Asymmetric Synthesis of (R)- and (S)-Moprolol

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CHEM. RES. CHINESE UNIVERSITIES 2008,24(6), 747-75 1 Article ID 1005-9040~2008~-06-747-05

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Asymmetric Synthesis of (R)- and (8-Moprolol WANG Zhao-yang', WANG Yan', SUN Li-wen2 and ZHU Jin-tao'* 1. Department of Chemisty, Zhejiang Sci-Tech Universiv, Hangzhou 310018, P R. China; 2. Institute of Materia Medica, Zhejiang Academy of Medical Science, Hangzhou 310013, P R. China Abstract A simple and effective procedure for the enantioselective synthesis of (R)- and (8-moprolol was described. The key step was the asymmetric synthesis of enantiopure (R)- and (8-guaifenesin, which were synthesized from enantioenriched (R)-3-chloro- 1,2-propanediol and (8-epichlorohydrin via kinetics of hydrolysis resolution of racemic epichlorohydrin by chiral Salen-CoIn complex. The e.e. values of both the optical compounds were above 98%, and the chemical structures of the target compounds were confirmed by 'H NMR, I3CNMR, IR, and MS. Keywords (R)- and (8-Moprolol; (R)- and (8-Guaifenesin; Asymmetric synthesis

1 Introduction

All the chemicals were of analytical grade or chemically pure.

Moprolol [(R,S)-l -isopropylamino-3-(2-methoxyPhenoxY)-ProP~e-2-o1]is an important P-adrenergic 2.1 Synthesis of Salen-Co"' (Compound 1) block["21. Currently, moprolol as a drug in clinic is Salen-Co" was synthesized according to the lialways used as a racemic drug for its research on terature pro~edure['~"~]. pharmacology and toxicology. In recently years, the difference between the two enantiomers in pharma2.2 Synthesis of (S)-Epichlorohydrin(Compound cology is attracting more and more attenti~n'~'~]. 3) Therefore, the synthesis of (R)- and (9-moprolol has Water(36.3 mL, 2.018 mol) was slowly added to become a key issue not only in academic research but a stirred mixture of racemic epichlorohydrin(comalso in the pharmaceutical industry. However, most of pound 2, 350 mL, 4.484 mol) and complex (R,R)the approaches toward the synthesis of (R)- and Salen-Co" (compound 1, 2.96 g, 0.00448 mol), and (8-moprolol require the expensive chiral auxiliathe resulting mixture was held at room temperature for ries[5-121 and generally provide a single one of the two days, the reaction was monitored by GC. After enantiomers, moreover, the reported procedures suffer reaction, the crude product was distilled by a water from drawbacks such as low optical p ~ r i t y [ ~ , ~ " low ','~], pump to get a colorless oil (S)-epichlorohydrin(comoverall and tedious multistep seq~ence[~'~''']. pound 3). The yield was 40%, b. p. 116 "C, [a];'= Herein lies a simple and effective method for the syn+35.l(c=1, MeOH){literature data[? [a];' =+33 thesis of (R)-and (3-moprolol. (c=1.126, MeOH)}. 2 Experimental IR(film), D/cm-': 3637, 3063, 2925, 1480, 1432, 1398, 1254, 1136, 1092. 'H NMR(CDC13,400 MHz), The melting points were determined on an X-4 6: 2.69-2.70(d, lH), 2.89-2.90(d, lH), 3.25(m, lH), microcopic apparatus and uncorrected. The 'H NMR 3.55-3.64(d, 2H). and I3C NMR spectra were recorded on a Bruker Avavce-AV 400 spectrometer with CDCl3 as the sol2.3 Synthesis of (R)-3-Chloro-1,2-propanediol vent, TMS as the internal standard; the IR spectra (Compound 4) were measured on a Nicolet Vatar370 spectrometer Compound 4 was synthesized as compound 3 with KBr film; the mass spectra were obtained with a except the dose of water(44 mL, 2.444 mol). After Varian Saturn 2200 spectrometer; the optical rotations reaction, compound 3 was evaporated by a water were measured via a WZZ-2B automatic polarimeter. *Corresponding author. E-mail: [email protected] Received July 9, 2007; accepted October 16,2007. Copyright 02008, Jilin University. Published by Elsevier Limited. All rights reserved.

