CN101792455B - Preparation method of high-purity 7-alpha-amino-7-methoxy-3-methyltetrazole thiomethyl cephalosporin benzyl ester - Google Patents
Preparation method of high-purity 7-alpha-amino-7-methoxy-3-methyltetrazole thiomethyl cephalosporin benzyl ester Download PDFInfo
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- CN101792455B CN101792455B CN2010101253625A CN201010125362A CN101792455B CN 101792455 B CN101792455 B CN 101792455B CN 2010101253625 A CN2010101253625 A CN 2010101253625A CN 201010125362 A CN201010125362 A CN 201010125362A CN 101792455 B CN101792455 B CN 101792455B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 229930186147 Cephalosporin Natural products 0.000 title abstract description 5
- 229940124587 cephalosporin Drugs 0.000 title abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 42
- 239000012535 impurity Substances 0.000 claims abstract description 26
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000012046 mixed solvent Substances 0.000 claims abstract description 12
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims abstract description 12
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims abstract description 11
- 238000000034 method Methods 0.000 claims abstract description 9
- 238000003756 stirring Methods 0.000 claims abstract description 9
- 238000002425 crystallisation Methods 0.000 claims abstract description 6
- 230000008025 crystallization Effects 0.000 claims abstract description 6
- 238000001035 drying Methods 0.000 claims abstract description 6
- 238000001914 filtration Methods 0.000 claims abstract description 6
- 239000002798 polar solvent Substances 0.000 claims abstract description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- 238000006198 methoxylation reaction Methods 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 208000012826 adjustment disease Diseases 0.000 claims description 3
- 239000012141 concentrate Substances 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims 2
- 229940126062 Compound A Drugs 0.000 claims 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- QGXKMJVEULWQSB-VWNXMTODSA-N benzhydryl (6r,7s)-7-amino-7-methoxy-3-[(1-methyltetrazol-5-yl)sulfanylmethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound S([C@@H]1[C@@](C(N1C=1C(=O)OC(C=2C=CC=CC=2)C=2C=CC=CC=2)=O)(N)OC)CC=1CSC1=NN=NN1C QGXKMJVEULWQSB-VWNXMTODSA-N 0.000 abstract description 23
- 230000000694 effects Effects 0.000 abstract description 6
- 238000000605 extraction Methods 0.000 abstract 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 18
- 239000000047 product Substances 0.000 description 17
- 239000000243 solution Substances 0.000 description 15
- 239000002253 acid Substances 0.000 description 10
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
- 235000017557 sodium bicarbonate Nutrition 0.000 description 9
- 229910052717 sulfur Inorganic materials 0.000 description 8
- 239000011593 sulfur Substances 0.000 description 8
- 239000007787 solid Substances 0.000 description 6
- -1 methoxyl group Chemical group 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 3
- SNBUBQHDYVFSQF-HIFRSBDPSA-N cefmetazole Chemical compound S([C@@H]1[C@@](C(N1C=1C(O)=O)=O)(NC(=O)CSCC#N)OC)CC=1CSC1=NN=NN1C SNBUBQHDYVFSQF-HIFRSBDPSA-N 0.000 description 3
- JSDXOWVAHXDYCU-VXSYNFHWSA-N cefminox Chemical class S([C@@H]1[C@@](C(N1C=1C(O)=O)=O)(NC(=O)CSC[C@@H](N)C(O)=O)OC)CC=1CSC1=NN=NN1C JSDXOWVAHXDYCU-VXSYNFHWSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000007086 side reaction Methods 0.000 description 3
- HSHGZXNAXBPPDL-HZGVNTEJSA-N 7beta-aminocephalosporanic acid Chemical compound S1CC(COC(=O)C)=C(C([O-])=O)N2C(=O)[C@@H]([NH3+])[C@@H]12 HSHGZXNAXBPPDL-HZGVNTEJSA-N 0.000 description 2
- 229960002676 cefmetazole sodium Drugs 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- XOHZHMUQBFJTNH-UHFFFAOYSA-N 1-methyl-2h-tetrazole-5-thione Chemical compound CN1N=NN=C1S XOHZHMUQBFJTNH-UHFFFAOYSA-N 0.000 description 1
