WO2010049455A1 - Process for preparing nebivolol - Google Patents
Process for preparing nebivolol Download PDFInfo
- Publication number
- WO2010049455A1 WO2010049455A1 PCT/EP2009/064230 EP2009064230W WO2010049455A1 WO 2010049455 A1 WO2010049455 A1 WO 2010049455A1 EP 2009064230 W EP2009064230 W EP 2009064230W WO 2010049455 A1 WO2010049455 A1 WO 2010049455A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- nebivolol
- debenzylation
- mixture
- bis
- butanol
- Prior art date
Links
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Definitions
- the present invention relates to a process for preparing Nebivolol and, more particularly, to an improved method of debenzylation of a compound of formula
- Nebivolol (hereafter, NBV), is a mixture of equal amounts of [2S [2R* [R [R*]]]]]] ⁇ , ⁇ '-[imino-bis (methylene)] bis [6-fluoro-chroman-2-methanol] (hereafter J-NBV) of formula (IA)
- Nebivolol is characterized by its adrenergic ⁇ -blocking properties and is useful in treating essential hypertension. It has basic properties and may be converted into its addition salts through treatment with suitable acids. The hydrochloric acid addition salt is the marketed product.
- Literature reports several processes for the preparation of nebivolol.
- Patent EP 145067 (Janssen Pharmaceutica NV) describes a method of preparing
- NBV which comprises synthesizing diastereoisomeric mixtures of chroman epoxide derivatives.
- Ri is hydrogen, Ci_ 6 alkyl, aryl, aryl-Ci_ 6 -alkyl, C 1-12 alkylcarbonyl or arylcarbonyl.
- Patent EP 334429 (Janssen Pharmaceutica NV) describes substantially the same synthetic process reported in the previous patent and is particularly directed to the preparation of single optical isomers (R,S,S,S) and (S,R,R,R) of NBV.
- the deprotection of the amine group is described as actuable through catalytic hydrogenation procedures such as Palladium or Platinum supported on carbon in a suitable solvent.
- catalytic hydrogenation procedures such as Palladium or Platinum supported on carbon in a suitable solvent.
- a mixture of three parts and a half of benzyl derivative and two hundred fifty parts of 2-methoxy ethanol is hydrogenated at atmospheric pressure and at room temperature with two parts of Palladium on carbon (10%).
- molecular hydrogen may be generated in situ by using alternative sources such as formic acid, ammonium formate, phosphoric acid, cyclohexene and cyclohexadiene, under catalytic hydrogen transfer reduction conditions.
- Example 10 of the same patent application describes the preparation of [2S, R,2'R, ⁇ 'R]- ⁇ , ⁇ '-[imino bis-methylene]bis [6-fluoro-3,4- dehydro-2H-l-benzopyran-2-methanol] in the form of formate salt from the corresponding N-benzyl derivative by treatment with ammonium formate in the presence of Pd/C (10% by weight) and methanol.
- CTH catalytic transfer hydrogenation
- Said CTH may be carried out in moderate conditions and, above all, they have proved to be selective in the debenzylation of protected substrates containing, in addition, aromatic halogen groups.
- an aspect associable to CTH methods is the fact that while they are chemo selective, they exhibit the drawback of being slow and of not leading to complete conversions and, thus, of generally being little compatible or at least little productive at industrial level.
- One of the possible causes is represented by the progressive poisoning of the catalyst by the amines which generate as products of the N-debenzylation reaction.
- a first object of the present invention is a process for the debenzylation of a compound of formula
- residue Bn it is meant a benzyl group (phenylmethyl) as known in the art.
- the compound of formula II can be prepared according to known techniques, for example, according to the processes described in international patent applications and patents EP 0145067, EP0334429, WO 2006/016376, WO 2008/064827 and WO
- the process object of the present invention is applied to the compound of formula II in the form of a single enantiomer RSSS (1-NBV benzyl derivative) or
- Solvents suitable for the debenzylation object of the invention are inert organic solvents such as aliphatic alcohols, ethers or esters.
