GB2206578A - Process for preparing penems - Google Patents
Process for preparing penems Download PDFInfo
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- GB2206578A GB2206578A GB08715992A GB8715992A GB2206578A GB 2206578 A GB2206578 A GB 2206578A GB 08715992 A GB08715992 A GB 08715992A GB 8715992 A GB8715992 A GB 8715992A GB 2206578 A GB2206578 A GB 2206578A
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- 238000004519 manufacturing process Methods 0.000 title claims description 5
- 150000002961 penems Chemical class 0.000 title description 3
- 102000004190 Enzymes Human genes 0.000 claims description 23
- 108090000790 Enzymes Proteins 0.000 claims description 23
- 150000001875 compounds Chemical class 0.000 claims description 21
- -1 methylphenoxymethyl group Chemical group 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 18
- 108090001060 Lipase Proteins 0.000 claims description 16
- 102000004882 Lipase Human genes 0.000 claims description 16
- 239000004367 Lipase Substances 0.000 claims description 16
- 235000019421 lipase Nutrition 0.000 claims description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 230000007071 enzymatic hydrolysis Effects 0.000 claims description 6
- 238000006047 enzymatic hydrolysis reaction Methods 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 108090000371 Esterases Proteins 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 230000003301 hydrolyzing effect Effects 0.000 claims description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 3
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 3
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 claims description 3
- 239000000758 substrate Substances 0.000 claims description 3
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 125000004043 oxo group Chemical group O=* 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 230000000813 microbial effect Effects 0.000 claims 2
- 239000005864 Sulphur Substances 0.000 claims 1
- 150000001450 anions Chemical class 0.000 claims 1
- 125000004185 ester group Chemical group 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- 229940088598 enzyme Drugs 0.000 description 19
- 238000006243 chemical reaction Methods 0.000 description 14
- 239000000203 mixture Substances 0.000 description 13
- 230000000694 effects Effects 0.000 description 9
- 239000008363 phosphate buffer Substances 0.000 description 9
- 229920005989 resin Polymers 0.000 description 8
- 239000011347 resin Substances 0.000 description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000004365 Protease Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 108091005804 Peptidases Proteins 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 210000004185 liver Anatomy 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 241000589774 Pseudomonas sp. Species 0.000 description 3
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 210000003734 kidney Anatomy 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 210000000496 pancreas Anatomy 0.000 description 3
- 235000019419 proteases Nutrition 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- NGHVIOIJCVXTGV-ALEPSDHESA-N 6-aminopenicillanic acid Chemical compound [O-]C(=O)[C@H]1C(C)(C)S[C@@H]2[C@H]([NH3+])C(=O)N21 NGHVIOIJCVXTGV-ALEPSDHESA-N 0.000 description 2
- NGHVIOIJCVXTGV-UHFFFAOYSA-N 6beta-amino-penicillanic acid Natural products OC(=O)C1C(C)(C)SC2C(N)C(=O)N21 NGHVIOIJCVXTGV-UHFFFAOYSA-N 0.000 description 2
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 2
- 101000968491 Pseudomonas sp. (strain 109) Triacylglycerol lipase Proteins 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 2
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 2
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 2
- 235000011130 ammonium sulphate Nutrition 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000011324 bead Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 238000000502 dialysis Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 2
- HHXMXAQDOUCLDN-RXMQYKEDSA-N penem Chemical compound S1C=CN2C(=O)C[C@H]21 HHXMXAQDOUCLDN-RXMQYKEDSA-N 0.000 description 2
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 241000228245 Aspergillus niger Species 0.000 description 1
- 101710084370 Lipase 6 Proteins 0.000 description 1
- 101710098554 Lipase B Proteins 0.000 description 1
- 108010013563 Lipoprotein Lipase Proteins 0.000 description 1
