CN102827191B - Method for preparing oxygen cephalosporin compound - Google Patents
Method for preparing oxygen cephalosporin compound Download PDFInfo
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- CN102827191B CN102827191B CN201210358059.9A CN201210358059A CN102827191B CN 102827191 B CN102827191 B CN 102827191B CN 201210358059 A CN201210358059 A CN 201210358059A CN 102827191 B CN102827191 B CN 102827191B
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- 0 *C1=CC=C([C@](N)O)C=I1 Chemical compound *C1=CC=C([C@](N)O)C=I1 0.000 description 5
- YEZNPSBCONTANX-UHFFFAOYSA-N CC(CNC(COC)=O)=C Chemical compound CC(CNC(COC)=O)=C YEZNPSBCONTANX-UHFFFAOYSA-N 0.000 description 1
- JWCSIUVGFCSJCK-BKZLJTMMSA-N C[n]1nnnc1SCC(CO[C@H]1[C@]2(NC(C(C(O)=O)c(cc3)ccc3O)=O)OC)=C(C(O)=O)N1C2=O Chemical compound C[n]1nnnc1SCC(CO[C@H]1[C@]2(NC(C(C(O)=O)c(cc3)ccc3O)=O)OC)=C(C(O)=O)N1C2=O JWCSIUVGFCSJCK-BKZLJTMMSA-N 0.000 description 1
Abstract
The invention relates to a method for preparing an oxygen cephalosporin compound, and belongs to the technical field of medicine synthesis. In order to solve the technical problems that a synthetic route of a compound is too long and the problem caused by chlorine in the oxygen cephalosporin compound formula I, the aims of simplified process and environment friendliness are fulfilled. The method for preparing the oxygen cephalosporin compound comprises the following steps of: reacting a compound, lithium methoxide and hypochlorous acid tert-butyl ester in a formula II to acquire a compound in a formula III in an organic solvent; and performing condensation reaction on the compound in the formula III and a compound of 1-methyl-5-tetrazole-thione in a formula IV under the condition of existence of an apply acid agent and a condensating agent to acquire corresponding final products. With the adoption of the method, the oxygen cephem and 1-methyl-5-tetrazole-thione are used as initial raw materials, the product is synthetized by means of one-pot, so that the side reaction influence is avoided; the production process is simplified; the product yield is high; the molar yield can reach over 65 percent; and the purity can reach over 95 percent.
Description
Technical field
The present invention relates to a kind of antibiotic medicinal compound, particularly relate to a kind of preparation method of oxygen cephalosporin compound, belong to technical field of medicine synthesis.
Background technology
Oxacephems microbiotic is because its special structure, as latamoxef, flomoxef etc., an alpha methoxy is had parent nucleus 7, due to the sterically hindered effect of methoxyl group, can stop enzyme molecule and antibiotic beta-lactam articulating near, made antibiotic beta-lactam ring before the synthesis of prevention bacteria cell wall not by enzyme molecule destroys, improve the stability of medicine to β-lactamase, and the activity that improve anerobe, bacterium seldom produces resistance, as oxacephems microbiotic latamoxef compound.
And in preparation process for existing oxacephems Antibiotique composition, generally first by with formula II compound for Material synthesis type I compound, then synthesize oxacephems Antibiotique composition further:
In formula I and formula II compound, R is selected from the one in hydrogen, methyl.And it is extremely important for the synthesis of type I compound in building-up process, in prior art normally first with oxacephem compound ii for raw material, addition reaction is carried out with chlorine, and then slough a part hydrogenchloride in the basic conditions and obtain chlorallylene intermediate, and then carrying out methoxylation, last and 1-methyl-5-mercapto tetrazole is obtained by reacting target product type I compound; The reaction formula of this synthetic method is as follows:
But there is following shortcoming in the method:
(1) reactions steps is long, needs four-step reaction, and reaction process side reaction is many, wayward;
(2) work becomes in process to need to use liquid chlorine, unfriendly to environment, and also higher to the requirement of production unit, is unfavorable for suitability for industrialized production.
Summary of the invention
The present invention is directed to the defect existed in above prior art, a kind of preparation method of oxygen cephalosporin compound is proposed, solve the synthetic route of oxygen cephalosporin compound type I compound in prior art long and adopt technical problem existing for chlorine, realize Simplified flowsheet, environment amenable object.
The object of the invention is to be achieved by the following technical programs, a kind of preparation method of oxygen cephalosporin compound, the method comprises the following steps:
A, make formula II compound and lithium methoxide, t-butyl hypochlorate carry out the formula that is obtained by reacting III compound in organic solvent;
Wherein, in formula II, R represents H, CH
3in one;
B, under acid-binding agent and condensing agent existent condition, make formula III compound and formula IV compound 1-methyl-5-mercapto tetrazole carry out condensation reaction, obtain type I compound;
In the preparation method of above-mentioned oxygen cephalosporin compound, the organic solvent described in steps A is selected from one or more in halogenated alkane, ether solvents, ester solvent.Described halogenated alkane is selected from one or more in methylene dichloride, chloroform, tetracol phenixin, monochloro methane, ethylene dichloride; Described ester solvent is selected from ethyl acetate, ethyl ester propyl etc.; Described ether solvents is selected from tetrahydrofuran (THF), glycol dimethyl ether, dioxane etc.As preferably, the organic solvent described in steps A is selected from one or more in methylene dichloride, chloroform, tetrahydrofuran (THF), dioxane, glycol dimethyl ether.Further preferably, described organic solvent is at least containing halogenated alkane.The product that raw material and reaction can be made to generate better dissolves, and increases reaction efficiency; On the other hand, consider price and the returnability of solvent in production process, and solvent is to the solvability of raw material and product, as further preferably, described organic solvent be selected from methylene dichloride, chloroform one or both.The restriction that the add-on of organic solvent is concrete, as preferably, the add-on of described organic solvent is formula II compound: the weight ratio of organic solvent is 1:8 ~ 12.
In the preparation method of above-mentioned oxygen cephalosporin compound, the temperature of the reaction described in steps A is-100 DEG C ~-40 DEG C.The generation of side reaction can be reduced, reduce the generation of impurity and improve product purity.As preferably, the temperature of described reaction is-60 DEG C ~-45 DEG C.The time of the reaction described in steps A is 0.5 ~ 3.0 hour.
In the preparation method of above-mentioned oxygen cephalosporin compound, the mol ratio of formula II compound described in steps A and lithium methoxide is 1:2.0 ~ 5.0, is preferably 1:2.5 ~ 3.5; Described formula II compound and the mol ratio of t-butyl hypochlorate are 1:1.0 ~ 3.0, are preferably 1:1.2 ~ 2.5.As further preferably, the lithium methoxide described in steps A is first dissolved in methanol solution, makes the mass concentration of lithium methoxide be 8.0% ~ 15%.
