- Synthesis of novel 3-[(2R*)-2-[(2S*)-6-fluoro-3,4-dihydro-2H-chromen-2-yl]-2-hydroxyethyl]-urea/thiourea derivatives and evaluation of their antimicrobial activities
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A new series of biologically active 3-[(2R*)-2-[(2S*)-6-fluoro-3,4-dihydro-2H-chromen-2-yl]-2-hydroxyethyl]-urea/thiourea derivatives (1) have been designed and synthesized in four steps from 6-fluoro-3,4-dihydro-2-(oxiran-2-yl)-2H-chromene (2). The structures of newly synthesized compounds (1a–j) were confirmed by 1H, 13C NMR, and HRMS. The major advantages of the present article include the development of an efficient eluent system for good separation of diastereomers (2a and 2b) with high yields and synthesis of (R*)-2-(benzylamino)-1-((S*)-6-fluoro-3,4-dihydro-2H-chromen-2-yl)ethanol (3) in high yields (87%) from epoxide (2a) through new reaction conditions. The synthesized compounds (1a–j) exhibited moderate to excellent antimicrobial activities against both bacterial strains (gram + Ve and gram –Ve strains) and fungal strains. Among the tested compounds, promising lead compounds were identified (compounds 1a and 1d against bacterial strains and compound 1h and 1j against fungal strains) and their antimicrobial activities are comparable with the reference standard.
- Mannam, Madhava Rao,Srimurugan,Kumar, Pramod,Chamarthi, Naga Raju,Prasad
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Read Online
- Synthesis of intermediate compound and [...] (by machine translation)
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Synthesis of intermediate compounds [a] and [...]. [Solution] a [...], asymmetric epoxidation, sulfonyl halide in the presence of base catalyst by sulfonation, alkylation of amines, such as synthesized by a series of cross-coupling reaction. [Effect] [...] important from the viewpoint of pharmacological value, high efficiency, low cost, and which meets the requirements of industrial, optical isomers may be prepared [...] and develop a method, which is very economical in social benefit. [Drawing] no (by machine translation)
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Paragraph 0242-0243; 0278-0279
(2020/04/09)
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- Preparation method and application of Smo inhibitor based on Nebivolol
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The invention discloses a preparation method and an application of a Smo inhibitor based on Nebivolol. The structural formula of the Smo inhibitor is as shown in a formula (I). The invention further discloses a synthetic method and an application of the Smo inhibitor. According to the Smo inhibitor, a beta-receptor retardant Nebivolol with inhibitory activity for Smo proteins serves as a lead compound, and optimization reconstruction is implemented based on the beta-receptor retardant Nebivolol to obtain the Smo inhibitor with good inhibitory activity.
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- NEBIVOLOL SYNTHESIS METHOD AND INTERMEDIATE COMPOUND THEREOF
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The present invention relates to nebivolol synthesis method and intermediate compound thereof. Specifically, the present invention relates to a method for synthesizing nebivolol, intermediate compound thereof, and a method for preparing the intermediate compound.
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Paragraph 0338-0341; 0398-0400
(2018/06/04)
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- Nebivolol synthetic method and intermediate compounds of the
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The present invention relates to a synthesis method and an intermediate compound of nebivolol. Specifically the invention relates to the method for synthesizing the nebivolol, the intermediate compound of the nebivolol, and a method for preparing the intermediate compound.
