MXPA00006618A - New process for the manufacture of cephalosporin derivatives - Google Patents
New process for the manufacture of cephalosporin derivativesInfo
- Publication number
- MXPA00006618A MXPA00006618A MXPA/A/2000/006618A MXPA00006618A MXPA00006618A MX PA00006618 A MXPA00006618 A MX PA00006618A MX PA00006618 A MXPA00006618 A MX PA00006618A MX PA00006618 A MXPA00006618 A MX PA00006618A
- Authority
- MX
- Mexico
- Prior art keywords
- process according
- lower alkyl
- formula
- toluene
- oxo
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 27
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 9
- 150000001780 cephalosporins Chemical class 0.000 title claims abstract description 7
- 150000004714 phosphonium salts Chemical class 0.000 claims abstract description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 6
- 230000000875 corresponding Effects 0.000 claims abstract description 5
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 92
- -1 carboxy, amino, aminoethyl Chemical group 0.000 claims description 63
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 52
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 34
- 125000000217 alkyl group Chemical group 0.000 claims description 29
- 150000001875 compounds Chemical class 0.000 claims description 15
- 150000001299 aldehydes Chemical class 0.000 claims description 14
- 125000000623 heterocyclic group Chemical group 0.000 claims description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 13
- 125000003118 aryl group Chemical group 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 125000006239 protecting group Chemical group 0.000 claims description 8
- 239000011541 reaction mixture Substances 0.000 claims description 8
- LPNYRYFBWFDTMA-UHFFFAOYSA-N Potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 7
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 239000011780 sodium chloride Substances 0.000 claims description 6
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
- 125000003342 alkenyl group Chemical group 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000000304 alkynyl group Chemical group 0.000 claims description 5
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 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 claims description 4
- BUKJBGNGPQXFTH-UHFFFAOYSA-N benzhydryl 2-methyloct-2-enoate Chemical compound C=1C=CC=CC=1C(OC(=O)C(C)=CCCCCC)C1=CC=CC=C1 BUKJBGNGPQXFTH-UHFFFAOYSA-N 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 239000011260 aqueous acid Substances 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-O phosphonium Chemical compound [PH4+] XYFCBTPGUUZFHI-UHFFFAOYSA-O 0.000 claims description 2
- 239000003495 polar organic solvent Substances 0.000 claims description 2
- 239000002798 polar solvent Substances 0.000 claims description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims 2
- NOSORVMYVRSPRB-IUODEOHRSA-M [O-]C(=O)C1=C(CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N12)C=O Chemical compound [O-]C(=O)C1=C(CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N12)C=O NOSORVMYVRSPRB-IUODEOHRSA-M 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- 239000003999 initiator Substances 0.000 claims 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 54
- 239000012071 phase Substances 0.000 description 24
- 239000000203 mixture Substances 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 239000008346 aqueous phase Substances 0.000 description 13
- XKRFYHLGVUSROY-UHFFFAOYSA-N argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 11
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 229910052938 sodium sulfate Inorganic materials 0.000 description 7
- 235000011152 sodium sulphate Nutrition 0.000 description 7
- 229910052786 argon Inorganic materials 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L mgso4 Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- SCNWTQPZTZMXBG-UHFFFAOYSA-N 2-methyloct-2-enoic acid Chemical compound CCCCCC=C(C)C(O)=O SCNWTQPZTZMXBG-UHFFFAOYSA-N 0.000 description 5
- 125000004432 carbon atoms Chemical group C* 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N Triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- 238000007792 addition Methods 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-M bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 239000012300 argon atmosphere Substances 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- SDTMFDGELKWGFT-UHFFFAOYSA-N 2-methylpropan-2-olate Chemical compound CC(C)(C)[O-] SDTMFDGELKWGFT-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-O Pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 125000002393 azetidinyl group Chemical group 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 125000002837 carbocyclic group Chemical group 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000011067 equilibration Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 238000005755 formation reaction Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 125000000842 isoxazolyl group Chemical group 0.000 description 2
- 230000005012 migration Effects 0.000 description 2
- ZBPYTVBKHKUNHG-UHFFFAOYSA-N non-3-enoic acid Chemical compound CCCCCC=CCC(O)=O ZBPYTVBKHKUNHG-UHFFFAOYSA-N 0.000 description 2
- 125000005936 piperidyl group Chemical group 0.000 description 2
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Inorganic materials [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- 125000003944 tolyl group Chemical group 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 2
- WTJCKFZRAGHNEG-UHFFFAOYSA-M (1-cyclopropyl-2-oxopyrrolidin-3-yl)-triphenylphosphanium;bromide Chemical compound [Br-].O=C1C([P+](C=2C=CC=CC=2)(C=2C=CC=CC=2)C=2C=CC=CC=2)CCN1C1CC1 WTJCKFZRAGHNEG-UHFFFAOYSA-M 0.000 description 1
- AFXSVYVBVMIRMU-GMSGAONNSA-M (6R,7R)-3-formyl-7-[(2-methylpropan-2-yl)oxycarbonylamino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound S1CC(C=O)=C(C([O-])=O)N2C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H]21 AFXSVYVBVMIRMU-GMSGAONNSA-M 0.000 description 1
- 125000004502 1,2,3-oxadiazolyl group Chemical group 0.000 description 1
- 125000004511 1,2,3-thiadiazolyl group Chemical group 0.000 description 1
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 description 1
- 125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 description 1
- 125000004514 1,2,4-thiadiazolyl group Chemical group 0.000 description 1
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 description 1
- 125000004517 1,2,5-thiadiazolyl group Chemical group 0.000 description 1
