CN101987837B - Preparation method of 1,2,4-thiadiazole oximido acetic acid compound - Google Patents
Preparation method of 1,2,4-thiadiazole oximido acetic acid compound Download PDFInfo
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Abstract
The invention provides a preparation method of a 1,2,4-thiadiazole oximido acetic acid compound, relating to the technical field of preparation technology of 7-site side chain 1,2,4-thiadiazole oximido acetic acid compound of fourth-generation cephalosporin and fifth-generation cephalosporin. The product is obtained by alkali hydrolysis reaction of the derivative of the 1,2,4-thiadiazole oximido acetic acid compound, and the temperature of the hydrolysis reaction system is controlled to be below 150 DEG C. The method of the invention has peculiar principle, and solves the problems of various technical steps, complex operation and the like in the prior art; in addition, product purification technology and operation technology are simple, the operation steps for manufacturing the thiadiazole oximido acetic acid compound are greatly shortened and reaction yield and product purity are higher. A byproduct which can be detected in a reaction mixture can be lower than 5%, reaction yield can be improved to 75-85%, and purity can be more than 97%. The method of the invention is especially suitable for producing the thiadiazole oximido acetic acid compound products with high purity.
Description
Technical field
The present invention relates to the 4th generation cynnematin and the 5th generation cynnematin 7-position side chain 1,2, the fabricating technology field of 4-thiadiazoles glyoxylic acid oxime series compound.
Background technology
In the medicine used of the whole world, anti-infective medication accounts for 13% of total share, and Cephalosporins is as a class of anti-infectives, and its consumption is sure to occupy first of anti-infective medication always.Cephalosporin analog antibiotic is of a great variety, and usage quantity is large, has occupied the closely market share of half of microbiotic.Along with continuing to optimize of the continuous renewal of cephalosporin compound structure, drug effect, the mankind entered for the 4th generation, or even the epoch of the 5th generation cynnematin use, solving first three for cephalosporin analog antibiotic at resisting gram-positive bacteria, golden staphylococci and Pseudomonas aeruginosa etc. the control on a difficult problem.
At present in the world the existing the several the 4th and the cynnematin in the 5th generation appear on the market, cefpirome as shown in Figure 1, cefclidin, Cefluprenam, Cefozopran, Ceftobiprole and Ceftaroline etc., and obtained the consistent approval in market.The many pharmacy corporations of China are paid special attention to the market requirement of this class cynnematin, along with expiring gradually of these product patents, domesticly also corresponding kind are accepted, and have carried out corresponding clinical trial, and bulk drug has also been registered by some enterprises.In the chemical structure of these cynnematin, the substituted radical that common characteristic are 7-positions is all thiadiazoles glyoxylic acid oxime series compounds in the 4th and the 5th generation.And the synthesis technique of thiadiazoles glyoxylic acid oxime series compound is long, total recovery is low, and three wastes discharge capacity is large, how to solve Problems Existing in synthesis technique, produces high-quality and 7-position side chain intermediate reasonable price, is the key of the final medicine cost of impact.Due to the 4th generation and the 5th generation cynnematin good anti-microbial activity and higher curative effect, not only improved patient's quality of medical care, also will change the structure of China's cynnematin kind.
Formula 1
Thiadiazoles glyoxylic acid oxime series compound (structure of product II in formula 2) be the 4th and the 5th generation cephalosporin analog antibiotic important intermediate, U.S. Pat 733642 has been enumerated preparation and the production technique of this compounds.These processing steps are many, complicated operation, and also yield is low, and especially the hydrolysis technique of thiadiazoles glyoxylic acid oxime series derivates (structure of reactant I in formula 2), still have some technical problems not to be resolved.
Formula 2
The Journal of Antibiotics (1984,37 (5), 558-571) reported that (5-amino-1 by 2-ethoxy imido grpup-2-with 1N NaOH, 2,4-thiadiazoles-3) technique that-methyl acetate hydrolysis is corresponding thiadiazoles oxime acetic acid, yield is only 53.2% (formula 3).Like this, make whole synthetic total recovery very low.
