CN1708501A - An improved process for the preparation of chloro methyl cephem derivatives - Google Patents
An improved process for the preparation of chloro methyl cephem derivatives Download PDFInfo
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- CN1708501A CN1708501A CNA2003801023937A CN200380102393A CN1708501A CN 1708501 A CN1708501 A CN 1708501A CN A2003801023937 A CNA2003801023937 A CN A2003801023937A CN 200380102393 A CN200380102393 A CN 200380102393A CN 1708501 A CN1708501 A CN 1708501A
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- solvent
- salt
- sulfinic acid
- compound
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- 238000000034 method Methods 0.000 title claims abstract description 36
- 238000002360 preparation method Methods 0.000 title claims description 23
- QNJLADIWFYPULV-NQPNHJOESA-N (6r)-4-(chloromethyl)-5-thia-1-azabicyclo[4.2.0]oct-2-en-8-one Chemical class C1=CC(CCl)S[C@@H]2CC(=O)N21 QNJLADIWFYPULV-NQPNHJOESA-N 0.000 title abstract 2
- 239000001257 hydrogen Substances 0.000 claims abstract description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 5
- 125000002927 2-methoxybenzyl group Chemical group [H]C1=C([H])C([H])=C(C(OC([H])([H])[H])=C1[H])C([H])([H])* 0.000 claims abstract description 4
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims abstract description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 4
- 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 claims abstract description 4
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims abstract description 4
- -1 chloromethyl cephalosporin Chemical class 0.000 claims description 83
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 42
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- 150000001875 compounds Chemical class 0.000 claims description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 23
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- 239000002904 solvent Substances 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- 239000003513 alkali Substances 0.000 claims description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- 229930186147 Cephalosporin Natural products 0.000 claims description 17
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 17
- 229940124587 cephalosporin Drugs 0.000 claims description 17
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 16
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 239000002585 base Substances 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 8
- 229910021529 ammonia Inorganic materials 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 8
- VLUWLNIMIAFOSY-UHFFFAOYSA-N 2-methylbenzenesulfinic acid Chemical compound CC1=CC=CC=C1S(O)=O VLUWLNIMIAFOSY-UHFFFAOYSA-N 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 claims description 5
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 238000005660 chlorination reaction Methods 0.000 claims description 4
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 claims description 4
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 3
- 229940073608 benzyl chloride Drugs 0.000 claims description 3
- 229940043232 butyl acetate Drugs 0.000 claims description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 238000010511 deprotection reaction Methods 0.000 claims description 3
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 claims description 3
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 3
- 235000012204 lemonade/lime carbonate Nutrition 0.000 claims description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 3
- 235000015320 potassium carbonate Nutrition 0.000 claims description 3
- 125000006239 protecting group Chemical group 0.000 claims description 3
- 235000017550 sodium carbonate Nutrition 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 2
- 239000005695 Ammonium acetate Substances 0.000 claims description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 2
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- 229940043376 ammonium acetate Drugs 0.000 claims description 2
- 235000019257 ammonium acetate Nutrition 0.000 claims description 2
- 150000003863 ammonium salts Chemical class 0.000 claims description 2
- AYXKXHJKXZKAMX-UHFFFAOYSA-N benzenesulfinic acid copper Chemical compound [Cu].C1(=CC=CC=C1)S(=O)O AYXKXHJKXZKAMX-UHFFFAOYSA-N 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 claims description 2
- 150000002500 ions Chemical class 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims 2
- PGIHOODRZRVPID-UHFFFAOYSA-N benzenesulfinic acid;silver Chemical compound [Ag].OS(=O)C1=CC=CC=C1 PGIHOODRZRVPID-UHFFFAOYSA-N 0.000 claims 1
- SRJQTHAZUNRMPR-UYQKXTDMSA-N spinosyn A Chemical compound O([C@H]1CCC[C@@H](OC(=O)C[C@H]2[C@@H]3C=C[C@@H]4C[C@H](C[C@H]4[C@@H]3C=C2C(=O)[C@@H]1C)O[C@H]1[C@@H]([C@H](OC)[C@@H](OC)[C@H](C)O1)OC)CC)[C@H]1CC[C@H](N(C)C)[C@@H](C)O1 SRJQTHAZUNRMPR-UYQKXTDMSA-N 0.000 claims 1
- 125000006282 2-chlorobenzyl group Chemical group [H]C1=C([H])C(Cl)=C(C([H])=C1[H])C([H])([H])* 0.000 abstract 1
- 125000000217 alkyl group Chemical group 0.000 abstract 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 abstract 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 17
- 239000011541 reaction mixture Substances 0.000 description 15
- 239000012044 organic layer Substances 0.000 description 14
- 239000002253 acid Substances 0.000 description 10
- 125000004119 disulfanediyl group Chemical group *SS* 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- YXIWHUQXZSMYRE-UHFFFAOYSA-N 1,3-benzothiazole-2-thiol Chemical compound C1=CC=C2SC(S)=NC2=C1 YXIWHUQXZSMYRE-UHFFFAOYSA-N 0.000 description 8
- 239000002002 slurry Substances 0.000 description 8
