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8
Procedure for the
Preparation of Compound 7
To a solution of tetramethylpiperidine
(31.9 mL, 0.19 mol) in THF (250 mL) at -20 ˚C
was added n-BuLi in hexane (90 mL, 2.1
M, 0.19 mol) dropwise over 0.5 h. The reaction was stirred at -10 ˚C
for 1 h, and then cooled to -70 ˚C. Then, Et2Zn
(240 mL, 0.88 M in hexane, 0.21 mol) was added, and the resulting
solution was warmed to 0 ˚C over 0.5 h and stirred at the
temperature for 2 h. The solution was then recooled to -70 ˚C.
2-Fluoro-5-bromobenzonitrile (36.7g, 0.18 mol) in THF (100 mL) was
then added, and the resulting solution was stirred at -70 ˚C
for 0.5 h. The reaction mixture was warmed to -30 ˚C
and stirred for 5 h. The solution was then re-cooled to -70 ˚C
and iodine
(162.6 g, 0.63 mol) in THF (300 mL) was added.
The reaction was left to warm to r.t. and stirred overnight. The reaction
was quenched with NaHSO3 (sat. 35 mL) and filtered. The
solvent was removed in vacuo and the resulting residue was re-dissolved
with EtOAc. The organic layer was washed with NaHSO3 (sat.),
brine, and dried over MgSO4. The solvent was removed
and the solid was recrystallized from EtOAc-PE to provide
the desired compound 7 (44.9 g, 75%). ¹H
NMR (400 MHz, CDCl3): δ = 8.13 (dd,
1 H, J = 4.8,
2.0 Hz), 7.74 (dd, 1 H, J = 4.8,
2.0 Hz).
9
Procedure of the
Preparation of Compound 8
To a solution of iodide 7 (45 g, 0.138 mol) in THF (100 mL) was
added i-PrMgBr (1.19 M in THF, 143 mL)
at -60 ˚C in 0.5 h. The reaction mixture was stirred
at -60 ˚C for 2 h. Meanwhile, a suspension of
anhyd CeCl3 (40.8 g, 0.17 mol) in THF (500 mL) was stirred
vigorously for 2 h at r.t. until it became a milky white suspension
mixture and then cooled to -60 ˚C. To the CeCl3 suspension
was added the above-mentioned Grignard reagent and the mixture was
stirred at
-60 ˚C for 0.5 h and -40 ˚C
for 0.5 h. The resulting mixture was recooled to -60 ˚C
and N-Boc-4-formylpiperidine (35.3 g,
0.17 mol) in THF (150 mL) was added via cannula. The reaction was
warmed slowly to r.t. and stirred overnight. The reaction was quenched
with NaHCO3 (sat.) and dried over Na2SO4.
The solution was removed, and the residue was purified by column
chromatography with EtOAc-hexane (1:1) to provide the desired
product 8 (30 g, 53%). ¹H
NMR (400 MHz, CDCl3): δ = 7.88 (dd,
1 H, J = 6.4,
2.8 Hz), 7.64 (dd, 1 H, J = 6.4,
2.8 Hz), 4.83 (s, 1 H), 4.23-4.00 (m, 2 H), 2.71-2.50
(m, 3 H), 1.80-1.67 (m, 2 H), 1.39 (s, 9 H), 1.38-1.25
(m, 2 H).
For reviews, see:
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Katrizky AR.
Rees
CW.
Pergamon
Press;
New York:
1984.
p.167
10b
Behr LC.
Fusco R.
Jarobe CH. In Pyrazoles, Pyrazolines,
Pyrazolidines, Indazoles and Condensed Rings
Wiley RH.
Wiley;
New York:
1969.
p.28
11a
Porter HD.
Peterson WD.
Org. Synth., Coll. Vol. 3
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Doyle MP.
Bryker WJ.
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Suzuki N.
Kaneko Y.
Nomoto T.
Isawa Y.
J. Chem. Soc., Chem. Commun.
1984,
1523
11e
Doyle MP.
Siegfried B.
Elliot RC.
Dellaria JF.
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12a
Snieckus V.
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12b
Gschwend HW.
Rodrigues HR.
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1
13
El Kazzouli S.
Bouissane L.
Khouili M.
Guillaumet G.
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14
Beak P.
Lee B.
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15a
Arbuzov AE.
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16 Compound 22 (200g,
0.63 mol), Pd/C (10%, 20 g) in EtOH (1 L) was
sealed in an autoclave. The reaction proceeded under H2 (50
psi) overnight. The solution was filtered through Celite and concentrated.
The residue was purified by column chromatography to provide the
aniline 23 (133 g, 73%). ¹H
NMR (400 MHz, CDCl3): δ = 7.12-7.08
(m, 1 H), 7.07-6.95 (m, 1 H), 6.82-6.68 (m, 2
H), 4.19-3.99 (m, 2 H), 2.73-2.55 (m, 2 H), 2.51-2.41
(m, 2 H), 1.82-1.58 (m, 3 H), 1.47 (s, 9 H), 1.26-1.07
(m, 2 H). LCMS [MH+]: t
R = 291.4, 1.81
min.
