CN110204556A - (RS)-methoxyl group Cefoxitin preparation method - Google Patents
(RS)-methoxyl group Cefoxitin preparation method Download PDFInfo
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- CN110204556A CN110204556A CN201910640215.2A CN201910640215A CN110204556A CN 110204556 A CN110204556 A CN 110204556A CN 201910640215 A CN201910640215 A CN 201910640215A CN 110204556 A CN110204556 A CN 110204556A
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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
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
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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
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/57—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with a further substituent in position 7, e.g. cephamycines
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Abstract
The invention discloses a kind of preparation methods of (RS)-methoxyl group Cefoxitin, it is characterized in that, preparing in accordance with the following steps: (1), using thiophene as starting material, normal heptane is as reaction dissolvent, it is reacted with trichloroacetaldehyde, vacuum distillation obtains after having reacted；(2), upper step product is reacted with methanol in the presence of a basic is made (RS)-α-methoxyl group -2- thiophene phenylacetic acid；(3), the first organic base in organic solvent by the dissolution of (RS)-α-methoxyl group -2- thiophene phenylacetic acid, is added, methylsufonyl chloride is added dropwise after stirring clarification or pivaloyl chloride is spare；HACA and organic solvent are added in another reaction vessel, the second organic base is added, stirs to clarify spare；Solution B is slowly added dropwise in solution A at -30 DEG C or less；Then chlorosulphonyl isocyanate is added dropwise to react to obtain off-white color crystalline powder；(4) it reacts off-white color crystalline powder to obtain product with sodium methoxide.Product purity is high.
Description
Technical field
The present invention relates to a kind of preparation method of (RS)-methoxyl group Cefoxitin, belongs to impurity analysis in pharmaceutical synthesis and lead
Domain.
Background technique
Cefoxitin (Cefoxitin), entitled (6R, the 7S) -3- carbamyl yloxymethyl -7- methoxyl group -8- oxygen of chemistry
Generation -7- [2- (2- thienyl) acetylamino] -5- thia -1- azabicyclo [4.2.0] oct-2-ene -2- formic acid, is by the U.S.
The semi-synthetic cephamycin-type antibiotic that Merck company develops.
In new drug research and development process, the quality of drug is to measure a major criterion of drug quality, the matter of drug
Amount is decided by the curative effect and toxic side effect of drug itself, the i.e. validity and safety of drug first.The effective component of drug
Content is to reflect the important symbol of pharmaceutical purity, and impurity present in drug directly influences the curative effect of drug and may cause
The generation of toxic side effect.The impurity of drug is other chemicals other than the drug of production, the introduction in storage and transport process or generation
Matter, the presence of impurity not only influence the purity of drug, can also bring the active toxic side effect of non-treatment, it is necessary to be controlled.For
Drug is safely and effectively used, the quality standard of drug has the purity of effective ingredient and the limit of impurity more stringent
Regulation.
For medicament research and development personnel, groundwork is not only only that how to obtain the bulk pharmaceutical chemicals (API) of high quality, open
Send out synthesis technology efficient, it is often more important that dopant species, source and the production for how controlling process impurity in research bulk pharmaceutical chemicals
It is raw.Usual researcher first can generated impurity in controlled syntheses technique, be secondly then exploitation efficient impurity synthesis road
Line, to obtain a large amount of impurity reference substance, guarantee every batch of bulk pharmaceutical chemicals quality detection work development (e.g., impurity HPLC positioning,
Dirt content test etc.).
(R, S)-methoxyl group Cefoxitin
(6R, 7S) -3- carbamyl oxygen methyl -7- methoxyl group -7- ((2RS) -2- methoxyl group -2- (thiophene -2- base)-acetyl
Amino) -8- oxo -5- sulphur -1- azabicyclo [4.2.0] oct-2-ene -2- carboxylic acid
(6R,7S)-3-((carbamoyloxy)methyl)-7-methoxy-7-((2RS)-2-methoxy-2-
(thiophen-2-yl)-acetyl)amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-
carboxylic acid
By European Pharmacopoeia clear stipulaties be E, F impurity, be need to study in Cefoxitin Control of drug quality it is important miscellaneous
Matter determines the preparation method of the impurity compound, provides qualified reference substance, can control the quality of the drugs such as Cefoxitin
It plays a positive role.
Summary of the invention
In view of the above technical problems, the purpose of the present invention is to provide a kind of preparation sides of (RS)-methoxyl group Cefoxitin
Method.
