CN116783203A - 一种高产率和高纯度的氟氧头孢的制备方法 - Google Patents
一种高产率和高纯度的氟氧头孢的制备方法 Download PDFInfo
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- CN116783203A CN116783203A CN202280009550.2A CN202280009550A CN116783203A CN 116783203 A CN116783203 A CN 116783203A CN 202280009550 A CN202280009550 A CN 202280009550A CN 116783203 A CN116783203 A CN 116783203A
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- flomoxef
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- UHRBTBZOWWGKMK-DOMZBBRYSA-N flomoxef Chemical compound O([C@@H]1[C@@](C(N1C=1C(O)=O)=O)(NC(=O)CSC(F)F)OC)CC=1CSC1=NN=NN1CCO UHRBTBZOWWGKMK-DOMZBBRYSA-N 0.000 title claims abstract description 62
- 229960002878 flomoxef Drugs 0.000 title claims abstract description 50
- 238000002360 preparation method Methods 0.000 title abstract description 6
- 238000000034 method Methods 0.000 claims abstract description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 27
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 claims description 20
- 239000002904 solvent Substances 0.000 claims description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- -1 (1- (2-hydroxyethyl) -1H-tetrazol-5-yl) thio Chemical group 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 14
- 238000004519 manufacturing process Methods 0.000 claims description 11
- QTWJRLJHJPIABL-UHFFFAOYSA-N 2-methylphenol;3-methylphenol;4-methylphenol Chemical compound CC1=CC=C(O)C=C1.CC1=CC=CC(O)=C1.CC1=CC=CC=C1O QTWJRLJHJPIABL-UHFFFAOYSA-N 0.000 claims description 10
- 229930003836 cresol Natural products 0.000 claims description 10
- IWDCLRJOBJJRNH-UHFFFAOYSA-N p-cresol Chemical compound CC1=CC=C(O)C=C1 IWDCLRJOBJJRNH-UHFFFAOYSA-N 0.000 claims description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 8
- QWVGKYWNOKOFNN-UHFFFAOYSA-N o-cresol Chemical compound CC1=CC=CC=C1O QWVGKYWNOKOFNN-UHFFFAOYSA-N 0.000 claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- XDTAQDOHGJKJDF-UHFFFAOYSA-N O=C1C=C(N2CCC2O1)C(=O)O Chemical compound O=C1C=C(N2CCC2O1)C(=O)O XDTAQDOHGJKJDF-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 239000012535 impurity Substances 0.000 claims description 2
- 241000894006 Bacteria Species 0.000 abstract description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 10
- 239000003242 anti bacterial agent Substances 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 229940088710 antibiotic agent Drugs 0.000 description 7
