GB2035298A - Preparation of beta -lactam compounds - Google Patents
Preparation of beta -lactam compounds Download PDFInfo
- Publication number
- GB2035298A GB2035298A GB7930152A GB7930152A GB2035298A GB 2035298 A GB2035298 A GB 2035298A GB 7930152 A GB7930152 A GB 7930152A GB 7930152 A GB7930152 A GB 7930152A GB 2035298 A GB2035298 A GB 2035298A
- Authority
- GB
- United Kingdom
- Prior art keywords
- ester
- group
- groups
- optionally substituted
- xis
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- -1 beta -lactam compounds Chemical class 0.000 title claims description 16
- 150000002148 esters Chemical class 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 19
- 239000002253 acid Substances 0.000 claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 5
- RQPRTOROWUUIIX-UHFFFAOYSA-L dipotassium;carbonotrithioate Chemical compound [K+].[K+].[S-]C([S-])=S RQPRTOROWUUIIX-UHFFFAOYSA-L 0.000 claims abstract description 4
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
- 125000006281 4-bromobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Br)C([H])([H])* 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000002668 chloroacetyl group Chemical group ClCC(=O)* 0.000 claims description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 1
- 125000001302 tertiary amino group Chemical group 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 241001558496 Talpa caeca Species 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 229940093499 ethyl acetate Drugs 0.000 description 2
- 235000019439 ethyl acetate Nutrition 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- BIIBYWQGRFWQKM-JVVROLKMSA-N (2S)-N-[4-(cyclopropylamino)-3,4-dioxo-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl]-2-[[(E)-3-(2,4-dichlorophenyl)prop-2-enoyl]amino]-4,4-dimethylpentanamide Chemical compound CC(C)(C)C[C@@H](C(NC(C[C@H](CCN1)C1=O)C(C(NC1CC1)=O)=O)=O)NC(/C=C/C(C=CC(Cl)=C1)=C1Cl)=O BIIBYWQGRFWQKM-JVVROLKMSA-N 0.000 description 1
- UTQNKKSJPHTPBS-UHFFFAOYSA-N 2,2,2-trichloroethanone Chemical group ClC(Cl)(Cl)[C]=O UTQNKKSJPHTPBS-UHFFFAOYSA-N 0.000 description 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- 239000003781 beta lactamase inhibitor Substances 0.000 description 1
- 229940126813 beta-lactamase inhibitor Drugs 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 229960003324 clavulanic acid Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 229940076405 detrol Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003512 tertiary amines Chemical group 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 229940126085 β‑Lactamase Inhibitor Drugs 0.000 description 1
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
A process for the preparation of an ester of 9-mercaptodeoxyclavulanic acid comprises the reaction of potassium trithiocarbonate with the corresponding ester of a compound of the formula (I): <IMAGE> wherein X is a readily displaceable moiety.n
Description
SPECIFICATION
Process for the preparation of p-lactam compounds
The present invention relates to the preparation of esters of 9-mercaptodeoxyclavulanic acid derivatives.
Esters of 9-mercaptodeoxyclavulanic acid (also called 3R, 5R,Z-2-(2-mercaptoethylidene)- clavam-3-carboxylic acid) and their use are described in French Patent Specification No. 2342292. A
Process has now been found for the preparation of said esters which gives better yields and which is more convenient to employ than the previously known process.
The present invention provides a process for the preparation of an ester of 9-mercaptodeoxyclavulanic acid which process comprises the reaction of potassium trithiocarbonate with the corresponding ester of a compound oftheformula (I):
wherein X is a readily displaceable moiety.
Suitable readily displaceable moieties include the chlorine or bromine atoms and the groups of the sub-formuiae (a) and (b): R1-O (a)
OSO3 HNR2R3R4 (b) where R1 is an optionally substituted phenylacetyl group, a C35 acyl group optionally substituted by one or more chlorine atoms, or an optionally substituted mesyl or tosyl group; and R2, R3 and R4 are groups such that NR2R3R4 is a tertiary amine.
Suitable groups R1 include acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl the like of which dichloroacetyl is preferred.
Suitable groups R2, R3 and R4 include C1-6 alkyl groups such as methyl, ethyl and like groups.
Suitable groups R1 include dichloroacetyl and the like.
Suitable groups R2, R3 and R4 include C-6 alkyl groups.
Most suitably an ester of 9-chlorodeoxy-clavulanic acid is employed.