- the reaction solvent is selected from methanol, ethanol, isopropanol, sec- butanol, ethyl acetate or tetrahydrofuran.
- reaction solvent is used as reaction solvent.
- the debenzylation of the invention can also be carried out en masse.
- Pd-based catalysts useful for the debenzylation object of the invention are Pd on carbon (Pd/C) either dry or wet, preferably up to about 50% w/w water.
- Pd/C Pd on carbon
- the present debenzylation of a compound of formula II with formic acid in the presence of a palladium-based catalyst is still more preferably carried out with 5% wet Pd/C (around 50% w/w water) in an amount of about 10% w/w relative to the substrate (about 5% w/w calculated on the dry catalyst).
- reaction of a compound of formula II with formic acid in the presence of a palladium-based catalyst is carried out at a temperature comprised between 25°C and 100 0 C.
- the reaction is carried out at around 70 0 C.
- stoichiometric ratios of at least 2 moles acid/mole substrate are used.
- 3 moles acid/mole substrate are used.
- the reaction of a compound of formula II with formic acid in the presence of a palladium-based catalyst is carried out by hot (70°C ⁇ 2°C) adding formic acid to a mixture containing substrate and 5% wet Pd/C in sec- butanol. After further hot stirring for a some hours, the reaction mixture is worked up with a basic aqueous solution (for example NaOH). The catalyst is then separated from the reaction mixture through, for example, filtration on celite and product is recovered according to known techniques.
- a basic aqueous solution for example NaOH
- the process object of the present invention leads to the formation of an addition salt of nebivolol, namely nebivolol formate salt, which is neutralized in a basic environment, optionally in situ, to nebivolol free base.
- Said NBV free base obtained from the process object of the present invention is particularly suitable, in terms of purity, for the subsequent steps of the end product synthesis.
- a further object of the present invention is a process for synthesizing nebivolol or an additional salt thereof which comprises the debenzylation of a compound of formula II with formic acid in the presence of a Palladium-based catalyst according to what reported above.
- a racemic mixture of the compounds of formula II mixture 1 :1 of isomers 1 and d NBV benzyl derivative
- NBV mixture 1 : 1 of isomers 1 and d
- the mixture of d-NBV and 1-NBV obtained from the corresponding mixture of benzyl derivative according to the invention is treated with hydrochloric acid in the presence of an organic solvent to give the respective NBV hydrochloride salt.
- Said salt may be further purified through methods known in the art such as for example crystallisation. Hence, it is readily apparent how the reduction method object of the invention constitutes an efficient and economical synthetic alternative in the preparation of active ingredient NBV hydrochloride.
- an important aspect of the process object of the invention is the capability of providing a highly pure end product wherein the titre of each impurity is less than 0.1% and the sum of all impurities is widely lower than 1%, making further expensive purification steps, for example by re-crystallisation, unnecessary.
- a further object of the present invention is nebivolol or an addition salt thereof, with a purity of at least 99.9% by weight.
- a further object of the present invention is nebivolol or an addition salt thereof, which comprises less than 0.1% "de-F" nebivolol by weight.
- a further object of the present invention is nebivolol or an addition salt thereof, which comprises less than 0.05% "de-F" nebivolol by weight. Therefore, a further object of the present invention is a process for the synthesis of nebivolol or an addition salt thereof, with a purity of at least 99.9 % by weight, which comprises a debenzylation according to what described above.
- a further object of the present invention is a process for the synthesis of nebivolol or an addition salt thereof, with less than 0.1% "de-F" nebivolol by weight, which comprises a debenzylation according to what described above. Therefore, a further object of the present invention is a process for the synthesis of nebivolol or an addition salt thereof, with less than 0.05% "de-F" nebivolol by weight, which comprises a debenzylation according to what described above.
- the main drawback of CTH lies in the need of very long reaction times and, sometimes, in the difficulty in completing the reaction.
- the use of formic acid according to the invention if compared to the method of CTH in the presence of ammonium formate described in the co-pending international patent application WO 2008/064827, allows accelerating the reaction kinetic making it selective and, in the meantime, fast.
