CN108727409A - A kind of preparation method of 3- hydroxy-cephams rhzomorph - Google Patents
A kind of preparation method of 3- hydroxy-cephams rhzomorph Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/08—Preparation by forming the ring or condensed ring systems
- C07D501/10—Preparation by forming the ring or condensed ring systems from compounds containing the penicillin ring system
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/59—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3 with hetero atoms directly attached in position 3
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Abstract
The invention discloses a kind of preparation methods of 3- hydroxy-cephams rhzomorph, including the reaction of sulfonylation, enamine, bromo-reaction and ring-closure reaction four-step reaction.Method provided by the invention has the advantages that high yield, low cost and low stain.
Description
Technical field
The invention belongs to pharmaceutical synthesis fields, and in particular to a kind of preparation method of 3- hydroxy-cephams rhzomorph.
Background technology
Cephalosporins are the semisynthetic antibiotics containing cephem in molecule, belong to beta-lactam antibiosis
Element, is the derivative of 7-amino-cephalosporanic acid (7-ACA), has similar bactericidal mechanism with 7-amino-cephalosporanic acid, can break
The cell wall of bad bacterium, and being sterilized in breeding period, be it is a kind of efficiently, low toxicity, can wide clinical application important antibiotic, not only
Have many advantages, such as that strong has a broad antifungal spectrum, antibacterial action, penicillin resistant enzyme, allergic reaction are rare compared with penicillins, and almost to people
There is no toxicity.
3- hydroxy-cepham rhzomorphs are the important intermediates for synthesizing cephalosporins, and preparation method is mainly with blueness
Mycin G sylvite (PGK) is raw material, carries out ring expansion and is transformed to obtain.Synthesis of the prior art for 3- hydroxy-cepham rhzomorphs, has following
Report：
(1) Yoshioka, M. et al. are reported in Pure Appl.Chem., 1987,59,1041 with potassium penicillin G
The method for preparing 3- hydroxy-cepham rhzomorphs is reacted by five steps for starting material, wherein preparing 3- with thiazoline enol ester derivatives
Hydroxy-cepham rhzomorph step uses one kettle way technology, and one kettle way yield is about 70%.The method need to use the sulfonyloxy methyl of severe toxicity
Chlorine is sulfonylation agent；
(2) Chinese patent CN101525341 is reported prepares 3- hydroxyls by raw material one kettle way of thiazoline enol ester derivatives
The method of base cephalosporin, using paratoluensulfonyl chloride as sulfonylation agent, yield reaches 75% or more, and the purity of product is more than
90%.The method repeats to find that sulfonylation speed is slow, feed stock conversion is relatively low, side reaction is more, and yield is relatively low.
Therefore, it is meaningful to be further improved to the preparation method of 3- hydroxy-cepham rhzomorphs.
Invention content
The purpose of the present invention is to provide a kind of preparation method of 3- hydroxy-cephams rhzomorph, have in high yield, it is low cost, low
The characteristics of pollution.
The present invention provides a kind of preparation method of 3- hydroxy-cephams rhzomorph, and the method includes sulfonylation, enamine, bromos
With four reaction steps of closed loop, as follows：
The preparation method of 3- hydroxy-cephams rhzomorph provided by the invention includes：
(1) sulfonylation：In water or organic solution, at a temperature of -20 DEG C~20 DEG C, in the presence of a catalyst, knot
II compound represented of structural formula is obtained by the reaction in thiazoline enol ester derivatives and paratoluensulfonyl chloride shown in structure formula I,
The catalyst is selected from pyridine, 4-dimethylaminopyridine, 4- lignocaines pyridine, 4- dipropyls aminopyridine, 4- first
At least one of oxygroup pyridine and 4- pyridones；
(2) enamine reacts：At a temperature of -30 DEG C~10 DEG C, keep II compound represented of structural formula and morpholine and alkali anti-
It should obtain III compound represented of structural formula；
(3) bromo-reaction：At a temperature of -40 DEG C~0 DEG C, in the presence of a base, make III compound represented of structural formula and liquid
Bromine reaction obtains IV compound represented of structural formula；
(4) ring-closure reaction：At a temperature of 0~30 DEG C, make the mixing of structural formula IV compound represented and hydrochloric acid and methanol
Solution reaction obtains the 3- hydroxy-cepham rhzomorphs shown in structural formula V；
Wherein：R1For benzyl or benzyloxy；R2For to nitrobenzyl, nitrobenzyl, to methoxy-benzyl or hexichol first
Base.