Formula 3
Bull Chem Soc Jpn (1993,66,2335-2338) reported that 2-fluorine methoxy imino-2-(5-amino-1,2,4-thiadiazoles-3)-acetonitrile is converted into the tediously long and complicated hydrolysis process (formula 4) of corresponding thiadiazoles oxime acetic acid.This itrile group compound of direct hydrolysis, can not get corresponding thiadiazoles oxime acetic acid, so will pass through, transforms itrile group to the imines ester, then to carboxylicesters, then protection is amino, just can obtain target product (formula 4).
Formula 4
Document US733642 and JP4-46990 also point out, the process recovery ratio that is hydrolyzed to corresponding thiadiazoles oxime acetic acid (formula 5) from 2-ethoxy imido grpup-2-(5-amino-1,2,4-thiadiazoles-3)-acetonitrile is too low, is unsuitable for industrialization.
Formula 5
At Advanced Organi c Chemi stry, Part B (work such as F.A.Carey, the third edition, 1991) on the 10th chapter, also point out, oxime compounds is easily reset, cracking and isomerization and decompose, especially oxime itrile group compound, so occur that the variety of problems of hydrolysis process also has theoretical foundation.
Summary of the invention
The purpose of this invention is to provide a kind of 1,2,4-thiadiazoles glyoxylic acid oxime series compound (or is called 1,2,4-thiadiazoles glyoxylic acid oxime, it itself is series compound, as follows) the preparation method, solved the problems such as the processing step always existed in the prior art is many, complicated operation, its method and principle uniqueness, purifying products technique and operating procedure are easy, have greatly shortened the operation steps of manufacturing thiadiazoles glyoxylic acid oxime series compound; And reaction yield and product purity are higher; Be particularly suitable for suitability for industrialized production.
The present invention is achieved in that a kind of 1,2, the preparation method of 4-thiadiazoles glyoxylic acid oxime series compound, it is characterized in that by 1,2, the derivative of 4-thiadiazoles glyoxylic acid oxime series compound obtains through basic hydrolysis, and the temperature of hydrolysis reaction system is controlled at below 150 ℃, and its reaction formula is:
Described 1,2, the derivative of 4-thiadiazoles glyoxylic acid oxime series compound can be, its R
2for the substituting group on oximido: methyl, ethyl, Bian Ji, diphenyl-methyl, trityl, fluoro methyl or tert-butyl isobutyrate base; Its R
1for various alkyl or hydrogen; Its R
3for carboxylicesters, acyl ammonia or nitrile compounds; Substituent R on Thiadiazole on amino is various acyl groups;
R
1＝H，alkyl
The temperature of described hydrolysis reaction system control be 100 ℃～30 ℃ better, the best is 80 ℃～40 ℃.The visual differential responses thing of actual temp degree and difference.
Described alkali is lithium hydroxide LiOH or Lithium Oxide 98min Li
2o, or mixed base LiOH adds NaOH; When described basic hydrolysis carries out in water, alkali concn is less than 4M.Alkali concn is that 2.0M～0.5M is better, and alkali concn is that 1.5M～0.5M is good.The concrete visual differential responses thing of concentration and difference.
Be preferably in reaction system and add organic solvent and/or phase-transfer catalyst; The add-on of organic solvent accounts for 60%～10% of reaction soln gross weight, and mole usage quantity of phase-transfer catalyst is less than 20% of reactant molar weight.
The phase transfer catalyst may be alkanes with a long chain quaternary ammonium, quaternary phosphonium salts, such as cetyl trimethyl ammonium chloride, cetyl trimethyl ammonium chloride or cetyl trimethyl butyl butyl chloride and the like; molar amount of phase transfer catalyst used is less than 20% equimolar amounts of the reactants used in an amount of 8% ~ 0.5 °% preferably used in an amount of from 3% to 1% of the best.
