GB1572912A - Clavulanic acid esters - Google Patents

Clavulanic acid esters Download PDF

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GB1572912A
GB1572912A GB2031/77A GB203177A GB1572912A GB 1572912 A GB1572912 A GB 1572912A GB 2031/77 A GB2031/77 A GB 2031/77A GB 203177 A GB203177 A GB 203177A GB 1572912 A GB1572912 A GB 1572912A
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compound
group
ethyl acetate
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silica gel
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Beecham Group PLC
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Priority to GB2031/77A priority Critical patent/GB1572912A/en
Priority to BE184209A priority patent/BE862764A/en
Priority to FR7800673A priority patent/FR2378035A1/en
Priority to JP323178A priority patent/JPS5390289A/en
Priority to NL7800604A priority patent/NL7800604A/en
Priority to DE19782802049 priority patent/DE2802049A1/en
Publication of GB1572912A publication Critical patent/GB1572912A/en
Expired legal-status Critical Current

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Plural Heterocyclic Compounds (AREA)

Description

(54) NOVEL CLAVULANIC ACID ESTERS (71) We, BEECHAM GROUP LIMITED, a British Company of Beecham House, Great West Road, Brentford, Middlesex, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: The present invention relates to esters of clavulanic acid and to their preparation.
British Patent No. 1508978 (see also Belgian Patent No. 827926) discloses inter alia that esters of clavulanic acid may be hydrolysed to yield salts of clavulanic acid. The Belgian Patent described how the methyl ester of clavulanic acid was useful for this purpose. The yields of these known hydrolysis reactions are acceptable but leave considerable scope for improvement. A class of esters has now been discovered that may be readily hydrolysed in good yield to salts of clavulanic acid. This makes these esters of use in the isolation of salts of clavulanic acid and its derivatives.
The present invention provides the compounds of the formula (I):
wherein R1 is an alkyl group of 1-6 carbon atoms optionally substituted by a lower alkoxy group or is an optionally substituted phenyl group or an alkyl group of 1-4 carbon atoms substituted by an optionally substituted phenyl group; and R2 is a hydrogen atom or an alkyl group of 1-4 carbon atoms or is joined to R1 to form part of a tetrahydrofuraryl or tetrahydropyraryl ring.
The term "optionally substituted phenyl" means a phenyl group unsubstituted or substituted by one or more fluorine, chlorine or bromine atoms or lower alkoxyl, lower alkoxycarbonyl or nitro groups. Any substituted group is most suitably mono-substituted or disubstituted and is preferably mono-substituted.
The term "lower" means that the group contains up to 4 carbon atoms. Suitably R1 is a methyl, ethyl, propyl, phenyl, p-chlorophenyl, p-methoxyphenyl, p-nitrophenyl, benzyl or p-chlorobenzyl group.
Suitably R2 is a hydrogen atom or methyl group or is joined to R1 to form the residue of a tetrahydrofuranyl or tetrahydropyranyl ring.
The preferred compounds of the formula (I) include those of the formula (11):
wherein R3 is a lower alkyl group, or an optionally substituted phenyl group of a lower alkyl group substituted by an optionally substituted phenyl grotp.ble group.
Suitable groups R3 include those named above as being suitable groups Rl in particular the lower alkyl groups.
The present invention provides a process for the preparation of the compounds of the formula (I) which process comprises the reaction of a salt of clavulanic acid with a compound of the formula (III):
wherein R1 and R2 are as defined in relation to formula (I) and X is a chlorine or bromine atom.
