CN108586490A - The preparation method of cefotaxime acid - Google Patents
The preparation method of cefotaxime acid Download PDFInfo
- Publication number
- CN108586490A CN108586490A CN201810296174.5A CN201810296174A CN108586490A CN 108586490 A CN108586490 A CN 108586490A CN 201810296174 A CN201810296174 A CN 201810296174A CN 108586490 A CN108586490 A CN 108586490A
- Authority
- CN
- China
- Prior art keywords
- preparation
- cefotaxime acid
- cefotaxime
- added
- acid according
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- 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
-
- 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
- C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group
- C07D501/34—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group with the 7-amino radical acylated by carboxylic acids containing hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The present invention relates to a kind of preparation methods of cefotaxime acid, belong to pharmaceutical technology field.The preparation method of the cefotaxime acid：Include the following steps：It is prepared by condensation liquid：Using dichloromethane, ethyl alcohol and triethylamine as mixed solvent, 7 ACA and MEAM are added, react 30~60min；Extraction decoloration：Condensation liquid obtained is carried out with purified water and alkali mixed liquor to extract to obtain water phase, activated carbon, which is added, in water phase decolourizes；It is prepared by finished product：After the completion of decoloration, alcohol is added, crystallization is carried out with dilute hydrochloric acid, then adjust pH value to 2.0 3.0, by cooling, growing the grain, suction filtration, wash material with purified water and acetone and dry after, obtain cefotaxime acid dry product.The preparation method of cefotaxime acid provided by the present invention, scientific and reasonable, simple and practicable, obtained cefotaxime acid impurity content is low, high income.
Description
Technical field
The present invention relates to a kind of preparation methods of cefotaxime acid, belong to pharmaceutical technology field.
Background technology
Cefotaxime Sodium is clinically widely applied Third generation Cephalosporins antibiotic, and the medicine is by German Hoechst
It with French Roussel companies in the success of joint research and development in 1977, was listed with 1980, has that wide spectrum, efficient, resistance to enzyme, poison is secondary makees
With small feature.It is mainly used for infection in respiratory system caused by sensitive bacteria, biliary tract and enteric infection, skin and soft tissue infection,
Burn and bone joint infection etc..Cefotaxime acid is the primary raw material for preparing Cefotaxime Sodium, as market competition is increasingly fierce,
Its synthesis technology is studied, production cost is reduced, improving product quality has certain realistic meaning.
The synthesis of cefotaxime acid mainly uses active ester method：Such as：Phosphorous active ester, triazinone active ester, AE- activity
Ester, thiadiazoles active ester and benzotriazole active ester.Industrialized producing technology mainly uses 2-(2-Amino-4-thiazolyl)-2-methoxyiminoacetic,thiobenzothiazole ester method at present, generally
It with acetone, dichloromethane and tetrahydrofuran etc. for reaction dissolvent, is reacted with 7-ACA under base catalysis, but all there is synthesis
Route is long, intermediate separating for several times, the problem low with yield complicated for operation.
Invention content
In view of the deficiencies of the prior art, the object of the present invention is to provide a kind of preparation method of cefotaxime acid, science is closed
Reason, simple and practicable, gained cefotaxime acid impurity content is low, high income.
The preparation method of cefotaxime acid of the present invention：Include the following steps：
1) prepared by condensation liquid
Using dichloromethane, ethyl alcohol and triethylamine as mixed solvent, 7-ACA and MEAM is added, reacts 30~60min；
2) extraction decoloration
Condensation liquid obtained is extracted with purified water and alkali mixed liquor, obtains water phase, activated carbon, which is added, in water phase carries out
Decoloration；
3) prepared by finished product
After the completion of decoloration, alcohol is added, crystallization is carried out with dilute hydrochloric acid, then adjust pH value to 2.0-3.0, by cooling, growing the grain, pumping
Filter after washing material and drying with purified water and acetone, obtains cefotaxime acid dry product.
In the step 1), 7-ACA：MEAM：Dichloromethane：Ethyl alcohol：Triethylamine dosage mass ratio is：1：1.2~
1.4：7.96~9.28：0.72~0.88：0.455~0.525.
In the step 1), reaction temperature is 20.0-25.0 DEG C.
It uses dichloromethane, ethyl alcohol and triethylamine for mixed solvent, accelerates extent of reaction, shorten the anti-of condensation course
Between seasonable.
