acetate (50ml) and filtrnte evaporated under reduced pressure to a dark oil, which was subjected to column chromatography on silica gel, eluting with cyclohexane-ethyl acetate graded from lOsl to 3:1, to yield 0.43g of the title product as a pale yellow oil.
I.r. 1805, 1755, 1698 cm-1; (liquid film). nmr. (CDC13)£ 0.83 (3H, t, J 7Hz, C^CHj), 1.11 (6H, s, (CH.,) ), 1.46 (2H, q, J 7Hz, CH2CH3), 2.96 (IH, d, J 17Hz, ό-β-CH), 3.40 (IH, dd, J 17 and 3Hz, 6-e-CH), 3.6 - 4.3 (2H, ra, =CHCH2), 4.74 (IH, dt, J 7 and 15 ~ 2Hz, CH=), 5.0 (IH, d, J—2Hz, 3-CH), 5.12 (2H, s, PhCf^), 5.59 (IH, d, J 3Hz, 5-CH), 7.27 (5H, s, C^). - 13 46478 Benzyl 9~0-(2-propyl)clavulanate Example 8 The process used for the preparation of the title compound (0.47g) was as described in Example --6 replacing the iodobutane with 2-iodopro5 pane (5ml)· X.r, 1805, 1750 1698 cm1.
N.m.r. (CDCl3)fe t 1.10 (6H, d, J 7Hz), 2.96 (lH, d, J 17Hz), 3.40 (IH, dd, J 17Hz and 3Hz),3.51 (IH, dq., J 7Hz), 3 „80-4.30 (2H, m), 4.77 (lH, t, J 7Hz), 5.02 (IH, s),5.13 (2H,s), 5.59 (lH, d, J 3Hz), 7.26 (5H, s). - 14 46478 Example, 9 Benzyl 9-0-n-butylclavulanate A mixture of benzyl clavulanate (2.89g) silver oxide (4g) calcium oxide (4g) and 1-iodobutane (5.7ml) in ethyl acetate (7ml) was heated and stirred under reflux for 2| hour. At this time tic (cyclopentanemethylacetate 2ll) shoved a mixture of starting material and product.
The insolube materials were filtered off, and washed with ethyl acetate (10ml). The filtrate was evaporated under reduced pressure to an orange oil, which was subjected to column chromatography on silica gel using cyclohexane and ethyl acetate graded from 10:1 to lsl ratio as eluents. Fractions containing the ether (by tic) were collected, combined, and evaporated to a pale yellow oil under reduced pressure, to yield 0.34g pure ether and 0,4g slightly less pure material.
I.r. 1805, 1750, 1695cm-1.
N.m.r. (CDC13)S « 0.90 (3H, t, J 6.5Hz, CH^), 1.12-1.70 (4H, m, (CH^CKj), 2.99 (IH, d, J 17Hz, 6-P-CT), 3.33 (2H, t, J 6.5Hz, OO^CH^ 3.44 (IH, dd, J 17Hz and 3Hz, 6-a-CH), 3.83-4.19 (2H, m, 9-CH/ 4.66-4.91 (IH, m, 8-CH), 5.05 (IH, a, 3-CH), 5.15 (2H, s, CH^h), 5.63 (IH, d, J 3Hz, 5-CH) and 7.29 (5H, s, CH.C^-H-). -15 46478 Example 10 Benzyl 9-0-n-hexylclavulanate The title compound (0.4g) was prepared as an oil by the method of Example 9, replacing the 1-iodobutane by 1-iodobexane (l0.6g).
I.r. 1805, 1757, 1698cm-1.
N.m.r. (CDC13)£ 0.88 (3H, t, J 6Hz), 1.12-1.50 (8H, bm), 2.99 (IH, d, J 17Hz) 3.32 (2H,'t, J 6Hz), 3.43 (IH, dd, J 17 and 3Hz), 4.02 (2H, <3b, J 7Hz), 4.79 (IH, t, J 7Hz), 5.05 (IH, s), 5.15 (2H, s), 5.64 (iH, hs) and 7.29 (5H, s). -1646478 Examples 11-1^ The reactions described in Examples 1-3 were repeated, but without the use of calcium oxide. The desired compounds were produced in each instance, but in reduced yields.