- 102100022119 Lipoprotein lipase Human genes 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 108090000526 Papain Proteins 0.000 description 1
- 241000371966 Penicillus <bivalve> Species 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical group C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- 241000235545 Rhizopus niveus Species 0.000 description 1
- 241000952054 Rhizopus sp. Species 0.000 description 1
- 102000000019 Sterol Esterase Human genes 0.000 description 1
- 108010055297 Sterol Esterase Proteins 0.000 description 1
- 241000209140 Triticum Species 0.000 description 1
- 235000021307 Triticum Nutrition 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 210000001557 animal structure Anatomy 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920001429 chelating resin Polymers 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 229940127249 oral antibiotic Drugs 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 229940055729 papain Drugs 0.000 description 1
- 235000019834 papain Nutrition 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004344 phenylpropyl group Chemical group 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- GCLGEJMYGQKIIW-UHFFFAOYSA-H sodium hexametaphosphate Chemical compound [Na]OP1(=O)OP(=O)(O[Na])OP(=O)(O[Na])OP(=O)(O[Na])OP(=O)(O[Na])OP(=O)(O[Na])O1 GCLGEJMYGQKIIW-UHFFFAOYSA-H 0.000 description 1
- 235000019982 sodium hexametaphosphate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000005504 styryl group Chemical group 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
Classifications
-
- 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
- C07D499/88—Compounds with a double bond between positions 2 and 3 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Description
2 2' 0 6 5 7 00 i T'rTLE PROCESS FOR THE PREPAPUkTION OF PENEME 1 The
present invention relates to a preparing 6-[(1R)-hvdroxyethyll peneir, antibacterial activity.
novel process for acids having More particularly the invention relates to a process for the preparation of compounds of formula I:
W_ - 1:5 S F' 1 1. - c:
1 i Ii 5- - --, F, wherein R represents a carboxy group or a carboxylate anion; RI is a tetrahydrofuranyl or an optionally substituted Cl-C4 alkyl, methylphenyl or methylphenoxymethyl group, the substituents being:
(i) hydroxy, amino, carbamoyloxy, ClC18 alkoxy or carboxy group or a halogen atom, (ii) optionally substituted heterocyclylthio radical having up to 10 carbon atoms and up to 4 ring heteroatoms, selected from nitrogen, oxygen and sulfur, the substituents being as defined above under (i) or Cl-C4 alkyl, oxo, carbamoyl group, (iii) optionally substituted or fused pyridinium. N-methylpyrrolidinium or piperidinium group, the substituents being as defined above under (i) or a Cl-C4 alkyl group optionally substituted by sulfonyloxy or carboxy group, and R2 represents a hydrogen atom or a hydroxy protecting group; by enzymatic hydrolysis of compounds of formula II:
2 1 - 1-1 r, F. c wherein RI and R2 are as defined above, R3 represents a hydrogen atoir, or an alkyl group having front 1 to-6 carbon atoms, and R4 is a hydrogen atom, an alkyl, alkenyl, phenyl, phenylalkenyl or phenylalkyl group having from 1 to 18 carbon atoms or an alkoxy group.
The hydroxy protecting groups which R2 may represent include pnitrobenzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, trimethylsilyl, benzyl, p-bromophenacyl, triphenylmethyl and pyranyl groups.
in a preferred aspect, the invention is directed to a process for the preparation of compounds of formula I, wherein R1 is carbamoyloxymethyl, methoxymethyl, pyridiniomethylphenyl, pyridiniomethylphenoxymethyl or carboxymethylpyridiniomethylphenyl group. Preferred protecting groups which R2 may represent are p-nitrobenzyloxycarbonyl, trimethylsilyl and pyranyl groups.
Both compounds of formula I and II are known and valuable antibacterial agents as in detail explained and claimed in UK Patent Applications No. 2043639A, 2097786-A, 2118181-A, 2133010-A, and in EP 0167100-A, EP 0166972-A, EP 0199446-A, EP 0201206-A and in European Patent Application No. 87 102825.4, filed on 27.2.87.
As described in the above cited Patent Applications and 3 also i n 11K Patent Application No. 2144743 and in EP 0188247-A, compounds of formula I and II are prepared by different chemical syntheses; alternatively, compounds of formula II can be prepared by esterification of compounds of formula I.
