The Journal of Organic Chemistry
Article
[(7R)-7-[[(4-Fluorophenyl)sulfonyl](methyl)amino]-6,7,8,9-
tetrahydropyrido[1,2-a]indol-10-yl]acetic acid (1, MK-7246).
Method A: Hydrolysis of Methyl Ester 29. To a stirred solution of
ester 29 (9.0 g, 20.5 mmol) in THF (45 mL) was added 1 M aq
LiOH (61.5 mL, 61.5 mmol) dropwise over 15 min at rt. After
a further 16 h, 1 M aq HCl (200 mL, 200 mmol) was added
dropwise over 1 h. The resulting crystalline product was collected
by filtration, washed with 1 M aq HCl (1 × 50 mL), and dried at
rt under vacuum to give the title compound (8.4 g,
99 wt %, 97.2 LCAP, 97% corrected yield) as a pale green powder.
Method B: Hydrolysis of Ethyl Ester 45. EtOH (38 mL) was added
to a stirred solution of ester 45 (15 g, 33.7 mmol) in THF (113 mL) at
rt, and the light yellow solution was then sparged with N2 for 15 min.
Aqueous LiOH (2 M, 56.2 mL, 105 mmol) was added dropwise over
15 min at a temperature below 15 °C. The mixture was then allowed
to warm to rt and stirred for 4 h. Aqueous HCl (1 M, 100 mL,
100 mmol) was added dropwise over 30 min at 15−20 °C to reach pH
6.5−7.0. The solution was then seeded with crystalline product 45
(50 mg) and the slurry aged for 1 h. Dropwise addition of additional
1 M aq HCl (35 mL) was then continued over 2 h until pH 2.5−3.5
was reached. The slurry was then cooled to 0 °C and stirred for 1 h.
The product was collected by filtration, washed with 2:1 water/EtOH
(1 × 30 mL) and then EtOH (1 × 30 mL), and dried at rt under
vacuum to give the title compound (13.98 g, >99 wt % purity, 99%
Method B: Direct Indole Synthesis. PhNHNH2·HCl (40 g,
277 mmol) then ZnCl2 (56.6 g, 415 mmol) were added to a stirred
solution of ketone 34 (58.9 mL, 277 mmol) in PhMe (375 mL) at rt.
The slurry was then heated to 105 °C over 30 min and maintained at
that temperature for 1.5 h. The mixture was cooled to 35 °C, and
water (300 mL) was added in one portion. Stirring was continued at rt
for 5 min until all the solid material had dissolved to give a biphasic
solution. The layers were separated, and the orange organic layer was
washed with water (1 × 150 mL), concentrated, and flushed with
toluene (200 mL) to a final volume of ∼150 mL. HPLC assay
indicated 78 g (93% assay yield) product 36 in the final organic
solution, which was used directly in the ylide formation step: IR (neat)
1
3385, 2979, 2935, 1716, 1621, 1461, 1155, 1030, 739 cm−1; H NMR
(400 MHz, CDCl3) δ 8.66 (1H, br s), 7.60−7.57 (1H, m), 7.31−7.29
(1H, m), 7.16 (1H, ddd, J = 7.5, 7.5, 1.5 Hz), 7.11 (1H, ddd, J = 7.5,
7.5, 1.0 Hz), 4.19 (2H, q, J = 7.0 Hz), 4.13 (2H, q, J = 7.0 Hz), 3.71
(2H, s), 3.11−3.08 (2H, m), 2.75−2.71 (2H, m), 1.28 (3H, t, J = 7.0
Hz), 1.25 (3H, t, J = 7.0 Hz); 13C NMR (100 MHz, CDCl3) δ 174.2,
171.9, 135.7, 135.1, 128.1, 121.5, 119.4, 118.4, 110.6, 104.6, 60.9, 60.7,
34.1, 30.4, 20.7, 14.2, 14.1; HRMS calcd for C17H21NO4Na [MNa]+
326.1368, found 326.1364.