The esterification reaction is most suitably performed in a polar organic solvent such as dimethylformamide, dimethylsulphoxide, or tetrahydrofuran. Generally the reaction is carried out at a temperature of -20"C to +300C, for example from 0 C to 100C.
Generally the reaction is performed on an alkali metal salt of clavulanic acid such as the sodium or potassium salt.
It is frequently more convenient to carry out the esterification using a compound of the formula (III) wherein X is a chlorine atom. An activator such as NaI or its equivalent may be present if desired.
The desired pure ester may be obtained from the reaction by conventional methods such as column chromatography, for example using silica gel as support and gradiently eluting with conventional mixed solvents such as ethyl acetate (polar component) and cyclohexane (non-polar component).
Once obtained the pure ester of the formula (I) may be converted to clavulanic acid salts of good purity by very mild base hydrolysis using such reagents as carefully added LiOH, NaOH or CaCO3 or NaHCO3 etc.
The solvent used for the hydrolysis will most suitably be water although homogenous mixtures of water and organic solvents such as tetrahydrofuran may also be used.
The base will normally be added at such a rate that the pH of the medium is maintained at approximately 8-9, for example 8.5-8.9. The pH may be maintained in this region automatically, for example by using a pH-Stat (such as that supplied by Metro, Herasau, Switzerland).
The esters of the formula (I) are also intermediates in the preparation of derivatives of clavulanic acid such as ethers or thioethers of clavulanic acid. For example the esters of formula (I) may be reacted at a low temperature with diazomethane in an inert solvent in the presence of a catalytic amount of boron trifluoride etherate to yield the corresponding methyl ether of the compound of the formula (I). The ester may then be hydrolysed by mild methods as already described.
The following Examples illustrate the invention: Example 1 Methoxymethyl clavulanate Sodium clavulanate (2.93g, 0.01 mol) was dissolved in dimethylformamide (20 ml).
Chloro dimethylether (0.8 ml, 0.86 g) was added with cooling and stirring. After 2 hours at room temperature, the DMF was evaporated in vacuo and the residue taken up in ethylacetate (40 ml) and cyclohexane (20 ml). Silica gel (t.l.c. grade 7g) was added, and the insoluble materials filtered off, washed with a little fresh solvent and discarded. The filtrate was evaporated under reduced pressure to small volume, and subjected to column chromatography on silica gel using ethyl acetate and cyclohexane as eluents. The product was isolated as a colourless oil (2 g). Ir. vmax (film) 1802 (p-lactam C=O) 1755 (ester C=O) 1695cm* (C=C); nmr (CDCl3) 2.3 (lH,bs, OH) 3.02 (1H, d,J 17 Hz, 6-p-CH) 3.42 (3H, s, OCH3) 3.47 (1H, dd.J 17 Hz, 3Hz, 6-a - CH) 4.16 (2H, d,J 6 Hz, CH20H) 4.89 (1H, bt,J 6Hz, CH=CH2) 5.03 (1H, bs, 3-CH) 5.21, 5.29 (2H, ABq,J 5.5hZ, CH2OCH3) 5.65 8 (1H, d,J 3Hz, 5-CH).
Example 2 Hydrolysis of methoxymethyl clavulanate Methoxymethyl clavulanate (100mp) in tetrahydrofuran (2ml) was added to water (25ml) at 22"C. The pH of the solution was maintained at 8.5-9 by the addition of 1m lithium hydroxide solution in a pH-Stat. When the uptake of LiOH became very slow (after about 10 minutes) the solution was evaporated (below 25"C) in vacuo to yield a white solid. Trituration with acetone followed by washing with ether and drying in vacuo yielded crystalline lithium clavulanate (60mp).