To achieve the goals above, the technical solution of the present invention is as follows:
A kind of preparation method of (RS)-methoxyl group Cefoxitin, which is characterized in that prepare in accordance with the following steps:
(1) using thiophene as starting material, normal heptane is reacted as reaction dissolvent with trichloroacetaldehyde, and decompression is steamed after having reacted
It evaporates to obtain (RS)-α-trichloromethyl -2- thenyl alcohol；
(2) (RS)-α-trichloromethyl -2- thenyl alcohol obtained step (1) is anti-with methanol in the presence of a basic
(RS)-α-methoxyl group -2- thiophene phenylacetic acid should be made；
(3) in organic solvent by the dissolution of (RS)-α-methoxyl group -2- thiophene phenylacetic acid, nitrogen protection is cooled to -10 DEG C
Hereinafter, the first organic base is added, -50 DEG C~-60 DEG C are cooled to after stirring clarification, methylsufonyl chloride or pivaloyl chloride is added dropwise, in -
35 DEG C or less reactions, it is spare to obtain solution A after having reacted；
It is added methylol -7-amino-cephalosporanic acid and organic solvent in another reaction vessel, under nitrogen protection, stirs
It mixes, is cooled to 0 DEG C hereinafter, the second organic base of addition, stirs to clarify, it is spare to obtain solution B；
Solution B is slowly dropped in solution A at -30 DEG C or less；- 30 DEG C of temperature control or less reactions, then cool to -40 DEG C
Hereinafter, acid solution is added, the reaction was continued, and chlorosulphonyl isocyanate is then added dropwise, and the reaction was continued in -30 DEG C or so；Water is eventually adding,
PH value 2-3 is adjusted, stratification after having reacted, the dry decoloration of organic phase is filtered, and acetone and methanol is added in filtrate, is added dropwise first
Organic base precipitates crystal, and filtration drying obtains off-white color crystalline powder；
(4) obtained off-white color crystalline powder is dissolved in organic solvent and methanol, under nitrogen protection, be cooled to-
60 DEG C~-80 DEG C, the methanol solution of sodium methoxide is added, t-butyl hypochlorate is added dropwise after adding, is stirred to react, after having reacted, adds
Enter sodium pyrosulfite, stir, adjusts pH6-7 with acetic acid, then heat to 0 DEG C~5 DEG C, adjust pH1~2, stratification is organic
After layer washing, saturated sodium bicarbonate is added to adjust pH7-8, layering, water layer adjusts pH1-2, is extracted with ethyl acetate, ethyl acetate layer
It dries, filters, is concentrated under reduced pressure to give grease crude product.
The corresponding reaction equation of each step are as follows:
In step (1), the molar ratio of the thiophene and trichloroacetaldehyde is 1:1~1.2.Be conducive to reaction to carry out, improve and receive
Rate.
The concrete operation step of step (1) are as follows: thiophene, normal heptane and trichloroacetaldehyde stirring are added in reaction vessel, rises
Temperature is to back flow reaction, and recycling design is concentrated under reduced pressure in cooling after having reacted, and residue is evaporated under reduced pressure, 98~100 DEG C of collection,
1.0mmHg fraction obtains RS)-α-trichloromethyl -2- thenyl alcohol.
In step (2), the alkaline matter is potassium hydroxide or sodium hydroxide, (R, the S)-α-trichloromethyl -2- thiophene
The molar ratio of pheno methanol and alkaline matter is 1:3~5.
The concrete operation step of step (2) are as follows: methanol and alkaline matter are added in the reaction vessel, stirring and dissolving is cooling
To -5 DEG C~0 DEG C, the methanol solution of (R, S)-α-trichloromethyl -2- thenyl alcohol, stirring, temperature rising reflux reaction, reaction is added
It is cooled to room temperature after complete, organic solvent is concentrated under reduced pressure away, be then added and methyl tertiary butyl ether(MTBE) or petroleum ether or different is then added
Propyl ether, stirring adjust pH2.5-3.5 with hydrochloric acid solution, separate organic layer, water layer methyl tertiary butyl ether(MTBE) or petroleum ether or isopropyl
Ether extracts, and merges organic layer, is washed with brine, dries, filters, be concentrated to get (RS)-α-methoxyl group -2- thiophene phenylacetic acid.
The organic solvent is methylene chloride or chloroform.In step (3), first organic base is diisopropylamine, three
One of ethamine, tri-n-butylamine, diisopropylethylamine, (RS)-α-methoxyl group -2- thiophene phenylacetic acid and the first organic base
Molar ratio is 1:1-1.2, the molar ratio of (RS)-α-methoxyl group -2- thiophene phenylacetic acid and methylsufonyl chloride or pivaloyl chloride
For 1:1-1.1.