- the reaction mechanism that allows such acceleration may lie in the fact that unlike ammonium formate, formic acid allows the precipitation of nebivolol formate salt during the reaction through an induced crystallisation process.
- nebivolol formate salt thus directly obtained, an essential intermediate for obtaining nebivolol with high purity, does not require further purifications such as preparative chromatography in formic acid environment carried out in the co- pending WO 2008/064827.
- a practical embodiment of the process object of the present invention comprises the debenzylation of a compound of formula II to give nebivolol free base through a catalytic hydrogenation by hydrogen transfer with formic acid, as a hydrogen source, and in the presence of a Palladium/based catalyst.
- a preferred practical embodiment of the process object of the present invention comprises reacting a racemic compound of formula II with formic acid in the presence of catalytic Pd/C and optionally in the presence of an alcoholic solvent to give nebivolol formate salt; which is neutralised to free base through a reaction with a base among which an alkaline hydroxide is preferred.
- the organic phase was then concentrated by vacuum distillation till a residual volume of about 40 ml.
- the mixture was then diluted with sec-butanol (35.3 g) and concentrated by vacuum distillation till a residual volume of about 45 ml.
- the organic solution was brought to 90 0 C, then it was cooled (in 4 hours) till 25°C and kept at this temperature for about 16 hours.
- the aqueous phase was then separated and the organic alcoholic phase was diluted with s-butanol (15.7 g) and then subjected to azeotropic distillation under vacuum (0.04 bar). The distillation was interrupted and the mixture was brought to volume with s-butanol (23.4 g). The distillation was resumed and, at the end of the operation, the mixture was diluted with s-butanol (13.8 g) to give about 9% solution (w/w) of [2R, ⁇ S,2'S, ⁇ 'S]- ⁇ - ⁇ '- [[(phenylmethyl)imino]bis-methylene]bis[6-fluoro-3,4-dehydro-2H-l-benzopyran-2- methanol] base.
- the mixture was hot filtered under vacuum on a Celite panel (1.6 g) and the panel was washed with s-butanol (12.2 g) preheated to 70 ⁇ 2°C.
- the aqueous phase was separated and stored while the organic was washed with an aqueous solution saturated with sodium bicarbonate (15.95 g) at 70 ⁇ 2°C and with demi water (15.2 g) at 70 ⁇ 2°C.
- the organic phase and the initial aqueous phase at 60 0 C were then combined and the biphasic mixture was diluted with demi water (15.2 g).
- the reaction mixture was kept under stirring at 70 ⁇ 2°C for about 2 hours, at the end a solution consisting of NaOH 30% (225 g) in water (1900 g) was added and it was kept under stirring at 70 ⁇ 2°C till dissolution of the suspension.
- the mixture was hot filtered on a celite panel washing with sec-butanol (726 g) and then toluene (530 g) was added.
- the biphasic mixture was kept at 70 ⁇ 2°C, then the aqueous phase was separated and the resulting organic phase was washed with an aqueous bicarbonate solution (180 g dissolved in 2400 g water) and then with water (2280 g).
- the organic solution was distilled under vacuum multiple times reintegrating the concentrated phase with fresh sec-butanol.
- the final organic phase (about 8000 ml) was heated to 85-90 0 C till complete solubilization and then gradually cooled to 20 0 C obtaining the product precipitation.
- Example 5 Comparison with prior art: N-debenzylation by conventional catalytic hydrogenation. dehydro-2H- 1 -benzopyran-2-methanoll .
- Example 6 Comparison with prior art: N-debenzylation by CTH according to International patent application WO 2008/064827, Example 10; isolation of Nebivolol free base and formation of Nebivolol hydrochloride has been carried out by following methods described in Examples 3 (part) and 4 above.
- Part A synthesis of ( ⁇ )rR*.S*.S*.S*l- ⁇ . ⁇ '-rimino-bis (methylene)! bis r6-fiuoro-3.4- dihydro-2H- 1 -benzopyran-2-methanoll .