Be preferably in above-mentioned reaction system and add superoxide; Superoxide can be 30%～5% hydrogen peroxide or 70% tertbutyl peroxide etc.
Under phase-transfer catalyst exists, in hydrolysis reaction system, can add the superoxide of 250%-50% mole; The hydrogen peroxide that superoxide is 30%～5% or 70% tertbutyl peroxide.
Positively effect of the present invention is: solved the problems such as the processing step always existed in the prior art is many, complicated operation, its method and principle uniqueness, purifying products technique and operating procedure are easy, have greatly shortened the operation steps of manufacturing thiadiazoles glyoxylic acid oxime series compound; And reaction yield and product purity are higher; Be particularly suitable for suitability for industrialized production.
The whole reaction side reaction of the present invention is less, the reaction solvent (comprise and use mixed solvent) as suitable as temperature of reaction and reaction solution concentration, selection of the processing parameter of select suitable alkali (comprise use mixed base), optimizing reaction, adds the ways such as superoxide and catalyzer can make side reaction more obviously reduce.The by product that can detect in reaction mixture can be less than 5%; Reaction yield and product purity obviously improve, and reaction yield can be brought up to 75-85%, and purity is to being greater than 97%.Be particularly suited for the highly purified thiadiazoles glyoxylic acid oxime of suitability for industrialized production compounds product.
Below in conjunction with embodiment, be described further, but not as a limitation of the invention.
Embodiment
Involved in the present invention is the production method of a series compound, and for each specific compound, preparation technology and the best conditions of preparation pr ocess etc. can be different.
For the problem existed in thiadiazoles glyoxylic acid oxime series derivates in prior art (reactant I structure in formula 2) hydrolytic process, embodiment can be by selecting suitable alkali, add phase-transfer catalyst, the processing parameter of optimizing reaction reaches as ways such as temperature of reaction and reaction solution concentration and change reaction solvents (comprise and use mixed solvent) purpose that improves yield.In test, we find, the substituting group on the oxygen base and amino substituent difference, on the impact of hydrolysis reaction yield also very large (R in formula 2, R
1, R
2).
Thiadiazoles oxime acetogenin involved in the present invention (reactant I structure in formula 2) comprises acid esters, acyl ammonia and nitrile compounds (R
3suc as formula 6, define).Substituent R on Thiadiazole on amino and R
1(defined suc as formula 6) comprises various alkyl and various acyl group.Substituent R on oxime oxygen base
2(defined suc as formula 6) comprises methyl, ethyl, Bian Ji, diphenyl-methyl, trityl, fluoro methyl and tert-butyl isobutyrate base etc.Their preparation is with reference to document Bioorg.Med. Chem.2003,11,2427-2437, Bull Chem Soc Jpn.1993, the method for 66,2335-2338 and US733642.
R
1＝H，alkyl
Formula 6
The preparation of 2-ethoxy imido grpup-2-(5-formamido group-1,2,4-thiadiazoles-3)-acetonitrile is with reference to document Bull ChemSoc Jpn.1993, the method for 66,2335-2338 and US733642.It is hydrolyzed to corresponding thiadiazoles oxime sodium acetate under alkaline condition, then obtains corresponding thiadiazoles oxime acetic acid (formula 7) through hcl acidifying.The present invention, except adopting NaOH as alkali, has also adopted respectively the oxide compound of all alkali and alkaline earth metal ions, and oxyhydroxide and carbonate is as alkali, or adopts several alkali combinations as alkali, and partial results is listed in table 1.