- 0 C*C1=C(*c([n]2C)nn*2IO)CS[C@]([C@@](C=O)(N)OC)N1C Chemical compound C*C1=C(*c([n]2C)nn*2IO)CS[C@]([C@@](C=O)(N)OC)N1C 0.000 description 1
- GQXBWKIZOVCJBJ-UHFFFAOYSA-N CCl.[S] Chemical compound CCl.[S] GQXBWKIZOVCJBJ-UHFFFAOYSA-N 0.000 description 1
- ITLHXEGAYQFOHJ-UHFFFAOYSA-N [diazo(phenyl)methyl]benzene Chemical compound C=1C=CC=CC=1C(=[N+]=[N-])C1=CC=CC=C1 ITLHXEGAYQFOHJ-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- SMSRCGPDNDCXFR-CYWZMYCQSA-N cefbuperazone Chemical compound O=C1C(=O)N(CC)CCN1C(=O)N[C@H]([C@H](C)O)C(=O)N[C@]1(OC)C(=O)N2C(C(O)=O)=C(CSC=3N(N=NN=3)C)CS[C@@H]21 SMSRCGPDNDCXFR-CYWZMYCQSA-N 0.000 description 1
- 229960001817 cefbuperazone Drugs 0.000 description 1
- 229960003585 cefmetazole Drugs 0.000 description 1
- 229960002025 cefminox Drugs 0.000 description 1
- SRZNHPXWXCNNDU-RHBCBLIFSA-N cefotetan Chemical compound N([C@]1(OC)C(N2C(=C(CSC=3N(N=NN=3)C)CS[C@@H]21)C(O)=O)=O)C(=O)C1SC(=C(C(N)=O)C(O)=O)S1 SRZNHPXWXCNNDU-RHBCBLIFSA-N 0.000 description 1
- 229960005495 cefotetan Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000006462 rearrangement reaction Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 235000019157 thiamine Nutrition 0.000 description 1
- 150000003544 thiamines Chemical class 0.000 description 1
Landscapes
- Cephalosporin Compounds (AREA)
Abstract
The invention discloses a preparation method of high-purity 7-MAC, which comprises the following steps: adding aluminum trichloride into methanol and a polar solvent for constituting mixed solvent, increasing the temperature, then carrying out reaction under stirring state for preparing methoxylated reagent solution, adding 7-thiamine-3-methyltetrazole thiomethyl cephalosporin benzyl ester into dichloromethane, stirring, then adding triphenylphosphine, carrying out reaction for 10-30 minutes under stirring, adding the methoxylated reagent solution, continuing the reaction at the temperature of -2-5 DEG C under stirring, and carrying out concentration, crystallization, filtration and drying when the residue of the 7-thiamine-3-methyltetrazole thiomethyl cephalosporin benzyl ester is below 1.0%. The increase of the use of the polar solvent and the control of pH value during the preparation process of the methoxylated reagent can be conductive to generating a main product and minimize the incidence of side effects; simultaneously, the adjustment of the pH at the end can lead the effects of the extraction and impurity removal process to be better and lead the proportion of the impurity of 7-alpha-amino-7-methylthio-3-methyltetrazole thiomethyl cephalosporin benzyl ester to be below 0.05%, thereby greatly improving the purity of the follow-up product.
Description
Technical field
The present invention relates to the important medicine intermediate of medicine building-up processes such as microbiotic cefmetazole sodium, Cefminox sodium salt, cefotetan, cefbuperazone, i.e. the preparation method of 7-alpha-amino-7-methoxy base-3-methly tetrazole sulfur methyl cafe-benzyl alkanoic acid (being called for short 7-MAC).
Background technology
At present; Domestic and international application mainly is to be parent with 7-amino-cephalosporanic acid (7-ACA) in large-scale production, the method for preparing 7-alpha-amino-7-methoxy base-3-methly tetrazole sulfur methyl cafe-benzyl alkanoic acid; On the 3-position, carry out condensation reaction with 1-methyl-5 mercapto tetrazole; Again with sulphur methyl chloride reaction, and generate carbobenzoxy through the diphenyl diazomethane reaction carboxy protective got up, on the last 7-position through under the effect of methoxylation reagent; The method that adds methoxyl group is carried out 7-alpha-amino-7-methoxy base-3-methly tetrazole sulfur methyl cafe-benzyl alkanoic acid, the i.e. production of 7-MAC.
