Chem. J. Chinese Universities ›› 2022, Vol. 43 ›› Issue (2): 20210663.doi: 10.7503/cjcu20210663
• Organic Chemistry • Previous Articles Next Articles
LI Jing1, SU Wei1, WANG Xueyuan2(), FU Peng1, SUN Yan3
Received:
2021-09-13
Online:
2022-02-10
Published:
2021-11-26
Contact:
WANG Xueyuan
E-mail:xueyuan.w@163.com
Supported by:
CLC Number:
TrendMD:
LI Jing, SU Wei, WANG Xueyuan, FU Peng, SUN Yan. Synthesis and Characterization of Antihypertensive Drug Aranidipine and Its Related Impurities[J]. Chem. J. Chinese Universities, 2022, 43(2): 20210663.
Reagent | Time/h | Solvent | Yield(%) | Purity(%) |
---|---|---|---|---|
TFA | 20 | DCM | 80.15 | 95.23 |
H2SO4 | 8 | DCM | 64.53 | 77.33 |
FA | 5 | — | 78.27 | 73.31 |
Table 1 Optimization of reaction conditions of compound 5
Reagent | Time/h | Solvent | Yield(%) | Purity(%) |
---|---|---|---|---|
TFA | 20 | DCM | 80.15 | 95.23 |
H2SO4 | 8 | DCM | 64.53 | 77.33 |
FA | 5 | — | 78.27 | 73.31 |
Reagent | Time/h | Solvent | Yield(%) | Purity(%) |
---|---|---|---|---|
MnO2 | 2 | PhMe | 90.65 | 96.99 |
(NH4)2S2O8 | 5 | DMK/H2O | 84.03 | 93.27 |
FeCl3?6H2O | 24 | HOAc | 58.54 | 85.44 |
Table 2 Optimization of reaction conditions for oxidization of Ara-ox Ⅰ
Reagent | Time/h | Solvent | Yield(%) | Purity(%) |
---|---|---|---|---|
MnO2 | 2 | PhMe | 90.65 | 96.99 |
(NH4)2S2O8 | 5 | DMK/H2O | 84.03 | 93.27 |
FeCl3?6H2O | 24 | HOAc | 58.54 | 85.44 |
n(5)∶n(acetol) | Time/h | Yield(%) |
---|---|---|
1∶1 | 5 | 65.5 |
1∶1.2 | 5 | 70.22 |
1∶1.3 | 4 | 74.41 |
1∶1.4 | 4 | 75.22 |
1∶1.5 | 4 | 75.21 |
Table 3 Optimization of reaction conditions of aranidipine
n(5)∶n(acetol) | Time/h | Yield(%) |
---|---|---|
1∶1 | 5 | 65.5 |
1∶1.2 | 5 | 70.22 |
1∶1.3 | 4 | 74.41 |
1∶1.4 | 4 | 75.22 |
1∶1.5 | 4 | 75.21 |
tR/min | Resolution | [M+H]+, m/z | Formula | M | Compd. |
---|---|---|---|---|---|
6.74 | 3.15 | 403.11 | C19H18N2O8 | 402.11 | Ara?ox Ⅲ |
8.71 | 0.94 | 250.07 | C12H11NO5 | 249.06 | Ara?1 |
12.44 | 1.99 | 387.12 | C19H18N2O7 | 386.11 | Ara?ox Ⅰ |
14.30 | 1.99 | 333.11 | C16H16N2O6 | 332.10 | Ara?acid |
15.56 | 1.19 | 371.12 | C19H18N2O6 | 370.12 | Ara?ox Ⅱ |
19.52 | 3.22 | 389.13 | C19H20N2O7 | 388.13 | Aranidipine |