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Paragraph 0418; 0420; 0494-0496
(2018/10/04)
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- PROCESS FOR THE SYNTHESIS OF INTERMEDIATES OF NEBIVOLOL
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The present invention relates to a novel process for the synthesis of the intermediate compounds constituted by chromanyl haloketones of formula III and 6-fluoro-2-(oxiran-2-yl) chromans of formula I. The intermediates thus obtained can be used for the sy
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Page/Page column 29
(2017/08/20)
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- PROCESS FOR PREPARATION OF NEBIVOLOL AND IT'S SALTS
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The present invention discloses a new process for preparation of Nebivolol or it's pharmaceutically acceptable salt. More particularly, the invention discloses an improved economical process for the preparation of intermediate, 6-fluoro-3,4- dihydro-2H-1-benzopyran-2-carboxaldehyde of Formula – II, converting the 6- fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde of Formula – II into mixture of [R*(S*)]-6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran and [R*(R*)]-6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran of Formula-V and separation of diastereomers of (R*)-6-Fluoro-3,4-dihydro-2-((S*)-oxiran-2-yl)- 2H-benzopran by forming azeotrope.
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- A NEW METHOD FOR PRODUCING NEBIVOLOL HYDROCHLORIDE OF HIGH PURITY
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The invention relates to a process for producing Nebivolol hydrochloride, (formula I) comprising the steps of: provision of a protected Nebivolol hydrochloride of the general formula (II), with P being an amine protecting group, and hydrogenation of said protected Nebivolol hydrochloride yielding Nebivolol hydrochloride of the formula (I).
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Page/Page column 20-21
(2015/09/22)
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- A PROCESS FOR THE PREPARATION OF 6-FLUORO-3,4-DIHYDRO-2H-CHROMENE- 2-CARBALDEHYDE
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The present invention relates to a process for ihe preparation of 6-f!uoro-3,4-dihydro- 2H-chromene-2-carbaidehyde which is useful as an Intermediate in the synthesis of Nebivolol or its pharmaceutical acceptable salts.
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Page/Page column 8
(2014/08/06)
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- METHOD FOR PRODUCING NEBIVOLOL
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The present invention relates to a method for producing racemic nebivolol represented by general formula (I) from the enantiomerically-pure compounds represented by formula (IVa) and (IVb); whereby racemic nebivolol is obtained through mixing enantiomerically-pure d-nebivolol and l-nebivolol which are synthesised independent of each other as enantiomerically-pure compounds through individual coupling of the 4 enantiomerically-pure key intermediates represented by formula (IIa-d) to the corresponding precursors represented by formula (IIIa-d); whereby d-nebivolol (Ia) is obtained through coupling (IIa) to (IIIb) or (IIb) to (IIIa) and l-nebivolol (Ib) is obtained through coupling (IIc) to (IIId) or (IId) to (IIIc), and PG in the intermediates represented by formula (IIa-d) is a hydrogen atom or an amine protection group, and X in the precursors represented by formula (IIIa-d) is a halogen atom, a hydroxyl group, an acyl group, an alkylsulfonyloxy group or an arylsulfonyloxy group, whereby intermediate (IIa) is formed from (IIIa), intermediate (IIb) is formed from (IIIb), intermediate (IIc) is formed from (IIIc), and intermediate (IId) is formed from (IIId), whereby the precursors represented by formula (IIIa) and (IIId) originate from the ketone precursor represented by formula (IVa), and the precursors represented by formula (IIIb) and (IIIc) originate from the ketone precursor represented by formula (IVb), and Z in the ketone precursors (IVa,b) is a halogen atom, a hydroxyl function, an acyl group, an alkylsulfonyloxy group or an arylsulfonyloxy group.
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- PROCESS FOR THE PREPARATION OF EPOXIDES AS INTERMEDIATES FOR THE SYNTHESIS OF NEBIVOLOL
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The present invention relates to a novel process of synthesis of epoxides, 6-fluoro-2- (oxiran-2-yl) chroman (Figure 1), intermediates for the synthesis of nebivolol, depicted in Scheme (1), enabling to obtain the above- mentioned epoxides in a racemic or semichiral form.
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Page/Page column 23; 24
(2013/03/26)
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- PROCESS FOR THE PREPARATION OF NEBIVOLOL
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The present invention relates to a novel process for the synthesis of the Nebivolol product depicted in Scheme 1, comprised of a reduced number of high-yield steps, and characterized by the enzymatic resolution of the chroman ester precursor.