However, no practical method is available to. transform compounds of formula II into compounds of formula I in good yield.
In order to avoid side reactions during the penem syntheses described in the above cited prior art, it is necessary to protect the 2-carboxy group; for this purpose a group of formula -CHR3-OCO-R4, wherein R3 and R4 are as defined above, may be employed.
Moreover, such compounds of formula II are useful orally adsorbed esters, as described ih UK 2133010-A.
A simple conversion of compounds of formula II into compounds of formula I would allow to prepare in few steps both the useful 'in vivol hydrolyzable esters and the corresponding acids.
Lastly, in case of incidental market requests, it would be convenient to have a method for converting a stored amount of a stable oral antibiotic drug of formula II into the corresponding acid or salt thereof, which may be formulated as useful parenteral drug.
The present invention provides a simple process for the preparation of compounds of formula I by selective and unexpensive enzymatic hydrolysis of compounds of formula II as defined above.
The process of the invention, using enzymatic hydrolysis, allows the final product to be obtained under very irild conditions, in very high yield and without undesired by-products.
The configuration of the compounds of formula II is [SR, 6S, (1RHO in order to obtain the preferred final [SR, 6S, (1WI stereochemistry of the penem nucleus. 1 In the meanings of R3 and R4 of the compounds of formula II, alkyl is preferably methyl, ethyl, propyl, butyl; alkenyl is allyl, methylallyl; phenylalkenyl is styryl; phenylalkyl is phenylethyl. phenylpropyl, and alkoxy is methoxy or ethoxy.
Preferably, R3 represents a hydrogen atom or a methyl group and R4 represents a methyl, ethyl or methoxy group. Most preferably, R3 is a hydrogen atom and R4 represents a methyl group.
The starting materials of formula II can be conveniently prepared in 8 steps from 6-aminopenicillanic acid as described in EP 0188247-A.' The present invention allows therefore to synthesize compounds of formula I directly from 6-aminopenicillanic acid, that is the most straightforward synthesis of penem acids of formula I.
Hydrolytic enzymes suitable for the present process are, for example, lipases, esterases or proteases which selectively hydrolyze the carboxylic ester of compounds of formula II without affecting other functional groups which may be present.
- 5 The hydrolytic process can be carried out either by Using directly the free or immobilized microbic cells or by isolating the specific enzymes which can be used in the free form, immobilized according to known techniques to resins, glass, cellulose or similar substances by ionic or covalent bonds, or grafted to fibres permeable to the substrate, or insolubilized by cross-linkage.
Immobilization or insolubilization is advantageous as the same enzyme can be used for many production cycles.
The use of the enzymes isolated and purified to the desired degree is preferred rather than the raw cellular extract since the extraction or purification process normally allows a reduction or elimination of the presence of contaminating enzymes which could lower the yield by formation of undesired by-products.
Also enzymatic preparations obtained by extraction of animal organs, such as porcine pancreas, Liver or Kidney, are able to cause hydrolysis of the ester bond.
