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WO2007083318A1 - Process for isolation of desired isomers of nebivolol intermediates - Google Patents

Process for isolation of desired isomers of nebivolol intermediates Download PDF

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Publication number
WO2007083318A1
WO2007083318A1 PCT/IN2006/000015 IN2006000015W WO2007083318A1 WO 2007083318 A1 WO2007083318 A1 WO 2007083318A1 IN 2006000015 W IN2006000015 W IN 2006000015W WO 2007083318 A1 WO2007083318 A1 WO 2007083318A1
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Prior art keywords
formula
compound
racemic
mixture
solvent
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PCT/IN2006/000015
Other languages
French (fr)
Inventor
Bandi Parthasaradhi Reddy
Kura Rathnakar Reddy
Rapolu Raji Reddy
Dasari Muralidhara Reddy
Itiyala Srinivas Reddy
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Hetero Drugs Limited
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Priority to PCT/IN2006/000015 priority Critical patent/WO2007083318A1/en
Priority to US11/718,593 priority patent/US7858812B2/en
Priority to EP06711356A priority patent/EP1973895A1/en
Publication of WO2007083318A1 publication Critical patent/WO2007083318A1/en

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    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4

Definitions

  • the present invention relates to a simple and commercially viable process for separation of desired isomers of nebivolol intermediates from a mixture containing undesired isomers of nebivolol intermediates.
  • EP Patent No. 0145067 disclosed 2,2'-iminobisethanol derivatives.
  • the compounds are antihypertensive agents.
  • nebivolol is racemic mixture of RSSS and its enantiomer of ⁇ , ⁇ '-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro- 2H-1-benzopyran-2-methanol] and the structures of these isomers are shown below with stereochemical notation at each chiral centre.
  • P' is a protecting group
  • racemic compounds of formula A are key intermediates having desired stereo chemistry in the preparation of nebivolol. These intermediates are subjected to deprotection to obtain nebivolol.
  • the process of the present invention enables us to isolate desired isomers of nebivolol intermediates from the mixture containing undesired and desired isomers just by suspending or dissolving the mixture containing undesired and desired isomers in a suitable solvent and crystallizing without the need for the expensive chromatographic separations.
  • the present invention also avoids the lengthy process for this separation of converting the mixture of isomers into their hydrochloride salts, fractional crystallization of desired isomers and converting back into desired isomers in free base form.
  • the process of the invention may be repeated any number of times very easily just by suspending or dissolving in a suitable solvent and isolating until we get desired isomeric purity.
  • the present invention provides extremely simple and commercially viable process for isolating desired racemic compound from mixture of isomers also containing undesired isomers.
  • P is -allyl or wherein X each independently is halo, nitro or C 1 -C 3 alkyl and n is 0 - 5; from the mixture of racemic compounds of formula II:
  • the said process comprises suspending or dissolving the mixture of a pair of racemic compounds represented by formula Il in an ether solvent and then isolating crystals to obtain the racemic compound of formula I.
  • Preferable ether solvent used is diisopropyl ether or diethyl ether and more preferable being diisopropyl ether.
  • the mixture of a pair of racemic compounds represented by formula Il is dissolved in the ether solvent, preferably at 30 0 C to reflux temperature of the solvent used, more preferably at 60 0 C to reflux temperature of the solvent used and still more preferably at reflux temperature of the solvent used, and precipitated the compound of formula I.
  • the precipitation of the racemic compound of formula I may be carried out by cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution or a combination thereof.
  • the precipitation of the racemic compound of formula I is carried out by cooling.
  • the more preferred compound of formula I prepared according to the present invention is the compound of formula Ia:
  • the mixture of a pair of racemic compounds represented by formula Il is dissolved in diisopropyl ether at 30 0 C to reflux temperature and cooled to obtain desired racemic compound of formula I as crystalline product.
  • a suspension of the mixture of a pair of racemic compounds represented by formula Il in diisopropyl ether is stirred for at least 30 minutes at 30 0 C to reflux temperature of the solvent used, more preferably for 1 hour to 4 hours at below 60 0 C and still more preferably for 1 hour to 3 hours at 10 - 40 0 C and isolating the desired racemic compound of formula I by known methods such as filtration or centrifugation.
  • Stereochemical description describing the configurations at chiral centers used here is in the order (1,2,3 and 4) mentioned in the structure.
  • R*S*S*S* shown in the formula I refers to R* configuration at the carbon '1 1 , S* configuration at 2 and so on and
  • R*S*S*S* has the meaning shown below:
  • the process can be repeated until the separation of the desired racemic compound is obtained in desired isomeric purity.
  • racemic compounds of formula I are intermediates for preparing nebivolol by removing the protecting group 1 P' by the processes known in the art and optionally converting nebivolol into a pharmaceutically acceptable salt.
  • the desired racemic compound of formula I may further be debenzylated by known methods to obtain nebivolol of formula III:
  • (+)-[1S*(R*)]-6-fluoro- 3,4-dihydro- ⁇ -[[(phenylmethyl)amino]methyl]-2H-1-benzopyran-2-methanol (69 gm, obtained in example 1) was added and stirred for 10 minutes.
  • reaction mass was cooled to 40 - 50 0 C, distilled off the solvent completely under reduced pressure until the mass temperature reaches 50 - 55 0 C and then co-distilled twice with diisopropyl ether (each time 65 ml) under reduced pressure until the mass temperature reaches 50 - 55 0 C.
  • diisopropyl ether (580 ml) was added, heated to reflux and refluxed for 1 hour 30 minutes.
  • the reaction mass was cooled to 25 - 35 0 C, stirred for 4 hours, filtered the material and washed with diisopropyl ether (85 ml). The resulting wet cake was added to diisopropyl ether (420 ml), heated to reflux and then stirred for 1 hour.
  • Example 4 The mixture of nebivolol (48.5 gm) and methanol (950 ml) was refluxed for

