Note: Descriptions are shown in the official language in which they were submitted.
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1 The invention is concerned generally with the
2 preparation of 2-deutero-3-fluoro-D-alanine which is
3 a potent antibacterial agent valuable in
4 inhibiting the growth of pathogenic bacteria of both
the gram-positive and gram-negative types. More
6 particularly, it relates to the production of
7 2-deutero-3-fluoro-D-alanine in substantially pure
8 form by direct resolution of 2-deutero-3-fluoro-DL-alanine
9 salts, preferably organic sulfonates such as the
2-deutero-3-fluoro-DL-alanine benzene sulfonate;
11 2-deutero-3-fluoro-DL-alanine p-toluenesulfonate;
12 2-deutero-3-fluoro-DL-alanine 2-naphthaline sulfonate,
13 and the like.
14 This direct resolution process comprises
dissolving the DL-mixture of 2-deutero-3-fluoro-DL-alanine
16 salt such as 2-deutero-3-fluoro-DL-alanine benzene
17 sulfonate in a lower alkanol, preferably ethanol, propanol,
18 or the like, transforming the resulting solution into
19 a supersaturated solution of said DL-mixture (which
is conveniently effected by raising the temperature in
21 the dissolver to about 30C. and maintaining approximately
22 a 5C. differential between the temperature in the
23 dissolver and that in the crystallizer). In accordance
24 with this procedure, a solution of 2-deutero-3-fluoro-DL-
alanine benzene sulfonate in propanol, prepared in the
26 dissolver, is transformed into a supersaturated propanol
27 solution, the latter is then contacted with crystalline
28 seed of 2-deutero-3-fluoro-L-alanine benzene sulfonate,
29 and the mother liquor is separated from the crystalline
material which separates. It is ordinarily preferred
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' 1 to first crystallize the unwanted L-isomer, since greater
2 chance of contamination occurs in this initial crystallizing
3 step. The said mother liquor, with or without increase
4 in supersaturation,is then contacted with crystalline
seed of 2-deutero-3-fluoro-D-alanine benzene sulfonate,
6 and the crystalline D-isomer which precipitates is
` 7 separated from the mother liquor; the propanolic mother
8 liquor from this second crystallization is returned to the
9 dissolver. In the continuous operation of this process,
the mother liquor from the second crystallization
11 (i.e. of the D-isomer) is recycled into the dissolver,
12 and the crystallized D- and L-isomers are withdrawn
13 from each crystallizer continuously or intermittently.
14 Similarl , a solution of the 2-deutero-3-fluoro-DL-
alanine benzene sulfonate in ethanol, prepared in the
16 dissolver, is transformed into a supersatured ethanol
17 solution, the latter is then contacted with crystalline
18 seed of 2-deutero-3-fluoro-L-alanine benzene sulfonate,
19 the mother liquor is separated from the crystalline
material which separates, and is then contacted with
21 crystalline seed of 2-deutero-3-fluoro-D-alanine benzene
22 sulfonate; the crystalline D-isomer which precipitates is
23 separated, and the ethanolic mother liquor fro~ this second
24 crystallization is returned to the dissolver.
Although it is preferred to conduct the con-
26 tinuous process as a series operation, it can be carried
27 out in parallel if desired, i.e. by dividing the solution
28 from the dissolver into two equal parts, forming a super-
; 29 saturated solution with each part, contacting one part
with seed of D-isomer and contacting the other with seed
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1 of L-isomer, and recycling both mother li~uors to the
2 dissolver, the crystallized D- and L-isomers being isolated
3 from their respective slurries continuously or inter-
4 mittently.
Alternatively, this continuous direct resolution
6 may be carried out in a process involving only two steps,
7 i.e~ a solution step and a crystallization step. In a
8 preferred embodiment of this two-step method, a
9 saturated propanolic solution of 2-deutero-3-fluoro-
10~ D~-alanine benzene sulfonate is prepared in the dissolver,
11 and the solution is transferred to a crystallization
12 zone where the solution is rendered supersaturated,
13 preferably by reducing the temperature thereof. The
14 supersaturated propanol solution of 2-deutero-3-fluoro-DL-
alanine benzene sulfonate is seeded with crystals of the
16 corresponding D-isomer, thereby effecting selective
17 crystallization of the said D-isomer in substantially
18 pure form, and this crystalline 2-deutero-3-fluoro-D-alanine
19 benzene sulfonate is then recovered by filtration
or centrifugation. The mother liquors are then returned
21 to the dissolver and the temperature is elevated to the
22 temperature of the original solution in the dissolver.
23 The resulting solution is then contacted with additional
24 2-deutero-3-fluoro-DL-alanine benzene sulfonate, thereby
selectively dissolving the D-isomer, leaving the L-isomer
26 undissolved in substantially pure form, thus continuously
27 effecting selective separation of one of the enantiomorphs
28 constituting the DL-mixture in the solution zone (i.e.
29 the L-isomer), and effecting separation of the other
enantiomorph (i.e. the D-isomer) in the crystallization
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1 zone, said D- and L-isomers being removed from the
2 crystallization and solution zones in a continuous or
3 intermittent fashion as they are formed.
4 As noted hereinabove, the 2-deutero-3-fluoro-D-
alanine is a potent and useful antibacterial agent, and
6 is useful in inhibiting the growth of pathogenic bacteria
7 of both gram positive and gram negative genera.
8 The following ~xamples illustrate methods of
9 carrying out the present invention, but it is to be
understood that these examples are given for purposes
11 of illustration and not of limitation.
