CN105085499B - The Crystallization Separation method of nebivolol hydrochloric acid intermediate mixture - Google Patents
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- CN105085499B CN105085499B CN201510481001.7A CN201510481001A CN105085499B CN 105085499 B CN105085499 B CN 105085499B CN 201510481001 A CN201510481001 A CN 201510481001A CN 105085499 B CN105085499 B CN 105085499B
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- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D311/20—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 hydrogenated in the hetero ring
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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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Abstract
The invention discloses the Crystallization Separation methods of nebivolol hydrochloric acid intermediate mixture, include the following steps：Step 1, the mixed solvent that alcohols solvent or alcohols and alkane are added into nebivolol hydrochloric acid intermediate mixture, normal-temperature dissolution is at clear solution, and then decrease temperature crystalline, obtains SS/RR type solids after filtering；Step 1 is crystallized filtered mother liquor concentrations to doing by step 2, adds the mixed solvent of alcohols solvent or alcohols and alkane, rising temperature for dissolving is at clear solution, and then decrease temperature crystalline, obtains RS/SR type solids after filtering.The present invention uses SS/RR types and RS/SR type diastereoisomers in Crystallization Separation intermediate mixture, it is easy to operate, manufacturing cycle is shorter, reduce the consumption of solvent simultaneously, reduce the post processing cost of production cost and solvent, it is advantageously implemented industrialized production, the once through yield of isolated product can reach 35 ~ 70%.
Description
Technical field
The present invention relates to a kind of Crystallization Separation methods of mixture, and in particular to nebivolol hydrochloric acid intermediate RS/SR types
With the Crystallization Separation method of SS/RR type mixtures.
Background technology
Nebivolol hydrochloric acid is different from other beta receptor antagonists as third generation beta receptor antagonist, has higher choosing
Selecting property will not cause bronchial smooth muscle and vascular smooth muscle contraction, be adapted to the treatment of light to moderate hypertensive patient,
It may be simultaneously used for the treatment of angina pectoris and congestive heart failure.
Formulas I
Formula II
RS/SR（Formulas I）It is two important intermediates of synthetic hydrochloric acid Nebivolol with SS/RR (Formula II), is a pair of non-
Enantiomter.Currently, Formulas I and Formula II are mainly detached using column chromatography method, but there are following problems for this method：
1, production efficiency is relatively low, and productive labor amount is larger；2, used quantity of solvent is big；3, yield is relatively low, and production cost is higher etc..Mesh
It is preceding that there has been no other separation methods of pertinent literature and patent report Formulas I and Formula II.
Invention content
Technical problem to be solved by the invention is to provide a kind of Crystallization Separations of nebivolol hydrochloric acid intermediate mixture
Method.
In order to solve the above technical problems, the technical solution adopted by the present invention is：
The Crystallization Separation method of nebivolol hydrochloric acid intermediate mixture, includes the following steps：
Step 1：The mixed solvent of alcohols solvent or alcohols and alkane is added into nebivolol hydrochloric acid intermediate mixture,
Then normal-temperature dissolution is cooled to -10 ~ 5 °C of crystallizations at clear solution, keep the temperature 8 ~ 20h, and the SS/RR types that Formula II is obtained after filtering are solid
Body：
Formula II；
Step 2:Step 1 is crystallized into filtered mother liquor concentrations to dry, adds the mixed of alcohols solvent or alcohols and alkane
Then bonding solvent, rising temperature for dissolving are cooled to 0 ~ 15 DEG C of crystallization at clear solution, keep the temperature 2 ~ 20h, the RS/SR of Formulas I is obtained after filtering
Type solid：
Formulas I.
The volume ratio of the in the mixed solvent of the step 1 and step 2, alcohols and alkane is 1:15~15:1.
The volume ratio of the in the mixed solvent of the step 1 and step 2, alcohols and alkane is 1:5.
The volume of the mixed solvent of alcohols solvent or alcohols and alkane in the step 1（ml）With the matter of intermediate mixture
Amount（g）Between numeric ratio be 1:1~5:1.
The volume of the mixed solvent of alcohols solvent or alcohols and alkane in the step 1（ml）With the matter of intermediate mixture
Amount（g）Between numeric ratio be 2:1.