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyrane Compounds (AREA)

Abstract

The present invention relates to a simple and commercially viable process for separation of desired isomers of nebivolol intermediates from a mixture containing undesired isomers of nebivolol intermediates. Thus, (+)-[2R*[1S*,5S*(S*)]]+[2R*[1S*,5R*(R*)]]-α,α'- [phenylmethyliminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] is dissolved in diisopropyl ether at reflux temperature and cooled to below 30°C to obtain the desired(+)-[2R*[1S*,5S*(S*)]]-alfa,alfa'-[phenylmethyliminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H- 1-benzopyran-2-methanol].

Description

PROCESS FOR ISOLATION OF DESIRED ISOMERS OF NEB)VOLOL
INTERMEDIATES
FIELD OF THE INVENTION
The present invention relates to a simple and commercially viable process for separation of desired isomers of nebivolol intermediates from a mixture containing undesired isomers of nebivolol intermediates.
BACKGROUND OF THE INVENTION
EP Patent No. 0145067 disclosed 2,2'-iminobisethanol derivatives. The compounds are antihypertensive agents. Among them nebivolol is racemic mixture of RSSS and its enantiomer of α,α'-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro- 2H-1-benzopyran-2-methanol] and the structures of these isomers are shown below with stereochemical notation at each chiral centre.
Figure imgf000002_0001
Processes for preparations of nebivolol and related compounds were described in EP Patent No. 0145067 and EP Patent No. 0334429. According to the processes described in these patents, chromatographic separations are required for the separation of diastereomeric pairs at the intermediate stage or at the final stage. The chromatographic separations involve additional operations, additional expensive setup adding to the cost of production. US Patent No. 5,759,580 described the separation of (±)-[2R*[1S*, 5S*(S*)]]-α,α'- [lminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] hydrochloride (nebivolol hydrochloride) from the mixture of (±)-[2R*[1S*, 5S*(S*)]]+[2R*[1S*,5R*(R*)]]-α,α'-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro- 2H-1-benzopyran-2-methanol]. The yield of the nebivolol hydrochloride is extremely low (6.6%). The PCT patent Application No. PCT/IN2004/000241 disclosed the isolation of racemic compound of formula A:
Figure imgf000003_0001
from the mixture of racemic compounds of formula B:
Figure imgf000003_0002
wherein P' is a protecting group; by converting the mixture of isomers into their hydrochloric acid salts, subjecting fractional crystallization of desired isomers as hydrochloride salts and neutralizing to obtain the corresponding free bases of desired isomers.
The racemic compounds of formula A are key intermediates having desired stereo chemistry in the preparation of nebivolol. These intermediates are subjected to deprotection to obtain nebivolol.
We have found that a process for separating the desired racemic compound of formula A from the mixture of a pair of racemic compounds represented by formula B by suspending or dissolving the mixture of a pair of racemic compounds of formula B in a suitable solvent and then isolating crystals to obtain the racemic compound of formula A.
The process of the present invention enables us to isolate desired isomers of nebivolol intermediates from the mixture containing undesired and desired isomers just by suspending or dissolving the mixture containing undesired and desired isomers in a suitable solvent and crystallizing without the need for the expensive chromatographic separations. The present invention also avoids the lengthy process for this separation of converting the mixture of isomers into their hydrochloride salts, fractional crystallization of desired isomers and converting back into desired isomers in free base form. Moreover, the process of the invention may be repeated any number of times very easily just by suspending or dissolving in a suitable solvent and isolating until we get desired isomeric purity.
