JP5022913B2 - セファクロルの合成方法 - Google Patents
セファクロルの合成方法 Download PDFInfo
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- JP5022913B2 JP5022913B2 JP2007548813A JP2007548813A JP5022913B2 JP 5022913 B2 JP5022913 B2 JP 5022913B2 JP 2007548813 A JP2007548813 A JP 2007548813A JP 2007548813 A JP2007548813 A JP 2007548813A JP 5022913 B2 JP5022913 B2 JP 5022913B2
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- cefaclor
- acca
- pga
- reaction
- enzyme
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- 229960005361 cefaclor Drugs 0.000 title claims description 110
- 238000000034 method Methods 0.000 title claims description 41
- 230000002194 synthesizing effect Effects 0.000 title claims description 12
- QYIYFLOTGYLRGG-GPCCPHFNSA-N cefaclor Chemical compound C1([C@H](C(=O)N[C@@H]2C(N3C(=C(Cl)CS[C@@H]32)C(O)=O)=O)N)=CC=CC=C1 QYIYFLOTGYLRGG-GPCCPHFNSA-N 0.000 title claims 14
- OQSAFIZCBAZPMY-AWFVSMACSA-N (6r,7r)-7-azaniumyl-3-chloro-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound S1CC(Cl)=C(C([O-])=O)N2C(=O)[C@@H]([NH3+])[C@H]21 OQSAFIZCBAZPMY-AWFVSMACSA-N 0.000 claims description 40
- 102000004190 Enzymes Human genes 0.000 claims description 27
- 108090000790 Enzymes Proteins 0.000 claims description 27
- 239000011541 reaction mixture Substances 0.000 claims description 26
- 238000003786 synthesis reaction Methods 0.000 claims description 25
- 239000000203 mixture Substances 0.000 claims description 22
- 239000000243 solution Substances 0.000 claims description 21
- ZGUNAGUHMKGQNY-SSDOTTSWSA-N D-alpha-phenylglycine Chemical compound OC(=O)[C@H](N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-SSDOTTSWSA-N 0.000 claims description 18
- 108010073038 Penicillin Amidase Proteins 0.000 claims description 18
- 239000013078 crystal Substances 0.000 claims description 17
- 238000006243 chemical reaction Methods 0.000 claims description 16
- 239000000725 suspension Substances 0.000 claims description 12
- 241000588724 Escherichia coli Species 0.000 claims description 10
- 238000002835 absorbance Methods 0.000 claims description 8
- 239000003929 acidic solution Substances 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 5
- 150000002148 esters Chemical class 0.000 claims description 4
- 239000012088 reference solution Substances 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- 125000003275 alpha amino acid group Chemical group 0.000 claims 1
- WKJGTOYAEQDNIA-IOOZKYRYSA-N (6r,7r)-7-[[(2r)-2-amino-2-phenylacetyl]amino]-3-chloro-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;hydrate Chemical compound O.C1([C@H](C(=O)N[C@@H]2C(N3C(=C(Cl)CS[C@@H]32)C(O)=O)=O)N)=CC=CC=C1 WKJGTOYAEQDNIA-IOOZKYRYSA-N 0.000 description 104
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- 230000002255 enzymatic effect Effects 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 108700023418 Amidases Proteins 0.000 description 11
- 102000005922 amidase Human genes 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 11
- 229910021529 ammonia Inorganic materials 0.000 description 10
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 8
- 101100136092 Drosophila melanogaster peng gene Proteins 0.000 description 7
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 239000012452 mother liquor Substances 0.000 description 6
- 238000011084 recovery Methods 0.000 description 6
- 239000006227 byproduct Substances 0.000 description 5
- 239000008139 complexing agent Substances 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000001413 amino acids Chemical group 0.000 description 3
- 239000011942 biocatalyst Substances 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000006482 condensation reaction Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 150000003840 hydrochlorides Chemical class 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 229940098779 methanesulfonic acid Drugs 0.000 description 3
- BHFLUDRTVIDDOR-MRVPVSSYSA-N methyl (2r)-2-amino-2-phenylacetate Chemical compound COC(=O)[C@H](N)C1=CC=CC=C1 BHFLUDRTVIDDOR-MRVPVSSYSA-N 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- 150000003952 β-lactams Chemical class 0.000 description 3