- the reaction mixture was heated at reflux (about 65°C) under stirring for about 11 hours then cooled to 45°C filtered on a celite pad, washing with methanol, and finally concentrated under vacuum.
- the crude residue (6.2 g) was diluted with 2-butanol (65.2 g) then a solution of aq. 30% sodium hydroxide (2.0 g) and water (29.8 g) was added under stirring.
- the resulting suspension was heated to 70 ⁇ 2°C until complete dissolution obtaining a clear two-phase mixture.
- the aqueous layer was separated and the resulting organic phase was washed with aq. sodium hydrogen carbonate (1.7 g dissolved in 22.6 g of water) and then with water (2x 21.5 g).
- Toluene (5.0 g) was also added to improve the aqueous-organic separation.
- the organic phase was concentrated two-times under reduced pressure while adding fresh 2-butanol (total 32.9 g) to the resulting residues.
- the final organic solution (about 60 ml) was further diluted with 2-butanol (9.5 g) heated to 85-90 0 C until complete dissolution and then gradually cooled to 20 0 C obtaining the product precipitation.
- the solid was isolated by filtration, washing with 2-butanol (3x 2.7 g), and dried under vacuum at 60 0 C to give the title compound as a white solid (3.5 g, 96.6% w/w assay (HPLC); 82.6% molar yield).
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Cardiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Heart & Thoracic Surgery (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Steroid Compounds (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Saccharide Compounds (AREA)
- Pyrane Compounds (AREA)
Abstract
Description
Claims
Priority Applications (13)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP09751854.2A EP2346845B1 (en) | 2008-10-31 | 2009-10-28 | Process for preparing nebivolol |
CN200980140649.0A CN102186835B (en) | 2008-10-31 | 2009-10-28 | Prepare the method for nebivolol |
US13/126,800 US8927742B2 (en) | 2008-10-31 | 2009-10-28 | Process for preparing Nebivolol |
SI200931205T SI2346845T1 (en) | 2008-10-31 | 2009-10-28 | Process for preparing nebivolol |
BRPI0921632A BRPI0921632B8 (en) | 2008-10-31 | 2009-10-28 | process for preparing nebivolol |
JP2011533712A JP5560279B2 (en) | 2008-10-31 | 2009-10-28 | Nebivolol preparation process |
PL09751854T PL2346845T3 (en) | 2008-10-31 | 2009-10-28 | Process for preparing nebivolol |
DK09751854.2T DK2346845T3 (en) | 2008-10-31 | 2009-10-28 | Process for the preparation of nebivolol |
AU2009309680A AU2009309680B2 (en) | 2008-10-31 | 2009-10-28 | Process for preparing nebivolol |
CA2737340A CA2737340C (en) | 2008-10-31 | 2009-10-28 | Process for preparing nebivolol |
ES09751854.2T ES2540092T3 (en) | 2008-10-31 | 2009-10-28 | Process to prepare nebivolol |
IL211497A IL211497A (en) | 2008-10-31 | 2011-03-01 | Process for preparing nebivolol |
HRP20150554TT HRP20150554T1 (en) | 2008-10-31 | 2015-05-25 | Process for preparing nebivolol |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ITMI2008A001924 | 2008-10-31 | ||
ITMI2008A001924A IT1392067B1 (en) | 2008-10-31 | 2008-10-31 | NEBIVOLOL PREPARATION PROCESS |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2010049455A1 true WO2010049455A1 (en) | 2010-05-06 |
Family
ID=40849284
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2009/064230 WO2010049455A1 (en) | 2008-10-31 | 2009-10-28 | Process for preparing nebivolol |
Country Status (17)
Country | Link |
---|---|
US (1) | US8927742B2 (en) |