In the step 2 quality of the mixed solvent of alcohols solvent or alcohols and alkane be concentrate Mother liquor quality 5% ~
25%.
The quality of the mixed solvent of alcohols solvent or alcohols and alkane is concentrate Mother liquor quality 10% in the step 2
~ 15%.
The alcohols is one or more mixing in methanol, ethyl alcohol, isopropanol, n-butanol, the tert-butyl alcohol, tert-pentyl alcohol.
The alkane is C5~ C9Alkane or one kind and a variety of mixtures.
Clear solution is cooled to -5 ~ 0 DEG C of crystallization in the step 1.
It is 12h that soaking time is crystallized in the step 1.
Clear solution is cooled to 4 ~ 10 DEG C of crystallizations in the step 2.
It is 12h that soaking time is crystallized in the step 2.
Compared with prior art, it is an advantage of the invention that：The present invention uses SS/RR types in Crystallization Separation intermediate mixture
With RS/SR type diastereoisomers, easy to operate, manufacturing cycle is shorter, while reducing the consumption of solvent, reduces and is produced into
The post processing cost of this and solvent, is advantageously implemented industrialized production, and the once through yield of isolated product can reach 35 ~
70%.
Description of the drawings
Present invention is further described in detail with reference to the accompanying drawings and detailed description.Fig. 1 is that embodiment 1 obtains
SS/RR type solids amplify the microscope figure after 10x10；
Fig. 2 is the microscope figure after the RS/SR type solids amplification 40x10 that embodiment 1 obtains；
Fig. 3 is the DSC spectrograms for the SS/RR type solids that example 1 obtains；
Fig. 4 is the DSC spectrograms for the RS/SR type solids that example 1 obtains.
Specific implementation mode：
Technical scheme of the present invention is further described with reference to specific embodiment.
Embodiment 1
Put into successively in 250mL four-hole bottles the intermediate mixtures of 50g nebivolol hydrochloric acids, 100mL hexamethylenes and
Then 20mL n-butanols, normal-temperature dissolution are cooled to -2 °C of crystallizations at clear solution, keep the temperature 20 hours, 18.26 are obtained after filtering
GSS/RR type solids, product purity >=97%；Hexamethylene is with n-butanol according to 5:1 volume ratio is configured to mixed solvent, will be above-mentioned
It crystallizes filtered mother liquor to be evaporated, adds 10% mixed solvent（Relative to the mother liquor quality after being evaporated）, rising temperature for dissolving at clarify it is molten
Then liquid is cooled to 8 °C of crystallizations, keep the temperature 20 hours, 20.32gRS/SR type solids, product purity >=98% are obtained after filtering.
In this method, the once through yield of Formulas I solid and Formula II solid is 70%.
The SS/RR type solids that above-mentioned embodiment 1 obtains, by measurement microscope its crystal appearance it is found that all having piece
Shape crystalline substance is practised, as shown in Figure 1；Its fusing point known to DSC test results is 45.3 °C, as shown in Figure 3；Meanwhile obtained RS/
SR type solids, by its crystal appearance of measurement microscope it is found that all having needle-shaped brilliant habit, as shown in Figure 2；By DSC test results
Understand that its fusing point is 34.5 °C, as shown in Figure 4.
Embodiment 2
Put into intermediate mixture, the 100mL normal heptanes and 20 of 60g nebivolol hydrochloric acids successively in 250mL four-hole bottles
Then mL n-butanols, normal-temperature dissolution are cooled to -2 °C of crystallizations at clear solution, keep the temperature 20 hours, 18.57 are obtained after filtering
GSS/RR type solids, product purity >=95%；Hexamethylene is with n-butanol according to 5:1 volume ratio is configured to mixed solvent, will be above-mentioned
It crystallizes filtered mother liquor to be evaporated, adds 10% mixed solvent（Relative to the mother liquor quality after being evaporated）, rising temperature for dissolving at clarify it is molten
Then liquid is cooled to 8 °C of crystallizations, keep the temperature 20 hours, 21.92gRS/SR type solids, product purity >=98% are obtained after filtering.
In this method, the once through yield of Formulas I solid and Formula II solid is 68%.
