94991-72-7Relevant articles and documents
Enantiodivergent syntheses of (+)- and (?)-1-(2,6-dimethylphenoxy)propan-2-ol: A way to access (+)- and (?)-mexiletine from D-(+)-mannitol
Manna, Avrajit,Chatterjee, Sandip,Chakraborty, Ipsita,Bhaumik, Tanurima
, (2020/01/08)
Chiron approach was used to acquire optically pure (R)- and (S)-1-(2,6-dimethylphenoxy)propan-2-ol, immediate precursors of (S)- and (R)-mexiletines, respectively. Two different routes were followed from a D-mannitol-derived optically pure common precursor to get the enantiomeric alcohols separately. Comparison of their specific rotation values with the corresponding literature values as well as exact mirror-image relationship between their CD curves proved their high enantiopurity. These alcohols were then transformed to the corresponding amine-drugs in an efficient one-step process instead of two steps described in the literature.
Preparation of polar group derivative β-cyclodextrin bonded hydride silica chiral stationary phases and their chromatography separation performances
Zhao, Baojing,Li, Lan,Wang, Yuting,Zhou, Zhiming
, p. 643 - 649 (2018/11/27)
Three novel β-cyclodextrin compounds derived with piperidine which is flexible, L-proline containing a chiral center, ionic liquid with 3,5-diamino-1,2,4-triazole as the cation were designed and synthesized as chiral selectors for enantiomer separation, whose name were (mono-6-deoxy-6-(piperidine)-β-cyclodextrin, mono-6-deoxy-6-(L-proline)-β-cyclodextrin, mono-6-deoxy-6-(3,5-diamino-1,2,4-triazole)-β-cyclodextrin, multi-substituted 3,5-diamino-1,2,4- triazole-(p-toluenesulfonic)-β-cyclodextrin), respectively. In addition, to enhance the polarity of chiral stationary phases, hydrosilylation and silylation reactions were implemented to derive ordinary silica, the common used selector carrier, to hydride silica, whose surface is covered with proton. 31 pyrrolidine compounds and some chiral drugs were tested in both polar organic mobile phase mode and normal mobile phase mode. 6-Deoxy-6-L-proline-β-cyclodextrin-CSP showed satisfactory separations in polar organic mobile phase mode and exihibited a strong separation capability in different pH values; multi-substituted 3,5-diamino-1,2,4-triazole-(p-toluenesulfonic)-β-cyclodextrin-CSP can separate pyrrolidine compounds in both mobile phase modes with high resolutions and separation efficiency compared to commercially available CSPs, making it to be the most valuable object to study. The composition of mobile phase, type of stationary phase as well as the peak problem of chromatograms was discussed deeply.
Chiral aziridine ring opening: facile synthesis of (R)-mexiletine and (R)-phenoxybenzamine hydrochloride
Viswanadh,Velayudham,Jambu,Sasikumar,Muthukrishnan
, p. 5269 - 5271 (2015/08/26)
Abstract A simple and efficient synthesis of chiral drugs (R)-mexiletine 1, an anti-arrhythmic drug and (R)-phenoxybenzamine hydrochloride 2, an anti-hypertensive drug has been described via controlled reductive ring opening of chiral aziridine as a key step. The target compounds 1 and 2 were obtained in overall yields of 34% and 10.5%, respectively.
Continuous flow synthesis of chiral amines in organic solvents: Immobilization of E. coli cells containing both ω-transaminase and PLP
Andrade, Leandro H.,Kroutil, Wolfgang,Jamison, Timothy F.
supporting information, p. 6092 - 6095 (2015/02/19)
E. coli cells containing overexpressed (R)-selective ω-transaminase and the cofactor PLP were immobilized on methacrylate beads suitable for continuous flow applications. The use of an organic solvent suppresses leaching of PLP from the cells; no addition
Liquid chromatographic resolution of mexiletine and its analogs on crown ether-based chiral stationary phases
Jin, Kab Bong,Kim, Hee Eun,Hyun, Myung Ho
, p. 272 - 278 (2014/05/06)
Mexiletine, an effective class IB antiarrhythmic agent, and its analogs were resolved on three different crown ether-based chiral stationary phases (CSPs), one (CSP 1) of which is based on (+)-(18-crown-6)-2,3,11,12- tetracarboxylic acid and the other two (CSP 2 and CSP 3) are based on (3,3'-diphenyl-1,1'-binaphthyl)-20-crown-6. Mexiletine was resolved with a resolution (RS) of greater than 1.00 on CSP 1 and CSP 3 containing residual silanol group-protecting n-octyl groups on the silica surface, but with a resolution (RS) of less than 1.00 on CSP 2. The chromatographic behaviors for the resolution of mexiletine analogs containing a substituted phenyl group at the chiral center on the three CSPs were quite dependent on the phenoxy group of analytes. Namely, mexiletine analogs containing 2,6-dimethylphenoxy, 3,4-dimethylphenoxy, 3-methylphenoxy, 4-methylphenoxy, and a simple phenoxy group were resolved very well on the three CSPs even though the chiral recognition efficiencies vary with the CSPs. However, mexiletine analogs containing 2-methylphenoxy group were not resolved at all or only slightly resolved. Among the three CSPs, CSP 3 was found to show the highest chiral recognition efficiencies for the resolution of mexiletine and its analogs, especially in terms of resolution (RS). Chirality 26:272-278, 2014. 2014 Wiley Periodicals, Inc.
