CN102942578A - Preparation method of 1-oxacephalosporin-3-epoxymethylene derivatives and use of the 1-oxacephalosporin-3-epoxymethylene derivatives in preparation of 1-oxacephalosporin - Google Patents
Preparation method of 1-oxacephalosporin-3-epoxymethylene derivatives and use of the 1-oxacephalosporin-3-epoxymethylene derivatives in preparation of 1-oxacephalosporin Download PDFInfo
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Abstract
The invention relates to the technical field of a synthesis method of 1-oxacephalosporin-3-epoxymethylene derivatives as a synthetic intermediate of 1-oxacephalosporin for resisting microbes and especially relates to a preparation method of 1-oxacephalosporin-3-epoxymethylene derivatives shown in the formula (I). The preparation method is characterized in that a 1-oxacephalosporin-3-methylene derivative shown in the formula (II) is efficiently and selectively epoxidized into a 1-oxacephalosporin-3-epoxymethylene derivative by hydrogen peroxide in the presence of a catalyst. The 1-oxacephalosporin-3-epoxymethylene derivative and a derivative of a mercaptotetrazole alkali metal salt shown in the formula (III) undergo a reaction and the reaction products are dehydrated under acidic conditions to form a corresponding 1-oxacephalosporin intermediate shown in the formula (IV). The preparation method has the advantages that a halogen addition reaction is avoided; the easily available catalyst is used; a clean and environmentally friendly oxygen source is used; a reaction process is not carried out at a low temperature; equipment corrosion caused by halogens in industrial production is avoided; an investment of expensive special-purpose equipment is reduced; a risk generation rate is greatly reduced; and 1-oxacephalosporin preparation processes are simple and can be operated easily. Therefore, the preparation method has large competitiveness in industrial production.
Description
Technical field
The present invention relates to a kind of synthetic synthetic method technical field with intermediate 1-oxacephalosporin-3-epoxy methylene derivatives of antimicrobial 1-oxacephalosporin that can be used as.
Background technology
1-oxacephalosporin such as latamoxef (Latamoxef) or flomoxef (Flomoxef) are the novel Broad spectrum antibioticss of a class, and it has good anti-microbial activity to multiple Gram-negative bacteria, and effect is stronger 4 ~ 16 times than general cynnematin.Because the synthetic difficulty of such oxygen cephalo is quite large, although the investigator is numerous, reality can realize that the factory that produces is very few.
The method for preparing at present the 1-oxacephalosporin is substantially all carried out take the 1-oxacephalosporin-3-chloromethyl derivatives as intermediate, is shown below:
Synthesizing at Tetrahedron Letter 1980,21 of 1-oxacephalosporin-3-chloromethyl derivatives, 351-354 and US4604460 all have the report its, all be to prepare by the method shown in following equation,
The logical chlorine of 1-oxacephalosporin-3-methylene derivatives (being formula II) obtains two chlorine compounds of two key additions, and then eliminates uncle's chlorine by alkalescence, obtains the 1-oxacephalosporin-3-chloromethyl derivatives.In experiment, find, the free radical reaction of the two keys of chlorine addition need to could controlled optionally addition on two keys under the utmost point low reaction temperatures, and the position free radical substitution reaction of unlikely generation allyl group, and when removing uncle's chlorine, also need very low temperature, because eliminating hydrochloric acid, dechlorination to use the highly basic such as DBU or lithium methoxide, chloromethyl derivative will be destroyed when temperature of reaction is higher than-20 ℃, therefore this route is being produced special introduce chlorine gas to make reaction equipment and the extremely low temperature of reaction that requires to use costliness, and the various safeguard procedures of logical chlorine must be arranged, these restrictions are very disadvantageous for industrial applications of this route.
The method for preparing the 1-oxacephalosporin from 1-oxacephalosporin-3-epoxy methylene derivatives there is not yet widely report, and reason may be the difficult preparation of 1-oxacephalosporin-3-epoxy methylene derivatives.US4443598 has described and has utilized in bromine addition 1-oxacephalosporin-3-methylene derivatives process; because the existence of water; two key adducts of generating portion hypobromous acid (HOBr); and then in the presence of salt of wormwood, obtain epoxide; whole process yield is low; and need to use the halogens such as bromine, and be unfavorable for environment protection, also can't truly be used for 1-oxacephalosporin industrial production.