The preparation method of 3- hydroxy-cephams rhzomorph provided by the invention, in first step sulfonylation, reaction condition can be with
It is：In water or organic solution, at a temperature of -20 DEG C~20 DEG C, in the presence of a catalyst, thiazoline alkene shown in structural formula I
II compound represented of structural formula is obtained by the reaction in ester derivative and paratoluensulfonyl chloride.
Preferably, the reaction condition is：In water or organic solution, at a temperature of -10 DEG C~0 DEG C, in catalyst
In the presence of, thiazoline enol ester derivatives and paratoluensulfonyl chloride shown in structural formula I, which are obtained by the reaction shown in structural formula II, to be changed
Close object.
The catalyst used in sulfonylation can be selected from pyridine, 4-dimethylaminopyridine, 4- lignocaines pyridine,
At least one of 4- dipropyls aminopyridine, 4-methoxypyridine and 4- pyridones.
Preferably, the catalyst is selected from 4-dimethylaminopyridine, 4- lignocaines pyridine and 4- dipropyl aminopyridines
At least one of.
The preparation method of 3- hydroxy-cephams rhzomorph provided by the invention, in the reaction of second step enamine, reaction condition can be with
It is：At a temperature of -30 DEG C~10 DEG C, II compound represented of structural formula is made to be obtained by the reaction shown in structural formula III with morpholine and alkali
Compound.
Preferably, the reaction condition is：At a temperature of -10 DEG C~0 DEG C, make II compound represented of structural formula with
III compound represented of structural formula is obtained by the reaction in quinoline and alkali.
The alkali used can be alkali commonly used in the art.
Preferably, the alkali is independently selected from trimethylamine, triethylamine, tri-n-butylamine, ammonium hydroxide, ammonia, pyridine, morpholine, 2,
6- lutidines, 2,4,6- trimethylpyridines, N-methylmorpholine, N, accelerine and N, in N- diethylanilines extremely
Few one kind.
It may further be preferable that the alkali is in trimethylamine, triethylamine, tri-n-butylamine, ammonium hydroxide, ammonia, pyridine and morpholine
At least one.
The preparation method of 3- hydroxy-cephams rhzomorph provided by the invention, third walk in bromo-reaction, and reaction condition can be：
At a temperature of -40 DEG C~0 DEG C, in the presence of a base, make III compound represented of structural formula and bromine that IV institute of structural formula be obtained by the reaction
The compound shown.
Preferably, the reaction condition is：At a temperature of -20 DEG C~0 DEG C, in the presence of a base, make shown in structural formula III
Compound and bromine IV compound represented of structural formula is obtained by the reaction.
The alkali used can be alkali commonly used in the art.
Preferably, the alkali is independently selected from trimethylamine, triethylamine, tri-n-butylamine, ammonium hydroxide, ammonia, pyridine, morpholine, 2,
6- lutidines, 2,4,6- trimethylpyridines, N-methylmorpholine, N, accelerine and N, in N- diethylanilines extremely
Few one kind.It may further be preferable that the alkali is in pyridine, morpholine, 2,6- lutidines and 2,4,6- trimethylpyridines
At least one.
The preparation method of 3- hydroxy-cephams rhzomorph provided by the invention, the 4th step ring-closure reaction, reaction condition can be：?
At a temperature of 0~30 DEG C, make IV compound represented of structural formula and the mixed solution of hydrochloric acid and methanol that V institute of structural formula be obtained by the reaction
The 3- hydroxy-cepham rhzomorphs shown.
Preferably, the reaction condition is：At a temperature of 10~30 DEG C, make IV compound represented of structural formula and hydrochloric acid
The 3- hydroxy-cepham rhzomorphs shown in structural formula V are obtained by the reaction with the mixed solution of methanol.
The hydrochloric acid used, it is preferred that a concentration of 5%~20% hydrochloric acid.
The preparation method of 3- hydroxy-cephams rhzomorph provided by the invention is suitble to prepare 3- hydroxyls shown in above structure Formula V
Cephalosporin, substituent group：R1For benzyl or benzyloxy, R2For to nitrobenzyl, nitrobenzyl, to methoxy-benzyl or two
Benzyl.
Preferably, the R1For benzyl.
Preferably, the R2For to nitrobenzyl.