In the step 2), 7-ACA：Purified water：Alkali mixed liquor：Quality of activated carbon ratio is：1：7.50~8.50：0.28
~0.35：0.03~0.06.
In the step 2), alkali mixed liquor is organic alkali solution or inorganic weak bases solution.
In the step 2), extraction temperature is 10.0-15.0 DEG C；Bleaching temperature is 10.0-15.0 DEG C.
Using purified water and alkali mixed liquor as extractant, product yield and quality are improved.
In the step 3), 7-ACA：Alcohol：Dilute hydrochloric acid：Purified water：Acetone quality ratio is：1：2.40~3.20：0.55
~0.82：4.00~6.00：3.20~4.80.
In the step 3), alcohol is monohydric alcohol.
In the step 3), recrystallization temperature is 15.0-20.0 DEG C；Temperature is -5-5.0 DEG C after cooling；Drying temperature is
50-60℃。
Compared with prior art, the present invention has the advantages that：
1. cefotaxime acid high income made from, reaches 1.6 or more；Product content is high, reaches 95.0% or more, impurity contains
Measure it is low, it is single it is miscellaneous is less than 0.3%, it is total miscellaneous to be less than 1.0%；
2. the used solvent price of the present invention is low, production cost is reduced, reaction is mild, easy to operate, scientific and reasonable, fits
For the big production of scale.
Specific implementation mode
With reference to embodiment, the present invention is described further.
Embodiment 1
1. 130ml dichloromethane, 20ml ethyl alcohol and 14ml triethylamines are added into there-necked flask, stirring is cooled to 0 DEG C, is added
20g7-ACA, 26gMEAM, 22 DEG C of reaction 40min of temperature control；
2. reaction is completed, it is added 160ml purified waters, 8ml triethylamine mixed liquors, 11 DEG C of temperature control, the reaction was continued 20min is quiet
20min is set, water phase is extracted to obtain；1g activated carbons are added in water phase, decolourize 20min, filtering；
3. after the completion of decoloration, 60ml ethyl alcohol is added, 18 DEG C of temperature control is adjusted with the dilute hydrochloric acid crystallization of a concentration of 10wt.% of 140g
PH value is cooled to 3 DEG C, growing the grain 30min to 2.8；It filters, washes material with 80ml purified waters and 100ml acetone, dry, obtain at 55 DEG C
Cefotaxime acid dry product 32.10g；Yield 1.605, content 95.12%, single miscellaneous 0.25%, total miscellaneous 0.82%.
Embodiment 2
1. 185ml dichloromethane, 31ml ethyl alcohol and 20ml triethylamines are added into there-necked flask, stirring is cooled to 0 DEG C, is added
30g7-ACA, 39gMEAM, 23 DEG C of reaction 45min of temperature control；
2. reaction is completed, it is added 255ml purified waters, 9g sodium bicarbonate mixed liquors, 12 DEG C of temperature control, the reaction was continued 20min is quiet
20min is set, water phase is extracted to obtain；1.2g activated carbons are added in water phase, decolourize 20min, filtering；
3. after the completion of decoloration, it is added 114ml ethyl alcohol, 16 DEG C of temperature control, with the dilute hydrochloric acid crystallization of a concentration of 15wt.% of 120g,
It adjusts pH value to 2.6, is cooled to 4 DEG C, growing the grain 30min；It filters, washes material with 120ml purified waters, 120ml acetone, dried at 58 DEG C,
Obtain cefotaxime acid dry product 32.18g；Yield 1.609, content 95.21%, single miscellaneous 0.21%, total miscellaneous 0.88%.
Embodiment 3
1. 277ml dichloromethane, 37ml ethyl alcohol and 28ml triethylamines are added into there-necked flask, stirring is cooled to 0 DEG C, is added
40g7-ACA, 48gMEAM, 22 DEG C of reaction 50min of temperature control；
2. reaction is completed, the ammonia water mixture of 340ml purified waters, 12g10% concentration is added, 13 DEG C of temperature control, the reaction was continued
20min stands 20min, extracts to obtain water phase；1.6g activated carbons are added in water phase, decolourize 20min, filtering；
3. after the completion of decoloration, it is added 127ml isopropanols, 19 DEG C of temperature control, with the dilute hydrochloric acid crystallization of 110g concentration 20wt.%,
It adjusts pH value to 2.4, is cooled to 2 DEG C, growing the grain 30min；It filters, washes material with 240ml purified waters, 203ml acetone, dried at 60 DEG C,
Obtain cefotaxime acid dry product 32.22g；Yield 1.611, content 95.28%, single miscellaneous 0.19%, total miscellaneous 0.91%.