In step (3), second organic base is tetramethylguanidine, triethylamine, diisopropylethylamine, tri-n-butylamine, diisopropyl
The molar ratio of one of base amine, the methylol -7-amino-cephalosporanic acid and the second organic base is 1:1.1-1.3；
The acid solution is one of methanesulfonic acid, hydrochloric acid, phosphoric acid, formic acid, acetic acid；
The molar ratio of (RS)-α-methoxyl group -2- thiophene phenylacetic acid and acid solution is 1:1-1.1；
The molar ratio of (RS)-α-methoxyl group -2- thiophene phenylacetic acid and chlorosulphonyl isocyanate is 1:1.5-1.6.
In step (4), the molar ratio of off-white color crystalline powder and sodium methoxide is 1:3-4；The off-white color crystallinity powder
The molar ratio of end and t-butyl hypochlorate is 1:2-3；The molar ratio of the off-white color crystalline powder and sodium pyrosulfite is 1:
1.2-2。
The grease crude product is purified using silica gel column chromatography.After purification by silica gel column chromatography, purity can reach
98% or more.
The utility model has the advantages that preparation method step provided by the invention is simple, and it is at low cost, it is appropriate for prepare with scale.This hair
The bright meticulous control by the addition sequence for reacting metering, reaction dissolvent, reaction temperature and reaction mass to each step
And adjustment, the sulfamic acid methyl esters purity finally prepared can achieve 98.0% or more.Theory is provided for drug safety use
Foundation provides effective data to the quality standard of Cefoxitin drug and supports, is provided with for the clinical safety use of drug
Effect ensures.
Specific embodiment
Below by embodiment, the invention will be further described:
Embodiment 1
(RS)-α-trichloromethyl -2- thenyl alcohol prepares chemical equation
84g (1.0mol) thiophene, 500ml normal heptane and 147g (1.0mol) trichloroacetaldehyde are added in 1000ml there-necked flask
Stirring, is warming up to reflux, and room temperature is cooled to after having reacted, and recycling design is concentrated under reduced pressure, and residue is evaporated under reduced pressure, and collection 98~
100 DEG C, 1.0mmHg fraction, yield about 46g.
Embodiment 2
(RS) preparation of-α-trichloromethyl -2- thenyl alcohol
84g (1.0mol) thiophene, 500ml normal heptane and 147g (1.2mol) trichloroacetaldehyde are added in 1000ml there-necked flask
Stirring, is warming up to reflux, and room temperature is cooled to after having reacted, and recycling design is concentrated under reduced pressure, and residue is evaporated under reduced pressure, and collection 98~
100 DEG C, 1.0mmHg fraction, yield about 52g.
Embodiment 3
(RS)-α-methoxyl group -2- thiophene phenylacetic acid prepares chemical equation
100ml methanol and 11.2g (0.2mol) potassium hydroxide, stirring is added in 500ml there-necked flask under nitrogen protection
Dissolution is cooled to -5~0 DEG C, and 11.6g (0.05mol) (R, S)-α-trichloromethyl -2- thenyl alcohol is added in 30ml methanol
Solution, stirring, is to slowly warm up to flow back, and room temperature is cooled to after having reacted, and is concentrated under reduced pressure and removes solvent, is added in residue
50ml methyl tertiary butyl ether(MTBE), stirring is lower to adjust pH to 3.0 with 0.1N dilute hydrochloric acid, separates organic layer, water layer uses methyl- tert fourth again
Base ether extracts, and merges organic layer, is washed with brine, anhydrous sodium sulfate dries, filters, and is concentrated under reduced pressure to give about 6.2g product.
Embodiment 4
(RS)-α-methoxyl group -2- thiophene phenylacetic acid
100ml methanol is added in 500ml there-necked flask under nitrogen protection and 0.25mol sodium hydroxide, stirring and dissolving are cold
But -5~0 DEG C is arrived, 11.6g (0.05mol) (R, S)-α-trichloromethyl -2- thenyl alcohol is added and, in the solution of 30ml methanol, stirs
It mixes, is to slowly warm up to flow back, room temperature is cooled to after having reacted, be concentrated under reduced pressure and remove solvent, 50ml isopropyl ether is added, stir lower use
0.1N dilute hydrochloric acid adjusts pH to 2.5, separates organic layer, and water layer is extracted with isopropyl ether, merges organic layer, is washed with brine, anhydrous
Sodium sulphate dries, filters, and is concentrated under reduced pressure to give about 5.9g product.
Embodiment 5
(RS)-α-methoxyl group -2- thiophene phenylacetic acid
100ml methanol and 8.4g (0.15mol) potassium hydroxide, stirring is added in 500ml there-necked flask under nitrogen protection
Dissolution is cooled to -5~0 DEG C, and 11.6g (0.05mol) (R, S)-α-trichloromethyl -2- thenyl alcohol is added in 30ml methanol
Solution, stirring, is to slowly warm up to flow back, and room temperature is cooled to after having reacted, and is concentrated under reduced pressure and removes solvent, and 50ml petroleum ether is added
(60-90 DEG C of boiling point), stirring is lower to adjust pH to 3.5 with 1N dilute hydrochloric acid, separates organic layer, water layer is extracted with petroleum ether, is associated with
Machine layer, is washed with brine, and anhydrous sodium sulfate dries, filters, and is concentrated under reduced pressure to give about 6.15g product.