Commercially available hydrolytic enzymes can be used in the enzymatic process, for example:
-6 Ldn LL Sett Pr Ppi Porcine pancreas 516MR [hem. Cc. - St.Louis (USP) Pancreatin Porcine pancreas UNIBIDS - Trecate (Italy) Esterase Porcine liver SIBM [hem. Co. - St.louis (USR) 11pase Chroinobacterium Viscosuln TOYO JOZO (Japan) Cholesterol esterase Pseudomonas Sp. TOYDDO (Japan) Lipase B Penicillu Litiacinur. FUMITR1H LERB9 (Italy) Lipase FRP 15 Rizopes javanicus RMPHE (Japan) Protease PsperqitLu5 sci2P SI6MP [heir.. Co. - St.louis (USP) Lipase h Conc. Rhizopus Niveus P M PIN G (Japan) Lipase P 5 Psperciltus Nicer MNED (Japan) Lipase whe21 SHMP [heir.. Cc. St.Louis (USP) Lip2Se Rnizopus Deta,,r,2- 516MP [hew. 10. - St.Louis (USP) Protease Rhizopus sp. SIGM9 [her, Co. - St.louis (USP) Lipase P PseudDm.Dies Sr. RMPNO (Japan) Rcilase 1 Porcine kidney SERVP (11.beraany) Lipase SP 225 NOVO Industri (Denturk) Papain SIEMP Chew. It. - St.louis (USP) Lipoprotein Lipase Pseudomonas Sp. TOYDRO (Japan) Protease fispergiltus 5aitoi SI6M Chem. Cc. - St.Louis (USP) Lipase OF Candide CyLindracea SRNKYO (Japan) Lipase 1ES Pseudomonas Sp. RMPHO (Japan) Lipase 6 Peniciltuin Cyclopium, RMPHO (Japan) Lipase R-10 Peniciltuip. RoQueforti MNO (Japan) Lipase 1-10 Candida Lipotytica RMPNO (Japan) Lipase D-20 Rhizopils Detartar RMPNO (Japan) 7 ipase AY 30 Candida Cv1indracea AMANO (Japan) The enzymes may be added to an aqueous suspension of from 1 to 100 9/1 of the ester of formula II, suitable mildly buffered at different pE according to the enzyme used, that is in a range from 4 to 10, preferably from 5 to.8.
The reaction may be carried out at a temperature of from 100C to 30 0 C, preferably from 20 0 C to 40 0 C, for 0.5 to 48 hours, operating in batch or column, according to the quantity of the enzyme present in the reaction mixture, and to the ratio between the quantity of the enzyme in solution or in the immoblizied form, and the quantity of substrate present in the reaction mixture.
The pH of the reaction mixture is kept constant at the desired value by adding a solution of an alkali hydroxide.
The yields of the reaction carried out under optimal conditions reach values higher than 90%.
At the end of the reaction, the reaction product can be recovered by conventional methods.
Hereunder, the present invention will be more fully described by means of the following examples, which, however, should not be construed to be limitative.
Example 1
9 of acetoxymethyl 6S)-2-carbamoyloxymethyl-6-[1-(R)hydroxyethyll-penem-3-carboxylate Iffl): R1 =CE20CONH2; R2 H. R3 H; R4 = CH3) were added to 300 ml of phosphate buffer (SR, 8 - Y O.IN (IpH = 6). The mixture was added with 4 M1 (40 mg) of a suspension of esterase from porcine liver (PLE) in 3.2M ammonium sulfate having an activity of 150 U/mg and stirred at 350C for 3 hours. The pH was kept at 6.0 by addition of 0.5N NaOH. At the end of the reaction the mixture was analyzed by HPLC (Column: Partisphere C18 Whatman 5 gm (110 x 4.7 mm). Mobile phase: A: 0.1 M Phosphate buffer (pH 2.5); B: Acetonitrile. Gradient: from 0% B to 80% B in 30 min. Flow rate: 1 ml/min. Detector: UV at 210.8 nm).
The analysis showed the presence of 3.55 9 (93%) of (SR, 6S)-2carbamoyloxym:Lthyl-6-[1-(R)-hydroxyethyll-penem-3- -carboxylic acid HI): R1 =CH2 OCONH2; R2 = H].
Example 2
The reaction was carried out as described in Example 1, except that the enzyme used was Lipase A6 (Amano) (500 mg), having an activity of 60 U/mg, and the pE was 7.
The mixture was stirred at 25 0 C for 16 hours and analyzed as described in Example 1, showing a yield of 58%.
Example 3
The reaction was carried out as described in Example 2, except that the pE was 5.5.
The mixture was stirred at 35 0 C for 20 hours and analyzed as described in Example 1, showing a yield of 90%.
v 9 Example 4
The reaction was carried out as described in Example 2, except that the pE was 6.
The mixture was stirred at 350C for 13 hours and analyzed as described in Example 1, showing a yield of 89%.
Example 5
The reaction was carried out as described in Example i, except that the enzyme used was lipase from wheat germ (Sigma) (500 mg), having an activity of 6.3 U/mg, and the pH was 6.