The preparation method of 3- hydroxy-cephams rhzomorph provided by the invention has following advantage compared with prior art：
(1) it uses one-pot preparation thereof, intermediate steps that need not isolate and purify, directly obtains target product, yield can
Up to 75% or more, and product purity is more than 90%；
(2) sulfonylation step speed is fast, and high conversion rate, side reaction is few, and product assay is relatively high in reaction solution, makes
It obtains target product to be easy to purify, yield is higher.
Specific implementation mode
With reference to specific embodiment, invention is further explained, but does not limit the invention to these tools
Body embodiment.One skilled in the art would recognize that present invention encompasses may include in Claims scope
All alternatives, improvement project and equivalent scheme.
Embodiment 1
150mL dichloromethane and 10g thiazolines enol ester (chemical compounds I, R are added in reaction bulb1For benzyl, R2For to nitre
Base benzyl) and paratoluensulfonyl chloride 4.4g, stirring and dissolving, it is cooled to 0 DEG C~5 DEG C, 134mg catalyst 4- diformazans is added into system
Weak aqua ammonia reaction is slowly added dropwise into system after adding stirring and dissolving for aminopyridine (DMAP).It reacts HPLC to monitor, after 10min
Display raw material reaction finishes, and branch vibration layer is cooled to -5 DEG C~0 DEG C, morpholine 2.0g is added, and triethylamine is added dropwise into system
2.23g.HPLC monitors raw material after completion of the reaction, is cooled to -20 DEG C~-10 DEG C, pyridine 1.83g is added, and be added dropwise into system
Bromine 3.5g.Insulation reaction after completion of the reaction, 20mL10% hydrochloric acid and 80mL first is added into system to HPLC monitorings intermediate III
The mixed solvent of alcohol continues stirring 8~10 hours after being back to room temperature.Reaction, which finishes, to be washed with water, after organic phase reduced pressure is dry
75% methanol mashing is added, filtering is dried to obtain V (R of compound1For benzyl, R2For to nitrobenzyl) 7.9g.By compound
The yield 76% of I prepare compound V, HPLC purity 92%.
Embodiment 2
150mL dichloromethane and 10g thiazolines enol ester (chemical compounds I, R are added in reaction bulb1For benzyl, R2For to nitre
Base benzyl) and paratoluensulfonyl chloride 4.4g, stirring and dissolving, it is cooled to 0 DEG C~5 DEG C, 134mg catalyst 4- diformazans is added into system
2.67g triethylamine reacts are slowly added dropwise into system after adding stirring and dissolving for aminopyridine (DMAP), and reaction HPLC is monitored,
Show that raw material reaction finishes after 10min, branch vibration layer is cooled to -5 DEG C~0 DEG C, morpholine 2.0g is added, and be added dropwise into system
Triethylamine 2.23g, HPLC monitor raw material after completion of the reaction, are cooled to -20 DEG C~-10 DEG C, pyridine 1.83g are added, into system
Be added dropwise bromine 3.5g, insulation reaction to HPLC monitoring intermediate III after completion of the reaction, into system be added 20mL10% hydrochloric acid and
The mixed solvent of 80mL methanol continues stirring 8~10 hours after being back to room temperature.Reaction, which finishes, to be washed with water, and organic phase decompression is dense
75% methanol mashing is added after contracting is dry, filtering is dried to obtain V (R of compound1For benzyl, R2For to nitrobenzyl) 8.2g.By
The yield 79% of chemical compounds I prepare compound V, HPLC purity 93%.
Embodiment 3
1500mL dichloromethane and 100g thiazolines enol ester (chemical compounds I, R are added in reaction bulb1For benzyl, R2It is right
Nitrobenzyl) and paratoluensulfonyl chloride 44.1g, stirring and dissolving, it is cooled to -5 DEG C~0 DEG C, 1.34g catalyst 4- is added into system
2.6% concentration weak aqua ammonia 170g progress sulphonyl is slowly added dropwise into system after adding stirring and dissolving for dimethylamino naphthyridine (DMAP)
Change reaction, after completion of the reaction, branch vibration layer is cooled to -5 DEG C~0 DEG C to reaction 20min raw materials, is added morpholine 20.1g, and to body
Triethylamine 22.3g, HPLC are added dropwise in system and monitors raw material after completion of the reaction, is cooled to -20 DEG C~-10 DEG C, pyridine 18.3g is added,
Bromine 35.3g, and insulation reaction 1 hour are added dropwise into system.After bromo-reaction, into system be added 200mL5% hydrochloric acid and
The mixed solvent of 800mL methanol continues stirring 10~12 hours after being back to room temperature.Reaction, which finishes, to be washed with water, organic phase decompression
Methanol mashing is added after concentration is dry, filtering is dried to obtain V (R of compound1For benzyl, R2For to nitrobenzyl) 83.2g.By changing
Close the yield 80% of I prepare compound V of object, HPLC purity 93%.