- 150000001780 cephalosporins Chemical class 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 7
- 229930186147 Cephalosporin Natural products 0.000 description 6
- 229940124587 cephalosporin Drugs 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- QXNSHVVNEOAAOF-RXMQYKEDSA-N (6R)-4-oxa-5-thia-1-azabicyclo[4.2.0]oct-2-en-8-one Chemical compound S1OC=CN2[C@H]1CC2=O QXNSHVVNEOAAOF-RXMQYKEDSA-N 0.000 description 5
- 230000000844 anti-bacterial effect Effects 0.000 description 5
- 230000003115 biocidal effect Effects 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 150000001782 cephems Chemical class 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 235000002639 sodium chloride Nutrition 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 238000007086 side reaction Methods 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 3
- PWEFRKZZBVCRQB-ZCFIWIBFSA-N (6r)-5-oxa-1-azabicyclo[4.2.0]oct-2-en-8-one Chemical class O1CC=CN2C(=O)C[C@H]21 PWEFRKZZBVCRQB-ZCFIWIBFSA-N 0.000 description 2
- SCNWTQPZTZMXBG-UHFFFAOYSA-N 2-methyloct-2-enoic acid Chemical compound CCCCCC=C(C)C(O)=O SCNWTQPZTZMXBG-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 2
- KXADPELPQCWDHL-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1.COC1=CC=CC=C1 KXADPELPQCWDHL-UHFFFAOYSA-N 0.000 description 2
- MZKWAVLUKXVPRK-SKGAVATQSA-N benzhydryl (6R,7R)-7-[[1-[(Z)-2-chloroethenoxy]-2-(difluoromethylsulfanyl)ethyl]amino]-3-(chloromethyl)-7-methoxy-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound CO[C@]([C@H]1OCC(CCl)=C(C(OC(C2=CC=CC=C2)C2=CC=CC=C2)=O)N11)(C1=O)NC(CSC(F)F)O/C=C\Cl MZKWAVLUKXVPRK-SKGAVATQSA-N 0.000 description 2
- 239000003781 beta lactamase inhibitor Substances 0.000 description 2
- 229940126813 beta-lactamase inhibitor Drugs 0.000 description 2
- 238000006757 chemical reactions by type Methods 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- AUZONCFQVSMFAP-UHFFFAOYSA-N disulfiram Chemical compound CCN(CC)C(=S)SSC(=S)N(CC)CC AUZONCFQVSMFAP-UHFFFAOYSA-N 0.000 description 2
- 238000000855 fermentation Methods 0.000 description 2
- 230000004151 fermentation Effects 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 229960003085 meticillin Drugs 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229940041009 monobactams Drugs 0.000 description 2
- ADIMAYPTOBDMTL-UHFFFAOYSA-N oxazepam Chemical compound C12=CC(Cl)=CC=C2NC(=O)C(O)N=C1C1=CC=CC=C1 ADIMAYPTOBDMTL-UHFFFAOYSA-N 0.000 description 2