12 Example 1
13 The apparatus consists of three vessels, each
14 equipped with a stirrer and a means of temperature control.
The three vessels are connected in a circle by delivery
16 lines, each of which begins in an internal filter and
17 passes through a pump to the next vessel. Additional
18 filters are also inserted after each pump. The first
19 vessel in the circuit, the dissolver, is further equipped
for the addition of solid 2-deutero-3-fluoro-DL-alanine
21 benzenesulfonate and solvent. The other two vessels are
22 the D and L crystallizers, respectively. The operation ~j
23 of the equipment is a follows.
24 Two liters of propanol are çharged to the dissolver
and 400 grams of 2-deutero-3-fluoro-DL-alanine benzenesulfonate
26 are added. The slurry is equilibrated at 25C for one
27 hour and then pumping is started to the L-crystallizer.
28 When the volume in the L-crystallizer reaches 500 ml.,
29 the pump between the L- and D-crystallizers is started,
and the rate is adjusted to maintain the 500 ml volume in
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1 the L-crystallizerO When the volume in the D-crystallizer
2 reaches 500 ml, the pump between the D-crystallizer and
3 the dissolver is started, and the rate is adjusted
4 to maintain the volume constant. An additional
one liter of propanol and 170 grams of 2-deutero-3-fluoro-
6 DL-alanine benzene sulfonate are added to the dissolver,
7 and the system equilibrated at 25C. by pumping from vessel
8 to vessel.
9 Twenty-five grams of 2-deutero-3-fluoro-L-alanine
benzenesulfonate are added to the L-crystallizer and
11 25 grams of 2-deutero-3-fluoro-D-alanine benzenesulfonate
12 are added to the D-crystallizer.
13 The temperature is then raised in the dissolver
14 to 30C which develops a supersaturation in the
crystallizers, which are maintained at 25C. Adaitional
16 solid 2-deutero-3-fluoro-DL-alanine benzenesulfonate is
17 added to the dissolver to maintain a solid phase.
18 The solid phase in each of the crystallizers
19 is maintained approximately constant by occasionally
removing some of the crystalline slurry from each
21 crystallizer. Filtration of the propanol slurry from
22 the L-crystallizer gives substantially pure 2-deutero-3-
23 fluoro-L-alanine benzenesulfonate: filtration of slurry
24 from the D-crystallizer gives substantizlly pure
2-deutero-3 fluoro-D-alanine benzenesulfonate. The
26 filtrates are returned to the dissolver.
27 Productivity can be increased by raising the
2~ temperature of the dissolver and maintenance of solid
29 phase. However, the risk of contamination and production
of less pure 2 deutero-3-fluoro-D-alanine benzenesulfonate
,
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1 increases with higher supersaturation. In the event
2 of contamination, the pxoduct can be purified by a simple
3 batchwise recrystallization from aqueous isopropanol.
4 The 2-deutero-3-fluoro-D-alanine benzenesulfonate
is converted to 2-deutero-3-fluoro-D-alanine by
6 dissolving the salt in water and adsorbing the amino
7 acid on a sulfonic acid (H+cycle) resin. The column is
8 washed with water and then eluted with dilute aqueous
9 ammonia solution. The eluate is concentrated to a
small volume and the 2-deutero-3-fluoro-D-alanine crystallized
11 by addition of isopropanol.
12 Example 2
13 In a manner analogous to that described in
14 Example 1, seven liters of n-propanol are charged to
an eight liter kinetic resolution system, equipped
16 with a dissolver, an L-column, a D-column and appropriate
17 temperature controllers and pumps. To the dissolver
18 are added 1200 grams of 2-deutero-3-fluoro-DL-alanine
19 benzenesulfonate, and the system is saturated at 27C
for one hour. The D- and L-columns are adjusted to 25C.,
21 and 100 grams of appropriate seed of 100-120 mesh
22 are added to each column. The column temperatures are
23 adjusted to 22C, while the dissolver is maintained
24 at 27C. A flow rate of 300-600 ml./minute is
maintained through each column for an eight hour period.
26 The flow rate is such as to maintain the maximum fluidized
27 bed height throughout the run. After eight hours, the
28 contents of the D-columns are filtered, the crystalline
29 material is washed with two 400 ml.-portions of n-propanol;
four 400 ml.-portions of n-hexane, and air-dried to give
31 400 grams of 2-deutero-3-fluoro-D-alanire
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1 benzenesulfonate of 100% optical purity. The
2 crvstalline 2-deutero-3-fluoro-L-alanine benzenesulfonate
3 is recovered from the L-column in a similar manner.
4 Ten grams of 2-deutero-3~fluoro-D-alanine
benzenesulfonate is dissolved with stirring in
; 6 30 ml. of 50% aqueous isopropanol at room temperature.
7 The clear colorless solution is cooled with stirring
8 to about 0C., and 3.8 grams of triethylamine are added
9 dropwise to this solution; crvstallization occurs following
addition of the first drops of triethylamine. The
11 crystalline slurry is stirred at 0C. for a period of
12 one-half hour and filtered. The recovered crystalline
13 material is washed with 50 ml. of cold 90% aqueous
14 isopropanol, 50 ml. isopropanol, then with hexane, and
air-dried at room temperature ~o give about 3.9 grams of
16 2-deutero-3-fluoro-D-alanine.
17 Various changes and modifications may be
18 made in carrying out the present invention without
19 departing from the spirit and scope thereof. Insofar
as these changes and modifications are within the purview
21 of the annexed claims, they are to be considered as
22 part of this invention.
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