31.47 | 1.34 | 347.12 | C17H18N2O6 | 346.12 | Ara?bis |
Table 4 System assessment of HPLC and mass spectral data of aranidipine and its impurities
tR/min | Resolution | [M+H]+, m/z | Formula | M | Compd. |
---|---|---|---|---|---|
6.74 | 3.15 | 403.11 | C19H18N2O8 | 402.11 | Ara?ox Ⅲ |
8.71 | 0.94 | 250.07 | C12H11NO5 | 249.06 | Ara?1 |
12.44 | 1.99 | 387.12 | C19H18N2O7 | 386.11 | Ara?ox Ⅰ |
14.30 | 1.99 | 333.11 | C16H16N2O6 | 332.10 | Ara?acid |
15.56 | 1.19 | 371.12 | C19H18N2O6 | 370.12 | Ara?ox Ⅱ |
19.52 | 3.22 | 389.13 | C19H20N2O7 | 388.13 | Aranidipine |
31.47 | 1.34 | 347.12 | C17H18N2O6 | 346.12 | Ara?bis |
Positiona | Aranidipineb | Ara?ox Ⅰb | Ara?ox Ⅱb | Ara?ox Ⅲb | Ara?cidc | Ara?bisb | Ara?1b |
---|---|---|---|---|---|---|---|
3 | 6.50(s, 1H) | ― | ― | ― | 8.96(s, 1H) | 5.99(s, 1H) | 2.51(s, 3H) |
4 | ― | ― | ― | ― | ― | ― | 8.25(dd, 1H) |
6 | 5.68(s, 1H) | ― | ― | ― | 5.00(s, 1H) | 5.73(s, 1H) | 7.60(dddd, 1H) |
7 | 2.23(s, 3H) | 2.58(s, 3H) | 2.60(s, 3H) | 2.53(s, 3H) | 2.29(d, 3H) | 2.34(s, 3H) | 7.48—7.41(m, 1H) |
8 | 2.27(s, 3H) | 2.68(s, 3H) | 2.71(s, 3H) | 2.65(s, 3H) | 2.29(d, 3H) | 2.34(s, 3H) | 8.10(s, 1H) |
10 | 3.50(s, 3H) | 3.42(s, 3H) | 3.31(s, 3H) | 3.44(s, 3H) | 3.56(s, 3H) | 3.60(s, 3H) | 7.68(td, 1H) |
12 | 7.45(dd, J=7.9, 1.6 Hz, 1H) | 8.13(dd, 1H) | 7.65(td, 1H) | 7.57(dt, 1H) | 7.97(m, 1H) | 7.58(m, 1H) | 3.62(s, 3H) |
13 | 7.40(td, J=8.0, 7.5, 1.4 Hz, 1H) | 7.50(td, 1H) | 7.48(dd, 1H) | 7.57(dt, 1H) | 7.60(dt, 1H) | 7.41(m, 1H) | ― |
14 | 7.22—7.14(m, 1H) | 7.17(dd, 1H) | 6.48(dd, 1H) | 7.25(d, 1H) | 7.54(t, 1H) | 7.26(ddd, 1H) | ― |
15 | 7.58(dd, J=8.1, 1.3 Hz, 1H) | 7.58(td, 1H) | 7.37(ddd, 1H) | 8.13(d, 1H) | 8.04(m, 1H) | 7.68(dd, 1H) | ― |
18 | 4.42—4.59(d, J=16.9 Hz, 1H) | 4.40—4.48 (d, 2H) | 4.26—4.34 (d, 2H) | 4.55—4.40 (m, 2H) | 11.88(s, 1H) | 3.60(s, 3H) | ― |
20 | 1.96(s, 3H) | 1.95(s, 3H) | 1.88(s, 3H) | 1.97(s, 3H) | ― | ― | ― |
Table 5 1H NMR data of aranidipine and its impurities
Positiona | Aranidipineb | Ara?ox Ⅰb | Ara?ox Ⅱb | Ara?ox Ⅲb | Ara?cidc | Ara?bisb | Ara?1b |
---|---|---|---|---|---|---|---|
3 | 6.50(s, 1H) | ― | ― | ― | 8.96(s, 1H) | 5.99(s, 1H) | 2.51(s, 3H) |