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pump, and the residue solvent was distilled by an oil pump to get a colorless oil (R)-3-chloro-1,2propanediol(compound 4). The yield was 42%, b. p. 100-105 "CI0.4 P a , [a]k0=-7.5(c=1, H20){literature data"']: [a];' =-7.4(c=I, H20)). IR(film), Clem-': 3340, 2950, 1710, 1636, 1432, 1337, 1266, 1100, 1067,931, 836, 819, 752. 'H NMR(CDC13, 400 lH), 3.60-3.70(m, 2H), MHz), 6: 3.55-3.58(d, 3.74-3.78(m, I H), 3.93-3.94(d, 1H).

2.4 Synthesis of (R)-3-(2-Methoxyphenoxy)-propane-1,2-diol [(R)-Guaifenesin, Compound 51 To a solution of Guaiacol(26.24 g, 0.21 mol) in 5% NaOH(200 mL), was added dropwise compound 4 (26.04 g, 0.24 mol), the resulting mixture was refluxed for 1.5 h. After reaction, it was cooled and extracted by CH2C12(100 mL X 3), the combined organic extract was evaporated and the residue was crystallized from toluene( 100 mL) to get a white solid. The crude product was recrystallized from ethyl acetate to give a pure compound 5. The yield is SO%, m. p. 97-99 "C, [a]$'=-9.5(c=l.O, MeOH) {literature data'? m. p. 96.8-99. l "C, [a];'=-9.4(~=1 .O, MeOH), 99.4% e.e.}. IR(KBr), Vlcm-': 3242, 2941, 2837, 1595, 1510, 1456, 1377, 1329, 1257, 1128, 1043, 1022, 993, 837, 744. 'H NMR(400 MHz, CDC13), 6: 3.77-3.83(m, 2H, CH2), 3.86(s, 3H, CH3), 4.06-4.09(m, 2H, CH2), 4.16-4.20(m, lH, CH), 6.89-7.01(m, 4H, Ar). I3CNMR( 100.6 MHz, CDC13), 6: 55.80(CH3), 63.87(CH20H), 7O.OO(CH2O), 72.13 (CH), 111.74 (c3Ar), 114.67(C6,r), 121.08(c4~,), 122.17(C5,4,), 147.91(C1~,),149.58(C2~,).MS, m/z(%): 198(M", 58), 163(33), 149(21), 124(100), 109(74), 95(12), 81(23), 63(12). 2.5 Synthesis of (4R)-4-(2-Methoxyphenoxy) Methyl-l,3,2-dioxathiolane-2-one (Compound 6) To a stirred and cooled(0 "C) solution of compound 5(5.0 g, 25 mmol) in CH2C12(200 mL) was added dropwise a solution of SOC12(3.1 g, 26 mmol) in CH2C12(50mL). The reaction mixture was stirred for extra 3 h, and the volatile material was removed under reduced pressure to afford compound 6(5.3 g), which was used in the next step without further purification. m.p. 65-69 "C, [a];'= 42.5(c= 1 '0, CH2C12) {literature data'16': m. p. 63-69 "C, [a]io=-42.3 (c= 1.0, CH2C12)}. IR(KBr), i7lcrn-I: 3018, 2933, 1592, 1508, 1460, 1330, 1257, 1228, 1126, 1018, 978, 876,

Vo1.24

736, 643. 'H NMR(400 MHz, CDC13), 6:3.85(~,3H, OCH3), 3.99-4.19[m, I . 14H, CH20Ar(trans)]; 4.25-4.46[m, 0.86H, CH20Ar(cis)]; 4.53-4.59, 4.68-4.71, 4.79-4.85[all m, totally 2H, CHzOS(cis, trans)]; 4.90-4.95[m, 0.43H, CHOS(cis)]; 5.235.32[m, 0.57H, CHOS(trans)]; 6.89-7.05(m, 4H, Ar). 13 C NMR(100.6 MHz, CDCl3), 6: 56.2(CH3); 68.8 [CH20S(cis)]; 69.0[CH20S(trans)]; 70.2[CH20Ar (trans)]; 70.9[CH20Ar(cis)J; 78.1[CHOS(trans)J; 80.2 [CHOS(cis)]; 112.8, 112.8(c3Ar), 116.4, 116.6(C6~,), 121.1, 121.1(c4Ar), 123.2, 123.4(c5Ar), 147.l(clAr), 150.4, 150.5(C2Ar).MS, m/z(%):244(M+, loo), 135(9), 121(52), 95(2), 63(4).