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Page/Page column 21-22
(2012/07/28)
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- PROCESS FOR THE CONVERSION OF (2R)-6-FLUORO-2-[(2S)-OXIRAN-2-YL]-3,4-DIHYDRO-2H-CHROMENE TO (2R)-6-FLUORO-2-[(2R)-OXIRAN-2-YL]-3,4-DIHYDRO-2H-CHROMENE
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The present invention relates to a novel process for the conversion of (2R)-6-fluoro- 2-[(2S)-oxiran-2-yl]-3,4-dihydro-2H-chromene (formula lll-A) to (2R)-6-fluoro-2-[(2R)-oxiran- 2-yl]-3,4-dihydro-2H-chromene (formula lll-B). The compound of formula lll-
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Page/Page column 11-12
(2011/11/06)
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- PROCESS FOR THE PREPARATION OF NEBIVOLOL
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The present invention relates to a novel process for the synthesis of Nebivolol product represented in Scheme (1), comprised of a reduced number of high-yield steps, and characterized by the kinetic resolution of the two epoxide pairs diastereoisomeric therebetween (mixture 1), allowing to avoid complex chromatographic separations.
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Page/Page column 14
(2011/09/15)
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- PREPARATION OF NEBIVOLOL
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Processes for the synthesis of pharmacologically active 2,2-iminobisethanol derivatives, e.g., 2H-1-benzopyran-2 methanol-α,α′-iminobis(methylene)]bis-[6-fluoro-3,4-dihydro-[2R*[R*[R*(S*)]]]], and their pharmaceutically acceptable salts.
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Page/Page column 14-15
(2011/10/19)
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- An improved process for the preparation of nebivolol hydrochloride
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The present invention provides an improved process for the synthesis of Nebivolol and its pharmaceutically acceptable salts, more particularly hydrochloride salt of formula (I). Invention involves one pot synthesis of Nebivolol from epoxy monomer, which proceeds stereo specifically in high yield, without isolation of benzylated Nebivolol intermediate or its purification and does not require an additional purification of final compound.
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Page/Page column 8
(2010/04/24)
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- PROCESS FOR ISOLATION OF A MIXTURE OF RRRS AND SSSR CONFIGURATIONS OF NEBIVOLOL INTERMEDIATES
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The invention discloses a process for isolation of a mixture of RRRS and SSSR configurations of nebivolol intermediates represented by formulae II and III respectively, which is optionally selected from one of the following two manners: (1) precipitation solvent is added to alcohol solvent comprising the mixture of RRRS, SSSR, RRSR and SSRS configurations of nebivolol intermediates represented by formula I, heating, cooling to precipitate crystals and filtrating; (2) the mixture of RRRS, SSSR, RRSR and SSRS configurations of nebivolol intermediates represented by formula I is added into the mixture solvent of alcohol solvent and precipitation solvent, heating, cooling to precipitate crystals and filtrating. In formulae I, II and III, X is H, C1-C6 alkyl or C1-C6 alkoxy, n is 1-5.
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Page/Page column 8
(2010/10/19)
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- PROCESS FOR ISOLATION OF DESIRED ISOMERS OF NEBIVOLOL INTERMEDIATES
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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 about 30° C. to obtain the desired (+)-[2R*[1S*,5S*(S*)]]-α,α′-[phenylmethyliminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol].
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Page/Page column 3
(2009/04/24)
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- PROCESS FOR PREPARING NEBIVOLOL
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The present invention relates to a process for preparing Nebivolol and, more particularly, to an improved process for synthesizing enantiomerically enriched 6-fluoro chroman alcohol or epoxide derivatives of formula, wherein R and X is defined in the description; as useful intermediates in the preparation of Nebivolol.