Embodiment 4
1500mL dichloromethane and 100g thiazolines enol ester (chemical compounds I, R are added in reaction bulb1For benzyl, R2It is right
Nitrobenzyl) and paratoluensulfonyl chloride 44.1g, stirring and dissolving, it is cooled to -5 DEG C~0 DEG C, 1.34g catalyst 4- is added into system
Dimethylamino naphthyridine (DMAP) 26.7g triethylamines progress sulfonylation is slowly added dropwise into system after adding stirring and dissolving, instead
Answer 20min raw materials after completion of the reaction, branch vibration layer is cooled to -5 DEG C~0 DEG C, morpholine 20.1g is added, and three are added dropwise into system
Ethamine 22.3g, HPLC monitor raw material after completion of the reaction, are cooled to -20 DEG C~-10 DEG C, pyridine 18.3g is added, is dripped into system
Add bromine 35.3g, and insulation reaction 1 hour.After bromo-reaction, 200mL5% hydrochloric acid and 800mL methanol are added into system
Mixed solvent, continue stirring 10~12 hours after being back to room temperature.Reaction, which finishes, to be washed with water, and is added after organic phase reduced pressure is dry
Enter methanol mashing, filtering is dried to obtain V (R of compound1For benzyl, R2For to nitrobenzyl) 84.5g.By chemical compounds I preparationization
Close the yield 82% of object V, HPLC purity 92%.
Embodiment 5
150mL dichloromethane and 10g thiazolines enol ester (chemical compounds I, R are added in reaction bulb1For benzyloxy, R2It is right
Nitrobenzyl) and paratoluensulfonyl chloride 4.3g, stirring and dissolving, it is cooled to 0 DEG C~5 DEG C, 130mg catalyst 4- bis- is added into system
Weak aqua ammonia reaction is slowly added dropwise into system after adding stirring and dissolving for methylamino pyridine (DMAP).React HPLC monitorings, 10min
Show that raw material reaction finishes afterwards, branch vibration layer is cooled to -5 DEG C~0 DEG C, morpholine 1.93g is added, and three second are added dropwise into system
Amine 2.15g.HPLC monitors raw material after completion of the reaction, is cooled to -20 DEG C~-10 DEG C, pyridine 1.77g is added, and drip into system
Add bromine 3.41g.Insulation reaction after completion of the reaction, 20mL10% hydrochloric acid and 80mL is added into system to HPLC monitorings intermediate III
The mixed solvent of methanol continues stirring 8~10 hours after being back to room temperature.Reaction, which finishes, to be washed with water, and organic phase is concentrated under reduced pressure dry
75% methanol mashing is added afterwards, filtering is dried to obtain V (R of compound1For benzyloxy, R2For to nitrobenzyl) 7.7g.By changing
Close the yield 74% of I prepare compound V of object, HPLC purity 92%.
Embodiment 6
150mL dichloromethane and 10g thiazolines enol ester (chemical compounds I, R are added in reaction bulb1For benzyl, R2For nitre
Base benzyl) and paratoluensulfonyl chloride 4.4g, stirring and dissolving, it is cooled to 0 DEG C~5 DEG C, 134mg catalyst 4- diformazans is added into system
Weak aqua ammonia reaction is slowly added dropwise into system after adding stirring and dissolving for aminopyridine (DMAP).It reacts HPLC to monitor, after 10min
Display raw material reaction finishes, and branch vibration layer is cooled to -5 DEG C~0 DEG C, morpholine 2.0g is added, and triethylamine is added dropwise into system
2.23g.HPLC monitors raw material after completion of the reaction, is cooled to -20 DEG C~-10 DEG C, pyridine 1.83g is added, and be added dropwise into system
Bromine 3.5g.Insulation reaction after completion of the reaction, 20mL10% hydrochloric acid and 80mL first is added into system to HPLC monitorings intermediate III
The mixed solvent of alcohol continues stirring 8~10 hours after being back to room temperature.Reaction, which finishes, to be washed with water, after organic phase reduced pressure is dry
75% methanol mashing is added, filtering is dried to obtain V (R of compound1For benzyl, R2For a nitrobenzyl) 7.9g.By compound
The yield 76% of I prepare compound V, HPLC purity 92%.