The technical matters of existing preparation 7-MAC has all been ignored the existence of an important impurity; It is the amino 7-methylthio group of 7-α-3-methly tetrazole sulfur methyl cafe-benzyl alkanoic acid (abbreviation impurity A); And this impurity A proportion is bigger, is about 0.2%～0.5% (HPLC), because this impurity has extremely similar chemical property with 7-MAC; But it does not have bacteriostatic activity; When application 7-MAC prepares cynnematin, can participate in 7-MAC in the reaction of synthetic cynnematin subsequent step, influence the quality index of subsequent product, cause final microbiotic drug quality not up to standard then.
Summary of the invention
Characteristics of the present invention mainly are the amino 7-methylthio group of the most important by-product impurities 7-α-3-methly tetrazole sulfur methyl cafe-benzyl alkanoic acids that exists in the 7-MAC process with preparation; Be that impurity A is reduced to below 0.05% (HPLC); Carry out more smoothly at the subsequent reactions of preparation process to satisfy some antibacterial cephalosporin element; Impurity A is dropped to minimum to the influence of cephalo microbiotic such as finished product quality such as cefmetazole sodium, Cefminox sodium salt, improve product purity.
Impurity A, promptly the molecular formula of the amino 7-methylthio group of 7-α-3-methly tetrazole sulfur methyl cafe-benzyl alkanoic acid is:
The mechanism that 7-MAC prepares the side reaction generation that generates impurity A in the process possibly be that 7-thiamines-3-methyl tetrazole thiomethyl Cephalosporanic acid benzyl ester is under the effect of catalyzer; The thiamines generation rearrangement reaction of C7-position; C7-position H and C7-α position N atom are connected to form amino; And methylthio group is directly gone up the C7-position, has hindered the formation of C7-position methoxyl group, thereby main reaction is affected.Because the structure and properties and the principal product 7-MAC of impurity A are extremely close, last handling process can't be removed, and more can participate in the various reactions of synthetic cynnematin with 7-MAC simultaneously, causes the cynnematin product gas purity on the low side.
The present invention realizes through following technical scheme: with 7-thiamines-3-methyl tetrazole thiomethyl Cephalosporanic acid benzyl ester is starting raw material, under the effect of methoxylation reagent, on the 7-position, adds methoxyl group, makes the side reaction that generates impurity A drop to minimum simultaneously.
Its chemical equation is:
7-thiamines-3-methyltetrazole sulfidomethyl cephalo acid benzyl ester 7-methoxy, 7-amino-3-methyltetrazole sulfidomethyl cephalo acid benzyl ester
The preparation method of this high-purity 7-alpha-amino-7-methoxy base-3-methly tetrazole sulfur methyl cafe-benzyl alkanoic acid, its characteristic may further comprise the steps:
1, the preparation of methoxylation reagent
A. the aluminum chloride of 10～20 weight parts is joined in the mixed solvent that the polar solvent of methyl alcohol and 10～25 weight parts of 150～220 weight parts forms, be warmed up to 25～40 ℃ after, under whipped state, react;
B. above-mentioned reaction is after 10～40 minutes, and the pH of adjustment reaction solution is 2.0～4.0, continues under whipped state then to react that to make the methoxylation reagent solution after 20～45 minutes subsequent use;
2, the preparation of 7-MAC
A. the 7-thiamines-3-methyl tetrazole thiomethyl Cephalosporanic acid benzyl ester with 30～48 weight parts joins in the methylene dichloride of 500～850 weight parts, adds the triphenylphosphine of 25～32 weight parts after stirring again, reaction under 3～7 ℃, whipped state then;
B. above-mentioned reaction is after 10～30 minutes, adds the methoxylation reagent solution that has prepared, continues down to react at-2～5 ℃, whipped state then;
C. when 7-thiamines in the above-mentioned reaction-3-methyl tetrazole thiomethyl Cephalosporanic acid benzyl ester residual＜1.0% the time, finish reaction, pH is after 7.0～9.0 in adjustment, through abstraction impurity removal, concentrate, crystallization, filtration, drying obtain the 7-MAC finished product.