- RBACIKXCRWGCBB-UHFFFAOYSA-N 1,2-Epoxybutane Chemical compound CCC1CO1 RBACIKXCRWGCBB-UHFFFAOYSA-N 0.000 description 1
- 125000001781 1,3,4-oxadiazolyl group Chemical group 0.000 description 1
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 1
- HWIVGBQUEUPWHG-UHFFFAOYSA-N 1-thia-2,3-diazacyclopent-2-en-4-yne Chemical group S1N=NC#C1 HWIVGBQUEUPWHG-UHFFFAOYSA-N 0.000 description 1
- DCGFQGGZQQTBOP-UHFFFAOYSA-N 2-$l^{1}-oxidanyl-4,5-dihydro-1,3-oxazole Chemical group O=C1[N]CCO1 DCGFQGGZQQTBOP-UHFFFAOYSA-N 0.000 description 1
- HPBPNWPROCLLAA-UHFFFAOYSA-N 2-bromoethanone Chemical group BrC[C]=O HPBPNWPROCLLAA-UHFFFAOYSA-N 0.000 description 1
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 1
- DJDGWVCBUNYBOO-UHFFFAOYSA-N 2-methylideneoctanoic acid Chemical compound CCCCCCC(=C)C(O)=O DJDGWVCBUNYBOO-UHFFFAOYSA-N 0.000 description 1
- SCNWTQPZTZMXBG-UHFFFAOYSA-M 2-methyloct-2-enoate Chemical compound CCCCCC=C(C)C([O-])=O SCNWTQPZTZMXBG-UHFFFAOYSA-M 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- JKFAIQOWCVVSKC-UHFFFAOYSA-N Furazan Chemical compound C=1C=NON=1 JKFAIQOWCVVSKC-UHFFFAOYSA-N 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- IPNPIHIZVLFAFP-UHFFFAOYSA-N Phosphorus tribromide Chemical compound BrP(Br)Br IPNPIHIZVLFAFP-UHFFFAOYSA-N 0.000 description 1
- MFRIHAYPQRLWNB-UHFFFAOYSA-N Sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 1
- SSXWZWLGONDRLH-UHFFFAOYSA-M [1-(cyclopropylmethyl)-2-oxopyrrolidin-3-yl]-triphenylphosphanium;bromide Chemical compound [Br-].O=C1C([P+](C=2C=CC=CC=2)(C=2C=CC=CC=2)C=2C=CC=CC=2)CCN1CC1CC1 SSXWZWLGONDRLH-UHFFFAOYSA-M 0.000 description 1
- OBRJBKJCXLWCTB-UHFFFAOYSA-M [O-]C(=O)C1=CC(=O)SC2CCN12 Chemical compound [O-]C(=O)C1=CC(=O)SC2CCN12 OBRJBKJCXLWCTB-UHFFFAOYSA-M 0.000 description 1
- 125000004849 alkoxymethyl group Chemical group 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- FUWQEBBYQHOKRU-UHFFFAOYSA-N benzhydryl 3-formyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound C1C(=O)N2C1SCC(C=O)=C2C(=O)OC(C=1C=CC=CC=1)C1=CC=CC=C1 FUWQEBBYQHOKRU-UHFFFAOYSA-N 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 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
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 125000002668 chloroacetyl group Chemical group ClCC(=O)* 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 231100000078 corrosive Toxicity 0.000 description 1
- 231100001010 corrosive Toxicity 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000005712 crystallization Effects 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 238000006392 deoxygenation reaction Methods 0.000 description 1
- 230000005595 deprotonation Effects 0.000 description 1
- 238000010537 deprotonation reaction Methods 0.000 description 1
- SYZWSSNHPZXGML-UHFFFAOYSA-N dichloromethane;oxolane Chemical compound ClCCl.C1CCOC1 SYZWSSNHPZXGML-UHFFFAOYSA-N 0.000 description 1
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- OAMZXMDZZWGPMH-UHFFFAOYSA-N ethyl acetate;toluene Chemical compound CCOC(C)=O.CC1=CC=CC=C1 OAMZXMDZZWGPMH-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 125000005842 heteroatoms Chemical group 0.000 description 1
- 239000008079 hexane Substances 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- ILPBINAXDRFYPL-UHFFFAOYSA-N oct-2-ene Chemical compound CCCCCC=CC ILPBINAXDRFYPL-UHFFFAOYSA-N 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-O oxadiazol-3-ium Chemical compound C1=CON=[NH+]1 WCPAKWJPBJAGKN-UHFFFAOYSA-O 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical group O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 125000005005 perfluorohexyl group Chemical group FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)* 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 229910052717 sulfur Chemical group 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000006000 trichloroethyl group Chemical group 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 125000005023 xylyl group Chemical group 0.000 description 1
Abstract
The present invention is concerned with a novel process for the manufacture of cephalosporin derivatives of the general formula wherein R<1>, R<2>and R are defined in the specification, the process is characterized in that it comprises converting a phosphonium salt of the general formula wherein R is as above and Ph represents phenyl, into the corresponding ylide of the general formula wherein R and Ph are as above, and reacting same with an aldehyde of the general formula wherein R<1>and R<2>are as above.
Description
NEW PROCESS FOR THE MANUFACTURE OF CEFALOSPORINE DERIVATIVES
DESCRIPTION OF THE INVENTION
The present invention relates to new processes for the manufacture of d-cephalosporin derivatives of the general formula
wherein R: is an amino protecting group R is a carboxy protecting group, and R is a hydrogen, lower alkyl, lower alkox, cycloalkyl, cycloalkenyl, cycloalkyl-lower aikyl, lower alkenyl, lower alkynyl, aryl, aryl lower alkyl, heterocyclyl heterocyclyl-lower alkyl; lower alkyl, cycloalkyl, lower alkenyl, cycloalkenyl, lower alkynyl, aryl lower alkyl, aryl and portions
REF: 12083 heterocyclics are substituted or unsubstituted with at least one group selected from carboxy, amino, aminoethyl, carbamoyl, nitro, cyano, lower alkyl, lower alkoxy, hydroxy, halogen and trifluoromethyl.
The process is characterized in that it comprises converting a phosphonium salt of the general formula
wherein R is as above and Ph represents phenyl, in toluene by treatment with a base in the corresponding ylido of the general formula
where R and Ph are as previously released, and the same is reacted with a solution in a solvent and an aldehyde of the general formula
wherein R1 and R2 are as previously deserved. at a temperature of from about -80 ° C to about 0 ° C, the phosphonium salt II, the base and the aldehyde IV are employed in a molar ratio of about 1.15: 1.1: 1.0 to 1.3: 1.25: 1.0.
The molar ratio is preferably about 1.2: 1.15: 1.0. It is important that the molar amount of base is less than that of the phosphonium salt II.
As used herein, the terms "lower alkyl" and "optionally substituted lower alkyl" refer to either straight or branched chain straight hydrocarbon groups having from 1 to 8, preferably 1 to 4 carbon atoms, for example , methyl, ethyl, n-propyl, isopropyl, tertiary butyl, and the like. The lower alkyl groups may be substituted or unsubstituted by at least one substituent such as halogen. Preferred substituents are fluoro, examples of substituted lower alkyl are trifluoromethyl, 2,2,2-trifluoroethyl, perfluorohexyl and the like.
