CN106967088B - A kind of preparation method of ticarcillin sodium - Google Patents
A kind of preparation method of ticarcillin sodium Download PDFInfo
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- CN106967088B CN106967088B CN201710260086.5A CN201710260086A CN106967088B CN 106967088 B CN106967088 B CN 106967088B CN 201710260086 A CN201710260086 A CN 201710260086A CN 106967088 B CN106967088 B CN 106967088B
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- ticarcillin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/21—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D499/44—Compounds with an amino radical acylated by carboxylic acids, attached in position 6
- C07D499/48—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical
- C07D499/58—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical
- C07D499/72—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical by carbon atoms having three bonds to hetero atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/04—Preparation
- C07D499/14—Preparation of salts
- C07D499/16—Preparation of salts of alkali or alkaline earth metals
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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of preparation methods of ticarcillin sodium.This method are as follows: in the presence of triethylamine, 3- thiophene malonic acid reacts to obtain mixed anhydride with pivaloyl chloride；Bis- (trimethyl silicon substrate) acetamides of 6-APA and N, O- react to obtain the 6-APA of silanization；Then the 6-APA of mixed anhydride and silanization is reacted, and obtains Ticarcillin acid；It further reacts to obtain ticarcillin sodium with sodium iso-octoate.This method has many advantages, such as that reaction condition is mild, easy to operate, post-processing is simple, environmental-friendly, and high income, the purity of product are good.
Description
Technical field
The present invention relates to a kind of preparation methods of ticarcillin sodium, belong to pharmaceutical technology field.
Background technique
Ticarcillin sodium, Chinese chemical name: (2S, 5R, 6R) -3,3- dimethyl -6- [2- carboxylic acid -2- (3- thienyl) second
Acylamino-] -7- oxo -4- thia -1- azabicyclo [3.2.0]-heptane -2- carboxylic acid disodium salt, structural formula is as follows:
Ticarcillin sodium is the semi-synthetic penicillins drug of the formulated research and development of Beecham company, Britain.Most early in Japan
Listing, is a kind of penicillin of new construction, especially effective for serious gram positive bacterial infection.Its common dosage forms is injection
Ticarcillin sodium/potassium clavulanate.Its antimicrobial spectrum is similar with carbenicillin.But it is carboxylic to the antibacterial activity of Pseudomonas aeruginosa
2-4 times of parasiticin.It is lower to Lan Shi positive bacteria relative activity, and it is high for Gram-negative bacteria activity.It is clinically more
With the compound preparation of ticarcillin sodium and potassium clavulanate, the two cooperation not only expands antimicrobial spectrum, but also enhances antibacterial activity.From
And play good antibacterial action.
Ticarcillin sodium disclosed in patent document CN1696133A the preparation method comprises the following steps: being with 3- thiophene diethyl malonate
Starting material and thionyl chloride, react in isopropyl ether, anti-with the sodium salt solution of 6-amino-penicillanic acid after being then concentrated
Answer, it is layered, decoloration, filtering, adjust acid, at salt, crystallization and etc. obtain Ticarcillin mono-sodium salt, last Ticarcillin mono-sodium salt
Be made into aqueous solution with sodium hydroxide, through decoloration, filtering, freeze-drying and etc. obtain ticarcillin sodium.The route preparation process is longer,
Processing step is cumbersome, sodium hydroxide highly basic is used in preparation process, lactam nucleus is easy to open loop in Ticarcillin molecular structure
Degradation, it is low, second-rate so as to cause products obtained therefrom yield, while using isopropyl ether, thionyl chloride, methyl iso-butyl ketone (MIBK) etc. pair
The biggish reagent of environmental pollution is not suitable for industrialized production.
Summary of the invention
The present invention overcomes above-mentioned the deficiencies in the prior art, provide a kind of preparation method of ticarcillin sodium.This method
It is easy to operate, it is with short production cycle, it is environmentally friendly, and also products obtained therefrom high income, purity are good, at low cost, are more suitable for industrializing
Mass production.
The technical scheme is that a kind of preparation method of ticarcillin sodium, characterized in that the following steps are included:
1) in the presence of triethylamine, 3- thiophene malonic acid reacts to obtain mixed anhydride with pivaloyl chloride；
2) bis- (trimethyl silicon substrate) acetamides of 6-APA and N, O- react to obtain the 6-APA of silanization；
3) 6-APA of the silanization of the mixed anhydride and step 2) of step 1) is reacted, and obtains Ticarcillin acid；
4) then Ticarcillin acid further reacts to obtain ticarcillin sodium with sodium iso-octoate.