The technical progress that the present invention obtains:
Technology of the present invention is in the preparation process of methoxylation reagent; Increase and use acetonitrile, water isopolarity solvent and pass through the control reacting liquid pH value at 2.0～4.0 o'clock; Help the generation of principal product 7-MAC, it is more complete that main reaction is carried out, and the incidence of the side reaction that reaction process is existed drops to minimum; PH value to 7.0～9.0 when adjustment reaction simultaneously finishes make the better effects if of abstraction impurity removal process; Impurity A proportion＜0.05% (HPLC) in the may command product thus; And then make and utilize 7-MAC can be largely increased: impurity A proportion 0.2%～0.5% (HPLC) in the 7-MAC product of existing prepared for the subsequent product purity of raw material production; It is constant basically to cause in the subsequent product this impurity to participate in the corresponding impurity proportion of reaction gained; Cause the total impurities proportion of finished products such as cefmetazole, cefminox higher; Purity is on the low side, and the corresponding impurity that prepared 7-MAC impurity A of the present invention is left in the subsequent product is merely below 0.05%, has guaranteed the high purity of finished product.
Embodiment
Embodiment 1:
1, the preparation of methoxylation reagent
A. the aluminum chloride with 15kg joins in the mixed solvent of being made up of methyl alcohol and the 12kg ethanol (or 12kg acetonitrile) of 150kg, be warmed up to 35 ℃ after, under whipped state, react;
B. above-mentioned reaction added 12～20kg sodium bicarbonate solid after 20 minutes in reaction solution, the pH that makes reaction solution is 2.0～4.0, and under whipped state, continuing reaction then, to make the methoxylation reagent solution after 25 minutes subsequent use;
2.7-MAC preparation
A. the 7-thiamines-3-methyl tetrazole thiomethyl Cephalosporanic acid benzyl ester with 40kg joins in the methylene dichloride of 550kg, adds the triphenylphosphine of 30kg after stirring again, reaction under 3～7 ℃, whipped state then;
B. above-mentioned reaction is after 10～30 minutes, adds the methoxylation reagent solution that has prepared, continues down to react at-2～5 ℃, whipped state then;
C. when 7-thiamines in the above-mentioned reaction-3-methyl tetrazole thiomethyl Cephalosporanic acid benzyl ester residual＜1.0% the time; Finish reaction; The sodium bicarbonate solid or the sodium bicarbonate aqueous solution that add 5kg then;, stirred then 20 minutes 7.0～9.0 with adjustment pH after abstraction impurity removal, concentrating under reduced pressure, crystallization, filtration, drying make the 7-MAC finished product.
Embodiment 2:
1, the preparation of methoxylation reagent
A. the aluminum chloride with 10kg joins in the mixed solvent of being made up of methyl alcohol and the 10kg purified water (or 10kg terepthaloyl moietie) of 200kg, be warmed up to 35 ℃ after, under whipped state, react;
B. above-mentioned reaction added 12～20kg sodium bicarbonate solid after 20 minutes in reaction solution, the pH that makes reaction solution is 2.0～4.0, and under whipped state, continuing reaction then, to make the methoxylation reagent solution after 25 minutes subsequent use;
2, the preparation of 7-MAC
A. the 7-thiamines-3-methyl tetrazole thiomethyl Cephalosporanic acid benzyl ester with 30kg joins in the methylene dichloride of 500kg, adds the triphenylphosphine of 25kg after stirring again, reaction under 3～7 ℃, whipped state then;
B. above-mentioned reaction is after 10～30 minutes, adds the methoxylation reagent solution that has prepared, continues down to react at-2～5 ℃, whipped state then;
C. when 7-thiamines in the above-mentioned reaction-3-methyl tetrazole thiomethyl Cephalosporanic acid benzyl ester residual＜1.0% the time; Finish reaction; The sodium bicarbonate solid or the sodium bicarbonate aqueous solution that add 5～10kg then;, stirred then 20 minutes 7.0～9.0 with adjustment pH after abstraction impurity removal, concentrating under reduced pressure, crystallization, filtration, drying make the 7-MAC finished product.
Embodiment 3:
1, the preparation of methoxylation reagent
A. the aluminum chloride with 20kg joins in the mixed solvent of being made up of methyl alcohol and the 25kg ethanol (or 25kg acetonitrile or 25kg purified water or 25kg terepthaloyl moietie) of 220kg, be warmed up to 35 ℃ after, under whipped state, react;
B. above-mentioned reaction added 12～20kg sodium bicarbonate solid after 20 minutes in reaction solution, the pH that makes reaction solution is 2.0～4.0, and under whipped state, continuing reaction then, to make the methoxylation reagent solution after 25 minutes subsequent use;
2, the preparation of 7-MAC
A. the 7-thiamines-3-methyl tetrazole thiomethyl Cephalosporanic acid benzyl ester with 48kg joins in the methylene dichloride of 850kg, adds the triphenylphosphine of 32kg after stirring again, reaction under 3～7 ℃, whipped state then;
B. above-mentioned reaction is after 10～30 minutes, adds the methoxylation reagent solution that has prepared, continues down to react at-2～5 ℃, whipped state then;
C. when 7-thiamines in the above-mentioned reaction-3-methyl tetrazole thiomethyl Cephalosporanic acid benzyl ester residual＜1.0% the time; Finish reaction; The sodium bicarbonate solid or the sodium bicarbonate aqueous solution that add 5～10kg then;, stirred then 20 minutes 7.0～9.0 with adjustment pH after abstraction impurity removal, concentrating under reduced pressure, crystallization, filtration, drying make the 7-MAC finished product.