- 150000007513 acids Chemical class 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- WHERMLSFDXCIQO-WPZCJLIBSA-N (6r)-3-(chloromethyl)-8-oxo-7-[(2-phenylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound C1([C@H]2SCC(CCl)=C(N2C1=O)C(=O)O)NC(=O)CC1=CC=CC=C1 WHERMLSFDXCIQO-WPZCJLIBSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- 238000013019 agitation Methods 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 235000019439 ethyl acetate Nutrition 0.000 description 6
- 239000012141 concentrate Substances 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 4
- 239000006227 byproduct Substances 0.000 description 4
- 150000001780 cephalosporins Chemical class 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 229940088710 antibiotic agent Drugs 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 235000011837 pasties Nutrition 0.000 description 3
- RBKMMJSQKNKNEV-RITPCOANSA-N penicillanic acid Chemical compound OC(=O)[C@H]1C(C)(C)S[C@@H]2CC(=O)N21 RBKMMJSQKNKNEV-RITPCOANSA-N 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- YMEXAAFKFVBTPW-UHFFFAOYSA-N 1-(chloromethyl)azetidin-2-one Chemical class ClCN1CCC1=O YMEXAAFKFVBTPW-UHFFFAOYSA-N 0.000 description 2
- DWDDFMFCVGDERN-UHFFFAOYSA-N 1-chloroazetidin-2-one Chemical compound ClN1CCC1=O DWDDFMFCVGDERN-UHFFFAOYSA-N 0.000 description 2
- NHYCGSASNAIGLD-UHFFFAOYSA-N Chlorine monoxide Chemical compound Cl[O] NHYCGSASNAIGLD-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 238000004140 cleaning Methods 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 125000001072 heteroaryl group Chemical group 0.000 description 2
- YHMYGUUIMTVXNW-UHFFFAOYSA-N 1,3-dihydrobenzimidazole-2-thione Chemical compound C1=CC=C2NC(S)=NC2=C1 YHMYGUUIMTVXNW-UHFFFAOYSA-N 0.000 description 1
- KYWXRBNOYGGPIZ-UHFFFAOYSA-N 1-morpholin-4-ylethanone Chemical compound CC(=O)N1CCOCC1 KYWXRBNOYGGPIZ-UHFFFAOYSA-N 0.000 description 1
- FLFWJIBUZQARMD-UHFFFAOYSA-N 2-mercapto-1,3-benzoxazole Chemical compound C1=CC=C2OC(S)=NC2=C1 FLFWJIBUZQARMD-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- BOYNILPHVAYVGO-UHFFFAOYSA-N 3-(chloromethyl)azetidin-2-one Chemical class ClCC1CNC1=O BOYNILPHVAYVGO-UHFFFAOYSA-N 0.000 description 1
- HDFGFMYFTNSFER-UHFFFAOYSA-N 5-methyl-2-sulfanyltetrazole Chemical compound CC=1N=NN(S)N=1 HDFGFMYFTNSFER-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- NSOXQYCFHDMMGV-UHFFFAOYSA-N Tetrakis(2-hydroxypropyl)ethylenediamine Chemical compound CC(O)CN(CC(C)O)CCN(CC(C)O)CC(C)O NSOXQYCFHDMMGV-UHFFFAOYSA-N 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 150000001782 cephems Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 125000000532 dioxanyl group Chemical group 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- LCEDQNDDFOCWGG-UHFFFAOYSA-N morpholine-4-carbaldehyde Chemical compound O=CN1CCOCC1 LCEDQNDDFOCWGG-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
-
- 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
-
- 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
- C07D501/02—Preparation
- C07D501/08—Preparation by forming the ring or condensed ring systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The present invention provides an improved process to produce the chloromethylcephem derivatives of the formula (I), wherein R<1> represents a carboxy-protecting group viz., substituted methyl group, which can be deprotected easily, such as t-butyl group, diphenylmethyl, 4-methoxybenzyl, 2-methoxybenzyl, 2-chlorobenzyl or benzyl group; R<2> represents hydrogen, (C<1>-C<4>)alkyl, substituted or unsubstituted phenyl or substituted or unsubstituted phenoxy group.
Description
Invention field
The invention provides the method for chloromethyl cephalosporin alkene (cephem) derivative of a kind of improved preparation formula (I):
R wherein
1The expression carboxy protective group, that is, the methyl of replacement, it is deprotection easily, such as the tertiary butyl, diphenyl-methyl, 4-methoxybenzyl, 2-methoxybenzyl, 2-benzyl chloride base or benzyl; R
2Expression hydrogen, (C
1-C
4) alkyl, replacement or unsubstituted phenyl or replacement or unsubstituted phenoxy.
The chloromethyl cephalosporin ene derivative of prepared according to the methods of the invention formula (I) can be used for the cephalosporin antibiotics of preparation formula (II):
R wherein
4Be carboxylic acid ion or COOR
d, R wherein
dExpression hydrogen, ester or the salifiable counter ion of shape; R
6Expression H, CH
3, CR
aR
bCOOR
c, R wherein
aAnd R
bRepresent hydrogen or methyl independently, R
cExpression hydrogen or (C
1-C
6) alkyl; R
5Expression CH
3, CH
2OCH
3, CH
2OCOCH
3, CH=CH
2, or
The cephalosporin antibiotics of formula (II) has wide biological activity.Specifically, the cephalosporin antibiotics of formula (II) has the excellent antibiotic activity.
Background of invention
In view of the importance that the key intermediate of multiple cephalosporin medicament is synthesized in the 3-chloromethyl cephalosporin alkene conduct of formula (I), various preparation methods (US4,853,468 have been reported; US4,789,740).In most of the cases, the alkylsulfonyl aza cyclo-butanone derivatives of formula (III) is carried out allyl type/alkene type chlorination, obtain the chloro azetidinone of formula (IV) with various chlorizating agents such as chlorine, chlorine monoxide etc.The chloro azetidinone of formula (IV) further at low temperatures, cyclisation in the presence of alkali obtains the chloromethyl cephalosporin alkene of formula (I):
R wherein
1And R
2Definition as above; R
3Expression phenyl, (C
1-C
4) alkyl phenyl, (C
1-C
4) alkoxyl phenyl or heteroaryl.
