WO2010034927A1 - Procede de preparation de nebivolol - Google Patents
Procede de preparation de nebivolol Download PDFInfo
- Publication number
- WO2010034927A1 WO2010034927A1 PCT/FR2009/051775 FR2009051775W WO2010034927A1 WO 2010034927 A1 WO2010034927 A1 WO 2010034927A1 FR 2009051775 W FR2009051775 W FR 2009051775W WO 2010034927 A1 WO2010034927 A1 WO 2010034927A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formula
- compound
- fluoro
- benzopyran
- derivative
- Prior art date
Links
- 0 *CC(C(CC1)Oc(cc2)c1cc2F)=O Chemical compound *CC(C(CC1)Oc(cc2)c1cc2F)=O 0.000 description 3
- GVZDIJGBXSDSEP-UHFFFAOYSA-N Fc(cc1)cc(CC2)c1OC2C1OC1 Chemical compound Fc(cc1)cc(CC2)c1OC2C1OC1 GVZDIJGBXSDSEP-UHFFFAOYSA-N 0.000 description 1
- KJIIQCNYDNCNRD-UHFFFAOYSA-N Nc(cc1CC2)ccc1OC2C1OC1 Chemical compound Nc(cc1CC2)ccc1OC2C1OC1 KJIIQCNYDNCNRD-UHFFFAOYSA-N 0.000 description 1
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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
-
- 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
- C07D311/66—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—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
- 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
Definitions
- the present invention relates to a process for the preparation of nebivolol and more particularly to an improved process for the synthesis of an alpha-haloketone of the formula
- NBV Nebivolol
- Nebivolol is characterized by its ⁇ -adrenergic receptor blocking properties and is useful for the treatment of essential hypertension. It has basic properties and can be converted into its addition salts by treatment with appropriate acids.
- the hydrochloric acid addition salt is the product on the market.
- EP 145067 discloses a process for the preparation of NBV which comprises the synthesis of diastereomeric mixtures of chromane-epoxide derivatives according to the synthesis scheme below.
- Ethyl 6-fluorochromancarboxylate derived from the esterification of the corresponding acid is reduced with dihydrobetric acid.
- Said epoxide derivatives are the key intermediates of the process.
- Patent EP 334429 mainly describes the same synthesis method mentioned in the previous patent and particularly relates to the preparation of the unique optical isomers (R, S, S, S) and (S, R, R, R) of NBV.
- 6-fluorochromancarboxylic acid is split into single enantiomers by treatment with
- (+) - dehydroabietylamine Said single enantiomers are separately transformed into their corresponding epoxides resulting in a mixture of two diastereoisomers.
- the following synthetic scheme describes, for example, the conversion of the S-acid derivative.
- Said conversion step is in particular carried out by reacting an alkyl or aryl chromancarboxylate with a sulfoxonium ylide to provide cetosulfoxonium ylide which is converted to an alpha-haloketone by reaction with optionally produced anhydrous halohydrogenic acids. in situ.
- R is hydrogen or COOR 'and wherein R 1 is C 1 -C 6 alkyl or aryl-C 1 alkyl;
- alpha-haloketones play an essential role in the preparation of 6-fluorophenone-epoxide derivatives and, in turn, the pharmaceutical ingredient, nebivolol.
- a first object of the present invention is therefore a process for preparing a compound of the formula
- X is a halogen atom, which comprises reacting a compound of the formula
- R is a C1-C6 alkyl group; with a derivative of hatomethyllithurn.
- the compounds of the formula VI are known intermediates in the preparation of NBV, the preparation of which is widely described in the art, such as those of EP 145067 and EP 334429 mentioned above.
- the halomethyllithium according to the invention can be represented by the formula
- X is defined above; and can be prepared by reaction of an organolithium compound and a di-halomethane.
- Said organolithium compound and said di-halomethane are in a preferred embodiment of the invention added to a reaction solvent and the halomethyllithium reactant is formed in the reaction system.
- the preferred halomethyllithium is chloromethyllithium and bromomethyllithium, the former being even more preferred.
- the preferred organolithium compound is methyllithium, n-butyllithium and sec-butyllithium, n-butyllithium being even more preferred.
