CN104059120A - Preparation process of high-purity betamethasone acetate - Google Patents
Preparation process of high-purity betamethasone acetate Download PDFInfo
- Publication number
- CN104059120A CN104059120A CN201410228178.1A CN201410228178A CN104059120A CN 104059120 A CN104059120 A CN 104059120A CN 201410228178 A CN201410228178 A CN 201410228178A CN 104059120 A CN104059120 A CN 104059120A
- Authority
- CN
- China
- Prior art keywords
- acetone
- becort
- preparation technology
- crude product
- acetate
- 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
Abstract
The invention discloses a preparation process of high-purity betamethasone acetate. The process comprises the following steps: adding acetone into a crude product of betamethasone acetate, and distilling and crystallizing to obtain high-purity betamethasone acetate. The process is efficient, simple and convenient, the 1,2-dichloroethane residue content of betamethasone acetate with the 1,2-dichloroethane residue content of reaching up to 20,000ppm can be reduced to within 5ppm and meets the national standards, and the process has wide industrial application prospects.
Description
Technical field
The invention belongs to the purification techniques field of bulk drug, be specifically related to a kind of high purity becort acetate preparation technology.
Background technology
Becort acetate, another name β-meter Song acetic ester, Betamethasone acetate, Betamethasone acetate, English Betamethasne acetate by name, chemical name: 9 α-fluoro-16 Beta-methyl-11 β, 17 α, 21-trihydroxy--1,4 pregnant diene-3,20-diketone 21-acetic acid.Becort acetate is a kind of white crystalline powder, is slightly soluble in propyl alcohol, ethanol, and the utmost point is insoluble in chloroform or ether, water insoluble, belong to adrenocortical hormone and thyroliberin, be mainly used in anti-inflammatory and antianaphylaxis, be applicable to rheumatic arthritis and various tetter.The same dexamethasone of effect of becort acetate, its anti-inflammatory action, than the few side effects of dexamethasone, triamcinolone, hydrocortisone, is now used for treating reactivity rheumatosis, rheumatoid arthritis, lupus erythematosus, serious bronchial asthma, serious dermatitis, acute leukemia etc.Its structural formula is as shown in formula I:
Chinese patent CN101417912 and CN101397319 disclose the preparation method of becort acetate, in preparation process, all have and use 1,2-ethylene dichloride, methylene dichloride equal solvent, wherein CN101417912 has in the end used 1 in a step replacement(metathesis)reaction, 2-ethylene dichloride, more easily causes dissolvent residual.But the residual solvent in medicine often can not be conducive to the curative effect of medicine, on the contrary, exceed residual molten standard and may cause serious safety of medicine problem, residual especially serious on the impact of drug safety as height poison one kind solvent that 1,2-ethylene dichloride is such.In actual production, because final step has used 1,2-ethylene dichloride, and it is below the mark to adopt forced air drying and vacuum drying method all the residual quantity of 1,2-ethylene dichloride can not be reduced to the 5ppm of national regulation.
In the preparation process of becort acetate, solvent has a strong impact on its purity, crystal formation, output etc., uses 1 in reality, and 2-ethylene dichloride product purity output is all higher than using methylene dichloride, but toxicology limit prepared by medicine is mandatory.Therefore, be necessary to provide a kind of process for refining of high purity becort acetate, the residual quantity of 1,2-ethylene dichloride is reduced to below the 5ppm of national regulation.
Summary of the invention
In order to obtain the preparation method of the becort acetate crystal with high security, in present inventor's long-term research, find, acetone is joined in becort acetate crystal, and distillation obtains mixture, then by operations such as condensing crystal filtrations, even to comprising up to 20000ppm1, the becort acetate of 2-ethylene dichloride residual quantity, also 1,2-ethylene dichloride residual quantity can be reduced in 5ppm.
Therefore, the object of the present invention is to provide a kind of high purity becort acetate preparation technology.
To achieve the above object of the invention, the present invention has adopted following technical scheme:
A preparation technology for high purity becort acetate, joins acetone in becort acetate crude product, by adding thermal distillation and cooling crystallization acquisition high purity becort acetate.
According to the present invention, the preparation technology of described high purity becort acetate comprises the following steps:
(a), by becort acetate dissolving crude product in acetone, and add thermal distillation;
(b), when being 1:1～2 times with the mass volume ratio of residue acetone, becort acetate crude product described in described step (a) stops distillation when being distilled to;
(c), be naturally cooled to room temperature, then frozen cooling to 0～5 DEG C, and stir;
(d), filter the high purity becort acetate that centrifugal collection is separated out, vacuum-drying.
