CN110041346A - A kind of preparation method of the Cefixime of low cost - Google Patents
A kind of preparation method of the Cefixime of low cost Download PDFInfo
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- CN110041346A CN110041346A CN201910307589.2A CN201910307589A CN110041346A CN 110041346 A CN110041346 A CN 110041346A CN 201910307589 A CN201910307589 A CN 201910307589A CN 110041346 A CN110041346 A CN 110041346A
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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
- C07D501/22—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with radicals containing only hydrogen and carbon atoms, attached in position 3
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Abstract
The present invention relates to a kind of preparation methods of the Cefixime of low cost, comprising: reacts D-7-ACA, Cefixime active ester to obtain the first intermediate；First intermediate, phosphorus pentachloride are reacted to obtain the reaction solution of the second intermediate；The reaction solution of second intermediate, sodium iodide, triphenylphosphine, formaldehyde are reacted to obtain third intermediate；Third intermediate is hydrolyzed using lye, acid for adjusting pH is added after hydrolysis, crystallization obtains Cefixime.Use D-7-ACA for starting material in the preparation method of the Cefixime of low cost of the invention, the molecular weight of the molecular weight ratio GCLE of D-7-ACA is about half, therefore using D-7-ACA as the high 2 times or more of effective molal quantity of effective mole ratio GCLE of starting material, obviously at low cost, quality is stablized, and process route is short.
Description
Technical field
The present invention relates to field of pharmaceutical technology, and in particular to a kind of preparation method of the Cefixime of low cost.
Background technique
Cefixime (Cefixime) is the Third generation Cephalosporins antibiotic for oral use of Teng Ze company, Japan research and development,
Suitable for treating the infection at the positions such as breathing caused by sensitive bacteria, uropoiesis and biliary tract.Cefixime generates gram negative bacilli
Beta-lactamase it is highly stable, the first generation and second generation cephalosporin are better than to gram negative bacilli antibacterial action, it is blue to leather
Positive cocci antibacterial action is not so good as the first generation and second generation cephalosporin.
China was just proposed domestic Cefixime bulk pharmaceutical chemicals early in 2000 or so, universal technique at that time be all with
(7-Phenylacetamido-3-chloromethylcephalosporanic acid p-methoxybenzyl ester, molecular formula are C to GCLE24H23O5N2SCl) it is raw material, leads to
Cross that iodine replaces, wittig reaction is at carbon double bond, enzyme hydrolysis, 7 side chains in active ester, then basic hydrolysis obtain finished product Cefixime.
The characteristics of technique is that raw material GCLE dosage is huge, and effective molal quantity is low, and at high cost, route is long, although classical, cost is occupied
It is high not under.There are also the Article 2 routes of Teng Ze company report first to connect 7 phenylacetyl groups using 7-ACA as raw material, then connect
The benzhydryl protecting group of upper 4 carboxyls, then hydrolyze 3 ester it is strong, obtain 3 methylols, it is then halogenated, obtain GCLE, phase
When the route as preparing GCLE with 7-ACA, then preparing Cefixime with GCLE prepares Cefixime, such route is superfluous
It is long, and 7-ACA price and GCLE price are substantially suitable, cause the cost ratio GCLE route cost for changing route higher, without real
Border utility value.
Summary of the invention
The object of the present invention is to provide a kind of preparation methods of the Cefixime of low cost, solve prior art environmental protection pressure
Big problem.
The technical proposal for solving the technical problem of the invention is: a kind of preparation method of the Cefixime of low cost,
Include:
A, it reacts D-7-ACA, Cefixime active ester to obtain the first intermediate；Wherein, the structural formula of the first intermediate
It is as follows:
B, the first intermediate, phosphorus pentachloride are reacted to obtain the reaction solution of the second intermediate；Wherein, the knot of the second intermediate
Structure formula is as follows:
C, the reaction solution of the second intermediate, sodium iodide, triphenylphosphine, formaldehyde are reacted to obtain third intermediate；Wherein,
The structural formula of three intermediates is as follows:
D, third intermediate is hydrolyzed using lye, acid for adjusting pH is added after hydrolysis, crystallization obtains Cefixime
In the preparation process in accordance with the present invention, in step, D-7-ACA and the mass ratio of Cefixime active ester are 1:1.7
~3.5, preferred mass ratio is 1:1.8~2.5.