The reaction is normally carried out in a non-hydroxylic medium such as dimethylformamide, hexamethyl-phosphoramide, tetrahydrofuran and the like organic solvent of relatively high dielectric constant.
It has been preferred to carry out this reaction at a slightly depressed or ambient temperature, for example -10 Cto +30"C although non-extreme temperatures outside this range may be employed if desired.
The desired ester may be obtained from the reaction mixture by neutralisation followed by evaporation.
However this method of recovery tends to produce an impure product so that it is desireable to dilute the reaction solution with a water imiscible organic solvent such as ethyl acetate prior to or after neutralisation and then recover the desired ester from this organic solution after it has been washed with water to remove the water-soluble impurities.
In general the organic solvent is removed by evaporation although other conventional methods may be employed if desired.
The product may be further purified chromatographically if thought desirable.
Since the compound prepared by the process of this invention will normally be employed as a chemical intermediate rather than a ss-lactamase inhibitor, it is preferred that the ester employed is one convertible to the free acid or its salt in mild manner. Suitable esters of this type include those described in the hereby incorporated French Patent specification No. 2342292 or Belgian Patent No. 850779 as suitable for 9-thioderivatives of deoxyclavulanic acid. Such esters are most aptly those which can be converted into corresponding acid or its salt by hydrogenation optionally in the presence of a base or those which can be converted into a salt of the corresponding acid by mild base hydrolysis. Such esters are described in the aforementioned Patents.These suitable esters include benzyl and substituted benzyl esters such as the p-methoxybenzyl, p-bromobenzyl, p-nitrobenzyl and the like or lower alkyl or alkoxyalkyl esters such as the methyl or methoxymethyl ester.
A particularly favoured ester is the p-nitrobenzyl ester since the product of the reaction is then a crystalline solid.
The following Example illustrates the invention.
EXAMPLE 4-Nitrobenzyl (3R, 5R, Z)-2-(2-mercapto eth ylldene)-cla vam-3-carboxylate
4-Nitrobenzyl (3R, 5R, Z)-2-(-chloroethylidene)-clavam-3-carboxylate (325.5 mg; 1 m.mole) was added i to a solution of dry dimethylformamide and potassium trithiocarbonate (232 mg; 1.25 m.mole) at 0-5 under nitrogen. The mixture was stirred for 2 min at 0-5 and then at room temperature for 10 min. after which time it was poured into a rapidly stirred solution of ethyl-acetate (90 ml), water (70 ml) in HCI (10 ml). (The operation carried out under nitrogen).The organic layer was separated and washed with water (4 x 50 ml) dried over anhydrous magnesium sulphate, and evaporated to give a yellow oil (0.3; 85%) which crystailised on standing in the fridge (5 ). Fecrystallisation from ethylacetate-Detrol (60-80 ) gave the title ester (260 mg) as pale yellow crystals, m.p.135-137 ; [α]D20 + 23.2 (C.0.34; CHCl3); Vmax (CHC13) 1803,1760,1525 and 1350 cm-1; b(DCCI3) 1.58 (1H,t,J7Hz, SH), 3.04 (1H, d, J 17 Hz,6ss-CH),3.21 (2H,t,J7 Hz, 9-CH2), 3.5 (1H, dd, d 17 Hz and 2.5 Hz, 6a-CH), 4.82 (1 H, t,J8 Hz, 8-CH), 5.1 (1H, s,3-CH),5.3 (2H, s, -CO2CH2), 5.69 (1H, d,J2.5 Jz, 5-CH), 7.5 and 8.21 (4H, 2d, aromatic-H).
Claims (10)
1. A process for the preparation of an ester of 9-mercaptodeoxyclavulanic acid which process comprises the reaction of potassium trithiocarbonate with the corresponding ester of a compound of the formula (I):
wherein Xis a readily displaceable moiety.
2. A process as claimed in claim 1 wherein X is a chlorine or bromine atom or groups of the subformulae (a) or (b):
wherein R1 is an optionally substituted phenyl acetyl group, a C26 acyl group optionally substituted by one or more chlorine atoms or an optionally substituted mesyl ortosyl group; and R2, R3 and R4 are groups such that NR2R3R4 is a tertiary amine.
3. A process as claimed in claim 2 wherein X is a group OR, where R is an acetyl, chloroacetyl, dichloroacetyl ortrichloroacetyl qrnuo.