- 229960004535 oxazepam Drugs 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 2
- 125000004299 tetrazol-5-yl group Chemical group [H]N1N=NC(*)=N1 0.000 description 2
- 238000006257 total synthesis reaction Methods 0.000 description 2
- KNKXKITYRFJDNF-UHFFFAOYSA-N 2-methylphenol Chemical compound CC1=CC=CC=C1O.CC1=CC=CC=C1O KNKXKITYRFJDNF-UHFFFAOYSA-N 0.000 description 1
- PLKZZSKEJCNYEQ-UHFFFAOYSA-N 4-methylphenol Chemical compound CC1=CC=C(O)C=C1.CC1=CC=C(O)C=C1 PLKZZSKEJCNYEQ-UHFFFAOYSA-N 0.000 description 1
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 1
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- JWCSIUVGFCSJCK-CAVRMKNVSA-N Disodium Moxalactam Chemical compound N([C@]1(OC)C(N2C(=C(CSC=3N(N=NN=3)C)CO[C@@H]21)C(O)=O)=O)C(=O)C(C(O)=O)C1=CC=C(O)C=C1 JWCSIUVGFCSJCK-CAVRMKNVSA-N 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 206010041925 Staphylococcal infections Diseases 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 241000534944 Thia Species 0.000 description 1
- 230000002730 additional effect Effects 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 description 1
- 229940041011 carbapenems Drugs 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- 229960002563 disulfiram Drugs 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- OCLXJTCGWSSVOE-UHFFFAOYSA-N ethanol etoh Chemical compound CCO.CCO OCLXJTCGWSSVOE-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 229960000433 latamoxef Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 208000015688 methicillin-resistant staphylococcus aureus infectious disease Diseases 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- RDOXTESZEPMUJZ-UHFFFAOYSA-N methyl phenyl ether Natural products COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229940124588 oral cephalosporin Drugs 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- HHXMXAQDOUCLDN-RXMQYKEDSA-N penem Chemical compound S1C=CN2C(=O)C[C@H]21 HHXMXAQDOUCLDN-RXMQYKEDSA-N 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- QVLTXCYWHPZMCA-UHFFFAOYSA-N po4-po4 Chemical compound OP(O)(O)=O.OP(O)(O)=O QVLTXCYWHPZMCA-UHFFFAOYSA-N 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- YGSFNCRAZOCNDJ-UHFFFAOYSA-N propan-2-one Chemical compound CC(C)=O.CC(C)=O YGSFNCRAZOCNDJ-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- PPPZBOLFWGINKN-YLCXCWDSSA-M sodium;(6r,7r)-7-[[2-(difluoromethylsulfanyl)acetyl]amino]-3-[[1-(2-hydroxyethyl)tetrazol-5-yl]sulfanylmethyl]-7-methoxy-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound [Na+].O([C@@H]1[C@@](C(N1C=1C([O-])=O)=O)(NC(=O)CSC(F)F)OC)CC=1CSC1=NN=NN1CCO PPPZBOLFWGINKN-YLCXCWDSSA-M 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 238000005406 washing Methods 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