4 | ― | ― | ― | ― | ― | ― | 8.25(dd, 1H) |
6 | 5.68(s, 1H) | ― | ― | ― | 5.00(s, 1H) | 5.73(s, 1H) | 7.60(dddd, 1H) |
7 | 2.23(s, 3H) | 2.58(s, 3H) | 2.60(s, 3H) | 2.53(s, 3H) | 2.29(d, 3H) | 2.34(s, 3H) | 7.48—7.41(m, 1H) |
8 | 2.27(s, 3H) | 2.68(s, 3H) | 2.71(s, 3H) | 2.65(s, 3H) | 2.29(d, 3H) | 2.34(s, 3H) | 8.10(s, 1H) |
10 | 3.50(s, 3H) | 3.42(s, 3H) | 3.31(s, 3H) | 3.44(s, 3H) | 3.56(s, 3H) | 3.60(s, 3H) | 7.68(td, 1H) |
12 | 7.45(dd, J=7.9, 1.6 Hz, 1H) | 8.13(dd, 1H) | 7.65(td, 1H) | 7.57(dt, 1H) | 7.97(m, 1H) | 7.58(m, 1H) | 3.62(s, 3H) |
13 | 7.40(td, J=8.0, 7.5, 1.4 Hz, 1H) | 7.50(td, 1H) | 7.48(dd, 1H) | 7.57(dt, 1H) | 7.60(dt, 1H) | 7.41(m, 1H) | ― |
14 | 7.22—7.14(m, 1H) | 7.17(dd, 1H) | 6.48(dd, 1H) | 7.25(d, 1H) | 7.54(t, 1H) | 7.26(ddd, 1H) | ― |
15 | 7.58(dd, J=8.1, 1.3 Hz, 1H) | 7.58(td, 1H) | 7.37(ddd, 1H) | 8.13(d, 1H) | 8.04(m, 1H) | 7.68(dd, 1H) | ― |
18 | 4.42—4.59(d, J=16.9 Hz, 1H) | 4.40—4.48 (d, 2H) | 4.26—4.34 (d, 2H) | 4.55—4.40 (m, 2H) | 11.88(s, 1H) | 3.60(s, 3H) | ― |
20 | 1.96(s, 3H) | 1.95(s, 3H) | 1.88(s, 3H) | 1.97(s, 3H) | ― | ― | ― |
Positiona | Aranidipineb | Ara?ox Ⅰb | Ara?ox Ⅱb | Ara?ox Ⅲb | Ara?acidc | Ara?bisb | Ara?1b |
---|---|---|---|---|---|---|---|
1 | 101.96(C) | 123.76(C) | 127.41(C) | 124.65(C) | 102.15(C) | 103.61(C) | 133.91(C) |
2 | 147.79(C) | 157.59(C) | 157.04(C) | 149.01(C) | 148.13(C) | 147.87(C) | 194.49(C) |
3 | ― | ― | ― | ― | ― | ― | 27.12(CH3) |
4 | 147.14(C) | 157.36(C) | 156.77(C) | 148.64(C) | 150.48(C) | 147.87(C) | 140.44(CH) |
5 | 103.92(C) | 124.37(C) | 128.96(C) | 124.65(C) | 100.82(C) | 103.61(C) | 166.31(C) |
6 | 34.53(CH) | 147.64(C) | 144.69(C) | 133.08(C) | 39.44(CH) | 34.55(CH) | 136.27(CH) |
7 | 19.23(CH3) | 23.69(CH3) | 23.53(CH3) | 16.50(CH3) | 18.67(CH3) | 19.47(CH3) | 129.89(CH) |
8 | 19.40(CH3) | 23.96(CH3) | 23.76(CH3) | 16.50(CH3) | 18.74(CH3) | 19.47(CH3) | 125.16(CH) |
9 | 166.34(C) | 166.08(C) | 166.50(C) | 164.06(C) | 167.57(C) | 167.61(C) | 147.01(C) |
10 | 51.02(CH3) | 52.21(CH3) | 52.08(CH3) | 52.72(CH3) | 51.25(CH3) | 51.05(CH3) | 130.61(CH) |
11 | 144.94(C) | 132.98(C) | 139.69(C) | 131.77(C) | 146.22(C) | 142.17(C) | 130.35(C) |