Example 3 p- Chlorophenoxym ethyl clavulanate A cooled (ice-water), stirred solution of sodium clavulanate tetrahydrate (6g, 0.02 mole) in dimethylformamide (60ml) was treated with pchlorophenoxymethyl chloride (3.5g, 0.02 mole). After 2+ hours at < 100, the dimethylformamide was largely evaporated in vacuo at room temperature (20 ). To this syrup was added ethyl acetate (200ml) and ice-cold water (20 ml). The ethyl acetate was dried over sodium sulphate, evaporated to a syrup, and the residue was subjected to column chromatography on silica gel using ethyl acetate and cyclohexane as eluents (graded from 1:2 to 2:1 ratio). A small quantity of the p-chlorophenoxymethyl ester of the diene of clavulanic acid eluted first, followed by the required pure p-chlorophenoxymethyl clavulanate (4.7 g). (This contained a very small quantity of the diene, detectable by thin layer chromatography sufficient to be seen in the n.m.r.) I.r.: 3400 (br, OH) 1805 (p-lactam C=O) 1765 (ester C=O) 1695cur" (C=C).
N.m.r.: (CDCl3) 1.5 (OH) 3.00 (1H, d, J 17Hz, 6-p-CH) 3.44 (1H, dd, J 17 and 3Hz, 6-a-CH) 4.14 (2H, d,J 7Hz, CH2OH) 4.77 (1H, bt,J 7Hz, CH=CH2 5.02 (1H, bs, 3-CH) 5.60 (1H, d,J 3Hz, 5-CH) 5.70, 5.77 (2H, ABq, J 7Hz, OCH20) 6.89, 7.218 (4H, A2B2q,J 9Hz, C6H4) Example 4 Benzyloxymethylclavulanate Sodium clavulanate tetrahydrate (2.93 g) was dissolved in dimethylformamide (20 ml) and the resulting cloudy solution filtered. The clear yellow solution was cooled with ice and stirred while benzyl chloromethyl ether 1.57 g, prepared according to the method of Graham and McQuillin. J Chem. Soc., 1963, 4634) was added dropwise. Stirring and cooling were maintained for 2+ hours. The reaction mixture was evaporated to give an orange coloured oil which was extracted several times with ethyl acetate. The combined ethyl acetate extracts were evaporated to a yellow oil.
Analysis of the oil by thin layer chromatography (on silica gel plates, eluted with methyl acetate: ethyl acetate: methylcyclopentane, 1:1:2, visualised with permanganate spray) showed two zones at Rf 0.21 and 0.55, of approximately equal intensity. The oil was chromatographed on a column packed with silica gel and eluted with a mixture of ethyl acetate and cyclohexane (1:1). The compositions of the eluted fractions was analysed by tlc and the slow running material collected free of any detectable impurity. Evaporation gave an almost colourless oil (0.7 g).
Nmr (CDCl3): 8 2.08 (1H, bs), 3.02 (1H, d, J16Hz), 3.38 (1H, dd, J16Hz, J'3Hz), 4.15 (2H, d, J7Hz). 4.64 (2H, s), 4.87 (1H, bt, J7Hz), 4.99 (1H, bs), 5.34 (2H, s), 5.58 (1H, d, J2Hz), 7.25 (5H, bs).
Example 5 Preparntion of p -nitrobenzyloxymethylelavulanate Sodium clavulanate tetrahydrate (2.93 g) was dissolved in dimethylformamide (20 ml) and the resulting cloudy solution filtered. The clear yellow solution was cooled with ice and stirred while chloromethyl p-nitrobenzylether (2.02 g) was added dropwise. (This reagent was prepared by the method used by D N Kursanov and P A Solodkov, J Applied Chem. (USSR) (1943), 16, pp 351-5). The reaction mixture was stirred for 2 hours and the progress of the reaction followed by tlc (silica gel plates, eluted with methyl acetate, ethyl acetate, methycyclopentane, 1:1:2). At the end of this time the major product was p -nitrobenzyloxymethylclavulanate (Rf 0.18) with a small amount of the ether ester as well (at Rf 0.35). Solvent was removed by evaporation and the crude reaction product purified by column chromatography on silica gel eluted with cyclohexane : ethyl acetate 5 : 4. The product was obtained by evaporation of the appropriate chromatography fractions and was initially a yellow oil, but later crystallized.
Infra-red spectrum attached. X-ray powder diffractogram (CuK radiation) reflections at 20 : 9.7, 11.65, 14.0, 15.6, 16.6, 18.0, 19.55,20.4,21.1,22.8, 23.5, 24.75, 26.3,28.05,29.95.
Nmr (CDCl3) 8 1.85 (1H, bs), 3.01 (1H, d, J=16Hz), 3.42 (1H, dd, J=16Hz, 3Hz) 4.14 2H, d, J=7Hz), 4.73 (2H, s), 4.85 (1H, bt, J=7Hz), 4.97 1H, s), 5.39 (2H, s), 5.59 (1H, d, J=3Hz), 7.75 4H, dd, J=62Hz, 8Hz).
WHAT WE CLAIM IS: 1. A compound of the formula (I):
**WARNING** end of DESC field may overlap start of CLMS **.