Claims (9)

CLAIMS: A process for the preparation of a compound of the Λ CH n -O-C-R. (II) wherein R^ is a group such that COgR-j is an esterified carboxyl group, Rj is a hydrogen atom or an alkyl group of
1.-4 carbon atoms, R^ is a hydrogen atom or an alkyl group of 1-4 carbon atoms and is a group such that the CR^R^R^ moiety is an inert organic group of up to 18 carbon atoms; which process comprises the reaction of a compound of the formula (III): wherein Rj is as defined in relation to formula (II) with a compound of the formula (IV); (IV) wherein X is I, Br, or CI and R-j, R^ and R^ are defined in relation to formula (II); in the presence of a source of silver ions. - 18 46478
2. A process as claimed in claim 1 wherein an alkaline earth metal oxide is also present. 3. A process as claimed in claim 2 wherein the oxide is calcium oxide. A. A process as claimed in any of claims 1-3 wherein the source of silver ions is silver oxide. 4. 5. A process as claimed in any of claims 1-4 wherein from 1 to 2 equivalents of silver ions are employed per equivalent of compound of the formula (III). 5. 6. A process as claimed in any of claims
3.-5 wherein from 1 to 2 equivalents of calcium oxide are employed per equivalent of compound of the formula (ill). 6. 7. A process as claimed in any of claims 1-6 wherein Rj is a hydrogen atom or a methyl, ethyl, n-propyl or n-butyl group. 7. 8. A process as claimed in any of claims 1-7 wherein R^ is a hydrogen atom or a methyl, ethyl, n-propyl or n-butyl group. 8. 9. A process as claimed in any of claims 1-8 wherein Ris a hydrogen atom. - 19 46478 9. 10. A process as claimed in any of claims 1-9 wherein is a hydrogen atom. 10. 11. A process as claimed in any of claims 1-6 wherein the Ί Ί CR^R^R^ moiety is a CH^R group where CH^R is an inert organic group of up to 18 carbon atoms. 11. 12. A process as claimed in any of claims 1-11 wherein is a hydrogen atomor-a methyl, ethyl, n-propyl, n-butyl, n-pentyl, iso-propyl, vinyl,benzyl or p-methoxybenzyl group. 12. 13. A process as claimed in any of claims 1-11 wherein R^ is a hydrogen atom or a methyl, ethyl, benzyl or vinyl group, 13. 1
4. A process as claimed in any of claims 1-11 wherein R^ is a hydrogen atom or a methyl or ethyl group. 14. 1
5. A process as claimed in any of claims 1-11 wherein is a hydrogen atom. 15. 1
6. A process as claimed in any of claims 1-11 wherein R^ is a methyl group. 16. 1
7. A process as claimed in any of claims 1-6 adapted to the preparation of a compound of the formula (II) as defined in claim 1 wherein CR^R^R^ is a methyl or ethyl group. 17. 1
8. A process as claimed in claim 17 wherein the adaption comprises the use of methyl iodide or ethyl iodide. 18. 1
9. A process as claimed in any of claims 1-18 wherein 1 2 3 1 is a group A or CHA A wherein A is an alkyl group of 1 — 8 carbon atoms, optionally substituted by halogen or by a group of the formula OA^, OCOa\ SA^, SOgA^ wherein -20 464 78 A 4 is a hydrocarbon group of up to 6 carbon atoms; tr is a hydrogen atom, an alkyl group of up to 4 carbon atoms or a phenyl group optionally subsituted by halogen or by 5 5 5 a group A or OA where A is an alkyl group of up to Z 5 6 carhon atoms; and hr is a phenyl group optionally 5 5 5 substituted by halogen or hy a group A or OA where A is an alkyl group. 19. 20. A process as claimed in any of claims 1-18 wherein is an alkenyl group of up to 8 carhon atoms. io 20. 21. A process as claimed in claim 20 wherein is an allyl group. 21. 22. A process as claimed in any of claims 1-19 adapted to the preparation of an in-vivo hydrolysable ester of the formula (ID. 15 22. 23. A process as claimed in claim 22 wherein the in-vivo hydrolysable ester is the acetoxymethyl, a-acetoxyethyl, pivaloyloxymethyl, phthalidyl, ethoxycarbonyloxymethyl, or ethoxycarbonyloxyethyl ester. 23. 24. A process as claimed in any of claims 1-19 adapted to the 20 preparation of a benzyl, p-methoxybenzyl, methyl or methoxymethyl ester of the formula (II). 24. 25. A process as claimed in any of claims 1 —18 adapted to the preparation of a £-nitrobenzyl ester of the formula (II) 25. 26. A process as claimed in any of claims 1-25 wherein the 25 reaction is carried out in an inert medium at a temperature of' from 10° to 1OO°C. 26. 27. A process as claimed in claim 26 wherein the medium is benzene, toluene, ethyl acetate, tetrahydrofuran or acetone. 27. 28. A process as claimed in claim 27 wherein the reaction is effected at a temperature of 30 - 80°C. 28. 29. A process as claimed in any of claims 1-28 wherein a compound of the formula (III) wherein Rj is a group is prepared 5 CR,R^Rc/ in situ by the esterification of a salt of clavulanic acid. 29. 30. A process for the preparation of a compound of the formula (II): wherein R^ is benzyl, p-methoxybenzyl, methyl or methoxymethyl 'and CR^R^Rg is methyl or ethyl, which comprises the reaction of a compound of the formula (III) (III) wherein R^ is as defined in relation to formula (II) with a compound of the formula (IV): (IV) wherein CR^R^Rg is a methyl or ethyl Br or Cl in the presence of a source group and X is 1, or silver ions. 30. 31. A process as claimed in claim 30 wherein CR 2 R 3 C 4 is a methyl group. 31. 32. A process as claimed in claim 30 wherein the compound of the formula (IV) is methyl iodide. 32. 33. A process as claimed in claim 30 wherein CR 2 R 3 R 4 is an ethyl group. 33. 34. A process as claimed in claim 30 wherein the compound of the formula (IV) is ethyl iodide. 34. 35. A process as claimed in any of claims 30 - 34 wherein the source of silver ions is silver oxide. 35. 36. A process as claimed in any of claims 30 - 35 carried out in the presence of calcium oxide. 36. 37. A compound of the formula (II) as defined in claim 1 whenever prepared by the process of any of claims 1-36. 37. 38. A process as claimed in any of claims 1-36 substantially as described in the Examples.
IE477/78A 1977-03-10 1978-03-09 Chemical process for the preparation of clavulanic acid derivatives IE46478B1 (en)