12 | 131.34(CH) | 130.95(CH) | 135.08(CH) | 130.63(CH) | 130.08(CH) | 131.07(CH) | 52.33(CH3) |
13 | 132.90(CH) | 129.63(CH) | 130.90(CH) | 128.78(CH) | 134.43(CH) | 132.78(CH) | ― |
14 | 127.11(CH) | 131.69(CH) | 135.08(CH) | 130.18(CH) | 121.98(CH) | 127.07(CH) | ― |
15 | 123.83(CH) | 124.90(CH) | 107.90(CH) | 127.81(CH) | 121.55(CH) | 123.91(CH) | ― |
Positiona | Aranidipineb | Ara?ox Ⅰb | Ara?ox Ⅱb | Ara?ox Ⅲb | Ara?acidc | Ara?bisb | Ara?1b |
16 | 142.25(C) | 145.47(C) | 161.72(C) | 147.98(C) | 147.29(C) | 145.03(CH) | ― |
17 | 167.45(C) | 167.25(C) | 167.66(C) | 165.25(C) | 168.87(C) | 167.61(C) | ― |
18 | 67.82(CH2) | 68.80(CH2) | 68.72(CH2) | 69.10(CH3) | ― | 51.05(CH3) | ― |
19 | 203.18(C) | 199.49(C) | 199.69((C)) | 198.78(C) | ― | ― | ― |
20 | 25.84(CH3) | 25.83(CH3) | 25.84(CH3) | 25.76(CH3) | ― | ― | ― |
Table 6 13C NMR data of aranidipine and its impurities
Positiona | Aranidipineb | Ara?ox Ⅰb | Ara?ox Ⅱb | Ara?ox Ⅲb | Ara?acidc | Ara?bisb | Ara?1b |
---|---|---|---|---|---|---|---|
1 | 101.96(C) | 123.76(C) | 127.41(C) | 124.65(C) | 102.15(C) | 103.61(C) | 133.91(C) |
2 | 147.79(C) | 157.59(C) | 157.04(C) | 149.01(C) | 148.13(C) | 147.87(C) | 194.49(C) |
3 | ― | ― | ― | ― | ― | ― | 27.12(CH3) |
4 | 147.14(C) | 157.36(C) | 156.77(C) | 148.64(C) | 150.48(C) | 147.87(C) | 140.44(CH) |
5 | 103.92(C) | 124.37(C) | 128.96(C) | 124.65(C) | 100.82(C) | 103.61(C) | 166.31(C) |
6 | 34.53(CH) | 147.64(C) | 144.69(C) | 133.08(C) | 39.44(CH) | 34.55(CH) | 136.27(CH) |
7 | 19.23(CH3) | 23.69(CH3) | 23.53(CH3) | 16.50(CH3) | 18.67(CH3) | 19.47(CH3) | 129.89(CH) |
8 | 19.40(CH3) | 23.96(CH3) | 23.76(CH3) | 16.50(CH3) | 18.74(CH3) | 19.47(CH3) | 125.16(CH) |
9 | 166.34(C) | 166.08(C) | 166.50(C) | 164.06(C) | 167.57(C) | 167.61(C) | 147.01(C) |
10 | 51.02(CH3) | 52.21(CH3) | 52.08(CH3) | 52.72(CH3) | 51.25(CH3) | 51.05(CH3) | 130.61(CH) |
11 | 144.94(C) | 132.98(C) | 139.69(C) | 131.77(C) | 146.22(C) | 142.17(C) | 130.35(C) |
12 | 131.34(CH) | 130.95(CH) | 135.08(CH) | 130.63(CH) | 130.08(CH) | 131.07(CH) | 52.33(CH3) |
13 | 132.90(CH) | 129.63(CH) | 130.90(CH) | 128.78(CH) | 134.43(CH) | 132.78(CH) | ― |
14 | 127.11(CH) | 131.69(CH) | 135.08(CH) | 130.18(CH) | 121.98(CH) | 127.07(CH) | ― |
