PAPER
Roflumilast via Copper-Catalyzed Hydroxylation
3601
phase A: MeOH, phase B: aq 10 mM NH4OAc; flow rate: 1 mL/min
at 30 °C.
13C NMR (400 MHz, CDCl3): δ = 166.9, 150.3, 145.5, 124.2, 122.2,
114.0, 112.9, 74.2, 52.2, 10.2, 3.4 (2 C).
Methyl 3-(Cyclopropylmethoxy)-4-iodobenzoate (9)
SOCl2 (473.0 g, 4.0 mol) was added slowly to a soln of 8 (700.0 g,
2.6 mol) in MeOH (5 L) at 0 °C. The resulting mixture was stirred
at 50 °C for 3 h. After completion of the reaction, the mixture was
cooled to r.t. and then concentrated to provide crude methyl 3-hy-
droxy-4-iodobenzoate (740.0 g) as a white solid,8a which was used
directly in the next step.
Methyl 3-(Cyclopropylmethoxy)-4-(difluoromethoxy)benzoate
(12)
A soln of sodium chlorodifluoroacetate (27.0 g, 0.18 mol) and phe-
nol 11 (19.8 g, 89 mmol) in DMF (60 mL) was added slowly over a
period of 1 h to a suspension of K2CO3 (18.4 g, 0.13 mol) in DMF
(40 mL) at 95 °C. When the addition was complete, the suspension
was stirred for a further 15 min and then cooled to 15 °C. H2O (0.3
L) was added and the resulting mixture was extracted with toluene
(0.1 L). The organic layer was washed with sat. aq NaCl soln (30
mL), dried, and concentrated to afford crude 12, which was purified
by column chromatography to provide 12 (23.7 g, 98%) as a white
crystalline solid;4b mp 44.5–46.4 °C; Rf = 0.7 (hexane–EtOAc,
10:1).
Cyclopropylmethyl bromide (522.0 g, 3.9 mol) was slowly added
into a mixture of K2CO3 (646.0 g, 4.7 mol) and methyl 3-hydroxy-
4-iodobenzoate (740.0 g, obtained in last step) in DMF (2 L), and
the resulting mixture was heated to 80 °C for 2 h. The mixture was
cooled to r.t. and diluted with H2O (10 L). The resulting mixture
was filtered and washed with H2O (1 L) to afford ester 9 (871.1 g,
99%) as a white solid; mp 76.0–77.5 °C; Rf = 0.6 (hexane–EtOAc,
10:1).
IR (neat): 3446, 2954, 1722, 1601, 1439, 1291, 1099, 1025, 756
cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.64 (d, J = 8.0 Hz, 1 H), 7.62 (s,
1 H), 7.20 (s, J = 8.0 Hz, 1 H), 6.73 (t, J = 76.0 Hz, 1 H), 3.94 (d,
J = 6.4 Hz, 2 H), 3.92 (s, 3 H), 1.19–1.36 (m, 1 H), 0.61–0.75 (m, 2
H), 0.32–0.45 (m, 2 H).
13C NMR (400 MHz, CDCl3): δ = 167.0, 150.1, 144.0, 128.2, 122.8,
121.8, 115.1 (t, OCHF2), 114.6, 74.0, 52.3, 10.2, 3.2 (2 C).
IR (neat): 3447, 3092, 2953, 2885, 1711, 1585, 1400, 1235, 1257,
1115, 1015, 753 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.87 (d, J = 8.0 Hz, 1 H), 7.42 (s,
1 H), 7.37 (d, J = 8.0 Hz, 1 H), 3.98 (d, J = 6.4 Hz, 2 H), 3.93 (s, 3
H), 1.25–1.40 (m, 1 H), 0.60–0.75 (m, 2 H), 0.40–0.49 (m, 2 H).
13C NMR (400 MHz, CDCl3): δ = 166.6, 157.7, 139.5, 131.4, 123.2,
112.7, 3.7, 73.7, 52.4, 10.1, 3.6, 3.3.
MS: m/z = 273.1 (M+ + 1).
MS: m/z = 332.9 (M+ + 1).
HRMS (ESI): m/z [M + H]+ calcd for C12H14IO3: 332.9988; found:
3-(Cyclopropylmethoxy)-4-(difluoromethoxy)benzoic Acid (2)
A soln of 12 (23.7 g, 87 mmol) in MeOH (60 mL) and 3 M NaOH
(80 mL) was heated at 50 °C for 3 h. The mixture was cooled to r.t.
and concentrated to remove MeOH. The resulting mixture was di-
luted with H2O (30 mL) and acidified with aq 4 M HCl to pH 2. Af-
ter cooling at 5 °C for 5 h, the precipitate was filtered off and
washed with H2O to give product 2 as a white crystalline solid (22.3
g, 99%). The crystalline solid was further purified by crystallization
(MeCN–petroleum ether, 3:2) to give white crystals; HPLC purity:
99.3%; mp 120.0–120.9 °C (lit.11 mp 118–118.5 °C); Rf = 0.3
(hexane–EtOAc, 1:1).
332.9981.