The preparation of alkylsulfonyl azetidinone intermediate, as by reported method it being prepared, invariably accompanying forms a large amount of impurity, causes the purity of alkylsulfonyl azetidinone lower, and this makes the yield of chloromethyl cephalosporin alkene of formula (I) low conversely.
In addition, the by product that forms in the process of preparation alkylsulfonyl azetidinone intermediate can not be removed fully by existing acetone system; And if this by product do not remove in this step, it will cause forming more impurity in the conversion of next step chlorination and cyclisation.Therefore, need find a kind of method, this method can be with respect to by product is removed away from alkylsulfonyl azetidinone intermediate.
In addition, carry out in last step of cyclisation with ammonia in DMF, we find that the formation degree of impurity is very high in the process that adds alkali.This just need develop the method that alternate can provide better conversion and therefore better yield is arranged.
Constantly make great efforts and deep research through us, we have determined a kind of method of cleaning at last, and it can solve above-mentioned all restrictions, and the chloromethyl cephalosporin ene derivative of production (I).
Goal of the invention
Main purpose of the present invention is that a kind of simply and effectively method of the chloromethyl cephalosporin ene derivative of the 3-chloromethyl azetidinone compounds preparation formula (I) of through type (VII) is provided.
Another object of the present invention is, the method for the chloromethyl azetidinone compounds of a kind of preparation formula (VII) is provided, and do not use reluctant dangerous reagent in industrial scale in the method.
Another object of the present invention is that the mode by the formation of control major impurity with a kind of cleaning prepares the alkylsulfonyl azetidinone, and the method for removing by product is provided.
Another object of the present invention is, the chloromethyl azetidinone compounds of a kind of cyclisation formula (VII) is provided, and simultaneously minimum level reduced in the formation of impurity and obtained the method for peak rate of conversion.
Summary of the invention
Therefore, the invention provides the method for the chloromethyl cephalosporin ene derivative of a kind of improved preparation formula (I),
R wherein
1The expression carboxy protective group, that is, the methyl of replacement, it is deprotection easily, such as the tertiary butyl, diphenyl-methyl, 4-methoxybenzyl, 2-methoxybenzyl, 2-benzyl chloride base or benzyl; R
2Expression hydrogen, (C
1-C
4) alkyl, replacement or unsubstituted phenyl or replacement or unsubstituted phenoxy, said method comprising the steps of:
(i) use aryl-sulfinic acid or (C
1-C
6) metal-salt, alkali and the solvent of alkyl sulfinic acid, in 25 ℃-40 ℃ temperature range, the compound of formula V is converted into the compound of formula (VI), wherein R
8Expression replaces or unsubstituted (C
1-C
6) alkyl or aryl, wherein improve the metal-salt that adds the aryl-sulfinic acid in the pH value scope that is included in 4-8.0,
(ii) in the presence of alkali and solvent, in 15 ℃-40 ℃ temperature range, use the compound of chlorizating agent chlorination formula (VI), obtain the compound of formula (VII), wherein R
8Expression replaces or unsubstituted (C
1-C
6) alkyl or aryl, every other symbol definition as above and
(vi) in solvent, in-60 ℃ to+50 ℃ temperature range, use the compound cyclisation of alkali, obtain the chloromethyl cephalosporin ene derivative of formula (I) formula (VII).
The synthetic method of the chloromethyl cephalosporin ene derivative of formula (I) is shown in scheme-I.
Scheme-I
R wherein
1And R
2Definition as above.
Invention is described
In embodiments of the invention, by R
7The heteroaryl of expression is selected from 2-mercaptobenzothiazole, 2-mercaptobenzoxazole, 2-mercaptobenzimidazole or 2-sulfydryl-5-methyl tetrazolium.
In another embodiment of the invention, the conversion of step (i) be selected from acetone, THF, dioxane, diglyme, methylethylketone, acetonitrile, such as the alcohol of methyl alcohol, ethanol or Virahol in the presence of, with being selected from toluenesulfinic acid copper (II), benzene sulfinic acid copper (II), the aryl-sulfinic acid metal-salt of toluenesulfinic acid silver (II), benzene sulfinic acid silver (II) etc. being carried out, be with or without water and all can.
In another embodiment of the present invention, when step (i) is carried out, use alkali that the pH value is controlled in the 4-8 scope, more preferably 5-7, described alkali are selected from ammonia, alkali/alkaline earth metal carbonate such as lime carbonate, sodium bicarbonate, yellow soda ash, salt of wormwood, saleratus or such as the organic bases of diisopropylethylamine, triethylamine etc.
In another embodiment of the invention, be used for step chlorizating agent (ii) and be selected from chlorine, HOCl, Cl in the presence of alkali
2O, CH
3OCl etc.
In another embodiment of the invention, be used for step (ii) chlorizating agent or use with the form of gas, perhaps use with the solution form in solvent, described solvent is selected from dioxane, tetracol phenixin, ethyl acetate, acetonitrile, diglyme, N,N-DIMETHYLACETAMIDE, tetrahydrofuran (THF), methylene dichloride, butylacetate, phenyl ether, toluene or its mixture.
In another embodiment of the invention, be used for step alkali (ii) and be selected from alkali/alkaline earth metal carbonate such as lime carbonate, sodium bicarbonate, yellow soda ash, salt of wormwood, saleratus etc.