- C07D503/02—Preparation
-
- 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
- A61K31/535—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 oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5365—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 oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
-
- 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
- C07D505/00—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D505/10—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with 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
- C07D505/12—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with 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 substituted in position 7
- C07D505/14—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with 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 substituted in position 7 with hetero atoms directly attached in position 7
- C07D505/16—Nitrogen atoms
- C07D505/18—Nitrogen atoms further acylated by radicals derived from carboxylic acids or by nitrogen or sulfur analogues thereof
- C07D505/20—Nitrogen atoms further acylated by radicals derived from carboxylic acids or by nitrogen or sulfur analogues thereof with the acylating radicals further substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D505/24—Nitrogen atoms further acylated by radicals derived from carboxylic acids or by nitrogen or sulfur analogues thereof with the acylating radicals further substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen further substituted by doubly-bound nitrogen atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Epidemiology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
本发明涉及一种高产率和高纯度的氟氧头孢的制备方法,具体涉及一种以高产率和高纯度制备作用于革兰氏阳性菌和阴性菌的奥沙西泮抗生素(6R,7R)‑7‑[[2‑(二氟甲基硫基)乙酰基]氨基]‑3‑[[1‑(2‑羟乙基)四唑‑5‑基]硫基甲基]‑7‑甲氧基‑8‑氧代‑5‑氧杂‑1‑氮杂双环[4.2.0]辛‑2‑烯‑2‑羧酸(也被称为氟氧头孢(Flomoxef)‑FA))的方法。
Description
技术领域
本发明涉及一种高产率和高纯度的氟氧头孢的制备方法,具体涉及一种以高产率和高纯度制备作用于革兰氏阳性菌和阴性菌的奥沙西泮(oxacephem)抗生素(6R,7R)-7-[[2-(二氟甲基硫基)乙酰基]氨基]-3-[[1-(2-羟乙基)四唑-5-基]硫基甲基]-7-甲氧基-8-氧代-5-氧杂-1-氮杂双环[4.2.0]辛-2-烯-2-羧酸(也被称为氟氧头孢(akaFlomoxef))。
背景技术