Asymmetric hydrolytic kinetic resolution with recyclable macrocyclic CoIII-salen complexes: A practical strategy in the preparation of (R)-mexiletine and (S)-propranolol
Sadhukhan, Arghya,Khan, Noor-Ul H.,Roy, Tamal,Kureshy, Rukhsana I.,Abdi, Sayed H. R.,Bajaj, Hari C.
, p. 5256 - 5260 (2012/06/01)
A chiral cobalt(III) complex (1 e) was synthesized by the interaction of cobalt(II) acetate and ferrocenium hexafluorophosphate with a chiral dinuclear macrocyclic salen ligand that was derived from 1R,2R-(-)-1,2-diaminocyclohexane with trigol bis-aldehyde. A variety of epoxides and glycidyl ethers were suitable substrates for the reaction with water in the presence of chiral macrocyclic salen complex 1 e at room temperature to afford chiral epoxides and diols by hydrolytic kinetic resolution (HKR). Excellent yields (47 % with respect to the epoxides, 53 % with respect to the diols) and high enantioselectivity (ee>99 % for the epoxides, up to 96 % for the diols) were achieved in 2.5-16 h. The CoIII macrocyclic salen complex (1 e) maintained its performance on a multigram scale and was expediently recycled a number of times. We further extended our study of chiral epoxides that were synthesized by using HKR to the synthesis of chiral drug molecules (R)-mexiletine and (S)-propranolol.
Immobilization of ω-transaminases by encapsulation in a sol-gel/celite matrix
Koszelewski, Dominik,Mueller, Nicole,Schrittwieser, Joerg H.,Faber, Kurt,Kroutil, Wolfgang
experimental part, p. 39 - 44 (2010/10/18)
Commercially available ω-transaminases ω-TA-117, -113, and Vibrio fluvialis (Vf-AT) have been immobilized in a sol-gel matrix. Improved results were obtained by employing Celite 545 as additive. The immobilized ω-transaminases ω-TA-117, -113, and V. fluvialis (Vf-AT) were tested in the kinetic resolution of α-chiral primary amines. In contrast to the free enzyme ω-TA-117, the sol-gel/celite immobilized enzyme showed activity even at pH 11. Recycling of the sol-gel/Celite 545 immobilized ω-transaminase ω-TA-117 was performed over five reaction cycles without any substantial loss in enantioselectivity and conversion. Finally, the immobilized ω-TA 117 was employed in a one-pot two-step deracemization of rac-mexiletine and rac-4-phenyl-2-butylamine, two pharmacologically relevant amines. The corresponding optically pure (S)-amines were obtained in up to 95% isolated yield (>99% ee).
Deracemisation of α-chiral primary amines by a one-pot, two-step cascade reaction catalysed by ω-transaminases
Koszelewski, Dominik,Clay, Dorina,Rozzell, David,Kroutil, Wolfgang
experimental part, p. 2289 - 2292 (2009/08/09)
Racemic a-chiral primary amines were deracemised to optically pure amines in up to >99 % conversion and >99 % ee within 48 h. The deracemisation was a result of a stereoinver- sion of one amine enantiomer; the formal stereoinversion was achieved by a one-pot, two-step procedure: in the first step, kinetic resolution of the chiral racemic amine was performed by employing a -transaminase to yield an intermediate ketone and the remaining optically pure amine; in the second step, the ketone intermediate was stereoselectively transformed into the amine by employing alanine as the amine donor and a -transaminase displaying opposite stereopref- erence than the -transaminase in the first step. In the second step, lactate dehydrogenase was used to remove the side product pyruvate to shift the unfavourable reaction equilibrium to the product side. Depending on the order of the en- antiocomplementary enzymes employed in the cascade, the (R), as well as the (S), enantiomer was accessible.
Deracemization of mexiletine biocatalyzed by ω-transaminases
Koszelewski, Dominik,Pressnitz, Desiree,Clay, Dorina,Kroutil, Wolfgang
supporting information; experimental part, p. 4810 - 4812 (2010/03/01)
(S)- as well as (R)-mexiletine [1-(2,6-dimethylphenoxy)-2-propanamine], a chiral orally effective antiarrhythmic agent, was prepared by deracemizatlon starting from the commercially available racemic amine using ω-transaminases In up to >99% ee and conver
A convenient synthesis of enantiomerically pure (R)-mexiletine using hydrolytic kinetic resolution method
Sasikumar, Murugesan,Nikalje, Milind D.,Muthukrishnan, Murugan
experimental part, p. 2814 - 2817 (2010/03/30)
Enantiopure (R)-mexiletine was prepared in a simple and practical way using hydrolytic kinetic resolution method of terminal epoxide by Jacobsen's catalyst. High enantiomeric purity (98% ee) was achieved and the method is well amenable to industrial scale-up.
