- Method for preparing levoterbutaline by using chiral prosthetic group
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The invention discloses a method for preparing levoterbutaline by using a chiral prothetic group, the method comprises the following steps: taking S-(-)-tert-butyl sulfinamide as a raw material, and sequentially reacting with tert-butyl bromide and 3, 5-dibenzyloxy bromoacetophenone to obtain a compound 5; performing reduction reaction on the compound 5 under the catalysis of quaternary ammonium salt to obtain a compound 6; and removing the protection of tert-butyl sulfinyl from the compound 6 to obtain a compound 7, and carrying out hydrogenolysis on the compound 7 in an alcohol solvent in the presence of a palladium catalyst and hydrochloric acid to obtain the levoterbutaline. The method is simple and reliable, the preparation cost is low, and the ee of the chiral product is as high as 99.9%.
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- Enantioselective resolution of Rac-terbutaline and evaluation of optically pure R-terbutaline hydrochloride as an efficient anti-asthmatic drug
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Terbutaline is a β2-adrenoceptor agonist for the treatment of asthma and chronic obstructive pulmonary disease (COPD). Among the two isomers of terbutaline (TBT 2), R-isomer was found to be the potent enantiomer in generating therapeutic effect, while S-isomer has been reported to show side effects. In this study, R-terbutaline hydrochloride (R-TBH 6) was synthesized through chiral resolution from the racemic terbutaline sulfate (rac-TBS 1) with 99.9% enantiomeric excess (ee) in good overall yield (53.6%). Further, R-TBH 6 nebulized solution was prepared in half dosage of Bricanyl, which is a marketed product of racemic terbutaline and evaluated in vitro aerosol performance and in vivo anti-asthmatic effect on guinea pigs via. pulmonary delivery. From the investigation, it is evident that R-TBH 6 nebulized solution of half dosage performed similar fine aerosol characteristics and anti-asthmatic effect with Bricanyl.
- Beng, Huimin,Zhang, Hao,Jayachandra,Li, Junxiao,Wu, Jie,Tan, Wen
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p. 759 - 768
(2018/03/27)
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- A method of preparing R-terbutaline
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A method of preparing R-terbutaline is disclosed for the first time. According to the method, 3,5-dibenzyloxyacetophenone is adopted as an initial material, is subjected to a bromination reaction, and then reduced by borane-methyl sulfide complex under catalysis by S-methyl-CBS; a product is coupled with N-benzyl-tert-butylamine, and then is hydrogenated to remove benzyl to prepare optically pure R-terbutaline; and the R-terbutaline is salted by utilizing a corresponding acid to prepare a medical salt of the R-terbutaline.
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- Chemo-enzymatic route for (R)-terbutaline hydrochloride based on microbial asymmetric reduction of a substituted α-chloroacetophenone derivative
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To synthesize (R)-terbutaline hydrochloride, a potent β2- adrenoceptor-stimulating agent, asymmetric reduction of a substituted α-chloroacetophenone derivative with cultured whole-cell biocatalyst of the yeast Williopsis californica JCM 3600 was developed as the key reaction. The reduction proceeded by a si-facial attack of hydride in a highly enantioselective manner. Co-factor generation was enhanced by applying glycerol as the carbon source.
- Taketomi, Shohei,Asano, Masayoshi,Higashi, Toshinori,Shoji, Mitsuru,Sugai, Takeshi
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- Synthesis of the Adrenergic Bronchodilators (R)-Terbutalinel and (R)-Salbutamol from (R)-Cyanohydrins
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Stereoselective syntheses of (R)-terbutaline and (R)-salbutamol acetal, which are important bronchodilators, starting from O-protected (R)-cyanohydrins are described. (R)-Terbutaline hydrochloride (R)-9·HCl is obtained in an overall yield of 44% with >98% ee from the O-bisallyl-protected cyanohydrin (R)-4k via a Ritter N-tertiary butylation to the amide (R)-6a, hydrogenation to the amino alcohol (R)-7a, and deprotection of the hydroxyl functions. (R)-Salbutamol acetals (R)-7b,c can be obtained from the corresponding O-protected (R)-cyanohydrins either via the route described for (R)-terbutaline or via selective hydrogenation of the protected cyanohydrin (R)-11 to the imino derivative, transimination with tert-butylamine, followed by hydrogenation with NaBH4 to give the 2-amino alcohol derivative (R)-12. Desilylation of (A)-12 to (R)-7c is performed with LiAlH4. Hydrolytic cleavage of the acetals (A)-7b and c to (R)-salbutamol was not yet possible without racemization.
- Effenberger, Franz,Jaeger, Juergen
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p. 3867 - 3873
(2007/10/03)
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