- the preferred dihalomethane used in the invention is bromochloromethane, dibromomethane and chloroiodomethane, the former being the most preferred. Since it is known in the art that halomethyllithium derivatives are thermally unstable, it is preferable to pre-dissolve an ester compound of formula VI and a dihalomethane in a solvent and then add the organolithium compound.
- the preferred solvent of the invention is an ether solvent, such as tetrahydrofuran, diethyl ether, tert-butyl methyl ether and the like. It is possible to use in the subject of the reaction of the invention a mixture of ether-type solvent and non-polar solvents, such as
- halomethyllithium reagent to the compound of the formula VI is generally carried out at a temperature of from -100 ° C. to 0 ° C.
- the reaction is preferably carried out in the range of -85 ° C to
- reaction it is generally preferable, when the reaction is complete, to treat the resulting reaction mixture with an aqueous solution of ammonium chloride, a phosphate buffer solution, water or an acid, preferably a weak acid, such as acetic acid and the like.
- the amount of organolithium compound and dihalomethane used in the invention is not particularly critical.
- the ester substrate, the dihalomethane reactant and the organolithium compound are preferably used in a molar ratio of about 1: 2: 2.
- Halogen indicates fluorine, chlorine, bromine and iodine in the present invention.
- X is preferably a chlorine or bromine atom, where a chlorine atom is even more preferred.
- Another object of the present invention is a process for preparing a compound of the formula
- Another object of the present invention is a process for preparing a compound of the formula
- step a The reduction of a compound of formula I to provide a compound of formula VIII (step a) is carried out according to known techniques.
- the reaction is preferably carried out by reacting a compound of formula I with sodium borohydride in the presence of an alcoholic solvent, optionally mixed with water.
- the preferred solvent is ethanol.
- reaction of a compound of formula VIII to provide a compound of formula VII is carried out in the presence of a base according to known techniques. Said cyclization reaction is carried out again in one embodiment of the invention according to the international patent application also in progress WO 2008/040528.
- the cyclization is preferably carried out by reacting a compound of formula VIII with alkaline alkoxides or hydroxides in the presence of alcoholic solvents or ethers optionally in admixture.
- a preferred embodiment of the invention is that the reaction is carried out with a base, such as potassium t-butoxide, in the presence of a mixture of isopropanol / THF.
- a base such as potassium t-butoxide
- the reaction is otherwise carried out with a base, such as sodium t-butoxide
- a compound of formula VII is prepared by a procedure in only one (one-pot type) reactor starting from an ester derivative of formula VI.
- Said procedure comprises reacting the ester substrate with a halomethyllithium derivative and in situ reduction / cyclization to directly provide epoxide compounds of the formula VII
- reaction mixture from the addition of the balomethyllithium derivative to the compound of formula VI is in practice reduced in situ to provide a haiohydrin of formula VIII which is in turn cyclized in the presence of a base.
- Another object of the present invention is therefore a process for preparing a compound of the formula
- R is defined above; with a halomethyllithium derivative to provide a reaction mixture; in situ reduction of said reaction mixture; and cyclization in the presence of a base.
- reaction mixture is in a preferred embodiment of the invention reduced in situ with a borane reagent; the lithium alkoxyborohydride thus obtained transposes in situ and is hydrolyzed to haiohydrin which is, in turn, cyclized in the presence of alkoxides or alkali hydroxides.
- the reduction in situ according to the invention is preferably carried out with BH 3 in THF.
- reaction mixture resulting from the addition of the halomethyllithium derivative to the compound of the formula VI comprises, as the main chemical entity, a compound of the formula
- Said compound of formula IX constitutes another subject of the invention. It is thus obvious that the object of the process of the invention constitutes an efficient and economical alternative of synthesis, suitable for industrial production for the preparation of chromane-epoxides; in addition, the availability of the raw materials used with the reduced number of synthetic steps and the almost quantitative yields obtained provide significant advantages in terms of cost and efficiency of the process.
- the efficiency of the chemical reactions in only one reactor (“one-pot” reaction) is more desirable by the chemists since a long process of separation and purification of the intermediate chemical compounds is avoided, which saves time and raw materials while increasing chemical efficiency.
