Preparation of (R)-2-chloro-l-(m-chlorophenyl)ethanol by Lipozyme TL IM-catalyzed second resolution

Availableonlineatwww.sciencedirect.comCHINESESciVerse scienceDirectCHEMICALLETTERSELSEVIERChinese Chemical Letters 23(2012)289-292www.elseviercomocate/ccletPreparation of (R)-2-chloro-1-(m-chlorophenyl)ethanol byLipozyme tL IM-catalyzed second resolutionShi Wen Xia * Hui Lin, Yong Zheng ChenCollege of Bio-information, Chongqing University of Posts and Telecommunications, Chongqing 400065, chinab Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, ChinaDepartment of Pharmacy, Zunyi Medical College, Zunyi 563003, ChinaReceived 9 October 2011Available online 28 January 2012Abstract(R)-2-Chloro-1-(m-chlorophenyl)ethanol, a precursor of (r)-3-chlorostyrene oxide which is the key chiral intermediate for thepreparation of several B3-adrenergic receptor agonists was prepared in 40% yield and 99%ee by the Lipozyme TL IM-catalyzedsecond resolution of the corresponding racemate in the presence of vinyl acetatC 2012 Shi Wen Xia. Published by elsevier B V. on behalf of Chinese Chemical Society. All rights reserved.Keywords:(R)-2-Chloro-1-(m-chlorophenyl)ethanol; LipozymeTL IM; Enzymatic transesterification; Vinyl acetate; Second resolution(R)-2-Chloro-l-(m-chlorophenyl)ethanol (-)-1 is a precursor of ( r)-3-chlorostyrene oxide which is the key chiralintermediate for the preparation of several B3-adrenergic receptor agonists that show antiobesity, antidiabetic andantidepression activities [1, 2](Scheme 1). To date, several chemical and biological methods for the preparation of(-)-I in enantiomerically pure or enriched form have been reported. Chemical reduction suffers from the problem of usingexpensive chiral catalysts and lower enantioselectivity. Asymmetric reduction of 2-chloro-1-(m-chloro-phenyl)ethanone using an oxazaborolidine-based catalyst gave ()-l in 87% yield and 86% ee [2]. The microbical synthesis of()-l was achieved by reduction of the corresponding ketone using an acetone powder of Geotrichum candidum in94% yield and 98%ee [3], or using the cell-free extract of Rhodotorula glutinis var. dairenensis Ifo 415 in 75% yieldand more than 99%ee [4] or using whole cells of Saccharomyces cerevisiae CGMCC 2. 396 in 90% yield and morethan 99%ee[5]. The enantiopure()-1 could be obtained from the bioreduction of the corresponding a-chloroketonewhile the low productivity of the bioreduction is still a challenge. The kinetic resolution of (=)-l is still an attractivemethod for the preparation of (-)-1 in case of the (+)-1 could be racemized efficiently. a practical synthesis of (R)-3-chlorostyrene oxide starting from 3-chloroethylbenzene was proposed in which(R)-2-bromo-(m-chlorophenyl)ethanol was obtained in more than 99% ee by the treatment of the corresponding racemate with lipase QLin the presence ofpropionic anhydride, the propionate was racemized in 92% yield by acid-catalyzed racemization [6]凵中国煤化工E-mailaddress:xiasw@cqupt.edu.cn(Sw.XiaCNMHG1001-8417/S-see front matter 2012 Shi Wen Xia. Published by Elsevier B V. on behalf of Chinese Chemical Society. All rights reserveddoi:101016 cclet201201008S.w. Xia et al. /Chinese Chemical Letters 23(2012)289-292、 C Lipozyme TL INCVA. TBMEA(-)-1Scheme 1. The resolution of racemic 1 by Lipozyme TL IMIn the present study, a novel and practical preparation of (-)-1 was achieved starting from(+)-1 in 40% yield and99% ee by commercially available