Embodiment 6
(6R, 7S) -3- carbamyl oxygen methyl -7- ((2RS) -2- methoxyl group -2- (thiophene -2- base)-acetylamino) -8- oxygen
The preparation of generation -5- sulphur -1- azabicyclo [4.2.0] oct-2-ene -2- carboxylic acid diisopropyl amine salt
1, chemical equation
17.2g (0.1mol) (RS)-α-methoxyl group -2- thiophene phenylacetic acid and 200ml are added in tetra- mouthfuls of reaction flasks of 500ml
Methylene chloride, nitrogen protection, stirring are cooled to -10 DEG C or less.11.1g (0.11mol) diisopropylamine is added, stirring and dissolving is clear
Clearly.- 50 DEG C are cooled to, 12g (0.105mol) methylsufonyl chloride is added dropwise, is reacted in -35 DEG C or less, end of reaction cools to -45
DEG C or less to obtain A liquid spare.
23.2g (0.1mol) HACA (methylol -7-amino-cephalosporanic acid) and 100ml bis- are added in 250ml there-necked flask
Chloromethanes, stirred under nitrogen atmosphere are cooled to 0 DEG C or less；13.8g (0.12mol) tetramethylguanidine, stirring to dissolution clarification is added；
It is cooled to -45 DEG C or less and obtains B liquid, it is spare.
B liquid is slowly dropped in A liquid in -30 DEG C or less；- 30 DEG C of temperature control or less are reacted 3~4 hours, cool to -40
DEG C, 9.6g (0.1mol) methanesulfonic acid is added, reacts 20 minutes, 21.2g (0.15mol) chlorosulphonyl isocyanate is added dropwise, in -30 DEG C
Left and right reaction 2 hours；150ml water is added, adjusts pH value 2 with sodium bicarbonate, reacts 60 minutes.Stratification separates organic phase
It is washed twice with water, each 150ml, 30g anhydrous sodium sulfate and 2g active carbon is added, stir 30 minutes, filtering, filtrate is added
11.1g (0.11mol) diisopropylamine is added dropwise in 250ml acetone 50ml methanol, and crystallization is precipitated, and stirs 30 minutes, filtering, acetone
Washing.Wet product vacuum drying, obtains 40g off-white color crystalline powder, yield 75%.
Embodiment 7
(6R, 7S) -3- carbamyl oxygen methyl -7- ((2RS) -2- methoxyl group -2- (thiophene -2- base)-acetylamino) -8- oxygen
The preparation of generation -5- sulphur -1- azabicyclo [4.2.0] oct-2-ene -2- carboxylic acid triethylamine salt
17.2g (0.1mol) (RS)-α-methoxyl group -2- thiophene phenylacetic acid and 200ml are added in tetra- mouthfuls of reaction flasks of 500ml
Methylene chloride, nitrogen protection, stirring are cooled to -10 DEG C or less.0.12mol triethylamine, stirring and dissolving clarification is added.Be cooled to-
50 DEG C, 0.11mol pivaloyl chloride is added dropwise, in -35 DEG C or less reactions, end of reaction, cooling to -45 DEG C or less, to obtain A liquid spare.
23.2g (0.1mol) HACA (methylol -7-amino-cephalosporanic acid) and 100ml bis- are added in 250ml there-necked flask
Chloromethanes, stirred under nitrogen atmosphere are cooled to 0 DEG C or less；0.13mol triethylamine, stirring to dissolution clarification is added；It is cooled to -45
DEG C or less obtain B liquid, it is spare.
B liquid is slowly dropped in A liquid in -30 DEG C or less；- 30 DEG C of temperature control or less are reacted 3~4 hours, cool to -40
DEG C, 0.11mol hydrochloric acid is added, reacts 20 minutes, 22.6g (0.16mol) chlorosulphonyl isocyanate is added dropwise, it is anti-in -30 DEG C or so
It answers 2 hours；150ml water is added, adjusts pH value 2.5 with sodium bicarbonate and reacts 60 minutes.Stratification separates organic phase and is washed with water
It washs twice, each 150ml, 30g anhydrous sodium sulfate and 2g active carbon is added, stir 30 minutes, 250ml third is added in filtering, filtrate
0.12mol triethylamine is added dropwise in ketone 50ml methanol, and crystallization is precipitated, and stirs 30 minutes, filtering, acetone washing.Wet product vacuum drying,
Obtain 38.9g off-white color crystalline powder.