2.6 Synthesis of (R)-l-Isopropylamino-3-(2-methoxyphenoxy)-propane-2-ol[(R)-moprolol, Compound 71 A solution of dioxathiolane(compound 6, 1.08 g, 4.4 mmol) and i-PrNH2(4 g, 68 mmol) in DMF( 10 mL) was heated at 60-70 "C for 45 h. After the reaction was finished, excess amine and DMF were removed in vacuo. A solution of NaOH(35 mL, 1 mol/L) was added to it, the mixture was extracted with AcOEt (40 mL X 3), and the extract was dried with Na2S04. After removal of the solvent in vacuo, the residue was crystallized from cyclohexane to give compound 7(1.01 g, 80%). m. p. 78-80 "C, [a]$'= -5.6(c=5, C2HSOH){literaturedata''': m. p. 84-85 "C, [a]i'= -3.9(c=5, C2HSOH), 68% e.e.}. IR(KBr), D/cm-': 3468, 3342, 3278, 2966, 2933, 1602, 1593, 1507, 1455, 1380, 1332, 1256, 1228, 1128, 1027, 738. 1 H NMR(400 MHz, CDCl3), 6: 1.1l(d, 3H, CH3), 1.12(d, 3H, CH3), 2.77-2.93(m, 3H, CH20, NCH), 3.85( S, 3H, OCH3), 3.99-4.08(m, 3H, CH20, CH), 6.88( m, 4H, ArH). I3C NMR(100.6 MHz, CDC13), 6: 22.95(CH3), 22.99(CH3), 48.90(CH2N), 49.3 1 (CHN), 55.8O(OCH3), 68.34(CH), 72.94(OCH2), 111.9(C3A,), 114.8(C5Ar), 121.1(c4Ar), 121.9(C5Ar), 148.2(C'Ar), 149.8(C2Ar).MS, m/z(%): 239(Mt, 29), 224(3), 195 (5 l), 124(8), 77( 12), 72( loo), 56( 14).

2.7 Synthesis of (S)-3-(2-Methoxyphenoxy)-propane-l,2-diol[(S)-Guaifenesin, Compound 81 To a stirred solution of compound 3 (23 g, 0.249 mol) in water(40 g, 2.22 mol) was added dropwise concentrated sulfuric acid(0.03 mL), the reaction mixture was heated and refluxed for 1.5 h, then it was cooled to room temperature and 25% sodium

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WANG Zhao-yang et al.

hydro- xide(40 mL) and Guaiacol(27 g, 0.211 mol) were added in turn. The mixture was heated and refluxed for 1.5 h to finish the reaction monitored by TLC. It was cooled at room temperature and extracted by CH2C12(40mL X 3). The mixture was disposed like compound 5 to get a white solid 8 with a yield of 65%. m. p. 96-98 "C, [a]k0=+9.5(c=1.0, MeOH){literature data"? m. p. 96.8-99.1 "C, [a]t0=9.4(c=1.O, MeOH), 99.4% e x . > . IR(KBr), D/cm-': 3242, 2941, 2837, 1595, 1510, 1456, 1377, 1329, 1257, 1128, 1043, 1022, 993, 837, 744. 'H NMR(400 MHz, CDC13),8: 3.77-3.83(m, 2H, CH2), 3.86(s, 3H, CH3), 4.06-4.09(m, 2H, CH2), 4.16-4.20(m, lH, CH), 6.89-7.01(m, 4H, Ar). I3C NMR(100.6 MHz, CDC13), 6: 55.8O(CH3), 63.87 (CHlOH), 70.OO(CH20), 72.13(CH), 111.74(C3A,), 114.67(C6& 121.08(C4& 122.17(C5k), 147.91(C1k), 149.58(C2~,).MS, rn/z(%): 198(M+, 58), 163(33), 149(21), 124(100), 109(74), 95( 12), 8 1(23), 63( 12). 2.8 Synthesis of (4@-4-(2-Methoxyphenoxy) Methyl-l,3,2- dioxathiolane-2-one (Compound 9) Compound 9 was prepared in a similar way to making compound 6 except using compound 8 instead of compound 5. [a];'= +43.0(c=1.0, CH2C12){literature data [? m. p. 63-69 "C, [a]k'= +42.3(c=l .O, CH2C12)}.IR(KBr), Clem-': 3018, 2933, 1592, 1508, 1460, 1330, 1257, 1228, 1126, 1018, 978, 876, 736, 643. 'HNMR(400 MHz, CDC13), 6: 3.85(s, 3H, OCH3), 3.99-4.19[m, 1.14 H, CH20Ar(trans)], 4.25-4.46 [m, 0.86 H, CH20Ar(cis)], 4.53-4.59, 4.68-4.71, 4.79-4.85[a11 m, totally 2H, CH20S(cis, trans)], 4.90-4.95[m, 0.43 H, CHOS(cis)], 5.235.32[m, 0.57 H, CHOS(trans)], 6.89-7.05(m, 4H, Ar). 13C NMR(100.6 MHz, CDC13), 6: 56.2(CH3), 68.8[CH20S(cis)], 69.0[CH20S(trans)], 70.2[CH20Ar (trans)], 70.9[CH20Ar(cis)], 78.1[CHOS(trans)], 80.2 [CHOS(cis)], 112.8, 112.8(C3k), 116.4, 116.6 (C6,), 121.1, 121.1(C4k) 123.2, 123.4(C5k), 147.1 (CIA), 150.4, 150.5(C2&). Synthesis of (S)-l-Isopropylamino-3-(2-methoxyphenoxy)-propane-2-ol[(S)-moprolol, Compound 101