Ethyl 3-[1-(2-tert-Butoxy-2-oxoethyl)-3-(2-ethoxy-2-oxoeth-
yl)-1H-indole-2-yl]propanoate (33). To a stirred solution of diester
36 (11.0 g, 36.3 mmol) in DMF (44 mL) was added Cs2CO3 (14.1 g,
43.5 mmol) in one portion at 5 °C, followed by tert-butyl bromo-
acetate (6.43 mL, 43.5 mmol) dropwise over 2 min. The mixture was
warmed to rt, stirred for 16 h, and then partitioned between MTBE
(100 mL) and water (100 mL). The layers were separated, and the
aqueous layer was extracted with MTBE (2 × 50 mL). The combined
organic layers were washed with water (1 × 50 mL) and satd aq NaCl
(1 × 50 mL), dried (MgSO4), filtered, and concentrated. The residue
was purified by column chromatography (gradient elution 10−20%
EtOAc in hexanes) to give the title compound (14.15 g, 93% yield) as
an orange oil: IR (neat) 2980, 2927, 1727, 1467, 1368, 1224, 1152,
25
corrected yield) as a white powder: mp 225 °C; [α]D +11.6 (c 0.2,
acetone); IR (neat) 1699, 1590, 1488, 1341, 1264, 1166, 1089 cm−1;
1H NMR (500 MHz, d6-DMSO) δ 12.13 (1H, br s), 8.04−8.02
(2H, m), 7.50−7.46 (3H, m), 7.29 (1H, d, J = 8.0 Hz), 7.08 (1H, dd, J
= 8.0, 1.0 Hz), 7.03 (1H, dd, J = 8.0, 1.0 Hz), 4.47−4.41 (1H, m), 4.13
(1H, dd, J = 11.5, 5.5 Hz), 3.88 (1H, dd, J = 11.5, 11.5 Hz), 3.56 (2H,
abq, J = 13.0 Hz), 3.04 (1H, ddd, J = 16.5, 5.0, 2.5 Hz), 2.83 (3H, s),
2.80 (1H, ddd, J = 16.5, 12.5, 5.5 Hz), 1.83 (1H, ddd, J = 12.5, 12.5,
5.0 Hz), 1.52−1.50 (1H, m); 13C NMR (125 MHz, d6-DMSO) δ
172.9, 164.6 (d, J = 252.0 Hz), 135.3, 135.3 (d, J = 3.0 Hz), 132.8,
130.0 (d, J = 9.5 Hz), 128.0, 120.3, 119.3, 117.8, 116.8 (d, J = 22.5
Hz), 108.9, 102.9, 52.5, 43.9, 29.7, 29.3, 23.8, 20.7; 19F NMR (376
MHz, CDCl3) δ −101.2; HRMS calcd for C21H22FN2O4S [M + H]+
417.1284, found 417.1287.
1
1030, 736 cm−1; H NMR (500 MHz, CDCl3) δ 7.62 (1H, d, J = 7.5
Hz), 7.20−7.18 (2H, m), 7.16−7.13 (2H, m), 4.77 (2H, s), 4.17 (2H,
q, J = 7.0 Hz), 4.14 (2H, q, J = 7.0 Hz), 3.76 (2H, s), 3.13 (2H, dd, J =
8.0, 8.0 Hz), 2.69 (2H, dd, J = 8.0, 8.0 Hz), 1.45 (9H, s), 1.27 (3H, t,
J = 7.0 Hz), 1.25 (3H, t, J = 7.0 Hz); 13C NMR (125 MHz, CDCl3) δ
172.3, 171.5, 167.6, 136.5, 136.2, 127.7, 121.5, 119.6, 118.5, 108.5,
105.5, 82.2, 60.4 (2C), 45.6, 38.8, 30.6, 27.7, 19.4, 13.9 (2C); HRMS
calcd for C23H32NO6 [M + H]+ 418.2230, found 418.2236.