In the preparation method of above-mentioned oxygen cephalosporin compound, after reaction terminates in steps A, also comprise last handling process.In particular, described aftertreatment is that reaction solution steps A obtained carries out washing, drying treatment.By washing step, can partial impurities in removing system, improve the purity of product.
In the preparation method of above-mentioned oxygen cephalosporin compound, the acid-binding agent described in step B is selected from organic bases or mineral alkali.Effectively by the acid neutralization in system, reaction can be made more to be conducive to carrying out to positive dirction, to improve the efficiency of reaction, meanwhile, the generation of side reaction can also be reduced, improve the quality of product by adding acid-binding agent.As preferably, described organic bases is selected from one or more in pyridine, piperidines, diethylamine, morpholine, triethylamine.Described mineral alkali is weakly alkaline mineral alkali, and described weakly alkaline mineral alkali is selected from one or more in sodium carbonate, sodium bicarbonate, salt of wormwood, saleratus.Adopt weakly alkaline acid-binding agent that reaction can either be made to carry out toward positive dirction, the stability of product in reaction system can be ensured again further, make not easily to decompose, reduce the production of by product, improve the quality of product.As further preferably, described acid-binding agent be selected from morpholine, triethylamine one or both.
In the preparation method of above-mentioned oxygen cephalosporin compound, the consumption of the acid-binding agent described in step B is the mol ratio of formula II compound and acid-binding agent is 1:2 ~ 4, is preferably 1:2.5 ~ 3.5.
In the preparation method of above-mentioned oxygen cephalosporin compound, the condensing agent described in step B is selected from SULPHURYL CHLORIDE, C
1~ C
3alkyl sulfonyl chloride, aryl sulfonyl chloride, one or more in NCS.Described NCS is also referred to as N-chlorosuccinimide.As preferably, described condensing agent is selected from one or more in methylsulfonyl chloride, benzene sulfonyl chloride, Tosyl chloride, SULPHURYL CHLORIDE, NCS.
In the preparation method of above-mentioned oxygen cephalosporin compound, described formula II compound and the mol ratio of condensing agent are 1:1.0 ~ 3.0, are preferably 1:1.2 ~ 2.0.
In the preparation method of above-mentioned oxygen cephalosporin compound, the mol ratio of described formula II compound and formula IV compound 1-methyl-5-mercapto tetrazole is 1:1.0 ~ 2.0.
In the preparation method of above-mentioned oxygen cephalosporin compound, the temperature of the condensation reaction described in step B is-10 DEG C ~ 35 DEG C.As preferably, the temperature of described condensation reaction is-5 DEG C ~ 5 DEG C.
In the preparation method of above-mentioned oxygen cephalosporin compound, the time of the condensation reaction described in step B is 0.5 ~ 10 hour.
In the preparation method of above-mentioned oxygen cephalosporin compound, after the condensation reaction described in step B terminates, also comprise last handling process.In particular, described aftertreatment is that the reaction solution obtained after step B condensation reaction being terminated carries out washing, dry, distillation process.By washing step, can partial impurities in removing system further, improve the purity of product.
In the preparation method of above-mentioned oxygen cephalosporin compound, after step B, also comprise crystallisation step.As preferably, the type I compound obtained is added in alcoholic solvent carry out crystallization in step B.The purity of product can be improved further.In particular, under room temperature condition, type I compound is added in alcoholic solvent, stir, then, then decrease temperature crystalline, corresponding product I compound after obtaining crystallization.As preferably, described alcoholic solvent is selected from C
1~ C
4alcoholic solvent, as methyl alcohol, ethanol, Virahol etc.
The reaction equation of the preparation method of oxygen cephalosporin compound of the present invention is as follows:
In sum, the present invention compared with prior art, has the following advantages:
1. the preparation method of oxygen cephalosporin compound of the present invention, by adopting oxygen cephalo and 1-methyl-5-mercapto tetrazole to be starting raw material, by " one kettle way " synthetic product, avoid the impact of other side reaction, effectively can utilize the reactive behavior of raw material, substantially increase yield, the reaction scheme of minimizing, simplify production technique, be more conducive to suitability for industrialized production.
2. the preparation method of oxygen cephalosporin compound of the present invention, by the improvement to method, avoid employing chlorine, the requirement of the safety in production both ensured, can realize again adopting general equipment just can meet the requirements, high request to equipment when not needing existing employing chlorine, reduces production cost.
3. the preparation method of oxygen cephalosporin compound of the present invention, has reaction scheme short, is conducive to the advantage of production operation, and the product yield finally obtained is high, and molar product yield can reach more than 65%, HPLC purity can reach more than 95%.
Accompanying drawing explanation
Fig. 1 is that the 7-(4-methyl-benzoyl) that obtains of method of the present invention is amino) the IR spectrogram of-7-methoxyl group-(3-((1-methyl isophthalic acid H-tetrazolium-5-base) sulphur) methyl)-8-oxo-5-oxa--1-azabicyclo [4.2.0] oct-2-ene-2-formic acid phenylbenzene methyl esters;
Embodiment
Below by specific embodiment, technical scheme of the present invention is described in further detail, but the present invention is not limited to these embodiments.