2.9

Compound 10 was prepared in a similar way to making compound 7 except using compound 9 instead of compound 6 , the yield was 82%. [a]$'= +5.5(c=5, C2H50H). IR(KBr), O/cm-': 3468, 3342, 3278, 2966,

749

2933, 1602, 1593, 1507, 1455, 1380, 1332, 1256, 1228, 1128, 1027, 738. 'H NMR(400 MHz, CDCI3),6: l.ll(d, 3H, CH3), 1.12(d, 3H, CH3), 2.77-2.93(m, 3H, CH20, NCH), 3.85(S, 3H, OCH3), 3.99-4.08(m, 3H, CH20, CH ), 6.88( m, 4H, ArH). I3C NMR(100.6 MHz, CDCl3), 6: 22.95(CH3), 22.99(CH3), 48.90 (CHzN), 49.3 l(CHN), 55.8O(OCH3), 68.34(CH), 72.94(0CH2), 111.9(C3~),1 14.8(CSh), 121.1(C4&), 121.9(Csk), 148.2(C'Ar), 149.8(C2h). MS, rn/z(%): 239(M+, 29), 224(3), 195(51), 124(8), 77(12), 72(100), 56( 14). 2.10 Synthesis of (R)-3-(2-Methoxypenyl)-1,2epoxypropane (Compound 11) from Compound 3

To a stirred solution of Guaiacol(21.5 g, 0.174 mol) and sodium hydroxide(7.6 g, 0.190 mol ) in anhydrous ethanol(250 mL) was added dropwise compound 3(48.2 g, 0.522 mol). The resulting reaction mixture was stirred for 8 h at room temperature. After completion of the reaction, the solvent was removed under reduced pressure to left a residue. Water( 100 mL)was added to the residue that was extracted by CH2C12(30 mL X 3). The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give a colorless oil(compound 11)(120 "C/ 0.1 kPa), the yield is 80%. [a];'= -9.2(c=1.0, CzHSOH), 65% e.e.{literature data"']: [a];'= -13.6 ( ~ 0 . 9 9 7 , CzHsOH), 97% e.e. >. IR(KBr), Okm-': 3001, 2929, 2837, 1593, 1504, 1454, 1255, 1224, 1180, 1027, 916, 779, 746. 'H NMR(400 MHz, CDC13), 6: 2.72-2.89(m, 2H, OCH2), 3.35-3.44(m, lH, OCH), 3.85(~,3H, OCH3), 3.97(d, lH, CH2), 4.20(d, lH, CH2), 6.93-7.01(m, 4H,ArH). 2.11 Synthesis of (R)-l-Isopropylamino-3-(2-methoxyphenoxy)-propane-2-ol[(R)-moprolol, Compound 71 from Compound 11

A solution of compound ll(12 g, 0.06 mol) and i-PrNH2(29 g, 0.49 mol) was refluxed for 8 h to finish the reaction monitored by TLC. After the reaction, excess amine was removed in vacuo. The residue was washed with HCl(25 mL, 2 moYL) and extracted with CHzC12(30 mLx2). The aqueous layer was neutralized with NaOH(2 mol/L) to pH 10 to get a crude product, which was recrystallized from cyclohexane to get a pure product 7 with a yield of 78%. [a]6'=-3.6 (c=5, C2H50H), 62% e.e.{literature dataig1:m. p. 84-

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CHEM. RES. CHINESE UNIVERSITIES

85 "C, [a];'= -3.9(c=5, CzHsOH), 68% e . e . } .