Thus, the present invention provides extremely simple and commercially viable process for isolating desired racemic compound from mixture of isomers also containing undesired isomers.
DETAILED DESCRIPTION OF THE INVENTION
The process for isolating racemic compound of formula I:
Figure imgf000004_0001
wherein
P is -allyl or
Figure imgf000004_0002
wherein X each independently is halo, nitro or C1-C3 alkyl and n is 0 - 5; from the mixture of racemic compounds of formula II:
Figure imgf000004_0003
wherein P is as defined in formula I; the said process comprises suspending or dissolving the mixture of a pair of racemic compounds represented by formula Il in an ether solvent and then isolating crystals to obtain the racemic compound of formula I.
Preferable ether solvent used is diisopropyl ether or diethyl ether and more preferable being diisopropyl ether.
The mixture of a pair of racemic compounds represented by formula Il is dissolved in the ether solvent, preferably at 300C to reflux temperature of the solvent used, more preferably at 600C to reflux temperature of the solvent used and still more preferably at reflux temperature of the solvent used, and precipitated the compound of formula I. The precipitation of the racemic compound of formula I may be carried out by cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution or a combination thereof. Preferably the precipitation of the racemic compound of formula I is carried out by cooling.
The more preferred compound of formula I prepared according to the present invention is the compound of formula Ia:
Figure imgf000005_0001
A preferable process of the invention is described below:
The mixture of a pair of racemic compounds represented by formula Il is dissolved in diisopropyl ether at 300C to reflux temperature and cooled to obtain desired racemic compound of formula I as crystalline product.
A more preferable process of the invention is described below:
The mixture of a pair of racemic compounds represented by formula II, wherein P is benzyl, is dissolved in diisopropyl ether at reflux temperature and cooled to below 300C, more preferably between 15 - 300C to obtain the desired racemic compound of formula I, wherein P is benzyl.
As another preferable process, a suspension of the mixture of a pair of racemic compounds represented by formula Il in diisopropyl ether is stirred for at least 30 minutes at 300C to reflux temperature of the solvent used, more preferably for 1 hour to 4 hours at below 600C and still more preferably for 1 hour to 3 hours at 10 - 400C and isolating the desired racemic compound of formula I by known methods such as filtration or centrifugation.
Stereochemical description describing the configurations at chiral centers used here is in the order (1,2,3 and 4) mentioned in the structure. Thus, for example, the stereochemical description R*S*S*S* shown in the formula I refers to R* configuration at the carbon '11, S* configuration at 2 and so on and
R*S*S*S* has the meaning shown below:
Figure imgf000006_0001
The stereochemical description R*S*R*R* used in the formula Il has the meaning shown below:
Figure imgf000006_0002
The process can be repeated until the separation of the desired racemic compound is obtained in desired isomeric purity.
The racemic compounds of formula I are intermediates for preparing nebivolol by removing the protecting group 1P' by the processes known in the art and optionally converting nebivolol into a pharmaceutically acceptable salt.
The desired racemic compound of formula I may further be debenzylated by known methods to obtain nebivolol of formula III:
Figure imgf000006_0003
The invention will now be further described by the following examples, which are illustrative rather than limiting.
Example 1
