CN107915750B - A kind of preparation method of Mandokef sodium powder-needle preparation - Google Patents
A kind of preparation method of Mandokef sodium powder-needle preparation Download PDFInfo
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- CN107915750B CN107915750B CN201711213546.5A CN201711213546A CN107915750B CN 107915750 B CN107915750 B CN 107915750B CN 201711213546 A CN201711213546 A CN 201711213546A CN 107915750 B CN107915750 B CN 107915750B
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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
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/36—Methylene radicals, substituted by sulfur atoms
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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
- C07D501/06—Acylation of 7-aminocephalosporanic acid
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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
- C07D501/12—Separation; Purification
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Abstract
The present invention provides a kind of preparation methods of Mandokef sodium powder-needle preparation, the following steps are included: (a) is by 7-ACT and silanizing agent, the temperature control in dichloromethane solvent carries out Silanization reaction, the dosage solid-to-liquid ratio of the 7-ACT and methylene chloride is 1g: 3 ~ 6ml, cool down after reaction, obtains reaction solution 1；(b) formoxyl almond acyl chlorides is added dropwise into reaction solution 1 and temperature control carries out acylation reaction, obtains reaction solution 2；(c) reaction solution 2 extracted, decolourized, dehydration；(d) temperature control crystallizes；(e) solid is after acetone washing, dry, then through aseptic subpackaged up to Mandokef sodium powder-needle preparation.The present invention uses high concentration methylene chloride reaction system, and silanization, acylation process are fast, and the reaction time is short, and reaction residual is low, and product yield is high, and impurity is few.After reaction, the organic solvents such as methylene chloride are more easily recycled, and can be reused, more environmentally friendly, and save the cost, are suitable for large-scale industrial production.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of preparation method of Mandokef sodium powder-needle preparation.
Background technique
Cefamandole Nafate belongs to second generation cephalosporin class antibiotic, and chemical name is 7-D- (2- methanoyl phenylacetyl
Amine) -3- ((- 5 base of 1- methyl-1 H- tetrazolium) thiopurine methyltransferase) -3- cephem -4- carboxylic acid sodium salt, it is the pro-drug of Cefamandole,
Effective component Cefamandole is hydrolyzed to after vein or intramuscular injection rapidly in vivo, with side effect is less, safety is higher, treats
More definite advantage is imitated, is widely recognized as by clinician, suitable for pulmonary infection caused by sensitive bacterial, urinary tract sense
Dye, infection of biliary tract, skin soft-tissue infection, bone and the infection of joint and septicemia, abdominal cavity infection etc..
Cefamandole Nafate is to be formulated successfully by Lilly company, the U.S. in 1972, lists within 1978, closes in Britain first
At Conventional processing methods mainly active ester process and two kinds of chloride method of Cefamandole Nafate, and mostly with 7-amino-cephalosporanic acid
(7-ACA) or 7- amino -3- (1- methyl-1 H- tetrazole -5- base)-sulfidomethyl -3- cephalo -4- carboxylic acid (7-ATCA) is used as
Beginning raw material.1. active ester method: reacted using formyl mandelic acid with first mercapto tetrazole and active ester be first made, then with 7-ACA or
7-ATCA reaction obtains Mandokef acid, Cefamandole Nafate is made through salt-forming reaction.There are complex process for this method, close
It is not high at total recovery, and part raw material have the shortcomings that high toxicity and high anaphylaxis, therefore are not suitable for industrialized production.②
Chloride method: being protected using 7-ATCA through silylation, then with formoxyl almond acyl chlorides carry out acylation reaction, through hydrolysis, decoloration,
Cefamandole Nafate is made after salt-forming reaction.This method process route is relatively easy, is suitable for industrial production.It wherein reacts molten
The selection of agent, silylation protection reagent, recrystallisation solvent etc. is to influence the key factor of product quality and yield.
