- An efficient enantioselective synthesis of (R,R)-formoterol, a potent bronchodilator, using lipases
-
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
-
-
Read Online
- Conformational toolbox of oxazaborolidine catalysts in the enantioselective reduction of α-bromo-ketone for the synthesis of (R,R)- formoterol
-
Several conformationally constrained oxazaborolidine catalysts have been evaluated in the reduction of ketone I. Readily accessible (1R, 2S) 1-amino- 2-tetralol (B-H) derived oxazaborolidine catalyst (6b) proves to be the most effective and practical catalyst in the reduction of bromo-ketone 1 (96% ee).
- Hett, Robert,Senanayake, Chris H.,Wald, Stephen A.
-
-
Read Online
- Diethylanilineborane: A practical, safe, and consistent-quality borane source for the large-scale enantioselective reduction of a ketone intermediate in the synthesis of (R,R)-formoterol
-
The development of a process for the use of N,N-diethylaniline - borane (DEANB) as a borane source for the enantioselective preparation of a key intermediate in the synthesis of (R,R)-formoterol L-tartrate, bromohydrin 2, from ketone 3 on kilogram scale is described. DEANB was found to be a more practical, safer, and higher-quality reagent when compared to other more conventional borane sources: borane - THF and borane - DMS.
- Wilkinson, H. Scott,Tanoury, Gerald J.,Wald, Stephen A.,Senanayake, Chris H.
-
-
Read Online
- Method for synthesizing arformoterol free alkali
-
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.
- -
-
Paragraph 0063; 0064; 0070; 0071; 0077; 0078
(2021/01/30)
-
- Preparation method of formoterol key intermediate
-
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.
- -
-
Paragraph 0080-0091; 0104; 0106; 0107
(2020/01/12)
-
- CLASS OF BIFUNCTIONAL COMPOUNDS WITH QUATERNARY AMMONIUM SALT STRUCTURE
-
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.
- -
-
Paragraph 0163
(2019/11/11)
-
- (S) or (R)-diphenyl-pyrrolidine methanol immobilized by pentaerythritol and its preparation method and application
-
The invention discloses a (S/R)-diphenyl-pyrrolidine methanol immobilized by pentaerythritol and its preparation method and application. The (S/R)-diphenyl-pyrrolidine methanol is shown as Formula (I). The preparation of the catalyst includes steps of reacting pentaerythritol with paratoluensulfonyl chloride to obtain pentaerythritol sulphonate; reacting with sodium azide to obtain pentaerythritecompound; reacting (S/R)-N-Cbz-4-hydroxyproline methyl ester with propargyl bromide to obtain (S/R)-N-Cbz-4-acetylene methoxy proline methyl ester; then reacting with chlorophenylmagnesium to obtain (S/R)-diphenyl-pyrrolidine methanol immobilized by pentaerythritol. The (S/R)-diphenyl-pyrrolidine methanol immobilized by pentaerythritol can be applied to the reaction of asymmetrical transformationand generation of prochiral phenyl ketones to be (R/S)- secondary alcohol; the catalyst can be recycled.
- -
-
Paragraph 0019; 0020; 0022
(2018/03/28)
-
- PROCESS FOR THE PREPARATION OF ARFORMOTEROL OR SALT THEREOF
-
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.
- -
-
Paragraph 0157
(2016/04/19)
-
- Design, synthesis and evaluation of dual pharmacology β2- adrenoceptor agonists and PDE4 inhibitors
-
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
-
p. 249 - 253
(2014/01/17)
-
- Dual β2-adrenoceptor agonists-PDE4 inhibitors for the treatment of asthma and COPD
-
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
-
p. 1523 - 1526
(2012/04/04)
-
- Corey-itsuno reduction of ketones: A development of safe and inexpensive process for synthesis of some API intermediates
-
A safe and inexpensive procedure for asymmetric reduction of ketones using in situ prepared N,N-diethylaniline borane (DEANB) and oxazaborolidine catalyst from sodium borohydride, N,N-diethylaniline hydrochloride and (S)-α,α-diphenylprolinol is described. This protocol is demonstrated successfully to manufacture enantiopure dapoxetine at the plant scale.