17 To a solution of aniline 23 (763 g, 2.67 mol) in CH2Cl2
(10
L) was added NBS (935 g, 5.25 mol) portionwise. The solution was
stirred at r.t. until TLC indicated the reaction was complete. The
solvent was evaporated in vacuo and the residue was re-dissolved
in hexane-Et2O (4 L, 1:1). The resulting solution
was passed through a silica plug, washed with hexane-Et2O
mixture and concentrated to provide the desired product 24 (1181 g, 98%). ¹H
NMR (400 MHz, CDCl3): δ = 7.44 (d,
1 H, J = 2.4
Hz), 7.04 (d, 1 H, J = 2.4 Hz),
4.30-4.00 (br m, 4 H), 2.67-2.61 (m, 2 H), 2.44-2.41 (m,
2 H), 1.73-1.61 (m, 3 H), 1.47 (s, 9 H), 1.20-1.16
(m,
2 H). LCMS [MH+ - Boc]: t
R = 346.8, 2.97
min.
18 To a solution of compound 24 (500 g, 1.12 mol) in 2.8 L of AcOH (certified
A.C.S. plus, Fisher) was added NaNO2 (2.26
mol, 97+%, Acros) portionwise at 20-30 ˚C.
The reaction mixture was stirred at r.t. for 30 min. The NaOH solution
was added to adjust the solution pH to 10, and the solution was
partitioned between EtOAc (4 L) and H2O (5.5 L). The
layers were separated, and the aqueous phase was extracted with
EtOAc. The combined organic extracts were washed with brine, dried
over MgSO4, and evaporated. The crude was filtered through
a silica plug to provide the cyclization product 25 as
a brown-yellow solid (360 g, 70%). The compound was used
toward next step without further purification. ¹H
NMR (400 MHz, CDCl3): δ = 7.85 (d,
1 H, J = 1.6
Hz), 7.66 (d, 1 H, J = 1.6
Hz), 4.34-4.18 (m, 2 H), 3.34-3.10 (m, 1 H), 3.02-2.88
(m, 2 H), 2.05-1.84 (m, 4 H), 1.51 (s, 9 H). LCMS [MH+]: t
R = 457.8, 459.8,
2.64 min.
19
Foster RH.
Leonhard MJ.
J. Org. Chem.
1979,
44:
4609
20 To a solution of indazole 25 (323 g, 0.703 mol) in 5.4 L of CH2Cl2 were
added Boc2O (242 mL, 1.06 mol), DMAP (26.6 g, 0.218 mol),
and Hünig’s base (133 mL). The resulting solution
was stirred at r.t. overnight and purified by filtering through
silica plug to provide the N-1 Boc-protected product
(348 g, 88%). The product was used without further purification.
To a solution of N-Boc indazole (348
g, 0.622 mol) in 5 L anhyd Et2O at -78 ˚C
was added 248 mL of n-BuLi (2.5 M in
hexanes, 0.62 mol) dropwise under N2. The reaction mixture
was stirred for 30 min at -78 ˚C, and CO2 was
bubbled through until the temperature stop rising and began to fall.
The reaction was warmed to r.t., and 5 L of H2O were
added. Then, NaOH (1 N) was added to adjust the pH to 12. The layer
was separated and the aqueous layer was washed with Et2O.
The resulting aqueous layer was heated to 90 ˚C until TLC
indicated that conversion to the desired de-Boc product was complete.
The suspension was filtered out though Celite pad. The filtrate
was cooled to r.t. and HCl (1 N) solution was added to adjust the
pH to 3-5. The precipitate was filtered and dried over
MgSO4. The desired carboxylic acid 26 was
obtained without further purification (187 g, 71%). ¹H
NMR (400 MHz, CDCl3): δ = 8.34 (d,
1 H, J = 1.6
Hz), 8.17 (d, 1 H, J = 1.6
Hz), 4.42-4.36 (m, 2 H), 3.33-3.30 (m, 1 H), 3.01-2.86
(m, 2 H), 2.24-2.17 (m, 2 H), 2.02-1.87 (m, 2
H) 1.56 (s, 9 H). LCMS [MH+ - Boc]: t
R = 324.2, 2.40
min. HRMS: m/z calcd for C18H22BrN3O4: 424.0872 [MH+];
found: 424.0863.
21 To a suspension of acid 26 (187 g, 0.44 mol) in 3 L of CH2Cl2 was
added EDC˙HCl (228 g, 1.19 mol) and HOBt˙H2O
(80 g, 0.53 mol). After the reaction mixture became clear, 240 mL
of concentrated NH4OH was added dropwise. The reaction
mixture was stirred overnight at r.t. The precipitate was filtered,
washed with CH2Cl2, and H2O. The
resulting solid was stirred in a combination solution of NaHCO3 and
Na2CO3 for 2 h. The solid was filtered, washed with
H2O, and dried to provide the desired amide 4 (84 g, 45%). Extra product (69
g, 37%) was obtained by purifying the filtrate with column
chromatography (EtOAc-hexane). ¹H NMR
(400 MHz, CDCl3): δ = 8.24 (d, 1 H, J = 1.6 Hz), 8.07
(d, 1 H, J = 1.6
Hz), 4.06-4.00 (m, 2 H), 3.33-3.30 (m, 1 H), 3.01-2.86
(m, 2 H), 1.99-1.89 (m, 2 H), 1.71-1.59 (m, 2
H), 1.43 (s, 9 H). LCMS [MH+]: t
R = 423.0, 2.45
min. HRMS: m/z calcd for C18H23BrN4O3:
423.1032 [MH+]; found: 423.1030.