- PROCESS FOR THE PREPARATION OF ARFORMOTEROL OR SALT THEREOF
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Provided is an improved process for the preparation of arformoterol L-(+)-tartrate, and more specifically provided is a novel process for the preparation of arformoterol L-(+)-tartrate via arformoterol D-(?)-tartrate.
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Paragraph 0167
(2016/04/19)
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- PROCESSES FOR PREPARING SUBSTANTIALLY PURE ARFORMOTEROL AND ITS INTERMEDIATES
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Provided herein are improved, convenient and industrially advantageous processes for the preparation of N-[2-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]formamide (Arformoterol) or a pharmaceutically acceptable salt thereof, in high yield and purity. Provided further herein is an improved and industrially advantageous process for the preparation of a substantially enantiomerically pure arformoterol intermediate, (R)-4-methoxy-α-methyl-N-(phenylmethyl)benzeneethanamine.
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Page/Page column 13
(2012/01/13)
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- Process for preparation of intermediates of arformoterol
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An improved method for the preparation of optically pure isomers of Formoterol is disclosed, particularly the (R,R)-isomer.A method of preparation of substantially enantiomerically pure (R,R)-1-(4-Benzyloxy-3-nitro-phenyl)-2-[[2-(4-methoxy-phenyl)-1-methyl-ethyl]-(1-phenyl-ethyl)-amino]-ethanol to use in the production of (R,R)-Formoterol is also disclosedAn improved method for the preparation of optically pure isomers of Formoterol is disclosed, particularly the (R,R)-isomer. A method of preparation of substantially enantiomerically pure (R,R)-1-(4-Benzyloxy-3-nitro-phenyl)-2-[[2-(4-methoxy-phenyl)-1-methyl-ethyl]-(1-phenyl-ethyl)-amino]-ethanol to use in the production of (R,R)-Formoterol is also disclosed
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- The asymmetric synthesis of (R,R)-formoterol via transfer hydrogenation with polyethylene glycol bound Rh catalyst in PEG2000 and water
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(R,R)-formoterol was synthesized in seven steps with 4-hydroxyl-3-nitro- acetophenone as the starting material. The key intermediate, the chiral secondary alcohol 4, was prepared via Rh-catalyzed asymmetric transfer hydrogenation with (S,S)-PEGBsDPEN as the ligand and sodium formate as the hydrogen donor under mild conditions. With a mixture of PEG 2000 and water as the reaction media, the catalyst system could be recycled four times.
- Huang, Ling,Liu, Juntao,Shan, Wenjun,Liu, Bao,Shi, Anding,Li, Xingshu
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experimental part
p. 206 - 211
(2010/11/18)
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- PROCESS FOR THE SYNTHESIS OF ARFORMOTEROL
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The present invention provides a process for preparing a compound of formula (Vl) or a salt thereof, the process comprising: (i) reacting 4-methoxyphenyl acetone with an amine of formula (VIII) under conditions of reductive amination to produce a compound of formula (II) or a salt thereof, wherein there is no isolation of an imine intermediate formed during the reductive amination; (ii) condensing the compound (II) or the acid addition salt thereof with an α-haloketone of formula (III) to produce the compound of formula (IV); (iii) reducing the compound (IV) to a compound of formula (V); and (iv) reducing the compound (V) to the compound of formula (Vl), wherein the reduction is carried out in the presence of either (1 ) a hydrogen donating compound in the presence of a hydrogen transfer catalyst; or (2) ammonium formate using a hydrogenation catalyst, wherein: R1 and R2 are independently optionally substituted arylalkyl, and Hal is selected from chloro or bromo.
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Page/Page column 35-36
(2009/12/28)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF HIGH PURITY FORMOTEROL AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS
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The present invention relates to an improved process for the preparation of high purity formoterol and its pharmaceutically acceptable salts of Formula-I(C).
