U.S. patent application number 09/851818 was filed with the patent office on 2002-02-28 for process for manufacture of l-dopa ethyl ester.
Invention is credited to Bahar, Eliezer, Frenkel, Anton, Lidor-Hadas, Ramy.
Application Number | 20020026069 09/851818 |
Document ID | / |
Family ID | 22318659 |
Filed Date | 2002-02-28 |
United States Patent
Application |
20020026069 |
Kind Code |
A1 |
Lidor-Hadas, Ramy ; et
al. |
February 28, 2002 |
Process for manufacture of L-DOPA ethyl ester
Abstract
A process for manufacturing a highly purified, stable,
non-hygroscopic, crystalline composition of L-DOPA ethyl ester. The
L-DOPA ethyl ester is an active ingredient in many pharmaceutical
preparations for the treatment of patients suffering from
Parkinson's Disease and related indications.
Inventors: |
Lidor-Hadas, Ramy; (Kfar
Saba, IL) ; Bahar, Eliezer; (Tel Aviv, IL) ;
Frenkel, Anton; (Modlin, IL) |
Correspondence
Address: |
Cooper & Dunham LLP
1185 Avenue of the Americas
New York
NY
10036
US
|
Family ID: |
22318659 |
Appl. No.: |
09/851818 |
Filed: |
May 9, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
09851818 |
May 9, 2001 |
|
|
|
PCT/US99/26548 |
Nov 10, 1999 |
|
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60107820 |
Nov 10, 1998 |
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Current U.S.
Class: |
560/39 |
Current CPC
Class: |
C07C 227/42 20130101;
C07C 229/36 20130101; A61P 25/16 20180101; C07C 227/42
20130101 |
Class at
Publication: |
560/39 |
International
Class: |
C07C 229/36 |
Claims
What is claimed:
1. A process for preparing a composition comprising
pharmaceutically acceptable, crystalline, non-hygroscopic L-DOPA
ethyl ester as free base in an amount which is at least 95% by
weight of the composition and L-DOPA in an amount which is less
than 2% by weight of the composition, which process comprises: (a)
reacting L-DOPA with ethanol in the presence of thionyl chloride or
an acid catalyst to produce a solution of crude L-DOPA ethyl ester
salt; (b) removing any residual volatiles from the solution of
crude L-DOPA ethyl ester salt produced in step (a); (c) diluting
the solution from step (b) with water, and adding a cosolvent and a
suitable antioxidant; (d) adding a suitable base to the solution
from step (c) under controlled conditions to precipitate a crude
L-DOPA ethyl ester free base; (e) drying the precipitated crude
L-DOPA ethyl ester free base from step (d); and (f) recrystallizing
the dried, precipitated crude L-DOPA ethyl ester free base from
step (e) in the presence of a suitable solvent containing an
antioxidant at a temperature of less than 10.degree. C. to produce
the composition of pharmaceutically acceptable, crystalline,
non-hygroscopic L-DOPA ethyl ester free base.
2. The process of claim 1, wherein the acid catalyst of step (a) is
hydrogen chloride or toluenesulfonic acid.
3. The process of claim 2, wherein the acid catalyst of step (a) is
hydrogen chloride.
4. The process of claim 1, wherein the crude L-DOPA ethyl ester
salt produced in step (a) is L-DOPA ethyl ester hydrochloride.
5. The process of claim 1, wherein the removing of residual
volatiles in step (b) is effected by vacuum distillation.
6. The process of claim 5, wherein the residual volatiles removed
in step (b) are ethanol and excess HCl.
7. The process of claim 1, wherein the cosolvent of step (c) is
toluene.
8. The process of claim 1, wherein the suitable antioxidant of step
(c) is selected from a group consisting of ascorbic acid, sodium
sulfite, sodium metabisulfite, propyl gallate, and vitamin E.
9. The process of claim 8, wherein the suitable antioxidant of step
(c) is sodium metabisulfite.
10. The process of claim 1, wherein the suitable base of step (d)
is sodium hydroxide or ammonium hydroxide.
11. The process of claim 10, wherein the suitable base of step (d)
is sodium hydroxide.
12. The process of claim 1, wherein the addition of a suitable base
in step (d) effects an adjustment in the pH of the solution to a pH
range between about 5.0 and about 9.0 to precipitate a crude L-DOPA
ethyl ester base.
13. The process of claim 12, wherein the addition of a suitable
base in step (d) effects an adjustment in the pH of the solution to
a pH range between 6.5 and 8.0 to precipitate a crude L-DOPA ethyl
ester base.
14. The process of claim 1, wherein the controlled conditions from
step (d) are conditions in which addition of the base solution is
slowly performed in a nitrogen atmosphere, and a trace amount of
L-DOPA ethyl ester is added to induce formation of precipitate.
