Organic Process Research & Development
Article
by H2O (60 kg) and agitated for 20 min, and the lower aqueous
layer was removed. The batch was then distilled to ∼50 L and
diluted with toluene (125 L). The batch was then warmed to 80
°C, aged for 30 min, cooled to 20 °C, and aged for 2 h, and
heptane (140 L) was added over 1 h, aged for 10 min, then
cooled to 0 °C. Filtration, washing with cold toluene/heptane
[15.7 kg:18.4 kg; 2 °C], and drying at 40 °C in vacuo gave the
product 52 as a white solid (10.48 kg, 100 A%, 85% yield, >99%
1.70 (ddd, J = 18.7, 8.0, 5.9 Hz, 1H); 13C NMR (150 MHz,
CDCl3) δ 196.8, 174.2, 144.5, 144.5, 134.1, 132.3, 124.5, 110.7,
93.1, 61.4, 58.7, 49.6, 43.3, 38.4, 36.9, 29.8, 26.4; Mp 223.2 °C
dec; HRMS (ES+) Calcd for C19H21IN3O (MH+) 434.0729.
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Found 434.0720. [α]D −170.7 (c 1.0, CHCl3); IR ν (cm−1)
2979, 2925, 1670, 1564. Separation of enantiomers was
accomplished by HPLC analysis (Chiralcel OJ-H, 5 μm, 1.0
mL/min, 20% ethanol/80% hexanes with 0.1% TFA, tR = 15.3,
25.1 min).
1
ee). H NMR (600 MHz, CDCl3) δ 7.60 (d, J = 8.7 Hz, 1H),
7.54 (d, J = 8.7 Hz, 1H), 7.13 (dd, J = 8.6, 7.4 Hz, 2H), 6.83 (t,
J = 7.3 Hz, 1H), 6.65 (d, J = 7.8 Hz, 2H), 6.29 (s, 1H), 3.95−
3.91 (m, 2H), 3.83 (d, J = 17.1 Hz, 1H), 3.16 (d, J = 17.1 Hz,
1H), 2.77 (ddd, J = 18.7, 13.7, 5.3 Hz, 1H), 2.54 (dd, J = 18.5,
4.5 Hz, 1H), 2.48−2.42 (m, 1H), 2.24−2.16 (m, 1H), 2.13 (td,
J = 13.4, 5.2 Hz, 1H), 2.06 (dt, J = 14.7, 5.5 Hz, 1H), 1.82 (s,
9H); 13C NMR (150 MHz, CDCl3) δ 199.0, 172.1, 158.4,
144.6, 140.0, 134.2, 133.6, 129.5, 120.9, 117.3, 117.2, 114.4,
112.2, 64.8, 61.3, 47.0, 41.9, 41.8, 37.0, 34.3, 32.8, 29.8; Mp
224.3 °C; HRMS (ES+) Calcd for C25H28N3O2 (MH+)
(8R,10aS)-3-(tert-Butyl)-6-(trifluoromethyl)-8,9,10,11-
tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-
d][1,2,3]triazol-7(3H)-one (57). Iodide 56 (35.6 kg, 80.0
mol), CuI (3.05 kg, 16.0 mol) were dissolved in DMF (505 kg).
2,6-Lutidine (1.7 kg, 16.0 mol) was then added and the mixture
heated to 90−92 °C. Methylfluorosulfonyldifluoroacetate (31.2
kg, 160 mol) was then added over 1 h, and the mixture was
aged for a further 1 h before cooling to 20 °C. Sodium
hydroxide (12 M, 26.8 kg, 240 mol) was then added followed
by a solution of N-2-(hydroxyethyl)ethylenediaminetriacetic
acid (29 kg, 80 mol) in water (290 kg). Further water (450 kg)
was then added, and the resultant slurry was aged for 14 h.