In another embodiment of the present invention, step cyclisation (iii) uses alkali to carry out, and described alkali is selected from ammonia, ammonium salt such as volatile salt, ammonium acetate, organic amine such as Diisopropylamine, quadrol, diethylamine, methylamine, triethylamine etc.
In another embodiment of the present invention; step cyclisation is (iii) carried out in solvent, and described solvent is selected from DMF, acetonitrile, N,N-DIMETHYLACETAMIDE, ethyl acetate, 4-formyl morpholine, 4-ethanoyl morpholine, dioxane, methyl-sulphoxide, THF, 1-methylpyrrolidin-2-ketone (NMP), methylene dichloride etc. or its mixture.
In another embodiment of the invention, raw material can prepare with the known literature method of prior art.
From industry, technology and ecological angle, it is attractive that aforesaid method has been considered to, and can obtain the chloromethyl aza cyclo-butanone derivatives of formula (VII).
Can obtain many other beneficial effects by using disclosed invention in a different manner or in the scope of disclosure, the present invention being carried out modification.
The present invention describes by following examples, and it should not be considered to be limiting the scope of the invention.
Embodiment 1:
Step-1
2-(2-[4-morpholinodithio base dithio)-α-(1-methyl ethylene)-4-oxo-3-phenylacetylamino-1-azetidine acetate is to methoxybenzyl ester (V)
Under 27 ℃ and nitrogen atmosphere, add 6-phenylacetylamino penicillanic acid in the dry toluene that in the round-bottomed flask that the Dean-Stark water trap is housed, is comprised (500 milliliters) to methoxybenzyl ester-1-oxide compound (25 gram) and 2-mercaptobenzothiazole (8.9 restrain).Reaction mixture refluxed heating 30 minutes, and under reflux temperature, kept 5 hours.After reaction finished, solvent removed in vacuo obtained that 2-(2-[4-morpholinodithio base dithio)-α-(1-methyl ethylene)-4-oxo-3-phenylacetylamino-1-azetidine acetate is to the methoxybenzyl ester, and it is used to carry out next step.
Step-2
2-(p-toluenesulfonyl sulfo-)-α-(1-methyl ethylene)-4-oxo-3-phenylacetylamino-1-azetidine acetate is to the preparation of methoxybenzyl ester (VI)
Under agitation, to 2-(2-[4-morpholinodithio base dithio)-α-(1-methyl ethylene)-4-oxo-3-phenylacetylamino-1-azetidine acetate to methoxybenzyl ester (methoxybenzyl ester-1-oxide compound being obtained) by 25 gram 6-phenylacetylamino penicillanic acids in adding acetone (220 milliliters), obtain 28-30 ℃ clear solution, and be cooled to 20-25 ℃.Under this temperature, under agitation add entry (32 milliliters).With saturated sodium hydrogen carbonate solution the pH value of solution is adjusted to 6.0-7.0.In 90-120 minute, under 20-25 ℃, in the solution that stirs, add toluenesulfinic acid copper (II) (13.0 gram) in batches, with saturated sodium hydrogen carbonate solution the pH value is remained on 5.5-6.5 simultaneously.After reaction finished, reaction mixture filtered by the hyflo bed, this bed washing with acetone.Filtrate vacuum concentration in rotatory evaporator, remove and desolvate.In the material of remnants, add ethyl acetate (125 milliliters) and water (125 milliliters), stirred 5-10 minute, add sodium-chlor subsequently.The separation organic layer also washes with water twice.Organic layer is at＜25 ℃ of following vacuum concentration, up to obtaining pasty substance.Add methyl alcohol, obtain slurries 28-30 ℃ of stirring, and be cooled to 2-5 ℃.Slurries were stirred 1 hour under this temperature, filter and with cold methanol wash.This filtrate is at＜25 ℃ of following vacuum concentration, obtains that 2-(p-toluenesulfonyl sulfo-)-α-(1-methyl ethylene)-4-oxo-3-phenylacetylamino-1-azetidine acetate is to the methoxybenzyl ester, and it is used for next step under situation about not being further purified.(HPLC purity is 89-90%).
Step-3
2-(p-toluenesulfonyl sulfo-)-α-(1-chloromethyl vinyl)-4-oxo-3-phenylacetylamino-1-azetidine acetate is to the preparation of methoxybenzyl ester (VII)
At 26-28 ℃; with 1; 4-dioxane (150 milliliters) join above 2-(p-toluenesulfonyl sulfo-)-α-(1-methyl ethylene)-4-oxo-3-phenylacetylamino-1-azetidine acetate to the methoxybenzyl ester (shown in step-2; by 25 gram 6-phenylacetylamino penicillanic acids methoxybenzyl ester-1-oxide compound is obtained) in, add sodium bicarbonate (90 gram) subsequently.Add Cl at leisure
2/ CCl
4(12.5%w/v) (60 milliliters).After reaction finishes, reaction mixture is filtered and wash with methylene dichloride (150 milliliters).In filtrate, add cold water (450 milliliters), separate organic layer, wash with water subsequently with hypo solution earlier.The organic layer activated carbon treatment; concentrate and use the method in common aftertreatment; obtain 2-(p-toluenesulfonyl sulfo-)-α-(1-chloromethyl vinyl)-4-oxo-3-phenylacetylamino-1-azetidine acetate to the methoxybenzyl ester, it is not purified just to be used to carry out next step.
