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Synthesis of (S) and (R)-tilisolol hydrochloride
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Chinese Chemical Letters 20 (2009) 648–650 www.elsevier.com/locate/cclet
Synthesis of (S) and (R)-tilisolol hydrochloride Shan Qian, Xiao Juan Ye, Fan Zheng, Li Yang, Yong Wu * Key Laboratory of Drug Targeting, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, China Received 27 October 2008
Abstract Tilisolol hydrochloride 1, a non-selective b-adrenoceptor blocker, was developed as a drug for the treatment of hypertension and angina pectoris. The optical active forms of 1, 1a and 1b were synthesized from inexpensive phthalic anhydride 2 in eight steps with 13% (S) and 15% (R) overall yield. # 2009 Yong Wu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved. Keywords: Tilisolol hydrochloride; Optical; Synthesis
Tilisolol hydrochloride 1, a non-selective b-adrenoceptor blocker, was developed as a drug for the treatment of hypertension and angina pectoris [1]. In addition to its effects as b-adrenoceptor blocker, 1 is likely to have additional effects that may include peripheral as well as coronary vasodilation and demand-independent anti-ischemic action [2]. 1 is commercialized in the racemic form, but there are not any reports about the synthesis of the optical forms, as well as biological activity [3] (Fig. 1). We plan to research biological activity of optical tilisolol hydrochloride. Therefore, in this paper, we describe the synthesis of 1a and 1b. The synthetic pathway was outlined in Scheme 1. Phthalic anhydride 2 was alcoholized by methanol as the known method [4] to afford the monomethylester 3. 3 were chlorinated with oxalyl chloride to give the activated chloride derivative [5], which was reacted with sarcosine methyl ester hydrochloride [6] to give amide 4. 4 were cyclizated in sodium methoxide–methanol solution to give isoquinoline derivative 5, which was decarboxylated in NaOH aq. to get the key immediate 6 [5]. Then 6 were substituted by optical active 2-(tosylmethyl) oxirane under the effectiveness of sodium hydride to obtain 7a and 7b, respectively (97%ee, determined by chiral HPLC analysis, Daicel chiralcel OD) [7]. Oxirane 7a and 7b were produced by ring cleavage with 2-methylpropan-2-amine in methanol and then converted to corresponding hydrochlorides 1a and 1b with chloride hydrogen–methanol [8]. Herein, we had to mention that Yao [9] quite recently reported the preparation of these two optical isomer 1a and 1b after we completed the synthesis of 1a and 1b. This method had a number of serious disadvantages [10]. In summary, we described an efficient route for the synthesis of optical active forms of tilisolol hydrochloride, 1a and 1b, from inexpensive phthalic anhydride in eight steps with 13% (S) and 15% (R) overall yield. Biological evaluation of them compared with racemic tilisolol hydrochloride is in progress.
* Corresponding author. E-mail address: [email protected] (Y. Wu). 1001-8417/$ – see front matter # 2009 Yong Wu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved. doi:10.1016/j.cclet.2008.12.048
S. Qian et al. / Chinese Chemical Letters 20 (2009) 648–650
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Fig. 1. The structure of the compound 1.
Scheme 1. The synthetic route of 1a and 1b. Condition and regent: (a) MeOH, 78%; (b) i: (COCl)2, DMF; ii: sarcosine methyl ester hydrochloride, 82% in two steps; (c) NaOMe, MeOH, 76%; (d) NaOH, 73%; (e) (S)-2-(tosylmethyl) oxirane, NaH, 55% for 7a: or (R)-2-(tosylmethyl) oxirane, NaH, 60% for 7b; (f) 2-methylpropan-2-amine; HCl–MeOH, 1a: 67% in two steps; 1b: 70% in two steps.
Acknowledgments This work was supported by the National Natural Science Foundation of China (No. 30672537).