Filtration, washing with water (2 × 150 kg), and drying at 50
°C afforded the product 57 as a brown solid (25.6 kg, 99.7 A%,
77% yield, >99% ee). 1H NMR (600 MHz, CDCl3) δ 7.87 (dd,
J = 9.1, 1.7 Hz, 1H), 7.69 (d, J = 9.1 Hz, 1H), 3.66 (q, J = 17.6
Hz, 2H), 3.12 (dd, J = 7.4, 4.0 Hz, 1H), 2.37−2.28 (m, 1H),
2.09 (d, J = 11.4 Hz, 1H), 2.02 (dd, J = 11.5, 4.1 Hz, 1H), 1.96
(ddd, J = 12.5, 11.3, 5.3 Hz, 1H), 1.86 (s, 9H), 1.83−1.77 (m,
1H), 1.76−1.69 (m, 1H); 13C NMR (150 MHz, CDCl3) δ
197.5, 174.4, 145.5, 144.3, 134.2, 129.6, 126.5, 123.3 (q, J =
275.8 Hz), 117.6 (q, J = 29.4 Hz), 111.7, 61.6, 57.5, 51.3, 40.9,
38.8, 36.6, 29.8, 27.3; Mp 206.3 °C; HRMS (ES+) Calcd for
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402.2182. Found 402.2178. [α]D −202.3 (c 1.0, CHCl3); IR
ν (cm−1) 2952, 1647, 1273, 1232. Analysis of enantiomeric
excess was accomplished by HPLC analysis (Chiralpak AD-H, 5
μm, 1.0 mL/min, 30% IPA in heptane, tR = 8.0, 11.0 min).
(8R,10aS)-3-(tert-Butyl)-8,9,10,11-tetrahydro-8,10a-
methanocyclohepta[1,2]indeno[4,5-d][1,2,3]triazol-
7(3H)-one (53). A solution of potassium tert-butoxide (18.0
kg, 161 mol) in DMF (81.2 kg) was added to a solution of 52
(43.0 kg, 107 mol) in DMF (96.5 kg). The resultant mixture
was heated to 100 °C and aged for 2 h. The mixture was then
cooled to 60 °C, and potassium hydroxide (45 wt %, 53.4 kg)
in water (36.8 kg) was added slowly at this temperature.
Further water (159 kg) was then added over 1 h, and the
mixture was cooled to 20 °C. The slurry was filtered and
washed with further aqueous potassium hydroxide and water.
Following drying at 50 °C with a nitrogen sweep, the product
53 was obtained as an off-white solid (29.07 kg, 97.3 A%, 85%
yield). 1H NMR (600 MHz, CDCl3) δ 7.69 (d, J = 8.8 Hz, 1H),
7.56 (d, J = 8.8 Hz, 1H), 6.17 (d, J = 1.3 Hz, 1H), 3.60 (q, J =
18.1 Hz, 2H), 3.10−3.01 (m, 1H), 2.37−2.26 (m, 1H), 2.05 (d,
J = 2.6 Hz, 2H), 2.01 (ddd, J = 12.5, 10.9, 5.5 Hz, 1H), 1.89−
1.82 (m, 10H), 1.71 (ddd, J = 14.4, 9.2, 5.5 Hz, 1H); 13C NMR
(150 MHz, CDCl3) δ 203.9, 174.1, 144.8, 142.0, 134.1, 132.1,
121.5, 114.3, 112.1, 61.4, 53.6, 51.4, 43.8, 38.1, 37.0, 29.8, 26.2;
Mp > 250 °C; HRMS (ES+) Calcd for C19H21N3O (MH+)
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C20H21F3N3O (MH+) 376.1637. Found 376.1635. [α]D
−248.4 (c 1.0, CHCl3); IR ν (cm−1) 2986, 1669, 1591, 1192,
1108. Analysis of enantiomeric excess was accomplished by
HPLC analysis (Lux Cellulose 2, 5 μm, 1.0 mL/min, 60%
H3PO4 (0.1% aqueous), 40% acetonitrile, tR = 10.9, 12.7 min).