Step-4
7-phenylacetylamino-3-chloromethyl-3-cephem-4-carboxylic acid is to the preparation of methoxybenzyl ester (I)
Under 28-30 ℃; add 1-methylpyrrolidin-2-ketone (125 milliliters) to 2-(p-toluenesulfonyl sulfo-)-α-(1-chloromethyl vinyl)-4-oxo-3-phenylacetylamino-1-azetidine acetate in to methoxybenzyl ester (methoxybenzyl ester-1-oxide compound being obtained), and stirring obtains clear solution by 25 gram 6-phenylacetylamino penicillanic acids.In this solution, add methylene dichloride (50 milliliters) and be cooled to-50 ℃ to-40 ℃.Under-50 ℃, in 2-5 minute, in this reaction mixture, be added in the ammonia soln in the 1-methylpyrrolidin-2-ketone (25 milliliters, 2-5 ℃), raise the temperature to-40 ℃.Reaction mixture was stirred 15-20 minute down at-45 ℃ to-40 ℃.Under-50 ℃ to-40 ℃, in 5 minutes, in this reaction mixture, dripped cold dilute hydrochloric acid (1: 1; 27 milliliters; 2-5 ℃).Reaction mixture is poured in 2-5 ℃ the cold water (900 milliliters).Add methylene dichloride, stirred 5-10 minute, separate organic layer.Water layer is further used dichloromethane extraction.Merge organic layer, and with 5-10 ℃ cold water washing 4 times.Remove fully in＜20 ℃ of following vacuum and to desolvate.Under 28-30 ℃, in the material of remnants, add methyl alcohol (175 milliliters), stirred 10-15 minute, obtain slurries and be cooled to 3-5 ℃.Slurries were stirred 1 hour under this temperature, filter and with cold methanol wash.With the material vacuum-drying that obtains like this 4-5 hour, obtain 7-phenylacetylamino-3-chloromethyl-3-cephem-4-carboxylic acid to methoxybenzyl ester, colorless solid.(15.1 gram).
Embodiment 2:
Step-1
2-(2-[4-morpholinodithio base dithio)-α-(1-methyl ethylene)-4-oxo-3-phenylacetylamino-1-azetidine acetate is to the preparation of methoxybenzyl ester (V)
Under 27 ℃ and nitrogen atmosphere, add 6-phenylacetylamino penicillanic acid in the dry toluene that in the round-bottomed flask that the Dean-Stark water trap is housed, is comprised (500 milliliters) to methoxybenzyl ester-1-oxide compound (25 gram) and 2-mercaptobenzothiazole (8.9 restrain).Reaction mixture refluxed heating 30 minutes also keeps 5 hours (this reaction also can be carried out as solvent with dioxane) under reflux temperature.After reaction finished, solvent removed in vacuo obtained that 2-(2-[4-morpholinodithio base dithio)-α-(1-methyl ethylene)-4-oxo-3-phenylacetylamino-1-azetidine acetate is to the methoxybenzyl ester, and it is used to carry out next step.
Step-2
2-(p-toluenesulfonyl sulfo-)-α-(1-methyl ethylene)-4-oxo-3-phenylacetylamino-1-azetidine acetate is to the preparation of methoxybenzyl ester
Under agitation, to 2-(2-[4-morpholinodithio base dithio)-α-(1-methyl ethylene)-4-oxo-3-phenylacetylamino-1-azetidine acetate to methoxybenzyl ester (methoxybenzyl ester-1-oxide compound being obtained) by 25 gram 6-phenylacetylamino penicillanic acids in adding acetone (220 milliliters), obtain 28-30 ℃ clear solution, and be cooled to 20-25 ℃.Under this temperature, under agitation add entry (32 milliliters).With saturated sodium hydrogen carbonate solution the pH value of solution is adjusted to 6.0-7.0.In 90-120 minute, under 20-25 ℃, in the solution that stirs, add toluenesulfinic acid copper (II) (13.0 gram) in batches, with saturated sodium hydrogen carbonate solution the pH value is remained on 5.5-6.5 simultaneously.After reaction finished, reaction mixture filtered by the hyflo bed, this bed washing with acetone.The filtrate vacuum concentration, in rotatory evaporator, remove and desolvate.In the material of remnants, add ethyl acetate (125 milliliters) and water (125 milliliters), stirred 5-10 minute, add sodium-chlor subsequently.The separation organic layer also washes with water twice.Organic layer is at＜25 ℃ of following vacuum concentration, up to obtaining pasty substance.Add methyl alcohol, obtain slurries 28-30 ℃ of stirring, and be cooled to 2-5 ℃.Slurries were stirred 1 hour under this temperature, filter and with cold methanol wash.This filtrate is at＜25 ℃ of following vacuum concentration, obtains that 2-(p-toluenesulfonyl sulfo-)-α-(1-methyl ethylene)-4-oxo-3-phenylacetylamino-1-azetidine acetate is to the methoxybenzyl ester, and it is used for next step under situation about not being further purified.(HPLC purity is 89-90%).
Step-3
2-(p-toluenesulfonyl sulfo-)-α-(1-chloromethyl vinyl)-4-oxo-3-phenylacetylamino-1-azetidine acetate is to the preparation of methoxybenzyl ester
At 26-28 ℃; with 1; 4-dioxane (150 milliliters) join above 2-(p-toluenesulfonyl sulfo-)-α-(1-methyl ethylene)-4-oxo-3-phenylacetylamino-1-azetidine acetate to the methoxybenzyl ester (shown in step-2; by 25 gram 6-phenylacetylamino penicillanic acids methoxybenzyl ester-1-oxide compound is obtained) in, add sodium bicarbonate (90 gram) subsequently.Add Cl at leisure
2/ CCl
4(12.5%w/v) (60 milliliters).After reaction finishes, reaction mixture is filtered and wash with methylene dichloride (150 milliliters).In filtrate, add cold water (450 milliliters), separate organic layer, wash with water subsequently with hypo solution earlier.The organic layer activated carbon treatment; concentrate and use the method in common aftertreatment; obtain 2-(p-toluenesulfonyl sulfo-)-α-(1-chloromethyl vinyl)-4-oxo-3-phenylacetylamino-1-azetidine acetate to the methoxybenzyl ester, it is not purified just to be used to carry out next step.