The mixture was stirred at 3SeC for 18 hours and-analyzed as described in Example 1, showing a yield of 70%.
Example 6
The reaction was carried out as described in Example 1, except that the enzyme used was Acilase 1 from porcine kidney (Serva) (500 mg), having an activity of 16 U/mg. and the pH was 6.
The mixture was stirred at 35 0 C for 24 hours and analyzed as described in Example 1, showing a yield of 33%.
Example 7
The reaction was carried out as described in Example 1, except that the enzyme used was Lipase A6 (Amano) (500 mg), having an activity of 60 U/mg, and the pH was 6.5.
The mixture was stirred at 35 0 C for 14 hours and analyzed as described in Example 1, showing a yield of 66%.
Example 8
The reaction was carried out as described in Example 1, except that the enzyme used was Lipase A6 (Amano) (500 mg). having an activity of 60 Ulmg, and the pH was 7.
The mixture was stirred at 35 0 C for 11 hours and analyzed as described in Example 1, showing a yield of 42%.
Example 9
The reaction was carried out as described in Example 1, except that the pH was 7.5.
The mixture was stirred at 35 0 C for one hour and analyzed as described in Example 1, showing a yield of 90%.
Example 10 g of Amberlite XAD-7 were added to a solution of 1 g Lipase A6 from Aspergillus Niger (Amano) in 250 mI of 0.01 N phosphate buffer (pB = 7.5).
The resin mixture was gently stirred overnight at room temperature.
Then, the resin was filtered and washed with 250 ml of the same buffer.
The immobilyzed resin was added to a suspension of 5 9 of acetoxymethyl (SR, 6S)-2-carbamoyloxymethyl-6- -[1-(R)-bydroxyethyll-penem-3-carboxylate HIP: R1 CH20CONE2; R2 H; R3 H; R4 CH31 in 300 m.1 of 0.1 N phosphate buffer (pH = 6). The reaction mixture was stirred at 350C for 20 hours. The resin containing the enzyme was separated off by filtration in vacuo through a glass filter and washed with 300 ml of phosphate buffer (pH = 6).
The filtrate was analyzed as described in Example 1, showing a yield of 55%.
The immobilyzed enzyme resin was used for three production cycles without appreciable loss of activity.
Example 11 mg (6 ml suspension in 3.2 M (NH4)2 so 4 solution. 9000 units) of PLE (Sigma) were transferred into a dialysis bag with 10 ml of 1 M phosphate buffer (pE = 7.5) and left for 48 hours in 1000 mI, of that buffer at 40 C.
The contents of the dialysis bag was diluted with 20 ml buffer and mixed with 4 g of acrylic beads (Eupergit C, Rohm Pharma, W. Germany). After 24 hours at room temperature the acrylic beads were filtered off, washed once with 250 mI, of buffer and added to a suspension of 5g of acetoxymethyl (SR, 6S)-2-carbamoyloxymethyl-6-[1-(R) -hydroxyethyll-penem-3-carboxylate HM: R1 CH 2 0CONH 2; R2 = H; R4 = CH 3 1 in 300 ml of 0.1 N 12 - phosphate buffer (pH = 6).
v The reaction mixture was stirred at 35 0 C for 2 hours.
The resin containing the enzyme was separated off by filtration in vacuo through a glass filter and washed with 300 ml of phosphate buffer (pB = 6).
The filtrate was analyzed as de scribed in Example 1, showing a yield of 92%.
The immobilyzed enzyme resin was used for 10 production cycles without appreciable loss of activity.
Example 12
9 of methoxycarbonyloxymethyl 6S)-2-carbamoyloxymethyl-6-[1-(R)-hydroxyethyll- -penem-3 -carboxylate [(II): RI = CH20CONH2; R2 H; R3 = B; R4 = OCH3] were added to 300 ml of phosphate buffer 0.1N (pH = 6). The mixture was added with 4 ml (40 mg) of a suspension of esterase from porcine liver (PLE) in 3.2M ammonium sulfate having an activity of 150 UImg and stirred at 35 0 C for 4 hours.