EP (1) | EP2346845B1 (en) |
JP (1) | JP5560279B2 (en) |
CN (1) | CN102186835B (en) |
AU (1) | AU2009309680B2 (en) |
BR (1) | BRPI0921632B8 (en) |
CA (1) | CA2737340C (en) |
DK (1) | DK2346845T3 (en) |
ES (1) | ES2540092T3 (en) |
HR (1) | HRP20150554T1 (en) |
HU (1) | HUE025673T2 (en) |
IL (1) | IL211497A (en) |
IT (1) | IT1392067B1 (en) |
PL (1) | PL2346845T3 (en) |
PT (1) | PT2346845E (en) |
SI (1) | SI2346845T1 (en) |
WO (1) | WO2010049455A1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 |
EP2907810A1 (en) | 2014-02-14 | 2015-08-19 | Corden Pharma International GmbH | A new method for producing nebivolol hydrochloride of high purity |
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 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004041805A1 (en) * | 2002-11-06 | 2004-05-21 | EGIS Gyógyszergyár Rt. | NEW PROCESS FOR THE PREPARATION OF RACEMIC ([2S[2R*[R[R*]]]] and ([2R[2S*[S[S*]]]]-(±)- α,α' -[imino-bis(methylene)]bis[6-fluorochroman-2-methanol] AND ITS PURE [2S[2R*[R[R*]& |
WO2008064827A2 (en) * | 2006-11-27 | 2008-06-05 | Zach System S.P.A. | Process for preparing nebivolol |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA1337429C (en) * | 1983-12-05 | 1995-10-24 | Guy Rosalia Eugene Van Lommen | Derivatives of 2,2'-iminobisethanol |
US8604222B2 (en) * | 2004-07-30 | 2013-12-10 | Forest Laboratories Holdings Limited | Nebivolol and its pharmaceutically acceptable salts, process for preparation and pharmaceutical compositions of nebivolol |
DE602004026789D1 (en) * | 2004-08-11 | 2010-06-02 | Hetero Drugs Ltd | NEW METHOD FOR THE PRODUCTION OF NEBIVOLOL INTERMEDIATE PRODUCTS |
EP1803716B1 (en) * | 2005-12-28 | 2012-07-25 | Acino Pharma AG | A process for preparation of racemic nebivolol |
-
2008
- 2008-10-31 IT ITMI2008A001924A patent/IT1392067B1/en active
-
2009
- 2009-10-28 DK DK09751854.2T patent/DK2346845T3/en active
- 2009-10-28 WO PCT/EP2009/064230 patent/WO2010049455A1/en active Application Filing
- 2009-10-28 JP JP2011533712A patent/JP5560279B2/en active Active
- 2009-10-28 PT PT97518542T patent/PT2346845E/en unknown
- 2009-10-28 HU HUE09751854A patent/HUE025673T2/en unknown
- 2009-10-28 SI SI200931205T patent/SI2346845T1/en unknown
- 2009-10-28 EP EP09751854.2A patent/EP2346845B1/en active Active
- 2009-10-28 AU AU2009309680A patent/AU2009309680B2/en active Active
- 2009-10-28 ES ES09751854.2T patent/ES2540092T3/en active Active
- 2009-10-28 CN CN200980140649.0A patent/CN102186835B/en active Active
- 2009-10-28 PL PL09751854T patent/PL2346845T3/en unknown
- 2009-10-28 BR BRPI0921632A patent/BRPI0921632B8/en active IP Right Grant
- 2009-10-28 CA CA2737340A patent/CA2737340C/en active Active
- 2009-10-28 US US13/126,800 patent/US8927742B2/en active Active
-
2011
- 2011-03-01 IL IL211497A patent/IL211497A/en active IP Right Grant
-
2015
- 2015-05-25 HR HRP20150554TT patent/HRP20150554T1/en unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004041805A1 (en) * | 2002-11-06 | 2004-05-21 | EGIS Gyógyszergyár Rt. | NEW PROCESS FOR THE PREPARATION OF RACEMIC ([2S[2R*[R[R*]]]] and ([2R[2S*[S[S*]]]]-(±)- α,α' -[imino-bis(methylene)]bis[6-fluorochroman-2-methanol] AND ITS PURE [2S[2R*[R[R*]& |
WO2008064827A2 (en) * | 2006-11-27 | 2008-06-05 | Zach System S.P.A. | Process for preparing nebivolol |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 |
EP2907810A1 (en) | 2014-02-14 | 2015-08-19 | Corden Pharma International GmbH | A new method for producing nebivolol hydrochloride of high purity |
