The Journal of Organic Chemistry
Page 6 of 9
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8
96% from 5. A sample of 7 was isolated as an amorphous
(m, 1 H), 1.75 (t, J=12.5 Hz, 1 H), 1.53 - 1.64 (m, 1 H), 1.38 (d,
J=7.2 Hz, 7 H), 1.24 - 1.33 (m, 1 H), 1.16 - 1.22 (m, 4 H).
13C{1H} NMR (150 MHz, chloroform-d) δ ppm 174.8, 174.0,
169.9, 169.2, 164.9, 160.8, 158.1, 151.8, 148.6, 135.6, 125.0,
121.8, 120.3, 116.9, 114.1, 112.3, 95.8, 77.4, 60.8, 56.2, 47.3,
45.7, 44.6, 41.9, 36.5, 33.7, 32.4, 31.1, 28.3, 26.2, 24.9, 24.6,
22.5, 22.4, 22.3, 14.4, 9.8.
foamy solid for characterization and reference purpose. This
transformation was further scaled up to around 35 kg (50 mol)
for plant production. mp: 64.4-67.2°C. [α]D: -26.4 (1%,
dichloromethane). HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C39H51N4O6S 703.3524; Found 703.3517. NMR: Two major
rotamers were observed at 300 K in chloroform-d in a 60/40
ratio. 1H NMR (600 MHz, chloroform-d) δ ppm 8.03 (d, J=9.1
Hz, 1 H), 8.01 (d, J=9.1 Hz, 1 H), 7.48 (s, 1 H), 7.47 (s, 1 H),
7.22 (d, J=9.1 Hz, 1 H), 7.01 (s, 1 H), 6.99 (s, 1 H), 6.89 (s, 1
H), 5.65 - 5.82 (m, 2 H), 5.30 - 5.34 (m, 1 H), 5.27 (d, J=17.4
Hz, 1 H), 5.11 (d, J=10.6 Hz, 1 H), 5.02 (dd, J=17.0, 1.5 Hz, 1
H), 4.98 (d, J=10.2 Hz, 1 H), 4.95 (dd, J=17.4, 1.5 Hz, 1 H),
4.89 (d, J=10.2 Hz, 1 H), 4.04 - 4.17 (m, 2 H), 3.97 (s, 3 H),
3.72 (ddd, J=12.1, 10.2, 7.2 Hz, 1 H), 3.66 (ddd, J=11.5, 10.4,
7.2 Hz, 1 H), 3.46 (ddd, J=13.6, 8.3, 6.4 Hz, 1 H), 3.28 - 3.35
(m, 2 H), 3.22 (spt, J=10.0 Hz, 1 H), 3.19 (tt, J=7.2, 3.4 Hz, 1
H), 3.02 (s, 3 H), 2.95 (s, 3 H), 2.76 - 2.86 (m, 1 H), 2.69 (s, 3
H), 2.47 - 2.56 (m, 1 H), 2.34 (dd, J=14.2, 7.0 Hz, 1 H), 2.05 -
2.13 (m, 2 H), 1.97 - 2.04 (m, 2 H), 1.83 - 1.88 (m, 3 H), 1.55 -
1.68 (m, 2 H), 1.47 - 1.54 (m, 3 H), 1.45 (ddd, J=9.3, 5.7, 3.2
Hz, 3 H), 1.38 (d, J=6.8 Hz, 6 H), 1.29 - 1.36 (m, 2 H), 1.20 (t,
J=7.2 Hz, 3 H). 13C{1H} NMR (150 MHz, chloroform-d) δ ppm
174.5, 174.3, 173.1, 172.9, 169.93, 169.90, 169.87, 164.9,
160.8, 160.7, 158.1, 151.77, 151.75, 148.7, 138.3, 137.9, 133.7,
121.8, 120.4, 117.74, 117.67, 116.88, 116.85, 115.2, 114.7,
114.13, 114.11 (br. s.), 112.3, 95.8, 77.69 (br. s.), 77.66, 61.12,
61.11, 56.2, 49.7, 48.2, 46.1 (d, J=12.1 Hz), 45.6, 45.4, 40.03,
40.00, 37.8, 37.2, 35.23, 35.20, 34.7, 33.7, 33.6, 33.4, 33.32,
33.30, 31.1, 27.9, 26.4, 25.94, 25.89, 23.2, 23.0, 22.51, 22.48,
22.44, 22.42, 14.3 (br. s.), 14.2, 9.8.
