Organic Process Research & Development
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(acetylacetonate) (723 mg, 2.045 mmol, 0.01 mol equiv) were
charged to a 1-L Morton flask fitted with an overhead stirrer
and a nitrogen inlet/outlet. Then THF (600 mL) and N-
methylpyrrolidinone (64 mL) were charged to the flask, and
the resulting slurry was cooled to −5 to 0 °C. To this was
added 532 mL of a 0.5 M solution of cyclopropylmagnesium
bromide (38.6 g, 265.9 mol, 1.3 mol equiv) over a 17 min
period, maintaining the temperature below 12 °C with active
cooling. The maximum temperature was 10 °C. After the
addition was complete, the reaction mixture was warmed to 20
°C and held at this temperature for 0.5 h after which time
HPLC analysis indicated that less than 1 rel. area % (RAP) of
the starting material remained. The reaction mixture was cooled
to −5 to 0 °C, and 400 mL of half-saturated ammonium
chloride was charged over a 2 min period. There was a 15 °C
exotherm during the addition. The biphasic mixture was
warmed to 20 °C, and 50 mL of heptane was added to facilitate
the phase split. Agitation was stopped, and the layers were
allowed to separate. The upper, rich organic layer was
concentrated under reduced pressure to a volume of about
100 mL with the bath temperature not exceeding 35 °C. The
crude organic stream was polish filtered through silica gel and
taken directly into the next reaction without further
ature between 40 and 45 °C. The resulting slurry was held at
this temperature for 1 h and then cooled to 20 °C. The slurry
was held at this temperature overnight. The crystals were
collected via filtration and washed with 50 mL of ethyl acetate.
The cake was deliquored for 1 h and then dried under vacuum
at 45−50 °C overnight to yield 45.5 g (59.2% for the five-step
telescope from 2-chloro-6-methyl-4-(trifluoromethyl)pyridine
7): 1H NMR (400 MHz, d6-DMSO) δ 10.15 (br s, 2H), 7.67−
7.62 (m, 2H), 7.60 (s, 1H), 7.59 (s, 1H), 7.37−7.32 (m, 3H),
4.63 (s, 2H), 2.36−2.29 (m, 2H), 1.12−1.02 (m, 4H). 13C
NMR (101 MHz, d6-DMSO) δ 162.4, 161.9, 146.8, 137.7 (q, J
= 33 Hz), 128.1, 127.1, 124.8, 123.0 (q, J = 273 Hz), 114.7−
114.5.4 (m), 112.4−112.2(m), 63.0, 16.5, 11.2. HRMS (ESI):
Calcd for C10H11F3NO (M+ + 1): 218.0787. Found: 218.07819.
Preparation of 2-Chloromethyl-6-cyclopropyl-4-
(trifluoromethyl)pyridine p-Toluenesulfonic Acid Salt
25. 2-Cyclopropyl-6-methyl-4-(trifluoromethyl)pyridine 23
(71 g, 352.9 mmol), N,N-dimethylformamide (2.6 g, 2.8 mL,
35.3 mmol, 0.1 mol equiv), and dichloromethane (426 mL)
were charged to a 1-L three-necked Morton flask fitted with a
nitrogen inlet/outlet and an overhead stirrer. Then trichlor-
oisocyanuric acid (93.0 g, 388.2 mmol, 1.1 mol equiv) was
charged to the flask in portions over a 0.5 h period. Caution:
This reagent, although not a respiratory dust hazard, has a pungent
odor and should be handled in a hood. On scale a full-faced
respirator should be used. The reaction mixture was warmed to
reflux and held at this temperature for 24 h after which time
HPLC analysis indicated that about 7 RAP of unreacted starting
material remained. The reaction was heterogeneous through-
out. The dichlorocyanuric acid byproduct was removed via
filtration and the cake washed with 100 mL of methylene
chloride. The filtrate and wash were charged back into the
Morton flask and the volume was adjusted to about 500 mL.
Then trichloroisocyanuric acid (10 g, 0.043 mol) was charged
to the flask. The slurry was warmed to reflux and held
overnight. HPLC analysis indicated that about 2 RAP of
unreacted starting material remained with about 5 RAP of the
bis-chloro impurity. The resulting thin slurry was filtered and
the clear filtrate charged back into the reactor. Then 300 mL of
saturated aqueous sodium bisulfate was charged to the reactor
and the biphasic mixture agitated for 15 min. The apparent pH
of the reaction mixture was 6. The biphasic stream was filtered
through a Celite pad, and the layers were allowed to separate.
