CN108947831A - A kind of purification process of salbutamol intermediate III - Google Patents
A kind of purification process of salbutamol intermediate III Download PDFInfo
- Publication number
- CN108947831A CN108947831A CN201810767215.4A CN201810767215A CN108947831A CN 108947831 A CN108947831 A CN 108947831A CN 201810767215 A CN201810767215 A CN 201810767215A CN 108947831 A CN108947831 A CN 108947831A
- Authority
- CN
- China
- Prior art keywords
- salbutamol
- intermediate iii
- iii
- purification process
- solvent
- 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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/48—Separation; Purification; Stabilisation; Use of additives
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Salbutamol is a kind of beta receptor agonist, the preparation process of salbutamol at present, it is main or ground based on technique with original, salbutamol intermediate III mainly uses esterification, the salbutamol intermediate III that esterification is prepared is at grease, remaining impurity will affect the quality of control and product that bromo-reaction feeds intake in oily intermediate III.Recrystallisation solvent is added in salbutamol intermediate III by a kind of purification process of salbutamol intermediate III of the present invention, is crystallized, after drying, the salbutamol intermediate III purified.The purity of salbutamol intermediate III is improved, while avoiding introducing new impurity, improves product purity.
Description
Technical field
The present invention relates to field of medicine and chemical technology, and in particular to a kind of purification process of salbutamol intermediate III.
Background technique
Salbutamol is a kind of beta receptor agonist, is mainly used for treating asthma type brochitis, bronchial asthma, lung qi
Swell caused bronchial spasm.Due to taking place frequently for global respiratory disease, it is also high for causing the dosage of salbutamol.Mesh
The preparation process of preceding salbutamol, main or ground based on technique with original, original grinds technique using parahydroxyacet-ophenone as starting material,
It by chloromethylation, is esterified, bromo, amination, salbutamol is prepared in hydrolysis, reduction, and process route is as follows:
Salbutamol intermediate III is synthesized in said synthesis route mainly uses esterification, what esterification was prepared
Salbutamol intermediate III is not easy to solidify at grease, and next step bromo-reaction requires strictly the control of reaction condition,
Therefore remaining solvent in oily intermediate III, impurity will affect the quality of the control that bromo-reaction feeds intake and product.
The preparation method of salbutamol has many reports, but wherein has no the side that intermediate III is purified with crystallization mode
Method, if patent CN106278910 discloses salbutamol preparation method, it is mentioned that the post-processing of intermediate III: wait react
Liquid is cooled to room temperature, and successively through the washing of 10wt% sodium carbonate liquor, saturated common salt water washing, evaporating solvent under reduced pressure and drying, is obtained
To compound III.Process program oily III residual impurity of intermediate is more, and remaining impurity is unfavorable for feeding intake and instead for next step
It answers, is easy to cause next step reaction impurities too many, so that it is unfavorable for amplification production.It can be seen that the purifying to salbutamol intermediate III
The Improvement of method is conducive to the control to Sha Dingan alcohol industrialization process and end product quality, has great industry
Change meaning.
Summary of the invention
The technical problem to be solved in the present invention is that providing a kind of purification process of salbutamol intermediate III, the present invention is mentioned
The preparation method of confession solves the problems, such as that the purity of salbutamol intermediate III is low, is conducive to the subsequent technique for preparing salbutamol
Product quality.
A kind of purification process of salbutamol intermediate III of the present invention, the structural formula of salbutamol intermediate III are
It is characterized by: recrystallisation solvent is added in the salbutamol intermediate III, after keeping the temperature -5~30 DEG C of dissolutions, crystallization
It is dried at 10~40 DEG C, the salbutamol intermediate III purified.
Further, the recrystallisation solvent is low polar solvent or low polar solvent and tetrahydrofuran, acetone, acetic acid second
Ester, methylene chloride, dehydrated alcohol, anhydrous methanol, the mixture of any solvent in isopropanol.
Further, the low polar solvent is selected from petroleum ether, ether, isopropyl ether, n-hexane, one of normal heptane.
Further, the recrystallisation solvent is selected from the mixture of isopropyl ether or isopropyl ether and ethyl acetate.