Claims (14)

**WARNING** start of CLMS field may overlap end of DESC **. dimethylformamide (60ml) was treated with pchlorophenoxymethyl chloride (3.5g, 0.02 mole). After 2+ hours at < 100, the dimethylformamide was largely evaporated in vacuo at room temperature (20 ). To this syrup was added ethyl acetate (200ml) and ice-cold water (20 ml). The ethyl acetate was dried over sodium sulphate, evaporated to a syrup, and the residue was subjected to column chromatography on silica gel using ethyl acetate and cyclohexane as eluents (graded from 1:2 to 2:1 ratio). A small quantity of the p-chlorophenoxymethyl ester of the diene of clavulanic acid eluted first, followed by the required pure p-chlorophenoxymethyl clavulanate (4.7 g). (This contained a very small quantity of the diene, detectable by thin layer chromatography sufficient to be seen in the n.m.r.) I.r.: 3400 (br, OH) 1805 (p-lactam C=O) 1765 (ester C=O) 1695cur" (C=C). N.m.r.: (CDCl3) 1.5 (OH) 3.00 (1H, d, J 17Hz, 6-p-CH) 3.44 (1H, dd, J 17 and 3Hz, 6-a-CH) 4.14 (2H, d,J 7Hz, CH2OH) 4.77 (1H, bt,J 7Hz, CH=CH2 5.02 (1H, bs, 3-CH) 5.60 (1H, d,J 3Hz, 5-CH) 5.70, 5.77 (2H, ABq, J 7Hz, OCH20) 6.89, 7.218 (4H, A2B2q,J 9Hz, C6H4) Example 4 Benzyloxymethylclavulanate Sodium clavulanate tetrahydrate (2.93 g) was dissolved in dimethylformamide (20 ml) and the resulting cloudy solution filtered. The clear yellow solution was cooled with ice and stirred while benzyl chloromethyl ether 1.57 g, prepared according to the method of Graham and McQuillin. J Chem. Soc., 1963, 4634) was added dropwise. Stirring and cooling were maintained for 2+ hours. The reaction mixture was evaporated to give an orange coloured oil which was extracted several times with ethyl acetate. The combined ethyl acetate extracts were evaporated to a yellow oil. Analysis of the oil by thin layer chromatography (on silica gel plates, eluted with methyl acetate: ethyl acetate: methylcyclopentane, 1:1:2, visualised with permanganate spray) showed two zones at Rf 0.21 and 0.55, of approximately equal intensity. The oil was chromatographed on a column packed with silica gel and eluted with a mixture of ethyl acetate and cyclohexane (1:1). The compositions of the eluted fractions was analysed by tlc and the slow running material collected free of any detectable impurity. Evaporation gave an almost colourless oil (0.7 g). Nmr (CDCl3): 8 2.08 (1H, bs), 3.02 (1H, d, J16Hz), 3.38 (1H, dd, J16Hz, J'3Hz), 4.15 (2H, d, J7Hz). 4.64 (2H, s), 4.87 (1H, bt, J7Hz), 4.99 (1H, bs), 5.34 (2H, s), 5.58 (1H, d, J2Hz), 7.25 (5H, bs). Example 5 Preparntion of p -nitrobenzyloxymethylelavulanate Sodium clavulanate tetrahydrate (2.93 g) was dissolved in dimethylformamide (20 ml) and the resulting cloudy solution filtered. The clear yellow solution was cooled with ice and stirred while chloromethyl p-nitrobenzylether (2.02 g) was added dropwise. (This reagent was prepared by the method used by D N Kursanov and P A Solodkov, J Applied Chem. (USSR) (1943), 16, pp 351-5). The reaction mixture was stirred for 2 hours and the progress of the reaction followed by tlc (silica gel plates, eluted with methyl acetate, ethyl acetate, methycyclopentane, 1:1:2). At the end of this time the major product was p -nitrobenzyloxymethylclavulanate (Rf 0.18) with a small amount of the ether ester as well (at Rf 0.35). Solvent was removed by evaporation and the crude reaction product purified by column chromatography on silica gel eluted with cyclohexane : ethyl acetate 5 : 4. The product was obtained by evaporation of the appropriate chromatography fractions and was initially a yellow oil, but later crystallized. Infra-red spectrum attached. X-ray powder diffractogram (CuK radiation) reflections at 20 : 9.7, 11.65, 14.0, 15.6, 16.6, 18.0, 19.55,20.4,21.1,22.8, 23.5, 24.75, 26.3,28.05,29.95. Nmr (CDCl3) 8 1.85 (1H, bs), 3.01 (1H, d, J=16Hz), 3.42 (1H, dd, J=16Hz, 3Hz) 4.14 2H, d, J=7Hz), 4.73 (2H, s), 4.85 (1H, bt, J=7Hz), 4.97 1H, s), 5.39 (2H, s), 5.59 (1H, d, J=3Hz), 7.75 4H, dd, J=62Hz, 8Hz). WHAT WE CLAIM IS:
1. A compound of the formula (I):