- Mahale, Rajendra D.,Chaskar, Sudhir P.,Patil, Kiran E.,Maikap, Golak C.,Gurjar, Mukund K.
-
supporting information; experimental part
p. 710 - 713
(2012/07/27)
-
- Development of an enabling route to PF-00610355: A novel inhaled β2-adrenoreceptor agonist
-
The initial route used to prepare PF-00610355 (8) for early clinical development is described. Through careful choice of solvent, an efficient, telescoped route to carboxylic acid 23 was developed, affording this late-stage intermediate in 80% yield over 4 steps. Deprotection of 23 to give sodium salt 24a and coupling with amine 6·HCl afforded the desired API. Effective synthetic routes to two of the starting materials, chiral bromide 1 and amine 6, are also described.
- De Koning, Pieter D.,Gladwell, Iain R.,Moses, Ian B.,Panesar, Maninder S.,Pettman, Alan J.,Thomson, Nicholas M.
-
p. 1247 - 1255
(2012/01/19)
-
- PROCESSES FOR PREPARING SUBSTANTIALLY PURE ARFORMOTEROL AND ITS INTERMEDIATES
-
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.
- -
-
Page/Page column 12-13
(2012/01/13)
-
- The asymmetric synthesis of (R,R)-formoterol via transfer hydrogenation with polyethylene glycol bound Rh catalyst in PEG2000 and water
-
(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
-
experimental part
p. 206 - 211
(2010/11/18)
-
- PHENYL SUBSTITUTED PYRAZINOYLGUANIDINE SODIUM CHANNEL BLOCKERS POSSESSING BETA AGONIST ACTIVITY
-
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.
- -
-
-
- ALIPHATIC PYRAZINOYLGUANIDINE SODIUM CHANNEL BLOCKERS WITH BETA AGONIST ACTIVITY
-
The present invention provides sodium channel blockers possessing beta-adrenergic receptor agonist activity.
- -
-
Page/Page column 51
(2010/11/29)
-
- Asymmetric transfer hydrogenation of ketones catalyzed by hydrophobic metal-amido complexes in aqueous micelles and vesicles
-
Asymmetric transfer hydrogenation of ketones, especially α-bromomethyl aromatic ketones, catalyzed by unmodified, hydrophobic transition metal-amido complexes (TsDPEN-M), was performed successfully with significant enhancement of activity, chemoselectivity, and enantio-selectivity (up to 99% ee) in aqueous media containing micelles and vesicles. The hydrophobic catalyst, embedded in micelles constructed from the surfactant cetyltrimethylammonium bromide (CTAB), could be separated from the organic phase along with the products and was recycled for at least six times.
- Wang, Fei,Liu, Hui,Cun, Linfeng,Zhu, Jin,Deng, Jingen,Jiang, Yaozhong
-
p. 9424 - 9429
(2007/10/03)
-
- Tricyclic compounds and drug compositions containing the same
-
Compounds having a β-3 adrenaline receptor agonist and are useful as drugs for the treatment and prevention of diabetes, obesity, hyperlipemia, etc., represented by a general formula (I) and salts thereof, and a process for producing these, and their intermediates, wherein R represents hydrogen or methyl; R1 represents hydrogen, halogen, hydroxy, benzyloxy, amino, or hydroxymethyl; R2 represents hydrogen, hydroxymethyl, NHR3, SO2 NR4 R4', or nitro; R6 represents hydrogen or lower alkyl; and X represents nitrogen, R9 represents hydrogen, one of R7 and R8 represent hydrogen, and the other thereof represents hydrogen, amino, acetylamino, or hydroxy.
- -
-
-
- Large-scale synthesis of enantio- and diastereomerically pure (R,R)-formoterol
-
(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.
-
-
- Enantio- and diastereoselective synthesis of all four stereoisomers of formoterol
-
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.
-
p. 1125 - 1128
(2007/10/03)
-