Step-4
7-phenylacetylamino-3-chloromethyl-3-cephem-4-carboxylic acid is to the preparation of methoxybenzyl ester
Join the 2-that obtains according to step-3 among the above embodiment-1 (p-toluenesulfonyl sulfo-)-α-(1-chloromethyl vinyl)-4-oxo-3-phenylacetylamino-1-azetidine acetate among the DMF (125 milliliters) to methoxybenzyl ester (methoxybenzyl ester-1-oxide compound being obtained) and be cooled to-40 ℃ by 25 gram 6-phenylacetylamino penicillanic acids.Add the solution of ammonia (11.5 milliliters) in DMF, and keep this temperature to finish up to reaction.With reaction mixture dilute hydrochloric acid acidifying, filter.The solid that obtains is used DMF in the presence of gac: methyl alcohol (2: 9) extraction, and concentrate and handle with cold methanol, obtain 7-phenylacetylamino-3-chloromethyl-3-cephem-4-carboxylic acid to methoxybenzyl ester (13.6 gram).
The comparative example 3:
Step-1
2-(2-[4-morpholinodithio base dithio)-α-(1-methyl ethylene)-4-oxo-3-phenylacetylamino-1-azetidine acetate is to the preparation of methoxybenzyl ester (V)
Under 27 ℃ and nitrogen atmosphere, add 6-phenylacetylamino penicillanic acid in the dry toluene that in the round-bottomed flask that the Dean-Stark water trap is housed, is comprised (500 milliliters) to methoxybenzyl ester-1-oxide compound (25 gram) and 2-mercaptobenzothiazole (8.9 restrain).Reaction mixture refluxed heating 30 minutes also keeps 5 hours (this reaction also can be carried out as solvent with dioxane) under reflux temperature.After reaction finished, solvent removed in vacuo obtained that 2-(2-[4-morpholinodithio base dithio)-α-(1-methyl ethylene)-4-oxo-3-phenylacetylamino-1-azetidine acetate is to the methoxybenzyl ester, and it is used to carry out next step.
Step-2
2-(p-toluenesulfonyl sulfo-)-α-(1-methyl ethylene)-4-oxo-3-phenylacetylamino-1-azetidine acetate is to the preparation of methoxybenzyl ester (VI)
Under agitation, to 2-(2-[4-morpholinodithio base dithio)-α-(1-methyl ethylene)-4-oxo-3-phenylacetylamino-1-azetidine acetate to methoxybenzyl ester (methoxybenzyl ester-1-oxide compound being obtained) by 25 gram 6-phenylacetylamino penicillanic acids in adding acetone (220 milliliters), obtain 28-30 ℃ clear solution, and be cooled to 20-25 ℃.Under this temperature, under agitation add entry (32 milliliters).In 90-120 minute, under 20-25 ℃, in the solution that stirs, add toluenesulfinic acid copper (II) (12.8 gram) in batches.After reaction finished, reaction mixture filtered by the hyflo bed, this bed washing with acetone.The filtrate vacuum concentration, in rotatory evaporator, remove and desolvate.In the material of remnants, add ethyl acetate (125 milliliters) and water (125 milliliters), stirred 5-10 minute, add sodium-chlor subsequently.The separation organic layer also washes with water twice.Organic layer is at＜25 ℃ of following vacuum concentration, up to obtaining pasty substance.Add methyl alcohol, obtain slurries 28-30 ℃ of stirring, and be cooled to 2-5 ℃.Slurries were stirred 1 hour under this temperature, filter and with cold methanol wash.This filtrate is at＜25 ℃ of following vacuum concentration, obtains that 2-(p-toluenesulfonyl sulfo-)-α-(1-methyl ethylene)-4-oxo-3-phenylacetylamino-1-azetidine acetate is to the methoxybenzyl ester, and it is used for next step under situation about not being further purified.(HPLC purity: 75-80%)
Step-3
2-(p-toluenesulfonyl sulfo-)-α-(1-chloromethyl vinyl)-4-oxo-3-phenylacetylamino-1-azetidine acetate is to the preparation of methoxybenzyl ester (VII)
At 26-28 ℃; with 1; 4-dioxane (150 milliliters) join above 2-(p-toluenesulfonyl sulfo-)-α-(1-methyl ethylene)-4-oxo-3-phenylacetylamino-1-azetidine acetate to the methoxybenzyl ester (shown in step-2; by 25 gram 6-phenylacetylamino penicillanic acids methoxybenzyl ester-1-oxide compound is obtained) in, add sodium bicarbonate (90 gram) subsequently.Add Cl at leisure
2/ CCl
4(12.5%w/v) (60 milliliters).After reaction finishes, reaction mixture is filtered and wash with methylene dichloride (150 milliliters).In filtrate, add cold water (450 milliliters), separate organic layer, wash with water subsequently with hypo solution earlier.The organic layer activated carbon treatment; concentrate and use the method in common aftertreatment; obtain 2-(p-toluenesulfonyl sulfo-)-α-(1-chloromethyl vinyl)-4-oxo-3-phenylacetylamino-1-azetidine acetate to the methoxybenzyl ester, it is not purified just to be used to carry out next step.
