Citation: Wei-Li Wan, Yun He, Mei Guan, Xiao-Long Li, Xu Cheng, Yong Wu. Synthesis of the major isomers of Aprepitant and Fosaprepitant[J]. Chinese Chemical Letters, ;2013, 24(12): 1118-1122. shu

Synthesis of the major isomers of Aprepitant and Fosaprepitant

Wei-Li Wan ^a ,
Yun He ^a ,
Mei Guan ^b ,
Xiao-Long Li ^a ,
Xu Cheng ^a ,
Yong Wu ^a,,

1.
a Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China;
2.
b West China Hospital, Sichuan University, Chengdu 610041, China

Corresponding author: Yong Wu,
Received Date: 13 May 2013
Available Online: 3 July 2013
Fund Project:

The synthesis of two isomers of Aprepitant (APT) and three isomers of Fosaprepitant (FPT), crucial components for quality control in manufacturing, is described. Herein, three chiral centers in the isomers of Aprepitant are established in high yield by induced crystallization and chiral reduction. Additionally, the isomers of Aprepitant are utilized to synthesize the isomers of Fosaprepitant with the same stereochemistry. All the target compounds were confirmed by elemental analyses, IR, NMR and MS data analysis.
- Aprepitant and Fosaprepitant,
- Major isomers,
- Chemical synthesis
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  [12] Physical and spectral data of the target compounds. SSR-APT: Mp: 253-255℃; [α]_D²⁵+ 69:1 (c 1.0, methanol); ¹H NMR (400 MHz, CD3OD): δ 7.70 (s, 1H), 7.51 (m, 2H), 7.32 (s, 2H), 7.04 (t, 2H, J = 8.7 Hz), 4.94 (q, 1H, J = 6.3 Hz), 4.35 (d, 1H, J = 2.8 Hz), 4.28 (td, 1H, J = 11.5, 2.8 Hz), 3.66 (ddd, 1H, J = 11.5, 3.3, 1.6 Hz), 3.54 (d, 1H, J = 14.3 Hz), 3.48 (d, 1H, J = 2.8 Hz), 2.88 (brd, 1H, J = 11.9 Hz), 2.86 (d, 1H, J = 14.3 Hz), 2.49 (td, 1H, J = 11.9, 3.6 Hz), 1.44 (d, 3H, J = 6.3 Hz); ¹³C NMR (100 MHz, CDCl₃): δ 22.775, 52.302, 53.654, 60.494, 70.536, 73.746, 97.132, 116.080, 116.293, 122.367, 123.306, 126.011, 127.841, 132.401, 132.614, 133.273, 134.204, 147.074, 147.653, 158.764, 162.906, 165.351; HRMS calcd. for C₂₃H₂₁F₇N₄O₃ m/z: 534.1502. Found: 557.1405 [M+Na]⁺. Anal. Calcd. for C₂₃H₂₁F₇N₄O₃: C, 51.69; H, 3.96; F, 24.88; N, 10.48. Found: C, 51.72; H, 3.98; F, 24.85; N, 10.50. RSR-APT: [α]_D²⁵ 25 D 37:1 (c 0.68, MeOH) (lit.[7]: [α]_D²⁵ 25 D 38:52), Mp: 201-204℃; ¹H NMR (400 MHz, CD3OD): δ 11.408 (s, 1H), 11.298 (s, 1H), 7.981 (d, 1H, J = 9.6 Hz), 7.927 (s, 2H), 7.622 (m, 2H), 7.169 (t, 2H, J = 8.8 Hz), 4.481 (d, 1H, J = 2.4), 4.732 (q, 1H, J = 6.4 Hz), 3.853 (t, 1H, J = 10.8 Hz), 3.638 (d, 1H, J = 2.4 Hz), 3.475 (d, 1H, J = 10.8 Hz), 2.905 (s, 2H), 2.850 (d, 1H, J = 13.6 Hz), 2.353 (dt, 1H, J = 8.8, J = 2.4 Hz), 1.017 (d, 3H, J = 6.4 Hz); ¹³C NMR (100 MHz, CDCl₃): δ 21.754, 50.805, 59.570, 67.764, 73.114, 96.774, 114.603, 114.843, 121.133, 122.292, 125.000, 128.920, 129.871, 130.201, 130.524, 131.772, 133.761, 144.239, 147.952, 156.571, 160.632, 163.051; HRMS calcd. for