Lipozyme TL IM in the presence of vinyl acetate based on the second resolutionstrategy(Scheme 1).1. ExperimentalRacemic 2-chloro-1-(m-chlorophenyl)ethanol was prepared from the reduction of 2-chloro-1-(3-chlorophenyl)-ethanone by NaBH4 Novozyme 435 and Lipozyme TL IM were a gift from Novo-Nordisk Co. Lipase CLL, LBK, HNand Dh were purchased from the domestic plants. All other chemicals used in this study were from commercial9o To a 500 mL Erlenmeyer shaking-flask were added 16g(0.084 mol)(+)-1, 1.6g Lipozyme TL IM, 14.6garces without further purification(0. 168 mol) vinyl acetate and 400 mL MTBE. The mixture was shaken for 48 h at 40C. After the reaction wascompleted, the enzyme was removed by filtration, and the filtrate was concentrated under certain vacuum. The residuewas subjected on silica gel chromatography with n-hexane: ethyl acetate(20: 1 )to give(-)-1: yellow oil, 9.4 g, 80%eeand(+)2: yellow solid,7.8g,99%ce.HNMR(300MHz,CDCl):81.18(,3H,J=7.5Hz),2342.54(m,2H,357(dd, IH, J=5.1 Hz and 10.8 Hz), 3.62(dd, 1H, J=7.5 Hz and 10.8 Hz), 5.94(dd, IH,J=5.1 Hz and 7. 5 Hz)7.22-7.31(m,1H,7.32(m,3H)To a 250 mL Erlenmeyer shaking-flask were added 9.4 g(-)-1(80% ee)obtained above, 0.8 g Lipozyme TL IM,7.4 g(0.084 mol) vinyl acetate and 200 mL TBME. The mixture was shaken for 12 h at 40C. After the reaction wascompleted, the enzyme was removed by filtration, and the filtrate was concentrated under reduced pressure.Theresidue was subjected on silica gel chromatography with n-hexane: ethyl acetate(20: 1)to give(-)-1: yellow oil, 7.648% yield, >99%ee. [alD4-3133(c09972, CHCl3)(lit. [6][a]D-33. 62(c 1.0, CH3OH). HNMR (300 MHzCDCl3):82.70(s,1H),3.61(d,1H,J=11.3 Hz and8.6Hz),3.74(d,1H,J=11.3 Hz and3.5Hz),4.90(d,1H,y1H NMR spectra were recorded on a Brucker-300(300/75 MHz) spectrometer in CDCl3. Gas chromatographic86 Hz and3.5Hz),7.247.32(m,3H),7.40(s,1Hanalyses were performed using a Fuli GC9790 with a chiral column( CP-Chirasil-DEX CB, Varian, USA)and usingflame ionization detector, nitrogen was used as the carrier gas at 1.5 mL/min, split ratio was 1: 50(v/v), the injector andthe detector temperatures were both set at 250C, the column temperature was programmed as being kept at80'Cfor3 min and then upgraded to 220C at a rate of 3C/min2. Results and discussionWe first examined the kinetic resolution of (+)-1 using different lipases with vinyl acetate at 30C and the resultsare illustrated in Table 1. Among the lipases examined, Lipozyme TL IM was effective for the resolution of (+)-1and(+)-2 was obtained in more than 99%ee, but(R)-1 remained moderate enantiomeric purity (56% eeThe enantiomeric excess of (-)-1 is determined by the yield of (+)-2 during the kinetic resolution of(+)-1.In orderto obtain(-)-1 with high enantiomeric excess, the kinetic resolution conditions, such as organic media, temperaturewater content, lipase/substrate ratio and reaction time, were investigated for the resolution of (+)-1 using LipozymeTL IM with vinyl acetate. In all cases, the enantioselectivity of (4)-2 by Linozvme TI. IM was not affected, thevariation of resolution conditions affected only the yield of (+)-2中国煤化工The reaction solvent always affects the enzyme activity and enaCNMHGresolution with lipaseThe effects of organic solvents to the kinetic resolution with LL lv were luusurateu in Table 2. Among thesolvents examined, the use of ether gave high yield and enantioselectivities. Especially with MTBE as the solvent, thereaction afforded(+)-2 with 36% yield and >99% ee(Table 2, entry 2)S.w. Xia et al./Chinese Chemical Letters 23(2012)289-292Table 1Resolution of ()-1 using various lipases with vinyl acetate.