Formula 7
When hydrolysis reaction carries out in water, alkali concn is most important to this hydrolysis reaction, and alkali concn should not surpass 4M, can, between 2.0M-0.5M, preferably be less than 1.5M.The alkali of high density can cause the decomposition of reaction product and reactant to cause yield decline (partial data is in Table 1).At same concentration, do not add under the condition of catalyzer, different alkali, also larger on the impact of reaction yield and product purity, as seen from the table, weak alkali LiOH is one of best alkali (in Table 1 experiment 7).Hydrolysising reacting temperature should be controlled at below 150 ℃, can be between 100 ℃ to 10 ℃, between best 80 ℃ to 40 ℃.For a concrete thiadiazoles oxime acetogenin, its hydrolysis yield is decided by temperature of reaction, alkali concn and alkali kind fully.Only have these parameters of reasonable conciliation, just can reach maximum yield.
Table 1, the part of test results of 2-ethoxy imido grpup-2-(5-formamido group-1,2,4-thiadiazoles-3)-acetonitrile hydrolysis.
Adding of organic solvent, greatly improve the yield (in Table 1 experiment 11) of reaction.Organic solvent comprises water-soluble solvent, methyl alcohol for example, and ethanol, ethylene glycol, propyl alcohol, Virahol, glycerol, acetonitrile, tetrahydrofuran (THF), dioxane etc., DMF, DMSO, and the solvent of poorly water-soluble is as toluene, organic acid ester, higher alcohols is as butanols, hexalin.The add-on of solvent from 60% to 10%.Organic solvent should add in initial reaction stage.
In order to reduce the use of organic solvent, add phase-transfer catalyst (PTC) in hydrolysis reaction system, can greatly improve the yield (in Table 1 experiment 12) of reaction.The phase-transfer catalyst used comprises quaternary amine, quaternary phosphonium salt, polyethylene glycols, aryl radical and alkyl Sulfonates, the phase-transfer catalyst of various oxide compounds and Polymer-supported.Preferably, the catalyst is a long chain alkane quaternary amines, quaternary phosphonium salts, such as cetyl trimethyl ammonium chloride, cetyl trimethyl ammonium chloride and butyl chloride, hexadecyl tributyl phosphonium with.The usage quantity of phase-transfer catalyst, at mole below 20% of reactant, can, between 15% to 0.5 ° of %, be preferably in 5% to 1%.Catalyzer can be used jointly with organic solvent.
Under phase-transfer catalyst exists, add the superoxide of 250%-50% mole in the reaction system of hydrolysis thiadiazoles oxime acetonitrile, can improve the yield (in Table 1 experiment 13) of reaction.The superoxide the present invention includes has 30%～5% hydrogen peroxide, 70% tertbutyl peroxide.
Embodiment 1:
(5-amino-1 for 2-methoxy imino-2-, 2,4-thiadiazoles-3) synthesizing of-acetic acid: 2-methoxy imino-2-(5-formamido group-1,2,4-thiadiazoles-3)-methyl acetate (265g, 97%, 1.0mol) be added to and add in the 5L there-necked flask, add 1.0M LiOH aqueous solution 3L (3.0mol) again in reaction flask, be warming up to 50-60 ℃ of reaction 12 hours.The TLC trace analysis, after having reacted, be down to room temperature, with concentrated hydrochloric acid, adjusts pH to 5, add the 50g decolorizing with activated carbon, then adjust pH to 1 with concentrated hydrochloric acid, a large amount of white crystals are separated out, and filter and use a small amount of cold methanol washing, drying obtains white solid 153g, yield 80%, content (HPLC) 97%, H
1nMR (500Hz, DMSO-d
e), δ 3.93 (3H, s), 8.21 (2H, s), mp.175 ~ 178 ℃ (dec).