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Page/Page column 20; 23-24
(2010/11/30)
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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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- Administration of medicinal dry powders
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A method as well as a therapeutic metered combined dose are disclosed for a combined administration of medicinal dry powders. A metered medicinal dry powder combined dosage comprising at least two medicaments of separate dry powder formulations is prepared, whereby the metered powder quantity per medicament is deposited in a dose forming step creating the medicinal combined dose. The deposits of the at least two medicaments are suitably kept separated from each other, such that the medicaments cannot detrimentally interact after forming of the combined dose, and the medicinal combined dose is introduced into an inhaler device for a delivery of the powder dose during the course of a single inhalation. The therapeutic metered medicinal, combined dosage of finely divided dry medication powders disclosed comprises metered quantities of at least two medicaments, separately deposited and the medicinal combined dosage is adapted for a user initiated delivery of the dosage during a single inhalation through an inhaler device. The at least two medicaments of the medicinal combined dosage will generally be aerosolized simultaneously or sequentially during the inhalation such that a large proportion of each medicament will settle in the intended target area of the airways and lungs of a user.
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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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- Bronchodilating compositions and methods
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Bronchodilating compositions and methods are provided. The compositions are intended for administration as a nebulized aerosol. In certain embodiments, the compositions contain formoterol, or a derivative thereof. Methods for treatment, prevention, or amelioration of one or more symptoms of bronchoconstrictive disorders using the compositions provided herein are also provided.
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- An efficient enantioselective synthesis of (R,R)-formoterol, a potent bronchodilator, using lipases
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The potent β2-adrenergic receptor agonist formoterol (R,R)-1 has been obtained in enantiomerically pure form by a convenient chemoenzymatic approach by coupling of epoxide (R)-6 with the unprotected primary amine (R)-9. Both chiral precursors have been prepared by enantiodifferentiation processes involving Pseudomonas cepacia (lipase PS) and Candida antarctica lipase (CALB), respectively. For the resolution of amine 9, we have found that utilization of triethylamine as non-reactive base enhances the reaction rate and the enantioselectivity of the process. The key coupling reaction of (R)-6 and (R)-9 has been conducted through derivatization of the amine with the labile trimethylsilyl group, which liberates the amino group of the resulting amino alcohol (R,R)-11 upon column chromatography purification. In this way, the overall approach is shorter than others previously described. Copyright (C) 2000 Elsevier Science Ltd.
- Campos, Francisco,Bosch, M. Pilar,Guerrero, Angel
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p. 2705 - 2717
(2007/10/03)
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- Large-scale synthesis of enantio- and diastereomerically pure (R,R)-formoterol
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(R,R)-Formoterol (1) is a long-acting, very potent β2-agonist, which is used as a bronchodilator in the therapy of asthma and chronic bronchitis. Highly convergent synthesis of enantio- and diastereomerically pure (R,R)-formoterol fumarate is achieved by a chromatography-free process with an overall yield of 44%. Asymmetric catalytic reduction of bromoketone 4 using as catalyst oxazaborolidine derived from (1R, 2S)-1-amino-2-indanol and resolution of chiral amine 3 are the origins of chirality in this process. Further enrichment of enantio- and diastereomeric purity is accomplished by crystallizations of the isolated intermediates throughout the process to give (R,R)-formoterol (1) as the pure stereoisomer (ee, de >99.5%).
- Hett, Robert,Fang, Qun K.,Gao, Yun,Wald, Stephen A.,Senanayake, Chris H.
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- Enantio- and diastereoselective synthesis of all four stereoisomers of formoterol
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Enantioselective syntheses of all four stereoisomers of formoterol are accomplished using asymmetric catalytic borane reductions with chiral oxazaborolidines as reducing agents.
- Hett, Robert,Fang, Qun Kevin,Gao, Yun,Hong, Yaping,Butler, Hal T.,Nie, Xiaoyi,Wald, Stephen A.
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p. 1125 - 1128
(2007/10/03)
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