The solution of benzyl amine (120 gm) in ethanol (730 ml) was added to a mixture of (+)-[1S*(R*)]-6-fluoro-3,4-dihydro-2~oxiranyl-2H-1-benzopyran (73 gm) and ethanol (730 ml) drop wise at reflux temperature for 15 minutes. The temperature of the reaction mixture was raised to reflux and maintained for 5 hours at reflux temperature. Then ethanol was distilled off under vacuum at 500C. To this residue diisopropyl ether (400 ml) was added and stirred for 30 minutes at 0 - 50C. Then the separated solid was filtered, washed with chilled diisopropylether and dried to give 69 gm of (+)-[1S*(R*)]-6-fluoro-3,4-dihydro-α- [[(phenylmethyl)amino]methyl]-2H-1 -benzopyran-2-methanol (HPLC purity: 97%).
Example 2 The mixture of (+)-[1 S*(S*)]-6-f luoro-3,4-dihydro-2-oxiranyl-2H-1 -benzopyran
(65 gm) and ethanol (1400 ml) was stirred for 10 minutes, (+)-[1S*(R*)]-6-fluoro- 3,4-dihydro-α-[[(phenylmethyl)amino]methyl]-2H-1-benzopyran-2-methanol (69 gm, obtained in example 1) was added and stirred for 10 minutes. The contents were heated to reflux and stirred for 26 hours at the same temperature to obtain (+)-[2R*[1S*,5S*(S*)]]+[2R*[1S*,5R*(R*)]]-α,α'-[phenylmethyliminobis(methyl ene)]bis[6-fluoro-3,4-dihydro-2H-1 -benzopyran-2-methanol] ((+)-[2R*[1S*,5S* (S*)]] to (+)-[2R*[1S*,5R*(R*)]] ratio was 0.83 : 1.0). Then the reaction mass was cooled to 40 - 500C, distilled off the solvent completely under reduced pressure until the mass temperature reaches 50 - 550C and then co-distilled twice with diisopropyl ether (each time 65 ml) under reduced pressure until the mass temperature reaches 50 - 550C. To the residue, diisopropyl ether (580 ml) was added, heated to reflux and refluxed for 1 hour 30 minutes. The reaction mass was cooled to 25 - 350C, stirred for 4 hours, filtered the material and washed with diisopropyl ether (85 ml). The resulting wet cake was added to diisopropyl ether (420 ml), heated to reflux and then stirred for 1 hour. The resulting mass was cooled to 25 - 350C and stirred for 4 hours at 25 - 350C. Filtered the solid, washed with 40 ml of diisopropyl ether and dried at 45 - 550C to give 48 gm of (+)-[2R*[1S*,5S*(S*)]]-α,α'-[phenylmethyliminobis(methylene)]bis[6-fluoro-3,4- dihydro-2H-1 -benzopyran-2-methanol] (HPLC purity 99.1%; (±)-[2R*[1S*, 5S*(S*)]] to (±)-[2R*[1 S*,5R*(R*)]] ratio is 98 : 1 ).
Example 3
The mixture of (+)-[2R*[1S*,5S*(S*)]]-α,αl-[phenylmethyliminobis (methylene)]bis[6-fluoro-3,4-dihydro-2H-1 -benzopyran-2-methanol] (48 gm), acetic acid (480 gm) and 5% palladium on charcoal (19 gm) was taken into a hydrogenation flask and subjected to hydrogenation under a hydrogen gas pressure of 1.5 kg/cm2 for 3 hours at 25 - 400C. Then the reaction mixture was filtered on hi-flo and washed with acetic acid (55 gm). The solvent was distilled off completely under reduced pressure and then co-distilled twice with ethyl acetate (each time 60 ml). To the resulting mass, ethyl acetate (480 ml) was added, refluxed for 1 hour and then cooled to 25 - 350C. The reaction mass was stirred for 4 hours, again cooled to 0 - 100C and stirred for 1 hour 30 minutes. Filtered the material and washed with ethyl acetate (60 ml). The resulting wet cake was stirred with methanol (850 ml) and 25% monomethyl amine (60 ml) for 1 hour at 25 - 350C, cooled to 0 - 100C and then stirred for 1 hour at 0 - 100C. Filtered the material and washed with methanol (60 ml) to give 40.5 gm of (+)- [2R*[1S*,5S*(S*)]]-α,α'-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1- benzopyran-2-methanol] (Nebivolol) (HPLC purity: 99.2%).
Example 4 The mixture of nebivolol (48.5 gm) and methanol (950 ml) was refluxed for
30 minutes and then subjected to carbon treatment. The resulting mass was cooled to 0 - 100C, hydrochloric acid (6.5 ml) was slowly added during 30 minutes and then stirred for 4 hours at 0 - 100C. Filtered the material, washed with 50 ml of methanol and dried at 50 - 600C to give 27.5 gm of Nebivolol hydrochloride salt (HPLC purity: 99.5%).