Summary of the invention
The objective of the invention is to develop the feasible preparation 1-oxacephalosporin of industrial production-3-epoxy methylene derivatives (
Formula I) method, to be used for the synthetic of 1-oxacephalosporin, solve many defectives that existing synthetic route uses the 1-oxacephalosporin-3-chloromethyl derivatives to exist, and make the preparation of 1-oxacephalosporin become simple.
Through a large amount of experimental studies, the present inventor finds, use cleaning oxygen source hydrogen peroxide can be in the situation that catalyzer exists, and efficient selective ground epoxidation 1-oxacephalosporin-3-methylene derivatives gets 1-oxacephalosporin-3-epoxy methylene derivatives.In the substantially immovable situation of reaction system, this epoxide can successfully react with the mercapto tetrazole an alkali metal salt, makes corresponding 1-oxacephalosporin intermediate.
The concrete technical scheme that the present invention takes is as follows:
1-oxacephalosporin-3-epoxy methylene derivatives (
Formula I) the preparation method, its step is included under the effect of catalyzer, 1-oxacephalosporin-3-methylene derivatives (
Formula II) and hydrogen peroxide (H
2O
2) the initial ring oxidizing reaction, generation 1-oxacephalosporin-3-epoxy methylene derivatives (
Formula I)
Wherein, R
1Be phenyl, 4-aminomethyl phenyl, benzyl, 4-cyano-phenyl or 4-p-methoxy-phenyl, R
2Be hydrogen or methoxyl group, R
3Be carboxyl-protecting group; Catalyzer is TS-1 molecular sieve or assorted many wolframic acids quaternary ammonium salt, and said quaternary ammonium salt cationic is: tetradecyl trimethyl ammonium, cetyl pyridinium base ammonium, cetyltrimethyl ammonium, octadecyl trimethyl ammonium, octadecyl dimethyl benzyl ammonium, tetrapropyl ammonium, TBuA, benzyl triethyl ammonium ammonium, methyl triethyl ammonium, two certain herbaceous plants with big flowers alkyl dimethyl ammonium or tricaprylmethylammonium.
Above-mentioned R
1Representative be acyl residue commonly used in the cepham rhzomorph chemical field in fact; they can be the acyl groups that can generate the 7-position side chain of target Antibiotique composition; also can be the acyl group that can in this compound synthetic, serve as amino protecting group, be preferably phenyl, 4-aminomethyl phenyl or benzyl.
Above-mentioned R
3Representative be a class carboxyl-protecting group in fact; comprise in the cynnematin industry well-known can with carboxyl reaction or remove and do not cause other parts in this molecule anyly do not wish the carboxyl-protecting group that changes; wherein better be diphenyl-methyl, to nitrobenzyl (PNB), benzyl or to methoxy-benzyl, best is diphenyl-methyl.
The used catalyzer of epoxidization reaction process is TS-1 molecular sieve or assorted many wolframic acids quaternary ammonium salt.The TS-1 molecular sieve belongs to heterogeneous catalyst, and it is the effective catalyst of hydrogen peroxide epoxidation of olefins, is easy to remove by filter method after reaction finishes.Another kind of assorted many wolframic acids quaternary ammonium salt catalyst has comprised heteropolyacid part and quaternary ammonium moiety, and preferably assorted many wolframic acids partly are [PO4 (WO3) 4]; Said quaternary ammonium salt cationic can for: tetradecyl trimethyl ammonium, cetyl pyridinium base ammonium, cetyltrimethyl ammonium, octadecyl trimethyl ammonium, octadecyl dimethyl benzyl ammonium, tetrapropyl ammonium, TBuA, benzyl triethyl ammonium ammonium, methyl triethyl ammonium, two certain herbaceous plants with big flowers alkyl dimethyl ammonium or tricaprylmethylammonium are preferably cetyl pyridinium base ammonium, tetrapropyl ammonium or octadecyl dimethyl benzyl ammonium.Assorted many wolframic acids quaternary ammonium salt catalyst that the present invention is selected, in reaction process, can generate the active oxidation species that are dissolved in reaction system, whole reaction system is homogeneous phase, giving full play to the catalysis epoxidation activity, and after reaction finishes, revert to again former assorted many wolframic acids quaternary ammonium salt catalyst, from reaction, separate out, be convenient to separate, reach the catalytic cycle purpose that is shown below:
。
When using the TS-1 molecular sieve as epoxidation catalyst, the consumption of TS-1 catalyzer be 1-oxacephalosporin-3-methylene derivatives (
Formula II) 0. 1wt% ~ 2.0wt% of weight, be preferably 0.4wt% ~ 0.8wt%.When using assorted many wolframic acids quaternary ammonium salt as epoxidation catalyst, the consumption of assorted many wolframic acids quaternary ammonium salt catalyst is 0. 005 ~ 0.1 times of 1-oxacephalosporin-3-methylene derivatives molar weight, is preferably 0.01 ~ 0.05 times.The consumption of hydrogen peroxide is 1.0 ~ 3.0 times of 1-oxacephalosporin-3-methylene derivatives molar weight, is preferably 1.2 ~ 1.8 times; The concentration of hydrogen peroxide is 5% ~ 90%, is preferably 25% ~ 30%.Concentration of hydrogen peroxide is too high, and the potential operating safety that brings can be larger, also can generate the by product of direct oxidation; Concentration is excessively low, and epoxidised efficient can be affected, and 25% ~ 30% concentration range both can guarantee epoxidation speed, had guaranteed simultaneously the safety of product and operating process.The temperature of catalysis epoxidation is 0 ℃ ~ 50 ℃, is preferably 20 ℃ ~ 40 ℃, and more preferably 25 ℃ ~ 35 ℃, excess Temperature can cause hydrogen peroxide self decomposed.
The used solvent of epoxidation reaction is not particularly limited, as long as they do not produce harmful effect to this reaction, such as ether solvent, produces easily superoxide, generally is not used in the oxidizing reaction of hydrogen peroxide.The solvent that can select is as follows: C1 ~ C4 alcohol, as: methyl alcohol, ethanol etc.; C1 ~ C4 halogenated alkane, as: methylene dichloride, chloroform, ethylene dichloride etc.; C1 ~ C4 nitrile, as: acetonitrile or propionitrile etc.; C1 ~ C8 acetic ester is such as ethyl acetate, methyl acetate etc.; C3 ~ C4 acid amides, as: dimethyl formamide, N,N-DIMETHYLACETAMIDE etc.; C6 ~ C10 contains benzene solvent, as: toluene, dimethylbenzene, chlorobenzene etc.Consider that a step is to react with mercapto tetrazole basic metal sodium salt subsequently, if select nitrile, acetate esters, amide solvent, reaction can produce unnecessary by product, increases post-processing difficulty, increases production cost.So preferred solvent is methyl alcohol, methylene dichloride.
If this reaction solvent is selected suitably not need special separation and purification
Formula ICompound can be according to behind the HPLC external standard method content, and the next step raw material that calculates required adding carries out subsequent reactions.
Another purpose of the present invention provide 1-oxacephalosporin-3-epoxy methylene derivatives (
Formula I) application in the 1-oxacephalosporin is synthetic, shown in the following reaction formula:
Comprise the following steps: that the epoxy group(ing) opening occurs for formula I epoxide and formula III mercapto tetrazole an alkali metal salt (M=Na or K), then dehydration can make corresponding 1-oxacephalosporin intermediate compound IV under acidic conditions, wherein, and R
1, R
2And R
3The formula of stating as defined above I described in, R
4Be methyl or 2-hydroxyethyl.
React used an alkali metal salt, can produce by mercapto tetrazole and sodium methylate (potassium) or sodium hydride (potassium) reaction in－situ, consider from production cost, be preferably sodium salt.The consumption of mercapto tetrazole an alkali metal salt is formula
I0.9 ~ 1.5 times of the molar weight that compound calculates according to theoretical value is preferably 1.1 ~ 1.2 times.
The used solvent of epoxy addition addition reaction is DMSO or C1 ~ C4 alcohol; C1 ~ C5 ether is such as ether, methyl tertiary butyl ether, THF etc.; C3 ~ C4 acid amides is such as DMF etc.; C1 ~ C4 chloroparaffin such as methylene dichloride etc. are preferably methyl alcohol.The used acid of dehydration reaction acidic conditions is hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid or methylsulfonic acid, tosic acid, is preferably phosphoric acid and polyphosphoric acid.The temperature of reaction is-20 ~ 80 ℃, and preferred temperature of epoxy addition addition stage is-10 ~ 10 ℃; The temperature of acidic conditions dehydration is preferably 30 ~ 50 ℃.
