CN109574861A - A kind of method for crystallising of three phenylacetate of Vilantro - Google Patents
A kind of method for crystallising of three phenylacetate of Vilantro Download PDFInfo
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- CN109574861A CN109574861A CN201910056347.0A CN201910056347A CN109574861A CN 109574861 A CN109574861 A CN 109574861A CN 201910056347 A CN201910056347 A CN 201910056347A CN 109574861 A CN109574861 A CN 109574861A
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- vilantro
- phenylacetate
- crystallising
- mixed solvent
- cooling
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/10—Separation; Purification; Stabilisation; Use of additives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Crystallography & Structural Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a kind of method for crystallising of three phenylacetate of Vilantro, belong to pharmaceutical synthesis field.This method using gradient cooling method, crystallizes three phenylacetate of Vilantro, method for crystallising provided by the invention improves the yield and chemical purity of reaction in chlorohydrocarbon and lower alcohol mixed solvent.
Description
Technical field
The invention belongs to pharmaceutical synthesis fields, are related to a kind of crystallization side of three phenylacetate of anti-asthmatic medicament Vilantro
Method.
Background technique
Three phenylacetate of Vilantro (Vilanterol trifenatate) is developed by GlaxoSmithKline PLC company (GSK)
Long-acting beta2Receptor stimulating agent.The compound preparation of itself and fluticasone furoate, the compound preparation with umeclidinium is respectively at 2013
May in year and December obtain FDA approval, the treatment for obstructive lung disease and asthma.Vilantro molecular weight is 486.4, molecular formula
For C24H33Cl2NO5, CAS:503068-34-6, Chinese are as follows: chemical name: (R) -4- [2- [[6- [(2,6- benzyl dichlorides
Base) oxygroup]-ethyoxyl] ethyl] amino] -1- hydroxyethyl] -2- hydroxyethyl] -2- hydroxymethylphenol, chemical structural formula is such as
Shown in lower:
World patent US2015239862A1 discloses a kind of method for crystallising of three phenylacetate of Vilantro, and this method is
Progress is crystallized at salt in non-alcohols solvent, such as is crystallized in acetone as solvent, and yield is only 69%, product chemistry
Purity is 99.79%.Chinese patent CN201310042387.2 discloses a kind of method for crystallising of three phenylacetate of Vilantro,
This method is to carry out crystallizing at salt in alcohol solvent, and yield 82%, product purity is not recorded.Document
A kind of method for crystallising of three phenylacetate of Vilantro, the party are reported in (J.Med.Chem.2010,53,4522-4530)
Use isopropanol for solvent in method, yield 88%, purity is not recorded.
Summary of the invention
The present invention provides a kind of method for crystallising of three phenylacetate of Vilantro for the deficiency in the prior art,
Technical solution is as follows:
It finds during the experiment, Vilantro alkali solubility in lower alcohols solvent is small, such as two in chlorinated solvent
Chloromethanes, chloroform have preferable solubility in 1,2- dichloroethanes；Then solubility is big in alcohols solvent for three phenylacetic acids, in chlorine
For in solvent as solubility in methylene chloride is small.It is found in crystallization process, the speed of cooling and the speed of stirring all crystallized
Journey all has an impact, and the too fast particle that precipitates crystal of cooling rate is bigger, and product purity is low；The speed that the faster crystal of mixing speed is precipitated
Also fast, product purity is equally low；Stationary crystallization product speed of separating out is slow, needs to grow for a long time, product purity is high, but yield
It is low.Therefore, the invention discloses one kind under in the mixed solvent, low stirring, crystallizes Vilantro using gradient cooling method
Method.
Experimentation: being added in the mixed solvent for Vilantro alkali and three phenylacetic acids, open stirring, be heated to 66 DEG C it is molten
Solution, using gradient cooling method crystallization, filtering is dried to obtain white solid, yield 91-93%, chemical purity 99.9%.
Mixed solvent described in technical solution is chlorohydrocarbon and lower alcohol, and the mixed solvent chlorohydrocarbon and lower alcohol are molten
The volume ratio of agent is 1:4~6；The amount that the mixed solvent is added is 20-30 times of Vilantro quality；The wherein chloro
Hydrocarbon solvent is one of methylene chloride, chloroform, 1,2- dichloroethanes, preferably methylene chloride；The lower alcohol is
One of ethyl alcohol, normal propyl alcohol, isopropanol, the tert-butyl alcohol, n-butanol, isobutanol, the preferably tert-butyl alcohol；Gradient cooling process, machine
The revolving speed of tool stirring is that 80-100 turns/min.The Crystallization Process that cools down uses gradient cooling, from 66 DEG C of near 30 DEG C of processes, cooling speed
Degree is 0.3 DEG C/min, and 30 DEG C keep the temperature 1 hour；From 30 DEG C of near 5 DEG C of processes, cooling rate is 0.2 DEG C/min, and 5 DEG C of heat preservations 3 are small
When.
Beneficial effects of the present invention:
The present invention improves yield and chemical purity.The yield reported in document (US2015239862A1) is 69%, is produced
Product chemical purity is 99.79%, and the yield reported in document (CN201310042387.2) is 82%, document
The yield reported in (J.Med.Chem.2010,53,4522-4530) is 88%, yield 91-93% in the present invention, and chemistry is pure
Degree 99.9%, has biggish promotion, phase compared to the yield in document (US2015239862A1, CN201310042387.2)
It is also promoted than the yield in document (J.Med.Chem. 2010,53,4522-4530).
Specific embodiment
Vilantro alkali is purchased from Guangdong Weng Jiang chemical reagent Co., Ltd, purity 98%.
Embodiment 1:
Vilantro alkali (8g) and three phenylacetic acids (4.75g) are added to the mixed of 33mL methylene chloride and the 167mL tert-butyl alcohol
In bonding solvent, stirring is opened, adjusting revolving speed is 400 turns/min, using low temperature thermostat bath (Shanghai public affairs more limited than bright instrument manufacturing
Department) 66 DEG C of dissolutions are heated to, adjusting revolving speed is 90 turns/min, cooling process is set, from 66 DEG C of near 30 DEG C of processes, cooling rate
For 0.3 DEG C/min, 30 DEG C keep the temperature 1 hour；From 30 DEG C of near 5 DEG C of processes, cooling rate is 0.2 DEG C/min, and 5 DEG C of heat preservations 3 are small
When.Filtering, 40 DEG C of vacuum drying obtain white solid 11.7g, yield 92%, chemical purity 99.9%.
Embodiment 2:
Vilantro alkali (8g) and three phenylacetic acids (4.75g) are added in 200 ethyl alcohol, stirring is opened, adjusting revolving speed is
400 turns/min, 66 DEG C of dissolutions are heated to using low temperature thermostat bath (Shanghai is than bright instrument manufacturing Co., Ltd), adjusting revolving speed is
90 turns/min, cooling process is set, from 66 DEG C of near 30 DEG C of processes, cooling rate is 0.3 DEG C/min, and 30 DEG C keep the temperature 1 hour；From
30 DEG C of near 5 DEG C of processes, cooling rate are 0.2 DEG C/min, and 5 DEG C keep the temperature 3 hours.Filtering, it is solid that 40 DEG C of vacuum drying obtain white
Body 10.2g, yield 80%, chemical purity 99.0%.
Embodiment 3:
Vilantro alkali (8g) and three phenylacetic acids (4.75g) are added in 1,2- dichloroethanes (200mL), unlatching is stirred
Mix, adjusting revolving speed be 400 turns/min, using low temperature thermostat bath (Shanghai is than bright instrument manufacturing Co., Ltd) be heated to 66 DEG C it is molten
Solution, adjustings revolving speed are 90 turns/min, set cooling process, and from 66 DEG C of near 30 DEG C of processes, cooling rate is 0.3 DEG C/min, 30
DEG C heat preservation 1 hour；From 30 DEG C of near 5 DEG C of processes, cooling rate is 0.2 DEG C/min, and 5 DEG C keep the temperature 3 hours.Filtering, 40 DEG C of vacuum
It is dried to obtain white solid 4.4g, the white solid obtained after measured is three phenylacetic acids.
Embodiment 4:
Vilantro alkali (8g) and three phenylacetic acids (4.75g) are added in isopropanol (200mL), stirring is opened, is adjusted
Revolving speed is 400 turns/min, is heated to 66 DEG C of dissolutions, stirring, Temperature fall crystallization 6 hours, filtering, 40 DEG C of vacuum drying obtained white
Color solid 10.6g, yield 83%, purity 97%.
Embodiment 5:
Vilantro alkali (8g) and three phenylacetic acids (4.75g) are added in isopropanol (200mL), stirring, heating are opened
It is dissolved to 66 DEG C, Temperature fall static state crystallization 12 hours, filtering, 40 DEG C of vacuum drying obtain white solid 8.6g, yield
67%, purity 99.9%.
Above-mentioned, although specific embodiments of the present invention have been described, not to the limit of the scope of the present invention
System, those skilled in the art should understand that, based on the technical solutions of the present invention, those skilled in the art do not need to pay
The various modifications or changes that creative work can be made out are still within protection scope of the present invention.