Embodiment 3
Put into successively in 250mL four-hole bottles the intermediate mixtures of 50g nebivolol hydrochloric acids, 10mL hexamethylenes and
Then 150mL n-butanols, normal-temperature dissolution are cooled to -5 °C of crystallizations at clear solution, keep the temperature 20 hours, 15.61 are obtained after filtering
GSS/RR type solids, product purity >=95%；Hexamethylene is with n-butanol according to 1:15 volume ratio is configured to mixed solvent, will be upper
It states the filtered mother liquor of crystallization to be spin-dried for, adds 15% mixed solvent（Relative to the mother liquor quality after being spin-dried for）, rising temperature for dissolving is at clarification
Then solution is cooled to 5 °C of crystallizations, keep the temperature 20 hours, 22.51gRS/SR type solids, product purity >=97% are obtained after filtering.
In this method, the once through yield of Formulas I solid and Formula II solid is 70%.
Embodiment 4
Put into successively in 500mL four-hole bottles the intermediate mixtures of 80g nebivolol hydrochloric acids, 150mL hexamethylenes and
Then 10mL n-butanols, normal-temperature dissolution are cooled to 5 °C of crystallizations at clear solution, keep the temperature 8 hours, 30.86 are obtained after filtering
GSS/RR type solids, product purity >=95%；Hexamethylene is with n-butanol according to 15:1 volume ratio is configured to mixed solvent, will be upper
It states the filtered mother liquor of crystallization to be spin-dried for, adds 25% mixed solvent（Relative to the mother liquor quality after being spin-dried for）, rising temperature for dissolving is at clarification
Then solution is cooled to 5 °C of crystallizations, keep the temperature 2 hours, 28.85gRS/SR type solids, product purity >=97% are obtained after filtering.
In this method, the once through yield of Formulas I solid and Formula II solid is 70%.
Embodiment 5
Put into successively in 250mL four-hole bottles the intermediate mixtures of 30g nebivolol hydrochloric acids, 125mL hexamethylenes and
Then 25mL n-butanols, normal-temperature dissolution are cooled to -10 °C of crystallizations at clear solution, keep the temperature 8 hours, 10.57 are obtained after filtering
GSS/RR type solids, product purity >=93%；Hexamethylene is with n-butanol according to 5:1 volume ratio is configured to mixed solvent, will be above-mentioned
It crystallizes filtered mother liquor to be spin-dried for, adds 5% mixed solvent（Relative to the mother liquor quality after being spin-dried for）, rising temperature for dissolving at clarify it is molten
Then liquid is cooled to 10 °C of crystallizations, keep the temperature 2 hours, 10.41gRS/SR type solids, product purity >=97% are obtained after filtering.
In this method, the once through yield of Formulas I solid and Formula II solid is 69%.
Embodiment 6
Put into successively in 500mL four-hole bottles the intermediate mixtures of 120g nebivolol hydrochloric acids, 120mL hexamethylenes and
Then 20mL n-butanols, normal-temperature dissolution are cooled to -10 °C of crystallizations at clear solution, keep the temperature 12 hours, obtained after filtering
45.78gSS/RR type solids, product purity >=93%；Hexamethylene is with n-butanol according to 6:1 volume ratio is configured to mixed solvent,
The filtered mother liquor of above-mentioned crystallization is spin-dried for, 10% mixed solvent is added（Relative to the mother liquor quality after being spin-dried for）, rising temperature for dissolving at
Clear solution, is then cooled to 4 °C of crystallizations, keeps the temperature 12 hours, obtains 50.05gRS/SR type solids after filtering, and product purity >=
97%。
In this method, the once through yield of Formulas I solid and Formula II solid is 70%.
Embodiment 7
Put into successively in 250mL four-hole bottles the intermediate mixtures of 60g nebivolol hydrochloric acids, 120mL hexamethylenes and
Then 20mL n-butanols, normal-temperature dissolution are cooled to 0 °C of crystallization at clear solution, keep the temperature 20 hours, 25.56 are obtained after filtering
GSS/RR type solids, product purity >=95%；Hexamethylene is with n-butanol according to 6:1 volume ratio is configured to mixed solvent, will be above-mentioned
It crystallizes filtered mother liquor to be spin-dried for, adds 10% mixed solvent（Relative to the mother liquor quality after being spin-dried for）, rising temperature for dissolving at clarify it is molten
Then liquid is cooled to 15 °C of crystallizations, keep the temperature 20 hours, 21.18gRS/SR type solids, product purity >=97% are obtained after filtering.