头孢烯(Cephem)类抗生素包括头孢菌素(cephalosporin)、头霉素(cephamycin)、口服头孢烯(oral cephem)、青霉烯(penem)、碳青霉烯(carbapenem)、单菌霉素(monobactam)和β-内酰胺酶抑制剂(β-lactamase inhibitors)和氧头孢烯(oxacephem)。另外,按给药途径分为注射剂和口服剂。
氟氧头孢钠(Flomoxef sodium)是一种注射用抗生素,属于氧头孢烯类,由日本盐野义制药研究所开发。在化学结构方面,它与拉氧头孢(Latamoxef)一样具有1-氧头孢烯(1-oxacephem)结构(参见下面的化学式1和2)。
[化学式1]
[化学式2]
此外,与现有的头孢烯类抗生素不同,氟氧头孢钠具有基于氧头孢烯的基本结构,通过在头孢菌素结构的第1位取代氧而不是硫原子来增加抗菌力,并具有出色的抗菌范围、药代动力学特性,就β-内酰胺酶的安全性而言,它是一种进一步增强的补充剂。
也就是说,氟氧头孢钠克服了第三代头孢烯***的共同弱点,同时保持了对革兰氏阴性菌的抗菌力,也对革兰氏阳性菌,尤其是对抗耐甲氧西林(Methicillin)金黄色葡萄球菌(MRSA),相较现有的头孢烯***,它是具有更强抗菌力的,最新的抗生素。
氟氧头孢是新一代广谱抗生素,改善了拉氧头孢的不足,同时保留了具有代表性的第三代头孢菌素类注射用抗生素拉氧头孢的优良特性。
为了实现上述两个目标,氟氧头孢是通过对1-氧头孢烯核的第7位和第3位进行化学修饰,同时合成多个化合物而制成。
其中,发现在1-氧头孢烯核的第7位具有烷硫代乙酰基和在第3位具有四唑硫甲基,对革兰氏阳性菌和革兰氏阴性菌都表现出优异的抗菌力。
再次,在药效方面,比较第7位的前面的R1和第3位四唑R2的抗菌力和体内动态,而且在安全性方面,以没有双硫仑(disulfiram)阳性作用和肾毒性为指标进行了各种测试。
结果,选择二氟甲基作为R1,选择羟乙基作为R2。
此外,证实了氟氧头孢对革兰氏阳性菌和革兰氏阴性菌的抗菌活性比相应的1-硫杂(thia)的头孢菌素衍生物强2至16倍。
在这些抗生素中,氟氧头孢(盐野义(Shionogi),1988)和乳氧头孢(礼来(Lilly),1981)等以氧头孢烯为基础的抗生素目前已经上市。但为了合成它们,必须通过发酵或全合成制备中间体,目前除了盐野义和礼来以外,全球尚无制备商可以供应中间体和成品原料。我们正在日本寻找用于仿制药开发的原材料,但除了我们自己生产外,没有其他供应商。
以氧头孢烯类抗生素为例,产品群小,在通过发酵开发中间体的过程中,没有开发出有效的菌株,在氟氧头孢的情况下,正如原始发行公司开发的示意图所示,原始抗生素和中间体必须通过全合成进行。这是一个很难轻易获得的项目,因为它必须通过共24步的合成路线才能制备出来,因此有必要开发一种新的合成方法。
另一方面,查阅关于制备氟甲硫氧头孢菌素的方法的文献,在进行以下化学反应式1(氟氧头孢的合成)时,使用溶解在二氯甲烷(Dichloromathane)中的苯甲醚(Anisol)和四氯化钛(Titanium tetrachloride)或氯化铝(Aluminum chloride)来进行羧基脱保护,或者用三氟乙酸代替氯化铝。
[化学反应式1]
因此,不仅反应混合物不易萃取,而且在反应过程中会产生多种副反应,从而降低化合物的纯度。
因此,仍然需要一种高产率和高纯度的氟氧头孢的制备方法。
发明内容
要解决的技术问题
本发明是将提供一种高产率和高纯度的(6R,7R)-7-[[2-(二氟甲基硫基)乙酰基]氨基]-3-[[1-(2-羟乙基)四唑-5-基]硫基甲基]-7-甲氧基-8-氧代-5-氧杂-1-氮杂双环[4.2.0]辛-2-烯-2-羧酸(本文中称其为氟氧头孢或氟氧头孢-FA)的制备方法作为技术课题,氟氧头孢是一种作用于革兰氏阳性菌和阴性菌的氧头孢烯类抗生素。
技术方案
为了解决上述技术问题,本发明提供的制备氟氧头孢的方法如下。
第一步
(6R,7R)-二苯甲基-7-(二氟甲硫基)乙酰氨基)-3-(((1-(2-羟乙基))-1H-四唑-5-基)硫基)甲基)-7-甲氧基-8氧代-5-氧杂-1-氮杂-双环[4.2.0]辛-2-烯-2-羧酸酯与选自甲酚、甲苯及它们的组合的溶剂反应;
第二步,将第一步的产物进行结晶以合成氟氧头孢。
有益效果
根据本发明,氟氧头孢-BH作为起始原料可以与选自甲酚、甲苯及它们的组合的溶剂反应以高产率和高纯度制备氟氧头孢。此外,根据本发明,SUS反应器和G/L反应器均可用于生产氟氧头孢。
具体实施方式
在下文中,将更详细地描述本发明。
在本文中氟氧头孢-Cl既(6R,7R)-二苯甲基3-(氯甲基)-7-((1-(((Z)-2-氯乙烯基)氧基)-2-((二氟甲基)硫基)乙基)氨基)-7-甲氧基-8-氧代-5-氧杂-1-氮杂双环[4.2.0]辛-2-烯-2-羧酸酯((6R,7R)-Benzhydryl3-(chloromethyl)-7-((1-(((Z)-2-chlorovinyl)oxy)-2-((difluoromethyl)thio)ethyl)amino)-7-methoxy-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate)。
氟氧头孢-BH既(6S,7R)-二苯甲基-7-(二氟甲硫基)乙酰氨基)-3-(((1-(2-羟乙基)-1H-四唑-5-基)硫基)甲基)-7-甲氧基-8氧代-5-氧杂-1-氮杂-双环[4.2.0]辛-2-烯-2-羧酸酯。
氯氧头孢既(6R,7R)-7-[[2-(二氟甲基硫基)乙酰基]氨基]-3-[[1-(2-羟乙基)四唑-5-基]硫基甲基]-7-甲氧基-8-氧代-5-氧杂-1-氮杂双环[4.2.0]辛-2-烯-2-羧酸。