C₂₃H₂₁F₇N₄O₃ m/z: 534.1502. Found: 557.1407 [M+Na]⁺; Anal. Calcd. for C₂₃H₂₁F₇N₄O₃: C, 51.69; H, 3.96; F, 24.88; N, 10.48. Found: C, 51.70; H, 3.95; F, 24.82; N, 10.44. SSR-FPT: Mp: 122-124℃, [α]_D²⁵+ 30:3. (c 1.0, methanol); ¹H NMR (400 MHz, DMSO-d6): δ 7.814 (s, 1H), 7.532 (m, 2H), 7.340 (s, 2H), 7.049 (t, 2H, J = 8.8 Hz), 5.766-6.121 (brs, 12H), 4.950 (t, 1H, J = 6.4 Hz), 4.309 (d, 1H, J = 2.4 Hz), 4.091 (t, 1H, J = 11.2 Hz), 4.004 (s, 2H), 3.653 (m, 1H), 3.558 (d, 1H, J = 2.4 Hz), 3.453 (m, 10H), 3.406 (d, 1H, J = 14.0 Hz), 3.036 (m, 4H), 2.891 (d, 1H, J = 11.2 Hz), 2.661 (d, 1H, J = 14.0 Hz), 2.528 (s, 6H), 2.330 (dt, 1H, J = 8.8, 2.8 Hz), 1.373 (d, 3H, J = 6.4 Hz); ¹³C NMR (100 MHz, CDCl₃): δ 22.288, 24.739, 33.712, 36.944, 51.157, 52.021, 59.133, 63.680, 68.480, 69.003, 70.227, 71.114, 71.459, 71.754, 114.862, 121.326, 121.986, 124.699, 126.775, 129.973, 130.303, 130.629, 131.299, 133.626, 143.204, 146.838, 156.970, 160.774, 163.199; HRMS calcd. for C₃₇H₅₆F₇N₆O₁₆P m/z: 1004.3379. Found: 1027.3279 [M+Na]⁺; Anal. Calcd. for C₃₇H₅₆F₇N₆O₁₆P: C, 44.52; H, 5.63; F, 13.25; N, 8.41; P, 3.11. RRR-FPT: Mp: 96- 98℃, [α]_D²⁵+ 3:8 (c 0.4, methanol); ¹H NMR (400 MHz, DMSO-d6): 7.875 (s, 1H), 7.352 (m, 2H), 7.260 (m, 2H), 7.000 (t, 2H, J = 8.4 Hz), 5.023 (t, 1H, J = 6.4 Hz), 4.749 (d, 1H, J = 16.8 Hz), 4.147 (d, 1H, J = 6.4 Hz), 4.004 (s, 2H), 3.907 (d, 1H, J = 11.6 Hz), 3.744 (m, 1H), 3.453 (m, 10H), 3.218 (m, 1H), 3.036 (m, 4H), 2.622 (d, 1H, J = 6.4 Hz), 2.528 (s, 6H), 2.501 (m, 1H), 2.209 (m, 1H), 1.275 (d, 3H, J = 6.4 Hz); ¹³C NMR (100 MHz, CDCl₃): δ 21.368, 27.191, 31.454, 39.322, 50.011, 52.071, 60.113, 62.520, 67.391, 69.053, 71.157, 71.184, 71.229, 71.714, 115.475, 123.133, 126.992, 128.700, 128.755, 129.167, 130.353, 130.721, 131.307, 138.625, 141.252, 142.310, 159.114, 161.241, 163.557; HRMS calcd. for C₃₇H₅₆F₇N₆O₁₆P m/z: 1004.3379. Found: 1027.3259 [M+Na]⁺; Anal. Calcd. for C₃₇H₅₆F₇N₆O₁₆P: C, 44.20; H, 5.59; F, 13.30; N, 8.42; P, 3.09. RSR-FPT: Mp: 142-144℃, [α]_D²⁵+ 2:0. (c 0.4, methanol); ¹H NMR (400 MHz, DMSO-d6): δ 7.953 (s, 1H), 7.900 (m, 2H), 7.601 (m, 2H), 7.147 (m, 2H), 4.955 (t, 1H, J = 6.4 Hz), 4.700 (m, 2H), 4.004 (s, 2H), 3.832 (m, 2H), 3.167-3.618 (m, 15H), 2.866 (d, 1H, J = 11.6 Hz), 2.775 (d, 1H, J = 13.6 Hz), 2.503 (s, 6H), 2.423 (m, 1H), 1.014 (d, 3H, J = 6.4 Hz); ¹³C NMR (100 MHz, CDCl₃): δ 20.161, 22.554, 36.581, 36.890, 50.657, 55.120, 61.516, 65.717, 65.992, 69.543, 70.250, 71.562, 71.691, 71.887, 116.442, 122.389, 122.806, 125.990, 128.715, 128.900, 130.471, 130.319, 132.469, 138.104, 141.546, 148.314, 159.814, 162.330, 167.102; HRMS calcd. for C₃₇H₅₆F₇N₆O₁₆P m/z: 1004.3379. Found: 1027.3263 [M+Na]⁺; Anal. Calcd. for C₃₇H₅₆F₇N₆O₁₆P: C, 44.48; H, 5.57; F, 13.25; N, 8.39; P, 3.08.
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沈阳化工大学材料科学与工程学院沈阳 110142