Claims (9)
1. a kind of preparation method of cefotaxime acid, it is characterised in that：Include the following steps：
1) prepared by condensation liquid
Using dichloromethane, ethyl alcohol and triethylamine as mixed solvent, 7-ACA and MEAM is added, reacts 30~60min；
2) extraction decoloration
Condensation liquid obtained is carried out with purified water and alkali mixed liquor to extract to obtain water phase, activated carbon, which is added, in water phase decolourizes；
3) prepared by finished product
After the completion of decoloration, alcohol is added, crystallization is carried out with dilute hydrochloric acid, then adjust pH value to 2.0-3.0, by cooling, growing the grain, suction filtration,
After washing material and drying with purified water and acetone, cefotaxime acid dry product is obtained.
2. the preparation method of cefotaxime acid according to claim 1, it is characterised in that：In step 1), 7-ACA：MEAM：
Dichloromethane：Ethyl alcohol：Triethylamine dosage mass ratio is：1：1.2~1.4：7.96~9.28：0.72~0.88：0.455~
0.525。
3. the preparation method of cefotaxime acid according to claim 1, it is characterised in that：In step 1), reaction temperature is
20.0-25.0℃。
4. the preparation method of cefotaxime acid according to claim 1, it is characterised in that：In step 2), 7-ACA：Purifying
Water：Alkali mixed liquor：Quality of activated carbon ratio is：1：7.50~8.50：0.28~0.35：0.03~0.06.
5. the preparation method of cefotaxime acid according to claim 1, it is characterised in that：In step 2), extraction temperature is
10.0-15.0℃；Bleaching temperature is 10.0-15.0 DEG C.
6. the preparation method of cefotaxime acid according to claim 1, it is characterised in that：In step 2), alkali mixed liquor is
Organic alkali solution or inorganic weak bases solution.
7. the preparation method of cefotaxime acid according to claim 1, it is characterised in that：In step 3), 7-ACA：Alcohol：It is dilute
Hydrochloric acid：Purified water：Acetone quality ratio is：1：2.40~3.20：0.55~0.82：4.00~6.00：3.20~4.80.
8. the preparation method of cefotaxime acid according to claim 1, it is characterised in that：In step 3), alcohol is monohydric alcohol.
9. the preparation method of cefotaxime acid according to claim 1, it is characterised in that：In step 3), recrystallization temperature is
15.0-20.0℃；Temperature is -5-5.0 DEG C after cooling；Drying temperature is 50-60 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810296174.5A CN108586490A (en) | 2018-04-04 | 2018-04-04 | The preparation method of cefotaxime acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810296174.5A CN108586490A (en) | 2018-04-04 | 2018-04-04 | The preparation method of cefotaxime acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108586490A true CN108586490A (en) | 2018-09-28 |
Family
ID=63624348
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810296174.5A Pending CN108586490A (en) | 2018-04-04 | 2018-04-04 | The preparation method of cefotaxime acid |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108586490A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109574899A (en) * | 2018-11-27 | 2019-04-05 | 江西如益科技发展有限公司 | A kind of refining methd of ertapenem side chain |
| CN114409677A (en) * | 2021-12-31 | 2022-04-29 | 艾美科健（中国）生物医药有限公司 | Preparation method of high-purity cefotaxime acid |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011042776A1 (en) * | 2009-10-09 | 2011-04-14 | Nectar Lifesciences Ltd. | Process for preparation of cefotaxime acid and pharmaceutically acceptable salt thereof |
| WO2011042775A1 (en) * | 2009-10-09 | 2011-04-14 | Nectar Lifesciences Ltd. | Process for preparation of cefotaxime acid |
| CN102702230A (en) * | 2012-05-30 | 2012-10-03 | 华北制药河北华民药业有限责任公司 | Method for preparing cefotaxime acid |
| CN105061470A (en) * | 2015-08-18 | 2015-11-18 | 齐鲁安替（临邑）制药有限公司 | One-pot synthesis method of cefotaxime acid |
