3156 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 17
Bourlot et al.
3-(4-Ben zyl-3,4-d ih yd r o-2H -1,4-b en zoxa zin -2-yl)p r o-
p a n oic Acid (17). To a solution of 16 (4.0 g, 20.0 mmol) in
dry toluene (50 mL) was added (carbethoxymethylene)triph-
enylphosphorane (8.25 g, 20.0 mmol), and the reaction mixture
was heated to reflux for 2 h. After removal of the toluene in
vacuo, the residue was purified on silica gel column (eluent:
CH2Cl2) to give 4-benzyl-3,4-dihydro-2H-1,4-benzoxazine-2-
acrylic acid, ethyl ester (4.0 g, 77%) as an oil (mixture of (E)
in general procedure. Purification on silica gel column (eluent:
CH2Cl2/MeOH, 99/1) led to 18d (5.37 g, 97%) as an oil: IR (film)
ν 1640 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.88-2.11 (m, 2H,
CH2), 2.58 (t, J ) 7.3 Hz, 2H, CH2CO), 3.00-3.06 (m, 4H,
NCH2), 3.16 (dd, J ) 7.3, 11.8 Hz, 1H, NCH), 3.28 (dd, J )
2.9, 11.8 Hz, 1H, NCH), 3.61-3.65 (m, 2H, NCH2), 3.71-3.78
(m, 2H, NCH2), 4.13-4.22 (m, 1H, OCH), 4.40 (s, 2H, NCH2-
Ph), 6.55-6.65 (m, 3H, ArH), 6.71-6.85 (m, 4H, ArH), 6.90-
6.97 (m, 2H, ArH), 7.21-7.30 (m, 4H, ArH); MS (CI/NH3) m/z
460 (M+ + 1). Anal. (C28H30N3FO2) C, H, N.
3-(4-Ben zyl-3,4-d ih yd r o-2H-1,4-ben zoxa zin -2-yl)-N-[2-
[[bis(4-flu or oph en yl)m eth yl]oxy]eth yl]pr opan am ide (18e).
The amide 18e was prepared from acid 17 (0.915 g, 3.08 mmol)
and 2-[[bis(4-fluorophenyl)methyl]oxy]ethylamine (0.910 g,
3.08 mmol). Purification on silica gel column (eluent: CH2-
Cl2) gave the amide 18e (1.41 g, 84%) as a solid: mp 108-109
°C; IR (KBr) ν 3300, 1640 cm-1; 1H NMR (CDCl3, 300 MHz) δ
1.77-2.01 (m, 2H, CH2CH2CO), 2.29-2.41 (m, 2H, CH2CO),
3.06 (dd, J ) 8.1, 11.8 Hz, 1H, NCH), 3.22 (dd, J ) 2.9, 11.8
Hz, 1H, NCH), 3.42-3.49 (m, 4H, NCH2, OCH2), 4.06-4.16
(m, 1H, OCH), 4.37 (s, 2H, NCH2Ph), 5.26 (s, 1H, OCH), 5.86
(s, 1H, NH), 6.54-6.65 (m, 5H, ArH), 6.70-6.78 (m, 4H, ArH),
6.91-7.00 (m, 4H, ArH), 7.16-7.31 (m, 4H, ArH). Anal.
(C33H32N2F2O3) C, H, N.
and (Z) isomers 1/2): (Z) isomer: IR (film) ν 1710, 1650 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 1.25 (t, J ) 7.2 Hz, 3H, CH3),
3.25 (dd, J ) 6.2, 11.9 Hz, 1H, NCH), 3.51 (dd, J ) 3.1, 11.9
Hz, 1H, NCH), 4.15 (q, J ) 7.2 Hz, 2H, OCH2), 4.38 (d, J )
16.5 Hz, 1H, NCHPh), 4.50 (d, J ) 16.5 Hz, 1H, NCHPh),
5.53-5.55 (m, 1H, OCH), 5.89 (dd, J ) 1.5, 11.9 Hz, 1H, d
CH), 6.34 (dd, J ) 7.2, 11.9 Hz, 1H, dCH), 6.62-6.70 (m, 3H,
ArH), 6.76-6.87 (m, 2H, ArH), 7.20-7.33 (m, 4H, ArH). (E)
isomer: IR (film) ν 1710, 1650 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 1.27 (t, J ) 7.2 Hz, 3H, CH3), 3.13 (dd, J ) 7.2, 11.9 Hz, 1H,
NCH), 3.35 (dd, J ) 2.6, 11.9 Hz, 1H, NCH), 4.19 (q, J ) 7.2
Hz, 2H, OCH2), 4.42 (s, 2H, NCH2Ph), 4.77-4.83 (m, 1H,
OCH), 6.17 (dd, J ) 1.5, 15.5 Hz, 1H, dCH), 6.62-6.72 (m,
3H, ArH), 6.78-6.86 (m, 2H, ArH), 6.92 (dd, J ) 4.7, 15.5 Hz,
1H, dCH), 7.26-7.35 (m, 4H, ArH). Anal. (C20H21NO3) C,
H, N.