Step-4
7-phenylacetylamino-3-chloromethyl-3-cephem-4-carboxylic acid is to the preparation of methoxybenzyl ester
Join the 2-that obtains according to step-3 among the above embodiment-1 (p-toluenesulfonyl sulfo-)-α-(1-chloromethyl vinyl)-4-oxo-3-phenylacetylamino-1-azetidine acetate among the DMF (125 milliliters) to methoxybenzyl ester (methoxybenzyl ester-1-oxide compound being obtained) and be cooled to-40 ℃ by 25 gram 6-phenylacetylamino penicillanic acids.Add the solution of ammonia (11.5 milliliters) in DMF, and keep this temperature to finish up to reaction.With reaction mixture dilute hydrochloric acid acidifying, filter.The solid that obtains is used DMF in the presence of gac: methyl alcohol (2: 9) extraction, and concentrate and handle with cold methanol, obtain 7-phenylacetylamino-3-chloromethyl-3-cephem-4-carboxylic acid to methoxybenzyl ester (11.4 gram).
Beneficial effect:
The comparison of embodiment
| Embodiment 1 | Embodiment 2 | The comparative example 3 | |
| The HPLC purity of step 2 | ??89-90％ | ??89-90％ | ??75-80％ |
| Yield (methoxybenzyl ester-1-oxide compound being begun to calculate) by 25 gram 6-phenylacetylamino penicillanic acids | 15.1 gram | 13.6 gram | 11.4 gram |
| The solvent that uses in the step 3 | ??NMP | ??DMF | ??DMF |
Can draw from this table,
* in step process (ii), adjust the purity that the pH value has increased 2-(p-toluenesulfonyl sulfo-)-α-(1-methyl ethylene)-4-oxo-3-phenylacetylamino-1-azetidine acetic ester.
When * cyclisation step is used NMP, compare with DMF, yield is higher.
Claims (11)
1. the method for the chloromethyl cephalosporin ene derivative of an improved preparation formula (I),
R wherein
1The expression carboxy protective group, that is, the methyl of replacement, it is deprotection easily, such as the tertiary butyl, diphenyl-methyl, 4-methoxybenzyl, 2-methoxybenzyl, 2-benzyl chloride base or benzyl; R
2Expression hydrogen, (C
1-C
4) alkyl, replacement or unsubstituted phenyl or replacement or unsubstituted phenoxy, said method comprising the steps of:
(i) use aryl-sulfinic acid or (C
1-C
6) metal-salt, alkali and the solvent of alkyl sulfinic acid, in 25 ℃-40 ℃ temperature range with the compound of formula V
Be converted into the compound of formula (VI),
R wherein
8Expression replaces or unsubstituted (C
1-C
6) alkyl or aryl, wherein improve the metal-salt that adds the aryl-sulfinic acid in the pH value scope that is included in 4.0-8.0,
(ii) in the presence of alkali and solvent, in 15 ℃-40 ℃ temperature range, use the compound of chlorizating agent chlorination formula (VI), obtain the compound of formula (VII),
R wherein
8Expression replaces or unsubstituted (C
1-C
6) alkyl or aryl, every other symbol definition as above and
(vi) in solvent, in-60 ℃ to+50 ℃ temperature range, use the compound cyclisation of alkali, obtain the chloromethyl cephalosporin ene derivative of formula (I) formula (VII).
2. according to the process of claim 1 wherein that the aryl-sulfinic acid metal-salt that uses in the step (i) is selected to toluenesulfinic acid copper (II), benzene sulfinic acid copper (II), benzene sulfinic acid sodium salt, to toluenesulfinic acid silver (II) or benzene sulfinic acid silver (II).
According to the process of claim 1 wherein the solvent that uses in the step (i) be selected from acetone, THF, dioxane, acetonitrile, such as the alcohol of methyl alcohol, ethanol or Virahol, be with or without water and all can.
4. according to the process of claim 1 wherein middle aryl-sulfinic acid or the (C of adding of step (i)
1-C
6) metal-salt of alkyl sulfinic acid preferably carries out under the pH of 5-7 value.
5. according to the process of claim 1 wherein that the middle alkali that uses of step (i) is selected from ammonia, lime carbonate, sodium bicarbonate, yellow soda ash, salt of wormwood, saleratus, diisopropylethylamine or triethylamine.
5. according to the process of claim 1 wherein that the chlorizating agent that uses during step (ii) is selected from the presence of the solvent or the chlorine in the presence of solvent-free, HOCl, Cl
2O, CH
3OCl.
6. according to the method for claim 5, wherein chlorizating agent is dissolved in dioxane, tetracol phenixin, ethyl acetate, acetonitrile, diglyme, dimethyl formamide, N,N-DIMETHYLACETAMIDE, tetrahydrofuran (THF), methylene dichloride, butylacetate, phenyl ether, toluene or its mixture.
7. according to the process of claim 1 wherein that the (ii) middle solvent that uses of step is selected from dioxane, tetracol phenixin, ethyl acetate, acetonitrile, diglyme, N,N-DIMETHYLACETAMIDE, tetrahydrofuran (THF), methylene dichloride, butylacetate, phenyl ether, toluene or its mixture.
8. according to the process of claim 1 wherein that step cyclisation use alkali (iii) carries out, described alkali is selected from ammonia, ammonium salt such as volatile salt, ammonium acetate, organic amine such as N, N-Diisopropylamine, N, N dimethylamine, methylamine or triethylamine.
