Chemistry Reference
In-Depth Information
source, see Chapter 7) was collected and quantified (200 mL, ca. 2.8 mol) in a three-
necked flask (capacity 5 L), and then a solution of t-amyl alcohol (176 g, 2 mol) in
dry diethyl ether (3 L) was added. A solution of dry pyridine (150 g, 1.9 mol) in dry
diethyl ether (3 L) was added slowly to the mixture at
20
C over a period
of 90 min, taking precautions to prevent the introduction of moisture. E
cient
stirring was necessary in order to obtain a homogeneous reaction mixture. Stirring
was continued for a further 30 min at the same temperature, and then the mixture
was kept overnight in a deep freezer at
30 to
20
C. The precipitate thus formed was
filtered off, again taking care to prevent the introduction of moisture; the filtrate
was then concentrated to a volume of about 400 mL under reduced pressure in an
ice/water bath. This solution was used as a stock solution of t-amyl chloroformate
without further purification. (It should be kept dry in a deep freezer and used
within 10 days).
A stock solution of t-amyl chloroformate (1 mol, calculated on the basis of t-amyl
alcohol) was slowly added to a solution of l-proline (69 g, 0.6 mol) in a mixture of
methanol (150 mL) and 2 n aqueous sodium hydroxide (600 mL) at
5to0
C.
The mixture was agitated vigorously with a mechanical stirrer during the addition
(over about 1 h). Stirring was continued for a further 2 h at 0
C, and then for an
additional 1 h at room temperature. (During the reaction, the solution should be
kept at above pH 8 by the addition of 4 n aqueous sodium hydroxide. After the
addition, the progress of the reaction should be monitored by TLC; if an apprecia-
ble amount of proline remains, more reagent should be added). The reaction mix-
ture was subsequently adjusted to pH 2-3 with 1 n hydrochloric acid, and the
product was extracted with ethyl acetate (1
100 mL). The combined
extracts were dried over sodium sulfate. On concentration of the dried solution,
crystals were obtained, which were subsequently recrystallized from ethyl acetate/
petroleum ether; yield 137 g (88%).
2-Methyl-2-propyl-1,3-propanediol dicarbamate (Meprobamate) 528, an active in-
gredient of pharmaceuticals (a general sedative), is synthesized with phosgene
[381, 382].
300 mL; 3
H
3
C
CH
3
H
3
C
CH
3
+
HCHO
CHO
OH
OH
526
527
1.
COCl
2
2. NH
3
H
3
C
CH
3
H
2
N
OO
NH
2
O
O
528
The method consists of low-temperature phosgenation of the substituted 1,3-
propanediol in an inert medium in the presence of a tertiary amine, followed