Embodiment 8
(6R, 7S) -3- carbamyl oxygen methyl -7- ((2RS) -2- methoxyl group -2- (thiophene -2- base)-acetylamino) -8- oxygen
The preparation of generation -5- sulphur -1- azabicyclo [4.2.0] oct-2-ene -2- carboxylic acid tri-n-butylamine salt
17.2g (0.1mol) (RS)-α-methoxyl group -2- thiophene phenylacetic acid and 200ml are added in tetra- mouthfuls of reaction flasks of 500ml
Methylene chloride, nitrogen protection, stirring are cooled to -10 DEG C or less.0.12mol tri-n-butylamine, stirring and dissolving clarification is added.Be cooled to-
50 DEG C, 0.108mol pivaloyl chloride is added dropwise, in -35 DEG C or less reactions, end of reaction, cooling to -45 DEG C or less, to obtain A liquid standby
With.
23.2g (0.1mol) HACA (methylol -7-amino-cephalosporanic acid) and 100ml bis- are added in 250ml there-necked flask
Chloromethanes, stirred under nitrogen atmosphere are cooled to 0 DEG C or less；0.11mol tri-n-butylamine, stirring to dissolution clarification is added；It is cooled to -45
DEG C or less obtain B liquid, it is spare.
B liquid is slowly dropped in A liquid in -30 DEG C or less；- 30 DEG C of temperature control or less are reacted 3~4 hours, cool to -40
DEG C, 0.105mol formic acid is added, reacts 20 minutes, 0.16mol chlorosulphonyl isocyanate is added dropwise, it is small in -30 DEG C or so reactions 2
When；150ml water is added, adjusts pH value 2.5 with sodium bicarbonate and reacts 60 minutes.Stratification separates organic phase and is washed with water two
Secondary, 30g anhydrous sodium sulfate and 2g active carbon is added in each 150ml, stirs 30 minutes, and 250ml acetone is added in filtering, filtrate
0.115mol tri-n-butylamine is added dropwise in 50ml methanol, and crystallization is precipitated, and stirs 30 minutes, filtering, acetone washing.Wet product vacuum drying, obtains
39.2g off-white color crystalline powder.
Embodiment 9
(6R, 7S) -3- carbamyl oxygen methyl -7- ((2RS) -2- methoxyl group -2- (thiophene -2- base)-acetylamino) -8- oxygen
The preparation of generation -5- sulphur -1- azabicyclo [4.2.0] oct-2-ene -2- carboxylic acid's amine salt
17.2g (0.1mol) (RS)-α-methoxyl group -2- thiophene phenylacetic acid, 200ml are added in tetra- mouthfuls of reaction flasks of 500ml
Chloroform, nitrogen protection, stirring are cooled to -10 DEG C or less.0.1mol diisopropylethylamine, stirring and dissolving clarification is added.Be cooled to-
50 DEG C, 0.1mol mesyl chloride is added dropwise, in -35 DEG C or less reactions, end of reaction, cooling to -45 DEG C or less, to obtain A liquid spare.
23.2g (0.1mol) HACA (methylol -7-amino-cephalosporanic acid) and 100ml tri- are added in 250ml there-necked flask
Chloromethanes, stirred under nitrogen atmosphere are cooled to 0 DEG C or less；0.11mol diisopropylethylamine, stirring to dissolution clarification is added；Drop
Temperature extremely obtains B liquid for -45 DEG C or less, spare.
B liquid is slowly dropped in A liquid in -30 DEG C or less；- 30 DEG C of temperature control or less are reacted 3~4 hours, cool to -40
DEG C, 0.1mol acetic acid is added, reacts 20 minutes, 22.6g (0.15mol) chlorosulphonyl isocyanate is added dropwise, is reacted in -30 DEG C or so
2 hours；150ml water is added, adjusts pH value 2.5 with sodium bicarbonate and reacts 60 minutes.Stratification separates organic phase and is washed with water
Twice, 30g anhydrous sodium sulfate and 2g active carbon is added in each 150ml, stirs 30 minutes, and 250ml acetone is added in filtering, filtrate
0.115mol cyclohexylamine is added dropwise in 50ml methanol, and crystallization is precipitated, and stirs 30 minutes, filtering, acetone washing.Wet product vacuum drying, obtains
40.2g off-white color crystalline powder.