Ethyl
(1R,2S)-1-[(tert-butoxycarbonyl){[(1R,2R,4S)-2-
carbamoyl]-4-({7-methoxy-8-
[hex-5-en-1-yl(methyl)
9
methyl-2-[4-(propan-2-yl)-1,3-thiazol-2-yl]quinolin-4-
yl}oxy)cyclopentyl]carbonyl}amino]-2-
10
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ethenylcyclopropanecarboxylate 8. A solution of 2.6 kg (3.7
mol) of 7 in 30 L of DCM was subject of a solvent switch to a
volume of 18.5 L toluene. To the resulting solution, 23 g of 4-
dimethylaminopyridine was added at room temperature before
a first portion of 970 g (19.7 mmol) of di-tert-butyl dicarbonate
was added and the reaction mixture was heated to 55°C under
an inert atmosphere. The reaction was stirred overnight before
HPLC analysis. In case of incomplete conversion an extra
portion of di-tert-butyl dicarbonate (650 g) was added and the
reaction mixture was stirred for another 4 hours before checking
the conversion. Upon complete conversion of the starting
material, the mixture was cooled to room temperature and
washed with 5.6 L of a 0.35 wt% HCl solution. After removal
of the water layer, the organic layer was dried using 370 g
magnesium sulfate. The solution was concentrated to a final
total weight of 8.04 kg and used as such in the next step. A
sample of 8 was isolated and purified for characterization and
reference material purpose. Assayed yield: 2.8 kg 8 (95 %). mp:
35.0-38.3°C. [α]D: +15.6 (1%, CH2Cl2). HRMS (ESI-TOF) m/z:
[M + H]+ Calcd for C44H59N4O8S 803.4054; Found 803.4052.
NMR: four rotamers were observed at 300 K in chloroform-d in
an approximately 40/30/20/15 ratio. 1H NMR (600 MHz,
chloroform-d) δ ppm 8.10 (d, J=9.1 Hz, 1 H), 8.09 (d, J=9.1 Hz,
1 H), 7.46 (s, 1 H), 7.23 (d, J=9.4 Hz, 1 H), 7.22 (d, J=9.1 Hz,
1 H), 7.01 (s, 1 H), 5.85 - 5.97 (m, 1 H), 5.80 (ddt, J=17.0, 10.2,
6.8, 6.8 Hz, 1 H), 5.74 (ddt, J=17.0, 10.2, 6.8, 6.8 Hz, 1 H), 5.22
- 5.33 (m, 2 H), 5.17 (t, J=11.0 Hz, 1 H), 5.03 (d, J=17.0 Hz, 1
H), 4.98 (d, J=9.8 Hz, 1 H), 4.97 (dd, J=17.2, 1.7 Hz, 1 H), 4.91
(d, J=10.2 Hz, 1 H), 4.63 (q, J=9.4 Hz, 1 H), 4.04 - 4.21 (m, 2
H), 3.98 (s, 3 H), 3.68 (quin, J=9.8 Hz, 1 H), 3.62 (quin, J=8.8
Hz, 1 H), 3.25 - 3.56 (m, 2 H), 3.18 (spt, J=6.8 Hz, 1 H), 3.08
(br. s., 3 H), 3.07 (br. s., 3 H), 2.92 (s, 3 H), 2.71 - 2.83 (m, 1
H), 2.69 (s, 3 H), 2.67 (br. s., 1 H), 2.59 (d, J=7.9 Hz, 1 H), 2.21
- 2.30 (m, 1 H), 2.16 (d, J=7.6 Hz, 2 H), 2.07 - 2.14 (m, 1 H),
2.03 (d, J=6.4 Hz, 1 H), 1.86 - 1.97 (m, 1 H), 1.65 - 1.72 (m, 1
H), 1.56 - 1.62 (m, 1 H), 1.46 - 1.51 (m, 1 H), 1.45 (br. s., 4 H),
1.42 (br. s., 1 H), 1.40 (s, 5 H), 1.38 (d, J=6.8 Hz, 6 H), 1.30 -
1.36 (m, 1 H), 1.15 - 1.24 (m, 3 H). 13C{1H} NMR (150 MHz,
chloroform-d) δ ppm 177.7 (br. s.), 177.5 (br. s.), 177.44 (br.