After the epoxy addition addition reaction finished, reaction system was used first the phosphoric acid cancellation, then adds the warm 1-oxacephalosporin intermediate compound IV that namely obtains of polyphosphoric acid.
The reagent that the inventive method is used and raw material be commercially available getting all.
Each step reaction can be carried out according to this area conventional treatment method after finishing.
Beneficial effect of the present invention: method use 1-oxacephalosporin of the present invention-3-epoxy methylene derivatives (
Formula I) as intermediate, got around dexterously in the process of preparation 1-oxacephalosporin, must use the route of 1-oxacephalosporin-3-chloromethyl derivatives, can avoid in its industrial production because the equipment corrosion that logical halogen addition reaction causes, reduce the investment of expensive specific equipment, also greatly reduce dangerous odds; The required catalyzer of catalytic epoxidation cheaply is easy to get, and easy recovery, used oxygen source hydrogen peroxide clean environment firendly, reaction process does not need cold condition, make the preparation of 1-oxacephalosporin become simple, therefore when industrial production, have larger competitive power.
Embodiment:
Further explain by the following examples and explanation content of the present invention.In the present invention, the embodiment of the following stated is in order to set forth better the present invention, is not to limit the scope of the invention.
Embodiment 1:
Be phenyl with Compound I I(R1, R2 is hydrogen atom, R3 is diphenyl-methyl) stirring and dissolving 10 times the amount methyl alcohol in, the lower TS-1 molecular sieve that adds Compound I I weight 0.8% of normal temperature (25 ℃), drip 1.8 times of 30% aqueous hydrogen peroxide solution of Compound I I molar weight under the control uniform temp, the TLC detection reaction is complete, filters and removes the TS-1 molecular sieve catalyst, reaction solution is concentrated into dried, the about 90%(HPLC external standard method of yield).Residual solid is dissolved with methylene dichloride, and with a small amount of hypo solution washing, organic layer evaporate to dryness, the residual solid ethyl acetate: normal heptane (4:1) recrystallization obtains off-white color Compound I (R1 is phenyl, and R2 is hydrogen atom, and R3 is diphenyl-methyl).Yield 61%.
1H-NMR(300MHz,?CDCl
3)：δ?8.45?(brs,?1H),?7.72~7.94?(m,?2H),?7.13~7.60?(m,?13H),?6.92?(s,?1H),?5.45?(s,?1H),?5.10?(d,?1H),?4.33?(s,?1H),?(3.42,?4.13)?(dd,?2H),?(2.70,?3.06)(dd,?2H)。
Embodiment 2:
Be phenyl with Compound I I(R1, R2 is hydrogen atom, and R3 is diphenyl-methyl) stirring and dissolving in 10 times of amount methyl alcohol, the lower [π-C that adds 0.01 times of Compound I I molar weight of normal temperature (25 ℃)
5H
5NC
16H
33]
3[PO
4(WO
3)
4] catalyzer, control and drip 1.2 times of 30% aqueous hydrogen peroxide solution of Compound I I molar weight under this temperature, the TLC detection reaction is complete, filter and remove assorted many wolframic acids quaternary ammonium salt catalyst of separating out, reaction solution is concentrated into dried Compound I, and (R1 is phenyl, R2 is hydrogen atom, and R3 is diphenyl-methyl), the about 95%(HPLC of yield).Reaction product need not be further purified, and can be directly used in the next step.
Embodiment 3:
Be phenyl with Compound I I(R1, R2 is hydrogen atom, and R3 is diphenyl-methyl) stirring and dissolving in 10 times of amount methylene dichloride, the lower [C that adds 0.05 times of Compound I I molar weight of normal temperature (25 ℃)
18H
37N (CH
2Ph) (CH
3)
2]
3[PO
4(WO
3)
4] catalyzer, control and drip 1.2 times of 30% aqueous hydrogen peroxide solution of Compound I I molar weight under this temperature, the TLC detection reaction is complete, filter and remove assorted many wolframic acids quaternary ammonium salt catalyst of separating out, reaction solution is concentrated into dried Compound I, and (R1 is phenyl, R2 is hydrogen atom, and R3 is diphenyl-methyl), the about 91%(HPLC of yield).
