Organic Process Research & Development
Article
ature at 20−25 °C. The resulting reaction mixture was stirred
for an additional 1 h 45 min at the same temperature and then
gradually warmed to 50−55 °C over 1 h. The temperature was
maintained at 50 °C for an additional 2.5 h. The mixture was
then cooled to ambient temperature and acidified to pH ∼3
with conc HCl (192 mL, 2.3 mol, 1.6 equiv). Solvent ethanol
(about 270 mL) was then removed by distillation under
reduced pressure and the residue was extracted with warm
toluene (600 mL × 3, ca. 55 °C). The organic layer was
concentrated to low volume (approx 200 mL) by distilling
toluene under reduced pressure, during which time some 3-
hydroxyisoxazole (9) precipitated from the solution. Cyclo-
hexane (600 mL) was added to the residue, and the resulting
suspension was then cooled to room temperature. The
precipitated product was then filtered and dried in vacuo at
ambient temperature to constant weight to provide 64 g of 9
(52% yield).
Table 2. Summary of Results from the Carius Tube Test
time from 200 to
400 psig
comments
• Not a potential explosive
260 ms
• Time from 300 to 500 psig: 147 ms
• Endotherm detected from 60 °C. Exotherm detected
from 206 °C
• Maximum recorded pressure: 59 barg
• Residual pressure data could not be obtained due to
test cell rupture
332 ms
• Not a potential explosive
• Time from 300 to 500 psig: 204 ms
• Endotherm detected from 60 °C. Exotherm detected
from 215 °C
• Maximum recorded pressure: 63 barg
• Residual pressure data could not be obtained due to
test cell rupture.
Preparation of 3-Hydroxyisoxazole (9)Solution
Isolation Method. Aqueous NaOH (10 M, 604 mL, 6.04
mol, 2.1 mol equiv) was added to a solution of hydroxylamine
hydrochloride (200 g, 2.88 mol, 1.0 mol equiv) in water (1.0 L)
below −3 °C under an inert atmosphere. The resulting mixture
was diluted with water (100 mL), and the clear solution was
then warmed to 12 °C over 15 min. A solution of ethyl
propiolate (254.82 g, 2.6 mol, 0.95 mol equiv) in tetrahy-
drofuran (THF) (400 mL) was then added at a uniform rate,
maintaining the reaction temperature below 15 °C. THF (100
mL) was added, and the resulting solution was warmed to 55
°C. The reaction temperature was further maintained at 55 °C
for an additional 3 h. The reaction mixture was then cooled to
−5 °C, and concentrated hydrochloric acid (300 mL) was
added through a pressure equalized dropping funnel,
maintaining the temperature below 3 °C. Water (30 mL) was
added through the funnel, and the mixture was warmed to 20
°C. THF (300 mL) and butyronitrile (1.0 L) were then added,
and the mixture was agitated for 10 min. The aqueous layer was
then separated and washed with butyronitrile (1.0 L). The
combined organic layer was washed with 2 M hydrochloric acid
(1.3 L). The organic layer was diluted with butyronitrile (2.0
L), and the solution was concentrated by distillation under
reduced pressure at 60 °C until the volume is equal to that of
the reaction mixture prior to addition of THF/butyronitrile
(approx 1.6 L). The moisture content of the solution was 0.05−
0.07% w/w, and the strength of the resulting 9 in butyronitrile
was about 11.8% (190.1 g of 9 in 1611 g of butyronitirile
solution, yield 81%)
Preparation of Oxaisoxazolidinone (1). Example 1:
Preparation of 1 Using Mitsunobu Reaction. Hydroxy
oxazolidinone 8a (9.5 g, 1.00 equiv) was added to a 500 mL
three necked flask. THF (95.0 mL), solution of 9 in
butyronitrile (1 equiv, 30.0 mL, 2.7 M solution), and
triphenylphosphine (1.37 equiv, 29.4 g) were then added to
the flask. The contents were stirred to give a clear solution, and
the solution was then cooled to 0 °C. Diisopropyl
azodicarboxylate (1.17 eq., 20.2 g) was added to the reaction
mixture dropwise at temperature 0−5 °C. On completion of
the addition, the mixture was stirred for an additional 2 h at 0
°C and stirred overnight at 22−25 °C. The reaction mixture
was concentrated under reduced pressure, and the resulting
residue was column chromatographed over 100−200 mesh
silica gel using 2% methanol in chloroform to provide 1 (3 g,
yield: 20%).
Scheme 6. Approach toward Preparing 1
Butyronitrile was the choice of solvent as 9 was made
available in butyronitrile. We started our optimization work
using racemic 8b/c at the beginning. Our initial attempts with
Cs2CO3 as base were successful, but the product formed gave
back hydroxyl oxazolidinone 8a during aqueous work up. The
ether 1 was found to be unstable at pH > 7.5 in the presence of
water. Our efforts toward the screening of organic bases such as
DBU, TEA, and DIPEA gave some positive indications where 1
was found to be stable during work up. DBU gave complete
conversion with both mesyl (8b) and tosyl (8c) as leaving
groups. However, our efforts toward purging out the p-
toluenesulfonic acid byproduct were not successful, as it needs
a base wash and under such basic conditions the product 1 was
not stable. Interestingly, using mesyl oxazolidinone (8b), the
isolation was easy as the methanesulfonic acid formed as a
byproduct from the reaction is purged out during aqueous work
up and the required product can be easily crystallized out.7 This
was demonstrated on 150 g scale multiple times.
CONCLUSIONS
■
A significant amount of chemical hazard assessment work has
been carried out toward making a safe and scalable process for
1. The modified processes evaluated have been shown to be
acceptable from both a product quality and yield standpoint.
This paper highlights the need for process development
chemists to be aware of the potential hazards that could be
associated with their processes and the advantages that can be
gained from the early involvement of process safety groups.
EXPERIMENTAL DETAILS
■
Synthesis of 3-Hydroxyisoxazole (9) by Solid Iso-
lation. 10 M aqueous NaOH (288 mL, 2.88 mol, 2.0 equiv)
was added to a solution of hydroxylamine hydrochloride (100
g, 1.44 mol, 1.0 equiv) in water (200 mL). Ethyl propiolate
(141.2 g, 1.44 mol, 1.0 equiv) in ethanol (300 mL) was then
added dropwise over 1.5 h, maintaining the reaction temper-
D
dx.doi.org/10.1021/op500063g | Org. Process Res. Dev. XXXX, XXX, XXX−XXX