Claims

We claim:
1. A process for isolating racemic compound of formula I:
Figure imgf000009_0001
wherein
Figure imgf000009_0002
wherein X each independently is halo, nitro or C1-C3 alkyl and n is 0 - 5; from the mixture of racemic compounds of formula II:
Figure imgf000009_0003
wherein P is as defined in formula I; the said process comprises suspending or dissolving the mixture of a pair of racemic compounds represented by formula Il in an ether solvent and then isolating crystals to obtain the racemic compound of formula I.
2. The process as claimed in claim 1 , wherein ether solvent used is diisopropyl ether or diethyl ether.
3. The process as claimed in claim 2, wherein ether solvent is diisopropyl ether.
4. The process as claimed in claim 1, wherein the mixture of a pair of racemic compounds represented by formula Il is dissolved in the ether solvent at 300C to reflux temperature of the solvent used and precipitated the compound of formula I.
5. The process as claimed in claim 4, wherein the compound of formula Il is dissolved in the ether solvent at 600C to reflux temperature of the solvent used.
6. The process as claimed in claim 4, wherein the precipitation of the racemic compound of formula I is carried out by cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution or a combination thereof.
7. The process as claimed in claim 6, wherein the precipitation is carried out by cooling.
8. The process as claimed in claim 1 , wherein the mixture of a pair of racemic compounds represented by formula Il is dissolved in diisopropyl ether at reflux temperature of the solvent used and precipitated the compound of formula I by cooling to below 300C.
9. The process as claimed in claim 8, wherein the compound of formula II, wherein P is benzyl, is dissolved in diisopropyl ether at reflux temperature and cooled to below 300C to obtain the desired racemic compound of formula I, wherein P is benzyl.
10. The process as claimed in claim 1, wherein the suspension of the mixture of a pair of racemic compounds represented by formula Il in diisopropyl ether is stirred for at least 30 minutes at 300C to reflux temperature of the solvent used and isolating the desired racemic compound of formula I.
11. The process as claimed in claim 10, wherein the suspension is stirred for 1 hour to 4 hours at below 600C.
12. The process as claimed in claim 11 , wherein the suspension is stirred for 1 hour to 3 hours at 10 - 400C.
13. The process as claimed in claim 10, wherein the isolation of the racemic compound of formula I is carried out by filtration or centrifugation.
14. The process as claimed in claim 1, wherein the racemic compound of formula I prepared according to the present invention is the compound of formula Ia:
Figure imgf000010_0001
15. The process as claimed in claim 1, wherein the desired racemic compound of formula I is further debenzylated by known methods to obtain nebivolol of formula III:
(+)-R*S*S*S*
Figure imgf000010_0002
PCT/IN2006/000015 2006-01-18 2006-01-18 Process for isolation of desired isomers of nebivolol intermediates WO2007083318A1 (en)