In this method, the once through yield of Formulas I solid and Formula II solid is 70%.
Embodiment 8
Put into the intermediate mixture and 100mL tert-pentyl alcohols of 50g nebivolol hydrochloric acids successively in 250mL four-hole bottles, often
Temperature is dissolved into clear solution, is then cooled to -2 °C of crystallizations, keeps the temperature 20 hours, 15.19gSS/RR type solids are obtained after filtering, produces
Product purity >=97%；The filtered mother liquor of above-mentioned crystallization is evaporated, 10% tert-pentyl alcohol is added（Relative to the mother liquor quality after being evaporated）,
Then rising temperature for dissolving is cooled to 4 °C of crystallizations at clear solution, keep the temperature 20 hours, 16.92gRS/SR type solids are obtained after filtering,
Product purity >=98%.
In this method, the once through yield of Formulas I solid and Formula II solid is 64%.
Embodiment 9
Put into successively in 250mL four-hole bottles the intermediate mixtures of 55g nebivolol hydrochloric acids, 100mL normal heptanes and
Then 20mL tert-pentyl alcohols, normal-temperature dissolution are cooled to -2 °C of crystallizations at clear solution, keep the temperature 20 hours, 16.06 are obtained after filtering
GSS/RR type solids, product purity >=95%；Normal heptane is with tert-pentyl alcohol according to 5:1 volume ratio is configured to mixed solvent, will be above-mentioned
It crystallizes filtered mother liquor to be evaporated, adds 10% mixed solvent（Relative to the mother liquor quality after being evaporated）, rising temperature for dissolving at clarify it is molten
Then liquid is cooled to 8 °C of crystallizations, keep the temperature 20 hours, 18.39gRS/SR type solids, product purity >=98% are obtained after filtering.
In this method, the once through yield of SS/RR types solid and RS/SR type solids is 63%.
Embodiment 10
Put into intermediate mixture, 50mL methanol and uncle 50mL of 50g nebivolol hydrochloric acids successively in 250mL four-hole bottles
Then butanol, normal-temperature dissolution are cooled to -3 °C of crystallizations at clear solution, keep the temperature 20 hours, 20.12 gSS/RR are obtained after filtering
Type solid, product purity >=90%；Methanol is with the tert-butyl alcohol according to 1:1 volume ratio is configured to mixed solvent, and above-mentioned crystallization is filtered
Mother liquor afterwards is evaporated, and adds 5% mixed solvent（Relative to the mother liquor quality after being evaporated）, then rising temperature for dissolving drops at clear solution
Temperature keeps the temperature 20 hours, 19.31gRS/SR type solids, product purity >=90% is obtained after filtering to 10 °C of crystallizations.
In this method, the once through yield of SS/RR types solid and RS/SR type solids is 42%.
Embodiment 11
Put into intermediate mixture, 50mL ethyl alcohol and uncle 50mL of 50g nebivolol hydrochloric acids successively in 250mL four-hole bottles
Then butanol, normal-temperature dissolution are cooled to -4 °C of crystallizations at clear solution, keep the temperature 20 hours, 16.88 gSS/RR are obtained after filtering
Type solid, product purity >=95%；Ethyl alcohol is with the tert-butyl alcohol according to 1:1 volume ratio is configured to mixed solvent, and above-mentioned crystallization is filtered
Mother liquor afterwards is evaporated, and adds 8% mixed solvent（Relative to the mother liquor quality after being evaporated）, then rising temperature for dissolving drops at clear solution
Temperature keeps the temperature 20 hours, 14.65gRS/SR type solids, product purity >=98% is obtained after filtering to 8 °C of crystallizations.
In this method, the once through yield of SS/RR types solid and RS/SR type solids is 55%.
Embodiment 12
Put into intermediate mixture, the 100mL isopropanols of 50g nebivolol hydrochloric acids, room temperature successively in 250mL four-hole bottles
It is dissolved into clear solution, is then cooled to -2 °C of crystallizations, 20 hours is kept the temperature, 16.38 gSS/RR type solids is obtained after filtering, is produced
Product purity >=90%；The filtered mother liquor of above-mentioned crystallization is evaporated, 5% isopropanol is added（Relative to the mother liquor quality after being evaporated）,
Then rising temperature for dissolving is cooled to 8 °C of crystallizations at clear solution, keep the temperature 20 hours, 15.73gRS/SR type solids are obtained after filtering,
Product purity >=90%.