(+)2Yld(%)ee(%)Novozyme 435292Lipase CLLn.d.eLipase LBKdLipozyme TL IMLipase DHn.L.ndLipase HBnd50 mg(+)-1,5 mg lipases, 2 eq. vinyl acetate, 5 mL TBME, 24 h, 30Not reactedNot detectedTable 2The effect of solvents on the resolution of (+)-1EntSolvent(+)-2Yeld(%2MTBE37i-PT2022Hexane50 mg(+)-1, 5 mg Lipozyme TL IM, 2 eq. vinyl acetate, 5 mL solvents, 48 h, 30CResolution of (E-l using Lipozyme TL IM with vinyl acetate in MTBE at different temperatures was carried outfor 48 h. The yield of (+)-2 increased initially with the reaction time at a relatively high rate, reaching 36.5% at 30CThereafter, the yield increased at a much lower rate, reaching the maximum (38.5%)at 40C.The water content in the reaction system was also discussed. Resolution of (E-1 using Lipozyme tL IM with vinylacetate in MTBE containing different water content(1-100%)was carried out for 48 h at 40C. The presence ofmicro-water in TBME greatly decreased the yield of (+)-2, which was decreased to 3% yield in the presence of 1%(v/v) water from 38. 5% without additional waterMass ratio of the enzyme and substrate affects the enantioselectivity of the kinetic resolution greatly. (+)-2 wasobtained with 24% yield with 1: 20 of Lipozyme TI LM/(+)-1. When the mass ratio of Lipozyme TI LM/(+)-1 was1: 10, the yield of (+)-2 reached 38%. With further increase in mass ratio to 1: 2, the yield increased slightly to 40%Thus, from the economical point of view, the mass ratio of 1: 10 would be an appropriate choice for the resolution of(士)-2The yield of (+)-2 increased initially with the reaction time at a relatively high rate, reaching 36% at 48 hhereafter, the yield increased at a much lower rate, reaching 38% at 96 h incubationUnder the optimal conditions(Lipozyme TL IM/(+)1=1: 10, 40C, 48 h), the first round kinetic resolution of(E-1 using Lipozyme TL IM with vinyl acetate in mTBe was carried out. The reaction afforded the yield and eeof (+)-2 reached 40% and more than 99% respectively, the enantiopurity of the()-1 with 80% ee. In order toprepare the enantiopure()-l, we applied the second round kinetic resolution strategy to resolute(-)-1 with 80%ee from the first round, according the similar procedure to the first resolution. (-)-1 was obtained in 40% yield3. Conclusions中国煤化工In conclusion, (R)-2-chloro-l-(m-chlorophenyl)ethanol, a prectCNMH Intermediate for B3-energic receptor agonists was prepared with >99% ee using Lc" iL uvI uiruugn second resolution. Theusefulness of the resolution system provides an important approach for the preparation of(R)-a-halohydrins which aremportant chiral building blocks of various pharmaceuticalS.W. Xia et al. /Chinese Chemical Letters 23(2012)289-292AcknowledgmentWe are grateful for financial support from the National Natural Science Foundation of China(No. 20672110)References[1] D. Badone, U. Guzzi, Bioorg. Med. Chem Lett. 4(1994)1921[2]J D. Bloom, M.D. Dutia, B D. Johnson, et al. J. Med. Chem. 35(1992)3081.[3] H. Hamada, T. Miura, H. Kumobayashi, et al. Biotechnol. Lett. 23(2001)1603[4]K. Tanaka, M. Yasuda, Tetrahedron: Asymmetry 9(1998)3275[5]H. Lin, Y.C. Chen, x.Y. Xu, et al. J. Mol Catal. B: Enzym. 57(2009)1[6]N. Kizaki, I. Sawa, M. Yano, et al. Biosci. Biotechnol. Biochem. 69(2005)中国煤化工CNMHG