In the preparation process in accordance with the present invention, in the reaction process of step A, in D-7-ACA and Cefixime active ester
Tetrahydrofuran and water is added, and tetrahydrofuran and triethylamine is slowly added dropwise in control temperature -10~30 DEG C under agitation, ties up
- 10~30 DEG C of reactions are held, are detected with HPLC, until the residual on HPLC map of D-7-ACA is lower than 0.5% (area normalization
Change method), obtain the reaction solution of the first intermediate.
In the preparation process in accordance with the present invention, the reaction solution of the first intermediate obtained after reaction is extracted with organic solvent, extraction
Organic solvent after taking mutually recycles, and water phase adjusts pH to 2.5~4.5 with acid solution, and filtration drying obtains the first intermediate.
In the preparation process in accordance with the present invention, in stepb, the mass ratio of phosphorus pentachloride and the first intermediate be 0.42~
0.85:1, preferred scope are 0.50~0.75:1.
In the preparation process in accordance with the present invention, in the reaction process of step B, in the first intermediate be added methylene chloride,
Dimethyl acetamide adjusts the temperature to -20~20 DEG C under stirring, phosphorus pentachloride is added portionwise, and maintains 0 DEG C and is stirred to react, and uses
HPLC detection obtains second until residual of the residual quantity of the first intermediate on HPLC is lower than 1.0% (area normalization method)
The reaction solution of intermediate.
In the preparation process in accordance with the present invention, in step C, the mass ratio of sodium iodide and the first intermediate is 0.31~
0.67:1, preferred scope are 0.33~0.48:1；The mass ratio of triphenylphosphine and the first intermediate is 0.5~1.8:1, preferably model
Enclosing is 0.6~1.2:1；The mass ratio of formaldehyde and the first intermediate is 0.05~3:1, and preferred scope is 0.8~1.8:1.
In the preparation process in accordance with the present invention, in the reaction process of step C, among reacted in step B second
The reaction solution of body stirs under the conditions of 0-20 DEG C is added sodium iodide and water, is warming up to 25-65 DEG C, triphenylphosphine is added, maintain 25-
65 DEG C stirring 1-6 hours, formaldehyde, acetone is added, is cooled to -10-20 DEG C, is added aqueous slkali, -10-20 DEG C of maintaining reaction temperature
Reaction 1-6 hours, the suspension of the third intermediate after being reacted.
In the preparation process in accordance with the present invention, after acetone to be added to suspension and the dissolution for the third intermediate that reaction obtains,
Acid solution extraction is added, organic phase be concentrated in vacuo to becoming cloudy after layering, and methanol is then added, is warming up to 25-60 DEG C, delays
Slow stirred crystallization, then be evaporated under reduced pressure to a large amount of crystal and be precipitated, water is then added, is cooled to -10~20 DEG C after adding, it is stirred
Filter, washing are dried to obtain third intermediate.
In the preparation process in accordance with the present invention, step D is specifically included: water is added in third intermediate, is cooled to 0~20
DEG C, aqueous slkali dissolution is added dropwise, 0~20 DEG C is cooled to after dissolution completely, aqueous slkali hydrolysis is added, is detected with HPLC, until third
The residual on HPLC of intermediate is lower than 1.0% (area normalization method), and adding acid solution and being neutralized to pH is 5.0~8.0,
Then active carbon is added, stirring dehydration, filtering, it is 1.0~3.0 that filtrate acid solution, which adjusts pH, is cooled down after crystallization, is filtered, and is done
It is dry to obtain Cefixime.