References [1] [2] [3] [4] [5] [6] [7]
M. Fosset, J.R. Dewille, R.D. Green, et al. J. Biol. Chem. 263 (1988) 7933. S. Takagi, Y. Kihara, T. Mitsuiye, et al. Cardiovas. Drug Rev. 16 (1998) 105. T. Imaizumi, A. Takeshita, N. Nakamura, et al. Arzneimittelforschung 38 (1988) 1342. E.L. Eliel, A.W. Burgstahler, J. Amer. Chem. Soc. 71 (1943) 2251. J.G. Lombardino, J. Heterocycl. Chem. 10 (1970) 1057. J.F. O’Connell, J. Parquette, W.E. Yelle, et al. Synthesis 10 (1988) 767. Typical experimental procedure for 7 is as follow: To the solution of 2-(tosylmethyl) oxirane (244 mg, 1 mmol) and sodium hydride (34 mg, 1.4 mmol) in dry N,N-dimethylformamide (DMF) (10 mL) was added the solution of immediate 6 (175 mg, 1 mmol) in DMF (10 mL), and then reaction mixture was stirred for 3 h at 50 8C under the protection of argon. After poured into water, the solution was extracted by dichloromethane and the collected organic layer was washed by water until DMF was vanished. After the solution was dried and concentrated in vacuum, 7 (7a: 127 mg, 55%; 7b: 139 mg, 60%) were obtained via recrystallization. Selected data for compound 7a: mp: 131–132 8C; IR (KBr): 1655, 1600, 1580, 1230, 750 cm1; 1H NMR (400 Mz, CDCl3, dppm): 8.44 (dd, 1H, J = 0.8, 8.0 Hz), 7.92 (d, 1H, J = 7.6 Hz), 7.48 (dt, 1H, J = 1.2, 7.6 Hz), 7.55 (dt, 1H, J = 1.2, 8.0 Hz), 4.25 (dd, 1H, J = 2.4, 10.8 Hz), 3.90 (dd, 1H, J = 6.0, 10.8 Hz), 3.60 (s, 3H), 3.42 (m, 1H), 2.96 (t, 1H, J = 4.4 Hz), 2.80 (dd, 1H, J = 2.4, 5.2 Hz); ESI-MS m/z: 232 (M+1)+; ½a20 D +22.8 (c 1.0, CH3OH); 7b: mp: 131–132 8C; IR (KBr): 1650, 1610, 1575, 1220, 760 cm1; 1H NMR (400 Mz, CDCl3, dppm): 8.48 (dd, 1H, J = 0.8, 8.0 Hz), 7.95 (d, 1H, J = 7.6 Hz), 7.43 (dt, 1H, J = 1.2, 7.6 Hz), 7.57 (dt, 1H, J = 1.2, 8.0 Hz), 4.28 (dd, 1H, J = 2.4, 10.8 Hz), 3.94 (dd, 1H, J = 6.0, 10.8 Hz), 3.63 (s, 3H), 3.42 (m, 1H), 2.92(t, 1H, J = 4.4 Hz), 2.84(dd, 1H, J = 2.8, 5.2 Hz); ESI-MS m/z: 232 (M+1)+; ½a20 D 22.9 (c 1.0, CH3OH).
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S. Qian et al. / Chinese Chemical Letters 20 (2009) 648–650
[8] Typical experimental procedure for 1 is as follow: The solution of oxirane 7 (231 mg, 1 mmol) and 2-methylpropan-2-amine (365 mg, 5 mmol) in MeOH (20 mL) was stirred for 4 h at 60 8C, and then was added prepared saturated chloride hydrogen–methanol (5 mL). The crude product was obtained after the solution was removed by evaporation. 1 (1a: 228 mg, 67%; 1b: 238 mg, 70%) was obtained via recrystallization. Selected data for compound 1a: mp: 205–206 8C; IR (KBr): 3312, 1655, 1630, 1580, 750 cm1; 1H NMR (400 Mz, H2O, dppm): 7.72–8.22 (m, 4H), 6.72 (s, 1H), 4.41 (m, 1H), 3.98 (m, 2H), 3.41 (m, 5H), 1.52 (s, 9H); ESI-MS m/z: 341 (M+1)+; ½a20 D 13.5 (c 1.0, CH3OH); 1b: mp: 205–206 8C; IR (KBr): 3325, 1657, 1620, 1590, 770 cm1; 1H NMR (400 Mz, H2O, dppm): 7.88–8.25 (m, 4H), 6.88 (s, 1H), 4.56 (m, 1H), 3.42 (m, 2H), 3.64 (m, 5H), 1.46 (s, 9H); ESI-MS m/z: 341 (M+1)+; ½a20 D +13.7 (c 1.0, CH3OH). [9] Y.G. Yao, CN 101255135A. [10] This approach was not economical because of multiple column chromatography and low overall yield (23–30% from isoquinolin derivate 6). Moreover, this literature had not reported optical analytic data of the oxirane intermediates 7a and 7b and two optical isomers 1a and 1b, such as optical rotation and value of ee%.