15. The process of claim 1, wherein the drying of step (e) is
effected by azeotropic distillation.
16. The process of claim 1, wherein the suitable solvent of step
(f) is selected from a group consisting of ethyl acetate, methylene
chloride, and toluene.
17. The process of claim 16, wherein the suitable solvent of step
(f) is ethyl acetate.
18. The process of claim 1, wherein the antioxidant of step (f) is
selected from a group consisting of ascorbic acid,
2,6-Di-tert-butyl-4-methylphenol (BHT), butylated hydroxy anisol
(BHA) propyl gallate, and vitamin E.
19. The process of claim 17, wherein the antioxidant of step (f) is
2,6-Di-tert-butyl-4-methylphenol (BHT).
20. A process for preparing a composition comprising
pharmaceutically acceptable, crystalline, non-hygroscopic L-DOPA
ethyl ester as free base in an amount which is at least 95% by
weight of the composition and L-DOPA in an amount which is less
than 2% by weight of the composition, which process comprises: (a)
reacting L-DOPA with ethanol in the presence of hydrogen chloride
(HCl) to produce a solution of crude L-DOPA ethyl ester
hydrochloride; (b) removing ethanol and excess HCl from the
solution of crude L-DOPA ethyl ester hydrochloride produced in step
(a); (c) diluting the solution from step (b) with water, toluene,
and sodium metabisulfite; (d) adding a suitable base to the
solution from step (c) under controlled conditions to precipitate a
crude L-DOPA ethyl ester free base; (e) drying the precipitated
crude L-DOPA ethyl ester free base from step (d); and (f)
recrystallizing the dried, precipitated crude L-DOPA ethyl ester
free base from step (e) in the presence of a suitable solvent
containing an antioxidant at a temperatures of less than 10.degree.
C. to produce the composition of pharmaceutically acceptable,
crystalline, non-hygroscopic L-DOPA ethyl ester free base.
21. The process of claim 20, wherein the amount of hydrogen
chloride gas of step (a) is between 1-3 equivalents.
22. The process of claim 21, wherein the hydrogen chloride gas of
step (a) is between 1.75-2 equivalents.
23. The process of claim 20, wherein the base solution in step (c)
is sodium hydroxide solution or ammonium hydroxide.
24. The process of claim 23, wherein the base solution in step (c)
is sodium hydroxide solution.
25. The process of claim 20, wherein the controlled conditions from
step (d) are conditions in which addition of the sodium hydroxide
solution is slowly performed in a nitrogen atmosphere, at a
reaction temperature between 10-30.degree. C. and a trace amount of
L-DOPA ethyl ester is added to induce formation of precipitate.
26. The process of claim 25, wherein reaction temperature is
between 25-30.degree. C.
27. The process of claim 20, wherein the addition of a suitable
base in step (d) effects an adjustment in the pH of the solution to
a pH range between 6.5 and 8.0 to precipitate a crude L-DOPA ethyl
ester base.
28. The process of claim 28, wherein the addition of a suitable
base in step (d) effects an adjustment in the pH of the solution to
a pH range between 7.6 and 7.8 to precipitate a crude L-DOPA ethyl
ester base.
Description
[0001] This application claims the priority of U.S. Provisional
Application No. 60/107,820, filed Nov. 10, 1998, the contents of
which are hereby incorporated by reference into this
application.
[0002] Throughout this application, various references are
identified by authors and full citation. Disclosure of these
publications in their entireties are hereby incorporated by
reference into this application to more fully describe the state of
the art to which this invention pertains.
BACKGROUND OF THE INVENTION
[0003] 1. Field of the Invention
[0004] The present invention relates to a process for manufacturing
a highly purified, stable, non-hygroscopic, crystalline composition
of L-DOPA ethyl ester. The L-DOPA ethyl ester (also known as LDEE)
is an active ingredient in many pharmaceutical preparations for the
treatment of patients suffering from Parkinson's disease and
related indications.
[0005] 2. Description of Related Art
[0006] Typically Parkinsonian patients are routinely treated with a
combination of levodopa (L-DOPA) and a DOPA decarboxylase inhibitor
such as carbidopa or benserazide. Unfortunately, after an initial
period of satisfactory, smooth and stable clinical benefit from
L-DOPA therapy lasting on the average 2-5 years, the condition of
many patients deteriorates and they develop complex dose-related as
well as unpredictable response fluctuations. The causes of the
response fluctuations are probably multiple and complex, but
pharmacokinetic problems (primarily faulty absorption of L-DOPA)
may play a critical role. There is a correlation between the
clinical fluctuations and the oscillations of L-DOPA plasma levels.