Embodiment 2:
(5-amino-1 for 2-ethoxy imido grpup-2-, 2,4-thiadiazoles-3) synthesizing of-acetic acid: 2-ethoxy imido grpup-2-(5-formamido group-1,2,4-thiadiazoles-3)-acetonitrile (520g, 95%, 2.1mol), water 3.5L adds in the 5L four-hole bottle, adds 48% aqueous sodium hydroxide solution 383g (4.60mol) under stirring, is warming up to 50-60 ℃ of reaction.The TLC trace analysis, (approximately 12 hours) cooling after having reacted, adjust pH to 4 with concentrated hydrochloric acid, add the 50g decolorizing with activated carbon, then adjust pH to 1 with concentrated hydrochloric acid, ethyl acetate (2LX2) extraction, add 1.5L acetonitrile recrystallization after the evaporated under reduced pressure solvent, obtain faint yellow solid powder-product 178g, yield 39%, content (HPLC) 92%, H
1nMR (500Hz, DMSO-d
e), δ 1.22 (3H, t, J=7Hz), 4.17 (2H, q, J=7Hz), 8.17 (NH2,2H, bs), mp.160 ~ 162 ℃ (dec).
Embodiment 3:
2 - ethoxyimino -2 - (5 - amino - 1 ,2,4-thiadiazol-3) - acetic acid: The mixture of 2 - ethoxyimino -2 - (5 - carboxamido - 1,2,4 - thiadiazol-3) - acetonitrile (258g, 95%, 1mol) was added to a 5L three-necked flask, was added to the reaction flask 3.5L LiOH (1.2M) solution, and adding ten six alkyl trimethyl ammonium chloride (7.8g), 30 ℃ -35 ℃ stirring 4 times added 120g 30% H <sub TranNum="160"> 2 </ sub> O <sub TranNum = "161 "> 2 </ sub> add 120g 30% H <sub TranNum="162"> 2 </ sub> O <sub TranNum="163"> 2 </ sub>, 30 ℃ -35 ℃ stirred for 6 hours .Be warmed up to 70 ℃-75 ℃ reactions 12 hours, TLC follows the tracks of reaction.After reaction solution cools to 5 ℃, being acidified to pH with concentrated hydrochloric acid is 1.5, separates out a large amount of white crystals.Solid is filtered, and wash with a small amount of cold methanol, product, through vacuum-drying, obtains white solid product 171g, content (HPLC) 97%.Yield 81%, H<sup TranNum="164">1</sup>nMR (500Hz, DMSO-d<sub TranNum="165">e</sub>), δ 1.22 (3H, t, J=7Hz), 4.17 (2H, q, J=7Hz), 8.17 (NH<sub TranNum="166">2</sub>, 2H, bs), mp.163 ~ 165 ℃ (dec)
Embodiment 4:
(5-amino-1 for 2-ethoxy imido grpup-2-, 2,4-thiadiazoles-3) synthesizing of-acetic acid: by 2-ethoxy imido grpup-2-(5-formamido group-1,2,4-thiadiazoles-3)-acetonitrile (258g, 95%, 1mol) be added in the 5L there-necked flask, add 3.5L LiOH (1.2M) aqueous solution again in reaction flask, 30 ℃ of-35 ℃ of stirrings add 120g 30%H lower minute 4 times
2o
2, 30 ℃ of-35 ℃ of stirring reactions 6 hours.Be warmed up to 70 ℃-75 ℃ reactions 12 hours, TLC follows the tracks of reaction.After reaction solution cools to 5 ℃, being acidified to pH with concentrated hydrochloric acid is 1.5, separates out a large amount of white crystals.Solid is filtered, and wash with a small amount of cold methanol, product, through vacuum-drying, obtains white solid product 158g, content (HPLC) 97%.Yield 75%, H
1nMR (500Hz, DMSO-d
e), δ 1.22 (3H, t, J=7Hz), 4.17 (2H, q, J=7Hz), 8.17 (NH2,2H, bs), mp.163 ~ 165 ℃ (dec).