3 Results and Discussion High pure compound 3 or 4 could be prepared on the basis of the reaction kinetics of hydrolysis resolution of racemic epichlorohydrin under the Salen-Co"' catalysis(compound l ) , the yield was 40% or 42% (Scheme 1). In this step, it is worth noting that the result of e.e. value of compound 3 or 4 was greatly

2

Vo1.24

influenced by the dose of water. When more than 0.55eq. H20 was added into resolution reaction, the e.e. value of compound 3 remained very high. When less than 0.45eq. H 2 0 was added, the very nice e.e. value of compound 4 was obtained. So we could get high optical pure compound 3 or 4, respectively, by addition of different doses of water under the same catalysis.

3

1

Scheme 1 Hydrolysis kinetics resolution of racemic epichlorohydrin

The anion of Guaiacol, generated by deprotonation with NaOH, substituted the chloride of compound 4 to afford (R)-guaifenesin(compound 5, another useful pharmaceutical substance"81) with a yield of 80% and an e.e. value of 99%. Compound 5 was treated with thiony chloride at 0 "C to get (R)-6 almost quantitatively. Finally, compound 6 was refluxed smoothly with isopropylamine to give R-moprolol desirably with a yield of 80% and an e.e. value of >98% [Scheme 2, route(I)]. In fact, there was an alternative

method of the synthesis of compound 6 we have ever tried on, which involved conversion of compound 3 to the chiral oxirane(compound 11) in the presence of a base and amination of the latter by reflux for 8 h to get compound 7. It appears convenient but suffers from an extraordinary low enantiomeric purity of (R)-7(62% e.e.) [Scheme 2, route (II)]. This may be due to the two paths for the anion of Guaincol attracted on compound 3(Scheme 3).

OCH,

7

8

Scheme 2

9

10

Synthetic route of the (R)-moprolol, (R)-moprolol from compound 3 and (3-moprolol

a. 5%NaOH, reflux, 1.5 h; b. 0 "C, SOC12,3 h; c. i-PrNH2. DMF, 65-70 "C, 45 h; d. 0.3% H2S04, H20,90-95 "C, 1.5 h; e. 25% NaOH, Guaiacol, reflux, 1.5 h; f. 0 "C, SOC12, 3 h; g. Pr'NH2, DMF, 65-70 "C, 45 h; h. NaOH, ethanol, 8 h; i. Pr'NH2, reflux, 8 h.

For the structure of C1-activated 2,3-epoxyprane, most of the nucleophiles attacked on the C3-activated atom with opening and subsequent closure of the oxirane ring to form compound 11, minority of them directly attacked on the C' atom to form S-isomer, thus

leading to racemization. To obtain high optical purity of compound 10, we used the same tactic[Scheme 2 route(III)]. The high optical purity of compound 3 was hydrolyzed with 0.3% H2SO4 under refluxing to get (5')-3-Chloro-1,

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2-propanediol(92% e.e.). The optical purity of (53-3Chloro-1,2-propanediolhad little descended compared to that of its precursor (9-3. We also found that the higher concentration of the acid used was, the lower the optical purity of (S)-3-Chloro-1,2-propanediol obtained was, which indicated the carbonium ion affection functioning on. But the shortage could be covered by followed procedure. In the next step, the material of (S)-3-Chloro-1,2-propanediol with 92% e.e. was treated with Guaiacol in the presence of a base to give the crude (9-Guaifenesin(compound 8), which was recrystallized twice from ethyl acetate to free compound 8 very optical purity(99Y0 e.e. and 65% yield). Similarly it is cyclized by thiony chloride to form compound 9 and the latter is refluxed with isopropylamine to afford (9-moprolol with a yield of 82% and an e.e. value of >98%. In summary, we have provided a concise route starting from readily available and inexpensive racemic epichlorohydrin to prepare high optically active(R)-, (9-moprolol for pharmacological and toxicological study and pharmaceutical industry.

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