Mainly pass through 7-ATCA when currently, synthesizing Cefamandole Nafate using chloride method and silylation protects reagent N, O-
Double trimethylsilyl acetamide reactions, then prepare Mandokef with formoxyl almond acyl chloride reaction under ethyl acetate system
Sodium.The substances such as the method reaction dissolvent ethyl acetate and byproduct of reaction silicon ether are not readily separated, and ethyl acetate recycling is difficult, and after
It is more to continue into organic reagent type used in salt and crystallization reaction, is unfavorable for recycling and cost control, it is big to environmental hazard.Also there is use
Other reaction dissolvents, but most complex process, the reaction time is long and product impurity is high.
Summary of the invention
It is an object of the invention to provide a kind of preparation methods of Mandokef sodium powder-needle preparation, to solve existing method
The high problem of Cefamandole, impurity equal size in reaction time length and product.
The purpose of the present invention is what is be achieved through the following technical solutions: a kind of preparation side of Mandokef sodium powder-needle preparation
Method, comprising the following steps:
(a) by 7-TMCA and silanizing agent in dichloromethane solvent temperature control carry out Silanization reaction, the 7-TMCA with
The dosage solid-to-liquid ratio of methylene chloride is 1g: 3 ~ 6ml, cools down after reaction, obtains reaction solution 1；
(b) formoxyl almond acyl chlorides is added dropwise into reaction solution 1 and temperature control carries out acylation reaction, obtains reaction solution 2；
(c) reaction solution 2 is transferred in water phase, 0~25 DEG C of temperature control, while it is 4.0~7.0 that lye, which is added, to adjust pH, is stirred
Split-phase is stood after mixing, organic phase is recycled, ethyl acetate is added into water phase, while it is 0.1~2.0 that acid solution, which is added, to adjust pH, is stirred
Split-phase is stood after mixing, and obtains ethyl acetate phase；
(d) it decolourized, be dehydrated to ethyl acetate phase obtained by step (c) using decolorising agent and dehydrating agent, collected after filtering
Filtrate is to crystallizer；
(e) ethyl acetate solution of sodium iso-octoate is configured, stream is added in crystallizer after dissolved clarification and filtering, controls between the stream added-time
In 30~120min, temperature control crystallization；Growing the grain 30min~120min after the ethyl acetate solution stream of sodium iso-octoate adds, then
Stream plus ethyl acetate and temperature control crystallization；
(f) ethyl acetate is recovered by filtration, solid is Cefamandole Nafate product after acetone washing, dry.
In step (a) of the present invention, the silanizing agent is appointing in BSA, trim,ethylchlorosilane and hexamethyldisilazane
It anticipates one kind.
In step (a) of the present invention, the control of the reaction temperature of the Silanization reaction at 25~44 DEG C, the reaction time is 30~
60min。
In step (b) of the present invention, the control of the reaction temperature of the acylation reaction at -25~5 DEG C, the reaction time is 5~
20min。
In step (c) of the present invention, the lye is any one in sodium bicarbonate, sodium carbonate and sodium hydrate aqueous solution
Kind.
In step (c) of the present invention, the acid solution is any one in hydrochloric acid, sulfuric acid, phosphoric acid and aqueous acetic acid.
In step (d) of the present invention, the decolorising agent is active carbon, and the dehydrating agent is anhydrous magnesium sulfate, is decolourized, at dehydration
Managing number is 1~3 time.
In step (e) of the present invention, crystallization temperature is controlled at 10~35 DEG C.
In step (e) of the present invention, the ethyl acetate solution of the sodium iso-octoate is by sodium iso-octoate and ethyl acetate by solid
Liquor ratio 3g: 25mL configures.
In step (e) of the present invention, control is in 60~90min between the stream added-time of the ethyl acetate.
The present invention uses high concentration methylene chloride reaction system, and silanization, acylation process are fast, and the reaction time is short, reacts residual
Stay low, product yield height.After reaction, methylene chloride is more easily recycled, and can be reused, more environmentally friendly, and save the cost.Greatly
Large-scale production is easily controllable, and the period is short, and can guarantee stable product quality.
Crystallizing system of the present invention uses single solvent ethyl acetate, and solvent recovery is easy, and crystalline product quality stability is good,
Product Cefamandole and impurity content are low.