本发明的制备氟氧头孢的方法包括:第一步,(6R,7R)-二苯甲基-7-(二氟甲硫基)乙酰氨基)-3-(((1-(2-羟乙基)乙基)-1H-四唑-5-基)硫基)甲基)-7-甲氧基-8氧代-5-氧杂-1-氮杂-双环[4.2.0]辛-2-烯-2-羧酸酯(氟氧头孢-BH)和甲酚发生反应;第二步,将第一步的产物进行结晶以合成氟氧头孢。
在一个实施例中,在本发明的制备氟氧头孢的方法中,可以将使用氟氧头孢-Cl和侧链合成的氟氧头孢-BH与甲酚例如间甲酚反应,然后将反应产物进行结晶以合成氟氧头孢(参见下面的化学反应式2)。
[化学反应式2]
与氟氧头孢-Cl((6R,7R)-二苯甲基3-(氯甲基)-7-((1-(((Z)-2-氯乙烯基)氧基)-2-((二氟甲基)硫基)乙基)氨基)-7-甲氧基-8-氧代-5-氧杂-1-氮杂双环[4.2.0]辛-2-烯-2-羧酸酯)起反应时,作为反应侧链(side-chain),可以使用1-(2-羟乙基)-1H-四唑-5-基硫醇钠盐(1-(2-Hydroxyethyl)-1H-tetrazol-5-ylthiol sodium salt)等。
本发明的制备氟氧头孢的方法可以包括:第一步,(6R,7R)-二苯甲基-7-(二氟甲硫基)乙酰氨基)-3-(((1-(2-羟乙基)-1H-四唑-5-基)硫基)甲基)-7-甲氧基-8氧代-5-氧杂-1-氮杂-双环[4.2.0]辛-2-烯-2-羧酸酯(氟氧头孢-BH与选自甲酚、甲苯及它们的组合的溶剂反应。
在现有技术中,在上述化学反应式2(氟氧头孢的合成)进行时,使用溶解在二氯甲烷中的苯甲醚和四氯化钛或氯化铝来进行羧基脱保护,或者用三氟乙酸代替氯化铝。因此,反应混合物不易萃取,反应过程中会产生数个副反应,导致化合物纯度下降.
在本发明的制备氟氧头孢的方法中,通过氟氧头孢-BH与甲酚反应进行羧基脱保护,不仅解决了现有技术中存在的问题,而且在原料成本方面具有很大的优势和收率的提高。特别是在制备氟氧头孢时,可以使用SUS反应器(由不锈钢制成的反应器)和G/L反应器(内部涂有玻璃的反应器)。以往的氟氧头孢的制备方法由于酸腐蚀而不能用于SUS反应器,而本发明的制备氟氧头孢的方法可以用于SUS反应器,因此,可以应用于各种生产场所。
本发明的制备氟氧头孢的方法的第一步中使用的溶剂可选自邻甲酚、间甲酚、对甲酚、甲苯及它们的组合组成的组,组合的实例使用62%的间甲酚+38%的对甲酚的混合物。
在本发明的制备氟氧头孢的方法的第一步中,每100重量份氟氧头孢-BH反应时,选自甲酚、甲苯及它们的组合的溶剂的重量可以为400重量份以上,或者420重量份以上,或者是450重量份以上,或者500重量份以上,也可以是800重量份以下,也可以是750重量份以下、700重量份以下,或者600重量份以下,例如可以是400~800重量份或420~750重量份、450~700重量份或500~600重量份。当所述溶剂的重量低于上述范围时,可能会发生副反应,导致收率显着降低,而当重量高于上述范围时,则不会产生额外的效果,但会增加生产成本。
在本发明的制备氟氧头孢-FA的方法中,第一步可以在合适的溶剂中在环境温度至作为所选溶剂的回流温度的50℃至70℃范围内的温度下进行,例如,可在55℃至65℃或60℃至70℃的反应温度下进行,可进行2至8小时,例如2至6小时或3至5小时。如果反应温度和反应时间超出上述范围,氟氧头孢的产率可能会降低。
本发明的制备氟氧头孢的方法中,可以进一步包括向第一步的产物中添加酸以去除杂质的步骤。所述酸可选自乙酸、三氟乙酸、磷酸、柠檬酸及它们的组合。
本发明的制备氟氧头孢的方法包括:第二步,将第一步的产物进行结晶以合成氟氧头孢。
在第二步中,可以通过向第一步的产物中加入作为丙酮和二氯甲烷的组合的溶剂来进行结晶。
根据本发明,氟氧头孢-BH作为起始原料可以与甲酚、甲苯及它们的组合的溶剂反应以高产率和高纯度制备氟氧头孢。此外,根据本发明,SUS反应器和G/L反应器均可用于制备氟氧头孢。
在下文中,将通过实施例和比较例更详细地描述本发明。然而,本发明的范围不限于此。
实施例
合成例:氟氧头孢-BH的合成
将100g的(6R,7R)-二苯甲基3-(氯甲基)-7-((1-(((Z)-2-氯乙烯基)氧基)-2-((二氟甲基)硫基)乙基)氨基)-7-甲氧基-8-氧代-5-氧杂-1-氮杂双环[4.2.0]辛-2-烯-2-羧酸酯溶解在237g的二甲基甲酰胺(Dimethylformamide)后,冷却至0±3℃来准备反应。将温度保持在0±3℃的同时缓慢加入36.5g的1-(2-羟乙基)-1H-四唑-5-基硫醇钠盐后,将混合物搅拌1至2小时。
当反应完成时,将335g的乙醇(Ethanol)+326g的纯净水加入到反应器中。结晶过程在20℃至30℃下进行3至4小时。添加500g的纯净水,搅拌1~2小时。过滤所得固体,并用103g的乙醇+100g的纯净水洗涤过滤的所得固体。获得120g的过滤获得的目标化合物(6R,7R)-7-[[2-(二氟甲硫基)乙酰基]氨基]-3-[[1-(2-羟乙基)四唑-5-基]硫基甲基]-7-甲氧基-8-氧代-5-氧杂-1-氮杂双环[4.2.0]辛-2-烯-2-羧酸酯((6R,7R)-7-[[2-(difluoromethylsulfanyl)acetyl]amino]-3-[[1-(2-hydroxyethyl)tetrazol-5-yl]sulfanylmethyl]-7-methoxy-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate)(氟氧头孢-BH)(收获率为99.9%,纯度为99.2%).
实施例1:氟氧头孢的合成(使用间甲酚(m-Cresol))