The preparation method for implementing the Cefixime of low cost of the invention, have the advantages that it is of the invention it is low at
Use D-7-ACA for starting material in the preparation method of this Cefixime, the molecular weight of the molecular weight ratio GCLE of D-7-ACA is about
It is half, therefore using D-7-ACA as the high 2 times or more of effective molal quantity of effective mole ratio GCLE of starting material, it is clear that at
This is low, and quality is stablized, and process route is short.
Specific embodiment
Below with reference to embodiment, the preparation method of the Cefixime of low cost of the invention is described further:
Now, reaching its maturity with D-7-ACA preparation process, cost constantly reduces, and quality is also highly stable, and should
The high 2 times or more of effective molal quantity of effective mole ratio GCLE of technique, GCLE molecular weight 489.96, D-7-ACA molecular weight
230.24, and GCLE and D-7-ACA price difference is not very big now, therefore is that starting material prepares head using D-7-ACA
The advantage of spore gram oxime is with regard to more obvious.The technique is using D-7-ACA as starting material, and first and Cefixime pendant reactive methyl ester is anti-
The first intermediate of 7 bit aminos protection should be obtained, then halogenated 3 hydroxyls obtain the second intermediate, then iodo again, then carry out
Wittig reacts to obtain the double strong third intermediates of carbon, then hydrolyzes Side chain protective group, has just obtained finished product Cefixime.The technique
Route is short, and cost of material is low, and then the subsequent cost such as environmental protection is less expensive, therefore is the green work for having very much economic value
Skill route.
The present invention provides a kind of preparation method of the Cefixime of low cost, comprising:
S1, by D-7-ACA (methylol -7-amino-cephalosporanic acid, No. CAS: 15690-38-7), Cefixime active ester
(MICA active ester, No. CAS: 246035-38-1) reaction obtains the first intermediate；Specifically, D-7-ACA and Cefixime activity
The mass ratio of ester is 1:1.7~3.5, i.e. 1:1.7 to 1:3.5, in the D-7-ACA and Cefixime active ester of above-mentioned mass ratio
Tetrahydrofuran and water is added, and tetrahydrofuran and triethylamine is slowly added dropwise in control temperature -10~30 DEG C under agitation, ties up
- 10~30 DEG C of reactions are held, are detected with HPLC, until the residual on HPLC map of D-7-ACA is lower than 0.5% (area normalization
Change method), the reaction solution of the first intermediate is obtained, the reaction solution of the first intermediate is extracted with organic solvent, extracted organic molten
Agent is mutually recycled, and water phase adjusts pH to 2.5~4.5 with acid solution, and filtration drying obtains the first intermediate；Wherein, extraction
Organic solvent includes but is not limited to esters, alcohols etc., such as ethyl acetate；Acid solution includes but is not limited to dilute hydrochloric acid, dilute sulfuric acid
Deng；Referring to following first reaction equation:
S2, the first intermediate, phosphorus pentachloride are reacted to obtain the reaction solution of the second intermediate；Specifically, phosphorus pentachloride with
The mass ratio of first intermediate is 0.42~0.85:1, i.e. 0.42:1 to 0.85:1；In the first intermediate be added methylene chloride,
Dimethyl acetamide adjusts the temperature to -20~20 DEG C under stirring, phosphorus pentachloride is added portionwise, and maintains 0 DEG C and is stirred to react, and uses
HPLC detection obtains in second until the residual quantity of the first intermediate is shown on HPLC lower than 1.0% (area normalization method)
The reaction solution of mesosome；Referring to following second reaction equation:
S3, the reaction solution of the second intermediate, sodium iodide, triphenylphosphine, formaldehyde are reacted to obtain third intermediate；Specifically
The mass ratio of ground, sodium iodide and the first intermediate is 0.31~0.67:1；The mass ratio of triphenylphosphine and the first intermediate is 0.5
~1.8:1；The mass ratio of formaldehyde and the first intermediate is 0.05~3:1；By the anti-of the second intermediate reacted in step B
It answers liquid to stir under the conditions of 0-20 DEG C and sodium iodide and water is added, be warming up to 25-65 DEG C, triphenylphosphine is added, maintain 25-65 DEG C and stir