According to the present invention, described in described step (a), the mass volume ratio of becort acetate crude product and described acetone is 1:40.
According to the present invention, the temperature that adds thermal distillation described in described step (a) is 50 DEG C.
According to the present invention, the time of stirring described in described step (a) is 2 hours.
According to the present invention, between described step (b) and step (c), also comprise step (b '): add again acetone, and adding thermal distillation, when being 1:1～2 times, becort acetate crude product described in described step (a) and the mass volume ratio of residue acetone stop distillation when being distilled to.
According to the present invention, described in becort acetate crude product and described step described in described step (a) (b '), adding the mass volume ratio of acetone is 1:5～10 again.
According to the present invention, 1 of described becort acetate crude product, 2-ethylene dichloride residual value is greater than 5ppm, and is less than or equal to 20000ppm.
According to the present invention, 1 of described high purity becort acetate, 2-ethylene dichloride residual value is less than or equal to 5ppm.
Beneficial effect of the present invention: method high-efficient simple of the present invention, can meet the high yield that becort acetate is produced, can reach again have compared with prior art lower by 1,2-ethylene dichloride is residual, to comprising up to 20000ppm1, the becort acetate of 2-ethylene dichloride residual quantity, also can be by 1,2-ethylene dichloride residual quantity is reduced in 5ppm, meet state-set standard, and the method need not increase other devices beyond existing apparatus in production application, is convenient to plant operations, under the condition of production, output is not almost affected continuously.
Therefore, no matter technical scheme disclosed in this invention is from technology or from economically, has good prospects for commercial application.
Embodiment
Below in conjunction with specific embodiment, the invention will be further described.Should be understood that following examples are only for the present invention is described but not for limiting scope of the present invention.
In following examples, adopt in gas chromatography determination becort acetate 1, the residual quantity of 2-ethylene dichloride.
(60m × 0.53mm × 3 μ is m) as analysis chromatographic column, fid detector to adopt AgilentDB-624 fused-silica capillary column
Chromatographic separation parameter: carrier gas: nitrogen; Flow rate of carrier gas: 3.0mL/min; Splitting ratio: 5:1
Detector temperature: 250 DEG C; Injector temperature: 200 DEG C
Column temperature: 45 DEG C of starting temperatures, keep 10min, with the temperature rise rate to 150 DEG C of 15 DEG C/min, keep 3min.
Head space detect parameters: heating container: 105 DEG C; Quantitatively ring: 115 DEG C; Transmission line: 125 DEG C
GC cycling time: 25min; Sample injection time: 1min
Sample starting time: 20min; Pressure balance time: 0.2min.
Embodiment 1:
By highly purified 10kg becort acetate (1, 2-ethylene dichloride residual value is 5805ppm, through containing 1, 2-ethylene dichloride solvent reaction liquid condensing crystal and obtain) put in the 500L reactor of suction 400L acetone, and stirring is warming up to 50 DEG C, after within 30 minutes, ensureing to dissolve, open vacuum-concentrcted and remain 10～20L solvent to still, close vacuum, and be naturally cooled to room temperature, then open and be freezingly cooled to 0～5 DEG C, continue to stir 2 hours, open bottom valve mixed solution is put into whizzer centrifuging, and with 20L ice acetone cleaning reaction still, after centrifuge dripping, collect solid, 60 DEG C of oven dry of vacuum drying oven, surveying dissolvent residual value is respectively: 1, the residual 2ppm of 2-ethylene dichloride, the residual 450ppm of acetone.
Embodiment 2:
By highly purified 10kg becort acetate (1, 2-ethylene dichloride residual value is 18962ppm, through containing 1, 2-ethylene dichloride solvent reaction liquid condensing crystal and obtain) put in the 500L reactor of suction 400L acetone, and stirring is warming up to 50 DEG C, after within 30 minutes, ensureing to dissolve, open vacuum-concentrcted and remain 10～20L solvent to still, close vacuum, to suction 50L acetone in reactor, continue underpressure distillation and again remain 10～20L solvent to reactor, close vacuum, and be naturally cooled to room temperature, then open and be freezingly cooled to 0～5 DEG C, continue to stir 2 hours, open bottom valve mixed solution is put into whizzer centrifuging, and with 20L ice acetone cleaning reaction still, after centrifuge dripping, collect solid, 60 DEG C of oven dry of vacuum drying oven, survey dissolvent residual is: 1, the residual 0ppm of 2-ethylene dichloride, the residual 653ppm of acetone.