Embodiment 10
(6R, 7S) -3- carbamyl oxygen methyl -7- ((2RS) -2- methoxyl group -2- (thiophene -2- base)-acetylamino) -8- oxygen
The preparation of generation -5- sulphur -1- azabicyclo [4.2.0] oct-2-ene -2- carboxylic acid diisopropyl amine salt
17.2g (0.1mol) (RS)-α-methoxyl group -2- thiophene phenylacetic acid, 200ml are added in tetra- mouthfuls of reaction flasks of 500ml
Chloroform, nitrogen protection, stirring are cooled to -10 DEG C or less.0.115mol diisopropylethylamine, stirring and dissolving clarification is added.Cooling
To -50 DEG C, 0.105mol mesyl chloride is added dropwise, is reacted in -35 DEG C or less, end of reaction cools to -45 DEG C or less and obtains A liquid
It is spare.
23.2g (0.1mol) HACA (methylol -7-amino-cephalosporanic acid) and 100ml bis- are added in 250ml there-necked flask
Chloromethanes, stirred under nitrogen atmosphere are cooled to 0 DEG C or less；0.12mol diisopropylamine, stirring to dissolution clarification is added；Cooling
B liquid is obtained to -45 DEG C or less, it is spare.
B liquid is slowly added dropwise in A liquid in -30 DEG C or less；- 30 DEG C of temperature control or less are reacted 3~4 hours, cool to -40 DEG C,
0.1mol phosphoric acid is added, reacts 20 minutes, 22.6g (0.15mol) chlorosulphonyl isocyanate is added dropwise, it is small in -30 DEG C or so reactions 2
When；150ml water is added, adjusts pH value 3 with sodium bicarbonate and reacts 60 minutes.Stratification separates organic phase and is washed twice with water,
30g anhydrous sodium sulfate and 2g active carbon is added in each 150ml, stirs 30 minutes, and 250ml acetone 50ml first is added in filtering, filtrate
0.115mol diisopropylamine is added dropwise in alcohol, and crystallization is precipitated, and stirs 30 minutes, filtering, acetone washing.Wet product vacuum drying, obtains
40.2g off-white color crystalline powder.
Embodiment 11
(R, S)-methoxyl group Cefoxitin prepares chemical equation
Operating process
Off-white color crystalline powder 5.3g (0.01mol) (6R, 7S) -3- ammonia obtained above is added in 50ml there-necked flask
Methanoyl methyl -7- ((2RS) -2- methoxyl group -2- (thiophene -2- base)-acetylamino) -8- oxo -5- sulphur -1- azabicyclo
[4.2.0] oct-2-ene -2- carboxylic acid diisopropyl amine salt, 50ml methylene chloride and 5ml methanol, stirring, cool down under nitrogen protection
To -70 DEG C, the solution of 1g (0.03mol) sodium methoxide and 20ml methanol is added, in -70 DEG C or so dropwise addition 2.73g after adding
(0.025mol) t-butyl hypochlorate solution stir about 1 hour, is added 2.8g (0.015mol) sodium pyrosulfite, stirs 10 points
Then clock is heated up between vinegar acid for adjusting pH value 6~7, in 0~5 DEG C of dropwise addition mass concentration be 5% salt acid for adjusting pH value 1~2,
Standing separates organic layer, and water layer is extracted once with methylene chloride, merges organic layer, is washed with water primary.Organic layer saturated carbon
Sour hydrogen sodium solution adjusts pH value 7~8, separates organic layer, and water layer is used salt acid for adjusting pH value 1~2 with 10%, mentioned with ethyl acetate
It takes, ethyl acetate layer is dried, filtered with anhydrous sodium sulfate, is concentrated under reduced pressure, is obtained light yellow oil about 4.4g, crude product is through silica gel
Column chromatographic purifying obtains product 3.5g.(eluent ethylacetate-petroleum ether=6:1).Purity 98.0%.Through MS,1H-NMR and13C-NMR structural confirmation is consistent with reference substance map.
Embodiment 12
The preparation of (R, S)-methoxyl group Cefoxitin
Off-white color crystalline powder 5.3g (0.01mol) (6R, 7S) -3- ammonia obtained above is added in 50ml there-necked flask
Methanoyl methyl -7- ((2RS) -2- methoxyl group -2- (thiophene -2- base)-acetylamino) -8- oxo -5- sulphur -1- azabicyclo
[4.2.0] oct-2-ene -2- carboxylic acid diisopropyl amine salt, 50ml chloroform and 5ml methanol, stirring, be cooled under nitrogen protection -
60 DEG C, the solution of 0.04mol sodium methoxide and 20ml methanol is added, in -60 DEG C or so the tertiary fourths of dropwise addition 0.02mol hypochlorous acid after adding
Ester solution stir about 1 hour, is added 0.012mol sodium pyrosulfite, stirs 10 minutes, between vinegar acid for adjusting pH value 6~7,
Then it heats up, in 0~5 DEG C of 5% salt acid for adjusting pH value 1~2 of dropwise addition, standing separates organic layer, and water layer extracts one with chloroform
It is secondary, merge organic layer, is washed with water primary.Organic layer adjusts pH value 7~8 with saturated sodium bicarbonate solution, separates organic layer, water
Layer uses salt acid for adjusting pH value 1~2 with 10%, is extracted with ethyl acetate, ethyl acetate layer is dried, filtered with anhydrous sodium sulfate, is subtracted
Pressure concentration, obtains light yellow oil about 3.8g, crude product is purified by silica gel column chromatography to obtain product 2.56g.(eluent acetic acid second
Ester-petroleum ether=6:1).Purity 98.2%.Through MS,1H-NMR and13C-NMR structural confirmation is consistent with reference substance map.