Further, the dosage of the recrystallisation solvent is 5~30 times of III mass of salbutamol intermediate.
Further, the dosage of the recrystallisation solvent is 10~20 times of III mass of salbutamol intermediate.
Further, the dissolution, the temperature crystallized are 10~20 DEG C.
Further, the drying temperature is 20~30 DEG C.
There is a kind of purification process of salbutamol intermediate III of the present invention following Advantageous to imitate compared with prior art
Fruit: the remaining subsequent bromo-reaction of solvent effect in oily salbutamol intermediate III is avoided, the quality of product is reduced；It improves
The purity of salbutamol intermediate III, while avoiding introducing new impurity, improve product purity and yield.
Specific embodiment
A kind of purification process of salbutamol intermediate III of the present invention are as follows: oily salbutamol intermediate III is added and is crystallized
Solvent is dried for 10~40 DEG C, the salbutamol intermediate III purified after keeping the temperature -5~30 DEG C of dissolutions, crystallizing.Technique
Route is as follows:
Wherein, recrystallisation solvent is low polar solvent or low polar solvent and tetrahydrofuran, acetone, ethyl acetate, dichloromethane
Alkane, dehydrated alcohol, anhydrous methanol, the mixture of any solvent in isopropanol.Low polar solvent is selected from petroleum ether, and ether is different
Propyl ether, n-hexane, one of normal heptane.
Embodiment one: the preparation of salbutamol intermediate III
100g parahydroxyacet-ophenone is added 450ml and is preheated to 45-50 DEG C of concentrated hydrochloric acid referring to patent US3642896,
The formalin of 66ml 40% maintains 50 DEG C and is stirred to react 2h after mixing, 450ml water, filtering, with 200ml heat is then added
Water washing, 60 DEG C are dried to obtain salbutamol intermediate II.
94g salbutamol intermediate I, 47g anhydrous sodium acetate, 220ml glacial acetic acid and 110ml acetic anhydride, stirred at reflux
2h is reacted, then vacuum distillation is added water, is extracted with ethyl acetate, obtain in grease salbutamol after ethyl acetate is concentrated
Mesosome III.
Embodiment two: the purifying of salbutamol intermediate III
50ml isopropyl ether is added in III grease of 5g salbutamol intermediate, keeps the temperature 15~20 DEG C stirred crystallization 30 minutes, mistake
Filter, 10ml isopropyl ether wash filter cake, and filter cake obtains the salbutamol intermediate III of 4.0g after purification after being dried under reduced pressure in 30 DEG C, pure
Degree 98.7%.
Embodiment three: the purifying of salbutamol intermediate III
III grease of 5g salbutamol intermediate, is added 0.5ml ethyl alcohol, and 50ml isopropyl ether keeps the temperature 15~20 DEG C of stirring knots
30 minutes brilliant, filtering, 10ml isopropyl ether washs filter cake, and filter cake obtains the salbutamol of 3.6g after purification after being dried under reduced pressure in 30 DEG C
Intermediate III, purity 99.0%.
Example IV: the purifying of salbutamol intermediate III
III grease of 5g salbutamol intermediate, is added 0.5ml ethyl acetate, 50ml isopropyl ether, and 15~20 DEG C of heat preservation is stirred
Crystallization 30 minutes, filtering are mixed, 10ml isopropyl ether washs filter cake, and filter cake obtains the husky fourth of 3.3g after purification after being dried under reduced pressure in 30 DEG C
Amine alcohol intermediate III, purity 99.3%.
Embodiment five: the purifying of salbutamol intermediate III
III grease of 5g salbutamol intermediate, is added 0.5ml ethyl acetate, 50ml n-hexane, and 15~20 DEG C of heat preservation is stirred
Crystallization 30 minutes, filtering are mixed, 10ml n-hexane washs filter cake, and filter cake obtains the husky fourth of 3.8g after purification after being dried under reduced pressure in 30 DEG C
Amine alcohol intermediate III, purity 98.8%.