It mixes 1-6 hours, formaldehyde, acetone is added, be cooled to -10-20 DEG C, aqueous slkali, such as sodium hydroxide solution is added, maintain reaction temperature
Reaction 1-6 hours of -10-20 DEG C of degree, the suspension of the third intermediate after being reacted after acetone solution then is added, are added
Acid solution (such as dilute hydrochloric acid, dilute sulfuric acid) extraction, be concentrated in vacuo to becoming cloudy, first is then added to organic phase extracted
Alcohol is warming up to 20-60 DEG C of crystallization, is slowly stirred crystallization 1-3h, starts vacuum distillation to a large amount of crystal are precipitated, water is then added,
- 10~20 DEG C, preferably 0 DEG C, agitation and filtration are cooled to, washing is dried to obtain third intermediate；Referring to following third reaction equation:
S4, third intermediate is hydrolyzed, such as sodium hydroxide solution using lye, sour (such as hydrochloric acid, sulfuric acid is added after hydrolysis
Deng) pH is adjusted, crystallization obtains Cefixime；Specifically, water is added in third intermediate, is cooled to 0~20 DEG C, alkali soluble is added dropwise
Liquid (such as sodium hydroxide solution) dissolution, is cooled to 0~20 DEG C after dissolution completely, be added aqueous slkali (such as sodium hydroxide solution)
Hydrolysis, is detected with HPLC, until the peak area residual of third intermediate is lower than 1.0% (area normalization method), it is molten to add acid
It is 5.0~8.0 that liquid (such as dilute hydrochloric acid solution, dilution heat of sulfuric acid), which is neutralized to pH, and active carbon is then added, and stirring dehydration is filtered,
It is 1.0~3.0 that filtrate acid solution (such as dilute hydrochloric acid solution, dilution heat of sulfuric acid), which adjusts pH, is cooled down after crystallization, is filtered, dry
Cefixime is obtained, referring to following 4th reaction equation:
It should be noted that the concentration of the sodium hydroxide solution referred in text is usually 3%-20%；What is referred in text is dilute
The concentration of hydrochloric acid solution is usually 3%-10%；The concentration of the dilution heat of sulfuric acid referred in text is usually 3%-10%.
It is described in detail below by specific embodiment.
Embodiment 1
In a 1000ml reaction flask, D-7-ACA40.0g is added, Cefixime active ester 80g, THF (tetrahydro is added
Furans) 280ml, pure water 268ml.Lower 0-5 DEG C of temperature of the control of stirring, is slowly added dropwise 40mlTHF+28ml TEA (triethylamine), ties up
It holds the temperature about 1 hour and finishes, the thermotonus is maintained after adding 10 hours, it is anti-lower than 0.5% that HPLC detects D-7-ACA residual
It should be to complete.Extracted in two times with 400ml ethyl acetate, after extraction ethyl acetate phase recycle, water phase with 9% dilute hydrochloric acid tune
Whole PH to 3.9-4.0 crystallization, filtering are dried to obtain the first intermediate about 80.2g.
In a dry anhydrous reaction flask, the first intermediate 60.0g is added, methylene chloride 250ml is added, is added
DMA20ml cools to 0~10 DEG C under stirring, be added portionwise phosphorus pentachloride 32g, and temperature is maintained to stir 2 hours, HPLC detection the
One intermediate is to complete lower than 1% reaction.After the reaction was completed, it is warming up to 10-20 DEG C, is added with stirring sodium iodide 19.5g, it is pure
Water 90ml is warming up to 25~30 DEG C, and triphenylphosphine 35g is added, and temperature is maintained to stir 2-3 hours.Formaldehyde 74g, acetone is added
200ml cools to 20 DEG C, and 5% sodium hydroxide 100ml is added dropwise, then reaction 2-3 hours of 15-20 DEG C of maintaining reaction temperature is added
After acetone 280ml dissolution, the hydrochloric acid 300ml extraction of 0.1N is added.Organic phase is transferred in another reaction flask, vacuum distillation,
Distillation to volume is about 450ml.Then methanol 700ml is added, is warming up to 30~35 DEG C of crystallizations, it is small to be then slowly stirred crystallization 1
When, start to be evaporated under reduced pressure, until 180ml water is added when volume is about 600ml, adds, cool to 0 DEG C, stirs 1 hour and filter, wash
Wash dry third intermediate about 48.1g.
