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G. B. Hill, A. A. Mortlock
PAPER
tert-Butyl 2-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}hydra-
zinecarboxylate (13)
with EtOAc (1 × 100 mL) and Et2O (1 × 50 mL) and air-dried; yield:
1.35 g (93%); white powder.
A solution of 12 (20 g, 80 mmol) in EtOAc (100 mL) was treated
with 20% aq KHCO3 and stirred for 1 min, then treated with a solu-
tion of tert-butyl carbazate (21.12 g, 160 mmol) in EtOAc (75 mL)
and heated to reflux for 4 h. The layers were separated, the organic
phase washed with brine (30 mL), dried (MgSO4) and evaporated to
a solid that was boiled in cyclohexane (100 mL) for 1 min, cooled,
and the solid was collected by filtration; yield: 20.68 g (86%); white
crystals.
1H NMR (DMSO-d6): d = 9.97 (br s, 1 H), 8.46 (br s, 1 H), 7.79 (m,
1 H), 7.16 (m, 2 H), 5.36 (m, 1 H), 3.29 (d, 2 H, J = 3.7 Hz), 1.36
(s, 9 H).
1H NMR (DMSO-d6): d = 10.48 (s, 1 H), 10.22 (br s, 3 H), 8.03 (s,
1 H), 7.68 (m, 1 H), 7.60 (s, 1 H), 7.19 (m, 2 H), 5.20 (s, 2 H).
MS: m/z = 252 (M+).
Anal. Calcd for C11H10F2N4O·HCl: C, 45.77; H, 3.84; N, 19.41; Cl,
12.28. Found: C, 45.9; H, 3.84; N, 19.0; Cl, 11.9.
2-(4-Amino-1H-pyrazol-1-yl)-N-(2,3-difluorophenyl)acet-
amide (1)
From 5: A solution of N-(2,3-difluorophenyl)-2-(4-nitro-1H-pyra-
zol-1-yl)acetamide (5.22 g, 18.5 mmol) and Pt2O (500 mg) in
EtOH–EtOAc (1:4, 300 mL) was stirred under an atmosphere of H2
(80 psi) for 2 h. The catalyst was removed by filtration and the res-
idue evaporated to a solid that was washed with Et2O (1 × 50 mL);
yield: 4.20 g (90%); pale purple solid. A sharp-melting sample was
obtained by chromatography on silica gel eluting with CH2Cl2–
MeOH–aqNH4OH 1000:20:2 to 1000:80:8, followed by recrystalli-
zation from THF, adding isohexane; mp 158.5–159.5 °C.
MS: m/z = 301 (M–).
Anal. Calcd for C13H17F2N3O3: C, 54.72; H, 4.92; N, 22.79. Found:
C, 51.9; H, 5.66; N, 13.9.
2-(4-Bromo-1H-pyrazol-1-yl)-N-(2,3-difluorophenyl)acet-
amide (14)
A solution of 12 (7.50 g, 30 mmol) and 4-bromopyrazole (4.41 g,
30 mmol) in DMA (20 mL) was treated with K2CO3 (5.06 g, 37
mmol) and stirred under N2 at 20 °C for 18 h. The mixture was
poured into H2O (300 mL), filtered, and the solid washed with H2O
(500 mL) and air-dried. The solid was dissolved in boiling THF (50
mL), filtered, diluted with cyclohexane (60 mL), and evaporated to
60 mL. The resultant slurry was diluted with isohexane (60 mL),
cooled and the product was collected by filtration; yield: 7.97 g
(79%); white crystals.
1H NMR (DMSO-d6): d = 10.32 (br s, 1 H), 8.00 (s, 1 H), 7.70 (m,
1 H), 7.59 (s, 1 H), 7.19 (m, 2 H), 5.14 (s, 2 H).
MS: m/z = 315, 317 (M+).
1H NMR (DMSO-d6): d = 10.06 (br s), 7.70 (m, 1 H), 7.17 (m, 2 H),
7.09 (s, 1 H), 6.97 (s, 1 H), 4.90 (s, 2 H), 3.86 (br s, 2 H).
MS: m/z = 252 (M+).
Anal. Calcd for C11H10F2N4O: C, 52.38; H, 4.00; N, 22.21. Found:
C, 52.2; H, 4.00; N, 21.9.
From 11: Compound 11 (2.44 g, 8 mmol) was dissolved in a boiling
mixture of H2O (50 mL) and n-PrOH (10 mL), allowed to cool to 50
°C, and treated dropwise with concd aq NH4OH (1.33 mL, 24
mmol). The solution was heated to reflux for 20 minutes, allowed to
cool to 70 °C and acidified to pH 7 with 5 M aq H2SO4 (ca. 0.5 mL)
followed by another 4.8 mL (24 mmol) of the same acid. After 90
min at 70 °C, the solution was cooled, basified to pH 7.5 with aq
NH4OH and evaporated to 60 mL. The product was extracted with
EtOAc (3 × 50 mL), the combined organic phases were dried
(MgSO4) and evaporated to an oil, which was purified by chroma-
tography on silica gel eluting with CH2Cl2–MeOH (100:3 to 100:8);
yield: 762 mg (45%); pale pink solid; mp 157–158.5 °C.
