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4.3.15. Ethyl 3-amino-3-iminopropanoate hydrochloride 18
dropwise acetyl chloride (0.35 mL, 4.85 mmol) at 0 ꢁC under ni-
trogen. The resulting mixture was allowed to warm to room tem-
perature and stirred for 1 h. The mixture was diluted with water
and the organic phase was washed with a 1 N HCl aqueous solution,
dried over magnesium sulfate, and concentrated. The crude mix-
ture was purified by flash chromatography on silica gel eluting with
0–80% of ethyl acetate in DCM. The solvent was evaporated to
dryness to give 470 mg (17%) of ethyl 2-(5-phenylmethoxy-
pyrimidin-2-yl)acetate 19 as an yellow oil.
To a stirred solution of ethylcyanoacetate (100 mL, 0.94 mol) in
CHCl3 (1 L) was added ethanol (65 mL, 1.13 mol). The solution was
cooled downtoꢀ10 ꢁC and HCl was bubbled through the solution for
1 h. The reaction mixture was then stirred at room temperature for
4 h. To complete the conversion, the solution was cooled down to
ꢀ10 ꢁC and HCl was bubbled through the solution for another 1 h.
The reaction mixture was then stirred at room temperature over-
night. The solvent was evaporated, the residue was triturated in
diethyl ether and the resulting solid was collected by filtration to
give 173 g (94%) of the intermediate ethyl 3-ethoxy-3-iminopropa-
noate hydrochloride as a white powder. 1H NMR (500 MHz, CDCl3):
4.3.17. Ethyl 2-amino-5-phenylmethoxypyridine-3-carboxylate 20
Ethyl 2-amino-5-phenylmethoxypyridine-3-carboxylate 20 was
characterized from the synthesis of 19 (Method BdFirst step). Ex-
d
12.70 (br s, 1H), 12.00 (br s, 1H), 4.73 (q, J¼7.1 Hz, 2H), 4.24 (q,
J¼7.1 Hz, 2H), 3.89 (s, 2H),1.51 (t, J¼7.1 Hz, 3H),1.29 (t, J¼7.1 Hz, 3H).
A solution of ethyl 3-ethoxy-3-iminopropanoate hydrochloride
(173 g, 0.88 mol) in ethanol (1 L) was cooled down to ꢀ10 ꢁC and
NH3 gas was bubbled through the solution for 1 h. The reaction
mixture was then stirred at room temperature overnight. The in-
solubles were removed by filtration and the solvent was evapo-
rated. The residue was triturated in diethyl ether, filtered and
washed with diethyl ether. The resulting solid was taken up into in
a 9/1 mixture of DCM and methanol and the solid residue (NH4Cl)
was removed by filtration. The filtrate was evaporated, the resulting
oil was diluted with diethyl ether and HCl gas was bubbled through
the solution for 10 min to give, after filtration, a mixture of methyl
and ethyl ester derivatives. The solid residue was dissolved in
ethanol (500 mL) and HCl was bubbled again through the solution
for 10 min. The mixture was stirred overnight at room temperature,
the solvent was evaporated and the resulting solid was triturated in
diethyl ether, collected by filtration and dried to give 75 g (51%) of
ethyl 3-amino-3-iminopropanoate hydrochloride 18 as a white
powder, which was used without any further purification. 1H NMR
trapolated 1H NMR (500 MHz, CDCl3):
d
8.05 (d, J¼3.1 Hz, 1H), 7.80
(d, J¼3.1 Hz, 1H), 7.44–7.32 (m, 5H), 6.11 (br s, 2H), 5.03 (s, 2H), 4.34
(q, J¼7.1 Hz, 2H), 1.38 (t, J¼7.1 Hz, 3H). MS (ESI) m/z 273 (MH)þ.
4.3.18. Ethyl 2-acetamido-5-phenylmethoxypyridine-
3-carboxylate 21
Ethyl 2-acetamido-5-phenylmethoxypyridine-3-carboxylate 21
wascharacterizedfrom thesynthesis of 19 (MethodBdSecondstep).
1H NMR (500 MHz, CDCl3):
d
10.40 (br s, 1H), 8.45 (d, J¼3.1 Hz, 1H),
7.99(d, J¼3.1 Hz,1H), 7.44–7.36 (m, 5H), 5.19 (s, 2H), 4.34 (q, J¼7.3 Hz,
2H), 2.26 (s, 3H), 1.35 (t, J¼7.3 Hz, 3H). MS (ESI) m/z 315 (MH)þ.