Embodiment 4 ~ 9:
Reaction uses solvent to be the methyl alcohol of 10 times of amounts of raw material, and temperature of reaction is 25 ℃, and the concentration of used hydrogen peroxide is 30%, and consumption is 1.5 times of feed molar amount.Concrete experimental implementation is with above embodiment.The concrete raw material of its result and use etc. sees the following form 1:
Table 1:
Embodiment 10:
(R1 is phenyl with above-described embodiment 2 gained Compound I, R2 is hydrogen atom, R3 is diphenyl-methyl) stirring and dissolving 10 times the amount methyl alcohol in, be cooled to-10 ℃, add the mercapto tetrazole sodium salt (R4 is methyl) of theoretical molar amount 1.1eq, continue stirring reaction to TLC monitor showing Compound I and transform fully, add a little phosphoric acid cancellation reaction, and add the equivalent polyphosphoric acid, and being warmed to 40 ℃, TLC monitor showing intermediates disappears and generates new point.Reaction solution is through neutralization, extraction, concentrated compound IV (R1 is phenyl, and R2 is hydrogen atom, and R3 is diphenyl-methyl, and R4 is methyl), the yield 83% of obtaining.Fusing point: 201 ~ 205 ℃.
1H-NMR(300MHz,?d
6-DMSO)：δ?7.95?(brs,?1H),?7.15~7.92?(m,?15H),?6.95?(s,?1H),?5.15?(s,?1H),?4.95?(d,?1H),?4.59?(s,?2H),?4.23?(s,?2H),?3.79?(s,?3H)。
Embodiment 11 ~ 17:
It can be to separate the Compound I that obtains that raw material is used in reaction, and perhaps the concentrated Compound I that obtains is directly carried out the next step in above-described embodiment 1 ~ 9; Solvent for use is the methyl alcohol of 10 times of amounts of raw material, and the ring-opening reaction temperature is-10 ℃; Concrete experimental implementation is with above embodiment 10.The concrete raw material of its result and use etc. sees the following form 2:
Table 2:
Claims (15)
1.1-oxacephalosporin-3-epoxy methylene derivatives (
Formula I) the preparation method, its step is included under the effect of catalyzer, 1-oxacephalosporin-3-methylene derivatives (
Formula II) and hydrogen peroxide (H
2O
2) the initial ring oxidizing reaction, generation 1-oxacephalosporin-3-epoxy methylene derivatives (
Formula I)
Wherein, R
1Can be phenyl, 4-aminomethyl phenyl, benzyl, 4-cyano-phenyl or 4-p-methoxy-phenyl, R
2Be hydrogen or methoxyl group, R
3Be carboxyl-protecting group; Catalyzer is TS-1 molecular sieve or assorted many wolframic acids quaternary ammonium salt, and the positively charged ion of described quaternary ammonium salt can be: tetradecyl trimethyl ammonium, cetyl pyridinium base ammonium, cetyltrimethyl ammonium, octadecyl trimethyl ammonium, octadecyl dimethyl benzyl ammonium, tetrapropyl ammonium, TBuA, benzyl triethyl ammonium ammonium, methyl triethyl ammonium, two certain herbaceous plants with big flowers alkyl dimethyl ammonium or tricaprylmethylammonium.
1-oxacephalosporin according to claim 1-3-epoxy methylene derivatives (
Formula I) application in the 1-oxacephalosporin is synthetic, it is characterized in that reaction formula as follows:
Comprise the following steps: the epoxide of formula I and the mercapto tetrazole an alkali metal salt of formula III (M=Na or K) initial ring oxygen compound opening, then dehydration can make corresponding 1-oxacephalosporin intermediate compound IV under the acidic conditions, wherein, and R
1, R
2And R
3The formula of stating as defined above I described in, R
4Be methyl or 2-hydroxyethyl.
3. described formula according to claim 1
IThe preparation method of compound is characterized in that: R
1Be phenyl, 4-aminomethyl phenyl, benzyl.
4. described formula according to claim 1
IThe preparation method of compound is characterized in that: R
3For diphenyl-methyl, to nitrobenzyl (PNB), benzyl or to methoxy-benzyl.