In a 1000ml reaction flask, third intermediate 40.0g is added, pure water 300ml is added, cools to 5 DEG C or less.
6% sodium hydroxide dissolution is added dropwise, after dissolution completely, cools to close to 0 DEG C, is hydrolyzed, used with 20% sodium hydroxide solution
HPLC monitoring is added dilute hydrochloric acid solution neutralization and arrives PH7 or so, be then added after the residual of third intermediate is lower than 0.3%
EDTA, sodium hydrosulfite and active carbon 5g, stirring dehydration 20 minutes, filtering, filtrate adjusts PH to 2.0~2.2 with dilute hydrochloric acid solution
Left and right crystallization.Cooling, filtering, dry finished product Cefixime about 38.6g.
Embodiment 2
In a 1000ml reaction flask, D-7-ACA 40.0g is added, Cefixime active ester 72g, THF (tetrahydro is added
Furans) 280ml, pure water 268ml.Stirring is lower to control temperature -10~5 DEG C, is slowly added dropwise 40mlTHF+28ml TEA (triethylamine),
It maintains finish within the temperature about 1 hour, the thermotonus is maintained after adding 12 hours, HPLC detects D-7-ACA residual and is lower than 0.5%
Reaction is to complete.Extracted in two times with 400ml ethyl acetate, after extraction ethyl acetate phase recycle, water phase with 9% dilute hydrochloric acid
It adjusts PH to 3.3~3.5 to crystallize, filtering is dried to obtain the first intermediate about 79.3g.
In a dry anhydrous reaction flask, the first intermediate 60.0g is added, methylene chloride 250ml is added, is added
DMA20ml cools to -10~0 DEG C under stirring, be added portionwise phosphorus pentachloride 30g, and temperature is maintained to stir 2 hours, HPLC detection the
One intermediate is to complete lower than 1% reaction.After the reaction was completed, it is warming up to 0-10 DEG C, is added with stirring sodium iodide 28.8g, it is pure
Water 130ml is warming up to 35~40 DEG C, and triphenylphosphine 36g is added, and temperature is maintained to stir 1 hour.Formaldehyde 108g, acetone is added
210ml cools to -10 DEG C, and 5% sodium hydroxide 100ml is added dropwise, and maintaining reaction temperature -10~5 DEG C are reacted 1 hour, are then added
After acetone 280ml dissolution, the hydrochloric acid 300ml extraction of 0.1N is added.Organic phase is transferred in another reaction flask, vacuum distillation,
Distillation to volume is about 450ml.Then methanol 800ml is added, is warming up to 40~45 DEG C of crystallizations, it is small to be then slowly stirred crystallization 1
When, start to be evaporated under reduced pressure, until 200ml water is added when volume is about 600ml, adds, cool to 5 DEG C, stirs 2 hours and filter, wash
Wash dry third intermediate about 46.9g.
In a 1000ml reaction flask, third intermediate 40g is added, pure water 300ml is added, cools to 0-5 DEG C or less.
6% sodium hydroxide dissolution is added dropwise, after dissolution completely, cools to close to 10 DEG C, is hydrolyzed, used with 20% sodium hydroxide solution
HPLC monitoring is added dilute hydrochloric acid solution and neutralizes to pH 7 or so, be then added after the residual of third intermediate is lower than 1.0%
EDTA, sodium hydrosulfite and active carbon 5g, stirring dehydration 20 minutes, filtering, filtrate adjusts PH to 1.5~1.6 with dilute hydrochloric acid solution
Left and right crystallization.Cooling, filtering, dry finished product Cefixime about 38.1g.