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 |
Also Published As
Publication number | Publication date |
---|---|
CN102186835B (en) | 2016-01-13 |
EP2346845B1 (en) | 2015-03-25 |
CA2737340C (en) | 2016-09-06 |
HUE025673T2 (en) | 2016-04-28 |
PL2346845T3 (en) | 2015-08-31 |
JP5560279B2 (en) | 2014-07-23 |
AU2009309680B2 (en) | 2015-08-06 |
CN102186835A (en) | 2011-09-14 |
BRPI0921632A2 (en) | 2015-08-18 |
PT2346845E (en) | 2015-07-30 |
CA2737340A1 (en) | 2010-05-06 |
IT1392067B1 (en) | 2012-02-09 |
ES2540092T3 (en) | 2015-07-08 |
IL211497A0 (en) | 2011-05-31 |
JP2012506894A (en) | 2012-03-22 |
US8927742B2 (en) | 2015-01-06 |
US20110207948A1 (en) | 2011-08-25 |
AU2009309680A1 (en) | 2010-05-06 |
HRP20150554T1 (en) | 2015-07-03 |
IL211497A (en) | 2014-12-31 |
BRPI0921632B8 (en) | 2021-05-25 |
DK2346845T3 (en) | 2015-06-08 |
SI2346845T1 (en) | 2015-10-30 |
EP2346845A1 (en) | 2011-07-27 |
BRPI0921632B1 (en) | 2021-03-23 |
BRPI0921632A8 (en) | 2017-07-11 |
ITMI20081924A1 (en) | 2010-05-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
KR100812046B1 (en) | PROCESS FOR PREPARATION OF 1-2S,3S-2-BENZHYDRYL-N-5-tert-BUTYL-2-METHOXYBENZYLQUINUCLIDIN-3-AMINE | |
EP2102196B1 (en) | Process for preparing nebivolol | |
KR101726468B1 (en) | Process for the preparation of nebivolol | |
JP2011521001A (en) | Preparation method of ezetimibe and composition containing the same | |
EP2346845B1 (en) | Process for preparing nebivolol | |
EP4097109B1 (en) | Process for the synthesis of buprenorphine | |
CN112939849B (en) | (S, S) -2, 8-diazabicyclo [4.3.0] nonane intermediate and preparation method and application thereof | |
CN110452157B (en) | Method for synthesizing halofuginone and intermediate thereof | |
CN115784922B (en) | Preparation method of (2S) -2-amino-4- (cyclopropyl/cyclobutyl) butyric acid | |
CN117756806A (en) | Preparation method of tofacitinib intermediate | |
US8785664B2 (en) | Process for the preparation of nebivolol | |
CN114349635A (en) | Synthesis method of dolutegravir core intermediate | |
CN115286504A (en) | Method for synthesizing (R) -2- (2- (tert-butoxy) -2-oxyethyl) pentanoic acid | |
CN115784959A (en) | Preparation method of brivaracetam | |
JP2001089470A (en) | Method for preparing trans-4,4'-(4'-hydroxycyclohexyl) cyclohexanone ketals | |
KR20100028200A (en) | New preparation of donepezil, donepezil hydrochloride and intermediate thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 200980140649.0 Country of ref document: CN |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 09751854 Country of ref document: EP Kind code of ref document: A1 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2737340 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2009309680 Country of ref document: AU |
|
ENP | Entry into the national phase |
Ref document number: 2009309680 Country of ref document: AU Date of ref document: 20091028 Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2011533712 Country of ref document: JP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2879/CHENP/2011 Country of ref document: IN |
|
WWE | Wipo information: entry into national phase |
Ref document number: 13126800 Country of ref document: US |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2009751854 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: PI0921632 Country of ref document: BR Kind code of ref document: A2 Effective date: 20110502 |