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Page/Page column 24
(2008/12/06)
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- PROCESS FOR PREPARING NEBIVOLOL
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The present invention relates to a process for preparing nebivolol and, more particularly, to a process for preparing d-nebivolol and its enantiomer /-nebivolol or acid addition salts thereof starting from commercially available or easily obtainable 2,2-dimethyl-l,3 dioxolane-4- carbaldehyde and a vinyl Grignard reagent.
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Page/Page column 30-31
(2008/12/06)
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- PROCESS FOR ISOLATION OF DESIRED ISOMERS OF NEBIVOLOL INTERMEDIATES
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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].
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Page/Page column 5-6
(2008/06/13)
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- A process for preparation of racemic nebivolol
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A process of making racemic [2S*[R*[R*[R*]]]] and [2R*[S*[S*[S*]]]]-(±)α,α'-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] of the compound of the formula (I) and its pure [2S*[R*[R*[R*]]]]- and [2R*[S*[S*[S*]]]]- enantiomer comp
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Page/Page column 46-47
(2008/06/13)
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- Process for preparation of racemic Nebivolol
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A process of making racemic [2S*[R*[R*[R*]]]] and [2R*[S*[S*[S*]]]]-(±)α,α′-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] of the compound of the formula (I) and its pure [2S*[R*[R*[R*]]]]- and [2R*[S*[S*[S*]]]]-enantiomer compo
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Page/Page column 51
(2008/06/13)
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- A NOVEL PROCESS FOR PREPARATION OF NEBIVOLOL INTERMEDIATES
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The present invention relates to a process for separation of desired diastereomeric pair from a mixture of diastereomeric pairs thereby obtaining nebivolol intermediates. Thus, the mixture of (+)-[1S*(R*)]-6-fluoro-3,4-dihydro-α-[[(phenylmethyl)amino]methyl]-2H-1-benzopyran-2-methanol, (+)-[1S*(S*)]-6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran and ethanol is heated to reflux temperature and stirred for 8 hours at the same temperature to obtain (+)-[2R*[1S*,5S*(S*)]]+[2R*[1S*,5R*(R*)]]-α,α'-[phenylmethyliminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol]. Then the reaction mass is cooled to 10oC, the pH is adjusted to 2 with HCl gas and stirred for 45 minutes at 25oC to 30oC. Then the separated solid is filtered and dried to give (+)-[2R*[1S*,5S*(S*)]]-α,α'-[phenylmethyliminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2- methanol] hydrochloride salt, which can be converted into nebivolol.
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Page/Page column 8
(2008/06/13)
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- A mild synthesis of α,α′-[iminobismethylene]bis[6-fluoro- 3,4-dihydro-2H-1 -benzopyran-2-methanol]
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A new synthesis of α,α′-[iminobismethylene]bis[6-fluoro- 3,4-dihydro-2H-1-benzopyran-2-methanol (1) is described, with most reactions being carried out at room temperature and normal pressure, that will further contribute to the development of new scalable synthesis of the related drug substance of Nebivolol (overall yield: 33%).
- Bai, Yihui,Chen, Xinzhi
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p. 807 - 808
(2007/10/03)
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- NEBIVOLOL AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS, PROCESS FOR PREPARATION AND PHARMACEUTICAL COMPOSITIONS OF NEBIVOLOL
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The present invention provides an improved process for the synthesis of nebivolol or its pharmaceutically acceptable salts, more particularly hydrochloride salt of formula (I). The present invention further provides a new Form T1 of nebivolol and its pharmaceutically acceptable salts. The present invention also provides pharmaceutical compositions and process for the preparation of a solid oral dosage form of nebivolol hydrochloride of formula (I), without the use of wetting agent, and optionally using binder and /or disintegrant.
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Page/Page column 17-18; 34
(2010/10/20)
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- Method of lowering the blood pressure
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A method of potentiating the effects of blood pressure reducing agents in warm-blooded animals, said method comprising administering to said warm-blooded animals of an effective amount of a blood pressure reducing agent and a 2,2′-iminobisethanol derivative.
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