Embodiment 3:
By highly purified 5kg becort acetate (1, 2-ethylene dichloride residual value is 4804ppm, through containing 1, 2-ethylene dichloride solvent reaction liquid condensing crystal and obtain) put in the 500L reactor of suction 200L acetone, and stirring is warming up to 50 DEG C, after within 30 minutes, ensureing to dissolve, open vacuum-concentrcted and remain 5～10L solvent to still, close vacuum, and be naturally cooled to room temperature, then open and be freezingly cooled to 0～5 DEG C, continue to stir 2 hours, open bottom valve mixed solution is put into whizzer centrifuging, and with 10L ice acetone cleaning reaction still, after centrifuge dripping, collect solid, 60 DEG C of oven dry of vacuum drying oven, survey dissolvent residual is: 1, the residual 1ppm of 2-ethylene dichloride, the residual 483ppm of acetone.
Embodiment 4:
By highly purified 5kg becort acetate (1, 2-ethylene dichloride residual value is 19740ppm, through containing 1, 2-ethylene dichloride solvent reaction liquid condensing crystal and obtain) put in the 500L reactor of suction 200L acetone, and stirring is warming up to 50 DEG C, after within 30 minutes, ensureing to dissolve, open vacuum-concentrcted and remain 5～10L solvent to still, close vacuum, to suction 50L acetone in reactor, continue underpressure distillation and again remain 5～10L solvent to reactor, close vacuum, and be naturally cooled to room temperature, then open and be freezingly cooled to 0～5 DEG C, continue to stir 2 hours, open bottom valve mixed solution is put into whizzer centrifuging, and with 10L ice acetone cleaning reaction still, after centrifuge dripping, collect solid, 60 DEG C of oven dry of vacuum drying oven, survey dissolvent residual is: 1, 2-ethylene dichloride 1ppm, acetone 721ppm.
Claims (9)
1. a preparation technology for high purity becort acetate, is characterized in that, acetone is joined in becort acetate crude product, by adding thermal distillation and cooling crystallization acquisition high purity becort acetate.
2. preparation technology as claimed in claim 1, is characterized in that, comprises the following steps:
(a), by becort acetate dissolving crude product in acetone, and add thermal distillation;
(b), when being 1:1～2 times with the mass volume ratio of residue acetone, becort acetate crude product described in described step (a) stops distillation when being distilled to;
(c), be naturally cooled to room temperature, then frozen cooling to 0～5 DEG C, and stir;
(d), filter the high purity becort acetate that centrifugal collection is separated out, vacuum-drying.
3. preparation technology as claimed in claim 2, is characterized in that, described in described step (a), the mass volume ratio of becort acetate crude product and described acetone is 1:40.
4. preparation technology as claimed in claim 2, is characterized in that, the temperature that adds thermal distillation described in described step (a) is 50 DEG C.
5. preparation technology as claimed in claim 2, is characterized in that, the time of stirring described in described step (a) is 2 hours.
6. preparation technology as claimed in claim 2, it is characterized in that, between described step (b) and step (c), also comprise step (b '): add again acetone, and adding thermal distillation, when being 1:1～2 times, becort acetate crude product described in described step (a) and the mass volume ratio of residue acetone stop distillation when being distilled to.
7. preparation technology as claimed in claim 6, is characterized in that, described in becort acetate crude product and described step described in described step (a) (b '), adding the mass volume ratio of acetone is 1:5～10 again.
8. the preparation technology as described in any one in claim 1～7, is characterized in that, 1 of described becort acetate crude product, and 2-ethylene dichloride residual value is greater than 5ppm, and is less than or equal to 20000ppm.