Chinese Chemical Letters 20 (2009) 648–650 www.elsevier.com/locate/cclet
Synthesis of (S) and (R)-tilisolol hydrochloride Shan Qian, Xiao Juan Ye, Fan Zheng, Li Yang, Yong Wu * Key Laboratory of Drug Targeting, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, China Received 27 October 2008
Abstract Tilisolol hydrochloride 1, a non-selective b-adrenoceptor blocker, was developed as a drug for the treatment of hypertension and angina pectoris. The optical active forms of 1, 1a and 1b were synthesized from inexpensive phthalic anhydride 2 in eight steps with 13% (S) and 15% (R) overall yield. # 2009 Yong Wu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved. Keywords: Tilisolol hydrochloride; Optical; Synthesis
Tilisolol hydrochloride 1, a non-selective b-adrenoceptor blocker, was developed as a drug for the treatment of hypertension and angina pectoris [1]. In addition to its effects as b-adrenoceptor blocker, 1 is likely to have additional effects that may include peripheral as well as coronary vasodilation and demand-independent anti-ischemic action [2]. 1 is commercialized in the racemic form, but there are not any reports about the synthesis of the optical forms, as well as biological activity [3] (Fig. 1). We plan to research biological activity of optical tilisolol hydrochloride. Therefore, in this paper, we describe the synthesis of 1a and 1b. The synthetic pathway was outlined in Scheme 1. Phthalic anhydride 2 was alcoholized by methanol as the known method [4] to afford the monomethylester 3. 3 were chlorinated with oxalyl chloride to give the activated chloride derivative [5], which was reacted with sarcosine methyl ester hydrochloride [6] to give amide 4. 4 were cyclizated in sodium methoxide–methanol solution to give isoquinoline derivative 5, which was decarboxylated in NaOH aq. to get the key immediate 6 [5]. Then 6 were substituted by optical active 2-(tosylmethyl) oxirane under the effectiveness of sodium hydride to obtain 7a and 7b, respectively (97%ee, determined by chiral HPLC analysis, Daicel chiralcel OD) [7]. Oxirane 7a and 7b were produced by ring cleavage with 2-methylpropan-2-amine in methanol and then converted to corresponding hydrochlorides 1a and 1b with chloride hydrogen–methanol [8]. Herein, we had to mention that Yao [9] quite recently reported the preparation of these two optical isomer 1a and 1b after we completed the synthesis of 1a and 1b. This method had a number of serious disadvantages [10]. In summary, we described an efficient route for the synthesis of optical active forms of tilisolol hydrochloride, 1a and 1b, from inexpensive phthalic anhydride in eight steps with 13% (S) and 15% (R) overall yield. Biological evaluation of them compared with racemic tilisolol hydrochloride is in progress.
* Corresponding author. E-mail address: [email protected] (Y. Wu). 1001-8417/$ – see front matter # 2009 Yong Wu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved. doi:10.1016/j.cclet.2008.12.048
S. Qian et al. / Chinese Chemical Letters 20 (2009) 648–650
649
Fig. 1. The structure of the compound 1.
Scheme 1. The synthetic route of 1a and 1b. Condition and regent: (a) MeOH, 78%; (b) i: (COCl)2, DMF; ii: sarcosine methyl ester hydrochloride, 82% in two steps; (c) NaOMe, MeOH, 76%; (d) NaOH, 73%; (e) (S)-2-(tosylmethyl) oxirane, NaH, 55% for 7a: or (R)-2-(tosylmethyl) oxirane, NaH, 60% for 7b; (f) 2-methylpropan-2-amine; HCl–MeOH, 1a: 67% in two steps; 1b: 70% in two steps.
Acknowledgments This work was supported by the National Natural Science Foundation of China (No. 30672537).