Embodiment 1
Type I compound 7-(benzoyl) is amino) preparation method of-7-methoxyl group-(3-((1-methyl isophthalic acid H-tetrazolium-5-base) sulphur) methyl)-8-oxo-5-oxa--1-azabicyclo [4.2.0] oct-2-ene-2-formic acid phenylbenzene methyl esters:
500mL methylene dichloride is added in the four-hole bottle of 2000mL, then 47g(0.1mol is added) formula II compound, in its Chinese style II compound, R is hydrogen, be stirred to and dissolve clarification, with liquid nitrogen cooling to-45 DEG C, slowly add 15g(0.14mol again) t-butyl hypochlorate, start the methanol solution dripping lithium methoxide, wherein lithium methoxide is 15g(0.4mol), methyl alcohol is 150mL, in dropping process, control temperature is-45 DEG C, after dropwising, continuing control temperature is react 2.0 hours under the condition of-45 DEG C, after reaction terminates, TLC is adopted to detect, moving phase is sherwood oil: ethyl acetate is 2:1, detected result is for reacting completely, then 20mL acetic acid is added, stir 20 minutes, add the sodium thiosulfate solution 500mL that mass concentration is 5% again, agitator treating 10 minutes again, leave standstill, layering, collect organic phase, remove aqueous phase, and then 100mL saturated sodium-chloride water solution is added in organic phase, agitator treating 30 minutes, leave standstill, layering, collect organic phase, remove aqueous phase, then, in organic phase, add 20g anhydrous sodium sulphate again carry out drying, stir 30 minutes, filter, obtain the dichloromethane solution of formula III compound,
14g(0.12mol is added in the dichloromethane solution of formula III compound obtained above) formula IV compound 1-methyl-5-mercapto tetrazole, under agitation condition, chilled brine is adopted to be cooled to-10 DEG C, then, drip 13g(0.11mol simultaneously) methylsulfonyl chloride and 32g(0.32mol) triethylamine, in dropping process, control temperature is at-10 DEG C, after dropwising, slowly be warming up to 25 DEG C, proceed condensation reaction 5 hours, after reaction terminates, TLC is adopted to detect, moving phase is sherwood oil and ethyl acetate is 2:1, result display reacts completely, then, slowly add 300mL water, stir 15 minutes, leave standstill, layering, collect organic phase, remove aqueous phase, again to collect organic phase in add 300mL mass concentration be 2% aqueous hydrochloric acid wash, agitator treating 15 minutes, leave standstill, layering, collect organic phase, remove aqueous phase, again to collect organic phase in add 200mL mass concentration be 5% the sodium bicarbonate aqueous solution wash, agitator treating 15 minutes, leave standstill, layering, collect organic phase, remove aqueous phase, then, in the organic phase of collecting, add the 200mL saturated common salt aqueous solution again to wash, agitator treating 15 minutes, leave standstill, layering, collect organic phase, remove aqueous phase, add 10g anhydrous sodium sulphate in the organic phase of the most backward collection and carry out drying, stir 30 minutes, filter, collect filtrate, the filtrate obtained is carried out underpressure distillation and reclaim methylene dichloride, control the temperature of underpressure distillation not higher than 40 DEG C, be distilled to dry, obtain corresponding product type I compound, in order to improve the purity of product further, the corresponding product type I compound obtained is added in 150mL methanol solvate, under room temperature, stir 1 hour, then, slow cooling to 5 DEG C, control temperature, stirring and crystallizing 1 hour again, filter, filter cake methanol wash 3 times, each 30mL methanol wash, dry, obtain corresponding product type I compound 40.2g, HPLC purity is 97.5%.
Embodiment 2
Type I compound 7-(benzoyl) is amino) preparation method of-7-methoxyl group-(3-((1-methyl isophthalic acid H-tetrazolium-5-base) sulphur) methyl)-8-oxo-5-oxa--1-azabicyclo [4.2.0] oct-2-ene-2-formic acid phenylbenzene methyl esters
550mL chloroform is added in the four-hole bottle of 2000mL, then 47g(0.1mol is added) formula II compound, in its Chinese style II compound, R is hydrogen, be stirred to and dissolve clarification, with liquid nitrogen cooling to-50 DEG C, slowly add 10.8g(0.1mol again) t-butyl hypochlorate, start the methanol solution dripping lithium methoxide, wherein, in the methanol solution of lithium methoxide, lithium methoxide is 19g(0.5mol), methyl alcohol is 200mL, in dropping process, control temperature is-50 DEG C, after dropwising, continuing control temperature is react 2.5 hours under the condition of-50 DEG C, after reaction terminates, TLC is adopted to detect, moving phase is sherwood oil: ethyl acetate is 2:1, detected result is for reacting completely, then 20mL acetic acid is added, stir 20 minutes, add the sodium thiosulfate solution 500mL that mass concentration is 5% again, stir 10 minutes again, leave standstill, layering, collect organic phase, remove aqueous phase, and then 100mL saturated sodium-chloride water solution is added in organic phase, agitator treating 30 minutes, leave standstill, layering, collect organic phase, remove aqueous phase, finally, in organic phase, add 20g anhydrous sodium sulphate again carry out drying, stir 30 minutes, filter, obtain the chloroformic solution of formula III compound,
11.6g(0.1mol is added in the chloroformic solution of formula III compound obtained above) formula IV compound 1-methyl-5-mercapto tetrazole, under agitation condition, chilled brine is adopted to be cooled to-5 DEG C, then, drip 21g(0.12mol simultaneously) benzene sulfonyl chloride and 25g(0.25mo l) triethylamine, in dropping process, control temperature is at-5 DEG C, after dropwising, slowly be warming up to 35 DEG C, control temperature proceeds condensation reaction 3.0 hours, after reaction terminates, TLC is adopted to detect, moving phase is sherwood oil and ethyl acetate is 2:1, result display reacts completely, slowly add 300mL water, stir 15 minutes, leave standstill, layering, collect organic phase, remove aqueous phase, again to collect organic phase in add 300mL mass concentration be 3.0% aqueous hydrochloric acid wash, agitator treating 20 minutes, leave standstill, layering, collect organic phase, remove aqueous phase, again to collect organic phase in add 200mL mass concentration be 5% the sodium bicarbonate aqueous solution wash, agitator treating 15 minutes, leave standstill, layering, collect organic phase, remove aqueous phase, then, in the organic phase of collecting, add the 200mL saturated common salt aqueous solution again to wash, agitator treating 15 minutes, leave standstill, layering, collect organic phase, remove aqueous phase, add 15g anhydrous sodium sulphate in the organic phase of the most backward collection and carry out drying, stir 30 minutes, filter, collect filtrate, the filtrate obtained is carried out underpressure distillation and reclaim chloroform, control the temperature of underpressure distillation not higher than 35 DEG C, be distilled to dry, obtain corresponding product type I compound, in order to improve the purity of product further, the corresponding product type I compound obtained is added in 150mL anhydrous ethanol solvent, under room temperature, stir 1 hour, then, slow cooling to 0 DEG C, control temperature, stirring and crystallizing 1.5 hours again, filter, filter cake absolute ethanol washing 3 times, each 30mL absolute ethanol washing, the solid matter obtained is dried, obtain corresponding product type I compound 40.2g, the molar yield of product is 66%, HPLC purity is 98.0%.