This mixture of (E) and (Z) isomers (0.250 g, 0.77 mmol)
was hydrogenated in the presence of Raney nickel (0.135 g,
suspension in water) in absolute EtOH (10 mL), under
hydrogen pressure (50 psi) at 20 °C. After 4 h, catalyst nickel
was removed by filtration and washed with EtOH and EtOAc.
The solvents were evaporated to dryness, and the residue was
purified on silica gel (eluent: CH2Cl2) to give 3-(4-benzyl-3,4-
dihydro-2H-1,4-benzoxazin-2-yl)propionoic acid, ethyl ester
(0.230 g, 92%) as an oil: IR (film) ν 1720 cm-1; 1H NMR (CDCl3,
300 MHz) δ 1.20 (t, J ) 7.3 Hz, 3H, CH3), 1.85-1.95 (m, 2H,
CH2), 2.43 (dd, J ) 7.3, 15.4 Hz, 1H, CHCO), 2.53 (dd, J )
6.6, 15.4 Hz, 1H, CHCO), 3.08 (dd, J ) 7.3, 11.8 Hz, 1H, NCH),
3.22 (dd, J ) 2.9, 11.8 Hz, 1H, NCH), 4.08 (q, J ) 7.3 Hz, 2H,
OCH2), 4.11-4.17 (m, 1H, OCH), 4.37 (s, 2H, NCH2Ph), 6.55-
6.62 (m, 3H, ArH), 6.69-6.77 (m, 2H, ArH), 7.17-7.29 (m, 4H,
ArH). Anal. (C20H23NO3) C, H, N.
The 3-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)pro-
panoic acid, ethyl ester (2.80 g, 8.64 mmol) was dissolved in
EtOH (30 mL). After addition of KOH (0.532 g, 9.5 mmol),
the mixture was heated to reflux overnight. The alcohol was
evaporated to dryness and the residue hydrolyzed. After
extraction with EtOAc, the aqueous phase was acidified (pH
3) with 2 M HCl. The acid was then extracted with CH2Cl2,
dried (MgSO4), and concentrated in vacuo. 17 was obtained
as a solid (2.52 g, 98%) and used in next step without further
purification: mp 102-103 °C; IR (KBr) ν 3100 (large), 1700
cm-1; 1H NMR (CDCl3 + D2O, 300 MHz) δ 1.87-2.00 (m, 2H,
CH2), 2.49-2.69 (m, 2H, CH2CO), 3.10 (dd, J ) 7.3, 11.8 Hz,
1H, NCH), 3.25 (dd, J ) 2.2, 11.8 Hz, 1H, NCH), 4.12-4.22
(m, 1H, OCH), 4.40 (s, 2H, NCH2Ph), 6.58-6.68 (m, 3H, ArH),
6.71-6.80 (m, 2H, ArH), 7.22-7.31 (m, 4H, ArH). Anal.
(C18H19NO3) C, H, N.
3-(4-Ben zyl-3,4-d ih yd r o-2H-1,4-ben zoxa zin -2-yl)-N-[2-
(3,4-d im eth oxyp h en yl)eth yl]p r op a n a m id e (18c). By ap-
plying the general procedure to acid 17 (0.945 g, 3.18 mmol)
with homoveratrylamine (0.91 mL, 5.4 mmol), the amide 18c
(1.22 g, 83%) was obtained as a solid, after purification on silica
gel column (eluent: CH2Cl2/MeOH, 99/1): mp 134-135 °C; IR
(KBr) ν 3230, 1630 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.79-
2.03 (m, 2H, CH2CH2CO), 2.24-2.42 (m, 2H, CH2CO), 2.72 (t,
J ) 7.0 Hz, 2H, CH2Ph), 3.08 (dd, J ) 7.3, 11.8 Hz, 1H, NCH),
3.24 (dd, J ) 2.9, 11.8 Hz, 1H, NCH), 3.42-3.51 (m, 2H,
NCH2), 3.79 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 4.04-4.15 (m,
1H, OCH), 4.39 (s, 2H, NCH2Ph), 5.55 (s, 1H, NH), 6.55-6.68
(m, 8H, ArH), 7.18-7.32 (m, 4H, ArH). Anal. (C28H32N2O4)
C, H, N.