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GB1011677 1977-03-10
GB10082/77A GB1582864A (en) 1977-03-10 1977-03-10 Chemical process for the preparation of clavulanic acid derivatives

Publications (2)

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IE780477L IE780477L (en) 1978-09-10
IE46478B1 true IE46478B1 (en) 1983-06-29

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IE477/78A IE46478B1 (en) 1977-03-10 1978-03-09 Chemical process for the preparation of clavulanic acid derivatives

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JP (1) JPS53112894A (en)
AR (1) AR216505A1 (en)
AT (1) AT359188B (en)
AU (1) AU519232B2 (en)
CH (1) CH632760A5 (en)
DE (1) DE2808116A1 (en)
DK (1) DK139377A (en)
ES (1) ES467513A1 (en)
FI (1) FI65252C (en)
FR (1) FR2383184A1 (en)
GR (1) GR64160B (en)
HK (1) HK15084A (en)
IE (1) IE46478B1 (en)
IL (1) IL54078A0 (en)
KE (1) KE3337A (en)
MX (1) MX4864E (en)
NL (1) NL7802596A (en)
NO (1) NO771106L (en)
SE (1) SE442748B (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2862254D1 (en) * 1977-12-02 1983-06-16 Beecham Group Plc A process for the preparation of ether derivatives of clavulanic acid
JPS58187371A (en) * 1982-04-27 1983-11-01 Nec Corp Controlling circuit for printing density
DE3725375A1 (en) * 1987-07-31 1989-02-09 Bayer Ag STABLE OXAPENEM-3-CARBONSAEURES

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1573503A (en) * 1975-12-17 1980-08-28 Glaxo Lab Ltd Clavulanic acid derivatives

Also Published As

Publication number Publication date
FI65252B (en) 1983-12-30
AR216505A1 (en) 1979-12-28
FR2383184B1 (en) 1980-08-29
FI771146A (en) 1978-09-11
JPS53112894A (en) 1978-10-02
SE442748B (en) 1986-01-27
FI65252C (en) 1984-04-10
MX4864E (en) 1982-11-10
GR64160B (en) 1980-02-05
DE2808116A1 (en) 1978-09-21
ES467513A1 (en) 1979-08-01
AU3384078A (en) 1979-09-06
CH632760A5 (en) 1982-10-29
IE780477L (en) 1978-09-10
FR2383184A1 (en) 1978-10-06
SE7704085L (en) 1978-09-11
AU519232B2 (en) 1981-11-19
IL54078A0 (en) 1978-04-30
NL7802596A (en) 1978-09-12
ATA145178A (en) 1980-03-15
KE3337A (en) 1983-11-25
HK15084A (en) 1984-02-24
NO771106L (en) 1978-09-12
DK139377A (en) 1978-09-11
AT359188B (en) 1980-10-27

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