4. A process as claimed in claim 2 wherein Xis a OSO3 - HNR2R3R4 group wherein R2, R3 and R4 are C1-6 alkyl groups.
5. A process as claimed in claim 1 wherein Xis chlorine.
6. A process as claimed in claims 1 to 5 which is carried out in a non-hydrolyic medium.
7. A process as claimed in claims 1 to 6 which is carried out at a temperature in the range -10Cto +30"C.
8. A process as claimed in any of claims 1 to 7 which comprises reacting a benzyl ester, a substituted benzyl ester, a lower alkyl or an alkoxyalkyl ester of the compound of the formula (I).
9. A process as claimed in claim 8 wherein the ester is the p-methoxybenzyl, p-bromobenzyl, p-nitrobenzyl, methyl or methoxylmethyl ester.
10. A process as claimed in claim 8 wherein the ester is the p-nitrobenzyl ester.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB7930152A GB2035298B (en) | 1978-09-30 | 1979-08-31 | Preparation of -lactam compounds |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB7838837 | 1978-09-30 | ||
| GB7930152A GB2035298B (en) | 1978-09-30 | 1979-08-31 | Preparation of -lactam compounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2035298A true GB2035298A (en) | 1980-06-18 |
| GB2035298B GB2035298B (en) | 1983-01-19 |
Family
ID=26269025
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB7930152A Expired GB2035298B (en) | 1978-09-30 | 1979-08-31 | Preparation of -lactam compounds |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB2035298B (en) |
-
1979
- 1979-08-31 GB GB7930152A patent/GB2035298B/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| GB2035298B (en) | 1983-01-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4155912A (en) | 2-Methylpenem-3-carboxylic acid antibiotics | |
| CH623331A5 (en) | Process for the preparation of 7beta-amino- and 7beta-acylamino-6alphaH-8-oxo-4-thia-1-azabicyclo[4.2.0]oct-2-ene-2-ca rboxylic acid derivatives | |
| CH628900A5 (en) | PROCESS FOR THE PREPARATION OF THIO-OXIMES DERIVED FROM CEPHALOSPORINS AND PENICILLINS. | |
| US4347355A (en) | Inhibitors of transpeptidase | |
| EP0000645B1 (en) | Isopenicillins, processes for their preparation, and compositions containing them | |
| US4708825A (en) | Process for the production of penicillins | |
| US4008229A (en) | Halo substituted β-lactam antibiotics | |
| FR2496666A1 (en) | NOVEL CEPHALOSPORINE DERIVATIVES AND PHARMACEUTICAL COMPOSITION CONTAINING SAME | |
| DE3889957T2 (en) | Process for the preparation of (+) - 1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid and related compounds. | |
| GB2035298A (en) | Preparation of beta -lactam compounds | |
| EP0465879B1 (en) | Derivatives of 4-(2,4-difluoro-biphenylyl)-2-methyl-4-oxo-butanoic acid | |
| US4051129A (en) | Process for preparing 7-methoxycephalosporin compounds | |
| CA1133896A (en) | Penicillanic acid derivative and process for preparing the same | |
| KR910005230B1 (en) | Process for producing azetidinones | |
| US4187228A (en) | Antibacterial agents 5R, 2S-hydroxymethyl-3Z (2-hydroxy- or 2-alkoxyethylidene-1-aza-4-oxabicyclo[3,2,0]heptanone | |
| US4075219A (en) | Epimerization process | |
| US4166904A (en) | ⊕-lactam containing compounds | |
| EP0117872A1 (en) | Process for preparing cephalosporin compounds | |
| KR870000313B1 (en) | Method for preparing 6- (aminomethyl) phenicylanic acid 1,1-dioxide and its derivatives | |
| US4192801A (en) | Novel phosphorane intermediates for use in preparing penem antibiotics | |
| US4889929A (en) | Preparation of 1'-ethoxycarbonyl-oxyethyl esters of penicillins | |
| DE2615621A1 (en) | Beta-lactam antibiotics - and beta-lactam precursors of penicillins and cephalosporins | |
| CH633290A5 (en) | Process for preparing derivatives of 7-oxo-1,3-diazabicyclo[3.2.0]heptane-2-carboxylic acid | |
| US4169833A (en) | Novel phosphorane intermediates for use in preparing penem antibiotics | |
| US4085113A (en) | Process for the preparation of azetidinone-thiazoline precursors for cephalosporin synthesis |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |