CN105085499A - Crystal separation method for nebivolol hydrochloride intermediate mixture - Google Patents
Crystal separation method for nebivolol hydrochloride intermediate mixture Download PDFInfo
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- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
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Abstract
The invention discloses a crystal separation method for a nebivolol hydrochloride intermediate mixture. The crystal separation method comprises the following steps that 1, alcohols solvent or mixed solvent of alcohol and alkane is added into the nebivolol hydrochloride intermediate mixture, the mixture is dissolved into a clear solution at room temperature, and the clear solution is cooled, crystallized and filtered to obtain an SS/RR type solid; 2, a mother solution is concentrated to be dry after being crystallized and filtered in the step 1, alcohols solvent or mixed solvent of alcohol and alkane is added again, and the mother solution is dissolved into a clear solution by raising the temperature, then cooled to be crystallized, and filtered to obtain an RS/SR type solid. SS/RR type and RS/SR type diastereomer is adopted in the nebivolol hydrochloride intermediate mixture, operation is easy, the preparation period is short, solvent consumption is reduced, the production cost and the aftertreatment cost of the solvent are reduced, industrial production can be achieved easily, and the once through yield of products obtained through separation can reach 35-70%.
Description
Technical field
The present invention relates to a kind of Crystallization Separation method of mixture, be specifically related to the Crystallization Separation method of nebivolol hydrochloric acid intermediate RS/SR type and SS/RR type mixture.
Background technology
Nebivolol hydrochloric acid is as third generation beta receptor antagonist, different from other beta receptor antagonists, there is higher selectivity, it can not cause bronchial smooth muscle and vascular smooth muscle contraction, be adapted to the treatment of light to moderate hypertensive patient, the treatment of stenocardia and congestive heart failure can also be used for simultaneously.
Formula I
Formula II
RS/SR(formula I) and SS/RR (formula II) be the important intermediates of two of synthetic hydrochloric acid nebivolol, be a pair diastereomer.At present, formula I and formula II mainly utilize column chromatography method to be separated, but the method exists following problem: 1, production efficiency is lower, and productive labor amount is larger; 2, the quantity of solvent used is large; 3, yield is lower, and production cost is higher.Not yet there is other separation method of pertinent literature and patent report formula I and formula II at present.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of Crystallization Separation method of nebivolol hydrochloric acid intermediate mixture.
For solving the problems of the technologies described above, the technical solution used in the present invention is:
The Crystallization Separation method of nebivolol hydrochloric acid intermediate mixture, comprises the following steps:
Step 1: the mixed solvent adding alcoholic solvent or alcohols and alkane in nebivolol hydrochloric acid intermediate mixture, normal-temperature dissolution becomes settled solution, is then cooled to-10 ~ 5 ° of C crystallizations, and insulation 8 ~ 20h, obtains the SS/RR type solid of formula II after filtration:
Formula II;
Step 2: the mother liquor concentrations after step 1 crystallization being filtered to dry, then adds the mixed solvent of alcoholic solvent or alcohols and alkane, and rising temperature for dissolving becomes settled solution, is then cooled to 0 ~ 15 DEG C of crystallization, insulation 2 ~ 20h, obtains the RS/SR type solid of formula I after filtration:
Formula I.
In the mixed solvent of described step 1 and step 2, the volume ratio of alcohols and alkane is 1:15 ~ 15:1.
In the mixed solvent of described step 1 and step 2, the volume ratio of alcohols and alkane is 1:5.
Numeric ratio in described step 1 between the volume (ml) of the mixed solvent of alcoholic solvent or alcohols and alkane and the quality (g) of intermediate mixture is 1:1 ~ 5:1.
Numeric ratio in described step 1 between the volume (ml) of the mixed solvent of alcoholic solvent or alcohols and alkane and the quality (g) of intermediate mixture is 2:1.
In described step 2, the quality of the mixed solvent of alcoholic solvent or alcohols and alkane is 5% ~ 25% of concentrated rear mother liquor quality.
In described step 2, the quality of the mixed solvent of alcoholic solvent or alcohols and alkane is 10% ~ 15% of concentrated rear mother liquor quality.
Described alcohols is one or more the mixing in methyl alcohol, ethanol, Virahol, propyl carbinol, the trimethyl carbinol, tertiary amyl alcohol.
Described alkane is C
5~ C
9alkane or a kind of and multiple mixture.
In described step 1, settled solution is cooled to-5 ~ 0 DEG C of crystallization.
In described step 1, crystallization soaking time is 12h.
In described step 2, settled solution is cooled to 4 ~ 10 DEG C of crystallizations.
In described step 2, crystallization soaking time is 12h.
Compared with prior art, advantage of the present invention is: the present invention adopts SS/RR type and RS/SR type diastereomer in Crystallization Separation intermediate mixture, simple to operate, preparation cycle is shorter, decrease the consumption of solvent simultaneously, reduce the aftertreatment cost of production cost and solvent, be conducive to realizing suitability for industrialized production, the once through yield being separated the product obtained can reach 35 ~ 70%.
Accompanying drawing explanation
Below in conjunction with the drawings and specific embodiments, the present invention is described in further detail.Fig. 1 is the microscope figure after the SS/RR type solid that obtains of embodiment 1 amplifies 10x10;
Fig. 2 is the microscope figure after the RS/SR type solid that obtains of embodiment 1 amplifies 40x10;
Fig. 3 is the DSC spectrogram of the SS/RR type solid that example 1 obtains;
Fig. 4 is the DSC spectrogram of the RS/SR type solid that example 1 obtains.
Embodiment:
Below in conjunction with specific embodiment, technical scheme of the present invention is further described.
Embodiment 1
The intermediate mixture of 50g nebivolol hydrochloric acid, 100mL hexanaphthene and 20mL propyl carbinol is dropped into successively in 250mL four-hole bottle, normal-temperature dissolution becomes settled solution, is then cooled to-2 ° of C crystallizations, is incubated 20 hours, 18.26gSS/RR type solid is obtained, product purity >=97% after filtration; Hexanaphthene and propyl carbinol are mixed with mixed solvent according to the volume ratio of 5:1, mother liquor evaporate to dryness after above-mentioned crystallization is filtered, add 10% mixed solvent (the mother liquor quality relative to after evaporate to dryness), rising temperature for dissolving becomes settled solution, then 8 ° of C crystallizations are cooled to, be incubated 20 hours, obtain 20.32gRS/SR type solid after filtration, product purity >=98%.
In the method, the once through yield of formula I solid and formula II solid is 70%.
The SS/RR type solid that above-mentioned embodiment 1 obtains, known through its crystal outward appearance of measurement microscope, all there is flake crystalline and practise, as shown in Figure 1; Be 45.3 ° of C by DSC test result its fusing point known, as shown in Figure 3; Meanwhile, the RS/SR type solid obtained, known through its crystal outward appearance of measurement microscope, all there is needle-like crystalline substance and practise, as shown in Figure 2; Be 34.5 ° of C by DSC test result its fusing point known, as shown in Figure 4.
Embodiment 2
The intermediate mixture of 60g nebivolol hydrochloric acid, 100mL normal heptane and 20mL propyl carbinol is dropped into successively in 250mL four-hole bottle, normal-temperature dissolution becomes settled solution, is then cooled to-2 ° of C crystallizations, is incubated 20 hours, 18.57gSS/RR type solid is obtained, product purity >=95% after filtration; Hexanaphthene and propyl carbinol are mixed with mixed solvent according to the volume ratio of 5:1, mother liquor evaporate to dryness after above-mentioned crystallization is filtered, add 10% mixed solvent (the mother liquor quality relative to after evaporate to dryness), rising temperature for dissolving becomes settled solution, then 8 ° of C crystallizations are cooled to, be incubated 20 hours, obtain 21.92gRS/SR type solid after filtration, product purity >=98%.
In the method, the once through yield of formula I solid and formula II solid is 68%.
Embodiment 3
The intermediate mixture of 50g nebivolol hydrochloric acid, 10mL hexanaphthene and 150mL propyl carbinol is dropped into successively in 250mL four-hole bottle, normal-temperature dissolution becomes settled solution, is then cooled to-5 ° of C crystallizations, is incubated 20 hours, 15.61gSS/RR type solid is obtained, product purity >=95% after filtration; Hexanaphthene and propyl carbinol are mixed with mixed solvent according to the volume ratio of 1:15, mother liquor after above-mentioned crystallization being filtered is spin-dried for, add 15% mixed solvent (the mother liquor quality relative to after being spin-dried for), rising temperature for dissolving becomes settled solution, then 5 ° of C crystallizations are cooled to, be incubated 20 hours, obtain 22.51gRS/SR type solid after filtration, product purity >=97%.
In the method, the once through yield of formula I solid and formula II solid is 70%.
Embodiment 4
The intermediate mixture of 80g nebivolol hydrochloric acid, 150mL hexanaphthene and 10mL propyl carbinol is dropped into successively in 500mL four-hole bottle, normal-temperature dissolution becomes settled solution, is then cooled to 5 ° of C crystallizations, is incubated 8 hours, 30.86gSS/RR type solid is obtained, product purity >=95% after filtration; Hexanaphthene and propyl carbinol are mixed with mixed solvent according to the volume ratio of 15:1, mother liquor after above-mentioned crystallization being filtered is spin-dried for, add 25% mixed solvent (the mother liquor quality relative to after being spin-dried for), rising temperature for dissolving becomes settled solution, then 5 ° of C crystallizations are cooled to, be incubated 2 hours, obtain 28.85gRS/SR type solid after filtration, product purity >=97%.
In the method, the once through yield of formula I solid and formula II solid is 70%.
Embodiment 5
The intermediate mixture of 30g nebivolol hydrochloric acid, 125mL hexanaphthene and 25mL propyl carbinol is dropped into successively in 250mL four-hole bottle, normal-temperature dissolution becomes settled solution, is then cooled to-10 ° of C crystallizations, is incubated 8 hours, 10.57gSS/RR type solid is obtained, product purity >=93% after filtration; Hexanaphthene and propyl carbinol are mixed with mixed solvent according to the volume ratio of 5:1, mother liquor after above-mentioned crystallization being filtered is spin-dried for, add 5% mixed solvent (the mother liquor quality relative to after being spin-dried for), rising temperature for dissolving becomes settled solution, then 10 ° of C crystallizations are cooled to, be incubated 2 hours, obtain 10.41gRS/SR type solid after filtration, product purity >=97%.
In the method, the once through yield of formula I solid and formula II solid is 69%.
Embodiment 6
The intermediate mixture of 120g nebivolol hydrochloric acid, 120mL hexanaphthene and 20mL propyl carbinol is dropped into successively in 500mL four-hole bottle, normal-temperature dissolution becomes settled solution, is then cooled to-10 ° of C crystallizations, is incubated 12 hours, 45.78gSS/RR type solid is obtained, product purity >=93% after filtration; Hexanaphthene and propyl carbinol are mixed with mixed solvent according to the volume ratio of 6:1, mother liquor after above-mentioned crystallization being filtered is spin-dried for, add 10% mixed solvent (the mother liquor quality relative to after being spin-dried for), rising temperature for dissolving becomes settled solution, then 4 ° of C crystallizations are cooled to, be incubated 12 hours, obtain 50.05gRS/SR type solid after filtration, product purity >=97%.
In the method, the once through yield of formula I solid and formula II solid is 70%.
Embodiment 7
The intermediate mixture of 60g nebivolol hydrochloric acid, 120mL hexanaphthene and 20mL propyl carbinol is dropped into successively in 250mL four-hole bottle, normal-temperature dissolution becomes settled solution, is then cooled to 0 ° of C crystallization, is incubated 20 hours, 25.56gSS/RR type solid is obtained, product purity >=95% after filtration; Hexanaphthene and propyl carbinol are mixed with mixed solvent according to the volume ratio of 6:1, mother liquor after above-mentioned crystallization being filtered is spin-dried for, add 10% mixed solvent (the mother liquor quality relative to after being spin-dried for), rising temperature for dissolving becomes settled solution, then 15 ° of C crystallizations are cooled to, be incubated 20 hours, obtain 21.18gRS/SR type solid after filtration, product purity >=97%.
In the method, the once through yield of formula I solid and formula II solid is 70%.
Embodiment 8
In 250mL four-hole bottle, drop into intermediate mixture and the 100mL tertiary amyl alcohol of 50g nebivolol hydrochloric acid successively, normal-temperature dissolution becomes settled solution, is then cooled to-2 ° of C crystallizations, is incubated 20 hours, obtains 15.19gSS/RR type solid, product purity >=97% after filtration; Mother liquor evaporate to dryness after above-mentioned crystallization being filtered, add 10% tertiary amyl alcohol (the mother liquor quality relative to after evaporate to dryness), rising temperature for dissolving becomes settled solution, is then cooled to 4 ° of C crystallizations, is incubated 20 hours, obtains 16.92gRS/SR type solid, product purity >=98% after filtration.
In the method, the once through yield of formula I solid and formula II solid is 64%.
Embodiment 9
The intermediate mixture of 55g nebivolol hydrochloric acid, 100mL normal heptane and 20mL tertiary amyl alcohol is dropped into successively in 250mL four-hole bottle, normal-temperature dissolution becomes settled solution, is then cooled to-2 ° of C crystallizations, is incubated 20 hours, 16.06gSS/RR type solid is obtained, product purity >=95% after filtration; Normal heptane and tertiary amyl alcohol are mixed with mixed solvent according to the volume ratio of 5:1, mother liquor evaporate to dryness after above-mentioned crystallization is filtered, add 10% mixed solvent (the mother liquor quality relative to after evaporate to dryness), rising temperature for dissolving becomes settled solution, then 8 ° of C crystallizations are cooled to, be incubated 20 hours, obtain 18.39gRS/SR type solid after filtration, product purity >=98%.
In the method, the once through yield of SS/RR type solid and RS/SR type solid is 63%.
Embodiment 10
The intermediate mixture of 50g nebivolol hydrochloric acid, 50mL methyl alcohol and the 50mL trimethyl carbinol is dropped into successively in 250mL four-hole bottle, normal-temperature dissolution becomes settled solution, is then cooled to-3 ° of C crystallizations, is incubated 20 hours, 20.12gSS/RR type solid is obtained, product purity >=90% after filtration; Methyl alcohol and the trimethyl carbinol are mixed with mixed solvent according to the volume ratio of 1:1, mother liquor evaporate to dryness after above-mentioned crystallization is filtered, add 5% mixed solvent (the mother liquor quality relative to after evaporate to dryness), rising temperature for dissolving becomes settled solution, then 10 ° of C crystallizations are cooled to, be incubated 20 hours, obtain 19.31gRS/SR type solid after filtration, product purity >=90%.
In the method, the once through yield of SS/RR type solid and RS/SR type solid is 42%.
Embodiment 11
The intermediate mixture of 50g nebivolol hydrochloric acid, 50mL ethanol and the 50mL trimethyl carbinol is dropped into successively in 250mL four-hole bottle, normal-temperature dissolution becomes settled solution, is then cooled to-4 ° of C crystallizations, is incubated 20 hours, 16.88gSS/RR type solid is obtained, product purity >=95% after filtration; Ethanol and the trimethyl carbinol are mixed with mixed solvent according to the volume ratio of 1:1, mother liquor evaporate to dryness after above-mentioned crystallization is filtered, add 8% mixed solvent (the mother liquor quality relative to after evaporate to dryness), rising temperature for dissolving becomes settled solution, then 8 ° of C crystallizations are cooled to, be incubated 20 hours, obtain 14.65gRS/SR type solid after filtration, product purity >=98%.
In the method, the once through yield of SS/RR type solid and RS/SR type solid is 55%.
Embodiment 12
In 250mL four-hole bottle, drop into the intermediate mixture of 50g nebivolol hydrochloric acid, 100mL Virahol successively, normal-temperature dissolution becomes settled solution, is then cooled to-2 ° of C crystallizations, is incubated 20 hours, obtains 16.38gSS/RR type solid, product purity >=90% after filtration; Mother liquor evaporate to dryness after above-mentioned crystallization being filtered, add 5% Virahol (the mother liquor quality relative to after evaporate to dryness), rising temperature for dissolving becomes settled solution, is then cooled to 8 ° of C crystallizations, is incubated 20 hours, obtains 15.73gRS/SR type solid, product purity >=90% after filtration.
In the method, the once through yield of SS/RR type solid and RS/SR type solid is 40%.
Embodiment 13
The intermediate mixture of 50g nebivolol hydrochloric acid, 50mL ethanol and 50mL normal heptane is dropped into successively in 250mL four-hole bottle, normal-temperature dissolution becomes settled solution, is then cooled to-3 ° of C crystallizations, is incubated 20 hours, 13.93gSS/RR type solid is obtained, product purity >=90% after filtration; Ethanol and normal heptane are mixed with mixed solvent according to the volume ratio of 1:1, mother liquor evaporate to dryness after above-mentioned crystallization is filtered, add 3% mixed solvent (the mother liquor quality relative to after evaporate to dryness), rising temperature for dissolving becomes settled solution, then 6 ° of C crystallizations are cooled to, be incubated 20 hours, obtain 12.03gRS/SR type solid after filtration, product purity >=90%.
In the method, the once through yield of SS/RR type solid and RS/SR type solid is 40%.
Embodiment 14
The intermediate mixture of 50g nebivolol hydrochloric acid, 10mL ethanol and 100mL hexanaphthene is dropped into successively in 250mL four-hole bottle, normal-temperature dissolution becomes settled solution, is then cooled to-2.5 ° of C crystallizations, is incubated 20 hours, 15.48gSS/RR type solid is obtained, product purity >=85% after filtration; Ethanol and hexanaphthene are mixed with mixed solvent according to the volume ratio of 1:10, mother liquor evaporate to dryness after above-mentioned crystallization is filtered, add 5% mixed solvent (the mother liquor quality relative to after evaporate to dryness), rising temperature for dissolving becomes settled solution, then 5 ° of C crystallizations are cooled to, be incubated 20 hours, obtain 15.19gRS/SR type solid after filtration, product purity >=90%.
In the method, the once through yield of SS/RR type solid and RS/SR type solid is 35%.
Embodiment 15
The intermediate mixture of 55g nebivolol hydrochloric acid, 50mL ethanol and 50mL sherwood oil is dropped into successively in 250mL four-hole bottle, normal-temperature dissolution becomes settled solution, is then cooled to-2 ° of C crystallizations, is incubated 20 hours, 14.32gSS/RR type solid is obtained, product purity >=90% after filtration; Ethanol and sherwood oil are mixed with mixed solvent according to the volume ratio of 1:1, mother liquor evaporate to dryness after above-mentioned crystallization is filtered, add 2% mixed solvent (the mother liquor quality relative to after evaporate to dryness), rising temperature for dissolving becomes settled solution, then 10 ° of C crystallizations are cooled to, be incubated 20 hours, obtain 12.05gRS/SR type solid after filtration, product purity >=90%.
In the method, the once through yield of SS/RR type solid and RS/SR type solid is 40%.
Embodiment 16
In 250mL four-hole bottle, drop into the intermediate mixture of 20g nebivolol hydrochloric acid, 80mL ethanol successively, normal-temperature dissolution becomes settled solution, is then cooled to-4 ° of C crystallizations, is incubated 20 hours, obtains 7.03gSS/RR type solid, product purity >=85% after filtration; Normal heptane and tertiary amyl alcohol are mixed with mixed solvent according to the volume ratio of 5:1, mother liquor evaporate to dryness after above-mentioned crystallization is filtered, add 10% mixed solvent (the mother liquor quality relative to after evaporate to dryness), rising temperature for dissolving becomes settled solution, then 8 ° of C crystallizations are cooled to, be incubated 20 hours, obtain 5.82gRS/SR type solid after filtration, product purity >=85%.
In the method, the once through yield of SS/RR type solid and RS/SR type solid is 35%.
The various embodiments described above are not limit practical range of the present invention, for those skilled in the art, as long as do not depart from the technology of the present invention principle, just to change or the amendment of the non-intrinsically safe that the present invention makes, are all considered as the scope of the claims in the present invention.
Claims (13)
1. the Crystallization Separation method of nebivolol hydrochloric acid intermediate mixture, is characterized in that, comprise the following steps:
Step 1: the mixed solvent adding alcoholic solvent or alcohols and alkane in nebivolol hydrochloric acid intermediate mixture, normal-temperature dissolution becomes settled solution, is then cooled to-10 ~ 5 ° of C crystallizations, and insulation 8 ~ 20h, obtains the SS/RR type solid of formula II after filtration:
Formula II;
Step 2: the mother liquor concentrations after step 1 crystallization being filtered to dry, then adds the mixed solvent of alcoholic solvent or alcohols and alkane, and rising temperature for dissolving becomes settled solution, is then cooled to 0 ~ 15 DEG C of crystallization, insulation 2 ~ 20h, obtains the RS/SR type solid of formula I after filtration:
Formula I.
2. the Crystallization Separation method of nebivolol hydrochloric acid intermediate mixture according to claim 1, is characterized in that, in the mixed solvent of described step 1 and step 2, the volume ratio of alcohols and alkane is 1:15 ~ 15:1.
3. the Crystallization Separation method of nebivolol hydrochloric acid intermediate mixture according to claim 2, is characterized in that, in the mixed solvent of described step 1 and step 2, the volume ratio of alcohols and alkane is 1:5.
4. the Crystallization Separation method of nebivolol hydrochloric acid intermediate mixture according to claim 1, it is characterized in that, the numeric ratio in described step 1 between the volume (ml) of the mixed solvent of alcoholic solvent or alcohols and alkane and the quality (g) of intermediate mixture is 1:1 ~ 5:1.
5. the Crystallization Separation method of nebivolol hydrochloric acid intermediate mixture according to claim 4, it is characterized in that, the numeric ratio in described step 1 between the volume (ml) of the mixed solvent of alcoholic solvent or alcohols and alkane and the quality (g) of intermediate mixture is 2:1.
6. the Crystallization Separation method of nebivolol hydrochloric acid intermediate mixture according to claim 1, is characterized in that, in described step 2, the quality of the mixed solvent of alcoholic solvent or alcohols and alkane is 5% ~ 25% of concentrated rear mother liquor quality.
7. the Crystallization Separation method of nebivolol hydrochloric acid intermediate mixture according to claim 6, is characterized in that, in described step 2, the quality of the mixed solvent of alcoholic solvent or alcohols and alkane is 10% ~ 15% of concentrated rear mother liquor quality.
8. the Crystallization Separation method of nebivolol hydrochloric acid intermediate mixture according to any one of claim 1 to 7, is characterized in that, described alcohols is one or more the mixing in methyl alcohol, ethanol, Virahol, propyl carbinol, the trimethyl carbinol, tertiary amyl alcohol.
9. the Crystallization Separation method of nebivolol hydrochloric acid intermediate mixture according to any one of claim 1 to 7, is characterized in that, described alkane is C
5~ C
9alkane or a kind of and multiple mixture.
10. the Crystallization Separation method of nebivolol hydrochloric acid intermediate mixture according to claim 1, is characterized in that, in described step 1, settled solution is cooled to-5 ~ 0 DEG C of crystallization.
The Crystallization Separation method of 11. nebivolol hydrochloric acid intermediate mixture according to claim 1, is characterized in that, in described step 1, crystallization soaking time is 12h.
The Crystallization Separation method of 12. nebivolol hydrochloric acid intermediate mixture according to claim 1, is characterized in that, in described step 2, settled solution is cooled to 4 ~ 10 DEG C of crystallizations.
The Crystallization Separation method of 13. nebivolol hydrochloric acid intermediate mixture according to claim 1, is characterized in that, in described step 2, crystallization soaking time is 12h.
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| WO2017024980A1 (en) * | 2015-08-07 | 2017-02-16 | 上海现代制药海门有限公司 | Crystallization separation method for nebivolol hydrochloride intermediate mixture |
| CN108929284A (en) * | 2017-05-27 | 2018-12-04 | 上海彩迩文生化科技有限公司 | The separation method of morpholine ketone isomers |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2017024980A1 (en) * | 2015-08-07 | 2017-02-16 | 上海现代制药海门有限公司 | Crystallization separation method for nebivolol hydrochloride intermediate mixture |
| CN108929284A (en) * | 2017-05-27 | 2018-12-04 | 上海彩迩文生化科技有限公司 | The separation method of morpholine ketone isomers |
| CN108929284B (en) * | 2017-05-27 | 2022-08-02 | 上海彩迩文生化科技有限公司 | Separation method of morpholone isomers |
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| CN105085499B (en) | 2018-09-25 |
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