References [1] [2] [3] [4] [5] [6] [7]
M. Fosset, J.R. Dewille, R.D. Green, et al. J. Biol. Chem. 263 (1988) 7933. S. Takagi, Y. Kihara, T. Mitsuiye, et al. Cardiovas. Drug Rev. 16 (1998) 105. T. Imaizumi, A. Takeshita, N. Nakamura, et al. Arzneimittelforschung 38 (1988) 1342. E.L. Eliel, A.W. Burgstahler, J. Amer. Chem. Soc. 71 (1943) 2251. J.G. Lombardino, J. Heterocycl. Chem. 10 (1970) 1057. J.F. O’Connell, J. Parquette, W.E. Yelle, et al. Synthesis 10 (1988) 767. Typical experimental procedure for 7 is as follow: To the solution of 2-(tosylmethyl) oxirane (244 mg, 1 mmol) and sodium hydride (34 mg, 1.4 mmol) in dry N,N-dimethylformamide (DMF) (10 mL) was added the solution of immediate 6 (175 mg, 1 mmol) in DMF (10 mL), and then reaction mixture was stirred for 3 h at 50 8C under the protection of argon. After poured into water, the solution was extracted by dichloromethane and the collected organic layer was washed by water until DMF was vanished. After the solution was dried and concentrated in vacuum, 7 (7a: 127 mg, 55%; 7b: 139 mg, 60%) were obtained via recrystallization. Selected data for compound 7a: mp: 131–132 8C; IR (KBr): 1655, 1600, 1580, 1230, 750 cm1; 1H NMR (400 Mz, CDCl3, dppm): 8.44 (dd, 1H, J = 0.8, 8.0 Hz), 7.92 (d, 1H, J = 7.6 Hz), 7.48 (dt, 1H, J = 1.2, 7.6 Hz), 7.55 (dt, 1H, J = 1.2, 8.0 Hz), 4.25 (dd, 1H, J = 2.4, 10.8 Hz), 3.90 (dd, 1H, J = 6.0, 10.8 Hz), 3.60 (s, 3H), 3.42 (m, 1H), 2.96 (t, 1H, J = 4.4 Hz), 2.80 (dd, 1H, J = 2.4, 5.2 Hz); ESI-MS m/z: 232 (M+1)+; ½a20 D +22.8 (c 1.0, CH3OH); 7b: mp: 131–132 8C; IR (KBr): 1650, 1610, 1575, 1220, 760 cm1; 1H NMR (400 Mz, CDCl3, dppm): 8.48 (dd, 1H, J = 0.8, 8.0 Hz), 7.95 (d, 1H, J = 7.6 Hz), 7.43 (dt, 1H, J = 1.2, 7.6 Hz), 7.57 (dt, 1H, J = 1.2, 8.0 Hz), 4.28 (dd, 1H, J = 2.4, 10.8 Hz), 3.94 (dd, 1H, J = 6.0, 10.8 Hz), 3.63 (s, 3H), 3.42 (m, 1H), 2.92(t, 1H, J = 4.4 Hz), 2.84(dd, 1H, J = 2.8, 5.2 Hz); ESI-MS m/z: 232 (M+1)+; ½a20 D 22.9 (c 1.0, CH3OH).
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S. Qian et al. / Chinese Chemical Letters 20 (2009) 648–650
[8] Typical experimental procedure for 1 is as follow: The solution of oxirane 7 (231 mg, 1 mmol) and 2-methylpropan-2-amine (365 mg, 5 mmol) in MeOH (20 mL) was stirred for 4 h at 60 8C, and then was added prepared saturated chloride hydrogen–methanol (5 mL). The crude product was obtained after the solution was removed by evaporation. 1 (1a: 228 mg, 67%; 1b: 238 mg, 70%) was obtained via recrystallization. Selected data for compound 1a: mp: 205–206 8C; IR (KBr): 3312, 1655, 1630, 1580, 750 cm1; 1H NMR (400 Mz, H2O, dppm): 7.72–8.22 (m, 4H), 6.72 (s, 1H), 4.41 (m, 1H), 3.98 (m, 2H), 3.41 (m, 5H), 1.52 (s, 9H); ESI-MS m/z: 341 (M+1)+; ½a20 D 13.5 (c 1.0, CH3OH); 1b: mp: 205–206 8C; IR (KBr): 3325, 1657, 1620, 1590, 770 cm1; 1H NMR (400 Mz, H2O, dppm): 7.88–8.25 (m, 4H), 6.88 (s, 1H), 4.56 (m, 1H), 3.42 (m, 2H), 3.64 (m, 5H), 1.46 (s, 9H); ESI-MS m/z: 341 (M+1)+; ½a20 D +13.7 (c 1.0, CH3OH). [9] Y.G. Yao, CN 101255135A. [10] This approach was not economical because of multiple column chromatography and low overall yield (23–30% from isoquinolin derivate 6). Moreover, this literature had not reported optical analytic data of the oxirane intermediates 7a and 7b and two optical isomers 1a and 1b, such as optical rotation and value of ee%.