The present invention successfully guarantees that product system moisture and color grade refer to by secondary filter using active carbon and anhydrous magnesium sulfate
Mark requires, and is not necessarily to concentration process, reduces power consumption, reduces costs.
Specific embodiment
Embodiment 1
Methylene chloride 75mL, 7-TMCA 25g, BSA 28.8g are added into 500mL four-hole bottle, is warming up to 35 DEG C, reaction
30min, dissolved clarification cool down after reaction.Temperature control -5~0 DEG C is added dropwise formoxyl almond acyl chlorides 15mL, reacts 5min after adding,
It detects 7-TMCA and remains < 2.0%, reaction terminates.In another four-hole bottle be added 50mL purified water, temperature control 15 DEG C with
Under, reaction solution is flowed into four-hole bottle and is added, while flowing the sodium hydroxide solution for adding 15wt%, pH=4.8 ± 0.1 is controlled, quickly stirs
5min is mixed, split-phase is stood, recycles organic phase.Into water phase be added ethyl acetate 150mL, with 6mol/L hydrochloric acid solution adjust pH=
1.25,10min is quickly stirred, split-phase is stood, discards water phase.
2.5g active carbon and 2.5g anhydrous magnesium sulfate are added into ethyl acetate phase, decolourize dehydration 30min, carbon removal
Filter, with ethyl acetate 50mL foam washing carbon-coating.After combined ethyl acetate phase and ethyl acetate washings secondary addition 2.5g active carbon and
2.5g anhydrous magnesium sulfate, decolourize dehydration 30min, washes layer of charcoal, merging filtrate to crystallizer with 75mL ethyl acetate after decarburization.
12g sodium iso-octoate is dissolved in 100mL ethyl acetate, and dissolved clarification and after being sterile filtered, 30min stream adds to crystallizer
In (Mandokef acid solution), stream plus process temperature control are at 10~13 DEG C.After sodium iso-octoate solution stream adds, growing the grain
30min measures greatly crystalline substance.Then stream plus ethyl acetate 200mL, control is 60min between the stream added-time, in 14~15 DEG C of growing the grain 30min.
Filtering is washed (50mL acetone * 2 times), then 40 DEG C of dryings obtain injection Cefamandole sodium powder-needle preparation through aseptic subpackaged,
Weight yield is 128.5%.Products obtained therefrom indices are measured, and result is included in table 1.
Embodiment 2
Methylene chloride 150mL, 7-TMCA 25g, BSA 20.6g, trim,ethylchlorosilane are added into 500mL four-hole bottle
5.5g is warming up to 42 DEG C, reacts 50min, dissolved clarification, and reaction terminates cooling.Formoxyl mandeloyl is added dropwise in temperature control -10~-5 DEG C
Chlorine 15mL reacts 20min after adding, detection 7-TMCA remains < 2.0%, and reaction terminates.50mL is added in another four-hole bottle
Purified water, temperature control adds at 15 DEG C hereinafter, reaction solution is flowed into four-hole bottle, while flowing the sodium bicarbonate solution for adding 10wt%,
PH=5.5 ± 0.1 is controlled, 5min is quickly stirred, stands split-phase, recycles organic phase.Ethyl acetate 150mL is added into water phase, uses
6mol/L hydrochloric acid solution adjusts pH=0.52, quickly stirs 10min, stands split-phase, discards water phase.
2.5g active carbon and 2.5g anhydrous magnesium sulfate are added into ethyl acetate phase, decolourize dehydration 30min, carbon removal
Filter, with ethyl acetate 50mL foam washing carbon-coating.After combined ethyl acetate phase and ethyl acetate washings secondary addition 2.5g active carbon and
2.5g anhydrous magnesium sulfate, decolourize dehydration 30min, washes layer of charcoal, merging filtrate to crystallizer with 75mL ethyl acetate after decarburization.