By the term "lower alkoxy" an ether group is suggested wherein alkyl is as defined above. Examples are methoxy, ethoxy, propyloxy and the like.
By the term "cycloalkyl" a saturated carbocyclic ring of 3 to 7 elements is suggested, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. . "Cycloalkyl-lower alkyl" is an alkyl group as defined above with a cycloalkyl ring attached. Preferred cycloalkyl lower alkyls are, for example, cyclopropylmethyl and cyclopropylethyl. By the term "cycloalkenyl" is suggested a carbocyclic ring of 4-7-elements having at least one olefinic double bond, for example, cyclopentenyl.
As used herein, "lower alkenyl" refers to a substituted or unsubstituted hydrocarbon chain radical having from 2 to 8 carbon atoms, preferably from 2 to 4 carbon atoms, and having at least one olefinic double bond , for example, vinyl, allyl and the like.
As used herein, "lower alkynyl" refers to a substituted or unsubstituted hydrocarbon chain radical having from 2 to 8 carbon atoms, preferably 2 to 4 carbon atoms, and having at least one triple bond, per example, ethynyl, 1-propynyl, 2-propynyl.
The term "halogen" used herein, refers to a chloride or chlorine, bromide or bromine; iodide or iodine; and fluoride or fluorine.
By the term "aryl", a radical derived from an aromatic hydrocarbon is suggested by the removal of a hydrogen atom which can be substituted or unsubstituted. Aromatic hydrocarbons can be either mononuclear or polynuclear. Examples of aryl radicals of the mononuclear type include phenyl, tolyl, xylyl, mesityl, cu enyl, and the like. Examples of aryl radicals of the polynuclear type include, naphthyl, anthryl, phenanthryl and the like. The aryl group may have at least one substituent selected from halogen, hydroxy, cyano, carboxy, carbamoyl, nitro, amino, aminomethyl, lower alkyl, lower alkoxy and trifluoromethyl. Examples include, 2-fluorophenyl, 3-nitrophenyl, 4-nitrophenyl, 4-methoxyphenyl, 4-hydroxy phenyl and the like.
By the term "aryl-lower alkyl" is suggested a lower alkyl group containing an aryl group as defined above, for example, benzyl or benzhydryl.
As used herein, "heterocyclyl" refers to a substituted or unsubstituted, saturated or unsaturated, 5, 6 or 7-membered heterocyclyl ring containing at least one heteroatom selected from the group consisting of oxygen, nitrogen and sulfur. Exemplary heterocyclic rings include, but are not limited to, for example, the following groups: pyrrolidinyl, pyridyl, pyridinium, pyrazinyl, piperidyl, piperidino, N-oxide-pyridyl, pyrimidyl, piperazinyl, pyrrolidinyl, pyridazinyl, N-oxide- pyridazinyl, pyrazolyl, triazinyl, imidazolyl, thiazolyl, 1,2,3-thiadiazolyl, 1, 2,4-thiadiazolyl, 1,3-thiadiazolyl, 1, 2, 5-thiadiazolyl, 1, 2, 3-oxadiazolium, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1, 2, 5-oxadiazole, 1, 2, 3-triazolyl, 1, 2,4-triazolyl, lH-tetrazolyl, 2H-tetrazolyl, thienyl , azetidinyl, furyl, hexamethyleneiminyl, oxapanyl, IH-azepinyl, thiophenyl, tetrahydrothiophenyl, 3H-1,2,3-oxathiazolyl, 1,2,3-oxadiazolyl, 1, 2, 5-oxadithiolyl, isoxazolyl, isoxazolyl, isothiazolyl, 4H-1,2, -oxadiazinyl, I, 2,5-oxathiazinyl, 1, 2, 3, 5-oxathiadiazinyl, 1,3,4-thiadiazepinyl, 1, 2, 5, 5, 6-oxatriazepinyl, oxazolidinyl, tetrahydrothienyl and Similar. Preferred heterocyclic rings are pyridyl, pyridinium, piperidyl, pyrrolidinyl (particularly 3-pyrrolidinyl) and azetidinyl. The substituents of the heterocyclyl ring include lower alkyl, lower alkoxy, halogen, trifluoromethyl, trichloroethyl, amino, mercapto, hydroxy, carboxy, and carbamoyl. Preferred examples of substituted heterocyclic rings include 5-methyl-isoxazol-3-yl, N-methyl-pyridinium-2-yl, N-methyl-pyrrolidinyl, 1-methyl-tetrazolyl and methyl-pyridinium-2-yl.
The heterocyclic ring can also be substituted by an optionally substituted phenyl ring such as 2,6-dichlorophenyl. 2,6-Dichlorophenyl-5-methyl-isoxazolyl is preferred. An additional substituent of the heterocyclic ring is oxo, such as 2-oxo-oxazolidin-3-yl and 1, l-dioxo-tetrahydrothien-3-yl. The heterocyclic ring can also be fused together with a benzene ring.
As used herein, "heterocyclyl-lower alkyl" refers to a lower alkyl group containing a heterocyclic group as defined above, for example, tetrazolyl-methyl, tetrahydrofuranyl-yl, thiophenyl- and yl or benzimidazolyl-methyl.
Possible amino protecting groups R1 are those used in peptide chemistry, such as an alkoxycarbonyl group, for example, t-butoxycarbonyl, etc., a substituted alkoxycarbonyl group, for example, trichloroethoxycarbonyl, etc., an arylalkanoyl group, for example , phenylacetyl, a heteroarylalkanoyl group, for example, 2-thienyl-acetyl or 2-furyl-acetyl; an optionally substituted aralkyloxycarbonyl group, for example, p-nitrobenzyloxycarbonyl or benzyloxycarbonyl, an aralkyl group such as trityl or benzhydryl or a halogeno-alkanoyl group such as chloroacetyl, bromoacetyl, iodoacetyl or trifluoroacetyl.
Preferred amino protecting groups are t-butoxycarbonyl (t-BOC), phenylacetyl and trityl.
As carboxy protecting groups R =, one can use an ester form which can easily be converted to a free carboxyl group under average conditions, the ester protecting group is exemplified for example by, t-butyl, p-nitrobenzyl, p-methoxybenzyl , allyl or benzhydryl.