5. described formula according to claim 4
IThe preparation method of compound is characterized in that: R
3Be diphenyl-methyl.
6. described formula according to claim 1
IThe preparation method of compound is characterized in that: assorted many wolframic acids partly are [PO4 (WO3) 4] in the assorted many wolframic acids quaternary ammonium salt of catalyzer; Quaternary ammonium salt cationic is cetyl pyridinium base ammonium, tetrapropyl ammonium or octadecyl dimethyl benzyl ammonium.
7. described formula according to claim 1
IThe preparation method of compound is characterized in that: the consumption of TS-1 catalyzer is 0. 1wt% ~ 2.0wt% of 1-oxacephalosporin-3-methylene derivatives weight, is preferably 0.4wt% ~ 0.8wt%.
8. described formula according to claim 1
IThe preparation method of compound is characterized in that: the consumption of assorted many wolframic acids quaternary ammonium salt catalyst is 0. 005 ~ 0.1 times of 1-oxacephalosporin-3-methylene derivatives molar weight, is preferably 0.01 ~ 0.05 times.
9. described formula according to claim 1
IThe preparation method of compound is characterized in that: the consumption of hydrogen peroxide is 1.0 ~ 3.0 times of 1-oxacephalosporin-3-methylene derivatives molar weight, is preferably 1.2 ~ 1.8 times; The concentration of hydrogen peroxide is 5% ~ 90%, is preferably 25% ~ 30%.
10. described formula according to claim 1
IThe preparation method of compound is characterized in that: the temperature of catalysis epoxidation is 0 ℃ ~ 50 ℃, is preferably 20 ℃ ~ 40 ℃, more preferably 25 ℃ ~ 35 ℃.
11. described formula according to claim 2
IThe application of compound in the 1-oxacephalosporin is synthetic, it is characterized in that: the basic metal of mercapto tetrazole an alkali metal salt is M=Na.
12. described formula according to claim 2
IThe application of compound in the 1-oxacephalosporin is synthetic, it is characterized in that: the consumption of mercapto tetrazole an alkali metal salt is formula
I0.9 ~ 1.5 times of compound molar weight is preferably 1.1 ~ 1.2 times.
13. described formula according to claim 2
IThe application of compound in the 1-oxacephalosporin is synthetic is characterized in that: react the alcohol that used solvent can be DMSO or C1 ~ C4; The ether of C1 ~ C5 is such as ether, methyl tertiary butyl ether, THF etc.; The acid amides of C3 ~ C4 is such as DMF etc.; The chloroparaffin of C1 ~ C4 such as methylene dichloride etc. are preferably methyl alcohol.
14. described formula according to claim 2
IThe application of compound in the 1-oxacephalosporin is synthetic, it is characterized in that: the used acid of the acidic conditions that reacts used is hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid or methylsulfonic acid, tosic acid, is preferably phosphoric acid and polyphosphoric acid.
15. described formula according to claim 2
IThe application of compound in the 1-oxacephalosporin is synthetic, it is characterized in that: temperature of reaction is-20 ~ 80 ℃, preferred temperature of epoxy addition addition stage is-10 ~ 10 ℃; The temperature of acidic conditions dehydration is preferably 30 ~ 50 ℃.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107325115A (en) * | 2017-07-31 | 2017-11-07 | 山西千岫制药有限公司 | A kind of preparation method of oxygen cephalosporin intermediate |
| CN110003242A (en) * | 2019-04-23 | 2019-07-12 | 山西千岫制药有限公司 | A kind of preparation method of Flomoxef acid contamination levels product |
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| CN101613330A (en) * | 2008-06-25 | 2009-12-30 | 中国科学院大连化学物理研究所 | The method of preparing cyclohexene oxide through hydrogen peroxide epoxidation |
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| CN101613330A (en) * | 2008-06-25 | 2009-12-30 | 中国科学院大连化学物理研究所 | The method of preparing cyclohexene oxide through hydrogen peroxide epoxidation |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107325115A (en) * | 2017-07-31 | 2017-11-07 | 山西千岫制药有限公司 | A kind of preparation method of oxygen cephalosporin intermediate |
| CN110003242A (en) * | 2019-04-23 | 2019-07-12 | 山西千岫制药有限公司 | A kind of preparation method of Flomoxef acid contamination levels product |
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