In this method, the once through yield of SS/RR types solid and RS/SR type solids is 40%.
Embodiment 13
Put into intermediate mixture, 50mL ethyl alcohol and the 50mL of 50g nebivolol hydrochloric acids successively in 250mL four-hole bottles just
Then heptane, normal-temperature dissolution are cooled to -3 °C of crystallizations at clear solution, keep the temperature 20 hours, 13.93 gSS/RR are obtained after filtering
Type solid, product purity >=90%；Ethyl alcohol is with normal heptane according to 1:1 volume ratio is configured to mixed solvent, and above-mentioned crystallization is filtered
Mother liquor afterwards is evaporated, and adds 3% mixed solvent（Relative to the mother liquor quality after being evaporated）, then rising temperature for dissolving drops at clear solution
Temperature keeps the temperature 20 hours, 12.03gRS/SR type solids, product purity >=90% is obtained after filtering to 6 °C of crystallizations.
In this method, the once through yield of SS/RR types solid and RS/SR type solids is 40%.
Embodiment 14
Put into intermediate mixture, 10mL ethyl alcohol and the 100mL of 50g nebivolol hydrochloric acids successively in 250mL four-hole bottles
Then hexamethylene, normal-temperature dissolution are cooled to -2.5 °C of crystallizations at clear solution, keep the temperature 20 hours, 15.48 are obtained after filtering
GSS/RR type solids, product purity >=85%；Ethyl alcohol is with hexamethylene according to 1:10 volume ratio is configured to mixed solvent, will be above-mentioned
It crystallizes filtered mother liquor to be evaporated, adds 5% mixed solvent（Relative to the mother liquor quality after being evaporated）, rising temperature for dissolving at clarify it is molten
Then liquid is cooled to 5 °C of crystallizations, keep the temperature 20 hours, 15.19gRS/SR type solids, product purity >=90% are obtained after filtering.
In this method, the once through yield of SS/RR types solid and RS/SR type solids is 35%.
Embodiment 15
Put into intermediate mixture, 50mL ethyl alcohol and the 50mL stones of 55g nebivolol hydrochloric acids successively in 250mL four-hole bottles
Then oily ether, normal-temperature dissolution are cooled to -2 °C of crystallizations at clear solution, keep the temperature 20 hours, 14.32 gSS/RR are obtained after filtering
Type solid, product purity >=90%；Ethyl alcohol is with petroleum ether according to 1:1 volume ratio is configured to mixed solvent, and above-mentioned crystallization is filtered
Mother liquor afterwards is evaporated, and adds 2% mixed solvent（Relative to the mother liquor quality after being evaporated）, then rising temperature for dissolving drops at clear solution
Temperature keeps the temperature 20 hours, 12.05gRS/SR type solids, product purity >=90% is obtained after filtering to 10 °C of crystallizations.
In this method, the once through yield of SS/RR types solid and RS/SR type solids is 40%.
Embodiment 16
Put into intermediate mixture, the 80mL ethyl alcohol of 20g nebivolol hydrochloric acids successively in 250mL four-hole bottles, room temperature is molten
Then solution is cooled to -4 °C of crystallizations at clear solution, keep the temperature 20 hours, 7.03g SS/RR type solids are obtained after filtering, product is pure
Degree >=85%；Normal heptane is with tert-pentyl alcohol according to 5:1 volume ratio is configured to mixed solvent, and the filtered mother liquor of above-mentioned crystallization is steamed
It is dry, add 10% mixed solvent（Relative to the mother liquor quality after being evaporated）, then rising temperature for dissolving is cooled to 8 °C at clear solution
Crystallization keeps the temperature 20 hours, 5.82gRS/SR type solids, product purity >=85% is obtained after filtering.
In this method, the once through yield of SS/RR types solid and RS/SR type solids is 35%.
The various embodiments described above are not the practical range for being the restriction present invention, for those skilled in the art, as long as not taking off
From the technology of the present invention principle, the change or modification of the non-intrinsically safe only made to the present invention are accordingly to be regarded as right of the present invention and want
The range asked.
