1H NMR (CDCl3) δ 1.30 (t, 3H), 2.87 (q, 2H), 8.65 (s,
1H) ppm.
a solution of sodium metabisulfite (5 g) in water (50 mL)
and then with water (50 mL). The organic layer was
concentrated at reduced pressure to give the product oil (9.40
g activity by H NMR, 96% yield).
1H NMR (CDCl3) δ 2.08 (d, 3H), 5.38 (q, 1H), 8.58 (1H),
9.03 (1H) ppm.
(viii) 4-Ethyl-5-fluoropyrimidine (10). A mixture of
compound 8 (10 g), sodium acetate (8.83 g), 5% palladium-
on-carbon (50% water wet, 2 g), and methanol (30 mL) was
hydrogenated at 50 °C and 50 psi for 5 h. The resulting slurry
was filtered through a cellulose-based filter aid, the pad was
washed with further methanol (5 mL), and the resulting
orange filtrate was distilled at 64 °C and atmospheric pressure
to provide a colourless distillate. This was partitioned
between water (300 mL) and ether (40 mL), and the two
phases were separated. The organic phase was washed with
water (4 × 500 mL) and dried over MgSO4, and the solvent
was removed at room temperature under reduced pressure
to provide the title compound as a pale yellow liquid (2.2 g,
35% yield).
1
(xiii) General Procedure for Reformatsky Reactions
of 4-(1-Bromoethyl)-5-fluoropyrimidines (17), (18), (19),
and (20) with Ketone (3). A stirred mixture of zinc powder
(2.40 g), lead (0.12 g), and tetrahydrofuran (10 mL) was
heated to reflux under a nitrogen atmosphere for 3 h. A
solution of iodine (2.29 g) in tetrahydrofuran (10 mL) was
added at reflux. After 30 min a combined solution of the
4-(1-bromoethyl)-5-fluoropyrimidine (11 mmol), 1-(2,4-
difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)-1-ethanone (3) (2.23
g) and iodine (0.25 g) in tetrahydrofuran (30 mL) was finally
added to the mixture at reflux over 30 min. After a further
30 min at reflux the mixture was cooled and a sample taken
and subjected to HPLC analysis according to the conditions
set out in (xiv).
(xiv) (R*,S*)-3-(6-Chloro-5-fluoro-4-pyrimidinyl)-2-
(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol hy-
drochloride (4) (X ) Cl, Y ) H) [Method with Lead]. A
stirred mixture of zinc powder (9.35 g), lead (0.47 g), and
tetrahydrofuran (53 mL) was heated under reflux under a
nitrogen atmosphere for 3 h. The mixture was then cooled
to 25 °C and stirring continued for 16 h. A solution of iodine
(7.42 g) in tetrahydrofuran (21 mL) was added over 80 min,
and the reaction temperature was allowed to rise to 45 °C
during the addition. The mixture was then cooled to between
0 and -5 °C. A solution of 1-(2,4-difluorophenyl)-2-(1H-
1,2,4-triazol-1-yl)-1-ethanone (3) (6.53 g) and 4-(1-bromo-
ethyl)-6-chloro-5-fluoropyrimidine (17) (7.01 g) in tetrahy-
drofuran (53 mL) was then added, maintaining the reaction
temperature below +5 °C during the addition. The mixture
was warmed to 25 °C, and glacial acetic acid (8.84 g) and
water (84 mL) were added. The solid metal residues were
separated by decantation, and 60 mL of tetrahydrofuran was
removed by distillation under reduced pressure. Ethyl acetate
(76 g) was added, and the distillation was continued to
remove 165 mL of solvent. The mixture was cooled and
extracted with ethyl acetate (2 × 84 mL), and the combined
extracts were washed with a solution of disodium ethylene-
diaminetetraacetate dihydrate (3.22 g) in water (161 mL),
followed by saturated brine (30 mL).
1H NMR (CDCl3) δ 1.31 (t, 3H), 2.89 (dq, 2H), 8.43 (s,
1H), 8.92 (d,1H) ppm.
(ix) 6-(1-Bromoethyl)-4-chloro-5-fluoropyrimidine (17).
A stirred mixture of compound 9 (38.5 g), azoisobutyronitrile
(AIBN) (1.92 g), NBS (49 g), and dichloromethane (198 mL)
was heated under reflux under nitrogen for 12 h. The mixture
was cooled to 25 °C and water (239 mL) added. The layers
were separated, and the aqueous layer was extracted with
dichloromethane (120 mL). The combined organic layers
were washed with a solution of sodium metabisulfite (22.8
g) in water (239 mL), followed by water (239 mL). The
organic layer was concentrated under reduced pressure,
toluene (240 mL) was added, and the resulting solution was
concentrated under reduced pressure to give the product as
1
an oil (54.5 g activity by H NMR, 95% yield).
1H NMR (CDCl3) δ 2.08 (d, 3H), 5.35 (q, 1H), 8.80 (s,
1H) ppm.
(x) 4-(1-Bromoethyl)-2-chloro-5-fluoropyrimidine (18).
A stirred mixture of compound 7 (3.60 g), AIBN (180 mg),
and NBS (5.30 g) in 1,1,1-trichloroethane (50 mL) was
heated to reflux for 30 h. The reaction mixture was cooled
and washed with a solution of sodium metabisulfite (2.5 g)
in water (25 mL) and then with water (25 mL). The organic
layer was concentrated at reduced pressure to give the
1
product oil (5.0 g activity by H NMR, 93% yield).
1H NMR (CDCl3) δ 2.07 (d, 3H), 5.28 (q, 1H), 8.47 (s,
1H) ppm.
(xi) 4-(1-Bromoethyl)-2,4-dichloro-5-fluoropyrimidine
(19). A stirred solution of compound 8 (14.0 g), AIBN (700
mg), NBS (14.2 g), and bromine (5.75 g) in dichloromethane
(70 mL) and water (21 mL) was heated to reflux for 96 h.
The reaction mixture was cooled and separated, and the
organic phase was subsequently washed with a solution of
sodium metabisulfite (9 g) in water (90 mL) and then with
water (90 mL). The organic layer was concentrated at
reduced pressure to give the product oil (19 g activity by 1H
NMR, 96% yield).
The ratio of the diastereomer pairs contained in the
organic layer was determined by HPLC analysis using a 25
cm C18 Dynamax 60 Å reverse phase column, a mobile
phase consisting of 65:35, by volume, acetonitrile:water and
a flow rate of 1 mL/min. The detector was set at 254 nm.
This analysis showed a 9:1 molar ratio of the (R*,S*) (tR )
5.53 min) to the (R*,R*) (tR ) 4.47 min) enantiomeric pair
of the free base of the title compound.
1H NMR (CDCl3) δ 2.06 (d, 3H), 5.29 (q, 1H) ppm.
(xii) 4-(1-Bromoethyl)-5-fluoropyrimidine (20). A stirred
mixture of compound 10 (6.0 g), AIBN (300 mg), and NBS
(9.32 g) in dichloromethane (100 mL) was heated to reflux
for 6 h. The reaction mixture was cooled and washed with
The organic layer was concentrated to a volume of 56
mL and a solution of hydrogen chloride (1.2 g) in 2-propanol
(6 mL) added at 25 °C. The title compound precipitated as
a solid. This was collected by filtration, washed with ethyl
acetate (5 mL), and dried (7.89 g, 65%), mp 126-130 °C.
Vol. 5, No. 1, 2001 / Organic Process Research & Development
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