Many of the problems are a result of the unfavorable
pharmacokinetic properties of L-DOPA, i.e., very poor solubility,
poor bio-availability and short half-life in vivo.
[0007] A more suitable L-DOPA ester for therapy would be the L-DOPA
ethyl ester. However, it has been difficult to develop the L-DOPA
ethyl ester in a form suitable for pharmaceutical use:
[0008] "In view of the potential toxicity that might arise from
methanol formation the ethyl ester would ideally have been most
suitable for assessment in humans. However, the ethyl ester could
not be crystallized as its hydrochloride salt because of its
hygroscopic potential. The methyl ester was therefore developed for
use in humans." Stocci, F. et al, Movement Disorders, 7:249-256,
(1992); at 254.
[0009] L-DOPA ethyl ester is described in the literature as the
hydrochloride salt. However, it is difficult to isolate as a
crystalline salt and therefore was described as an amorphous solid
(Fix, et al., Pharm. Research 6(6):501-505 (1989)) which is not
suitable for pharmaceutical use. Cooper, et al., Clinical
Neuropharmacology 7:88-89 (1984) note that L-DOPA ethyl ester
hydrochloride salt is hygroscopic and difficult to crystallize
during synthesis. Clearly, a pure, stable, non-hygroscopic form of
L-DOPA ethyl ester is needed for pharmaceutical purposes.
[0010] Salts and esters of L-DOPA, including the L-DOPA ethyl
ester, are mentioned in Patent GB 1,342,286 for the treatment of
alopecia. The only disclosure regarding the nature of the L-DOPA
ethyl ester is that it can be prepared from L-DOPA by conventional
methods. However, as noted above, preparation of L-DOPA ethyl ester
by conventional methods yields a product which is not suitable for
pharmaceutical use due to its impurity, its hygroscopicity, and its
lack of stability.
[0011] Great Britain Patent No. 1,364,505 and corresponding U.S.
Pat. No. 3,803,120, assigned to Hoffman-La Roche, describe the
synthesis of L-DOPA ethyl ester hydrochloride salt and free base.
This compound is used as an intermediate in the synthesis of other
compounds and is not characterized in the patent specification. In
agreement with the literature (Fix, et al., Pharm. Research
6(6):501-505 (1989); and Cooper, et al., Clin. Pharmacol. 7:88-89
(1984)) we have found that the L-DOPA ethyl ester hydrochloride
salt synthesized by the methods described in these patents is
hygroscopic, not stable, difficult to crystallize, and, as a
result, difficult to purify. This material cannot be used for
pharmaceutical compositions. Likewise, the L-DOPA ethyl ester free
base as prepared in these two patents is impure and not stable and
thus also is not suitable for pharmaceutical compositions. At best
it can be used as a synthetic intermediate for further chemical
synthesis as described in the cited patents.
[0012] Two references note the synthesis of racemic ethyl ester.
(Ginssburg, et al., Zh. Obshch. Khim. 39:1168-1170 (1969) and
Venter, et al., S. Afr. Tydskr. Chem. 31:135-137(1978)). Neither of
these references prepare crystalline L-DOPA ethyl ester in a form
suitable for pharmaceutical use and certainly there is no teaching
or suggestion of the preparation of crystalline L-DOPA ethyl ester
in a form suitable for pharmaceutical use. Both references prepare
the material as an intermediate for the synthesis of other
materials of interest.
[0013] More recently, Milman et al. (U.S. Pat. No. 5,354,885)
described a new process for preparing pharmaceutically acceptable,
crystalline, non-hygroscopic L-DOPA ethyl ester as free base. The
Milman process provides L-DOPA ethyl ester of high purity, wherein
at least 97% by weight is the L-DOPA ethyl ester while L-DOPA, as
an impurity, is present in less than 1% by weight of the
composition.
[0014] The crystalline, non-hygroscopic L-DOPA ethyl ester
composition produced according to the Milman process is highly
stable and remains as at least 97% by weight L-DOPA ethyl ester
after incubation for 6 months at 40.degree. C. The availability of
L-DOPA ethyl ester in such high purity made feasible the
preparation of pharmaceutical compositions of L-DOPA ethyl ester,
which compositions could not be successfully developed on a
commercial scale until the development of the process.
[0015] The potential for increased demand of highly purified L-DOPA
ethyl ester described in the U.S. Pat. No. 5,354,885, warrants
research to find a simpler, more economical process for producing
L-DOPA ethyl ester of high purity. While the Milman process
produced a highly purified L-DOPA ethyl ester, the process is
lengthy and complicated because it involves extraction steps.