Claims (11)
1. the Crystallization Separation method of nebivolol hydrochloric acid intermediate mixture, which is characterized in that include the following steps：
Step 1：The mixed solvent of alcohols solvent or alcohols and alkane, room temperature are added into nebivolol hydrochloric acid intermediate mixture
It is dissolved into clear solution, is then cooled to -10 ~ 5 °C of crystallizations, 8 ~ 20h is kept the temperature, the SS/RR type solids of Formula II is obtained after filtering：
Formula II；
Step 2:Step 1 is crystallized into filtered mother liquor concentrations to doing, the mixing for adding alcohols solvent or alcohols and alkane is molten
Then agent, rising temperature for dissolving are cooled to 0 ~ 15 DEG C of crystallization at clear solution, keep the temperature 2 ~ 20h, the RS/SR types that Formulas I is obtained after filtering are solid
Body：
Formulas I；
In the step 1 between the volume and the quality of intermediate mixture of the mixed solvent of alcohols solvent or alcohols and alkane
Numeric ratio is 1:1~5:1, wherein the unit of volume is ml, and the unit of quality is g；
In the step 2 quality of the mixed solvent of alcohols solvent or alcohols and alkane be concentrate Mother liquor quality 5% ~
25%.
2. the Crystallization Separation method of nebivolol hydrochloric acid intermediate mixture according to claim 1, which is characterized in that institute
State the in the mixed solvent of 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, which is characterized in that institute
State the in the mixed solvent of 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, which is characterized in that institute
State the numeric ratio between the volume and the quality of intermediate mixture of the mixed solvent of alcohols solvent or alcohols and alkane in step 1
It is 2:1, wherein the unit of volume is ml, and the unit of quality is g.
5. the Crystallization Separation method of nebivolol hydrochloric acid intermediate mixture according to claim 1, which is characterized in that institute
The quality for stating the mixed solvent of alcohols solvent or alcohols and alkane in step 2 is concentrate Mother liquor quality 10% ~ 15%.
6. the Crystallization Separation method of nebivolol hydrochloric acid intermediate mixture according to any one of claim 1 to 5,
It is characterized in that, the alcohols is one or more mixing in methanol, ethyl alcohol, isopropanol, n-butanol, the tert-butyl alcohol, tert-pentyl alcohol.
7. the Crystallization Separation method of nebivolol hydrochloric acid intermediate mixture according to any one of claim 1 to 5,
It is characterized in that, the alkane is one or more mixtures in C5 ~ C9 alkane.
8. the Crystallization Separation method of nebivolol hydrochloric acid intermediate mixture according to claim 1, which is characterized in that institute
It states clear solution in step 1 and is cooled to -5 ~ 0 DEG C of crystallization.
9. the Crystallization Separation method of nebivolol hydrochloric acid intermediate mixture according to claim 1, which is characterized in that institute
It is 12h to state and crystallize soaking time in step 1.
10. the Crystallization Separation method of nebivolol hydrochloric acid intermediate mixture according to claim 1, which is characterized in that
Clear solution is cooled to 4 ~ 10 DEG C of crystallizations in the step 2.
11. the Crystallization Separation method of nebivolol hydrochloric acid intermediate mixture according to claim 1, which is characterized in that
It is 12h that soaking time is crystallized in the step 2.
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| EP1803716B1 (en) * | 2005-12-28 | 2012-07-25 | Acino Pharma AG | A process for preparation of racemic nebivolol |
| CN103910704B (en) * | 2013-01-05 | 2016-06-22 | 重庆福安药业(集团)股份有限公司 | A kind of Preparation Method And Their Intermediate compound of nebivolol |
| CN105085499B (en) * | 2015-08-07 | 2018-09-25 | 上海现代制药海门有限公司 | The Crystallization Separation method of nebivolol hydrochloric acid intermediate mixture |
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2015
- 2015-08-07 CN CN201510481001.7A patent/CN105085499B/en active Active
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2016
- 2016-08-04 WO PCT/CN2016/093201 patent/WO2017024980A1/en active Application Filing
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| WO2017024980A1 (en) | 2017-02-16 |
| CN105085499A (en) | 2015-11-25 |
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