15 | 123.83(CH) | 124.90(CH) | 107.90(CH) | 127.81(CH) | 121.55(CH) | 123.91(CH) | ― |
Positiona | Aranidipineb | Ara?ox Ⅰb | Ara?ox Ⅱb | Ara?ox Ⅲb | Ara?acidc | Ara?bisb | Ara?1b |
16 | 142.25(C) | 145.47(C) | 161.72(C) | 147.98(C) | 147.29(C) | 145.03(CH) | ― |
17 | 167.45(C) | 167.25(C) | 167.66(C) | 165.25(C) | 168.87(C) | 167.61(C) | ― |
18 | 67.82(CH2) | 68.80(CH2) | 68.72(CH2) | 69.10(CH3) | ― | 51.05(CH3) | ― |
19 | 203.18(C) | 199.49(C) | 199.69((C)) | 198.78(C) | ― | ― | ― |
20 | 25.84(CH3) | 25.83(CH3) | 25.84(CH3) | 25.76(CH3) | ― | ― | ― |
Compd. | IR, |
---|---|
Aranidipine | 3330(νNH, NH), 3100—3000(νArH, phenyl), 2950(νCH, CH3), 1710(νC=O, ketocarbonyl), 1679(νC=O, ester carbonyl), 1643, 1619, 1494(νC=C, phenyl and DHPR), 1525, 1349(νasNO2+νsNO2, Ar—NO2), 1430(δCH2, O—CH2), 1382(δCH3, CH3), 1203(νC—O, ester), 715(δArH, 1,2?substituted phenyl) |
Ara?ox Ⅰ | 3100—3000(νArH, phenyl), 2952(νCH, CH3), 1741(νC=O, ketocarbonyl), 1725(νC=O, ester carbonyl), 1556, 1438(νC=C, phenyl and Pyridine), 1531, 1351(νasNO2+νsNO2, Ar—NO2), 1423(δCH2, O—CH2), 1373(δCH3, CH3), 1236(νC—O, ester), 705(δArH, 1,2?substituted phenyl) |
Ara?ox Ⅱ | 3100—3000(νArH, phenyl), 2950(νCH, CH3), 1745(νC=O, ketocarbonyl), 1724(νC=O, ester carbonyl), 1560, 1436(νC=C, phenyl and pyridine), 1500(νNO, Ar—NO), 1421(δCH2, O—CH2), 1374(δCH3, CH3), 1241(νC—O, ester), 775(δArH, 1,2?substituted phenyl) |
Ara?ox Ⅲ | 3100—3000(νArH, phenyl), 2954(νCH, CH3), 1739(νC=O ketocarbonyl), 1725(νC=O, ester carbonyl), 1436(νC=C, phenyl and pyridine), 1529, 1349((νasNO2+νsNO2, Ar—NO2), 1419(δCH2, O—CH2), 1349(δCH3, CH3), 1299(νN—O, nitrogen), 1241(νC—O, ester), 705(δArH, 1,2?substituted phenyl) |
Ara?acid | 3342(νNH, NH), 3100—3000(νArH, phenyl), 2964(νCH, CH3), 1662(νC=O, ester carbonyl), 1606, 1477(νC=C, phenyl and pyridine), 1529, 1344(νasNO2+νsNO2, Ar—NO2), 1315(δCH3, CH3), 1230(νC—O, ester), 705(δArH, 1,2?substituted phenyl) |
Ara?bis | 3330(νNH, NH), 3100—3000(νArH, phenyl), 2952(νCH, CH3), 1679(νC=O, ester carbonyl), 1646, 1496, 1439(νC=C, phenyl and pyridine), 1529, 1349(νasNO2+νsNO2, Ar—NO2), 1309(δCH3, CH3), 1120, 1101, 1022(νC—O, ester), 713(δArH, 1,2?substituted phenyl) |