Embodiment 7
150mL dichloromethane and 10g thiazolines enol ester (chemical compounds I, R are added in reaction bulb1For benzyl, R2For to first
Oxy-benzyl) and paratoluensulfonyl chloride 4.6g, stirring and dissolving, it is cooled to 0 DEG C~5 DEG C, 139mg catalyst 4- bis- is added into system
Weak aqua ammonia reaction is slowly added dropwise into system after adding stirring and dissolving for methylamino pyridine (DMAP).React HPLC monitorings, 10min
Show that raw material reaction finishes afterwards, branch vibration layer is cooled to -5 DEG C~0 DEG C, morpholine 2.08g is added, and three second are added dropwise into system
Amine 2.31g.HPLC monitors raw material after completion of the reaction, is cooled to -20 DEG C~-10 DEG C, pyridine 1.89g is added, and drip into system
Add bromine 3.65g.Insulation reaction after completion of the reaction, 20mL10% hydrochloric acid and 80mL is added into system to HPLC monitorings intermediate III
The mixed solvent of methanol continues stirring 8~10 hours after being back to room temperature.Reaction, which finishes, to be washed with water, and organic phase is concentrated under reduced pressure dry
75% methanol mashing is added afterwards, filtering is dried to obtain V (R of compound1For benzyl, R2For to methoxy-benzyl) 7.6g.By changing
Close the yield 74% of I prepare compound V of object, HPLC purity 91%.
Embodiment 8
150mL dichloromethane and 10g thiazolines enol ester (chemical compounds I, R are added in reaction bulb1For benzyl, R2For hexichol
Methyl) and paratoluensulfonyl chloride 4.13g, stirring and dissolving, it is cooled to 0 DEG C~5 DEG C, 125mg catalyst 4- diformazans is added into system
Weak aqua ammonia reaction is slowly added dropwise into system after adding stirring and dissolving for aminopyridine (DMAP).It reacts HPLC to monitor, after 10min
Display raw material reaction finishes, and branch vibration layer is cooled to -5 DEG C~0 DEG C, morpholine 1.88g is added, and triethylamine is added dropwise into system
2.09g.HPLC monitors raw material after completion of the reaction, is cooled to -20 DEG C~-10 DEG C, pyridine 1.71g is added, and be added dropwise into system
Bromine 3.31g.Insulation reaction after completion of the reaction, 20mL10% hydrochloric acid and 80mL first is added into system to HPLC monitorings intermediate III
The mixed solvent of alcohol continues stirring 8~10 hours after being back to room temperature.Reaction, which finishes, to be washed with water, after organic phase reduced pressure is dry
75% methanol mashing is added, filtering is dried to obtain V (R of compound1For benzyl, R2For benzhydryl) 7.8g.By chemical compounds I
The yield 75% of prepare compound V, HPLC purity 92%.
Comparative example 1
This comparative example is operated according to patent CN101525341 reaction conditions described in embodiment 1.
150mL dichloromethane and 10g thiazolines enol ester (chemical compounds I, R are added in reaction bulb1For benzyl, R2For to nitre
Base benzyl) and paratoluensulfonyl chloride 4.4g, stirring and dissolving, it is cooled to 0 DEG C~5 DEG C, weak aqua ammonia reaction is slowly added dropwise into system, instead
HPLC is answered to track, conversion ratio is not further added by after 2h, and a small amount of raw material I is remaining until 15h still has, and there are small impurity peaks to occur.Divide and removes water
Layer is cooled to -10 DEG C~0 DEG C, and morpholine 2.0g is added, and triethylamine 2.23g is added dropwise into system, and it is anti-that HPLC monitors intermediate II
After answering, -30 DEG C~-15 DEG C are cooled to, pyridine 1.83g is added, and bromine 3.5g, insulation reaction to HPLC are added dropwise into system
It monitors intermediate III after completion of the reaction, reaction system is added to the in the mixed solvent of 20mL10% hydrochloric acid and 80mL methanol, 0 DEG C~
10 DEG C are continued stirring 6~7 hours.Reaction, which finishes, to be washed with water, and 75% methanol mashing, mistake are added after organic phase reduced pressure is dry
Filter, is dried to obtain V (R of compound1For benzyl, R2For to nitrobenzyl) 4.7g.Yield by chemical compounds I prepare compound V is
45%, HPLC purity 91%.