Embodiment 5:
2 - fluoro-methoxyimino -2 - (5 - amino - 1 ,2,4-thiadiazol-3) - Synthesis of acetic acid: 2 - fluoro-methoxyimino -2 - (5 - amino-1 , 2,4 - thiadiazol-3) - acetic acid methyl ester (300g, 1.28mol) was added to 3.1L of 1.0M LiOH aqueous solution, and adding cetyl trimethyl ammonium chloride (8.2g, 0.0256mol).Under 60-70 ℃, reaction is 6 hours, and TLC follows the tracks of reaction.It is 1 that reaction solution is acidified to pH with concentrated hydrochloric acid, separates out a large amount of white crystals.Solid is filtered, and washs with a small amount of cold methanol, and product, through vacuum-drying, obtains the solid 221.5g of off-white color, yield 78.6%, content (HPLC) 97.6%, H
1nMR (500Hz, DMSO-d
e), δ 5.75 (2H, d, J=52Hz), 8.3 (2H, br.), mp.203 ℃ (dec).
Embodiment 6:
2 - [2 - (tert-butyloxycarbonyl) - propyl-2] - imino-oxo -2 - (5 - amino - 1 ,2,4-thiadiazol-3) - Synthesis of acetic acid: 2 - (2 - tert-butyloxycarbonyl) - propyl-2] - imino-oxo -2 - (5 - amino - 1 ,2,4-thiadiazol-3) - acetonitrile (385g, 95%, 0.95mol ) added to 1.0MLiOH 3.8L of water, and adding cetyl trimethyl ammonium chloride (10g), stirred for 30 ℃ -35 ℃ under 4 times added 120g 30% H <sub TranNum = "185" > 2 </ sub> O <sub TranNum="186"> 2 </ sub>, 30 ℃ -35 ℃ reaction was stirred for 6 hours.Be warmed up to 70 ℃-75 ℃ reactions 12 hours, TLC follows the tracks of reaction.After reaction solution cools to 5 ℃, being acidified to pH with concentrated hydrochloric acid is 1.5, separates out a large amount of white crystals.Solid is filtered, wash with water to pH be 6 left and right, and with the washing of a small amount of cold methanol, product, through vacuum-drying, obtains off-white color solid 265g, yield 83%, content (HPLC) 98.6%, H<sup TranNum="187">1</sup>nMR (500Hz, DMSO-d<sub TranNum="188">e</sub>), δ 1.39 (9H, s), 1.43 (6H, s), 8.25 (2H, br).
Embodiment 7:
(5-amino-1 for 2-triphenyl methoxy imino-2-, 2,4-thiadiazoles-3) synthesizing of-acetic acid: 2-triphenyl methoxy imino-2-(5-formamido group-1,2,4-thiadiazoles-3)-methyl acetate (510g, 95%, 1.1mol) be added to and add in the 5L there-necked flask, add 1.0MLiOH aqueous solution 2.3L (2.3mol) and 1.2L ethanol again in reaction flask, be warming up to 50-60 ℃ of reaction 8 hours.The TLC trace analysis, after having reacted, most of ethanol is removed in underpressure distillation.Be down to room temperature, with concentrated hydrochloric acid, adjust pH to 5, add the 50g decolorizing with activated carbon, then adjust pH to 1 with concentrated hydrochloric acid, a large amount of white crystals are separated out, and filter and use a small amount of cold methanol washing, and drying obtains white solid 386g, yield 80%, content (HPLC) 97%, H
1nMR (500Hz, DMSO-d
e), δ 7.25-7.35 (15H, m), 8.3 (2H, s).
Embodiment 8:
2 - [(2 - tert-butyloxycarbonyl) - propyl-2] - imino-oxo -2 - (5 - methyl-1 ,2,4 - thiadiazol-3) - acetic acid: The 2 - [2 - tert-butyloxycarbonyl) propyl-2) - oxyethylene amino-2 - (5 - methyl-1 ,2,4 - thiadiazol-3) - acetic acid methyl ester (450g, 96% , 1.2mol) was added to 2.5L of 1.0M LiOH aqueous solution, and adding cetyl trimethyl ammonium chloride (9.8g), heated to 65 ℃ -70 ℃ for 12 hours, TLC tracking response.After reaction solution cools to 5 ℃, being acidified to pH with concentrated hydrochloric acid is 1.5, separates out a large amount of white crystals.Solid is filtered, wash with water to pH be 6 left and right, and with the washing of a small amount of cold methanol, product, through vacuum-drying, obtains off-white color solid 308g, yield 78%, content (HPLC) 98%, H
1nMR (500Hz, DMSO-d
e), δ 1.39 (9H, s), 1.43 (6H, s), 2.75 (3H, S), 8.25 (1H, br).Other embodiment slightly.
