Organic Process Research & Development
Article
20 °C and then diluted with DMF (71 kg) to give 138.8 kg of
PMB-Cl solution (38.9 wt %) and stored at 5 °C for use in the
next step. Analytical data matched that of a commercially
obtained sample.
Diethyl 2-(2-(2-(Bis(4-methoxybenzyl)amino)pyrimidin-4-
yl)ethyl)malonate (12). To a solution of diethyl malonate
(22.9 kg, 143 mol, 3.0 equiv) in DMF (103.8 kg, 110 L) was
added DBU (21.8 kg, 143 mol, 3.0 equiv), and the resulting
mixture was aged at 20 °C for 15 min. A solution of 11 in
toluene (104.8 kg, 17.2 kg assay, 47.6 mol) was charged over 40
min, and the resulting mixture aged at rt for 18 h affording
complete conversion to 12. A solution of 10% aq. AcOH (11 kg
AcOH and 99 kg water) was charged over 30 min followed by
MTBE (81.5 kg, 110L). The layers were separated, and the
lower aqueous layer was extracted twice with MTBE (81.5 kg).
The combined organics were then washed with 10% aq LiCl
(11 kg of LiCl and 99 kg of water). The organic layer was
assayed at 24.88 kg (47.7 mol, 100%) for 12 and then
concentrated under reduced pressure to approximately 50 L
and then diluted with acetonitrile (120.0 kg) to afford a 170.2
4-Chloro-N,N-bis(4-methoxybenzyl)pyrimidin-2-amine (7).
4-Chloropyrimidin-2-amine (6, 15.84 kg, 122 mol) was added
to a 38.9 wt % DCM/DMF solution of PMB-Cl (129.6 kg, 50.4
kg by assay, 257 mol, 2.1 equiv) prepared in the previous step,
and the resulting mixture was cooled to −10 °C. A solution of
NaOtBu (28.8 kg, 293 mol, 2.4 equiv) in DMF (78 kg) was
cooled to 0 °C and then added to the mixture of 6 and PMB-Cl
mixture over 45 min maintaining the temperature below 10 °C.
After 80 min at 0 °C, a further charge of 38.9% PMB-Cl (5.1
kg, 2.0 kg assay, 10.2 mol, 0.08 equiv) and NaOtBu (1.5 kg,
15.6 mol, 0.128 equiv) was made to drive complete conversion.
After a further 2 h age methyl tert-butylether (MTBE, 105.8 kg,
143 L) was added followed by water (143 kg) maintaining the
temperature below 20 °C. The temperature was then adjusted
to 20 °C; the lower aqueous layer was separated, and the
organic layer was washed twice with 10% aq. LiCl (15.8 kg of
LiCl in 142.2 kg of water). The organic layer was concentrated
to a residue under reduced pressure maintaining temperature
below 40 °C. Toluene (45 kg) was charged, and the batch was
again concentrated to a residue before being diluted with
toluene (100 kg) and passed through a pad of silica gel (40 kg).
The silica pad was eluted with toluene (173.2 kg) and the
combined organics concentrated under reduced pressure to a
186.2 kg (207 L) solution. HPLC assay indicated 33.0 kg of 7
1
kg solution. H NMR (400 MHz, CDCl3): δ 8.24 (d, J = 5.1
Hz, 1H), 7.19 (dt, J = 8.6 Hz, 2.4 Hz, 4H), 6.85 (dt, J = 8.6 Hz,
2.4 Hz, 4H), 6.41 (d, J = 5.1 Hz, 1H), 4.78 (s, 4H), 4.24−4.12
(m, 4H), 3.81 (s, 6H), 3.47 (t, J = 7.4 Hz, 1H), 2.67 (t, J = 7.4
Hz, 2H), 2.33 (app. q, J = 7.4 Hz, 2H), 1.25 (t, J = 7.0 Hz, 6H).
13C NMR (100 MHz, CDCl3): δ 169.5, 169.3, 162.0, 158.7,
157.5, 130.5, 129.1, 113.8, 109.0, 61.4, 55.2, 51.1, 48.0, 34.8,
26.8, 14.1. HRMS (ES): [M + H]+ calcd for C29H36N3O6:
522.2604; found 522.2584.