The lower, rich organic stream was drawn off for further
processing. The upper, spent aqueous stream was discarded.
The methylene chloride stream was washed with 200 mL of
half-saturated brine. The methylene chloride stream was solvent
exchanged into isopropyl acetate, the volume was adjusted to
300 mL and charged to a 1-L reactor fitted with an overhead
stirrer. In a separate reactor 67 g (0.353 mol, 1 mol equiv) of p-
toluenesulfonic acid monohydrate was dissolved in 250 mL of
isopropyl acetate, and this was charged to the free base solution
in the 1-L reactor. The resulting slurry was stirred overnight at
rt. The crystals were collected via filtration and washed with
100 mL of cold (0−5 °C) isopropyl acetate. The cake was
deliquored for 1 h and then dried under vacuum at 50 °C to
yield 111.5 g (74.0%) of a white crystalline solid. The salt
formation step completely removed the bis-chloro impurity: 1H
NMR (400 MHz, d6-DMSO) δ 7.69−7.60 (m, 4H), 7.39−7.33
(m, 3H), 4.67 (s, 2H), 2.39−2.31 (m, 1H), 1.16−1.05 (m, 4H),
13C NMR (101 MHz, d6-DMSO) δ 163.4, 162.6, 147.5, 139.03
(q, J = 33 Hz), 129.0, 127.9, 125.6, 123.0 (q, J = 273 Hz),
115.6−115.4 (m), 113.4−113.2(m), 62.9 16.2, 11.2. HRMS
1
purification: H NMR (400 MHz, CDCl3) δ 7.09 (s, 1H),
7.08 (s, 1H), 2.53 (s, 3H), 2.03−2.10 (m, 1H), 1.08−0.98 (m,
4H). 13C NMR (101 MHz, d6-DMSO) δ 163.2, 158.6, 137.8 (q,
J = 33 Hz), 122.8 (q, J = 271 Hz), 114.9 (q, J = 3 Hz), 113.2(q,
J = 4 Hz), 24.9, 17.8, 10.7.
Preparation of 2-Hydroxymethyl-6-cyclopropyl-4-
(trifluoromethyl)pyridine Benzenesulfonic Acid Salt 12.
To 800 mL of a methylene chloride stream containing 2-
cyclopropyl-6-methyl-4(-trifluoromethyl)pyridine (40.0 g,
0.199 mol) was added m-CPBA (58.0 g, 0.238 mol based on
a measured potency of 71%, 1.2 mol equiv), and the resulting
solution was stirred at room temperature for 5 h after which
time HPLC analysis indicated complete reaction. Then 400 mL
of a 5 wt % solution of sodium thiosulfate was charged to the
reaction mixture, and it was stirred for 15 min. Agitation was
stopped, and the layers were allowed to separate. The lower,
rich organic stream was drawn off for further processing. To the
separated organic stream, 400 mL of saturated aqueous sodium
carbonate was added, and the biphasic mixture was stirred until
the m-chlorobenzoic acid was completely removed. The rich
organic stream was washed with 400 mL of half-saturated brine.
The methylene chloride solution was concentrated via
rotoevaporation to a volume of 150 mL. Caution: The N-
oxide is thermally unstable, and the distillation was performed
under vacuum to a concentration of ∼4 mL/g. The KF went from
0.12% to <0.01% after the distillation. The N-oxide stream was
adjusted to a concentration of 10 mL/g with methylene chloride
and then used immediately in the Boekelheide reaction. To this
solution was added trifluoroacetic anhydride (64.4 mL, 96.3 g,
0.458 mol, 2.3 mol equiv) over a 0.5 h period, maintaining the
temperature below 30 °C. The temperature was adjusted to 20
°C, and the reaction mixture was stirred at this temperature
overnight after which time HPLC analysis indicated complete
reaction. The solution was solvent exchanged into 400 mL of
methanol and then warmed to 40−45 °C for 2 h. The solution
was solvent exchanged into 300 mL of ethyl acetate. In a
separate 125 mL Erlenmeyer flask benzenesulfonic acid (29.0 g,
0.183 mol) was dissolved in 75 mL of ethyl acetate. The
benzenesulfonic acid solution was charged to the rich ethyl
acetate solution of benzylic alcohol, maintaining the temper-
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dx.doi.org/10.1021/op300323k | Org. Process Res. Dev. 2013, 17, 257−264