12g sodium iso-octoate is dissolved in 100mL ethyl acetate, and dissolved clarification and after being sterile filtered, 40min stream adds to crystallizer
In (Mandokef acid solution), stream plus process temperature control are at 20~22 DEG C.After sodium iso-octoate solution stream adds, growing the grain
30min measures greatly crystalline substance.Then ethyl acetate 200mL is added, control is 90min between the stream added-time, in 14~15 DEG C of growing the grain 30min.
Filtering is washed (50mL acetone * 2 times), then 40 DEG C of dryings obtain injection Cefamandole sodium powder-needle preparation through aseptic subpackaged,
Weight yield is 129.3%.Products obtained therefrom indices are measured, and result is included in table 1.
Embodiment 3
Methylene chloride 125mL, 7-TMCA 25g are added into 500mL four-hole bottle, BSA 30.5g is added, is warming up to 30 DEG C,
60min, dissolved clarification are reacted, reaction terminates cooling.Temperature control -10~-5 DEG C are added dropwise formoxyl almond acyl chlorides 15mL, react after adding
10min, detection 7-TMCA remain < 2.0%, and reaction terminates.50mL purified water is added in another four-hole bottle, temperature control exists
15 DEG C add hereinafter, reaction solution is flowed into four-hole bottle, while flowing the sodium carbonate liquor for adding 10wt%, control pH=6.5 ± 0.1, fastly
Speed stirring 5min, stands split-phase, recycles organic phase.Ethyl acetate 150mL is added into water phase, is adjusted with 6mol/L hydrochloric acid solution
10min is quickly stirred in pH=1.35, stands split-phase, discards water phase.
2.5g active carbon and 2.5g anhydrous magnesium sulfate are added into ethyl acetate phase, decolourize dehydration 30min, carbon removal
Filter, with ethyl acetate 50mL foam washing carbon-coating.After combined ethyl acetate phase and ethyl acetate washings secondary addition 2.5g active carbon and
2.5g anhydrous magnesium sulfate, decolourize dehydration 30min, and 75mL ethyl acetate washes layer of charcoal, merging filtrate to crystallizer after decarburization.
12g sodium iso-octoate is dissolved in 100mL ethyl acetate, and dissolved clarification and after being sterile filtered, 45min stream adds to crystallizer
In (Mandokef acid solution), stream plus process temperature control are at 15~18 DEG C.After sodium iso-octoate solution stream adds, growing the grain
30min measures greatly crystalline substance, and ethyl acetate 200mL, 70min between the control stream added-time, in 14~15 DEG C of growing the grain 30min is then added.It crosses
Filter is washed (50mL acetone * 2 times), 40 DEG C of dryings, then obtains injection Cefamandole sodium powder-needle preparation, weight through aseptic subpackaged
Measure yield 129.8%.Products obtained therefrom indices are measured, and result is included in table 1.
Comparative example 1
Methylene chloride 50mL, 7-TMCA 25g, BSA 28.8g are added into 500mL four-hole bottle, is warming up to 35 DEG C, reaction
180min, reaction solution is slightly cloudy, and reaction is not exclusively, subsequent to operate according to embodiment 1, obtains injection cephalo Meng through aseptic subpackaged
More sodium powder-needle preparations, weight yield are only 100.6%, thus the dosage solid-to-liquid ratio of 7-TMCA and methylene chloride be 1g: 2ml when without
Method meets industrial production demand.
Table 1:
Standard source: Pharmacopoeia of People's Republic of China, version two in 2015.