Comparative example 2
This comparative example is operated according to the reaction condition described in patent CN101525341 embodiments 2.
150mL tetrahydrofurans and 10g thiazolines enol ester (chemical compounds I, R are added in reaction bulb1For benzyl, R2For to nitre
Base benzyl) and paratoluensulfonyl chloride 4.4g, stirring and dissolving, it is cooled to 5 DEG C~10 DEG C, ammonia reaction is slowly introducing into system, instead
HPLC is answered to track, conversion ratio is not further added by after 20min, and a small amount of raw material I is remaining until 1h still has, and there are small impurity peaks to occur.Decompression
Tetrahydrofuran is removed, dichloromethane 150mL is added and is dried with anhydrous magnesium sulfate, is cooled to -20 DEG C~-10 DEG C, morpholine is added
2.0g, and triethylamine 2.23g, HPLC monitoring intermediate II is added dropwise after completion of the reaction into system, -45 DEG C~-20 DEG C are cooled to,
Pyridine 1.83g is added, and bromine 3.5g is added dropwise into system, insulation reaction to HPLC monitorings intermediate III after completion of the reaction, will be anti-
System is answered to be added to the in the mixed solvent of 16mL15% hydrochloric acid and 80mL methanol, 10 DEG C~20 DEG C are continued stirring 5~6 hours.Reaction
It finishes and is washed with water, 75% methanol mashing is added after organic phase reduced pressure is dry, filtering is dried to obtain V (R of compound1For
Benzyl, R2For to nitrobenzyl) 4.8g.It is 46%, HPLC purity 92% by the yield of chemical compounds I prepare compound V.
Claims (10)
1. a kind of preparation method of 3- hydroxy-cephams rhzomorph, it is characterised in that the method includes：
(1) sulfonylation：In water or organic solution, at a temperature of -20 DEG C~20 DEG C, in the presence of a catalyst, structural formula I
Shown in thiazoline enol ester derivatives and paratoluensulfonyl chloride II compound represented of structural formula is obtained by the reaction,
The catalyst is selected from pyridine, 4-dimethylaminopyridine, 4- lignocaines pyridine, 4- dipropyls aminopyridine, 4- methoxyl groups
At least one of pyridine and 4- pyridones；
(2) enamine reacts：At a temperature of -30 DEG C~10 DEG C, II compound represented of structural formula is made to be reacted with morpholine and alkali
To III compound represented of structural formula；
(3) bromo-reaction：At a temperature of -40 DEG C~0 DEG C, in the presence of a base, keep III compound represented of structural formula and bromine anti-
It should obtain IV compound represented of structural formula；
(4) ring-closure reaction：At a temperature of 0~30 DEG C, make the mixed solution of structural formula IV compound represented and hydrochloric acid and methanol
The 3- hydroxy-cepham rhzomorphs shown in structural formula V are obtained by the reaction；
Wherein：R1For benzyl or benzyloxy；R2For to nitrobenzyl, nitrobenzyl, to methoxy-benzyl or benzhydryl.
2. the preparation method of 3- hydroxy-cephams rhzomorph described in accordance with the claim 1, it is characterised in that the R1It is described for benzyl
R2For to nitrobenzyl.
3. the preparation method of 3- hydroxy-cephams rhzomorph described in accordance with the claim 1, it is characterised in that in step (1), catalyst
Selected from least one of 4-dimethylaminopyridine, 4- lignocaines pyridine and 4- dipropyl aminopyridines.
4. the preparation method of 3- hydroxy-cephams rhzomorph described in accordance with the claim 1, it is characterised in that described to have in step (1)
Solvent in dichloromethane, chloroform, 1,2- dichloroethanes, tetrahydrofuran, acetonitrile, acetoneand ethyl acetate at least one
Kind.
5. the preparation method of 3- hydroxy-cephams rhzomorph described in accordance with the claim 1, it is characterised in that in step (1), in water or
In organic solution, at a temperature of -10 DEG C~0 DEG C, in the presence of a catalyst, thiazoline enol ester derivatives shown in structural formula I
II compound represented of structural formula is obtained by the reaction with paratoluensulfonyl chloride.
