Pharmaceuticals 2017, 10, 76
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365; found 386 [M + Na]+, ESI+/MS/MS m/z: 371 (100), 198 (16).
2-(3-(5-Hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl)-7-methoxy-1,2,3,4-tetrahydroisoquinolin-6-ol (12a).
A solution of 11a (140 mg, 0.36 mmol) in EtOH (50 mL) and a pinch of Pd/C 10% were stirred overnight
at room temperature under hydrogen. The catalyst was filtered off and the solvent was evaporated
under pressure. The residue was purified by silica gel column chromatography (CHCl3/MeOH
9:1 v/v). The yield of white solid 12a was 110 mg (0.50 mmol, 85%). ESI+/MS m/z calculated for
C23H29NO3: 367; found 368 [M + H]+. ESI+/MS/MS m/z: 218 (41), 187 (100), 165 (62).
2-(3-(5-(2-Fluoroethoxy)-1,2,3,4-tetrahydronaphthalen-1-yl)propyl)-7-methoxy-1,2,3,4-tetrahydroisoquinol-in-
6-ol (13a). Compound 13a was prepared in the same way as reported above for compound 7a
.
The residue was purified on silica gel column chromatography (CHCl3/MeOH 9:1 v/v). The yield
of yellow solid 13a was 320 mg (0.77 mmol, 22%). ESI−/MS m/z calculated for C25H32FNO3: 413;
1
found 412 [M
−
H]−. ESI−/MS/MS m/z: 392 (100). H-NMR (CDCl3)
δ: 6.84–7.10 (m, 2H, aromatic
tetrahydro-naphtalene), 6.58–6.63 (m, 2H, aromatic), 6.52 (s, 1H, aromatic), 5.6 (bs, 1H, OH), 4.83 (t,
1H, J = 3 Hz, OCH2CH2F), 4.66 (t, 1H, J = 3 Hz, OCH2CH2F), 4.24 (t, 1H, J = 3 Hz, OCH2CH2F), 4.14
(t, 1H, J = 3 Hz, OCH2CH2F), 3.83 (s, 3H, CH3), 3.55 (s, 2H, NCH2 isoquinoline), 2.60–2.84 (m, 8H,
NCH2CH2CH2CH, CH2CH2CH2CH tetrahydronaphtalene, NCH2CH2 isoquinoline),1.63–1.85 (m, 9H,
NCH2CH2CH2CH, CH2CH2CH2CH tetrahydronaphthalene).
(E)-2-(3-(5-(2-Fluoroethoxy)-3,4-dihydronaphthalen-1(2H)-ylidene)propyl)-7-methoxy-1,2,3,4-tetrahydro-
isoquinolin-6-ol (14a). Compound 14a was prepared in the same way as reported above for compound
7a. The residue was purified on silica gel column chromatography (CHCl3/MeOH 9:1 v/v). The yield
of yellow solid 14a was 280 mg (0.71 mmol, 12%). ESI−/MS m/z calculated for C25H30FNO3: 411;
1
found 410 [M
−
H]−. ESI−/MS/MS m/z: 390 (100), 364 (52). H-NMR (CDCl3)
δ: 6.48–7.2 (m, 5H,
aromatic), 6.0 (t, 1H, J = 6 Hz, NCH2CH2CH=C), 5.6 (bs, 1H, OH), 4.83 (t, 1H, J = 3 Hz, OCH2CH2F),
4.66 (t, 1H, J = 3 Hz, OCH2CH2F), 4.24 (t, 1H, J = 3 Hz, OCH2CH2F), 4.14 (t, 1H, J = 3 Hz, OCH2CH2F),
3.83 (s, 3H, CH3), 3.55 (s, 2H, NCH2 isoquinoline), 2.60–2.84 (m, 8H, NCH2CH2CH=C, CH2CH2CH2C
tetrahydronaphtalene, NCH2CH2 isoquinoline), 1.63–1.85 (m, 6H, NCH2CH2CH=C, CH2CH2CH2C
tetrahydronaphtalene).
(E)-2-(3-(5-(2-Fluoroethoxy)-3,4-dihydronaphthalen-1(2H)-ylidene)propyl)-6,7-dimethoxy-1,2,3,4-tetra-
hydroisoquinoline (MC198). MC198 was prepared in the same way as reported above for compound 7a
.
The residue was purified on silica gel column chromatography (CHCl3/MeOH 9:1 v/v). The yield
of yellow oil MC198 was 230 mg (0.87 mmol, 15%). ESI+/MS m/z calculated for C26H32FNO3: 425;
1
found 426 [M + H]+. ESI+/MS/MS m/z: 262 (33), 235 (100), 179 (65). H-NMR (CDCl3)
δ: 6.48–7.30
(m, 5H, aromatic), 6.0 (t, 1H, J = 6 Hz, NCH2CH2CH=C), 4.83 (t, 1H, J = 3 Hz, OCH2CH2F), 4.66 (t,
1H, J = 3 Hz, OCH2CH2F), 4.24 (t, 1H, J = 3 Hz, OCH2CH2F), 4.14 (t, 1H, J = 3 Hz, OCH2CH2F), 3.83
(s, 3H, CH3), 3.55 (s, 2H, NCH2 isoquinoline), 2.40–2.84 (m, 8H, NCH2CH2CH=C, CH2CH2CH2C
tetrahydronaphtalene, NCH2CH2 isoquinoline), 1.73–1.80 (m, 6H, NCH2CH2CH=C, CH2CH2CH2C
tetrahydronaphtalene).
0
Methyl 4-(4 -hydroxybiphenyl-4-yloxy)butanoate (17). Dihydroxybifenyl (1.5 g, 8.0 mmol) dissolved in dry
DMF (5 mL) was added to a suspension of NaH (100 mg, 4.1 mmol) in dry DMF (5 mL). The mixture
was stirred at room temperature for 20 min. Methyl-4-chlorobutanoate (3.5 g, 28 mmol) was added
and the mixture was refluxed overnight. Water (20 mL) was added until the effervescence ceased.
The aqueous layer was extracted with CH2Cl2 (3
×
20 mL), the organic layer was separated, dried
over Na2SO4 and evaporated under reduced pressure. The residue was purified on silica gel column
chromatography (CH2Cl2). The yield of yellow solid 17 was 450 mg (1.57 mmol, 20%). ESI−/MS m/z
calculated for C17H18O4: 286; found 285 [M − H]−. ESI−/MS/MS m/z: 184 (100).
Methyl 4-(40-(2-Fluoroethoxy)biphenyl-4-yloxy)butanoate (18). Compound 18 was prepared in the same
way as reported above for compound 7a. The residue was purified on silica gel column chromatography