The compounds of the formula I are known to be valuable intermediates for the manufacture of pharmacologically employed cephalosporins, for example, as described in EP-A-620 225 and in EP-A-849 269. In a known process, The compounds of the formula I are prepared from the compounds II and IV in the presence of a base such as
1, 2-butylene oxide or triethylamine in an inert solvent to provide the? 3 isomer of compound I. This is due to the fact that the double bond? 2 is very sensitive towards the bases in solution and easily migrates to the 3-position. Formation of aldehyde? 3, requires correction of the position of the double bond to position 2 desired by a two-stage redox sequence. In a known process this has been effected by oxidation to the corresponding sulfoxide with hydrogen peroxide or a perácids and the deoxygenation thereof with phosphorus tribromide. These reagents, particularly the last one, are corrosive and dangerous to use on a large scale.
Efforts to obtain the compounds I directly via the reaction of the compounds II and IV are impeded by the sensitivity of the cephalosoporins? 2, such as compounds I and IV, to the bases in solution. However, it has been found that the aldehyde? 2 IV as well as the product of reaction I, dissolved in toluene, are stable and are not isomerized in the presence of an illido III formed from the phosphonium salt II with respect to the molar ratio of the bases are not in excess of such starting salt of phosphonium II. Apparently, the basicity of the III ilide, which is present in a slight excess, is also weak to induce the isomerization of compounds IV and I in toluene.
In order to carry out the process, according to the invention, the phosphonium salt is preferably dispersed in toluene, or a mixture of toluene and methylene chloride, and admitted to treatment with a base, for example, with an aqueous alkali, example, 0.1N-1N aqueous NaOH or KOH, or, in the absence of water, with potassium or sodium tert-butylate in a polar organic solvent, such as tetrahydrofuran or dioxane, preferably in tetrahydrofuran. By adding the alkali tert-butylate in tetrahydrofuran, the deprotonation step in the formation of the III-Ilide is accelerated and at a disadvantage it is reacted, such that the addition of a solid to the system is avoided, which is advantageous due to the low reaction temperature. Also, the system can in this way advantageously be pre-cooled to the reaction temperature before the addition of the alkali tert-butylate in tetrahydrofuran.
The resulting solution / suspension of illide III, if not already cooled to the reaction temperature as above, is now brought to that, i.e., between about 0 ° C and about -80 ° C, preferably at about -60 ° C. to about -80 ° C, more preferably to about -70 ° C, and reacted with the aldehyde IV in a solution in an organic polar solvent such as tetrahydrofuran or dioxane, preferably tetrahydrofuran. The molar ratio of the reactants (phosphonium salt II: alkali: aldehyde IV as given above) prevents unwanted migration? 2 /? 3 of the double bond of the resulting final product I, particularly when the molar ratio is about 1.2: 1.15: 1.0.
The reaction times vary between approximately hour and 2 hours.
In preferred embodiments of the process of the invention, (6R, 7R) -7 (1-tert-butoxy form ido) -3-formyl-8-oxo-5-thia-1-azabicyl [4.2.0] oct-2- diphenylmethyl ene-2-carboxylate or 4-methoxybenzyl (6R, 7R) 7-phenylacetylamino-3-formyl-8-oxo-5-t a-1-azabicyclo [4.2.0] oct-2-ene-2- carboxylate, were used as the starting aldehyde of formula IV.
Preferred starting phosphonium salts of formula II are such, wherein R is 2,2,2-trifluoroethyl, cyclopropyl, cyclopropylmethyl or N-substituted 3-pyrrolidinyl, such as N-allyloxycarbonyl-3-pyrrolidinyl. The allyloxycarbonyl group is a protecting group, which is subsequently fractionated to provide final products of formula V below, in which, it is 3-pyrrolidinyl.
When R is N-substituted 3-pyrrolidinyl, such as N-allyloxycarbonyl-3-pyrrolidinyl, the process preferably carries out, in a non-aqueous phase and a mixture of toluene, methylene chloride tetrahydrofuran, preferably in a weight ratio between approximately 2: 1: 1 and 5: 2: 1. In a preferred embodiment, the phosphonium salt II is dissolved in methylene chloride, toluene is added, followed by potassium tert-butylate in a solution of tetrahydrofuran and finally - by aldehyde IV in tetrahydrofuran, and is reacted by hours at about -80 ° C to -60 ° C.
The resulting toluene reaction mixture contains the crude reaction product of the formula I. To prevent the migration of the double bond? 2 to position 3, the removal is carried out in aqueous acid, for example, by the addition of HCl or citric acid 0.1-1 N. By extracting the reaction mixture thus acidified in a usual manner, recovering the toluene solution and evaporating it, a crude product of the formula I is obtained, which can be used for additional reactions to pharmacologically employed cephalosporins. If desired, the crude product may also be purified in a known manner, for example, by flash chromatography on silica gel with a suitable solvent or solvent mixture, for example, methylene chloride, toluene: ethyl acetate or -hexane: ethyl acetate.
The process of the present invention offers easier access to pharmacologically employed cephalosporins for example of the formula
wherein R is as above, X is -CH or nitrogen, and R1 is hydrogen, optionally substituted lower alkyl, cycloalkyl, benzyl, trityl, acetyl or tetrahydropyranyl,
and its pharmaceutically acceptable salts and split esters in vivo.
The processes to carry compounds V is thus shortened, offering high yields and avoiding problematic reagents. Compounds V can be obtained from compounds I in accordance with the instructions given in EP-A 620 225 and EP-A 849 269.
In a preferred embodiment of compounds I, R is 2,2,2-trifluoroethyl, cyclopropyl, cyclopropylmethyl or 3-pyrrolidinyl, X is -CH and R 1 is hydrogen.
The following examples illustrate the invention in more detail.
Example 1
Under an argon atmosphere, 85.5 g of (R, S) (1-cyclopropylmethyl-2-oxo-pyrrolidin-3-yl) -triphenyl-phosphonium bromide was dispersed in 1 l of toluene. To the suspension, it was added in the form of drops, a solution of 19.5 g of potassium tert-butylate in 450 ml of tetrahydrofuran (THF) within 40 minutes. The white suspension turned yellow and resulted in a slight exothermic reaction (the temperature rose from 22 to 25 ° C).