9. the preparation technology as described in any one in claim 1～7, is characterized in that, 1 of described high purity becort acetate, and 2-ethylene dichloride residual value is less than or equal to 5ppm.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410228178.1A CN104059120A (en) | 2014-05-27 | 2014-05-27 | Preparation process of high-purity betamethasone acetate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410228178.1A CN104059120A (en) | 2014-05-27 | 2014-05-27 | Preparation process of high-purity betamethasone acetate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104059120A true CN104059120A (en) | 2014-09-24 |
Family
ID=51547079
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410228178.1A Pending CN104059120A (en) | 2014-05-27 | 2014-05-27 | Preparation process of high-purity betamethasone acetate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104059120A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112358522A (en) * | 2020-05-18 | 2021-02-12 | 河南利华制药有限公司 | Method for refining betamethasone dipropionate and betamethasone dipropionate |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1720239A (en) * | 2003-01-13 | 2006-01-11 | 大日本制药株式会社 | Process for the preparation of 1,2-dichloroethane free crystals of zonisamide and high pure crystals of zonisamide |
| CN101406765A (en) * | 2008-10-21 | 2009-04-15 | 浙江大学 | Method for removing organic solvent residual in raw medicine |
| CN101417912A (en) * | 2008-11-10 | 2009-04-29 | 湖南甾体化学品有限公司 | Method for preparing becort acetate |
-
2014
- 2014-05-27 CN CN201410228178.1A patent/CN104059120A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1720239A (en) * | 2003-01-13 | 2006-01-11 | 大日本制药株式会社 | Process for the preparation of 1,2-dichloroethane free crystals of zonisamide and high pure crystals of zonisamide |
| CN101406765A (en) * | 2008-10-21 | 2009-04-15 | 浙江大学 | Method for removing organic solvent residual in raw medicine |
| CN101417912A (en) * | 2008-11-10 | 2009-04-29 | 湖南甾体化学品有限公司 | Method for preparing becort acetate |
Non-Patent Citations (2)
| Title |
|---|
| 宋连珍等: "《制药过程原理及设备》", 31 January 2013, 中国医药科技出版社 * |
| 柯学 等: "不同晶型倍他米松醋酸酯形成机理研究", 《中国药科大学学报》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112358522A (en) * | 2020-05-18 | 2021-02-12 | 河南利华制药有限公司 | Method for refining betamethasone dipropionate and betamethasone dipropionate |
| CN112358522B (en) * | 2020-05-18 | 2021-11-16 | 河南利华制药有限公司 | Method for refining betamethasone dipropionate and betamethasone dipropionate |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102600631B (en) | Device and method for purifying delta-decalactone by vacuum batch distillation | |
| CN110734359B (en) | Extraction and purification method of cannabidiol | |
| CN108102100A (en) | A kind of production method and production system of low volatilization vinyl silicone oil | |
| CN102070567A (en) | Method for preparing high-purity orlistat by using reverse phase high-performance liquid chromatogram | |
| CN104059120A (en) | Preparation process of high-purity betamethasone acetate | |
| CN103772442A (en) | Method for separating and purifying n-octylferrocene through reduced pressure distillation process in combination with chromatography | |
| CN102675108B (en) | Refining method of pyrethrin crude extract | |
| CN102838455A (en) | Method for extracting high-content resveratrol from polygonum cuspidatum | |
| CN110684589A (en) | Extraction and purification method of hemp oil | |
| CN110256208A (en) | A method of utilizing supercritical extract cannabidiol | |
| CN110613739A (en) | Method for separating flavonoid compounds in cotton rose based on high-speed countercurrent chromatography | |
| CN101691323B (en) | Method for separating and purifying patchouli alcohol | |
| CN104370694A (en) | Separation method of isobutanol-ethyl isobutyrate azeotrope by batch extraction rectification | |
| CN110028384B (en) | Method for preparing 2-phenethyl alcohol from biotransformation liquid by molecular distillation and separation | |
| CN104744406A (en) | Method for preparing epoxy caryophyllene from heavy turpentine oil and separating longifolene | |
| CN110627802B (en) | Method for extracting sesame lignan from by-product generated in sesame oil production | |
| CN103304398B (en) | A kind of method of purification of carboxylic acid aqueous solution | |
| WO2015058116A1 (en) | Methods for producing alkyl hydroxyalkanoates | |
| US10239814B2 (en) | Process for the purification of levulinic acid | |
| CN108101745A (en) | The method that natural d-borneol is extracted from camphor tree branches and leaves | |
| CN104693003A (en) | Method for separating isobutanol and ethyl isobutyrate azeotrope by continuous extractive distillation | |
| CN111960922B (en) | Method for separating natural terpineol from heavy turpentine | |
| CN102060700B (en) | Method for recycling beta-3,5-di-tert-butyl-4-hydroxyphenylpropionic methyl ester from alcoholysis liquor of antioxidant 1010 production mother liquor | |
| CN114133318B (en) | Method for reducing and removing propofol impurity O in propofol product | |
| CN111302908B (en) | Method for extracting and separating triethylene glycol and triethylene glycol monomethyl ether by using supercritical carbon dioxide |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into 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: 20140924 |