- Modulation of catalyst reactivity for the chemoselective hydrogenation of a functionalized nitroarene: Preparation of a key intermediate in the synthesis of (R,R)-formoterol tartrate
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In the synthesis of the β2-adrenoceptor agonist (R,R)-formterol, a key step in the synthesis was the development of a highly chemoselective reduction of (IR)-2-bromo-1-[3-nitro-4-(phenyl-methoxy)phenyl]ethan-1-ol to give (1R)-1-[3-amino-4-(phenyl-methoxy)phenyl]-2-bromoethan-1-ol. The aniline product was isolated as the corresponding formamide. The reaction required reduction of the nitro moiety in the presence of a phenyl benzyl ether, a secondary benzylic hydroxyl group, and a primary bromide, and with no racemization at the stereogenic carbinol carbon atom. The development of a synthetic methodology using heterogeneous catalytic hydrogenation to perform the required reduction was successful when a sulfur-based poison was added. The chemistry of sulfur-based poisons to temper the reacitivty of catalyst was studied in depth. The data show that the type of hydrogenation catalyst, the oxidation state of the poison, and the substituents on the sulfur atom had a dramatic effect on the chemoselectivity of the reaction. Dimethyl sulfide was the poison of choice, possessing all of the required characteristics for providing a highly chemoselective and high yielding reaction. The practicality and robustness of the process was demonstrated by preparing the final formamide product with high chemoselectivity, chemical yield, and product purity on a multi-kilogram scale.
- Wilkinson, H. Scott,Hett, Robert,Tanoury, Gerald J.,Senanayake, Chris H.,Wald, Stephen A.
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- Method for synthesizing arformoterol free alkali
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The invention discloses a method for synthesizing arformoterol free alkali, which comprises the following steps of: (1) performing carbonyl chiral reduction reaction on a compound shown as a formula SM1 serving as a raw material in a first solvent to obtain a reaction solution containing a compound shown as a formula M1, and concentrating to dryness; (2) dissolving the material obtained in the step (1) with a second solvent, carrying out a hydrogenation reaction to obtain a reaction liquid containing a compound represented by a formula M2, filtering the reaction liquid, and cooling the filtrate; (3) carrying out formylation reaction on the filtrate cooled in the step (2) to obtain a reaction solution containing a compound as shown in a formula M3, and concentrating to dryness; (4) dissolving the material obtained in the step (3) with a third solvent, carrying out a cyclization reaction to obtain a reaction liquid containing a compound represented by a formula M4 and free SM2, filtering, and concentrating the filtrate to dryness; and (5) dissolving the material obtained in the step (4) with a fourth solvent, carrying out a condensation reaction to obtain an arformoterol precursor represented by a formula M5, and carrying out hydrogenation debenzylation on the M5 to obtain arformoterol.
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Paragraph 0063; 0066; 0070; 0073; 0077; 0080
(2021/01/30)
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- CLASS OF BIFUNCTIONAL COMPOUNDS WITH QUATERNARY AMMONIUM SALT STRUCTURE
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The invention provides a class of compounds represented by formula (I), having bifunctional active quaternary ammonium salt structure of a β2-adrenoreceptor agonist and an M receptor antagonist, a pharmaceutically acceptable salt, solvate, and optical isomer thereof. A pharmaceutical composition comprising such a compound with quaternary ammonium salt structure, a method for preparing such a compound with quaternary ammonium salt structure and an intermediate thereof, and uses thereof in treating pulmonary disorders are also provided. The compounds of the invention have high selectivity to the M receptor subtype, and have less adverse reaction and lower toxic and side effects in the treatment of pulmonary diseases such as COPD and asthma.