将120g的(6R,7R)-7-[[2-(二氟甲硫基)乙酰基]氨基]-3-[[1-(2-羟乙基)四唑-5-基]硫基甲基]-7-甲氧基-8-氧代-5-氧杂-1-氮杂双环[4.2.0]辛-2-烯-2-羧酸酯(氟氧头孢-BH)添加到加热至60℃~70℃的620g的间甲酚中,溶解后,保持在65℃~70℃,搅拌3小时。
反应完成后,将1080g的乙酸乙酯(Ethyl acetate)和1200g的盐水(brine)加入到反应溶液中,同时,保持温度在5至10℃。此处,在保持相同温度的同时加入16.7g的碳酸氢钠(Sodium bicarbonate),搅拌调至中性,静置分液,收集水层。再次向有机层中加入600g的盐水,萃取后分层。收集水层后,加入540g的乙酸乙酯,洗涤水层后分层。分取水层后,加入360g的食盐、1080g的乙酸乙酯,加入31.3g的磷酸(Phosphoric acid),调整酸度后,萃取分取有机层。使用540g的乙酸乙酯再次萃取水层,并收集有机层,向有机层中加入24g的硫酸镁(Magnesium sulfate),除去水后,使用12g的活性炭对有机层进行脱色,过滤,用108g的乙酸乙酯洗涤。真空浓缩有机层后,将235g的丙酮(Acetone)溶解在浓缩的残余物中,然后缓慢加入3192g的二氯甲烷(Dichloromethane),将温度保持在0℃的同时搅拌12小时后,将所得固体过滤并用160g的二氯甲烷洗涤。滤出的固体在30±3℃下真空干燥12小时,得到79g的目标化合物(6R,7R)-7-[[2-(二氟甲硫基)乙酰基]氨基]-3-[[1-(2-羟乙基)四唑-5-基]硫基甲基]-7-甲氧基-8-氧代-5-氧杂-1-氮杂双环[4.2.0]辛-2-烯-2-羧酸((6R,7R)-7-[[2-(difluoromethylsulfanyl)acetyl]amino]-3-[[1-(2-hydroxyethyl)tetrazol-5-yl]sulfanylmethyl]-7-methoxy-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid)(氟氧头孢-FA)(收获率为87.8%,溶剂校准值,纯度为99.8%)。
实施例2:氟氧头孢的合成(使用邻甲酚(o-Cresol))
将120g的(6R,7R)-7-[[2-(二氟甲基硫基)乙酰基]氨基]-3-[[1-(2-羟乙基)四唑-5-基]硫基甲基]-7-甲氧基-8-氧代-5-氧杂-1-氮杂双环[4.2.0]辛-2-烯-2-羧酸酯(氟氧头孢-BH)添加到加热至60℃~70℃的邻甲酚中。除了邻甲酚代替间甲酚,其他步骤完全同上(实施例1),得到69.6g的目标化合物(6R,7R)-7-[[2-(二氟甲硫基)乙酰基]氨基]-3-[[1-(2-羟乙基)四唑-5-基]硫基甲基]-7-甲氧基-8-氧代-5-氧杂-1-氮杂双环[4.2.0]辛-2-烯-2-羧酸(氟氧头孢-FA)(收获率为77.4%,溶剂校准值,纯度为99.8%)。
实施例3:氟氧头孢的合成(使用对甲酚(p-Cresol))
将120g的(6R,7R)-7-[[2-(二氟甲基硫基)乙酰基]氨基]-3-[[1-(2-羟乙基)四唑-5-基]硫基甲基]-7-甲氧基-8-氧代-5-氧杂-1-氮杂双环[4.2.0]辛-2-烯-2-羧酸酯(氟氧头孢-BH)添加到加热至60℃~70℃的对甲酚中,除了对甲酚代替间甲酚,其他步骤完全和实施例1相同,得到58.3g的目标化合物(6R,7R)-7-[[2-(二氟甲硫基)乙酰基]氨基]-3-[[1-(2-羟乙基)四唑-5-基]硫基甲基]-7-甲氧基-8-氧代-5-氧杂-1-氮杂双环[4.2.0]辛-2-烯-2-羧酸(氟氧头孢-FA)(收获率为64.8%,溶剂校准值,纯度为99.4%)。
比较例1:氟氧头孢的合成(使用间甲酚)
将120g的(6R,7R)-7-[[2-(二氟甲基硫基)乙酰基]氨基]-3-[[1-(2-羟乙基)四唑-5-基]硫基甲基]-7-甲氧基-8-氧代-5-氧杂-1-氮杂双环[4.2.0]辛-2-烯-2-羧酸酯(氟氧头孢-BH)添加到加热至60℃~70℃的370.8g的间甲酚中,除此之外,其他步骤完全和实施例1相同,得到69.6g的目标化合物(6R,7R)-7-[[2-(二氟甲硫基)乙酰基]氨基]-3-[[1-(2-羟乙基)四唑-5-基]硫基甲基]-7-甲氧基-8-氧代-5-氧杂-1-氮杂双环[4.2.0]辛-2-烯-2-羧酸(氟氧头孢-FA)(收获率为70.2%,溶剂校准值,纯度为99.3%)。
Claims (7)
1.一种制备氟氧头孢的方法,包括:
第一步,(6R,7R)-二苯甲基-7-(二氟甲硫基)乙酰胺基)-3-(((1-(2-羟乙基)-1H-四唑-5-基)硫基)甲基)-7-甲氧基-8氧代-5-氧杂-1-氮杂-双环[4.2.0]辛-2-烯-2-羧酸酯与选自甲酚、甲苯及它们的组合的溶剂反应;
第二步,将第一步的产物进行结晶以合成氟氧头孢。
2.根据权利要求1所述的制备氟氧头孢的方法,其中,所述溶剂选自邻甲酚、间甲酚、对甲酚、甲苯及它们的组合。
3.根据权利要求1所述的制备氟氧头孢的方法,其中,在第一步中,每100重量份的氟氧头孢-BH与400至800重量份的选自甲酚、甲苯及它们的组合的溶剂反应。
4.根据权利要求1所述的制备氟氧头孢的方法,其中,第一步在50℃至70℃的反应温度下进行。
5.根据权利要求1所述的制备氟氧头孢的方法,其中,第一步进行2至8小时。
6.根据权利要求1所述的制备氟氧头孢的方法,其中,进一步包括向第一步的产物中加入选自乙酸、三氟乙酸、磷酸、柠檬酸及它们的组合的酸以除去杂质的步骤。
7.根据权利要求1所述的制备氟氧头孢的方法,其中,在第二步中,通过向第一步的产物中加入作为丙酮和二氯甲烷的组合的溶剂来进行结晶。
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