Ara?1 | 2932(νCH, CH3), 1726(νC=O, ketocarbonyl), 1672(νC=O, ester carbonyl), 1438(νC=C, phenyl and pyridine), 1531, 1351(νasNO2+νsNO2, Ar—NO2), 1391(δCH3, CH3), 1236(νC—O, ester), 750(δArH, 1,2?substituted phenyl) |
Table 7 Data of IR analysis of aranidipine and its impurities
Compd. | IR, |
---|---|
Aranidipine | 3330(νNH, NH), 3100—3000(νArH, phenyl), 2950(νCH, CH3), 1710(νC=O, ketocarbonyl), 1679(νC=O, ester carbonyl), 1643, 1619, 1494(νC=C, phenyl and DHPR), 1525, 1349(νasNO2+νsNO2, Ar—NO2), 1430(δCH2, O—CH2), 1382(δCH3, CH3), 1203(νC—O, ester), 715(δArH, 1,2?substituted phenyl) |
Ara?ox Ⅰ | 3100—3000(νArH, phenyl), 2952(νCH, CH3), 1741(νC=O, ketocarbonyl), 1725(νC=O, ester carbonyl), 1556, 1438(νC=C, phenyl and Pyridine), 1531, 1351(νasNO2+νsNO2, Ar—NO2), 1423(δCH2, O—CH2), 1373(δCH3, CH3), 1236(νC—O, ester), 705(δArH, 1,2?substituted phenyl) |
Ara?ox Ⅱ | 3100—3000(νArH, phenyl), 2950(νCH, CH3), 1745(νC=O, ketocarbonyl), 1724(νC=O, ester carbonyl), 1560, 1436(νC=C, phenyl and pyridine), 1500(νNO, Ar—NO), 1421(δCH2, O—CH2), 1374(δCH3, CH3), 1241(νC—O, ester), 775(δArH, 1,2?substituted phenyl) |
Ara?ox Ⅲ | 3100—3000(νArH, phenyl), 2954(νCH, CH3), 1739(νC=O ketocarbonyl), 1725(νC=O, ester carbonyl), 1436(νC=C, phenyl and pyridine), 1529, 1349((νasNO2+νsNO2, Ar—NO2), 1419(δCH2, O—CH2), 1349(δCH3, CH3), 1299(νN—O, nitrogen), 1241(νC—O, ester), 705(δArH, 1,2?substituted phenyl) |
Ara?acid | 3342(νNH, NH), 3100—3000(νArH, phenyl), 2964(νCH, CH3), 1662(νC=O, ester carbonyl), 1606, 1477(νC=C, phenyl and pyridine), 1529, 1344(νasNO2+νsNO2, Ar—NO2), 1315(δCH3, CH3), 1230(νC—O, ester), 705(δArH, 1,2?substituted phenyl) |
Ara?bis | 3330(νNH, NH), 3100—3000(νArH, phenyl), 2952(νCH, CH3), 1679(νC=O, ester carbonyl), 1646, 1496, 1439(νC=C, phenyl and pyridine), 1529, 1349(νasNO2+νsNO2, Ar—NO2), 1309(δCH3, CH3), 1120, 1101, 1022(νC—O, ester), 713(δArH, 1,2?substituted phenyl) |
Ara?1 | 2932(νCH, CH3), 1726(νC=O, ketocarbonyl), 1672(νC=O, ester carbonyl), 1438(νC=C, phenyl and pyridine), 1531, 1351(νasNO2+νsNO2, Ar—NO2), 1391(δCH3, CH3), 1236(νC—O, ester), 750(δArH, 1,2?substituted phenyl) |
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