Diethyl 2-(2-(2-(Bis(4-methoxybenzyl)amino)-5-iodopyri-
midin-4-yl)ethyl)malonate (14). To a mixture of N-iodosucci-
nimide (16.1 kg, 71.4 mol, 1.5 equiv) in acetonitrile (97.5 kg)
at 0 °C was added trifluoroacetic acid (1.63 kg, 14.3 mol, 0.3
equiv) followed by the acetonitrile solution of 12 (169.7 kg,
24.8 kg assay, 47.5 mol) over 35 min maintaining internal
temperature between 0 and 5 °C. After a 2 h age at 0−5 °C,
HPLC indicated complete conversion, and MTBE (138 kg,
186L) was charged followed by an aqueous solution of Na2S2O3
(10 kg Na2S2O3 and 100 kg of water). The aqueous layer was
separated and the organic layer washed with a 5% NaHCO3 (5
kg NaHCO3 and 95 kg water). The organics were then washed
with 2% NaCl (2 kg NaCl and 98 kg water) before being
concentrated under reduced pressure to approximately 50 L
maintaining the temperature below 40 °C. Toluene (86.5 kg,
100 L) was added and the batch concentrated under reduced
pressure to approximately 50 L before being diluted with THF
(20 kg, 22.5 L). The 84.8 kg solution contained 28.7 kg (44.3
mol, 93%) of 14 by HPLC assay. 1H NMR (400 MHz, CDCl3):
δ 8.44 (s, 1H), 7.18 (dt, J = 9.0 and 2.5 Hz, 4H), 6.85 (dt, J =
8.6 Hz, 2.5 Hz, 4H), 4.75 (s, 4H), 4.24−4.11 (m, 4H), 3.81 (s,
6H), 3.51 (t, J = 7.4 Hz, 1H), 2.81 (t, J = 7.4 Hz, 2H), 2.33
(app. q, J = 7.4 Hz, 2H), 1.24 (t, J = 7.0 Hz, 6H). 13C NMR
(100 MHz, CDCl3): δ 169.3, 168.9, 164.2, 161.2, 158.8, 130.1,
129.0, 113.9, 78.9, 61.4, 55.3, 51.0, 48.4, 37.3, 25.9, 14.1. HRMS
(ES): [M + H]+ calcd for C29H35IN3O6: 648.1571; found
648.1594.
Diethyl 2-(Bis(4-methoxybenzyl)amino)-6,7-dihydro-5H-
cyclopenta[d]pyrimidine-5,5-dicarboxylate (9). To a mixture
of Cs2CO3 (57.8 kg, 177 mol, 4.0 equiv), 2-picolinic acid (1.36
kg, 11.1 mol, 0.25 equiv), and CuI (2.11 kg, 11.1 mol, 0.25
equiv) was added to the toluene/THF solution of 14 (84.8 kg,
28.7 kg assay, 44.3 mol) followed by THF (158.6 kg, 178 L),
water (799 g, 44.3 mol, 1 equiv), and N,N-dimethylacetamide
(DMAc, 188.2 kg, 200 L). The mixture was degassed by
subsurface nitrogen sparging for 15 min becoming a green
color, thoroughly agitated, and heated to 60 °C over 50 min.
After 40 min at 60 °C HPLC indicated >99% conversion, and
1
(89.2 mol, 73%) was present in the toluene solution. H NMR
(400, MHz, CDCl3): δ 8.21 (d, J = 5.1 Hz, 1H), 7.20 (d, J = 8.2
Hz, 4H), 6.87 (d, J = 8.6 Hz, 4H), 6.57 (d, J = 5.1 Hz, 1H),
4.76 (s, 4H), 3.82 (s, 6H). 13C NMR (100 MHz, CDCl3): δ
162.2, 161.2, 159.0, 158.9, 129.7, 129.2, 113.9, 109.2, 55.3, 48.2.
HRMS (ES): [M + H]+ calcd for C20H21ClN3O2: 370.1322;
found 370.1308.
N,N-Bis(4-methoxybenzyl)-4-vinylpyrimidin-2-amine (11).
To a 17.7 wt % solution of 7 in toluene (93.1 kg, 16.5 kg assay
for 7, 44.6 mol) was charged PdCl2(dppf)·CH2Cl2 (1.82 kg,
2.23 mol, 0.05 equiv). The resulting mixture was thoroughly
degassed by three vacuum/nitrogen cycles followed by
subsurface sparging for 10 min with nitrogen before heating
to 80 °C. A 1.9 M solution of vinylmagnesium chloride in THF
(26.1 kg, 23.9L, 45.5 mol, 1.02 equiv) was then added over 105
min maintaining the temperature between 80 and 85 °C. After
a further 20 min HPLC indicated 88% conversion, and the
batch was cooled to 20 °C and assayed at 66% yield. The batch
was repeated and assayed at 74% yield. The reaction mixtures
were combined and quenched into a solution of 5% acetic acid
(200 L) over 1 h maintaining the temperature <35 °C. The
layers were separated, and the aqueous layer was back-extracted
with MTBE (123 kg, 165L). The organic layers were combined
and passed through a 1.0 μm inline filter before being
concentrated under reduced pressure to a 104.8 kg (110 L)
toluene solution. HPLC assay indicated a yield of 17.2 kg (47.6
1
mol, 53%) of 11. H NMR (400 MHz, CDCl3): δ 8.35 (d, J =
5.1 Hz, 1H), 7.23 (d, J = 8.6 Hz, 4H), 6.87 (dt, J = 8.6 Hz, 2.5
Hz, 4H), 6.64 (dd, J = 10.2 and 17.2 Hz, 1H), 6.55 (d, J = 5.1
Hz, 1H), 6.42 (dd, J = 17.6 Hz, 1.6 Hz, 1H), 5.57 (dd, J = 10.6
Hz, 1.6 Hz, 1H), 4.84 (s, 4H), 3.82 (s, 6H). 13C NMR (100
MHz, CDCl3): δ 162.7, 162.2, 158.7, 158.5, 136.2, 130.7, 129.1,
121.4, 113.8, 107.3, 55.3, 48.0. HRMS (ES): [M + H]+ calcd for
C22H24N3O2: 362.1869; found 362.1864.
J
Org. Process Res. Dev. XXXX, XXX, XXX−XXX