s.), 177.38 (br. s.), 172.9 (br. s.), 172.8 (br. s.), 172.7 (br. s.),
172.4 (br. s.), 170.0 (br. s.), 169.94 (br. s.), 169.90 (br. s.), 169.5
(br. s.), 169.4 (br. s.), 169.3 (br. s.), 164.8, 161.2 (br. s.), 161.12
(br. s.), 161.08 (br. s.), 158.0, 152.3 (br. s.), 152.2 (br. s.), 151.6
(br. s.), 148.6, 138.5 (br. s.), 138.4 (br. s.), 138.04 (br. s.),
138.00 (br. s.), 133.6, 133.1 (br. s.), 121.5 (br. s.), 120.7 (br. s.),
120.6 (br. s.), 118.0 (br. s.), 117.8 (br. s.), 116.8, 115.0 (br. s.),
114.9 (br. s.), 114.6 (br. s.), 114.5 (br. s.), 114.0, 112.1, 95.6
(br. s.), 83.5, 83.42, 77.84 (br. s.), 77.79 (br. s.), 77.7, 61.24,
61.18 (br. s.), 56.1, 49.8 (br. s.), 48.6 (br. s.), 48.0 (br. s.), 48.0
(br. s.), 47.90, 47.85, 47.8 (br. s.), 44.4 (br. s.), 44.11, 44.06,
43.4 (br. s.), 42.2 (br. s.), 41.7 (br. s.), 37.3 (br. s.), 37.2 (br. s.),
Ethyl
(2R,3aR,10Z,11aS,12aR,14aR)-2-({7-methoxy-8-
methyl-2-[4-(propan-2-yl)-1,3-thiazol-2-yl]quinolin-4-
yl}oxy)-5-methyl-4,14-dioxo-
2,3,3a,4,5,6,7,8,9,11a,12,13,14,14a-
tetradecahydrocyclopenta[c]cyclopropa[g][1,6]diazacyclot
etradecine-12a(1H)-carboxylate 10 from 7. A well stirred
solution of 35.15 kg (50 mol) of diene 7 and 480 g (5 mol) of
methanesulfonic acid in 1,2-dichloroethane (5500 L) was
refluxed under nitrogen before addition of 750 g (1.25 mol) of
GH1. After 6 hours of reflux, the conversion was checked and
reached >95%. The reaction mixture was cooled to room
temperature and the catalyst was deactivated by addition of
1164 g (7.7 mol) of 2-mercaptonicotinic acid and 627 ml (15
mol) of triethylamine to neutralize the methanesulfonic acid.
After a washing with 250 L water, the organic layer was
collected and the in-situ yield was determined at 74 %. Solvent
was switched to 1-butanol, from which 10 crystallized out after
seeding (20.6 kg obtained). Isolated yield: 60.9%. mp: 219.8-
221.2°C. [α]D: +21.8 (1%, CH2Cl2). HRMS (ESI-TOF) m/z: [M
1
+ H]+ Calcd for C37H47N4O6S 675.3216; Found 675.3210. H
NMR (600 MHz, chloroform-d) δ ppm 8.02 (d, J=9.4 Hz, 1 H),
7.48 (s, 1 H), 7.21 (d, J=9.1 Hz, 1 H), 7.18 (s, 1 H), 7.00 (s, 1
H), 5.57 - 5.69 (m, 1 H), 5.31 (dd, J=10.6, 6.0 Hz, 1 H), 5.20
(dd, J=10.6, 6.0 Hz, 1 H), 4.65 (td, J=12.8, 4.5 Hz, 1 H), 4.12
(ddd, J=14.4, 11.0, 7.2 Hz, 1 H), 4.06 (ddd, J=14.3, 10.7, 7.2
Hz, 1 H), 3.97 (s, 3 H), 3.84 (td, J=11.4, 7.4 Hz, 1 H), 3.36 (q,
J=10.2 Hz, 1 H), 3.19 (spt, J=6.8 Hz, 1 H), 3.05 (s, 3 H), 2.84
(ddd, J=14.7, 9.1, 6.4 Hz, 1 H), 2.69 (s, 3 H), 2.63 (td, J=12.8,
6.8 Hz, 2 H), 2.38 (ddd, J=23.0, 12.3, 6.2 Hz, 1 H), 2.29 (dd,
J=14.5, 7.4 Hz, 1 H), 2.05 (ddd, J=14.0, 11.0, 3.4 Hz, 1 H), 2.00
(q, J=7.9 Hz, 1 H), 1.94 (dd, J=7.9, 5.3 Hz, 1 H), 1.80 - 1.88
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