Embodiment six: the purifying of salbutamol intermediate III
III grease of 4.8g salbutamol intermediate is added 60ml n-hexane, keeps the temperature 15 DEG C of stirred crystallizations after twenty minutes, mistake
Filter takes 10ml n-hexane to wash filter cake, and filter cake obtains the salbutamol intermediate III of 3.5g after purification after being dried under reduced pressure in 25 DEG C,
Purity 99.0%.
Embodiment seven: the purifying of salbutamol intermediate III
III grease of 4.6g salbutamol intermediate is added 50ml petroleum ether, keeps the temperature 18 DEG C of stirred crystallizations after twenty minutes, mistake
Filter, obtains the salbutamol intermediate III of 3.2g after purification after taking 10ml petroleum ether filter cake, filter cake to be dried under reduced pressure in 20 DEG C,
Purity 98.8%.
Embodiment eight: the purifying of salbutamol intermediate III
III grease of 4.9g salbutamol intermediate is added 50ml normal heptane, keeps the temperature 18 DEG C of stirred crystallizations after 30 minutes, mistake
Filter takes 10ml normal heptane to wash filter cake, and filter cake obtains the salbutamol intermediate III of 3.6g after purification after being dried under reduced pressure in 30 DEG C,
Purity 98.9%.
Embodiment nine: the purifying of salbutamol intermediate III
III grease of 5.1g salbutamol intermediate is added 65ml ether, keeps the temperature 20 DEG C of stirred crystallizations after twenty minutes, mistake
Filter takes 10ml ether to wash filter cake, and filter cake obtains the salbutamol intermediate III of 4.1g after purification after being dried under reduced pressure in 25 DEG C, pure
Degree 98.6%.
The above description of the embodiment is only used to help understand the method for the present invention and its core ideas, not to limit
The present invention, it is noted that for those skilled in the art, without departing from the principle of the present invention, can also be right
Some improvement and modification can also be carried out by the present invention, and these improvements and modifications also fall within the scope of protection of the claims of the present invention.
Claims (8)
1. a kind of purification process of salbutamol intermediate III, the structural formula of salbutamol intermediate III are
It is characterized by: recrystallisation solvent is added in the salbutamol intermediate III, 10 after keeping the temperature -5~30 DEG C of dissolutions, crystallizing
~40 DEG C are dried, the salbutamol intermediate III purified.
2. a kind of purification process of salbutamol intermediate III as described in claim 1, it is characterised in that: the recrystallisation solvent is
Low polar solvent or low polar solvent and tetrahydrofuran, acetone, ethyl acetate, methylene chloride, dehydrated alcohol, anhydrous methanol are different
The mixture of any solvent in propyl alcohol.
3. a kind of purification process of salbutamol intermediate III as claimed in claim 2, it is characterised in that: the low polar solvent
Selected from petroleum ether, ether, isopropyl ether, n-hexane, one of normal heptane.
4. a kind of purification process of salbutamol intermediate III as claimed in claim 3, it is characterised in that: the recrystallisation solvent choosing
From isopropyl ether or the mixture of isopropyl ether and ethyl acetate.
5. a kind of purification process of salbutamol intermediate III as described in claim 1, it is characterised in that: the recrystallisation solvent
Dosage is 5~30 times of III mass of salbutamol intermediate.
6. a kind of purification process of salbutamol intermediate III as claimed in claim 5, it is characterised in that: the recrystallisation solvent
Dosage is 10~20 times of III mass of salbutamol intermediate.
7. a kind of purification process of salbutamol intermediate III as described in claim 1, it is characterised in that: the dissolution, crystallization
Temperature be 10~20 DEG C.