(SR, The pE was kept at 6.0 by addition of 0.5N NaOH. At the end of the reaction the mixture was analyzed as described in Example 1. The analysis showed the presence of 3.4 9 (89%) of (SR, 6S)-2-carbamoyloxymethyl-6-[1-(R)- -hydroxyethyll-penem-3-carboxylic acid [(I)- R1 CH 2 OCONE 2; R2 = H].
- 13
Claims (6)
1. A process for preparing a compound of the formula I F c //I--- I wherein R represents a carboxy group or a carboxylat anion; R, represents a tetrahydrofuranyl group or an optionally substituted c I-C 4 alkyl, methylphenyl or methylphenoxymethyl group, the substituents being:
(i) hydroxy, amino, carbamoyloxy, CI-C 18 alkoxy or carboxy group or halogen atom; (ii) optionally substituted heterocyclylthio radical having up to 10 carbon atoms and up to 4 ring hetero atoms selected from nitrogen, oxygen and sulphur, the substituents being as defined above under (i) or Cl-C4 alkyl, oxo or carbamoyl group; (iii) optionally substituted or fused pyridinio, N-methyl pyrrolidinio or piperidinio group, the substituents being as defined above under (i) or a Cl-C4 alkyl group optionally substituted by sulphonyloxy or carboxy group; and R 2 represents a hydrogen atom or a hydroxy protecting group, which process comprises hydrolysing a compound of the formula II 1 14 - OIR - 0 _r -, -L - COD--jti-O-C-R 4 1 g, Rl:k wherein Ri and R 2 are as defined' above, R 3 represents a hydrogen atom or a c l-C 6 alkyl group, and R 4 represents a hydrogen atom or a C l-cl. alkyl, alkenyl, phenyl, phenylalkenyl, phenylalkyl, or alkoxy group, by means of an enzyme capable of selectively hydrolysing the ester group at the 3-position.
2. A process according to claim 1, in which R 2 represents pnitrobenzyloxy, trimethylsilyl or pyranyl group, R 3 represents a hydrogen atom and R 4 represents a methyl.
3. A process according to claim 1 or 2, in which the enzymatic hydrolysis is carried out by means of an esterase, lipase or acilase.
4. A process according to any one of the preceding claims, in which the enzymatic hydrolysis is carried out either in the presence of microbial cells which secrete a said enzyme or by isolating a said enzyme and then by using it on the compound of the formula II.
5. A process according to claim 4, in which the microbial cells or the isolated enzyme are either immoblized on an is - inert substrate or insolubilized by cross-linkace.
6. A process according to any one of the preceding claims, in which the enzymatic hydrolysis is carried out in augeous solution, the concentration of compou-nd of the formula II being 1 to 100 g/1, buffered at pH from 4 to '10, at the temperature of from 10 0 to 500C "for a period of from 0.5 to 48 hours.