- the process for converting an ester to an alpha-haloketone and the "one-pot" conversion of ester to epoxide according to the invention are also stereoconservative for substrates with chiral centers.
- optically active esters of formula VI which can be obtained by esterification of the corresponding optically active acid or else by chiral chromatography according to known techniques. It is therefore clear to those skilled in the art that the object of the process of the invention leads to the preparation of alpha-haloketone of formula I enriched in enantiomer and epoxide derivatives in a racemic form comprising a mixture of two of the stereoisomers, conferring on the diagrams below;
- X is a halogen atom
- R is a C1-CO alkyl group; with a halomethyllithium derivative.
- Another object of the present invention is a method of synthesizing nebivolol which comprises a one-pot conversion of a compound of formula VI to a compound of formula VII as mentioned above.
- a practical embodiment of the object of the process of the present invention comprises converting a 6-fluorochromancarboxylate of formula VI to an alpha-haloketone of formula I by addition of a halomethyllithium derivative; said alpha-haloketone of the formula I is reduced to a halohydrin of the formula VIII and is cyclized to an epoxide derivative of the formula VII in the presence of a base.
- a preferred practical embodiment of the process object of the present invention comprises the conversion of a C 1 -C 6 alkyl 6-fluorochromancarboxylate of formula VI to the corresponding alpha-chloroketone of formula I by addition of a chloromethylithium derivative, preferably obtained in situ by reaction of bromochloromethane or iodochloromethane with an organolithium derivative, such as n-butyllithium; said alpha-chloroketone of the formula I is reduced to a chlorohydrin of the formula VIII by means of a reaction with sodium borohydride in the presence of an alcoholic solvent and is cyclized to an epoxide derivative of the formula VII by reaction with alkaline alkoxides or hydroxides in the presence of alcoholic solvents or ethers optionally in admixture.
- a chloromethylithium derivative preferably obtained in situ by reaction of bromochloromethane or iodochloromethane with an organolithium derivative, such as
- Another practical embodiment of the subject of the process of the present invention comprises the one-pot conversion of a 6-fluorochromancarboxylate of formula VI to an epoxide derivative of formula VII by addition of a halomethyllithium derivative; in situ reduction of the reaction mixture thus obtained; and cyclization in the presence of a base.
- Another preferred practical embodiment of the object of the process of the present invention comprises the conversion of a C 1 -C 6 alkyl 6-fluorochromancarboxylate of the formula VI to an epoxide derivative of the formula VII by addition of a chloromethylithium derivative preferably obtained in situ by reaction of bromochloromethane or iodochloromethane with an organolithium derivative, such as n-butyllithium, to provide a reaction mixture; said mixture is reduced in situ with BH 3 in the presence of THF and is cyclized to an epoxide derivative of formula VII by reaction with alkoxides or alkali hydroxides.
- a chloromethylithium derivative preferably obtained in situ by reaction of bromochloromethane or iodochloromethane
- an organolithium derivative such as n-butyllithium
- Example 1 In the examples all the percentages are given by weight, the temperature is in degree celcius and the pressure is the atmospheric pressure, unless otherwise indicated, Example 1
- a second crop after concentration of the mother liquor and after heating the residue in 50 ml of glacial acetic acid and 50 ml of water under reflux for 20 h can be obtained to hydrolyze the ester to provide an additional batch of the compound. indicated in the title (2-3 g).
- Diast. RR, SS ⁇ H (400 MHz, CDCl 3 ) 6.81-6.72 (3H, m), 3.88-3.82 (1H, m), 3.21-3.17 (1H, m, m.p. ), 2.89-2.76 (4H, m), 2.1-2.00 (1H, m), 1.97-1.87 (1H, m); Diast. SR, SR: ⁇ H (400 MHz, CDCl 3 ) 6.84-6.73 (3H, m), 3.87- 3.81 (1H, m), 3.15-3.10 (1H, m.p. 2.91-2.78 (4H, m), 2.18-2.10 (1H, m), 1.96-1.84 (1H, m).