| CN105503904A (en) * | 2015-12-30 | 2016-04-20 | 河南康达制药有限公司 | Preparation method for cefotaxime acid |
-
2018
- 2018-04-04 CN CN201810296174.5A patent/CN108586490A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011042776A1 (en) * | 2009-10-09 | 2011-04-14 | Nectar Lifesciences Ltd. | Process for preparation of cefotaxime acid and pharmaceutically acceptable salt thereof |
| WO2011042775A1 (en) * | 2009-10-09 | 2011-04-14 | Nectar Lifesciences Ltd. | Process for preparation of cefotaxime acid |
| CN102702230A (en) * | 2012-05-30 | 2012-10-03 | 华北制药河北华民药业有限责任公司 | Method for preparing cefotaxime acid |
| CN105061470A (en) * | 2015-08-18 | 2015-11-18 | 齐鲁安替（临邑）制药有限公司 | One-pot synthesis method of cefotaxime acid |
| CN105503904A (en) * | 2015-12-30 | 2016-04-20 | 河南康达制药有限公司 | Preparation method for cefotaxime acid |
Non-Patent Citations (4)
| Title |
|---|
| JUAN CRODRÍGUEZ ET AL.: "A rapid procedure to prepare cefotaxime", 《IL FARMACO》 * |
| 孙津鸽 等: "头孢噻肟酸合成工艺的研究", 《广东化工》 * |
| 胡文滨等: "新方法合成头孢噻肟酸", 《河北省科学院学报》 * |
| 郭新营: "头孢噻肟钠的工艺优化", 《中国优秀硕士学位论文全文数据库 工程科技Ⅰ辑》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109574899A (en) * | 2018-11-27 | 2019-04-05 | 江西如益科技发展有限公司 | A kind of refining methd of ertapenem side chain |
| CN114409677A (en) * | 2021-12-31 | 2022-04-29 | 艾美科健（中国）生物医药有限公司 | Preparation method of high-purity cefotaxime acid |
| CN114409677B (en) * | 2021-12-31 | 2023-08-25 | 艾美科健（中国）生物医药有限公司 | Preparation method of high-purity cefotaxime acid |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| DK156069B (en) | USE OF THE TERT.BUTYLAMINE SALT OF CLAVULANIC ACID AS INTERMEDIATE IN THE PREPARATION OF CLAVULANIC ACID AND PHARMACEUTICAL TOLERABLE SALTS AND ESTERS THEREOF | |
| CN110790805B (en) | Method for extracting chenodeoxycholic acid from pig bile paste | |
| CN108947881B (en) | Method for preparing optically pure L-type selenium-methyl selenocysteine | |
| CN115011661B (en) | Synthesis method of 3 beta-ursodeoxycholic acid | |
| CN108586490A (en) | The preparation method of cefotaxime acid | |
| CN103897025B (en) | A kind of preparation method of Pidotimod | |
| CN112645912B (en) | Preparation method of high-purity M2 crystal form meclofenol sodium | |
| WO2021212535A1 (en) | Method for refining benzhexol hydrochloride | |
| CN110128412B (en) | Preparation method of dextro-ilaprazole potassium salt mother liquor, dextro-ilaprazole and preparation method thereof | |
| CN106008660B (en) | The preparation method of deflazacort | |
| US2534250A (en) | Process of isolating quercitrin | |
| CN103804265B (en) | The synthesis of a kind of Sulpiride or its optical isomer and post-processing approach | |
| CN110862429A (en) | Preparation method of sodium aescinate | |
| CN111454333A (en) | Preparation method of high-purity oxytocin | |
| CN111187255B (en) | Preparation method of dextro-ilaprazole potassium salt and preparation method of dextro-ilaprazole | |
| CN115089559B (en) | Preparation method of microsphere for injection | |
| CN111440154B (en) | Synthetic method of tegaserod dimer impurity | |
| CN116497081A (en) | Lithocholic acid production process | |
| CN111606837A (en) | Synthetic method of vildagliptin | |
| CN109535184A (en) | A kind of method that clavulanic acid t-octanylamine prepares potassium clavulanate | |
| CN106496191B (en) | A kind of preparation method of S-pantoprazole sodium | |
| JP2022074008A (en) | Treprostinil monohydrate crystals and methods for preparation thereof | |
| RU2228750C1 (en) | METHOD FOR PREPARING CHLORINE e6. | |
| JPH02212473A (en) | L-tartaric acid salt of (2r,4r)-4-methyl-2-piperidine-carboxylic acid ethyl ester and its desalted substance | |
| CN102408310B (en) | Method for preparing high-purity solanesol by utilizing prepared opium paste |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20180928 |