Claims (7)
1. a kind of preparation method of Mandokef sodium powder-needle preparation, which comprises the following steps:
(a) by 7-TMCA and silanizing agent, temperature control carries out Silanization reaction, the 7-TMCA and dichloro in dichloromethane solvent
The dosage solid-to-liquid ratio of methane is 1g: 3 ~ 6ml, cools down after reaction, obtains reaction solution 1；The silanizing agent is BSA, front three
At least one of base chlorosilane and hexamethyldisilazane；The reaction temperature of the Silanization reaction is controlled at 25~44 DEG C,
Reaction time is 30~60min；
(b) formoxyl almond acyl chlorides is added dropwise into reaction solution 1 and temperature control carries out acylation reaction, obtains reaction solution 2；The acylation is anti-
At -25~5 DEG C, the reaction time is 5~20min for the reaction temperature control answered；
(c) reaction solution 2 is transferred in water phase, 0~25 DEG C of temperature control, while it is 4.0~7.0, after stirring that lye, which is added, to adjust pH
Split-phase is stood, organic phase is recycled, ethyl acetate is added into water phase, while it is 0.1~2.0, after stirring that acid solution, which is added, to adjust pH
Split-phase is stood, ethyl acetate phase is obtained；
(d) it decolourized, be dehydrated, filtering and collecting filter liquid to ethyl acetate phase obtained by step (c) using decolorising agent and dehydrating agent
To crystallizer；
(e) ethyl acetate solution of sodium iso-octoate is configured, stream is added in crystallizer after dissolved clarification and filtering, and control is 30 between flowing the added-time
~120min, temperature control crystallization；30~120min of growing the grain after the ethyl acetate solution stream of sodium iso-octoate adds, then stream adds acetic acid
Ethyl ester and temperature control crystallization；
(f) it is recovered by filtration ethyl acetate, solid is after acetone washing, dry, then through aseptic subpackaged up to Mandokef sodium powder
Needle preparation.
2. the preparation method of Mandokef sodium powder-needle preparation according to claim 1, which is characterized in that in step (c),
The lye is any one in sodium bicarbonate, sodium carbonate and sodium hydrate aqueous solution.
3. the preparation method of Mandokef sodium powder-needle preparation according to claim 1, which is characterized in that in step (c),
The acid solution is any one in hydrochloric acid, sulfuric acid, phosphoric acid and aqueous acetic acid.
4. the preparation method of Mandokef sodium powder-needle preparation according to claim 1, which is characterized in that in step (d),
The decolorising agent is active carbon, and the dehydrating agent is anhydrous magnesium sulfate, and decoloration, dehydration number are 1~3 time.
5. the preparation method of Mandokef sodium powder-needle preparation according to claim 1, which is characterized in that in step (e),
Crystallization temperature is controlled at 10~35 DEG C.
6. the preparation method of Mandokef sodium powder-needle preparation according to claim 1, which is characterized in that in step (e),
The ethyl acetate solution of the sodium iso-octoate is to configure sodium iso-octoate and ethyl acetate by solid-to-liquid ratio 3g: 25mL.
7. the preparation method of Mandokef sodium powder-needle preparation according to claim 1, which is characterized in that in step (e),
Control is in 60~90min between the stream added-time of the ethyl acetate.
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| CN109836438A (en) * | 2019-03-19 | 2019-06-04 | 河北科技大学 | The synthetic method of cefalexin impurity |
| CN110204557B (en) * | 2019-07-02 | 2021-08-20 | 苏州盛达药业有限公司 | Preparation method of cefamandole nafate derivative |
| CN110974832B (en) * | 2019-11-06 | 2021-03-02 | 华北制药河北华民药业有限责任公司 | Preparation method of cefamandole nafate for injection |
| CN112694488B (en) * | 2020-12-28 | 2022-04-22 | 苏州盛达药业有限公司 | Synthesis method of L-type cefamandole nafate |
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| US3928334A (en) * | 1974-06-06 | 1975-12-23 | Bristol Myers Co | Process for the production of cefamandole |
| CN100484516C (en) * | 2007-08-14 | 2009-05-06 | 山东罗欣药业股份有限公司 | Cefamandole nafate powder injection, production method of powder injection and raw machine thereof |
| CN104530086B (en) * | 2014-12-16 | 2015-12-09 | 天津大学 | The new crystal of Cefamandole nafate compounds and crystallization preparation method thereof |
| CN105399754B (en) * | 2015-12-17 | 2018-05-15 | 苏州中联化学制药有限公司 | A kind of preparation method of Cefamandole Nafate |
| CN106562972A (en) * | 2016-09-30 | 2017-04-19 | 华北制药河北华民药业有限责任公司 | Method for preparing cefamandole nafate powder preparation for injection |
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