The suspension was stirred 10 minutes at room temperature, and subsequently cooled to -10 ° C. A solution of 77.0 g of (6R, 7R) -7- (1-tert-butoxyformamido) -3-formyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate from diphenylmethyl
300 ml of THF, were slowly added as drops within 1.15 hours. After stirring for 20 minutes at -10 ° C, 170 ml of 1N aqueous hydrochloric acid and 500 ml of water were added, the mixture was taken at room temperature and stirred for 20 minutes at room temperature; Two clear phases were obtained. The mixture was extracted twice, each with 500 ml of toluene and the organic phase was each washed with 350 ml of a 5% aqueous sodium bicarbonate solution and 300 ml of water. The toluene phase was dried and evaporated to dryness. 159.2 g of the crude reaction product were obtained as a dark red mass. This was purified by dissolving it in 1.2 1 of methylene chloride, 300 g of silica gel (Merck 60, 0.040-0.063 mm) were added, the mixture was stirred for 10 minutes, filtered and washed as portions with approximately 1 liter of methylene chloride. The filtrate was evaporated to dryness and dried. 95 g of the yellow-brown crude product were obtained, which were dissolved in 400 ml of n-hexane: ethyl acetate 3: 2 and 40 ml of methylene chloride. The solution was chromatographed instantaneously (fractions of 200-300 ml) in 1.3 kg of silica gel (Merck 60; 0.040-0.063 mm) with n-hexane: ethyl acetate 3: 2 (23 1) as the eluent. fractions (approximately 10 1), evaporated to crystallization, filtered and washed with n-hexane; 35.3 g of white crystals were obtained as snow from the benzylhydride ester of (E) - (6R, 7R) -7-tert-butoxycarbonylamino-3- (1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl) -8- oxo-5-thia-l-aza-bicyclo- [.2.0] oct-2-ene-2-carboxylic acid (39% yield) melting at 175-180 ° C.
From the mother liquor, a second crop of the product was obtained.
. 3 g of white crystals / yellow yield 11.3%) that melted at 175-180 ° C.
Example 2
Under an argon atmosphere, 1.40 g of (R, S) (l-cyclopropyl-2-oxo-pyrrolidin-3-yl) -triphenyl-phosphonium bromide was dispersed in 20 ml of toluene. At room temperature, a solution of
0. 33 g < 3e potassium tert-butylate in 8m of THF in 20 minutes. It turned out an exothermic reaction
(the temperature rose from 22 to 25 ° C), and the suspension became yellow and stirred for 30 minutes at room temperature, cooled to -10 ° C, where subsequently a solution of 1.34 g of (6R, 7R ) -7- (1-tert-butoxiformamido) -3-formyl-8-oxo-5-thia-l-azabicyclo [.2.0] oct-2-ene-2-diphenylmethylcarboxylate, in 4 ml of THF, They added in the form of drops for 20 minutes. After the addition of a mixture of 5 ml of 1 N aqueous hydrochloric acid and
ml of water, stirring was maintained for 10 minutes at room temperature. The aqueous phase was separated and washed with two 25 ml portions of toluene, the collected organic phases were washed with about 20 ml of a 5% aqueous sodium bicarbonate solution and subsequently with 20 ml of water. The toluene phases were combined, dried over 15 g of magnesium sulfate, and evaporated to dryness. They were obtained
2. 16 g of the diphenyl ethyl ester of [6R- [3 (E) -6R, 7R]] - 3 - [(l-cyclopropyl-2-oxo-3-pyrrolidinylidene] methyl] -7 - [[(l, l-dimethylethoxy) carbonylamino] -8-oxo-d-thia-l-azabicyclo [4.2.0] oct-ene-2-carboxylic acid, which were dissolved in 20 ml of toluene / ethyl acetate 3: 2 were coriatographed Instantaneously (fractions of 1 ml) in 30 g of silica gel (Merck 60; 0.040-0.063 mm) with approximately 500 ml of toluene / ethyl acetate 3: 2 as the eluent: Fr 1 0.07 g was obtained as an orange oil Fr 2 0.60 g as light yellow crystals Fr 3 0.46 g as orange crystals Total: 1.13 g, corresponding to 75% yield
Example 3
An argon atmosphere was dissolved in 11.2 g of (R, S) - (1-cyclopropyl-2-oxo-3-pyrrolidinyl) -triphenyl phosphonium bromide in 60 ml of toluene and 30 ml of water and cooled to 0 ° C. ° C (crystallizes again). 24 ml of 1 N of saturated sodium hydroxide in the form of drops was added within 20 minutes; the toluene phase colored yellow and the aqueous phase was colored white (suspension). After stirring for 10 minutes at 0 ° C the toluene phase is cooled to -10 ° C and the aqueous phase extracted with 20 ml of toluene which is added to the toluene phase. A solution of 10.4 g of (6R, 7R) -7- (1-tert-butoxyformamido) -3-formyl-8-oxo-5-thia-1-aza-cyclo [4.2.0] oct-2-ene was added. -2-Diphenylmethyl carboxylate in 35 ml of THF as drops within 1 hour; The resulting brown suspension was stirred for 10 minutes. After stirring at 0 ° C for 45 minutes, a mixture of 25 ml of 1 N hydrochloric acid and 25 ml of water was added and the stirring continued for 10 minutes without cooling (room temperature) to provide 2 clear phases; the toluene phase is red and the aqueous phase is pale yellow. After separation of the phases, the aqueous phase is extracted twice each with 50 ml of toluene, the combined organic phase is washed with 50 ml of a 5% aqueous sodium bicarbonate solution and then with 50 ml of water . The combined toluene phases were dried over 25 g of magnesium sulfate and evaporated. 20.47 g of the resulting red-orange crude product, which was dissolved in 50 ml of toluene / ethyl acetate (30 minutes) and subsequently flash chromatographed (fractions 50-75 ml) in 200 g of silica gel (Merck 60; 0.040-0.063 mm) with 4 1 of toluene ethyl acetate 4: 1 as eluent.
Yield: 9.5 g of [6R- [3 (E) -6R, 7R]] - 3- [(1-cyclopropi-1-2-oxo-3-pyrrolidinylidene) methyl] -7- [[(1-diphenylmethyl) ester [6R- [3 (E) -6R, 7R]] , 1-dimethylethoxy) carbonyl] amino] -8-oxo-5-thia-l-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid as yellow crystals (49% based on converted aldehyde).
