- Structural isomers of saligenin-based β2-agonists: Synthesis and insight into the reaction mechanism
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Salmeterol and albuterol are well-known β2-adenoreceptor agonists widely used in the treatment of inflammatory respiratory diseases, such as bronchial asthma and chronic obstructive pulmonary disease. Here we report the preparation of structural isomers of salmeterol and albuterol, which can be obtained from the same starting material as the corresponding β2-agonists, depending on the synthetic approach employed. Using 1D and various 2D NMR measurements, we determined that the structure of prepared isomers holds the β-aryl-β-aminoethanol moiety, in contrast to the α-aryl-β-aminoethanol moiety found in salmeterol and albuterol. We investigated the reaction of β-halohydrin and amines responsible for the formation of β-aryl-β-amino alcohol-both experimentally and using computational methods. The structure of β-halohydrin with the methyl salicylate moiety imposes the course of the reaction. The solvent plays a relevant, yet ambiguous role in the direction of the reaction, while the strength of the base influences the reaction yield and isomer ratio in a more evident way. Using computational methods, we have shown that the most probable reaction intermediate responsible for the formation of the unexpected isomer is the corresponding para-quinone methide, which can be formed due to phenol present in the methyl salicylate moiety. After successful preparation of albuterol and salmeterol isomers, we tested their inhibition potency to human acetylcholinesterase (AChE) and usual and atypical butyrylcholinesterase (BChE). Kinetic studies revealed that both isomers are low-potency reversible inhibitors of human cholinesterases.
- Kne?evi?, Anamarija,Novak, Jurica,Bosak, Anita,Vinkovi?, Marijana
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p. 9675 - 9688
(2020/12/28)
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- Preparation method of Salmeterol Xinafoate
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The invention discloses a preparation method of Salmeterol Xinafoate. The method comprises the following steps: condensation reaction of a compound 2 and a compound 3 under alkaline conditions to obtain an intermediate 4; acidic hydrolysis to obtain an intermediate 5, and reduction reaction of the intermediate 5 to obtain an intermediate 6; debenzylation of the intermediate 6 by use of palladium carbon (Pd / C) to obtain a salmeterol basic group; and salification from the salmeterol basic group and 1-hydroxy-2-naphthoic acid to obtain the Salmeterol Xinafoate. The preparation method has the advantages of mild reaction condition, simple post-treatment, low cost, high yield, high product purity and easy industrialization.
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- Preparation method of salmeterol base
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The invention discloses a preparation method of salmeterol. The method includes the following steps: carrying out a condensation reaction on a compound 2 and a compound 3 under an alkaline condition to obtain an intermediate 4; carrying out acidic hydrolysis to obtain an intermediate 5, and reducing the intermediate 5 to obtain an intermediate 6; and removing a benzyl group from the intermediate 6 by using palladium on carbon (Pd/C) to obtain a salmeterol base. The preparation method has the advantages of mild reaction conditions, simple post-treatment, low cost, high yield high product purity, and easiness in realization of industrialization.
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Paragraph 0042; 0047
(2017/11/08)
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- PROCESS FOR THE PREPARATION OF SALMETEROL XINAFOATE
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The present invention relates to an improved process for the preparation of Salmeterol Xinafoate of Formula (I).
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Page/Page column 14; 15
(2017/11/03)
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- PROCESS FOR THE PREPARATION OF SALMETEROL AND ITS INTERMEDIATES
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The present invention discloses a process for the preparation of methyl 2-(benzyloxy)- 5-(2-bromoacetyl)benzoate (V), comprising: (d) benzylating methyl-5-acetyl-2-hydroxybenzoate (VIII) with benzyl chloride in the presence of a base and a catalyst in a suitable polar solvent to obtain 5-acetyl-2- benzyloxy benzoate (VII); (e) brominating methyl 5-acetyl-2-(benzyloxy)benzoate (VII) with a suitable brominating agent in one or more suitable' solvents in the presence of an acid catalyst to obtain methyl 2-(benzyloxy)-5-(2-bromoacetyl)benzoate V; (c) optionally, purifying the methyl 2-(benzyloxy)-5-(2-bromoacetyl)benzoate (V) in a suitable solvent; and (f) isolating the methyl 2-(benzyloxy)-5-(2-bromoacetyl)benzoate (V).
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Page/Page column 29
(2012/03/27)
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- SUBSTITUTED ETHANOLAMINES
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The present invention relates to new substituted ethanolamine adrenergic receptor modulators, pharmaceutical compositions thereof, and methods of use thereof.
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Page/Page column 22-23
(2010/02/17)
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- Compositions and methods for inducing adipose tissue cell death
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Pharmaceutical compositions, methods for increasing the rate of apoptosis in adipose tissue cells, and methods of reducing adipose tissue mass in a host, are described. One exemplary pharmaceutical composition, among others, includes at least one catecholamine in combination with a pharmaceutically acceptable carrier. The catecholamine is present in a dosage level effective to increase the rate of apoptosis in adipose tissue cells in a host.