Embodiment 3
Type I compound 7-(benzoyl) is amino) preparation method of-7-methoxyl group-(3-((1-methyl isophthalic acid H-tetrazolium-5-base) sulphur) methyl)-8-oxo-5-oxa--1-azabicyclo [4.2.0] oct-2-ene-2-formic acid phenylbenzene methyl esters
550mL methylene dichloride and 50ml dioxane is added in the four-hole bottle of 2000mL, then 47g(0.1mo l is added) formula II compound, in its Chinese style II compound, R is hydrogen, be stirred to and dissolve clarification, with liquid nitrogen cooling to-60 DEG C, slowly add 21.7g(0.2mol again) t-butyl hypochlorate, start the methanol solution dripping lithium methoxide, wherein, in the methanol solution of lithium methoxide, lithium methoxide is 13.3g(0.35mol), methyl alcohol is 180mL, in dropping process, control temperature is-60 DEG C, after dropwising, continuing control temperature is react 3.0 hours under the condition of-60 DEG C, after reaction terminates, TLC is adopted to detect, moving phase is sherwood oil: ethyl acetate is 2:1, detected result is for reacting completely, then 20mL acetic acid is added, stir 20 minutes, add the sodium thiosulfate solution 500mL that mass concentration is 5% again, stir 10 minutes again, leave standstill, layering, collect organic phase, remove aqueous phase, and then 100mL saturated sodium-chloride water solution is added in organic phase, agitator treating 30 minutes, leave standstill, layering, collect organic phase, remove aqueous phase, finally, in organic phase, add 20g anhydrous sodium sulphate again carry out drying, stir 30 minutes, filter, obtain the dichloromethane solution of corresponding formula III compound,
17.4g(0.15mo l is added in the dichloromethane solution of formula III compound obtained above) formula IV compound 1-methyl-5-mercapto tetrazole, under agitation condition, frozen water is adopted to be cooled to 0 DEG C, then, drip 38g(0.2mol simultaneously) condensing agent Tosyl chloride and 30.5g(0.35mol) acid-binding agent morpholine, in dropping process, control temperature is at 0 DEG C, after dropwising, slowly be warming up to 20 DEG C, control temperature proceeds condensation reaction 8.0 hours, after reaction terminates, TLC is adopted to detect, moving phase is sherwood oil and ethyl acetate is 2:1, result display reacts completely, slowly add 300mL water, stir 15 minutes, leave standstill, layering, collect organic phase, remove aqueous phase, again to collect organic phase in add 300mL mass concentration be 5% aqueous hydrochloric acid wash, agitator treating 20 minutes, leave standstill, layering, collect organic phase, remove aqueous phase, again to collect organic phase in add 200mL mass concentration be 5% the sodium bicarbonate aqueous solution wash, agitator treating 15 minutes, leave standstill, layering, collect organic phase, remove aqueous phase, then, in the organic phase of collecting, add the 200mL saturated common salt aqueous solution again to wash, agitator treating 15 minutes, leave standstill, layering, collect organic phase, remove aqueous phase, add 15g anhydrous sodium sulphate in the organic phase of the most backward collection and carry out drying, stir 30 minutes, filter, collect filtrate, the filtrate obtained is carried out underpressure distillation and reclaim methylene dichloride, control the temperature of underpressure distillation not higher than 35 DEG C, be distilled to dry, obtain corresponding product type I compound, in order to improve the purity of product further, to obtain corresponding product type I compound adds in 150mL isopropanol solvent, under room temperature, stir 1 hour, then, slow cooling is to-5 DEG C, control temperature, stirring and crystallizing 1.0 hours again, filter, filter cake washed with isopropyl alcohol 3 times, each 30mL washed with isopropyl alcohol, gained solid is dried, obtain corresponding product type I compound 40.9g, the molar yield of product is 67%, HPLC purity is 98.2%.
Embodiment 4
Type I compound 7-(benzoyl) is amino) preparation method of-7-methoxyl group-(3-((1-methyl isophthalic acid H-tetrazolium-5-base) sulphur) methyl)-8-oxo-5-oxa--1-azabicyclo [4.2.0] oct-2-ene-2-formic acid phenylbenzene methyl esters
550mL chloroform and 50ml tetrahydrofuran (THF) is added in the four-hole bottle of 2000mL, then 47g(0.1mol is added) formula II compound, in its Chinese style II compound, R is hydrogen, be stirred to and dissolve clarification, with liquid nitrogen cooling to-40 DEG C, slowly add 16.3g(0.15mol again) t-butyl hypochlorate, start the methanol solution dripping lithium methoxide, wherein, in the methanol solution of lithium methoxide, lithium methoxide is 7.8g(0.2mol), methyl alcohol is 110mL, in dropping process, control temperature is-40 DEG C, after dropwising, continuing control temperature is react 0.5 hour under the condition of-40 DEG C, after reaction terminates, TLC is adopted to detect, moving phase is sherwood oil: ethyl acetate is 2:1, detected result is for reacting completely, then 20mL acetic acid is added, stir 20 minutes, add the sodium thiosulfate solution 500mL that mass concentration is 5% again, stir 10 minutes again, leave standstill, layering, collect organic phase, remove aqueous phase, and then 100mL saturated sodium-chloride water solution is added in organic phase, agitator treating 30 minutes, leave standstill, layering, collect organic phase, remove aqueous phase, finally, in organic phase, add 20g anhydrous sodium sulphate again carry out drying, stir 30 minutes, filter, obtain the chloroformic solution of formula III compound,
23.2g(0.2mol is added in the chloroformic solution of formula III compound obtained above) formula IV compound 1-methyl-5-mercapto tetrazole, under agitation condition, chilled brine is adopted to be cooled to-10 DEG C, then, drip 12g(0.1mol simultaneously) condensing agent methylsulfonyl chloride and 0.2mo l acid-binding agent piperidines, in dropping process, control temperature is at-10 DEG C, after dropwising, slowly be warming up to 10 DEG C, control temperature proceeds condensation reaction 10 hours, after reaction terminates, TLC is adopted to detect, moving phase is sherwood oil and ethyl acetate is 2:1, result display reacts completely, slowly add 300mL water, stir 15 minutes, leave standstill, layering, collect organic phase, remove aqueous phase, again to collect organic phase in add 300mL mass concentration be 5% aqueous hydrochloric acid wash, agitator treating 20 minutes, leave standstill, layering, collect organic phase, remove aqueous phase, again to collect organic phase in add 200mL mass concentration be 5% the sodium bicarbonate aqueous solution wash, agitator treating 15 minutes, leave standstill, layering, collect organic phase, remove aqueous phase, then, in the organic phase of collecting, add the 200mL saturated common salt aqueous solution again to wash, agitator treating 15 minutes, leave standstill, layering, collect organic phase, remove aqueous phase, add 15g anhydrous sodium sulphate in the organic phase of the most backward collection and carry out drying, stir 30 minutes, filter, collect filtrate, the filtrate obtained is carried out underpressure distillation and reclaim chloroform, control the temperature of underpressure distillation not higher than 35 DEG C, be distilled to dry, obtain product type I compound, in order to improve the purity of product further, the product type I compound obtained is added in 150mL methanol solvate, under room temperature, stir 1 hour, then, slow cooling is to-5 DEG C, control temperature, stirring and crystallizing 1.0 hours again, filter, filter cake methanol wash 3 times, each 30mL methanol wash, gained solid is dried, obtain corresponding product type I compound 40g, the molar yield of product is 65.8%, HPLC purity is 98.1%.