Embodiment 13
The preparation of (R, S)-methoxyl group Cefoxitin
Off-white color crystalline powder 5.3g (0.01mol) (6R, 7S) -3- ammonia obtained above is added in 50ml there-necked flask
Methanoyl methyl -7- ((2RS) -2- methoxyl group -2- (thiophene -2- base)-acetylamino) -8- oxo -5- sulphur -1- azabicyclo
[4.2.0] oct-2-ene -2- carboxylic acid diisopropyl amine salt, 50ml chloroform and 5ml methanol, stirring, be cooled under nitrogen protection -
80 DEG C, the solution of 0.035mol sodium methoxide and 20ml methanol is added, in -80 DEG C or so dropwise addition 0.03mol hypochlorous acid uncles after adding
Butyl acetate solution stir about 1 hour, is added 0.02mol sodium pyrosulfite, stirs 10 minutes, between vinegar acid for adjusting pH value 6~7,
Then it heats up, in 0~5 DEG C of 5% salt acid for adjusting pH value 1~2 of dropwise addition, standing separates organic layer, and water layer extracts one with chloroform
It is secondary, merge organic layer, is washed with water primary.Organic layer adjusts pH value 7~8 with saturated sodium bicarbonate solution, separates organic layer, water
Layer uses salt acid for adjusting pH value 1~2 with 10%, is extracted with ethyl acetate, ethyl acetate layer is dried, filtered with anhydrous sodium sulfate, is subtracted
Pressure concentration, obtains light yellow oil about 3.9g, crude product is purified by silica gel column chromatography to obtain product 2.95g.(eluent acetic acid second
Ester-petroleum ether=6:1).Purity 98.0%., through MS,1H-NMR and13C-NMR structural confirmation is consistent with reference substance map.
The present invention is not limited to the above embodiment, it will be understood by those skilled in the art that: do not departing from the present invention
Principle and objective in the case where a variety of change, modification, replacement and modification, the scope of the present invention can be carried out to these embodiments
It is defined by the claims and their equivalents.
Claims (10)
1. a kind of preparation method of (RS)-methoxyl group Cefoxitin, which is characterized in that prepare in accordance with the following steps:
(1) using thiophene as starting material, normal heptane is reacted as reaction dissolvent with trichloroacetaldehyde, is evaporated under reduced pressure to after having reacted
To (RS)-α-trichloromethyl -2- thenyl alcohol；
(2) (RS)-α-trichloromethyl -2- thenyl alcohol for obtaining step (1) system of reacting with methanol in the presence of a basic
Obtain (RS)-α-methoxyl group -2- thiophene phenylacetic acid；
(3) by (RS)-α-methoxyl group -2- thiophene phenylacetic acid dissolution in organic solvent, nitrogen protection, be cooled to -10 DEG C hereinafter,
The first organic base is added, is cooled to -50 DEG C~-60 DEG C after stirring clarification, methylsufonyl chloride or pivaloyl chloride is added dropwise, in -35 DEG C
It reacts below, it is spare to obtain solution A after having reacted；
It is added methylol -7-amino-cephalosporanic acid and organic solvent in another reaction vessel, under nitrogen protection, stirs, drop
Temperature is to 0 DEG C hereinafter, the second organic base of addition, stirs to clarify, it is spare to obtain solution B；
Solution B is slowly dropped in solution A at -30 DEG C or less；- 30 DEG C of temperature control or less reaction, then cool to -40 DEG C with
Under, acid solution is added, the reaction was continued, and chlorosulphonyl isocyanate is then added dropwise, and the reaction was continued in -30 DEG C or so；It is eventually adding water, is adjusted
PH value 2-3 is saved, stratification after having reacted, the dry decoloration of organic phase is filtered, and acetone and methanol is added in filtrate, and being added dropwise first has
Machine alkali, precipitates crystal, and filtration drying obtains off-white color crystalline powder；
(4) obtained off-white color crystalline powder is dissolved in organic solvent and methanol, under nitrogen protection, is cooled to -60 DEG C
~-80 DEG C, the methanol solution of sodium methoxide is added, t-butyl hypochlorate is added dropwise after adding, is stirred to react, after having reacted, is added burnt
Sodium sulfite, stirring adjust pH6-7 with acetic acid, then heat to 0 DEG C~5 DEG C, adjust pH1~2, stratification, and organic layer is washed
After washing, saturated sodium bicarbonate is added to adjust pH7-8, layering, water layer adjusts pH1-2, is extracted with ethyl acetate, and ethyl acetate layer is dry
Dry, filtering is concentrated under reduced pressure to give grease crude product.
