-
ethyl 4-cyclobutyl-3-oxobutanoate
- CAS No.: 885280-12-6
- Formula:
C10H16O3
- Molecular Weight: 184.23200
-
Synonyms:
Cyclobutanebutanoicacid,b-oxo-,ethyl ester; AB1425
MERCK SHARP and DOHME CORP.; WU, George, G.; ITOH, Tetsuji; MCLAUGHLIN, Mark; LIU, Zhijian; QIAN, Gang Patent:
WO2013/66734 A1, 2013 ;
Example 1: Cyclobutylacetonitrile
Step 1 : Cyclobutylmethyl methanesulfonate
A
50-L jacket vessel was charged with DCM (20 L) (KF 34 ppm), and
cyclobutylmethyl alcohol (5.0 kg, 58.0 mol) followed by TEA (8850 mL,
63.5 mol). The reaction mixture was cooled to approximately -10°C, and
MsCl (4735 mL, 60.8 mol) was added via an addition funnel dropwise over
approximately 3 hours, while the temperature was maintained below -5°C.
The reaction resulted in a yellow slurry after 70 minutes of aging. H
20 (8 L) was added to give a clear solution, which was agitated for 15 minutes. Then, the organic layer was separated. H
20
(8 L) was charged to the organic layer. The mixture was agitated for 20
minutes, and then the organic layer was separated. Brine (10% solution,
4 L) was charged to the organic layer. The mixture was agitated for 20
minutes, and then the organic layer was separated. The organic phase was
concentrated by vacuum distillation at approximately 30°C to 40°C and
28 inches Hg, resulting in a light brown residue (10.0 kg crude,
approximately 9.5 kg product assumed, 58.0 mol, approximately 100%
yield). A portion of the material was purified by distillation for
characterization.
1H NMR (CDC1
3, 400 MHz): δ 4.18 (d, J = 6.8 Hz, 2H), 3.00 (s, 3H), 2.71 (m, 1H), 2.11 (m, 2H), 2.00-1.80 (m, 4H).
Step 2: Cyclobutylacetonitrile
A 100-L RB flask was set up with a mechanical stirrer, a thermocouple, an addition funnel, a N
2
inlet, and a condenser that is connected to a scrubber (11 L bleach and
5 L 2N NaOH). DMSO (30.3 L) (KF approximately 680 ppm) and NaCN (3030
g, 61.8 mol) were charged to the flask. The mixture was heated to
approximately 75 °C by steam to dissolve most chunks of NaCN, resulting
in a turbid solution. The product of Step 1 (9476 g, 57.7 mol) in DMSO
(4 L) was added dropwise in 1 hour, 40 minutes while the temperature was
maintained below approximately 87°C. The reaction was aged at
approximately 85°C for 3 hours and cooled down to RT. H
20 (24
L) and MTBE (24 L) were charged. The mixture was agitated, and the
organic layer was separated. The aqueous layer was extracted with MTBE
(18 L), and the combined organic layer was agitated with H
20
(12 L) and separated. The organic layer was washed with 10% brine (4 L
and 2 L), and concentrated by vacuum distillation at approximately 45°C
and approximately 20 inches Hg, giving a light brown liquid (7.235 kg
crude, 73.3% by GC assay, 5.30 kg product assay, 55.7 mol, 96.5% for two
steps).
Ή NMR (CDCI
3, 400 MHz): δ 2.65 (m, 1H), 2.41 (d, J - 5.2 Hz , 2H), 2.18 (t, J = 6.8 Hz, 2H), 2.00-1.80 (m, 4H).
Example 2: Ethyl 4-cyclobutyl-3-oxobutanoate
THF (20 L) and zinc dust (2.75 kg, 42.0 mol) were charged under N
2
to a 50-L jacketed vessel with a thermocouple, an addition funnel and a
condenser. The mixture was stirred, and chlorotrimethylsilane (0.571
kg, 5.26 mol) was added at RT. The mixture was heated at 67°C for 30
minutes. Cyclobutylacetonitrile (2.5 kg, 26.3 mol, product of Example 1)
was added at 67°C. Ethyl bromoacetate (6.108 kg, 36.6 mol) was added to
the mixture at approximately 67°C to 70°C for over 3 hours. After the
addition, the mixture was heated at approximately 70°C for 1 hour and
then cooled to approximately 0°C to 5°C. 10% H
2S0
4 (aq.)
(35 L, 33.9 mol, approximately 1.3 eq.) was added slowly. The mixture
was aged at RT for 1 hour. The organic layer was separated and
subsequently washed with 10% aqueous citric acid (15 L, 7.88 mol, 0.3
eq.), 10% aqueous Na
2S
20
5 (25 L), 10% Na
2S
20
5 (aq.)
(10 L), and 10% brine (10 L). The organic layer was concentrated in
vacuo to afford the crude product (4.08 kg assay, 22.15 mol) in 84%
yield. A part of the material was purified by distillation for
characterization (with NMR in CDC1
3, approximately 10-15% enol-form of the compound was observed, major keto-form as shown.)
1H NMR (CDC1
3,
400 MHz): δ 4.19 (q, J = 7.1 Hz, 2 H), 3.38 (s, 2 H), 2.75-2.65 (m,
1H), 2.65-2.63 (m, 2 H), 2.19-2.08 (m, 2 H), 1.95-1.79 (m, 2 H),
1.73-1.60 (m, 2 H), 1.27 (t, J = 7.1 Hz, 3 H).
13C NMR (CDC1
3, 400 MHz): δ 202.2, 167.2, 61.3, 50.0, 49.3, 31.1, 28.4, 18.7,
14.1.
P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.
P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.
P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.
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