Embodiment 3
In a 1000ml reaction flask, D-7-ACA40.0g is added, Cefixime active ester 100g, THF (tetrahydro is added
Furans) 380ml, pure water 355ml.Lower 0~30 DEG C of temperature of the control of stirring, is slowly added dropwise 60mlTHF+40ml TEA (triethylamine),
It maintains finish within the temperature about 2 hours, the thermotonus is maintained after adding 10 hours, HPLC detects D-7-ACA residual and is lower than 0.5%
Reaction is to complete.Extracted in two times with 550ml ethyl acetate, after extraction ethyl acetate phase recycle, water phase with 9% dilute hydrochloric acid
It adjusts PH to 3.6~3.7 to crystallize, filtering is dried to obtain the first intermediate about 80.9g.
In a dry anhydrous reaction flask, the first intermediate 60.0g is added, methylene chloride 250ml is added, is added
DMA20ml cools to 0 DEG C under stirring, phosphorus pentachloride 45g is added portionwise, and temperature is maintained to stir 3 hours, in HPLC detection first
Mesosome is to complete lower than 1% reaction.After the reaction was completed, it is warming up to 10-20 DEG C, is added with stirring sodium iodide 19.8g, pure water
170ml is warming up to 45-50 DEG C, and triphenylphosphine 72g is added, and temperature is maintained to stir 6 hours.Formaldehyde 48g, acetone 300ml is added,
20 DEG C are cooled to, 5% sodium hydroxide 100ml is added dropwise, 5~20 DEG C of maintaining reaction temperature are reacted 6 hours, and acetone is then added
After 280ml dissolution, the hydrochloric acid 300ml extraction of 0.1N is added.Organic phase is transferred in another reaction flask, is evaporated in vacuo, distillation
It is about 480ml to volume.Then methanol 750ml is added, is warming up to 25-35 DEG C of crystallization, is then slowly stirred crystallization 1 hour, opens
Begin to be evaporated under reduced pressure, until 210ml water is added when volume is about 600ml, adds, cool to -10~0 DEG C, stirs 1 hour and filter, wash
Wash dry third intermediate about 47.5g.
In a 1000ml reaction flask, be added third intermediate 40g, be added pure water 300ml, cool to 10~20 DEG C with
Under.The sodium hydroxide dissolution of dropwise addition 6% is cooled to close to 10~20 DEG C, after dissolution completely with 20% sodium hydroxide solution water
Solution, is monitored with HPLC, after the residual of third intermediate is lower than 1.0%, dilute hydrochloric acid solution neutralization is added and arrives pH7 or so, then
EDTA, sodium hydrosulfite and active carbon 5g is added, stirring dehydration 20 minutes is filtered, and filtrate is left with dilute hydrochloric acid solution adjustment PH to 2.0
Right crystallization.Cooling, filtering, dry finished product Cefixime about 37.9g.
It should be understood that for those of ordinary skills, it can be modified or changed according to the above description,
Within all these improvement or transformation should all belong to the protection domain of appended claims of the present invention.
Claims (10)
1. a kind of preparation method of the Cefixime of low cost characterized by comprising
A, it reacts D-7-ACA, Cefixime active ester to obtain the first intermediate；Wherein, the structural formula of the first intermediate is as follows:
B, the first intermediate, phosphorus pentachloride are reacted to obtain the reaction solution of the second intermediate；Wherein, the structural formula of the second intermediate
It is as follows:
C, the reaction solution of the second intermediate, sodium iodide, triphenylphosphine, formaldehyde are reacted to obtain third intermediate；Wherein, in third
The structural formula of mesosome is as follows:
D, third intermediate is hydrolyzed using lye, acid for adjusting pH is added after hydrolysis, crystallization obtains Cefixime
2. preparation method according to claim 1, which is characterized in that in step, D-7-ACA and Cefixime activity
The mass ratio of ester is 1:1.7~3.5.