4-Ben zyl-3,4-d ih yd r o-2-[3-[[2-(3,4-d im et h oxyp h en yl)-
eth yl]-N-(ter t-bu toxycar bon yl)am in o]pr opyl]-2H-1,4-ben -
zoxa zin e (19). Compound 19 was isolated following the
procedure described for 14 applied to the compound 3c (1.60
g, 3.58 mmol). Purification of the residue on silica gel column
(eluent: CH2Cl2) led to 19 (1.94 g, 98%) as an oil: IR (film) ν
1680 cm-1 1H NMR (CDCl3, 300 MHz) δ 1.41 (s, 9H, CH3),
;
1.42-1.80 (m, 4H, CH2), 2.68-2.80 (m, 2H, CH2Ph), 3.06 (dd,
J ) 8.1, 11.8 Hz, 1H, NCH), 3.09-3.19 (m, 2H, NCH2), 3.20
(dd, J ) 2.2, 11.8 Hz, 1H, NCH), 3.26-3.39 (m, 2H, NCH2),
3.81 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 4.04-4.13 (m, 1H,
OCH), 4.39 (s, 2H, NCH2Ph), 6.55-6.80 (m, 8H, ArH), 7.18-
7.32 (m, 4H, ArH). Anal. (C33H42N2O5) C, H, N.
2-(4-Ben zyl-3,4-d ih yd r o-2H-1,4-ben zoxa zin -2-yl)a ceta l-
d eh yd e (20). The ester 11c (5.30 g, 17.0 mmol) was first
reduced into its corresponding alcohol following the procedure
described in the preparation of 16. A purification on silica
gel column (eluent CH2Cl2/MeOH, 99/1) furnished 2-(4-benzyl-
3,4-dihydro-2H-1,4-benzoxazin-2-yl)-1-ethanol (3.70 g, 80%) as
an oil: IR (film) ν 3400 cm-1 1H NMR (CDCl3, 300 MHz) δ
;
1.71-1.96 (m, 2H, CH2), 3.14 (dd, J ) 7.3, 11.8 Hz, 1H, NCH),
3.24 (dd, J ) 2.2, 11.8 Hz, 1H, NCH), 3.79-3.87 (m, 2H,
OCH2), 4.27-4.37 (m, 1H, OCH), 4.38 (s, 2H, NCH2Ph), 6.53-
6.65 (m, 2H, ArH), 6.69-6.79 (m, 3H, ArH), 7.15-7.32 (m, 4H,
ArH). Anal. (C17H19NO2) C, H, N.
This intermediate alcohol (3.60 g, 13.0 mmol) was then
oxidized into the expected aldehyde, applying the same
methodology used in the preparation of 16. The residue was
then purified by flash chromatography (eluent CH2Cl2/MeOH,
99/1), providing 20 (2.97 g, 85%) as an oil, which was relatively
unstable: IR (film) ν 1720 cm-1; 1H NMR (CDCl3, 300 MHz) δ
2.61 (dd, J ) 5.1, 16.9 Hz, 1H, CHCO), 2.82 (dd, J ) 7.3, 16.9
Hz, 1H, CHCO), 3.11 (dd, J ) 7.3, 11.8 Hz, 1H, NCH), 3.31
(dd, J ) 2.2, 11.8 Hz, 1H, NCH), 4.36 (d, J ) 15.4 Hz, 1H,
NCHPh), 4.42 (d, J ) 15.4 Hz, 1H, NCHPh), 4.62-4.72 (m,
1H, OCH), 6.57-6.81 (m, 5H, ArH), 7.17-7.33 (m, 4H, ArH),
9.83 (s, 1H, CHO). Anal. (C17H17NO2) C, H, N.
4-(4-Ben zyl-3,4-dih ydr o-2H-1,4-ben zoxazin -2-yl)bu tan o-
ic Acid (21). The procedure used for the preparation of the
acid 17 was repeated from the aldehyde 20 (2.95 g, 11.0 mmol).
This allowed (E)-4-(4-benzyl-3,4-dihydro-2H-1,4-benzoxazin-
2-yl)-2-butenoic acid, ethyl ester (3.37 g, 88%) to be isolated
after purification on silica gel column (eluent: petroleum ether/
1
CH2Cl2, 3/7) as an oil: IR (film) ν 1700, 1650 cm-1; H NMR
(CDCl3, 300 MHz) δ 1.31 (t, J ) 7.3 Hz, 3H, CH3), 2.39-2.50
(m, 1H, OCHCH), 2.53-2.64 (m, 1H, OCHCH), 3.09 (dd, J )
7.3, 11.8 Hz, 1H, NCH), 3.21 (dd, J ) 2.9, 11.8 Hz, 1H, NCH),
4.14 (q, J ) 7.3 Hz, 2H, OCH2), 4.19-4.28 (m, 1H, OCH), 4.34
(d, J ) 15.4 Hz, 1H, NCHPh), 4.41 (d, J ) 15.4 Hz, 1H,
NCHPh), 5.86 (d, J ) 16.2 Hz, 1H, dCH), 6.55-6.66 (m, 3H,
3-(4-Ben zyl-3,4-d ih yd r o-2H-1,4-ben zoxa zin -2-yl)-N-[4-
(4-flu or op h en yl)-1-p ip er a zin yl]p r op a n a m id e (18d ). The
amide 18d was obtained using (4-fluorophenyl)piperazine (2.50
g, 12.0 mmol) with the acid 17 (3.70 g, 12.0 mmol), as reported