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- Combined doses
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The present invention discloses a method and a pharmaceutical dry powder combined dose for the prophylaxis or treatment of a respiratory disorder in a mammalian host by inhalation of a metered dry powder combined dose of finely divided dry medication powders. At least one dry powder medicament is selected from a first group of bronchodilating medicaments and at least one dry powder medicament from a second group of anti-inflammatory medicaments. A metered dry powder medicinal combined dose comprising separately metered deposits of medicinally suitable quantities of each of the selected medicaments is prepared, in which the sum of the metered deposits constitutes the metered quantities of powder of the combined dose and the medicinal combined dose is introduced into an adapted inhaler device for a generally simultaneous delivery of the medicinal combined dose during the course of a single inhalation by a user, such that the delivered medicinal combined dose is composed of a high proportion of mixed de-aggregated fine particles of the selected medicaments, whereby an desired therapeutic or treating effect to the user is achieved.
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- Method and apparatus for producing dry particles
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Method and apparatus for producing dry particles. Two liquid components are combined in a static mixer, atomized into droplets, and the droplets dried to form dry particles. Use of the static mixer enables incompatible liquid components to be rapidly and homogeneously combined. The present invention optimizes process conditions for increasing and controlling particle porosity. The present invention also allows for optimization of particle size in real-time during particle production.
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- Method and apparatus for producing dry particles
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Method and apparatus for producing dry particles. Two liquid components are combined in a static mixer, atomized into droplets, and the droplets dried to form dry particles. Use of the static mixer enables incompatible liquid components to be rapidly and homogeneously combined. The present invention optimizes process conditions for increasing and controlling particle porosity. The present invention also allows for optimization of particle size in real-time during particle production.
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- Derivatives of 6-(4-phenylbutoxy)hexylamine and process for producing Salmeterol
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The present invention refers to new derivatives of the 6-(4-phenylbutoxy)hexylamine of the general formula (I): wherein: R1is CHO or CHOR3OR4, where R3and R4independently are C1-C6alkyl, aralkyl, or they form 5 or 6 membered cyclic acetals; and R2is H, benzyl or an alkyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl or acyl group; and to a process for its obtention. The invention also refers to a new process for obtaining Salmeterol or its pharmaceutically acceptable salts, characterized in that reaction of an organometallic compound of the general formula (13) is carried out in an inert solvent at low temperature with a synthetic intermediate of the general formula (I), wherein R1is CHO, and R2is an alkyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl or acyl group.
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Page column 12-13
(2010/02/05)
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- A convenient stereoselective synthesis of (R)-(-)-denopamine and (R)-(-)-salmeterol
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β-Adrenoreceptor agonists (R)-(-)-denopamine (R)-1 and (R)-(-)-salmeterol (R)-2 have been prepared in good overall yield and high enantioselectivity through a biotransformative pathway.
- Goswami, Jonali,Bezbaruah, Rajiv L.,Goswami, Amrit,Borthakur, Naleen
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p. 3343 - 3348
(2007/10/03)
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- A new synthetic approach to salmeterol
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In the present work a short and convenient route for the synthesis of salmeterol from salicylaldehyde has been developed.
- Rong, Yajing,Ruoho, Arnold E.
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p. 2155 - 2162
(2007/10/03)
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- Substituted oxazolidines
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The invention relates to novel substituted oxazolidines of formula (I) wherein R1 and R2 are simultaneously hydrogen or both together are the identical lower alkyl radical, and to the salts thereof in racemic and chiral form, to a process for the preparation of said compounds, to pharmaceutical compositions containing them, and to the use thereof as medicaments. The compounds have a stimulating effect on beta-adrenergic receptors and can be used, inter alia, for the treatment of diseases associated with reversible obstruction of the respiratory tract, typically asthma and chronic bronchitis, and also for inflammation of different origin.
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- PHENETHANOLAMINE DERIVATIVES
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Phenethanolamine derivatives are disclosed of formula STR1 wherein m is 2 to 8; n is 1 to 7 provided that m+n is 4 to 12; Ar is phenyl or phenyl substituted by one or two halogen atoms, alkyl or alkoxy groups or by an alkylenedioxy group;R. sup.1 and R 2 are hydrogen or alkyl provided that the sum total of carbon atoms in R 1 and R 2 is not more than 4; and the physiologically acceptable salts and solvates thereof. The compounds have a selective stimulant action at β 2-adrenoreceptors and may be used inter alia in the treatment of diseases associated with reversible airways obstructions such as asthma and chronic bronchitis. The compounds may be formulated in conventional manner as pharmaceutical compositions with physiologically acceptable carriers or excipients.The compounds may be prepared, for example by alkylation of an amine: STR2 where R 3, R 5 and R 6 is hydrogen or a protecting group, followed by removal of any protecting group.
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