3-(Cyclopropylmethoxy)-4-hydroxybenzoic Acid (10)
A soln of KOH (22.4 g, 0.4 mol) in H2O (0.1 L) was slowly added
to a mixture of 9 (33.2 g, 0.1 mol), CuI (1.9 g, 0.01 mol), and 8-hy-
droxyquinoline (2.9 g, 0.02 mol) in DMSO (0.1 L), the mixture was
stirred at 100 °C for 30 h under a N2 atmosphere (TLC monitoring).
The mixture was cooled to r.t. and the copper catalyst was filtered
off. The resulting soln was acidified with aq 1 M HCl to pH 2. The
precipitate was filtered off and the filtercake was washed with H2O
(50 mL) to give product 10 (20.1 g) as a yellow solid, which was pu-
rified by column chromatography (CH2Cl2–MeOH, 15:1) to afford
10 (18.7 g, 90%) as a light yellow powder; mp 145.5–147.2 °C;
Rf = 0.5 (CH2Cl2–MeOH, 10:1). Crude 10 was used directly for the
next step in a 200-gram scale preparation.
IR (neat): 3421, 3015, 2931, 2879, 1690, 1601, 1517, 1442, 1297,
1215, 1095, 886, 846, 766 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.75 (d, J = 8.0 Hz, 1 H), 7.70 (s,
1 H), 7.26 (d, J = 8.0 Hz, 1 H), 6.77 (t, J = 76.0 Hz, 1 H), 3.97 (d,
J = 7.2 Hz, 2 H), 1.18–1.42 (m, 1 H), 0.63–0.78 (m, 2 H), 0.36–0.49
(m, 2 H).
13C NMR (400 MHz, CDCl3): δ = 171.6, 150.1, 144.8, 127.2, 123.7,
121.7, 115.7, 115.5 (t, OCHF2), 74.1, 10.0, 3.3 (2 C).
19F NMR (400 MHz, CDCl3): δ = –82.0 (d, J = 78.8 Hz, 2 F).
HRMS (ESI): m/z [M – H]+ calcd for C12H11F2O4: 257.0625; found:
IR (neat): 3512, 3407, 3007, 1676, 1596, 1516, 1444, 1239, 1112,
834, 768 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.74 (d, J = 8.0 Hz, 1 H), 7.57 (s,
1 H), 7.00 (d, J = 8.0 Hz, 1 H), 3.97 (J = 6.4 Hz, 2 H), 1.19–1.37 (m,
1 H), 0.61–0.75 (m, 2 H), 0.32–0.45 (m, 2 H).
13C NMR (400 MHz, CDCl3): δ = 171.8, 151.1, 145.6, 125.2, 121.2,
257.0623.
114.2, 113.3, 74.3, 10.2, 3.4 (2 C).
MS: m/z = 209.1 (M+ + 1).
HRMS (ESI): m/z [M + H]+ calcd for C11H13O4: 209.0814; found:
209.0814.
Roflumilast (1)
Roflumilast (1) was prepared according to the procedure3b devel-
oped by Nycomed®; yield: 122.0 g (93%); HPLC purity: 99.4%; mp
158.1–159.9 °C (lit.11 mp 159 °C); Rf = 0.5 (hexane–EtOAc, 2:1).
IR (neat): 3448, 3259, 2940, 2878, 1653, 1596, 1557, 1502, 1402,
1305, 1199, 1156, 1008, 808, 748 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 10.67 (s, 1 H), 8.78 (s, 2 H),
7.71 (s, 1 H), 7.66 (d, J = 8.0 Hz, 1 H), 7.37 (d, J = 8.0 Hz, 1 H),
7.25 (t, J = 76.0 Hz, 1 H), 3.99 (d, J = 8.0 Hz, 2 H), 1.19–1.40 (m,
1 H), 0.63–0.76 (m, 2 H), 0.32–0.46 (m, 2 H).
13C NMR (400 MHz, DMSO-d6): δ = 164.3, 150.2, 148.8 (2 C),
143.5, 141.6, 131.2 (2 C), 130.8, 121.4, 120.9, 117.0 (t, OCHF2),
114.1, 73.8, 10.4, 3.5 (2 C).
Methyl 3-(Cyclopropylmethoxy)-4-hydroxybenzoate (11)
SOCl2 (16.0 g, 0.14 mol) was added slowly to a soln of 10 (18.7 g,
90 mmol) in MeOH (0.1 L) at 0 °C. The resulting mixture was
stirred at 50 °C for 3 h. After completion of the reaction, the mixture
was cooled to r.t. and then concentrated to provide crude phenol 11,
which was purified by column chromatography to afford 11 (19.8 g,
99%) as a colorless oil;4b Rf = 0.7 (hexane–EtOAc, 2:1).
IR (neat): 3420, 2952, 1711, 1597, 1513, 1441, 1288, 1218, 1102,
1010, 765 cm–1.
19F NMR (400 MHz, DMSO-d6): δ = –81.8 (d, J = 79.2 Hz, 2 F).
1H NMR (400 MHz, CDCl3): δ = 7.65 (d, J = 8.0 Hz, 1 H), 7.52 (s,
1 H), 6.97 (d, J = 8.0 Hz, 1 H), 3.95 (d, J = 6.4 Hz, 2 H), 3.90 (s, 3
H), 1.18–1.37 (m, 1 H), 0.60–0.75 (m, 2 H), 0.31–0.45 (m, 2 H).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3598–3602