Embodiment 5
Type I compound 7-(benzoyl) is amino) preparation method of-7-methoxyl group-(3-((1-methyl isophthalic acid H-tetrazolium-5-base) sulphur) methyl)-8-oxo-5-oxa--1-azabicyclo [4.2.0] oct-2-ene-2-formic acid phenylbenzene methyl esters:
500mL methylene dichloride is added in the four-hole bottle of 2000mL, then 47g(0.1mol is added) formula II compound, in its Chinese style II compound, R is hydrogen, be stirred to and dissolve clarification, with liquid nitrogen cooling to-55 DEG C, slowly add 14g(0.13mo l again) t-butyl hypochlorate, start the methanol solution dripping lithium methoxide, in the methanol solution of wherein lithium methoxide, lithium methoxide is 9.5g(0.25mo l), the mass concentration of lithium methoxide is 15%, in dropping process, control temperature is-55 DEG C, after dropwising, continuing control temperature is react 1.5 hours under the condition of-55 DEG C, after reaction terminates, TLC is adopted to detect, moving phase is sherwood oil: ethyl acetate is 2:1, detected result is for reacting completely, then 20mL acetic acid is added, stir 20 minutes, add the sodium thiosulfate solution 500mL that mass concentration is 5% again, stir 10 minutes again, leave standstill, layering, collect organic phase, remove aqueous phase, and then 100mL saturated sodium-chloride water solution is added in organic phase, agitator treating 30 minutes, leave standstill, layering, collect organic phase, remove aqueous phase, then, in organic phase, add 20g anhydrous sodium sulphate again carry out drying, stir 30 minutes, filter, obtain the dichloromethane solution of formula III compound,
16.3g(0.14mo l is added in the dichloromethane solution of formula III compound obtained above) formula IV compound 1-methyl-5-mercapto tetrazole, under agitation condition, chilled brine is adopted to be cooled to-5 DEG C, then, drip 0.3mo l condensing agent NCS and 29.4g(0.35mo l simultaneously) sodium bicarbonate, in dropping process, control temperature is at-5 DEG C, after dropwising, slowly be warming up to 15 DEG C, proceed condensation reaction 7 hours, after reaction terminates, TLC is adopted to detect, moving phase is sherwood oil and ethyl acetate is 2:1, result display reacts completely, then, slowly add 300mL water, stir 15 minutes, leave standstill, layering, collect organic phase, remove aqueous phase, again to collect organic phase in add 300mL mass concentration be 2% aqueous hydrochloric acid wash, agitator treating 15 minutes, leave standstill, layering, collect organic phase, remove aqueous phase, again to collect organic phase in add 200mL mass concentration be 5% the sodium bicarbonate aqueous solution wash, agitator treating 15 minutes, leave standstill, layering, collect organic phase, remove aqueous phase, then, in the organic phase of collecting, add the 200mL saturated common salt aqueous solution again to wash, agitator treating 15 minutes, leave standstill, layering, collect organic phase, remove aqueous phase, add 10g anhydrous sodium sulphate in the organic phase of the most backward collection and carry out drying, stir 30 minutes, filter, collect filtrate, the filtrate obtained is carried out underpressure distillation and reclaim methylene dichloride, control the temperature of underpressure distillation not higher than 40 DEG C, be distilled to dry, obtain product type I compound, in order to improve the purity of product further, the product type I compound obtained is added in 150mL methanol solvate, under room temperature, stir 1 hour, then, slow cooling to 5 DEG C, control temperature, stirring and crystallizing 1 hour again, filter, filter cake methanol wash 3 times, each 30mL methanol wash, gained solid is dried, obtain product type I compound 41g, the molar yield of product is 67.2%, HPLC purity is 97.5%.
Embodiment 6
Type I compound 7-(benzoyl) is amino) preparation method of-7-methoxyl group-(3-((1-methyl isophthalic acid H-tetrazolium-5-base) sulphur) methyl)-8-oxo-5-oxa--1-azabicyclo [4.2.0] oct-2-ene-2-formic acid phenylbenzene methyl esters:
Concrete preparation method is consistent with the preparation method described in embodiment 5, difference is, acid-binding agent used in the present embodiment is the one in sodium carbonate, salt of wormwood, condensing agent described in the present embodiment is the one in benzene sulfonyl chloride, SULPHURYL CHLORIDE, wherein, described formula II compound and the mol ratio of acid-binding agent are 1:3.0, and II described compound and the mol ratio of condensing agent are 1:1.3.The molar yield of final gained corresponding product reaches more than 65%, HPLC purity and reaches more than 95%.
Embodiment 7
Type I compound 7-(benzoyl) is amino) preparation method of-7-methoxyl group-(3-((1-methyl isophthalic acid H-tetrazolium-5-base) sulphur) methyl)-8-oxo-5-oxa--1-azabicyclo [4.2.0] oct-2-ene-2-formic acid phenylbenzene methyl esters:
Concrete preparation method is consistent with the method described in embodiment 1, difference is, acid-binding agent used in the present embodiment is two or more in pyridine, piperidines, morpholine, triethylamine, condensing agent described in the present embodiment is methylsulfonyl chloride, wherein, described formula II compound and the mol ratio of acid-binding agent are 1:2.5, and II described compound and the mol ratio of condensing agent methylsulfonyl chloride are 1:1.2.The molar yield of the corresponding product of final gained reaches more than 65%, HPLC purity and reaches more than 95%.
Embodiment 8
Type I compound 7-(benzoyl) is amino) preparation method of-7-methoxyl group-(3-((1-methyl isophthalic acid H-tetrazolium-5-base) sulphur) methyl)-8-oxo-5-oxa--1-azabicyclo [4.2.0] oct-2-ene-2-formic acid phenylbenzene methyl esters:
Concrete preparation method is consistent with the method described in embodiment 1, difference is, acid-binding agent used in the present embodiment is two or more in salt of wormwood, sodium carbonate, sodium bicarbonate, condensing agent described in the present embodiment is methylsulfonyl chloride, wherein, described formula II compound and the mol ratio of acid-binding agent are 1:3.0, and II described compound and the mol ratio of condensing agent methylsulfonyl chloride are 1:1.3.The molar yield of the corresponding product of final gained reaches more than 65%, HPLC purity and reaches more than 95%.