9. according to the process of claim 1 wherein that the (iii) middle solvent that uses of step is selected from 1-methylpyrrolidin-2-ketone (NMP), DMF, acetonitrile, N,N-DIMETHYLACETAMIDE, ethyl acetate, dioxane, THF, methylene dichloride.
10. according to formula (I) compound of claim 1, be used for the compound of preparation formula (II):
R wherein
4Be carboxylic acid ion or COOR
d, R wherein
dExpression hydrogen, ester or the salifiable counter ion of shape; R
6Expression H, CH
3, CR
aR
bCOOR
c, R wherein
aAnd R
bRepresent hydrogen or methyl independently, R
cExpression hydrogen or (C
1-C
6) alkyl; R
5Expression CH
3, CH
2OCH
3, CH
2OCOCH
3, CH=CH
2, or
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| IN808/MAS/2002 | 2002-11-01 |
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|---|---|
| JP (1) | JP2006507289A (en) |
| KR (1) | KR20050087791A (en) |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009129662A1 (en) * | 2008-04-21 | 2009-10-29 | 湖南有色凯铂生物药业有限公司 | Process for preparation of 7-phenylacetamido-3-chloromethyl-3-cephem-4- carboxylic acid p-methoxybenzyl ester |
| CN102344459A (en) * | 2011-07-27 | 2012-02-08 | 山西新天源医药化工有限公司 | Preparation method of cephalosporin intermediate GCLE |
| CN102643294A (en) * | 2012-04-18 | 2012-08-22 | 山东普洛得邦医药有限公司 | Preparation method of cephalosporin nucleus intermediate |
Families Citing this family (1)
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| CN100398547C (en) * | 2003-09-09 | 2008-07-02 | 日本化学工业株式会社 | Process for producing 3-chloromethyl-3-cephem derivative |
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|---|---|---|---|---|
| IE35152B1 (en) * | 1969-08-26 | 1975-11-26 | Glaxo Lab Ltd | Improvements in or relating to cephalosporin compounds |
| NL7411505A (en) * | 1973-09-06 | 1975-03-10 | Rhone Poulenc Sa | PROCEDURE FOR THE PREPARATION AND USE OF NEW 7-TRICHLORACETAMIDO-3-DESACETOXY-CEFA-LOSPORANIC ACID PREPARATIONS. |
| AU498131B2 (en) * | 1974-02-26 | 1979-02-15 | Ciba-Geigy Ag | Production of cephems by cyclization |
| JPS6043340B2 (en) * | 1981-04-10 | 1985-09-27 | 大塚化学薬品株式会社 | Chlorinated azetidinone derivatives and their production method |
| JPS5874689A (en) * | 1981-10-29 | 1983-05-06 | Otsuka Chem Co Ltd | Preparation of 3-chloromethyl-3-cephem derivative |
| GB2099817B (en) * | 1981-04-10 | 1985-05-15 | Otsuka Kagaku Yakuhin | Azetidinone derivatives and process for the preparation of the same |
| JPS59164771A (en) * | 1983-03-10 | 1984-09-17 | Otsuka Chem Co Ltd | Preparation of chlorinated azetidinone derivative |
| JPS60115562A (en) * | 1983-11-28 | 1985-06-22 | Otsuka Chem Co Ltd | Production of azetidinone derivative |
| JPS60237061A (en) * | 1984-05-08 | 1985-11-25 | Otsuka Chem Co Ltd | Preparation of azetidinone derivative |
| DE3933934A1 (en) * | 1989-10-03 | 1991-04-11 | Bayer Ag | METHOD FOR PRODUCING 7-AMINO-3 - ((Z) -1-PROPEN-1-YL) -3-CEPHEM-4-CARBONIC ACID |
| JP3224279B2 (en) * | 1992-07-27 | 2001-10-29 | 大塚化学株式会社 | Method for producing cefm compound |
| JP4157177B2 (en) * | 1997-06-04 | 2008-09-24 | 大塚化学ホールディングス株式会社 | Method for producing 3-alkenylcephem compound |
-
2003
- 2003-10-23 JP JP2004547902A patent/JP2006507289A/en active Pending
- 2003-10-23 CN CNB2003801023937A patent/CN1315841C/en not_active Expired - Fee Related
- 2003-10-23 WO PCT/IB2003/004721 patent/WO2004039813A1/en active Application Filing
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009129662A1 (en) * | 2008-04-21 | 2009-10-29 | 湖南有色凯铂生物药业有限公司 | Process for preparation of 7-phenylacetamido-3-chloromethyl-3-cephem-4- carboxylic acid p-methoxybenzyl ester |
| CN102344459A (en) * | 2011-07-27 | 2012-02-08 | 山西新天源医药化工有限公司 | Preparation method of cephalosporin intermediate GCLE |
| CN102344459B (en) * | 2011-07-27 | 2014-08-06 | 山西新天源医药化工有限公司 | Preparation method of cephalosporin intermediate GCLE |
| CN102643294A (en) * | 2012-04-18 | 2012-08-22 | 山东普洛得邦医药有限公司 | Preparation method of cephalosporin nucleus intermediate |
| CN102643294B (en) * | 2012-04-18 | 2014-11-26 | 山东普洛得邦医药有限公司 | Preparation method of cephalosporin nucleus intermediate |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1315841C (en) | 2007-05-16 |
| WO2004039813A1 (en) | 2004-05-13 |
| KR20050087791A (en) | 2005-08-31 |
| JP2006507289A (en) | 2006-03-02 |
| AU2003269416A1 (en) | 2004-05-25 |
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