Specific reaction step is as follows:
1) 3- thiophene malonic acid is added in methylene chloride, -10-10 DEG C of temperature control, triethylamine, reaction to material is added dropwise
Liquid clarification, is then added dropwise pivaloyl chloride, is added dropwise, and reacts 0.5-2h；
2) by 6-APA and N, bis- (trimethyl silicon substrate) acetamides of O- are added in methylene chloride, and 20-40 DEG C of temperature control,
It reacts to feed clarification；
3) reaction solution of step 2) is cooled to -5-5 DEG C, be then added drop-wise in the reaction solution of step 1), -5-5 DEG C of temperature control,
It is added dropwise, reacts 1-2h；Then depressurize it is whole evaporate, stratification after ethyl acetate and water is added in gained grease, obtains for cassie
The ethyl acetate solution of woods acid；
4) into resulting Ticarcillin acid ethyl acetate solution, methanol and sodium iso-octoate is added, after stirring dissolved clarification, temperature control
20-30 DEG C, crystallization 1-3h obtains ticarcillin sodium.
Reaction equation is as follows:
Preferably, in the step 1), reaction temperature is -5-0 DEG C.
Preferably, in the step 1), the molar ratio of 3- thiophene malonic acid, pivaloyl chloride and triethylamine is 1:2.0-3.0:
2.0-3.0。
Preferably, in the step 2), 6-APA and N, the molar ratio of the bis- trimethyl silicane yl acetamides of O- are 1:1.8-2.5,
It is preferred that 1:2.
Preferably, in the step 4), the volume ratio of methanol and ethyl acetate is 1:2-4, preferably 1:3.
The beneficial effects of the present invention are: preparation method of the invention has, reaction condition is mild, easy to operate, post-processing is simple
The advantages that list, high income (>=90%), purity good (>=99.5%) of product, and synthesis technology more safety and environmental protection, have wide
Wealthy market prospects and economic benefit.
Specific embodiment
Case study on implementation 1
In 250ml three-necked flask, 100ml methylene chloride is added, 18.6g (0.1mol) 3- thiophene malonic acid stirs, drop
22.2g (0.22mol) triethylamine is added dropwise to -5-0 DEG C in temperature, and after feed clarification, 25.0g (0.21mol) pivaloyl chloride, drop is added dropwise
Finish, reacts 30min, obtain mixed anhydride.
In 250ml three-necked flask, 100ml methylene chloride, 21.6g (0.1mol) 6-APA, 40.6g (0.2mol) is added
N, O- bis- trimethyl silicane yl acetamides, stir to feed clarification, obtain the Silanization reaction product of 6-APA by 25-30 DEG C of temperature control.
The dichloromethane solution of 6-APA Silanization reaction product is cooled to 0 DEG C, is added drop-wise to above-mentioned gained mixed anhydride solution
In, -5-0 DEG C of temperature control, drop finishes, and reacts 1h, then removes methylene chloride under reduced pressure, obtain grease.It is added into gained grease
210ml ethyl acetate, 210ml water stir 5min, and stratification obtains Ticarcillin acid ethyl acetate phase.
70ml methanol is added into gained Ticarcillin acid ethyl acetate phase, 32g sodium iso-octoate stirs dissolved clarification, then controls
It warm 20-30 DEG C, stirring and crystallizing 1.5h, is filtered, washed, dries to obtain ticarcillin sodium 38.5g, purity 99.5%, yield
90.9%.
Case study on implementation 2
In 250ml three-necked flask, 100ml methylene chloride is added, 18.6g (0.1mol) 3- thiophene malonic acid stirs, drop
22.2g (0.22mol) triethylamine is added dropwise to -5-0 DEG C in temperature, and after feed clarification, 25.0g (0.21mol) pivaloyl chloride, drop is added dropwise
Finish, reacts 30min, obtain mixed anhydride；
In 250ml three-necked flask, 100ml methylene chloride, 21.6g (0.1mol) 6-APA, 40.6g is added
(0.2mol) N, O- bis- trimethyl silicane yl acetamides, are stirred to feed clarification, the silanization for obtaining 6-APA is anti-by 30-40 DEG C of temperature control
Answer product.
The dichloromethane solution of 6-APA Silanization reaction product is cooled to 0 DEG C, is added drop-wise to above-mentioned gained mixed anhydride solution
In, -5-0 DEG C of temperature control, drop finishes, and reacts 2h, then removes methylene chloride under reduced pressure, obtain grease.It is added into gained grease
210ml ethyl acetate, 200ml water stir 5min, and layering obtains Ticarcillin acid ethyl acetate phase.
65ml methanol is added into gained Ticarcillin acid ethyl acetate phase, 32g sodium iso-octoate stirs dissolved clarification, temperature control 20-
It 30 DEG C, stirring and crystallizing 3h, is filtered, washed, dries to obtain ticarcillin sodium 39.0g, purity 99.6%, yield 91.9%.