- the solid material was then optionally recrystallized from a mixture of ethyl acetate and hexane to provide 1.73 g of 2-chloro-1 - ((R) -6-fluoro-1-benzopyran-2- yl) -ethanone in the form of a beige solid (yield 80%, ee: 99%, 97.6% A, [ ⁇ ] D : -27 °).
- CHIRAL OB-H 250 * 4.6 mm particles 5 ⁇ m, N-heptane-IPOH (95 V-5 V), 200 nm, enantiomer (R) TR 20.6 minutes, enantiomer (S) 22.2 minutes.
- the solution was then acidified by adding 2 ml of glacial acetic acid in 2 ml of THF at -70 ° C. at -80 ° C. 10 ml of water were then added at -20 ° C. and the aqueous layer was then removed after decantation. The organic layer was concentrated under reduced pressure to afford the title compound (2.54 g) as a yellow oil (ee: 99%, 94.8% A).
- reaction mixture was then diluted with toluene (14 ml) and the pH adjusted with acetic acid (0.305 g). Toluene (14 ml) and water (1.5 ml) were then further added to the mixture and the phases separated after extraction. The collected organic phases were then washed with water (14 ml). The anhydrous toluene phase was then made by azeotropic distillation and concentrated to dryness in a rotary evaporator to provide a mixture of (R) -6-fluoro-2- (S) - diastereoisomers. oxyranyl-1-benzopyran and (R) -6-Fluoro-2- (R) -oxyranyl-1-benzopyran 55:48 (0.56 g, 95% yield, 94.4% A).
- RR ⁇ H (400 MHz, CDCl 3 ) 6.81-6.72 (3H, m), 3.88-3.82 (1H, m), 3.21-3.17 (1H, m), 2.89-2.76 (4H, m), 2.1-2.00 (1H, m), 1.97-1.87 (1H, m); Diast. RS: ⁇ H (400 MHz, CDCl 3 ) 6.84-6.73 (3H, m), 3.87-3.81 (1H, m), 3.15-3.10 (1H, m), 2.91-2.78 (4H, m), 2.18-2.10 (1H, m), 1.96- 1.84 (1H, m)
- reaction mixture was then diluted with toluene (14 ml) and the pH adjusted with acetic acid (0.305 g). Toluene (14 ml) and water (1.5 ml) were then further added to the mixture and the phases separated after extraction. The collected organic phases were then washed with water (14 ml). .
- the anhydrous toluene phase was then made by azeotropic distillation and concentrated to dryness in a rotary evaporator to provide a mixture of (S) -6-fluoro-2- (R) -type diastereoisomers.
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Abstract
Description
Claims
Priority Applications (11)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2009801373139A CN102164906A (zh) | 2008-09-24 | 2009-09-22 | 用于制备奈必洛尔的方法 |
CA2736600A CA2736600C (fr) | 2008-09-24 | 2009-09-22 | Procede de preparation de nebivolol |
US13/120,690 US8981127B2 (en) | 2008-09-24 | 2009-09-22 | Method for preparing nebivolol |
AU2009295730A AU2009295730B2 (en) | 2008-09-24 | 2009-09-22 | Method for preparing nebivolol |
EP09747893.7A EP2328883B1 (fr) | 2008-09-24 | 2009-09-22 | Procede de preparation de nebivolol |
BRPI0919257A BRPI0919257B8 (pt) | 2008-09-24 | 2009-09-22 | processo de preparação de nebivolol |
JP2011528395A JP5744738B2 (ja) | 2008-09-24 | 2009-09-22 | ネビボロールの調製方法 |
ES09747893.7T ES2523343T3 (es) | 2008-09-24 | 2009-09-22 | Procedimiento de preparación de nebivolol |
PL09747893T PL2328883T3 (pl) | 2008-09-24 | 2009-09-22 | Sposób wytwarzania nebivololu |
IL211410A IL211410A (en) | 2008-09-24 | 2011-02-24 | A method of making nevivol |