Embodiment 9
Type I compound 7-(4-methyl-benzoyl) is amino) preparation method of-7-methoxyl group-(3-((1-methyl isophthalic acid H-tetrazolium-5-base) sulphur) methyl)-8-oxo-5-oxa--1-azabicyclo [4.2.0] oct-2-ene-2-formic acid phenylbenzene methyl esters:
500mL methylene dichloride is added in the four-hole bottle of 2000mL, then 48g(0.1mol is added) formula II compound, in its Chinese style II compound, R is methyl, be stirred to and dissolve clarification, with liquid nitrogen cooling to less than-50 DEG C, slowly add 15g(0.14mol again) t-butyl hypochlorate, start the methanol solution dripping lithium methoxide, in the methanol solution of wherein lithium methoxide, lithium methoxide is 19g(0.5mol), and the mass concentration 10% of lithium methoxide, in dropping process, control temperature is-50 DEG C, after dropwising, continuing control temperature is react 3.0 hours under the condition of-50 DEG C, after reaction terminates, TLC is adopted to detect, moving phase is sherwood oil: ethyl acetate is 2:1, detected result is for reacting completely, then 20mL acetic acid is added, stir 20 minutes, add the sodium thiosulfate solution 500mL that mass concentration is 5% again, stir 10 minutes again, leave standstill, layering, collect organic phase, remove aqueous phase, and then 100mL saturated sodium-chloride water solution is added in organic phase, agitator treating 30 minutes, leave standstill, layering, collect organic phase, remove aqueous phase, then, in organic phase, add 20g anhydrous sodium sulphate again carry out drying, stir 30 minutes, filter, obtain the dichloromethane solution of formula III compound,
14g(0.12mo l is added in the dichloromethane solution of formula III compound obtained above) formula IV compound 1-methyl-5-mercapto tetrazole, under agitation condition, chilled brine is adopted to be cooled to-5 DEG C, then, drip 11.8g(0.10mol simultaneously) condensing agent methylsulfonyl chloride and 30.5g(0.35mol) acid-binding agent morpholine, in dropping process, control temperature is at-5 DEG C, after dropwising, slowly be warming up to 10 DEG C, proceed condensation reaction 10 hours, after reaction terminates, TLC is adopted to detect, moving phase is sherwood oil and ethyl acetate is 2:1, result display reacts completely, then, slowly add 300mL water, stir 15 minutes, leave standstill, layering, collect organic phase, remove aqueous phase, again to collect organic phase in add 300mL mass concentration be 2% aqueous hydrochloric acid wash, agitator treating 15 minutes, leave standstill, layering, collect organic phase, remove aqueous phase, again to collect organic phase in add 200mL mass concentration be 5% the sodium bicarbonate aqueous solution wash, agitator treating 15 minutes, leave standstill, layering, collect organic phase, remove aqueous phase, then, in the organic phase of collecting, add the 200mL saturated common salt aqueous solution again to wash, agitator treating 15 minutes, leave standstill, layering, collect organic phase, remove aqueous phase, add 10g anhydrous sodium sulphate in the organic phase of the most backward collection and carry out drying, stir 30 minutes, filter, collect filtrate, the filtrate obtained is carried out underpressure distillation and reclaim methylene dichloride, control the temperature of underpressure distillation not higher than 40 DEG C, be distilled to dry, obtain product type I compound, in order to improve the purity of product further, the product type I compound obtained is added in 150mL methanol solvate, under room temperature, stir 1 hour, then, slow cooling to 5 DEG C, control temperature is at 5 DEG C, stirring and crystallizing 1 hour again, filter, filter cake methanol wash 3 times, each 30mL methanol wash, gained solid is dried, obtain corresponding product type I compound 41.4g, molar yield is 66%, HPLC purity is 97.8%.
Embodiment 10
Type I compound 7-(4-methyl-benzoyl) is amino) preparation method of-7-methoxyl group-(3-((1-methyl isophthalic acid H-tetrazolium-5-base) sulphur) methyl)-8-oxo-5-oxa--1-azabicyclo [4.2.0] oct-2-ene-2-formic acid phenylbenzene methyl esters:
500mL chloroform is added in the four-hole bottle of 2000mL, then 48g(0.1mol is added) formula II compound, in its Chinese style II compound, R is methyl, be stirred to and dissolve clarification, with liquid nitrogen cooling to-40 DEG C, slowly add 21.7g(0.2mol again) t-butyl hypochlorate, start the methanol solution dripping lithium methoxide, wherein, in the methanol solution of lithium methoxide used, lithium methoxide is 13.3g(0.35mol), the mass concentration of lithium methoxide is 7%, in dropping process, control temperature is-40 DEG C, after dropwising, continuing control temperature is react 2.5 hours under the condition of-40 DEG C, after reaction terminates, TLC is adopted to detect, moving phase is sherwood oil: ethyl acetate is 2:1, detected result is for reacting completely, then 20mL acetic acid is added, stir 20 minutes, add the sodium thiosulfate solution 500mL that mass concentration is 5% again, stir 10 minutes again, leave standstill, layering, collect organic phase, remove aqueous phase, and then 100mL saturated sodium-chloride water solution is added in organic phase, agitator treating 30 minutes, leave standstill, layering, collect organic phase, remove aqueous phase, then, in organic phase, add 20g anhydrous sodium sulphate again carry out drying, stir 30 minutes, filter, obtain the chloroformic solution of formula III compound,
17.4g(0.15mol is added in the chloroformic solution of formula III compound obtained to above-mentioned steps) formula IV compound 1-methyl-5-mercapto tetrazole, under agitation condition, chilled brine is adopted to be cooled to 5 DEG C, then, drip 0.2mo l condensing agent Tosyl chloride and 21g(0.25mol simultaneously) acid-binding agent piperidines, in dropping process, control temperature is at 5 DEG C, after dropwising, continue control temperature at 5 DEG C, carry out condensation reaction 9 hours, after reaction terminates, TLC is adopted to detect, moving phase is sherwood oil and ethyl acetate is 2:1, result display reacts completely, then, slowly add 300mL water, stir 15 minutes, leave standstill, layering, collect organic phase, remove aqueous phase, again to collect organic phase in add 300mL mass concentration be 2% aqueous hydrochloric acid wash, agitator treating 15 minutes, leave standstill, layering, collect organic phase, remove aqueous phase, again to collect organic phase in add 200mL mass concentration be 5% the sodium bicarbonate aqueous solution wash, agitator treating 15 minutes, leave standstill, layering, collect organic phase, remove aqueous phase, then, in the organic phase of collecting, add the 200mL saturated common salt aqueous solution again to wash, agitator treating 15 minutes, leave standstill, layering, collect organic phase, remove aqueous phase, add 10g anhydrous sodium sulphate in the organic phase of the most backward collection and carry out drying, stir 30 minutes, filter, collect filtrate, the filtrate obtained is carried out underpressure distillation and reclaim chloroform, control the temperature of underpressure distillation not higher than 35 DEG C, be distilled to dry, obtain corresponding product type I compound, in order to improve the purity of product further, under room temperature, the corresponding product type I compound obtained is added in 150mL anhydrous ethanol solvent, stir 1 hour, then, slow cooling to 0 DEG C, control temperature is at 0 DEG C, stirring and crystallizing 1 hour again, filter, filter cake absolute ethanol washing 3 times, each 30mL absolute ethanol washing, gained solid is dried, obtain corresponding product type I compound 41.7g, molar yield is 66.5%, HPLC purity is 98.2%.