(8R,10aS)-6-(Trifluoromethyl)-8,9,10,11-tetrahydro-
8,10a-methanocyclohepta[1,2]indeno[4,5-d][1,2,3]-
triazol-7(3H)-one (1). Sulfuric Acid Procedure. To 96%
sulfuric acid (18.1 kg, 9.84 L) was added 20% fuming sulfuric
acid (14.08 kg, 7.22 L) at such a rate that the internal
temperature did not exceed 40 °C. Trifluoromethylenone 57
(2.58 kg, 6.52 mol) was then added portionwise ensuring the
reaction temperature did not exceed 29 °C. Additional 96%
sulfuric acid (1.84 kg, 1.0 L) was then added and the mixture
heated to 75 °C. After aging for 4 h, the mixture was cooled to
10 °C, and acetonitrile (18 L) was added. A solution of 5 M
sodium hydroxide (40 L) was added slowly. The resultant
slurry was filtered, and the cake was washed with water (2 × 13
L). Drying under a nitrogen sweep gave 1 as a light-brown solid
(2.08 kg, 97.8 A%, 89% yield, >99% ee).
Zinc Triflate Procedure. To a slurry of trifluoromethylenone
57 (45.4 kg, 121 mol) and zinc triflate (8.80 kg, 48.4 mol) in
acetonitrile (61.5 kg) was added acetic anhydride (61.8 kg, 605
mol). After refluxing for 48 h, further zinc triflate (8.80 kg, 48.4
mol) was added, and reflux was continued for a further 12 h.
Acetonitrile (71.5 kg) was added, followed by water (91 kg)
and NMP (46.8 kg). After aging for 3 h at 75 °C, water (113
kg) was added and the batch cooled to 25 °C. After formation
of a seed bed, further water (424 kg) was added. The resultant
slurry was filtered, and the solids were washed with water (2 ×
50 kg) to give 1 as a light-brown solid (31.6 kg, 87.2 A%, 82%
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308.1763. Found 308.1760. [α]D −72.5 (c 1.0, CHCl3); IR ν
(cm−1) 2971, 1649, 1606.
(8R,10aS)-3-(tert-Butyl)-6-iodo-8,9,10,11-tetrahydro-
8,10a-methanocyclohepta[1,2]indeno[4,5-d][1,2,3]-
triazol-7(3H)-one (56). To a solution of enone 53 (26.8 kg,
87.2 mol) in acetonitrile (165 kg) was added trifluoroacetic acid
(10.94 kg, 95.9 mol). The solution was heated to 84 °C, and N-
iodosuccinimide (23.5 kg, 105 mol) in acetonitrile (120 kg)
was then added over 40 min. After 1 h aging, the slurry was
cooled to 20 °C. Sodium sulfite (5.50 kg, 43.6 mol) in water
(44 kg) was then added followed by water (338 kg). After 18 h
aging, the slurry was filtered and washed with an acetonitrile/
water mixture (16.5 and 21 kg, respectively) and then water (42
kg). Drying at 50 °C in vacuo afforded the iodide 56 as an off-
white solid (36.7 kg, >99.5 A%, 95% yield, >99% ee). 1H NMR
(600 MHz, CDCl3) δ 8.92 (d, J = 9.1 Hz, 1H), 7.78 (d, J = 9.1
Hz, 1H), 3.63 (q, J = 17.9 Hz, 2H), 3.37 (dd, J = 7.2, 4.1 Hz,
1H), 2.37−2.27 (m, 1H), 2.11 (d, J = 11.4 Hz, 1H), 2.05 (dd, J
= 11.5, 4.3 Hz, 1H), 1.99−1.91 (m, 1H), 1.90−1.84 (m, 10H),
537
dx.doi.org/10.1021/op5000489 | Org. Process Res. Dev. 2014, 18, 528−538