Employ
Argon was dispersed under 11.4 g of (R, S) - [2-oxo-l- (2,2,2-trifluoroethyl) -3-pyrrolidinyl] -triphenylphosphonium bromide in 100 ml of toluene and 80 ml of water. The resulting mixture in three phases was stirred at room temperature and 22.4 ml of 1 N aqueous sodium hydroxide was added within 30 minutes. The toluene phase is yellow, the aqueous phase is colorless and a weak emulsion is obtained. After 30 minutes the phases were separated and the aqueous phase was extracted with 20 ml of toluene, the organic extracts were washed with 30 ml of a 5% aqueous sodium acetate solution and then with 30 ml of water. The combined toluene phase was cooled to -10 ° C, and 10.0 g of (6R, 7R) -7- (1-tert-butoxy formamido) -3-formyl-8-oxo-5-thia-l-aza iciclo [ 4.2.0] diphenylmethyl oct-2-ene-2-carboxylate in 40 ml of THF were added dropwise over 30 minutes; The yellow solution was stirred for 20 minutes at -10 ° C. Subsequently, a mixture of 40 ml of 1 N aqueous hydrochloric acid and 40 ml of water is added and the stirring continued for 15 minutes. The phases are separated, the aqueous phase extracted with two 60 ml portions of toluene each, the organic phases are washed with 50 ml of a 5% aqueous sodium bicarbonate solution and subsequently with 50 ml of water. The combined toluene phases were dried over 85 g of magnesium sulfate and evaporated to dryness. 22.28 g of a dark yellow crude reaction product is obtained, which was dissolved in 40 ml of n-hexane: ethyl acetate 3: 2 and 3 ml of methylene chloride (30 minutes). The solution is chromatographed instantaneously in. 100 g of silica gel (Merck
60; 0.040-0.063 mm; diameter 3 cm, length 30 cm) and filtered. As eluent 1 1 of n-hexane: ethyl acetate 3: 2 is used; 50 ml of fractions are collected. 11.55 g of an orange-yellow product are obtained (yield 96%).
The product was crystallized by the solution and 20 ml of ethyl acetate at 75 ° C and 25 ml of n-hexane are added dropwise over the course of 15 minutes; the solution was slowly cooled to 60 ° C, seeded with crystals purified at 60 ° C, diluted with 25 ml of n-hexane and stirred for 12 hours at room temperature, filtered, washed and dried for a yield of 8.79 g of [6R- [3 (E), 6R, 7R]] - 7 - [[(1, 1 -dimethylethoxy) carbonyl] amino] -8-oxo-3- [[2-oxo] diphenylmethyl ester. - (2,2,2-trifluoroethyl) -3-pyrrolidinylidene] methyl] -5-thia-l-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid as white crystals (73% yield), melting at 179-181 ° C.
Example 5
Argon was dispersed under 27.6 g of (R, S) - [2-oxo-l- (2,2, 2-trifluoroethyl) -3-pyrrolidinyl] -triphenylphosphonium bromide in 240 ml of toluene and 180 ml of water. room temperature. 54.3 ml of a 1 N aqueous sodium hydroxide solution was added dropwise over 20 minutes. After 30 minutes the phases were separated and the liquid phase was extracted three times with 150 ml of toluene each. The toluene phase was extracted three times with 150 ml of water each. The combined toluene phase was cooled to -10 ° C and 22 g of 4-methoxy-benzyl- (6R, 7R) -7-phenylacetylamino-3-formyl-8-oxo-5-thia-1-azabicyclo [.2.0] Oct-2-ene-2-carboxylate in 100 ml of THF was added dropwise over 1 hour. After further stirring for 10 minutes, the phases were separated and the aqueous phase was extracted twice each with 150 ml of toluene. Each of the toluene phases is washed three times with 150 ml of water each. The combined organic phases were dried over sodium sulfate, filtered and evaporated to approximately 20 ml. The crystallized product was filtered and washed with ice-cold toluene. 18.73 g of 4-methoxybenzyl ester of [6R- [3 (E), 6R, 7R]] -7-phenylacetylamino- 8 -oxo-3- [[2-oxo- (2, 2, 2 trifluoroethyl) -3-pyrrolidinylidene] methyl] -5-thia-l-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid as yellowish-beige crystals (56% yield) melting at 177 ° C.
Example 6
Argon was dissolved under 753 mg (1.3 mmol) of a mixture of (1R, 3R) and (1S, 3'R) - (i >) bromide; α ± iloxycarbonyl-2-oxo- [1,3 '] bipyrrolidinyl-3-yl) -triphenyl-phosphonium (1: 1) in 20 ml of methylene chloride, 3.0 g of sodium sulfate and the mixture were added. it was stirred 10 minutes at room temperature. Sodium sulfate is filtered and the solution completely evaporated. The residue was dissolved in a mixture of 2 ml of methylene chloride and 5 ml of toluene and the solution was cooled to -70 ° C. 35 mg (1.2 mmol) of potassium tert-butylate in 2 ml of THF was added within 5 minutes at this temperature. The mixture was stirred for another 5 minutes and then a solution of (6R, 7R) -7- (1-tere-butoxyformamido) -3-formyl-8-oxo-5-thia-1-azabicyclo [4.2.0] was added. ] diphenylmethyl oct-2-ene-2-carboxylate in 2 ml of THF dropwise within 15 minutes. The reaction mixture was stirred at 2 ° to -70 ° C and subsequently brought slowly to -10 ° C. After 1 hour at -10 ° C a solution of 300 mg of citric acid in 3 ml of water and 4 ml of ethyl acetate was added slowly and the reaction mixture was brought to room temperature. The extraction of the resulting solution of two phases was carried out, in which after equilibration the aqueous phase was extracted again with 10 ml of ethyl acetate and the two organic phases were each extracted with 3 ml of a bicarbonate solution. of saturated aqueous sodium, each followed by 3 ml of a solution of aqueous sodium chloride. The organic phases were combined, dried and evaporated to provide 1.34 g of an orange-brown residue. This was filtered through a 27 g column of finely powdered Si02, using as eluent ethyl acetate: n-hexane 2: 1 (5 fractions each of 15 ml discharged) then only ethyl acetate (fractions 6-11). each of 15 ml discharged), fractions 12-20 each of 15 ml providing, after evaporation, 640 mg of benzhydryl ester of (E) - (6R, 7R) -3- [(R) -1 ') -alloyloxycarbonyl-2-oxo- [1-3 '] bipyrrolidinyl-3-ylidenemethyl] -7-tert-butoxycarnone lamino-8 -oxo-5-thia-1-azabicyclo [4.0.2] oct-2-ene- 2-carboxylic acid, as a yellow resinous residue (90%).