- KIYRSYYOVDHSPG-SSDOTTSWSA-N (2r)-2-amino-2-phenylacetamide Chemical compound NC(=O)[C@H](N)C1=CC=CC=C1 KIYRSYYOVDHSPG-SSDOTTSWSA-N 0.000 description 2
- KJCVRFUGPWSIIH-UHFFFAOYSA-N 1-naphthol Chemical compound C1=CC=C2C(O)=CC=CC2=C1 KJCVRFUGPWSIIH-UHFFFAOYSA-N 0.000 description 2
- JWAZRIHNYRIHIV-UHFFFAOYSA-N 2-naphthol Chemical compound C1=CC=CC2=CC(O)=CC=C21 JWAZRIHNYRIHIV-UHFFFAOYSA-N 0.000 description 2
- 241000589220 Acetobacter Species 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 2
- 241000721603 Mycoplana Species 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- 101710123388 Penicillin G acylase Proteins 0.000 description 2
- 241000588769 Proteus <enterobacteria> Species 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 235000010265 sodium sulphite Nutrition 0.000 description 2
- IEJPPSMHUUQABK-UHFFFAOYSA-N 2,4-diphenyl-4h-1,3-oxazol-5-one Chemical compound O=C1OC(C=2C=CC=CC=2)=NC1C1=CC=CC=C1 IEJPPSMHUUQABK-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- UHPMCKVQTMMPCG-UHFFFAOYSA-N 5,8-dihydroxy-2-methoxy-6-methyl-7-(2-oxopropyl)naphthalene-1,4-dione Chemical compound CC1=C(CC(C)=O)C(O)=C2C(=O)C(OC)=CC(=O)C2=C1O UHPMCKVQTMMPCG-UHFFFAOYSA-N 0.000 description 1
- OZTBHAGJSKTDGM-UHFFFAOYSA-N 9,10-dioxoanthracene-1,5-disulfonic acid Chemical compound O=C1C=2C(S(=O)(=O)O)=CC=CC=2C(=O)C2=C1C=CC=C2S(O)(=O)=O OZTBHAGJSKTDGM-UHFFFAOYSA-N 0.000 description 1
- JAJIPIAHCFBEPI-UHFFFAOYSA-N 9,10-dioxoanthracene-1-sulfonic acid Chemical compound O=C1C2=CC=CC=C2C(=O)C2=C1C=CC=C2S(=O)(=O)O JAJIPIAHCFBEPI-UHFFFAOYSA-N 0.000 description 1
- 241000607534 Aeromonas Species 0.000 description 1
- 241000588986 Alcaligenes Species 0.000 description 1
- 241000726092 Aphanocladium Species 0.000 description 1
- 241000194107 Bacillus megaterium Species 0.000 description 1
- 241000194110 Bacillus sp. (in: Bacteria) Species 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 229920001661 Chitosan Polymers 0.000 description 1
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N D-alpha-Ala Natural products CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 description 1
- 241000588722 Escherichia Species 0.000 description 1
- 241000589565 Flavobacterium Species 0.000 description 1
- 241000223218 Fusarium Species 0.000 description 1
- 241000223221 Fusarium oxysporum Species 0.000 description 1
- 241000427940 Fusarium solani Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 102000004157 Hydrolases Human genes 0.000 description 1
- 108090000604 Hydrolases Proteins 0.000 description 1
- 241000588752 Kluyvera Species 0.000 description 1
- QNAYBMKLOCPYGJ-UWTATZPHSA-N L-Alanine Natural products C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-Phenylalanine Natural products OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- 125000003412 L-alanyl group Chemical group [H]N([H])[C@@](C([H])([H])[H])(C(=O)[*])[H] 0.000 description 1
- ZGUNAGUHMKGQNY-ZETCQYMHSA-N L-alpha-phenylglycine zwitterion Chemical compound OC(=O)[C@@H](N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-ZETCQYMHSA-N 0.000 description 1
- 125000002435 L-phenylalanyl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000586779 Protaminobacter Species 0.000 description 1
- 241000589516 Pseudomonas Species 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical compound ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 1
- 241000589634 Xanthomonas Species 0.000 description 1
- 241000589655 Xanthomonas citri Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229960003767 alanine Drugs 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- 229950011260 betanaphthol Drugs 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 239000003431 cross linking reagent Substances 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000003349 gelling agent Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- -1 isopropyl ester Chemical class 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- MNZMMCVIXORAQL-UHFFFAOYSA-N naphthalene-2,6-diol Chemical compound C1=C(O)C=CC2=CC(O)=CC=C21 