CN105037177B - A kind of method that supercritical crystallization prepares S metoprolol - Google Patents
A kind of method that supercritical crystallization prepares S metoprolol Download PDFInfo
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- CN105037177B CN105037177B CN201510309226.4A CN201510309226A CN105037177B CN 105037177 B CN105037177 B CN 105037177B CN 201510309226 A CN201510309226 A CN 201510309226A CN 105037177 B CN105037177 B CN 105037177B
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- metoprolol
- supercritical
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- racemization
- povidone
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/54—Improvements relating to the production of bulk chemicals using solvents, e.g. supercritical solvents or ionic liquids
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Abstract
The invention provides a kind of method that supercritical crystallization prepares S metoprolol, is prepared by the following method：Racemization metoprolol and 30 POVIDONE K 30 BP/USP 15 are dissolved in supercritical CO2In fluid, in the range of certain pressure, by changing supercritical CO2The temperature of fluid, the S metoprolol for making solubility low crystallize precipitation first.Compared with prior art, the present invention is environment friendly and pollution-free；Preparation process is simple, it is easy to industrialization；S and R configuration metoprolol is completely separated.
Description
Technical field
The invention belongs to medicine splits technical field, S- Mei Tuoluo is prepared in particular to a kind of supercritical crystallization
Your method.
Background technology
In order to safety and precise ground medication, the demand of the chiral medicine of people becomes increasingly urgent.Beta-blocker
It is clinically wide variety for the treatment of hypertension and anginal class important drugs, at present beyond most of beta-blockers
Racemate form is listed.Beta-blocker metoprolol has two kinds of optical isomers:R- (+)-metoprolol and S- (-)-U.S.
Tuo Luoer, they show the huge difference on pharmacokinetics and pharmacodynamics.Research shows the beta receptor parent of metoprolol S- enantiomer
It is 25 times of its R- enantiomer with power, in isolated heart, the adenylate ring of its S- enantiomer blocking isoprel activation
Change enzymatic activity is 33 times of its enantiomer, there is also stereoselectivity in metabolic process, and the first pass effect of its S- enantiomer is relatively
Low.Therefore, develop and prepare optical voidness metoprolol significant.
Research about photolytic activity metoprolol is concentrated mainly on analytic type method for splitting at present, such as chiral liquid phase method, hair
Cons electrophoresis method, thin-layered chromatography, chiral derivatization method etc., it is not suitable for the separation of a large amount of photolytic activity metoprolols.Relevant light is lived
The asymmetric syntheses of property metoprolol is also due to haveing the characteristics that part racemization and causing optical purity not high in building-up process.
CN102070469B discloses a kind of method that Split Method prepares optical voidness metoprolol, with cyclic phosphoric acid as tearing open
Agent is divided to prepare optical voidness metoprolol, cyclic phosphoric acid resolving agent can be used alone and can also be used in mixed way.Racemization Mei Tuoluo
You and cyclic phosphoric acid resolving agent form diastereomeric salt in a solvent, by less for solubility diastereomeric salt mistake
Filter, obtains optical voidness metoprolol after filter cake is dissociated；Another isomers of metoprolol is obtained after filtrate is dissociated.But prepare
There is problems with complex process, method：One be it is difficult to thoroughly separate diastereoisomer, two is to also need to slough fractionation
Agent.
Content of the invention
In view of the deficiencies in the prior art, a kind of process is simple of inventor's plan offer, after fractionation, the high separation mapping of purity is different
The method of structure body.
Specifically, the present invention is realized by following technology：
The invention provides a kind of method that supercritical crystallization prepares S- metoprolol, is prepared by the following method：To disappear
Rotation metoprolol is dissolved in supercritical fluid CO 2 with 30 POVIDONE K 30 BP/USP 15, in the range of certain pressure, by changing supercritical CO 2
The temperature of fluid, the S- metoprolol for making solubility low crystallize precipitation first.
Described pressure limit is 40-60MPa, and preferably pressure is 50MPa.
Described temperature range is 35-55 DEG C, and preferred range is 45-55 DEG C.
The racemization metoprolol is 1 with the weight ratio of 30 POVIDONE K 30 BP/USP 15:2-4, preferred racemization metoprolol and PVP
The weight ratio of K15 is 1:3.
Compared with prior art, the present invention has following advantage：
(1) environment friendly and pollution-free；
(2) preparation process is simple, it is easy to industrialization；
(3) S and R configuration metoprolol is completely separated.
Specific embodiment
Preparation process and the implementation result of the present invention now further described by following examples, but the protection of the present invention
Scope is not limited to following examples.
Embodiment 1
50g racemization metoprolol, 100g 30 POVIDONE K 30 BP/USP 15 are dissolved in supercritical CO2In fluid, under 40MPa pressure, will
Supercritical CO2The temperature of fluid is down to 35 DEG C by 55 DEG C, keeps 20min, then sprays supercritical fluid CO2 from spout, spray
Collect after going out for R- metoprolol, collect the low S- metoprolol of solubility in tank body.
Embodiment 2
50g racemization metoprolol, 200g 30 POVIDONE K 30 BP/USP 15 are dissolved in supercritical CO2In fluid, under 60MPa pressure, will
Supercritical CO2The temperature of fluid is down to 35 DEG C by 55 DEG C, keeps 30min, then sprays supercritical fluid CO2 from spout, spray
Collect after going out for R- metoprolol, collect the low S- metoprolol of solubility in tank body.
Embodiment 3
50g racemization metoprolol, 150g 30 POVIDONE K 30 BP/USP 15 are dissolved in supercritical CO2In fluid, under 50MPa pressure, will
Supercritical CO2The temperature of fluid is down to 45 DEG C by 55 DEG C, keeps 40min, then sprays supercritical fluid CO2 from spout, spray
Collect after going out for R- metoprolol, collect the low S- metoprolol of solubility in tank body.
Comparative example 1
50g racemization metoprolol is dissolved in supercritical CO2In fluid, under 50MPa pressure, by supercritical CO2Fluid
Temperature is down to 45 DEG C by 55 DEG C, keeps 40min, then sprays supercritical fluid CO2 from spout, and that collected after ejection is beautiful for R-
Tuo Luoer, collects the low S- metoprolol of solubility in tank body.
Comparative example 2
(1) metoprolol and the 242.35g (1mol) of 267.37g (1mol) racemization are added in 2L methyl tertiary butyl ether(MTBE)
(-) -4- phenyl -2- hydroxyl -5,5- dimethyl -2- oxo -1,3,2- dioxaphosphorinanes, it is heated to reflux stirring clear to solution
Clearly, continuation stirring 1h, gradually has crystal to separate out, filters, wash filter cake with 200mL methyl tertiary butyl ether(MTBE), obtains filter cake after drying
244.5g；
(2) by above-mentioned filter cake, be dissolved in 500mL water, pH=8 adjusted with 10%NaOH solution, stir 1h, second under room temperature
Acetoacetic ester is extracted three times, and each consumption 100mL dries organic layer, organic solvent is evaporated off, obtains S- (-)-metoprolol
120.33g, water layer adjust pH to highly acid, gradually have solid to separate out, filter, reclaim cycli phosphate resolving agent；
(3) filtrate in step (1) and washing lotion are merged, organic solvent is evaporated off, will be water-soluble with 500mL for the solid for obtaining
Solution, adjusts pH=8 with 10%NaOH solution, stirs 1h, be extracted with ethyl acetate three times, each consumption 100mL under room temperature, dries
Organic layer, is evaporated off organic solvent, obtains R- (+)-metoprolol 122.33g, and water layer adjusts pH to highly acid, gradually has solid to analyse
Go out, filter, reclaim cycli phosphate resolving agent；
(4) the common 230.83g of above-mentioned steps (2) and (3) are reclaimed resolution reagent, the rate of recovery are 95.24%, by tearing open for reclaiming
Agent is divided to be combined recycling.
Comparative example 3
50g racemization metoprolol, 150g PVP K30 are dissolved in supercritical CO2In fluid, under 50MPa pressure, will
Supercritical CO2The temperature of fluid is down to 45 DEG C by 55 DEG C, keeps 40min, then sprays supercritical fluid CO2 from spout, spray
Collect after going out for R- metoprolol, collect the low S- metoprolol of solubility in tank body.
Checking embodiment
Isomers is detected：According to high performance liquid chromatography, using chiral chromatographic column (Chiral-PH), high with 0.025mol/L
Sodium chlorate-acetonitrile (70:30) it is mobile phase, Detection wavelength 223nm.Precision weighs metoprolol tor product in right amount, plus mobility
The solution for making 0.4mg/ml is dissolved and dilute, precision measures 10 microlitres, liquid chromatograph is injected, chromatogram is recorded, the U.S. support of S-
Luo Er should meet regulation with the separating degree at R- metoprolol peak.
Determination method：It is appropriate that precision weighs this product, plus flowing phased soln dilutes the solution for making 0.2mg/ml, used as control
Solution；Precision measures 10 microlitres of contrast solution, injects liquid chromatograph, and adjusting detector sensitivity makes main peak peak height for full scale
10-20%；Precision measures need testing solution and reference substance solution is each 10 microlitres again, is injected separately into liquid chromatograph, records color
Spectrogram.In need testing solution chromatogram, R- metoprolol peak area must not cross 0.5 times (0.5%) of comparison liquid main peak area.
Embodiment measurement result
| Embodiment | R- metoprolol content (%) |
| Embodiment 1 | 0.003 |
| Embodiment 2 | 0.002 |
| Embodiment 3 | 0.001 |
| Comparative example 1 | 0.7 |
| Comparative example 2 | 1.2 |
| Comparative example 3 | 0.35 |
As seen from the table, the embodiment of the present invention, R- metoprolol are examined substantially and are not measured；And in comparative example 1, it is 0.7%, because
Which does not add 30 POVIDONE K 30 BP/USP 15, it is impossible to be kept completely separate the two；Comparative example 2, using prior art, R- metoprolol content
Highest；Comparative example 3, use PVP K30 instead, and effect is not so good as the embodiment of the present invention.
Claims (4)
1. a kind of method that supercritical crystallization prepares S- metoprolol, it is characterised in that prepare by the following method：Racemization is beautiful
Tuo Luoer is dissolved in supercritical CO with 30 POVIDONE K 30 BP/USP 152In fluid, in the range of certain pressure, by changing supercritical CO2Fluid
Temperature, the S- metoprolol for making solubility low crystallizes precipitation first, and the pressure limit is 40-60MPa, the temperature range
For 35-55 DEG C, the racemization metoprolol is 1 with the weight ratio of 30 POVIDONE K 30 BP/USP 15:2-4.
2. the method for preparing S- metoprolol according to a kind of supercritical crystallization described in claim 1, it is characterised in that described excellent
Pressure is selected for 50MPa.
3. the method for preparing S- metoprolol according to a kind of supercritical crystallization described in claim 1, it is characterised in that described excellent
Temperature range is selected for 45-55 DEG C.
4. the method for preparing S- metoprolol according to a kind of supercritical crystallization described in claim 1, it is characterised in that described excellent
It is 1 with the weight ratio of 30 POVIDONE K 30 BP/USP 15 to select racemization metoprolol:3.
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| WO2010033832A2 (en) * | 2008-09-19 | 2010-03-25 | Evestra, Inc. | Estriol formulations |
| CN104274387A (en) * | 2013-07-03 | 2015-01-14 | 广东东阳光药业有限公司 | Metoprolol slow-release composition |
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