MS 687 (MH +), 704 (MNH), 709 (MNa +)
Example 7
Under argon, 15.53 g (26 mmol) of a mixture of (1R, 3'R) and (ÍS, 3'R) - (1'-allyloxy-carbonyl-2-oxo- [1, 3 '] bromide was dissolved under argon. bipyrrolidinyl-3-yl) -triphenyl-phosphonium (1: 1) in 200 ml of methylene chloride, about 5 g of. Sodium sulfate is added, and the suspension is stirred at room temperature for 10 minutes. The sodium sulfate was filtered and the filtrate evaporated. The residue was dissolved in 40 ml of methylene chloride and 100 ml of toluene were added. The resulting red-brown solution was cooled to -70 ° C. At this temperature, a solution of 2.69 g (24 mmol) of potassium tert-butylate in 40 ml of THF was added as drops within 15 minutes. The resulting brown solution was further stirred for 10 minutes, and subsequently, a solution of 9.89 g (20 mmol) of (6R, 7R) -7- (1-tert-butoxyformamide) was added as drops within 20 minutes. 3-formyl-8-oxo-5-thia-l-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid diphenylmethyl ester, in 40 ml of THF. The brown solution is further stirred for about 3 hours and then brought to 0 ° C. After 40 minutes at 0 ° C, a solution of 6 g of citric acid in 60 ml of water and 60 ml of ethyl acetate is added within 5 minutes. The reaction mixture is further stirred for 10 minutes and then stored at about 5 ° C overnight. The resulting two-phase solution is extracted, in which after equilibration of the aqueous phase it is further extracted with 60 ml of ethyl acetate; 60 ml of a saturated sodium chloride solution is extracted with the two organic phases. The organic phases are then combined, dried and evaporated to dryness to provide 31.11 g of (E) - (6R, 7R) - [3 (R) -1 '-alloyloxycarbonyl-2-oxo [1,3] -hydric acid ester. ] bipyrrolidinyl-3-ylidene-methyl] -7-tert-butoxycarbonylamino-8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-carboxylic acid, as a red-brown residue. The residue was dissolved in 20 ml of methylene chloride and, with stirring, slowly poured into 180 ml of n-hexane. The resulting suspension was stirred 5 minutes at room temperature then filtered. The residue, in accordance with HPLC, contains a considerable amount of triphenylphosphine d-oxide (TPPO), and the above procedure is therefore repeated once and the residue dried (45 ° C / 30 mbar / 15 minutes) to provide 11.78. gd (E) - (6R, 7R) - [3 (R) -1'-Allyloxycarbonyl-2-oxo- [1,3 '] bipyrrolidinyl-3-ylidenemethyl] -7-tert-butoxycarbonylamino-8-benzhydride ester oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-carboxylic acid as beige crystal (82%). This HPLC-compliant product still contains approximately 9.5% triphenylphosphine d-oxide (TPPO), which leads to a corrected yield of 75%.
Example
Under argon, 75.33 g (130.0 mmol) of a mixture of bromide of (1R, 3'R) and (ÍS, 3 'R) - (1'-alkyloxycarbonyl-2-oxo- [1, 3'] bipyrrolidinyl-3-yl) -trifeni1-phosphonium
(1: 1) is dissolved in 500 ml of methylene chloride; 20 g of sodium sulfate are added and stirred at room temperature for 15 minutes. Sodium sulfate is filtered, washed well with methylene chloride and the filtrate evaporated. The residue was dissolved in 200 ml of methylene chloride, 500 ml of toluene were added and the solution was cooled to -70 ° C. At this temperature, a solution of 13.60 g (120.0 mmol) of potassium tert-butylate in 200 ml of THF is added dropwise within 20 minutes. The mixture is further stirred for 20 minutes and a solution of 50.71 g (100 mmol) of 4-methoxybenzyl- (6R, 7R) -7-phenylacetylamino-3-formyl-8- is added in the form of drops within 30 minutes. oxo-5-thia-l-azabicyclo [4.2.0] oct-2-ene-2-carboxylate in 220 ml of THF. After 2 hours at -70 ° C, the reaction mixture is brought to -10 ° C. This reaction mixture is rapidly quenched in a mixture of 400 ml of ethyl acetate and a solution of 30.02 g (156 mmol) of citric acid is added in 300 ml of water, everything is previously adjusted to 0 ° C. The resulting mixture of two phases is brought to room temperature, the aqueous phase is separated and extracted once with 400 ml of ethyl acetate. The two organic phases are extracted once with 300 ml of a saturated aqueous sodium chloride solution; the organic phases are combined, dried and evaporated to provide 256.76 g of (E) - (6R.7R) - [3 (R) -1'-allyloxycarbonyl-2-oxo- [1, 3 '] 4-methoxybenzyl ester ] bipyrrolidinyl-3-ylidenemethyl] -8-oxo-7- phenylacetylamino-5-ti to aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid, as a dark suspension. In accordance with HPLC, this product still obtains TPPO and toluene residues. Physical characteristics:
MS 687 (MH *), 704 (MNHJ), 709 (MNa +)
NMR 1.9-2.25 (m, 2H), 2.6-2.9 (m, 2H), 3.25-3.7 (m, 10H), 3.8 (s> 3H), 4.6 (d, 2H), 4.8 (q, 1H), 4.9 (d, lH), 5.2 (s, 2H), 5.2-5.3 (m, 2H), 5.8 (dd, 1H), 5.9 (m, 1H), 6.5 (m, 1H), 7.3 (m, 9H)
It is noted that in relation to this date, the best method known by the applicant to carry out the present invention is that which is clear from the manufacture of the objects to which it refers.