3. preparation method according to claim 1, which is characterized in that in the reaction process of step A, in D-7-ACA and
Tetrahydrofuran and water are added in Cefixime active ester, and tetrahydro is slowly added dropwise in control temperature -10~30 DEG C under agitation
Furans and triethylamine maintain -10~30 DEG C of reactions, are detected with HPLC, until the residual on HPLC map of D-7-ACA is lower than
0.5%, obtain the reaction solution of the first intermediate.
4. preparation method according to claim 3, which is characterized in that the reaction solution of the first intermediate obtained after reaction is used
Organic solvent extraction, organic solvent extracted mutually recycle, and water phase adjusts pH to 2.5~4.5 with acid solution, and filtration drying obtains
To the first intermediate.
5. preparation method according to claim 1, which is characterized in that in stepb, phosphorus pentachloride and the first intermediate
Mass ratio is 0.42~0.85:1.
6. preparation method according to claim 1, which is characterized in that in the reaction process of step B, in the first intermediate
Middle addition methylene chloride, dimethyl acetamide, adjust the temperature to -20~20 DEG C under stirring, phosphorus pentachloride is added portionwise, and maintain 0
It DEG C is stirred to react, is detected with HPLC, until the residual quantity of the first intermediate show on HPLC is lower than 1.0%, obtained in second
The reaction solution of mesosome.
7. preparation method according to claim 1, which is characterized in that in step C, the matter of sodium iodide and the first intermediate
Measuring ratio is 0.31~0.67:1；The mass ratio of triphenylphosphine and the first intermediate is 0.5~1.8:1；Formaldehyde and the first intermediate
Mass ratio be 0.05~3:1.
8. preparation method according to claim 7, which is characterized in that, will be anti-in step B in the reaction process of step C
The reaction solution for the second intermediate that should be obtained stirs under the conditions of 0-20 DEG C is added sodium iodide and water, is warming up to 25-65 DEG C, is added
Triphenylphosphine maintains 25-65 DEG C stirring 1-6 hours, and formaldehyde, acetone is added, and is cooled to -10-20 DEG C, and aqueous slkali is added, and maintains
Reaction 1-6 hours of -10-20 DEG C of reaction temperature, the suspension of the third intermediate after being reacted.
9. preparation method according to claim 8, which is characterized in that the third intermediate that reaction obtains is added in acetone
After suspension and dissolution, acid solution extraction is added, organic phase be concentrated in vacuo to becoming cloudy after layering, methanol is then added,
It is warming up to 25-60 DEG C, is slowly stirred crystallization, then is evaporated under reduced pressure to a large amount of crystal and is precipitated, water is then added, be cooled to after adding-
10~20 DEG C, agitation and filtration, washing is dried to obtain third intermediate.
10. preparation method according to claim 1, which is characterized in that step D is specifically included: adding in third intermediate
Enter water, be cooled to 0~20 DEG C, aqueous slkali dissolution is added dropwise, 0~20 DEG C is cooled to after dissolution completely, aqueous slkali hydrolysis is added, uses
HPLC detection, until the peak area residual of third intermediate is lower than 1.0%, adding acid solution and being neutralized to pH is 5.0~8.0,
Then active carbon is added, stirring dehydration, filtering, it is 1.0~3.0 that filtrate acid solution, which adjusts pH, is cooled down after crystallization, is filtered, and is done
It is dry to obtain Cefixime.
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Denomination of invention: A low-cost preparation method of Cefixime Effective date of registration: 20230609 Granted publication date: 20220607 Pledgee: Agricultural Bank of China Limited Zijin County Sub branch Pledgor: GUANGDONG LIGUO PHARMACY Co.,Ltd. Registration number: Y2023980043407 |