Claims (5)
1. a kind of preparation method of ticarcillin sodium, characterized in that the following steps are included:
1) 3- thiophene malonic acid is added in methylene chloride, -10-10 DEG C of temperature control, triethylamine is added dropwise, reacted clear to feed liquid
Clearly, pivaloyl chloride is then added dropwise, is added dropwise, reacts 0.5-2h, obtains the reaction solution containing mixed anhydride；The 3- thiophene malonic acid,
The molar ratio of pivaloyl chloride and triethylamine is 1:2.0-3.0:2.0-3.0；
2) by 6-APA and N, bis- (trimethyl silicon substrate) acetamides of O- are added in methylene chloride, and 20-40 DEG C of temperature control, reaction
To feed clarification, the reaction solution of the 6-APA of siliceous alkanisation is obtained；
3) reaction solution of step 2) is cooled to -5-5 DEG C, be then added drop-wise in the reaction solution of step 1), -5-5 DEG C of temperature control, is added dropwise
After react 1-2h；Then it is evaporated under reduced pressure, stratification after ethyl acetate and water is added in gained grease, obtains Ticarcillin acid
Ethyl acetate solution；
4) into resulting Ticarcillin acid ethyl acetate solution, methanol and sodium iso-octoate is added, after stirring dissolved clarification, temperature control 20-
30 DEG C, crystallization 1-3h obtains ticarcillin sodium；The volume ratio of the methanol and ethyl acetate is 1:2-4.
2. a kind of preparation method of ticarcillin sodium as described in claim 1, characterized in that in the step 1), reaction temperature
Degree is -5-0 DEG C.
3. a kind of preparation method of ticarcillin sodium as described in claim 1, characterized in that in the step 2), 6-APA with
The molar ratio of the bis- trimethyl silicane yl acetamides of N, O- is 1:1.8-2.5.
4. a kind of preparation method of ticarcillin sodium as claimed in claim 3, characterized in that in the step 2), 6-APA with
The molar ratio of the bis- trimethyl silicane yl acetamides of N, O- is 1:2.
5. a kind of preparation method of ticarcillin sodium as described in claim 1, characterized in that in the step 4), methanol with
The volume ratio of ethyl acetate is 1:3.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1696133A (en) * | 2004-05-10 | 2005-11-16 | 河北张药股份有限公司 | Method for synthesizing ticarcillin sodium |
| CN1995043A (en) * | 2006-12-29 | 2007-07-11 | 珠海联邦制药股份有限公司 | Preparation process of ticarcillin disodium salt |
| CN101735244A (en) * | 2008-11-05 | 2010-06-16 | 鲁南制药集团股份有限公司 | Method for preparing broad-spectrum penicillin antibiotic ticarcillin sodium |
| CN101875659A (en) * | 2009-04-29 | 2010-11-03 | 瑞阳制药有限公司 | Preparation process of ticarcillin disodium |
| CN104402904A (en) * | 2014-11-04 | 2015-03-11 | 齐鲁天和惠世制药有限公司 | Preparation method for flucloxacillin sodium |
-
2017
- 2017-04-20 CN CN201710260086.5A patent/CN106967088B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1696133A (en) * | 2004-05-10 | 2005-11-16 | 河北张药股份有限公司 | Method for synthesizing ticarcillin sodium |
| CN1995043A (en) * | 2006-12-29 | 2007-07-11 | 珠海联邦制药股份有限公司 | Preparation process of ticarcillin disodium salt |
| CN101735244A (en) * | 2008-11-05 | 2010-06-16 | 鲁南制药集团股份有限公司 | Method for preparing broad-spectrum penicillin antibiotic ticarcillin sodium |
| CN101875659A (en) * | 2009-04-29 | 2010-11-03 | 瑞阳制药有限公司 | Preparation process of ticarcillin disodium |
| CN104402904A (en) * | 2014-11-04 | 2015-03-11 | 齐鲁天和惠世制药有限公司 | Preparation method for flucloxacillin sodium |
Non-Patent Citations (2)
| Title |
|---|
| 替卡西林钠的合成工艺改进;王迷娟等;《中国药物化学杂志》;20060630;全文 |
| 替卡西林钠的合成新工艺;郭剑虹等;《临床医药实践》;20121110;第841页摘要，第842页图1 |
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Effective date of registration: 20200226 Address after: No. 10678, Wenliang Road, Dongjia street, Licheng District, Jinan City, Shandong Province Patentee after: Shandong Anxin Pharmaceutical Co., Ltd Address before: 250105 No. 849 Dong Jia town, Licheng District, Shandong, Ji'nan Patentee before: QILU TIANHE PHARMACEUTICAL Co.,Ltd. |
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