Embodiment 11
Type I compound 7-(4-methyl-benzoyl) is amino) preparation method of-7-methoxyl group-(3-((1-methyl isophthalic acid H-tetrazolium-5-base) sulphur) methyl)-8-oxo-5-oxa--1-azabicyclo [4.2.0] oct-2-ene-2-formic acid phenylbenzene methyl esters:
500mL methylene dichloride and 50mL glycol dimethyl ether is added in the four-hole bottle of 2000mL, and then add 48g(0.1mol) formula II compound, in its Chinese style II compound, R is methyl, be stirred to dissolving, with liquid nitrogen cooling to-100 DEG C, slowly add 11g(0.1mol again) t-butyl hypochlorate, start the methanol solution dripping lithium methoxide, in the methanol solution of wherein lithium methoxide, lithium methoxide is 7.6g(0.2mol), methyl alcohol is 100mL, in dropping process, control temperature is-42 DEG C, after dropwising, continuing control temperature is react 2.0 hours under the condition of-42 DEG C, after reaction terminates, TLC is adopted to detect, moving phase is sherwood oil: ethyl acetate is 2:1, detected result is for reacting completely, then 20mL acetic acid is added, stir 20 minutes, add the sodium thiosulfate solution 500mL that mass concentration is 5% again, stir 10 minutes again, leave standstill, layering, collect organic phase, remove aqueous phase, and then 100mL saturated sodium-chloride water solution is added in organic phase, agitator treating 30 minutes, leave standstill, layering, collect organic phase, remove aqueous phase, then, in organic phase, add 20g anhydrous sodium sulphate again carry out drying, stir 30 minutes, filter, obtain the dichloromethane solution of formula III compound,
23.2g(0.2mol is added in the dichloromethane solution of formula III compound obtained to above-mentioned steps) formula IV compound 1-methyl-5-mercapto tetrazole, under agitation condition, chilled brine is adopted to be cooled to-10 DEG C, then, drip 16g(0.12mol simultaneously) condensing agent NCS and 28g(0.2mol) acid-binding agent salt of wormwood, in dropping process, control temperature is at-10 DEG C, after dropwising, continue control temperature at-10 DEG C, carry out condensation reaction 8 hours, after reaction terminates, TLC is adopted to detect, moving phase is sherwood oil and ethyl acetate is 2:1, result display reacts completely, then, slowly add 300mL water, stir 15 minutes, leave standstill, layering, collect organic phase, remove aqueous phase, again to collect organic phase in add 300mL mass concentration be 2% aqueous hydrochloric acid wash, agitator treating 15 minutes, leave standstill, layering, collect organic phase, remove aqueous phase, again to collect organic phase in add 200mL mass concentration be 5% the sodium bicarbonate aqueous solution wash, agitator treating 15 minutes, leave standstill, layering, collect organic phase, remove aqueous phase, then, in the organic phase of collecting, add the 200mL saturated common salt aqueous solution again to wash, agitator treating 15 minutes, leave standstill, layering, collect organic phase, remove aqueous phase, add 10g anhydrous sodium sulphate in the organic phase of the most backward collection and carry out drying, stir 30 minutes, filter, collect filtrate, the filtrate obtained is carried out underpressure distillation and reclaim methylene dichloride, control the temperature of underpressure distillation not higher than 35 DEG C, be distilled to dry, obtain corresponding product type I compound, in order to improve the purity of product further, under room temperature, the corresponding product type I compound obtained is added in 150mL water, stir 0.5 hour, then, slow cooling to 5 DEG C, control temperature is at 5 DEG C, stirred crystallization 1 hour again, filter, with ethanol, washing is carried out 3 times to filter cake, each 20mL, gained solid is dried, obtain corresponding product type I compound 42g, molar yield is 67%, HPLC purity is 98.1%.
Embodiment 12
Type I compound 7-(4-methyl-benzoyl) is amino) preparation method of-7-methoxyl group-(3-((1-methyl isophthalic acid H-tetrazolium-5-base) sulphur) methyl)-8-oxo-5-oxa--1-azabicyclo [4.2.0] oct-2-ene-2-formic acid phenylbenzene methyl esters:
500mL chloroform and 50mL dioxane is added in the four-hole bottle of 2000mL, and then add 48g(0.1mol) formula II compound, in its Chinese style II compound, R is methyl, be stirred to dissolving, with liquid nitrogen cooling to-45 DEG C, slowly add 17.4g(0.16mol again) t-butyl hypochlorate, start the methanol solution dripping lithium methoxide, wherein, in the methanol solution of lithium methoxide, lithium methoxide is 8.7g(0.23mol), methyl alcohol is 125mL, in dropping process, control temperature is-45 DEG C, after dropwising, continuing control temperature is react 2.5 hours under the condition of-45 DEG C, after reaction terminates, TLC is adopted to detect, moving phase is sherwood oil: ethyl acetate is 2:1, detected result is for reacting completely, then 20mL acetic acid is added, stir 20 minutes, add the sodium thiosulfate solution 500mL that mass concentration is 5% again, stir 10 minutes again, leave standstill, layering, collect organic phase, remove aqueous phase, and then 100mL saturated sodium-chloride water solution is added in organic phase, agitator treating 30 minutes, leave standstill, layering, collect organic phase, remove aqueous phase, then, in organic phase, add 20g anhydrous sodium sulphate again carry out drying, stir 30 minutes, filter, obtain the chloroformic solution of formula III compound,
12.7g(0.11mol is added in the chloroformic solution of formula III compound obtained to above-mentioned steps) formula IV compound 1-methyl-5-mercapto tetrazole, under agitation condition, frozen water is adopted to be cooled to-0 DEG C, then, drip 57g(0.3mo l simultaneously) condensing agent benzene sulfonyl chloride and 33.6g(0.4mol) acid-binding agent sodium bicarbonate, in dropping process, control temperature is at-0 DEG C, after dropwising, continue slowly to be warming up to 35 DEG C, and control temperature carries out condensation reaction 0.5 hour at 35 DEG C, after reaction terminates, TLC is adopted to detect, moving phase is sherwood oil and ethyl acetate is 2:1, result display reacts completely, then, slowly add 300mL water, stir 15 minutes, leave standstill, layering, collect organic phase, remove aqueous phase, again to collect organic phase in add 300mL mass concentration be 2% aqueous hydrochloric acid wash, agitator treating 15 minutes, leave standstill, layering, collect organic phase, remove aqueous phase, again to collect organic phase in add 200mL mass concentration be 5% the sodium bicarbonate aqueous solution wash, agitator treating 15 minutes, leave standstill, layering, collect organic phase, remove aqueous phase, then, in the organic phase of collecting, add the 200mL saturated common salt aqueous solution again to wash, agitator treating 15 minutes, leave standstill, layering, collect organic phase, remove aqueous phase, add 10g anhydrous sodium sulphate in the organic phase of the most backward collection and carry out drying, stir 30 minutes, filter, collect filtrate, the filtrate obtained is carried out underpressure distillation and reclaim chloroform, control the temperature of underpressure distillation not higher than 35 DEG C, be distilled to dry, obtain corresponding product type I compound, in order to improve the purity of product further, under room temperature, the corresponding product type I compound obtained is added in 150mL methanol solvate, stir 0.5 hour, then, slow cooling to 0 DEG C, control temperature is at 0 DEG C, stirring and crystallizing 1 hour again, filter, with methyl alcohol, washing is carried out 3 times to filter cake, each 20mL methyl alcohol, gained solid is dried, obtain corresponding product type I compound 42g, molar yield is 67%, HPLC purity is 98.3%.