6. the preparation method of 3- hydroxy-cephams rhzomorph described in accordance with the claim 1, it is characterised in that in step (2), at -10 DEG C
At a temperature of~0 DEG C, make II compound represented of structural formula that III compound represented of structural formula be obtained by the reaction with morpholine and alkali.
7. the preparation method of 3- hydroxy-cephams rhzomorph described in accordance with the claim 1, it is characterised in that in step (3), at -20 DEG C
At a temperature of~0 DEG C, in the presence of a base, make III compound represented of structural formula and bromine that chemical combination shown in structural formula IV be obtained by the reaction
Object.
8. the preparation method of 3- hydroxy-cephams rhzomorph described in accordance with the claim 1, it is characterised in that step (2) and step (3)
In, the alkali independently selected from trimethylamine, triethylamine, tri-n-butylamine, ammonium hydroxide, ammonia, pyridine, morpholine, 2,6- lutidines, 2,
4,6- trimethylpyridines, N-methylmorpholine, N, accelerine and N, at least one of N- diethylanilines.
9. the preparation method of 3- hydroxy-cephams rhzomorph according to claim 8, it is characterised in that：
In step (2), the alkali in trimethylamine, triethylamine, tri-n-butylamine, ammonium hydroxide, ammonia, pyridine and morpholine at least one
Kind；
In step (3), the alkali is selected from pyridine, morpholine, 2,6- lutidines and 2, and at least one in 4,6- trimethylpyridines
Kind.
10. the preparation method of 3- hydroxy-cephams rhzomorph described in accordance with the claim 1, it is characterised in that in step (4)：
At a temperature of 10~30 DEG C, make IV compound represented of structural formula and the mixed solution of hydrochloric acid and methanol that structure be obtained by the reaction
3- hydroxy-cepham rhzomorphs shown in formula V, a concentration of the 5%~20% of the hydrochloric acid.
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| US4079181A (en) * | 1975-02-17 | 1978-03-14 | Shionogi & Co., Ltd. | Certain 7-oxo-4-thio-2,6-diazabicyclo-3,2,0-hept-2-ene compounds |
| US4332722A (en) * | 1975-02-17 | 1982-06-01 | Shionogi & Co., Ltd. | Cyclization to form cephem ring and intermediates therefor |
| CN101525341A (en) * | 2009-04-01 | 2009-09-09 | 浙江东邦药业有限公司 | Preparation method of 3-hydroxy-cepham compound |
| CN102140103A (en) * | 2011-01-24 | 2011-08-03 | 石家庄柏奇化工有限公司 | Method for preparing 7-amino-3-hydro cephalosporanic acid by taking penicillin G/K as raw material |
| CN105693748A (en) * | 2015-10-10 | 2016-06-22 | 浙江沙星医药化工有限公司 | Synthesis method of 7-amino-3-chloro-3-cephalosporin-4-carboxylic acid |
| CN107056817A (en) * | 2016-08-31 | 2017-08-18 | 浙江沙星药业有限公司 | Preparation method of the carboxylic acid of 7 phenylacetylamino, 3 hydroxyl, 3 cephalo ring 4 to nitrobenzyl ester |
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| US4079181A (en) * | 1975-02-17 | 1978-03-14 | Shionogi & Co., Ltd. | Certain 7-oxo-4-thio-2,6-diazabicyclo-3,2,0-hept-2-ene compounds |
| US4332722A (en) * | 1975-02-17 | 1982-06-01 | Shionogi & Co., Ltd. | Cyclization to form cephem ring and intermediates therefor |
| CN101525341A (en) * | 2009-04-01 | 2009-09-09 | 浙江东邦药业有限公司 | Preparation method of 3-hydroxy-cepham compound |
| CN102140103A (en) * | 2011-01-24 | 2011-08-03 | 石家庄柏奇化工有限公司 | Method for preparing 7-amino-3-hydro cephalosporanic acid by taking penicillin G/K as raw material |
| CN105693748A (en) * | 2015-10-10 | 2016-06-22 | 浙江沙星医药化工有限公司 | Synthesis method of 7-amino-3-chloro-3-cephalosporin-4-carboxylic acid |
| CN107056817A (en) * | 2016-08-31 | 2017-08-18 | 浙江沙星药业有限公司 | Preparation method of the carboxylic acid of 7 phenylacetylamino, 3 hydroxyl, 3 cephalo ring 4 to nitrobenzyl ester |
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