HRP20140922AT HRP20140922T1 (hr) | 2008-09-24 | 2014-09-26 | Postupak dobivanja nebivolola |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR0856415 | 2008-09-24 | ||
FR0856415 | 2008-09-24 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2010034927A1 true WO2010034927A1 (fr) | 2010-04-01 |
Family
ID=40527387
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/FR2009/051775 WO2010034927A1 (fr) | 2008-09-24 | 2009-09-22 | Procede de preparation de nebivolol |
Country Status (12)
Country | Link |
---|---|
US (1) | US8981127B2 (fr) |
EP (1) | EP2328883B1 (fr) |
JP (1) | JP5744738B2 (fr) |
CN (1) | CN102164906A (fr) |
AU (1) | AU2009295730B2 (fr) |
BR (1) | BRPI0919257B8 (fr) |
CA (1) | CA2736600C (fr) |
ES (1) | ES2523343T3 (fr) |
HR (1) | HRP20140922T1 (fr) |
IL (1) | IL211410A (fr) |
PL (1) | PL2328883T3 (fr) |
WO (1) | WO2010034927A1 (fr) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102180855A (zh) * | 2011-03-01 | 2011-09-14 | 浙江华海药业股份有限公司 | 一种奈必洛尔中间体的提纯方法 |
ITRM20110418A1 (it) * | 2011-08-02 | 2013-02-03 | Menarini Int Operations Lu Sa | Processo per la preparazione di epossidi quali intermedi per la sintesi del nebivololo. |
EP2907809A1 (fr) | 2014-02-14 | 2015-08-19 | Corden Pharma International GmbH | Procédé pour la préparation de cétones utiles en tant qu'intermédiares pour la synthèse du nebivolol |
ITUB20160227A1 (it) * | 2016-01-21 | 2017-07-21 | Menarini Int Operations Luxembourg Sa | Processo per la sintesi di intermedi di Nebivololo |
KR102669221B1 (ko) | 2016-01-21 | 2024-05-24 | 메나리니 인터내셔날 오퍼레이션즈 룩셈부르크 에스.아. | 네비볼롤의 중간체의 합성 공정 |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104610215A (zh) * | 2015-01-19 | 2015-05-13 | 浙江海翔药业股份有限公司 | 一种奈必洛尔中间体的制备方法及奈必洛尔的制备方法 |
CN108997297B (zh) * | 2018-07-17 | 2020-12-01 | 浙江海翔药业股份有限公司 | 一种奈必洛尔中间体的制备方法、用于制备该奈必洛尔中间体的中间体及其制备方法 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008040528A2 (fr) * | 2006-10-03 | 2008-04-10 | Zach System S.P.A. | Procédé de préparation du nébivolol |
Family Cites Families (8)
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US5523463A (en) * | 1994-09-23 | 1996-06-04 | Hoffmann-La Roche Inc. | Method of producing halogenated and alpha-aminoalchohols |
US5591885A (en) * | 1994-09-23 | 1997-01-07 | Hoffman-La Roche Inc. | Process for the preparation of halogenated α-aminoketone compounds |
US6127556A (en) * | 1996-12-31 | 2000-10-03 | G. D. Searle & Co. | Epoxide formation by continuous in-situ synthesis process |
CA2489428A1 (fr) * | 2002-06-27 | 2004-01-08 | Nitromed, Inc. | Inhibiteurs selectifs de la cyclooxygenase 2, compositions associees et methodes d'utilisation |
JP2009511547A (ja) * | 2005-10-14 | 2009-03-19 | ノイロサーチ アクティーゼルスカブ | 不安及び関連疾患の治療のためのイミダゾール誘導体 |
US7560575B2 (en) * | 2005-12-28 | 2009-07-14 | Acino Pharma Ag | Process for preparation of racemic Nebivolol |
EP2061759B1 (fr) * | 2006-10-04 | 2013-03-27 | Bristol-Myers Squibb Company | Modulateurs cycliques de l'activité de récepteurs de chimiokines |
MX2010000334A (es) * | 2007-06-28 | 2010-04-22 | Intervet Int Bv | Piperazinas sustituidas como antagonistas de cannabinoides 1. |
-
2009
- 2009-09-22 CA CA2736600A patent/CA2736600C/fr active Active