Anal. Calcd for C11H8BrF2NO: C, 41.80; H, 2.55; N, 13.29. Found:
C, 42.2; H, 2.46; N, 13.0.
N-(2,3-Difluorophenyl)-2-{4-[(diphenylmethylene)amino]-1H-
pyrazol-1-yl}acetamide (15)
A solution of 14 (9.48 g, 30 mmol) and (9,9-dimethyl-9H-xanthene-
4,5-diyl)bis(diphenylphosphine) (‘xantphos’) (1.74 g, 3 mmol) in
anhyd 1,4-dioxane (50 mL) was treated with tris(dibenzylideneace-
tone)dipalladium(0) (1.37 g, 1.5 mmol) and the mixture stirred for
5 min under N2. Benzophenone imine (5.7 g, 31.5 mmol) was added
in one portion, followed by t-BuONa (8.64 g, 90 mmol). The mix-
ture was degassed with N2, then heated under N2 to 90 °C for 4 h. It
was then cooled, diluted with Et2O (100 mL) and poured into sat. aq
NH4Cl (100 mL), and filtered through Celite. The layers were sep-
arated, the organic phase dried (MgSO4) and concentrated to an oil
which was extracted with boiling cyclohexane (1 × 200 mL, 1 × 100
mL). The cyclohexane solution was evaporated to a gum which was
triturated with 1:1 isohexane–Et2O (50 mL) and washed with cold
Et2O (10 mL) to give a solid; yield: 5.50 g (44%); pale yellow crys-
tals.
1H NMR (DMSO-d6): d = 10.07 (br s, 1 H), 7.71 (m, 1 H), 7.18 (m,
2 H), 7.09 (s, 1 H), 6.98 (s, 1 H), 4.91 (s, 2 H), 3.86 (br s, 2 H).
MS: m/z = 252 (M+).
Anal. Calcd for C11H10F2N4O: C, 52.38; H, 4.00; N, 22.21. Found:
C, 52.2; H, 3.86; N, 22.0.
From 16: Compound 16 (1.685 g, 5.84 mmol) was suspended in
EtOAc (70 mL) and sat. aq NaHCO3 (35 mL), and stirred for 1 h.
The clear layers were separated and the aqueous phase was extract-
ed with EtOAc (4 × 30 mL). The combined organic solutions were
dried (MgSO4) and evaporated to a solid that was washed with Et2O
(1 × 50 mL); yield: 1.377 g (94%); pink solid; mp 159–159.5 °C.
1H NMR (DMSO-d6): d = 10.06 (br s, 1 H), 7.70 (m, 1 H), 7.17 (m,
2 H), 7.08 (s, 1 H), 6.98 (s, 1 H), 4.90 (s, 2 H), 3.84 (br s, 2 H).
MS (+ve ESI): m/z = 253 (M + H)+.
1H NMR (DMSO-d6): d = 10.21 (br s, 1 H), 7.66 (m, 3 H), 7.56 (m,
3 H), 7.44 (m, 3 H), 7.35 (s, 1 H), 7.24 (m, 2 H), 7.18 (m, 2 H), 6.48
(s, 1 H), 4.98 (s, 2 H).
Anal. Calcd for C11H10F2N4O: C, 52.38; H, 4.00; N, 22.21. Found:
C, 52.2; H, 3.90; N, 22.1.
MS: m/z = 416 (M+).
2-(4-{[7-(3-Chloropropoxy)quinazolin-4-yl]amino}-1H-pyra-
zol-1-yl)-N-(2,3-difluorophenyl)acetamide Hydrochloride (3)
4 N HCl in 1,4-dioxane (622 mL, 2.49 mmol) was added to a solu-
tion of 1 (627 mg, 2.49 mmol) and 4-chloro-7-(3-chloropro-
poxy)quinazoline1 (640 mg, 2.49 mmol) in DMA (24 mL) and the
mixture heated under N2 at 80 °C for 30 min. The mixture was
cooled, diluted with Et2O (24 mL), and filtered. The solid was
washed with DMA–Et2O (1:1, 100 mL) and Et2O (200 mL), air-
dried, and then stirred in 10% aq NaHCO3 (125 mL) for 15 min. The
Anal. Calcd for C24H18F2N4O: C, 69.22; H, 4.36; N, 13.45. Found:
C, 69.1; H, 4.28; N, 13.1.
2-(4-Amino-1H-pyrazol-1-yl)-N-(2,3-difluorophenyl)acet-
amide Hydrochloride (16)
A well-stirred solution of 15 (2.08g, 5 mmol) in EtOAc (25 mL) was
treated dropwise with 37% aq HCl (496 mL, 6 mmol) over 1 min at
r.t. The initial sticky precipitate rapidly became powdery on stir-
ring. After 1 h, the solid was collected by filtration, washed well
Synthesis 2007, No. 11, 1697–1701 © Thieme Stuttgart · New York