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US11/718,593 US7858812B2 (en) 2006-01-18 2006-01-18 Process for isolation of desired isomers of nebivolol intermediates
EP06711356A EP1973895A1 (en) 2006-01-18 2006-01-18 Process for isolation of desired isomers of nebivolol intermediates

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009082913A1 (en) 2007-12-21 2009-07-09 Shanghai Modern Pharmaceutical Co., Ltd. Process for isolation of a mixture of rrrs and sssr configurations of nebivolol intermediates
DE102010005953A1 (en) 2010-01-27 2011-07-28 Corden PharmaChem GmbH, 68305 Process for the preparation of nebivolol
WO2011098474A1 (en) 2010-02-11 2011-08-18 Menarini International Operations Luxembourg S.A. Process for the preparation of nebivolol
WO2012095707A1 (en) 2010-11-30 2012-07-19 Menarini International Operations Luxembourg S.A. Process for the preparation of nebivolol
EP2907810A1 (en) 2014-02-14 2015-08-19 Corden Pharma International GmbH A new method for producing nebivolol hydrochloride of high purity
EP2907809A1 (en) 2014-02-14 2015-08-19 Corden Pharma International GmbH Base-free process for the preparation of ketone intermediates usable for manufacture of nebivolol
CN105085499A (en) * 2015-08-07 2015-11-25 上海现代制药海门有限公司 Crystal separation method for nebivolol hydrochloride intermediate mixture
DE102014107132A1 (en) 2014-05-20 2015-11-26 Corden Pharma International Gmbh Process for the preparation of epoxides which can be used in the preparation of nebivolol and its derivatives

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CA1337432C (en) 1988-03-23 1995-10-24 Raymond M. Xhonneux Method of lowering the blood pressure
PL1776354T3 (en) 2004-08-11 2010-09-30 Hetero Drugs Ltd A novel process for preparation of nebivolol intermediates

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2236510A4 (en) * 2007-12-21 2011-11-16 Shanghai Modern Pharmaceutical Co Ltd METHOD FOR ISOLATING A MIXTURE OF THE RRRS AND SSSR CONFIGURATIONS OF NEBIVOLOL INTERMEDIATES
EP2236510A1 (en) * 2007-12-21 2010-10-06 Shanghai Modern Pharmaceutical Co., Ltd. Process for isolation of a mixture of rrrs and sssr configurations of nebivolol intermediates
CN101463024B (en) * 2007-12-21 2011-06-08 上海现代制药股份有限公司 Method for preparing RRRS and SSSR type nebivolol intermediate mixture
WO2009082913A1 (en) 2007-12-21 2009-07-09 Shanghai Modern Pharmaceutical Co., Ltd. Process for isolation of a mixture of rrrs and sssr configurations of nebivolol intermediates
DE102010005953A1 (en) 2010-01-27 2011-07-28 Corden PharmaChem GmbH, 68305 Process for the preparation of nebivolol
WO2011091968A1 (en) 2010-01-27 2011-08-04 Corden Pharmachem Gmbh Method for producing nebivolol
WO2011098474A1 (en) 2010-02-11 2011-08-18 Menarini International Operations Luxembourg S.A. Process for the preparation of nebivolol
WO2012095707A1 (en) 2010-11-30 2012-07-19 Menarini International Operations Luxembourg S.A. Process for the preparation of nebivolol
EP2907810A1 (en) 2014-02-14 2015-08-19 Corden Pharma International GmbH A new method for producing nebivolol hydrochloride of high purity
EP2907809A1 (en) 2014-02-14 2015-08-19 Corden Pharma International GmbH Base-free process for the preparation of ketone intermediates usable for manufacture of nebivolol
DE102014107132A1 (en) 2014-05-20 2015-11-26 Corden Pharma International Gmbh Process for the preparation of epoxides which can be used in the preparation of nebivolol and its derivatives
CN105085499A (en) * 2015-08-07 2015-11-25 上海现代制药海门有限公司 Crystal separation method for nebivolol hydrochloride intermediate mixture
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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