- 2009-09-22 US US13/120,690 patent/US8981127B2/en active Active
- 2009-09-22 PL PL09747893T patent/PL2328883T3/pl unknown
- 2009-09-22 WO PCT/FR2009/051775 patent/WO2010034927A1/fr active Application Filing
- 2009-09-22 JP JP2011528395A patent/JP5744738B2/ja active Active
- 2009-09-22 BR BRPI0919257A patent/BRPI0919257B8/pt active IP Right Grant
- 2009-09-22 AU AU2009295730A patent/AU2009295730B2/en active Active
- 2009-09-22 ES ES09747893.7T patent/ES2523343T3/es active Active
- 2009-09-22 EP EP09747893.7A patent/EP2328883B1/fr active Active
- 2009-09-22 CN CN2009801373139A patent/CN102164906A/zh active Pending
-
2011
- 2011-02-24 IL IL211410A patent/IL211410A/en active IP Right Grant
-
2014
- 2014-09-26 HR HRP20140922AT patent/HRP20140922T1/hr unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008040528A2 (fr) * | 2006-10-03 | 2008-04-10 | Zach System S.P.A. | Procédé de préparation du nébivolol |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102180855A (zh) * | 2011-03-01 | 2011-09-14 | 浙江华海药业股份有限公司 | 一种奈必洛尔中间体的提纯方法 |
ITRM20110418A1 (it) * | 2011-08-02 | 2013-02-03 | Menarini Int Operations Lu Sa | Processo per la preparazione di epossidi quali intermedi per la sintesi del nebivololo. |
WO2013018053A1 (fr) | 2011-08-02 | 2013-02-07 | Menarini International Operations Luxembourg S.A. | Procédé de préparation d'époxydes en tant qu'intermédiaires pour la synthèse du nébivolol |
EP2907809A1 (fr) | 2014-02-14 | 2015-08-19 | Corden Pharma International GmbH | Procédé pour la préparation de cétones utiles en tant qu'intermédiares pour la synthèse du nebivolol |
ITUB20160227A1 (it) * | 2016-01-21 | 2017-07-21 | Menarini Int Operations Luxembourg Sa | Processo per la sintesi di intermedi di Nebivololo |
WO2017125900A1 (fr) | 2016-01-21 | 2017-07-27 | Menarini International Operations Luxembourg S.A. | Procédé de synthèse d'intermédiaires du nébivolol |
US10392361B2 (en) | 2016-01-21 | 2019-08-27 | Menarini International Operations Luxembourg S.A. | Process for the synthesis of intermediates of Nebivolol |
AU2017210249B2 (en) * | 2016-01-21 | 2020-06-18 | Menarini International Operations Luxembourg S.A. | Process for the synthesis of intermediates of Nebivolol |
EA036157B1 (ru) * | 2016-01-21 | 2020-10-07 | Менарини Интернэшнл Оперэйшнс Люксембург С.А. | Способ синтеза промежуточных соединений небиволола |
KR102669221B1 (ko) | 2016-01-21 | 2024-05-24 | 메나리니 인터내셔날 오퍼레이션즈 룩셈부르크 에스.아. | 네비볼롤의 중간체의 합성 공정 |
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JP2012503636A (ja) | 2012-02-09 |
BRPI0919257A2 (pt) | 2015-08-18 |
JP5744738B2 (ja) | 2015-07-08 |
CN102164906A (zh) | 2011-08-24 |
CA2736600C (fr) | 2017-03-21 |
US20110237808A1 (en) | 2011-09-29 |
BRPI0919257B8 (pt) | 2021-05-25 |
AU2009295730B2 (en) | 2013-12-19 |
EP2328883A1 (fr) | 2011-06-08 |
HRP20140922T1 (hr) | 2014-11-07 |
ES2523343T3 (es) | 2014-11-25 |
PL2328883T3 (pl) | 2015-01-30 |
EP2328883B1 (fr) | 2014-08-06 |
IL211410A0 (en) | 2011-05-31 |
US8981127B2 (en) | 2015-03-17 |
IL211410A (en) | 2015-10-29 |
BRPI0919257B1 (pt) | 2021-05-04 |
CA2736600A1 (fr) | 2010-04-01 |
AU2009295730A1 (en) | 2010-04-01 |
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