Claims (14)
- CLAIMS Having described the above invention, the content of the following claims is claimed as property: 1. Process for the manufacture of cephalosporin derivatives of the general formula wherein R1 is an amino protecting group R? is a carboxy protecting group, and R is a hydrogen, lower alkyl, lower alkoxy, cycloalkyl, cycloalkenyl, cycloalkyl-lower alkyl, lower alkenyl, lower alkynyl, aryl, aryl-lower alkyl, heterocyclic or heterocyclic-lower alkyl; the lower alkyl, cycloalkyl, lower alkenyl, cycloalkenyl, lower alkynyl, aryl lower alkyl, aryl and the heterocyclic portions are substituted or unsubstituted with at least one group selected from carboxy, amino, aminoethyl, carbamoyl, nitro, cyano , lower alkyl, lower alkoxy, hydroxy, halogen and trifluoromethyl. which is characterized in that it comprises converting a phosphonium salt of the general formula wherein R is as previously defected and Ph represents phenyl, in toluene by treatment with a base in the corresponding ylido of the general formula wherein R and Ph. are as described above, and the same is reacted with a solution in a polar solvent of an aldehyde of the general formula wherein R1 and R2 are as described above. at a temperature of from about -80 ° C to about 0 ° C, the phosphonium salt II, the base and the aldehyde IV are employed in a molar ratio of about 1.15: 1.1: 1.0 to 1.3: 1.25: 1.0.
- 2. Process according to claim 1, characterized in that the salt of phosphonium II, base and aldehyde IV are used in a molar ratio of approximately 1.2: 1.15: 1.0.
- 3. Process according to claim 1 or 2, characterized in that the polar organic solvent used is tetrahydrofuran.
- 4. Process according to any one of claims 1-3, characterized in that the base is presented as aqueous sodium hydroxide.
- 5. Process according to any one of claims 1-3, characterized in that the base is presented as potassium tert-butoxide in tetrahydrofuran.
- 6. Process according to claim 1 or 2, characterized in that the reaction is carried out in a solvent consisting of toluene, methylene chloride and tetrahydrofuran.
- 7. Process according to claim 5, characterized in that the weight ratio of toluene, methylene chloride and tetrahydrofuran is between about 2: 1: 1 to 5: 2: 1.
- 8. Process according to one of claims 1-7, characterized in that the reaction temperature is conducted between about -80 ° C and about -60 ° C, preferably between -70 ° C.
- 9. Process according to one of claims 1-8, characterized in that (6R, 7R) -7- (1-tert-butoxiformamido) -3-formyl-8-oxo-5-thia-l-azabicyclo [4.2.0] diphenylmethyl oct-2-ene-2-carboxylate or (6R, 7R) -7-phenylacetylamino-3-formyl-8-oxo-5-thia-l-azabicyclo [4.2.0] oct-2-ene-2 -carboxylate are used as aldehyde initiators of formula IV.
- 10. Process according to one of claims 1-5 and 9, characterized in that a phosphonium salt of formula II is used, in which R is 2,2,2-trifluoroethyl, cyclopropyl or cyclopentyl.
- 11. Processes according to one of claims 5-9, characterized in that a phosphonium salt of formula II is used in which R is N-substituted 3-pyrrolidinyl, which is 3-pyrrolidinyl N-allyloxycarbonyl.
- 12. Process according to one of claims 1-10, characterized in that the reaction mixture containing the compound of formula I is raised with aqueous acid.
- 13. Use of the compounds of formula I obtained by the process according to one of claims 1-12 for the manufacture of cephalosporins of the formula wherein R is as in claim 1, X is -CH or nitrogen, and R1 is hydrogen, optionally substituted lower alkyl, cycloalkyl, benzyl, trityl, acetyl or tetrahydropyranyl, its pharmaceutically acceptable salts and split esters in vivo
- 14. Use according to claim 13 for the manufacture of the compounds of the formula V wherein R is 2,2,2-trifluoroethyl, cyclopropyl, cyclopropylmethyl or 3-pyrrolidinyl, X is -CH and R 1 is hydrogen. where R and Ph are conro is described artically, and it is reacted with an aldehyde of the general formula where R * and R ~ are as before
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH99112911.5 | 1999-07-05 |
Publications (1)
Publication Number | Publication Date |
---|---|
MXPA00006618A true MXPA00006618A (en) | 2002-05-09 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
SU442602A1 (en) | The method of obtaining 3-methylene compounds | |
KR100515273B1 (en) | Process for the selective preparation of z-isomers of 3-(2-substituted vinyl)cephalosporins | |
EP0864564B1 (en) | Method for the preparation of alpha-bromolactam derivatives | |
JPS6113477B2 (en) | ||
EP0018546B1 (en) | Process for the production of phenylglycyl chloride hydrochlorides | |
EP1067131B1 (en) | New process for the manufacture of cephalosporin derivatives | |
MXPA00006618A (en) | New process for the manufacture of cephalosporin derivatives | |
IE47037B1 (en) | Isopenicillins, processes for their preparation, and compositions containing them | |
EP0812846B1 (en) | Preparation of cephem- and isooxacephem derivatives | |
EP0011369B1 (en) | Process for preparing 3-exomethylenecepham sulfoxides | |
CA1338607C (en) | Process for the preparation of 3-exomethylenecepham derivatives | |
JPH07247286A (en) | Method for optically resolving nitrogen-containing cyclic compound | |
US4616084A (en) | Process for the preparation of 7-acylamino-3-hydroxy-cephem-4-carboxylic acids and 7-acylamino-3-hydroxy-1-dethia-1-oxacephem-4-carboxylic acids | |
Ernest | 2‐Oxocephems. Synthesis and Properties of 7‐Acylamino‐2‐oxocephem‐4‐carboxylic Acids | |
EP0262202B1 (en) | Method for preparing penicillanic acid derivatives | |
AU581541B2 (en) | Method of preparing 6-betahalopenicillanic acids | |
EP0081824B1 (en) | Processes for the production of antibiotic 1-oxadethiacephalosporins | |
SE501501C2 (en) | 1- (2-methyl) -1-oxo-3-rhodanidopropyl-proline and a process for the preparation of 1 - / (2S) -3-mercaptomethyl-1-oxopropyl / -L-proline | |
CA2557798A1 (en) | Process for preparing cephalosporin intermediates using alpha-iodo-1-azetidineacetic acid esters and trialkylphosphites | |
KR100241089B1 (en) | Novel process for preparation of 2-mercapto-4-methyl-1,3-thiazole-5-acetic acid | |
KR950011746B1 (en) | 3-propenylcephem derivative, preparation thereof, chemica intermediates therein, pharmaceutical composition and use | |
US3926965A (en) | Phthalimido derivatives and processes | |
JPH0247995B2 (en) | ||
WO1996028453A1 (en) | Processes for the production of 2-isocephem derivatives | |
JPH0517229B2 (en) |