Ethyl 3-(6-Oxo-1-phenyl-1,4,5,6-tetrahydropyridazin-3-yl)-
propanoate (35). PhNHNH2·HCl (30 g, 207 mmol) was added to
a solution of ketone 34 (44.2 mL, 207 mmol) in toluene (180 mL),
and the mixture was heated at reflux under Dean−Stark conditions for
16 h. The solution was then cooled to rt and concentrated. The
residue was purified by column chromatography (gradient elution 10−
75% EtOAc in hexanes) to give the title compound (53.1 g, 93 wt %,
87% corrected yield) as an orange oil: IR (neat) 2977, 2905, 1728,
tert-Butyl 10-(2-Ethoxy-2-oxoethyl)-7-oxo-6,7,8,9-
tetrahydropyrido[1,2-a]indole-6-carboxylate (37). A solution of
indole 33 (14.0 g, 33.5 mmol) in THF (90 mL) was added dropwise
over 15 min to a stirred mixture of THF (100 mL) and KO-t-Bu (1 M
in THF, 36.9 mL, 36.9 mmol) at −25 °C. After a further 15 min
at −20 °C, the reaction was quenched by the addition of 1 M aq HCl
(120 mL). The mixture was warmed to rt and partitioned between
MTBE (80 mL) and water (50 mL). The layers were separated, and
the aqueous layer was extracted with MTBE (1 × 80 mL). The
combined organic layers were washed with satd aq NaCl (1 × 50 mL),
dried (MgSO4), filtered, and concentrated. The residue was purified by
column chromatography (gradient elution 10−15% EtOAc in
hexanes) to give the title compound (7.94 g, 64% yield) as a yellow
oil: IR (neat) 2979, 2941, 1724, 1463, 1368, 1147, 1028, 729 cm−1; 1H
NMR (500 MHz, CDCl3) δ 7.61 (1H, dd, J = 7.0, 1.5 Hz), 7.22−7.14
(3H, m), 5.37 (2H, s), 4.11 (2H, q, J = 7.0 Hz), 3.72 (2H, abq, J = 10.0
Hz), 3.31 (1H, ddd, J = 16.0, 6.0, 4.0 Hz), 3.18 (1H, ddd, J = 16.0,
12.5, 4.0 Hz), 2.86 (1H, ddd, J = 16.0, 4.0, 4.0 Hz), 2.61 (1H, ddd, J =
16.0, 12.5, 6.0 Hz), 1.38 (9H, s), 1.22 (3H, t, J = 7.0 Hz); 13C NMR
(125 MHz, CDCl3) δ 199.7, 171.0, 164.5, 134.9, 132.4, 128.2, 121.3,
120.1, 118.3, 108.2, 103.5, 83.2, 66.0, 60.2, 36.2, 29.8, 27.2, 18.7, 13.8;
HRMS calcd for C21H26NO5 [M + H]+ 372.1811, found 372.1812.
Ethyl (7-Oxo-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)-
acetate (32). Method A: Decarboxylation of Ester 37. Silica
gel (24 g) was added to a stirred solution of ester 37 (8 g,
21.5 mmol) in PhMe (240 mL) at rt. The mixture was heated
to reflux for 70 min, cooled rt, and filtered. The cake was
washed with EtOAc (2 × 50 mL), and the combined filtrates
1
1677, 1595, 1320, 1302, 1211, 1170, 754 cm−1; H NMR (400 MHz,
CDCl3) δ 7.44−7.42 (2H, m), 7.29−7.25 (2H, m), 7.14−7.10 (1H,
m), 4.02 (2H, q, J = 7.0 Hz), 2.61−2.51 (4H, m), 2.50−2.39 (4H, m),
1.11 (3H, t, J = 7.0 Hz); 13C NMR (100 MHz, CDCl3) δ 172.1, 164.6,
154.6, 140.7, 127.7, 125.5, 123.8, 59.9, 30.8, 29.4, 27.3, 25.1, 13.7;
HRMS calcd for C15H19N2O3 [M + H]+ 275.1396, found 275.1393.
Ethyl 3-[3-(2-Ethoxy-2-oxoethyl)-1H-indol-2-yl]propanoate
(36). Method A: From Pyridazinone 35. Concentrated H2SO4
(30 mL, 563 mmol) was added over 2 min to a solution of
pyridazinone 35 (15 g, 54.7 mmol) and EtOH (120 mL)
(CAUTION: exotherm from rt to 70 °C was observed upon
the addition of H2SO4). The mixture was heated to gentle reflux
(90−92°(C) for 2.5 h, cooled to 5 °C, and neutralized to pH =
7.0 by the addition of aq NaOH (stock solution prepared by
diluting 25 mL 50 wt % aq NaOH with 100 mL water), main-
taining the temperature below 18 °C. The slurry was then
concentrated to remove most of the EtOH, and the residue was
partitioned between MTBE (200 mL) and water (50 mL). The
layers were separated, and the aqueous layer was extracted with
MTBE (1 × 50 mL). The combined organic layers were dried
(MgSO4), filtered, and concentrated. The residue was purified
by column chromatography (gradient elution 10−20% EtOAc
in hexanes) to give the title compound (12.47 g, 75% yield) as
an orange oil.
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dx.doi.org/10.1021/jo202620r | J. Org. Chem. 2012, 77, 2299−2309