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Paragraph 0165
(2019/11/11)
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- Preparation method of formoterol key intermediate
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The invention provides a preparation method of a formoterol key intermediate (R)-N-(2-(benzyloxy)-5-(2-bromo-1-hydroxyethyl)phenyl)formamide represented by a formula I, wherein asymmetric reduction isperformed by using 1-(4-(benzyloxy)-3-nitrophenyl)-2-bromoethanone (II) as a raw material and using (3aS-cis)-(-)-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazole-2-isopropylborane (IV) as a catalyst toobtain a chiral alcohol intermediate (R)-1-(4-(benzyloxy)-3-nitrophenyl)-2-bromoethanol (III) with high enantioselectivity, and then nitro reduction and formylation one-pot reaction are performed to obtain a target product represented by the formula I. Compared with the traditional resolution method, the method of the invention has advantages of high chiral purity of the product, short productionperiod, easy operation, mild condition, convenient post-treatment and high yield, and is suitable for large-scale industrial production.
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Paragraph 0092-0103; 0104; 0105; 0108; 0109
(2020/01/12)
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- 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 0159
(2016/04/19)
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- Design, synthesis and evaluation of dual pharmacology β2- adrenoceptor agonists and PDE4 inhibitors
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A novel series of formoterol-phthalazinone hybrids were synthesised and evaluated as dual pharmacology β2-adrenoceptor agonists and PDE4 inhibitors. Most of the hybrids displayed high β2-adrenoceptor agonist and moderate PDE4 inhibitory activities. The most potent compound, (R,R)-11c, exhibited agonist (EC50 = 1.05 nM, pEC50 = 9.0) and potent PDE4B2 inhibitory activities (IC50 = 0.092 μM).
- Huang, Ling,Shan, Wenjun,Zhou, Qi,Xie, Jiaxing,Lai, Kefang,Li, Xingshu
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p. 249 - 253
(2014/01/17)
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- Dual β2-adrenoceptor agonists-PDE4 inhibitors for the treatment of asthma and COPD
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We designed and synthesized a novel class of dual pharmacology bronchodilators targeting both b2-adrenoceptor and PDE4 by applying a multivalent approach. The most potent dual pharmacology molecule, compound 29, possessed good inhibitory activity on PDE4B2 (IC50 = 0.278 μM, which was more potent than phthalazinone, IC50 = 0.520 lM) and possessed excellent relaxant effects on tracheal rings precontracted by histamine (pEC50 = 9.3).
- Shan, Wen-Jun,Huang, Ling,Zhou, Qi,Jiang, Huai-Lei,Luo, Zong-Hua,Lai, Ke-Fang,Li, Xing-Shu
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p. 1523 - 1526
(2012/04/04)
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- BI-FUNCTIONAL QUINOLINE ANALOGS
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Provided are compounds of Formula I: wherein X is: R1 and R2 together with the phenyl to which they are bound may form a bicyclic, fused heterocyclic ring, and all other variables are as defined herein, as well as their use in treating pulmonary inflammation or bronchoconstriction and compositions comprising and processes for preparing the same.
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Paragraph 0294
(2013/03/26)
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- BI-FUNCTIONAL PYRAZOLOPYRIDINE COMPOUNDS
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This invention provides compounds of the formula: wherein X is wherein R1 and R2 together with the phenyl to which they are bound may form a bicyclic, fused heterocyclic ring and all other variables are as defined herein, their use in pulmonary inflammation or bronchoconstriction therapy and compositions comprising and processes for preparing the same are provided.
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Page/Page column 27
(2011/11/13)
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- ALIPHATIC PYRAZINOYLGUANIDINE SODIUM CHANNEL BLOCKERS WITH BETA AGONIST ACTIVITY
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The present invention provides sodium channel blockers possessing beta-adrenergic receptor agonist activity.
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Page/Page column 51-52
(2010/11/29)
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- PHENYL SUBSTITUTED PYRAZINOYLGUANIDINE SODIUM CHANNEL BLOCKERS POSSESSING BETA AGONIST ACTIVITY
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The present invention relates to sodium channel blockers. The present invention also includes a variety of methods of treatment using these inventive sodium channel blockers.
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Page/Page column 41; 69-70
(2008/06/13)
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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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