Embodiment 13
Type I compound 7-(4-methyl-benzoyl) is amino) preparation method of-7-methoxyl group-(3-((1-methyl isophthalic acid H-tetrazolium-5-base) sulphur) methyl)-8-oxo-5-oxa--1-azabicyclo [4.2.0] oct-2-ene-2-formic acid phenylbenzene methyl esters:
Concrete preparation method is consistent with the method described in embodiment 8, difference is, acid-binding agent used in the present embodiment is triethylamine, condensing agent described in the present embodiment is SULPHURYL CHLORIDE, wherein, described formula II compound and the mol ratio of acid-binding agent triethylamine are 1:2.5, and II described compound and the mol ratio of condensing agent SULPHURYL CHLORIDE are 1:1.5.The molar yield of final corresponding product is that 66.4%, HPLC purity reaches 97.6%.
Embodiment 14
Type I compound 7-(4-methyl-benzoyl) is amino) preparation method of-7-methoxyl group-(3-((1-methyl isophthalic acid H-tetrazolium-5-base) sulphur) methyl)-8-oxo-5-oxa--1-azabicyclo [4.2.0] oct-2-ene-2-formic acid phenylbenzene methyl esters:
Concrete preparation method is consistent with the method described in embodiment 10, difference is, acid-binding agent used in the present embodiment is pyridine, condensing agent described in the present embodiment is methylsulfonyl chloride, wherein, described formula II compound and the mol ratio of acid-binding agent pyridine are 1:3.0, and II described compound and the mol ratio of condensing agent methylsulfonyl chloride are 1:1.3.The molar yield of final corresponding product is that 66.7%, HPLC purity reaches 97.3%.
Embodiment 15
Type I compound 7-(4-methyl-benzoyl) is amino) preparation method of-7-methoxyl group-(3-((1-methyl isophthalic acid H-tetrazolium-5-base) sulphur) methyl)-8-oxo-5-oxa--1-azabicyclo [4.2.0] oct-2-ene-2-formic acid phenylbenzene methyl esters:
Concrete preparation method is consistent with the method described in embodiment 10, difference is, acid-binding agent used in the present embodiment is two or more in pyridine, piperidines, morpholine, condensing agent described in the present embodiment is methylsulfonyl chloride, wherein, described formula II compound and the mol ratio of acid-binding agent are 1:2.8, and II described compound and the mol ratio of condensing agent methylsulfonyl chloride are 1:1.4.The molar yield of final corresponding product reaches more than 65%, HPLC purity and reaches more than 95%.
Embodiment 16
Type I compound 7-(4-methyl-benzoyl) is amino) preparation method of-7-methoxyl group-(3-((1-methyl isophthalic acid H-tetrazolium-5-base) sulphur) methyl)-8-oxo-5-oxa--1-azabicyclo [4.2.0] oct-2-ene-2-formic acid phenylbenzene methyl esters:
Concrete preparation method is consistent with the method described in embodiment 11, difference is, acid-binding agent used in the present embodiment is two or more in salt of wormwood, sodium carbonate, sodium bicarbonate, condensing agent used in the present embodiment is methylsulfonyl chloride, wherein, described formula II compound and the mol ratio of acid-binding agent are 1:3.2, and II described compound and the mol ratio of condensing agent methylsulfonyl chloride are 1:1.2.The molar yield of final corresponding product reaches more than 65%, HPLC purity and reaches more than 95%.
Specific embodiment described in the present invention is only to the explanation for example of the present invention's spirit.Those skilled in the art can make various amendment or supplement or adopt similar mode to substitute to described specific embodiment, but can't depart from spirit of the present invention or surmount the scope that appended claims defines.
Although made a detailed description the present invention and quoted some specific embodiments as proof, to those skilled in the art, only otherwise it is obvious for leaving that the spirit and scope of the present invention can make various changes or revise.
Claims (6)
1. a preparation method for oxygen cephalosporin compound, is characterized in that, the method comprises the following steps:
A, in organic solvent formula II compound and lithium methoxide, t-butyl hypochlorate are carried out being obtained by reacting formula III compound under the condition of-100 DEG C ~-40 DEG C; Described organic solvent is selected from one or more in halogenated alkane, ether solvents; Described halogenated alkane is selected from one or more in methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride; Described ether solvents is selected from tetrahydrofuran (THF), glycol dimethyl ether or dioxane;
Wherein, in formula II, R is selected from H, CH
3in one;
B, under acid-binding agent and condensing agent existent condition, make formula III compound and formula IV compound 1-methyl-5-mercapto tetrazole carry out condensation reaction under the condition of-10 DEG C ~ 35 DEG C, obtain type I compound oxygen cephalosporin compound; Described acid-binding agent is selected from organic bases or mineral alkali; Described condensing agent is selected from condensing agent and is selected from SULPHURYL CHLORIDE, C
1~ C
3alkyl sulfonyl chloride, aryl sulfonyl chloride, one or more in NCS;
2. the preparation method of oxygen cephalosporin intermediate according to claim 1, is characterized in that, the organic solvent described in steps A is selected from one or more in methylene dichloride, chloroform, tetracol phenixin, tetrahydrofuran (THF), dioxane, glycol dimethyl ether.
3. the preparation method of oxygen cephalosporin compound according to claim 1, is characterized in that, described organic bases is selected from one or more in pyridine, piperidines, diethylamine, morpholine, triethylamine.
4. the preparation method of oxygen cephalosporin compound according to claim 1, is characterized in that, described mineral alkali is weakly alkaline mineral alkali, and described weakly alkaline mineral alkali is selected from one or more in sodium carbonate, sodium bicarbonate, salt of wormwood, saleratus.
5. the preparation method of the oxygen cephalosporin compound according to claim 1 or 2 any one, it is characterized in that, the condensing agent described in step B is selected from one or more in methylsulfonyl chloride, benzene sulfonyl chloride, Tosyl chloride, SULPHURYL CHLORIDE, NCS.
6. the preparation method of oxygen cephalosporin compound according to claim 1 and 2, is characterized in that, described formula II compound and the mol ratio of condensing agent are 1:1 ~ 3.
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