MNZMMCVIXORAQL-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 229960005190 phenylalanine Drugs 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 125000001749 primary amide group Chemical group 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 150000003334 secondary amides Chemical class 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000003511 tertiary amides Chemical class 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/16—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing two or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P35/00—Preparation of compounds having a 5-thia-1-azabicyclo [4.2.0] octane ring system, e.g. cephalosporin
- C12P35/04—Preparation of compounds having a 5-thia-1-azabicyclo [4.2.0] octane ring system, e.g. cephalosporin by acylation of the substituent in the 7 position
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic 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; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/58—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3 with a nitrogen atom, which is a member of a hetero ring, attached in position 7
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P35/00—Preparation of compounds having a 5-thia-1-azabicyclo [4.2.0] octane ring system, e.g. cephalosporin
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biotechnology (AREA)
- Microbiology (AREA)
- Genetics & Genomics (AREA)
- General Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biochemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Epidemiology (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Cephalosporin Compounds (AREA)
Description
本明細書中で使用されるペニシリンアシラーゼは、国際公開第A−98/20120号パンフレットに記載されるような大腸菌PenGアシラーゼ変異Phe−B24−Alaであった。EP222462号明細書および国際公開第97/04086号パンフレットに記載されるように、ゲル化剤としてゼラチンおよびキトサン、そして架橋剤としてグルタルアルデヒドを用いて酵素を固定化した。
a)セファクロルの酵素合成
175μmのふるい底部を有する反応器に、5.0gの固定化PenGアシラーゼ変異Phe−B24−Alaを入れた。13.9g(58.1mmol)の7−ACCA、0.1gの亜硫酸ナトリウムおよび60gの水を20℃で添加し、pHをアンモニアで7.0に調整した。
上方で攪拌しながら底部ふるいを通して反応器を排出させた。得られたセファクロル懸濁液をガラスフィルタによりろ過した。得られた母液を反応器内に戻した。この順序のステップを5回繰り返した。このようにして、95%よりも多い固体セファクロルを固体生体触媒から分離した。
a)セファクロルの酵素合成
175μmのふるい底部を有する反応容器に、5.0gの固定化PenGアシラーゼ変異Phe−B24−Alaを入れた。13.9g(58.1mmol)の7−ACCA、0.1gの亜硫酸ナトリウムおよび81gの水を20℃で添加し、pHをアンモニアで7.0に調整した。12.9g(63.8mmol)のPGMのHCl塩を反応器に添加し、酵素縮合反応が開始された。pHをアンモニアで7.0に保持した。非常に粘性のソルベ様の懸濁液が形成された。
上方で攪拌しながら底部ふるいを通して反応器を排出させる試みをした。しかしながら、非常に高い粘度のために、セファクロル懸濁液を固定化生体触媒から分離することは不可能であった。
a)セファクロルの酵素合成
175μmのふるい底部を有する反応容器に、10.0gの固定化PenGアシラーゼ変異Phe−B24−Alaを入れた。13.9g(58.1mmol)の7−ACCAおよび52.5gの水を10℃で添加し、pHをアンモニアで7.0に調整した。
上方で攪拌しながら底部ふるいを通して反応器を排出させた。得られたセファクロル懸濁液をガラスフィルタによりろ過した。得られた母液を反応器内に戻した。この順序のステップを5回繰り返した。次に、2×10mlの水で酵素を洗浄した。このようにして、95%以上のセファクロルを固体生体触媒からから分離した。
セファクロルの着色
400nmにおける吸光度を測定することによって、実施例2から得られたセファクロル一水和物の着色を決定した。
Claims (13)
- 10mlの1NのHCl溶液中に溶解された0.5gの結晶形態のセファクロルの溶液のA400を、1NのHCl基準溶液に対して室温で90秒後に測定することによって、0.250未満である400nmにおける吸光度(A400)を有する結晶形態のセファクロル。
- 反応混合物中で酵素の存在下、7−アミノ−3−クロロセファロスポラン酸(7−ACCA)と、活性型D−フェニルグリシン(PGa)とを反応させてセファクロルを形成することを含む、セファクロルの合成方法であって、PGaが、反応の過程において反応混合物に添加されることを特徴とする請求項1に記載のセファクロルの合成方法。
- 7−ACCAおよびPGaが、7−ACCAに対して2よりも低いPGaのモル比で反応混合物に添加されることを特徴とする請求項2に記載の方法。
- PGaがD−フェニルグリシンのエステルであることを特徴とする請求項2〜3のいずれか一項に記載の方法。
- 前記酵素が変異酵素であることを特徴とする請求項2〜4のいずれか一項に記載の方法。
- 前記変異酵素が、大腸菌のペニシリンアシラーゼのβ−サブユニットに相当するβ−サブユニットの24位においてアミノ酸置換を有する変異ペニシリンアシラーゼであることを特徴とする請求項5に記載の方法。
- 6と8の間のpHで合成反応が実行されることを特徴とする請求項2〜6のいずれか一項に記載の方法。
- 5℃と35℃の間の温度で合成反応が実行されることを特徴とする請求項2〜7のいずれか一項に記載の方法。
- 10(w/w)%よりも多い量のセファクロル、2(w/w)%よりも少ない量の7−アミノ−3−クロロセファロスポラン酸、および2(w/w)%よりも少ない量のD−フェニルグリシンを含む水性混合物からセファクロルを回収することをさらに含む、請求項2〜8のいずれか一項に記載の方法。
- 前記方法が、前記水性混合物を4と6の間のpHにすることを含む請求項9に記載の方法。
- 前記方法が、上方で攪拌しながら底部ふるいを通してセファクロルを回収して、セファクロル結晶を含む懸濁液を得ることを含む請求項9に記載の方法。
- 請求項9に記載の水性混合物または請求項11に記載のセファクロル結晶を含む懸濁液を0.5と2の間のpHまで酸性にして、溶解したセファクロルを含む酸性溶液を得ることを含む、請求項9に記載の方法。
- さらに、溶解したセファクロルを含む前記酸性溶液が、適切な塩基により4と6の間のpHにされ、それによりセファクロル結晶が形成されることを特徴とする請求項12に記載の方法。
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WO2012175587A2 (en) | 2011-06-23 | 2012-12-27 | Dsm Sinochem Pharmaceuticals Netherlands B.V. | Novel crystalline cefoperazone intermediate |
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