Claims (8)
1. a kind of method for crystallising of three phenylacetate of Vilantro, which is characterized in that under in the mixed solvent, low stirring,
Three phenylacetate of Vilantro is crystallized using gradient cooling method, technology path is as follows:
2. a kind of method for crystallising of three phenylacetate of Vilantro according to claim 1, which is characterized in that this method
Described in mixed solvent be chlorohydrocarbon and lower alcohol.
3. a kind of method for crystallising of three phenylacetate of Vilantro according to claim 2, which is characterized in that described
Chlorinated hydrocarbon solvent is one of methylene chloride, chloroform, 1,2- dichloroethanes or a variety of.
4. a kind of method for crystallising of three phenylacetate of Vilantro according to claim 2, which is characterized in that described
Lower alcohol is one of ethyl alcohol, normal propyl alcohol, isopropanol, the tert-butyl alcohol, n-butanol, isobutanol or a variety of.
5. a kind of method for crystallising of three phenylacetate of Vilantro according to claim 2, which is characterized in that described
The volume ratio of mixed solvent chlorohydrocarbon and lower alcohol solvent is 1:4~6.
6. a kind of method for crystallising of three phenylacetate of Vilantro according to claim 2, which is characterized in that described
The amount that mixed solvent is added is 20-30 times of Vilantro quality.
7. a kind of method for crystallising of three phenylacetate of Vilantro according to claim 1, which is characterized in that gradient drop
Warm process, churned mechanically revolving speed are that 80-100 turns/min.
8. a kind of method for crystallising of three phenylacetate of Vilantro according to claim 1, which is characterized in that cooling analysis
Brilliant process uses gradient cooling, and from 66 DEG C of near 30 DEG C of processes, cooling rate is 0.3 DEG C/min, and 30 DEG C keep the temperature 1 hour；From 30
DEG C near 5 DEG C of processes, cooling rate are 0.2 DEG C/min, and 5 DEG C keep the temperature 3 hours.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201910056347.0A CN109574861A (en) | 2019-01-22 | 2019-01-22 | A kind of method for crystallising of three phenylacetate of Vilantro |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113121492A (en) * | 2019-12-31 | 2021-07-16 | 天津药业研究院股份有限公司 | Vilandiolo intermediate, preparation method and application thereof |
| CN116209654A (en) * | 2020-07-27 | 2023-06-02 | Inke股份公司 | Method for purifying vilantro triphenyl acetate |
| CN116283512A (en) * | 2023-02-24 | 2023-06-23 | 博诺康源(北京)药业科技有限公司 | Method for synthesizing vilanabro and salts thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014041565A2 (en) * | 2012-09-13 | 2014-03-20 | Laurus Labs Private Limited | An improved process for the preparation of vilanterol and intermediates thereof |
| CN103288793B (en) * | 2001-09-14 | 2015-09-23 | 葛兰素集团有限公司 | The Phenethanolamine derivative for the treatment of respiratory disease |
| WO2017001907A1 (en) * | 2015-06-29 | 2017-01-05 | Teva Pharmaceuticals International Gmbh | Biocatalytic processes for the preparation of vilanterol |
-
2019
- 2019-01-22 CN CN201910056347.0A patent/CN109574861A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103288793B (en) * | 2001-09-14 | 2015-09-23 | 葛兰素集团有限公司 | The Phenethanolamine derivative for the treatment of respiratory disease |
| WO2014041565A2 (en) * | 2012-09-13 | 2014-03-20 | Laurus Labs Private Limited | An improved process for the preparation of vilanterol and intermediates thereof |
| WO2017001907A1 (en) * | 2015-06-29 | 2017-01-05 | Teva Pharmaceuticals International Gmbh | Biocatalytic processes for the preparation of vilanterol |
Non-Patent Citations (1)
| Title |
|---|
| PANAYIOTIS A. PROCOPIOU等: "Synthesis and Structure-Activity Relationships of Long-acting β2 Adrenergic Receptor Agonists Incorporating Metabolic Inactivation: An Antedrug Approach", 《J. MED. CHEM.》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113121492A (en) * | 2019-12-31 | 2021-07-16 | 天津药业研究院股份有限公司 | Vilandiolo intermediate, preparation method and application thereof |
| CN116209654A (en) * | 2020-07-27 | 2023-06-02 | Inke股份公司 | Method for purifying vilantro triphenyl acetate |
| CN116283512A (en) * | 2023-02-24 | 2023-06-23 | 博诺康源(北京)药业科技有限公司 | Method for synthesizing vilanabro and salts thereof |
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Application publication date: 20190405 |