Embodiment 4: present embodiment and embodiment 1 difference are the mixed solvent replacement 12kg ethanol with 10kg ethanol, 10kg acetonitrile.
Embodiment 5: present embodiment and embodiment 1 difference are the mixed solvent replacement 12kg ethanol with 8kg acetonitrile, 10kg water.
Embodiment 6: present embodiment and embodiment 1 difference are the mixed solvent replacement 12kg ethanol with 10kg water, 11kg terepthaloyl moietie.
Embodiment 7: present embodiment and embodiment 1 difference are the mixed solvent replacement 12kg ethanol with 10kg ethanol, 14kg terepthaloyl moietie.
Embodiment 8: present embodiment and embodiment 1 difference are the mixed solvent replacement 12kg ethanol with 8kg ethanol, 10kg water.
Embodiment 9: present embodiment and embodiment 1 difference are the mixed solvent replacement 12kg ethanol with 10kg acetonitrile, 14kg terepthaloyl moietie.
Claims (1)
1. method for preparing formula 1 compound, its characteristic may further comprise the steps:
(1). the preparation of methoxylation reagent
A. the aluminum chloride of 10～20 weight parts is joined in the mixed solvent that the polar solvent of methyl alcohol and 10～25 weight parts of 150～220 weight parts forms; After being warmed up to 25～40 ℃; Under whipped state, react, said polar solvent is a kind of or wherein any two kinds mixture in ethanol, acetonitrile, water, the terepthaloyl moietie;
B. above-mentioned reaction is after 10～40 minutes, and the pH of adjustment reaction solution continues reaction then and makes the methoxylation reagent solution after 20～45 minutes 2.0～4.0 under whipped state;
(2). the preparation of formula 1 compound
A. the 7-thiamines-3-methyl tetrazole thiomethyl Cephalosporanic acid benzyl ester with 30～48 weight parts joins in the methylene dichloride of 500～850 weight parts, adds the triphenylphosphine of 25～32 weight parts after stirring again, reaction under 3～7 ℃, whipped state then;
B. above-mentioned reaction is after 10～30 minutes, adds the methoxylation reagent solution that has prepared, continues down to react at-2～5 ℃, whipped state then;
C. when 7-thiamines in the above-mentioned reaction-3-methyl tetrazole thiomethyl Cephalosporanic acid benzyl ester residual＜1.0% the time, finish reaction, pH is after 7.0～9.0 in adjustment, through abstraction impurity removal, concentrate, crystallization, filtration, drying make formula 1 compound,
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007105253A2 (en) * | 2006-03-15 | 2007-09-20 | Carthesia S.A.S. Di Emanuela Migliavacca & C. | PREPARATION OF (1-OXA- OR l-THIA-)3- CEPHEM DERIVATIVES |
| CN101117337A (en) * | 2006-08-03 | 2008-02-06 | 四平市精细化学品有限公司 | Method for preparing 7-alpha methoxy-7-amino-3-methyl amitrole sulfur methyl cepham alkanoates dimethyl |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007105253A2 (en) * | 2006-03-15 | 2007-09-20 | Carthesia S.A.S. Di Emanuela Migliavacca & C. | PREPARATION OF (1-OXA- OR l-THIA-)3- CEPHEM DERIVATIVES |
| CN101117337A (en) * | 2006-08-03 | 2008-02-06 | 四平市精细化学品有限公司 | Method for preparing 7-alpha methoxy-7-amino-3-methyl amitrole sulfur methyl cepham alkanoates dimethyl |
Non-Patent Citations (1)
| Title |
|---|
| 刘沫毅等.甲氧头孢中间体7-MAC的合成工艺改进.《化学试剂》.2009,第31卷(第2期),第146-148页. * |
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