wherein R1 is an alkyl group of 1-6 carbon atoms optionally substituted by a lower aloxyl group or is an optionally substituted phenyl group of an alkyl group of 1-4 carbon atoms substituted by an optionally substituted phenyl group; and R2 is a hydrogen atom or an alkyl group of 1-4 carbon atoms or is joined to R1 to form part of a tetrahydrofurenyl or tetrahydropyranyl ring.
2. A compound as claimed in claim 1 wherein R1 is methyl, ethyl, propyl, phenyl, p-chlorophenyl, p-methoxyphenyl, p-nitrophenyl, benzyl or p-chlorobenzyl group.
3. A compound as claimed in claim 1 or claim 2 wherein R2 is a hydrogen atom or methyl group.
4. A compound as claimed in claim 1 wherein R1 is joined to R2 to form the residue of a tetrahydrofuranyl or tetrahydropyranyl ring.
5. A compound of the formula (II):
wherein R3 is a lower alkyl group or an optionally substituted phenyl group or a lower alkyl group substituted by an optionally substituted phenyl group.
6. A compound as claimed in claim 5 wherein R3 is a lower alkyl group.
7. The compound as claimed in claim 5 wherein R3 is a methyl group.
8. The compound as claimed in claim 5 wherein R3 is an ethyl group.
9. A compound as claimed in claim 5 wherein R3 is a propyl group.
10. The compound as claimed in claim 5 wherein R3 is a benzyl group.
11. The compound as claimed in claim 5 wherein R3 is a p-nitrobenzyl group.
12. A process for the preparation of a compound as claimed in any of claims 1-11 which comprises the reaction of a salt of clavulanic acid with a compound of the formula (III): wherein R1 and R2 are as defined in relation to formula (I) and X is a chlorine or bromine atom.
13. A process as claimed in claim 12 wherein the salt of clavulanic acid is the sodium or potassium salt.
14. A compound as claimed in any of claims 1-11 whenever prepared by a process as claimed in claims 12 or 13.
GB2031/77A 1977-01-19 1977-01-19 Clavulanic acid esters Expired GB1572912A (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
GB2031/77A GB1572912A (en) 1977-01-19 1977-01-19 Clavulanic acid esters
BE184209A BE862764A (en) 1977-01-19 1978-01-09 CLAVULANIC ACID ESTERS
FR7800673A FR2378035A1 (en) 1977-01-19 1978-01-11 CLAVULANIC ACID ESTERS
JP323178A JPS5390289A (en) 1977-01-19 1978-01-14 Curabalanic esters and process for preparing same
NL7800604A NL7800604A (en) 1977-01-19 1978-01-18 CLAVULAN ACID ESTERS AND PROCEDURE FOR PREPARING THESE ESTERS.
DE19782802049 DE2802049A1 (en) 1977-01-19 1978-01-18 CLAVULANIC ACID ESTER AND METHOD OF MANUFACTURING IT

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GB2031/77A GB1572912A (en) 1977-01-19 1977-01-19 Clavulanic acid esters

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JP (1) JPS5390289A (en)
BE (1) BE862764A (en)
DE (1) DE2802049A1 (en)
FR (1) FR2378035A1 (en)
GB (1) GB1572912A (en)
NL (1) NL7800604A (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3063683D1 (en) * 1979-08-24 1983-07-14 Beecham Group Plc Amine salt of clavulanic acid, its preparation and use
DE3165543D1 (en) * 1980-06-11 1984-09-20 Beecham Group Plc Process for the preparation of beta-lactam antibiotics

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2635477A1 (en) * 1975-08-20 1977-03-03 Beecham Group Ltd PROCESS FOR THE PRODUCTION OF SOLID, PRACTICALLY PURE SODIUM AND POTASSIUM SALT OF CLAVULANIC ACID

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FR2378035A1 (en) 1978-08-18
BE862764A (en) 1978-07-10
JPS5390289A (en) 1978-08-08
NL7800604A (en) 1978-07-21
DE2802049A1 (en) 1978-07-20
FR2378035B1 (en) 1982-11-19

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