8. a kind of purification process of salbutamol intermediate III as described in claim 1, it is characterised in that: the drying temperature is
20~30 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810767215.4A CN108947831A (en) | 2018-07-13 | 2018-07-13 | A kind of purification process of salbutamol intermediate III |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810767215.4A CN108947831A (en) | 2018-07-13 | 2018-07-13 | A kind of purification process of salbutamol intermediate III |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108947831A true CN108947831A (en) | 2018-12-07 |
Family
ID=64484094
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810767215.4A Pending CN108947831A (en) | 2018-07-13 | 2018-07-13 | A kind of purification process of salbutamol intermediate III |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108947831A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112500291A (en) * | 2020-12-14 | 2021-03-16 | 上海医药集团(本溪)北方药业有限公司 | Preparation and purification method of beta 2 receptor agonist intermediate |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3642896A (en) * | 1966-09-23 | 1972-02-15 | Allen & Hanburys Ltd | Process for the preparation of alpha**1-tertiary butylaminomethyl - 4 - hydroxy-m-xylene-alpha**1 alpha**3-diol |
-
2018
- 2018-07-13 CN CN201810767215.4A patent/CN108947831A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3642896A (en) * | 1966-09-23 | 1972-02-15 | Allen & Hanburys Ltd | Process for the preparation of alpha**1-tertiary butylaminomethyl - 4 - hydroxy-m-xylene-alpha**1 alpha**3-diol |
Non-Patent Citations (1)
| Title |
|---|
| 赵临襄: "《化学制药工艺学 第4版》", 31 August 2015, 中国医药科技出版社 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112500291A (en) * | 2020-12-14 | 2021-03-16 | 上海医药集团(本溪)北方药业有限公司 | Preparation and purification method of beta 2 receptor agonist intermediate |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2016062212A1 (en) | Method for preparing 3-carbamoymethyl-5-methylhexanoic acid in recycling way | |
| CN108623486A (en) | A kind of preparation method of V hydrochloride of salbutamol intermediate | |
| CN113121416A (en) | Preparation method of lefenacin | |
| CN105503638A (en) | Sacubitril dicyclohexylamine salt, crystal form and preparation method of crystal form | |
| CN108947831A (en) | A kind of purification process of salbutamol intermediate III | |
| CN112500291B (en) | Preparation and purification method of beta 2 receptor agonist intermediate | |
| CN105884644B (en) | Neutral endopeptidase inhibitor salt dominant form and preparation method thereof | |
| CN112125943A (en) | Preparation method of high-purity 16 alpha-hydroxy prednisolone | |
| CN111635375A (en) | Synthetic method of thiazoie | |
| CN110698335A (en) | Synthesis method of terbutaline intermediate | |
| CN103755577B (en) | A kind of method reclaiming Transbroncho alkali from Ambroxol HCl refinement mother liquor | |
| CN102731340A (en) | Preparation method of demethyl aureomycin hydrochloride | |
| CN112250586A (en) | Preparation method of terbutaline sulfate and B crystal form thereof | |
| CN101492388A (en) | Method for synthesis of Miqujing medicament material | |
| CN106957235B (en) | A kind of preparation method of tamoxifen | |
| CN110590591A (en) | Preparation method of iodixanol and iohexol impurities | |
| CN109879775A (en) | A kind of environment-friendly preparation method of 5-ALA hydrochloride intermediate | |
| CN111187161B (en) | Preparation method of dihydrocapsaicin and dihydrocapsaicin ester | |
| CN115010616B (en) | Synthesis method of 1-aminocyclopropane hydrochloride | |
| CN110183355B (en) | Refining method of high-purity o-chloro mandelonitrile | |
| CN109836322B (en) | Preparation method of royal jelly acid | |
| CN108558676B (en) | Preparation method of N, N-dibenzylethylenediamine diacetate | |
| AT216495B (en) | Process for the production of new phenylalanine derivatives and their salts | |
| CN106674030A (en) | Preparation method of N-fluorenylmethyloxycarbonyl-L-2-amino-4-cyclohexylbutyric acid | |
| CN118239835A (en) | Method for reducing residual quantity of rearranged ester in ibuprofen preparation process |
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 | ||
| CB02 | Change of applicant information | ||
| CB02 | Change of applicant information |
Address after: 401120 Yubei District, Chongqing, 101 Jinyu Road, Kaiyuan. Applicant after: Chongqing kangkere Pharmaceutical Co., Ltd Address before: 401120 Yubei District, Chongqing, 101 Jinyu Road, Kaiyuan. Applicant before: CHONGQING CONQUER PHARMACEUTICAL Co.,Ltd. |
|
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20181207 |