Claims (5)
1. one kind 1,2, the preparation method of 4-thiadiazoles glyoxylic acid oxime series compound, it is characterized in that derivative by 1,2,4-thiadiazoles glyoxylic acid oxime series compound is after alkaline hydrolysis, through hydrochloric acid acidizing reaction, obtain, the temperature of hydrolysis reaction system is controlled at 150 again
obelow C, its reaction formula is:
Its R
2for the substituting group on oximido: methyl, ethyl, sec.-propyl, benzyl, diphenyl-methyl, trityl, fluoro methyl or 2-methyl tert-butyl isobutyrate base; Its R
1for various alkyl or hydrogen;
Described alkali is that lithium hydroxide LiOH or mixed base LiOH add NaOH; Described basic hydrolysis carries out in water, and alkali concn is less than 4M;
Also add organic solvent and/or phase-transfer catalyst in reaction system; The add-on of organic solvent is 60%～10% of gross weight, and the usage quantity of phase-transfer catalyst is at mole below 20% of reactant;
In reaction system, also add superoxide.
2. the preparation method of thiadiazoles glyoxylic acid oxime series compound according to claim 1, is characterized in that the temperature of hydrolysis reaction system is controlled at 100
oc～30
oc.
3. the preparation method of thiadiazoles glyoxylic acid oxime series compound according to claim 1, is characterized in that described alkali concn is 2M～0.5M.
4. the preparation method of thiadiazoles glyoxylic acid oxime series compound according to claim 1, it is characterized in that described phase-transfer catalyst for the long chain alkane quaternary ammonium salt or season phosphonium salt; Described quaternary ammonium salt is palmityl trimethyl ammonium chloride or hexadecyl tributyl ammonium chloride; Described season, phosphonium salt was phosphonium hexadecanyl-3-butyl chloride; The usage quantity of phase-transfer catalyst is at mole below 20% of reactant.
5. the preparation method of thiadiazoles glyoxylic acid oxime series compound according to claim 4, is characterized in that described phase-transfer catalyst usage quantity is at mole 3%～1% of reactant.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5202315A (en) * | 1989-05-11 | 1993-04-13 | Lucky, Ltd. | Cephalosporin compounds |
| EP0536900A2 (en) * | 1991-09-12 | 1993-04-14 | KATAYAMA SEIYAKUSYO CO. Ltd. | Process for preparing 1,2,4-Thiadiazole Derivatives |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5202315A (en) * | 1989-05-11 | 1993-04-13 | Lucky, Ltd. | Cephalosporin compounds |
| EP0536900A2 (en) * | 1991-09-12 | 1993-04-14 | KATAYAMA SEIYAKUSYO CO. Ltd. | Process for preparing 1,2,4-Thiadiazole Derivatives |
Non-Patent Citations (3)
| Title |
|---|
| Jiro Goto, et al..Studies of 7β-[2-(aminoaryl)acetamido]-cephalosporin derivatives Ⅲ.Synthesis and structure-activity relationships in the aminothiadiazole series.《The Journal of Antibiotics》.1984,第XXXⅦ卷(第5期),第557-571页. * |
| Takeo KANAI, et al..Efficient Preparation of (Z)-2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-[(fluoromethoxy)imino]acetic Acid.《Bulletin of the Chemical Society of Japan》.1993,第66卷(第8期),第2335-2338页. * |
| TakeoKANAI et al..Efficient Preparation of (Z)-2-(5-Amino-1 |
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