4.3.19. Methyl tert-butyl 2-(5-bromopyrimidin-2-yl)-
propanedioate 22
NaH, 60% dispersion in mineral oil (42 g, 1 mol) was added por-
tion wise (while keeping the internal temperature around 20 ꢁC)
under nitrogen to a stirred solution of tert-butyl methyl malonate
(175 mL,1 mol) in DMF (800 mL). The orange solution was stirred at
room temperature for 15 min and 5-bromo-2-chloropyrimidine
(100 g, 518 mmol) was added. The reaction mixture was heated at
80 ꢁC overnight, then cooled to 10 ꢁC and 250 mL of a saturated
aqueous solution of ammonium chloride was added dropwise, fol-
lowed by 2 L of water. The pH was adjusted to 3 by addition of a 1 N
HCl aqueous solution and the aqueous phase was extracted with
diethyl ether (3ꢂ500 mL). The combined organic layers were
washed with water (2ꢂ1 L), brine (500 mL), dried over magnesium
sulfate, and concentrated to give 250 g of methyl tert-butyl 2-(5-
bromopyrimidin-2-yl)propanedioate 22 as an orange oil, contami-
nated with 1 mol of starting tert-butyl methyl malonate, which was
used in the next step without any further purification. Extrapolated
(500 MHz, DMSO-d6):
2H), 3.64 (s, 2H), 1.22 (t, J¼7.1 Hz, 3H).
d
9.22 (s, 2H), 8.94 (s, 2H), 4.15 (q, J¼7.1 Hz,
4.3.16. Ethyl 2-(5-phenylmethoxypyrimidin-2-yl)acetate 19
Method A: To a stirred suspension of 17 (64 g, 274 mmol) and 18
(58 g, 302 mmol) in CH3CN (1 L) was added K2CO3 (114 g,
824 mmol). The reaction mixture was heated at 80 ꢁC for 3 h,
cooled to room temperature and insolubles were removed by fil-
tration. The filtrate was concentrated and the residue was taken up
into in diethyl ether (800 mL) and a 2 N HCl aqueous solution was
added until pH 1. The organic layer was dried over magnesium
sulfate and solvent was evaporated. The crude mixture was purified
twice by flash chromatography on silica gel eluting with 15% of
ethyl acetate in DCM. Solvents were removed under vacuum, the
residue was taken up into in diethyl ether and washed again with
a 2 N HCl aqueous solution to remove the remaining pyridine res-
idues. The organic layer was dried over magnesium sulfate and
solvent was evaporated to give 23 g (31%) of ethyl 2-(5-phenyl-
methoxypyrimidin-2-yl)acetate 19 as an orange oil. 1H NMR
1H NMR (500 MHz, CDCl3):
d 8.79 (s, 2H), 4.99 (s, 1H), 3.81 (s, 3H),
1.48 (s, 9H). MS (ESI) m/z 331 and 333 (MH)þ.
4.3.20. Methyl 2-(5-bromopyrimidin-2-yl)acetate 23a
To a cooled solution of crude diester 22 (171 g) in DCM (1.5 L)
was added dropwise TFA (1 L) at 0 ꢁC. Once the addition was
complete (1 h), the reaction mixture was allowed to warm to room
temperature and stirred for 2 h. The solvent was evaporated, the
mixture was taken up in toluene and evaporated again. The
resulting oil was taken up in ethyl acetate and washed with a sat-
urated aqueous solution of NaHCO3 until pH 7–8. The aqueous layer
was extracted with ethyl acetate and the combined organic layers
were washed with brine, dried over magnesium sulfate and con-
centrated. The crude mixture was purified by flash chromatography
on silica gel eluting with 30% of ethyl acetate in petroleum ether to
give 96 g (80% over the two steps) of methyl 2-(5-bromopyrimidin-
(500 MHz, DMSO-d6):
d 8.43 (s, 2H), 7.39 (m, 5H), 5.15 (s, 2H), 4.20
(q, J¼7.1 Hz, 2H), 3.97 (s, 2H), 1.26 (t, J¼7.1 Hz, 3H). MS (ESI) m/z 273
(MH)þ.
Method B: First step. To a stirred suspension of [(Z)-3-dimethyl-
amino-2-phenylmethoxyprop-2-enylidene]-dimethylazanium perchlo-
rate20 (4.1 g, 12.35 mmol) and 18 (4.3 g, 33.3 mmol) in CH3CN (50 mL)
was added K2CO3 (4.3 g, 30.9 mmol). The reaction mixture was heated
at 80 ꢁC for 3 h, cooled to room temperature, and the insolubles were
removed by filtration. After evaporation, the residue was dissolved in
DCM, washed with water, dried over magnesium sulfate, concentrated,
and passed through a silica gel column eluting with 0–20% of ethyl
acetate in DCM. The solvents were evaporated to dryness to give 1.7 g
of a 3/2 mixture of 19 and 20.
2-yl)acetate 23a as a yellow oil. 1H NMR (500 MHz, CDCl3):
d 8.77 (s,
2H), 4.00 (s, 2H), 3.75 (s, 3H). MS (ESI) m/z 231 and 233 (MH)þ.
4.3.21. tert-Butyl 2-(5-bromopyrimidin-2-yl)acetate 23b
A solution of crude diester 22 (2.6 g) and NaOH (600 mg,
15 mmol) in a mixture of water (20 mL) and methanol (50 mL) was
stirred at room temperature for 4 h. A 2 N HCl aqueous solution was
Second step. To a solution of 850 mg of the precedent mixture
and DIPEA (1.13 mL, 6.47 mmol) in DCM (10 mL) was added