1 qAR At 1Ine Patc,-.' OffIV:e. State Hcuse- CE - 1 High, Hc:born. London WC1R 4TP. Parmcr copies may be obtained from The Patent office,
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8715992A GB2206578B (en) | 1987-07-07 | 1987-07-07 | Process for the preparation of penems |
| IT8821221A IT1227126B (en) | 1987-07-07 | 1988-07-04 | PROCESS FOR THE PREPARATION OF PENEM COMPOUNDS. |
| JP63166651A JP2688065B2 (en) | 1987-07-07 | 1988-07-04 | Penems production method |
| DE3822595A DE3822595C2 (en) | 1987-07-07 | 1988-07-04 | Process for the preparation of 6 - [(1R) -hydroxyethyl] -penemic acids |
| US07/940,784 US5364768A (en) | 1987-07-07 | 1992-09-04 | Process for the preparation of penems |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8715992A GB2206578B (en) | 1987-07-07 | 1987-07-07 | Process for the preparation of penems |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB8715992D0 GB8715992D0 (en) | 1987-08-12 |
| GB2206578A true GB2206578A (en) | 1989-01-11 |
| GB2206578B GB2206578B (en) | 1991-07-03 |
Family
ID=10620252
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8715992A Expired - Fee Related GB2206578B (en) | 1987-07-07 | 1987-07-07 | Process for the preparation of penems |
Country Status (4)
| Country | Link |
|---|---|
| JP (1) | JP2688065B2 (en) |
| DE (1) | DE3822595C2 (en) |
| GB (1) | GB2206578B (en) |
| IT (1) | IT1227126B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5079146A (en) * | 1988-04-08 | 1992-01-07 | Sclavo S.P.A. | Method of protection of the carboxy groups in the chemistry of β-lactam compounds |
| US5242816A (en) * | 1990-07-10 | 1993-09-07 | Lonza Ltd. | Microbiological oxidation of alkyl groups in heterocycles |
| GB2286391A (en) * | 1994-02-09 | 1995-08-16 | Erba Carlo Spa | Process for preparing penems |
| US5830889A (en) * | 1990-08-20 | 1998-11-03 | Suntory Limited | Antibacterial penem esters derivatives |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2043639A (en) * | 1979-02-24 | 1980-10-08 | Erba Farmitalia | 3-optionally substituted methyl-2- penem derivatives |
| GB2118181A (en) * | 1982-04-08 | 1983-10-26 | Erba Farmitalia | Substituted penem derivatives and new process for their preparation |
| GB2133010A (en) * | 1983-01-06 | 1984-07-18 | Erba Farmitalia | Penem Esters |
| GB2144743A (en) * | 1983-08-11 | 1985-03-13 | Erba Farmitalia | Process for the preparation of penems |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8624686D0 (en) * | 1986-10-15 | 1986-11-19 | Erba Farmitalia | Preparing penems |
-
1987
- 1987-07-07 GB GB8715992A patent/GB2206578B/en not_active Expired - Fee Related
-
1988
- 1988-07-04 DE DE3822595A patent/DE3822595C2/en not_active Expired - Fee Related
- 1988-07-04 JP JP63166651A patent/JP2688065B2/en not_active Expired - Fee Related
- 1988-07-04 IT IT8821221A patent/IT1227126B/en active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2043639A (en) * | 1979-02-24 | 1980-10-08 | Erba Farmitalia | 3-optionally substituted methyl-2- penem derivatives |
| GB2118181A (en) * | 1982-04-08 | 1983-10-26 | Erba Farmitalia | Substituted penem derivatives and new process for their preparation |
| GB2133010A (en) * | 1983-01-06 | 1984-07-18 | Erba Farmitalia | Penem Esters |
| GB2144743A (en) * | 1983-08-11 | 1985-03-13 | Erba Farmitalia | Process for the preparation of penems |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5079146A (en) * | 1988-04-08 | 1992-01-07 | Sclavo S.P.A. | Method of protection of the carboxy groups in the chemistry of β-lactam compounds |
| US5242816A (en) * | 1990-07-10 | 1993-09-07 | Lonza Ltd. | Microbiological oxidation of alkyl groups in heterocycles |
| US5830889A (en) * | 1990-08-20 | 1998-11-03 | Suntory Limited | Antibacterial penem esters derivatives |
| EP0544907B1 (en) * | 1990-08-20 | 1999-10-27 | Suntory Limited | Antibacterial penem esters derivatives |
| GB2286391A (en) * | 1994-02-09 | 1995-08-16 | Erba Carlo Spa | Process for preparing penems |
| GB2286391B (en) * | 1994-02-09 | 1998-04-15 | Erba Carlo Spa | Process for preparing penems |
Also Published As
| Publication number | Publication date |
|---|---|
| DE3822595A1 (en) | 1989-01-19 |
| DE3822595C2 (en) | 1997-09-11 |
| JP2688065B2 (en) | 1997-12-08 |
| IT1227126B (en) | 1991-03-19 |
| GB2206578B (en) | 1991-07-03 |
| IT8821221A0 (en) | 1988-07-04 |
| JPS6434295A (en) | 1989-02-03 |
| GB8715992D0 (en) | 1987-08-12 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 20030707 |