2. the preparation method of (RS)-methoxyl group Cefoxitin according to claim 1, it is characterised in that: in step (1), institute
The molar ratio for stating thiophene and trichloroacetaldehyde is 1:1~1.2.
3. the preparation method of (RS)-methoxyl group Cefoxitin according to claim 2, it is characterised in that: step (1) it is specific
Operating procedure are as follows: thiophene, normal heptane and trichloroacetaldehyde stirring are added in reaction vessel, back flow reaction is warming up to, after having reacted
Recycling design is concentrated under reduced pressure in cooling, and residue vacuum distillation, 98~100 DEG C of collection, 1.0mmHg fraction obtain (RS)-α-trichlorine
Methyl -2- thenyl alcohol.
4. the preparation method of (RS)-methoxyl group Cefoxitin described in -3 any one according to claim 1, it is characterised in that: step
(2) in, the alkaline matter be potassium hydroxide or sodium hydroxide, (R, the S)-α-trichloromethyl -2- thenyl alcohol and alkalinity
The molar ratio of substance is 1:3~5.
5. the preparation method of (RS)-methoxyl group Cefoxitin according to claim 4, which is characterized in that step (2) it is specific
Operating procedure are as follows: methanol and alkaline matter, stirring and dissolving are added in the reaction vessel, is cooled to -5 DEG C~0 DEG C, is added (R, S) -
α-trichloromethyl -2- thenyl alcohol methanol solution, stirring, temperature rising reflux reaction are cooled to room temperature after having reacted, are concentrated under reduced pressure
It goes out organic solvent, methyl tertiary butyl ether(MTBE) or petroleum ether or isopropyl ether is then added, stirring adjusts pH2.5- with hydrochloric acid solution
3.5, it separates organic layer, water layer methyl tertiary butyl ether(MTBE) or petroleum ether or isopropyl ether extracts, merge organic layer, be washed with brine,
It dries, filters, is concentrated to get (RS)-α-methoxyl group -2- thiophene phenylacetic acid.
6. the preparation method of (RS)-methoxyl group Cefoxitin according to claim 5, it is characterised in that: the organic solvent
For methylene chloride or chloroform.
7. the preparation method of (RS)-methoxyl group Cefoxitin according to claim 6, it is characterised in that: in step (3), institute
Stating the first organic base is one of diisopropylamine, triethylamine, tri-n-butylamine, diisopropylethylamine, (RS)-α-methoxy
The molar ratio of base -2- thiophene phenylacetic acid and the first organic base be 1:1-1.2, (RS)-α-methoxyl group -2- thiophene phenylacetic acid with
The molar ratio of methylsufonyl chloride or pivaloyl chloride is 1:1-1.1.
8. the preparation method of (RS)-methoxyl group Cefoxitin according to claim 7, it is characterised in that: in step (3), institute
Stating the second organic base is tetramethylguanidine, triethylamine, diisopropylethylamine, one of tri-n-butylamine, diisopropylamine, the hydroxyl first
The molar ratio of base -7-amino-cephalosporanic acid and the second organic base is 1:1.1-1.3；
The acid solution is one of methanesulfonic acid, hydrochloric acid, phosphoric acid, formic acid, acetic acid；
The molar ratio of (RS)-α-methoxyl group -2- thiophene phenylacetic acid and acid solution is 1:1-1.1；
The molar ratio of (RS)-α-methoxyl group -2- thiophene phenylacetic acid and chlorosulphonyl isocyanate is 1:1.5-1.6.
9. the preparation method of (RS)-methoxyl group Cefoxitin according to claim 8, it is characterised in that: in step (4), class
The molar ratio of white crystalline powder and sodium methoxide is 1:3-4；The off-white color crystalline powder and t-butyl hypochlorate rub
You are than being 1:2-3；The molar ratio of the off-white color crystalline powder and sodium pyrosulfite is 1:1.2-2.
10. the preparation method of (RS)-methoxyl group Cefoxitin according to claim 9, it is characterised in that: the grease is thick
Product are purified using silica gel column chromatography.
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