[0016] The Milman process comprises reacting L-DOPA with ethanol in
the presence of thionyl chloride or an acid catalyst to yield crude
L-DOPA ethyl ester hydrochloride. Then volatiles are removed from
the crude L-DOPA ethyl ester hydrochloride by vacuum distillation.
The residue is then dissolved with water containing a suitable
antioxidant and the pH is adjusted to between 6.0 and 7.0 using a
suitable base to yield a solution containing L-DOPA ethyl ester
free base. To obtain the free base in the solvent phase, the
solution is extracted with a suitable solvent in the presence of a
suitable antioxidant. The solvent phase is then concentrated at a
temperature lower than 40.degree. C. to form a precipitate. The
precipitate is then recrystallized in the presence of a second
suitable solvent containing a second suitable antioxidant to yield
the composition of pharmaceutically acceptable, crystalline,
non-hygroscopic L-DOPA ethyl ester free base.
[0017] The present invention discloses an unexpectedly simpler
process for manufacturing a composition comprising pharmaceutically
acceptable, crystalline, non-hygroscopic L-DOPA ethyl ester as free
base in an amount which is at least 95% by weight of the
composition and L-DOPA in an amount which is less than 2% by weight
of the composition.
SUMMARY OF THE INVENTION
[0018] This invention provides a novel and simplified process for
preparing a composition comprising pharmaceutically acceptable,
crystalline, non-hygroscopic L-DOPA ethyl ester as free base in an
amount which is at least 95%, and preferably 97% and more
preferably 98% by weight of the composition and L-DOPA in an amount
which is less than 2% and preferably less than 0.5% by weight of
the composition. The process disclosed herein is significantly
simpler and more economical than prior art processes while
providing the L-DOPA ethyl ester of the same high or higher purity
as that of the Milman process disclosed in the U.S. Pat. No.
5,354,885.
BRIEF DESCRIPTION OF THE FIGURES
[0019] FIG. 1: A block flow diagram summarizing the Milman Process
for Preparing L-DOPA Ethyl Ester as disclosed in U.S. Pat. No.
9,354,885 to Milman et al. The process comprises six (6) main
steps, including an extraction procedure (step (d)).
[0020] FIG. 2: A block flow diagram summarizing the Process for
Manufacture of L-DOPA Ethyl Ester according to the subject
invention. The process according to the subject invention is
distinguished from the Milman process of FIG. 1 because it achieves
the same or higher purity of L-DOPA ethyl ester suitable for
pharmaceutical use in less steps.
DETAILED DESCRIPTION OF THE INVENTION
[0021] This invention provides a process for preparing a
composition comprising pharmaceutically acceptable, crystalline,
non-hygroscopic L-DOPA ethyl ester as free base in an amount which
is at least 95% by weight of the composition and L-DOPA in an
amount which is less than 2% by weight of the composition. This
process comprises the following steps (a) through (f):
[0022] (a) reacting L-DOPA with ethanol in the presence of thionyl
chloride or an acid catalyst to produce a solution of crude L-DOPA
ethyl ester salt;
[0023] (b) removing any residual volatiles from the solution of
crude L-DOPA ethyl ester salt produced in step (a);
[0024] (c) diluting the solution from step (b) with water, and
adding a cosolvent and a suitable antioxidant;
[0025] (d) adding a suitable base to the solution from step (c)
under controlled conditions to precipitate a crude L-DOPA ethyl
ester free base;
[0026] (e) drying the precipitated crude L-DOPA ethyl ester free
base of step (d); and
[0027] (f) recrystallizing the dried, precipitated crude L-DOPA
ethyl ester free base from step (e) in the presence of a suitable
solvent containing an antioxidant at a temperature of less than
10.degree. C. to produce the composition of pharmaceutically
acceptable, crystalline, non-hygroscopic L-DOPA ethyl ester free
base.
[0028] In one embodiment of the invention, the acid catalyst of
step (a) is hydrogen chloride or toluenesulfonic acid. In the
preferred embodiment of the invention, the acid catalyst of step
(a) is hydrogen chloride.
[0029] In one embodiment of the invention, the crude L-DOPA ethyl
ester salt produced in step (a) is crude L-DOPA ethyl ester
hydrochloride.
[0030] In one embodiment of the invention, the removing of residual
volatiles from step (b) is effected by vacuum distillation.
[0031] In one embodiment of the invention, the residual volatiles
from step (b) are ethanol and excess HCl.
[0032] In one embodiment of the invention, the cosolvent of step
(c) is toluene.
[0033] In one embodiment of the invention, a suitable antioxidant
of step (c) is selected from a group comprising ascorbic acid,
sodium sulfite, sodium metabisulfite, propyl gallate, and vitamin
E. In a specific embodiment of the invention, the antioxidant of
step (c) is sodium metabisulfite.
[0034] In one embodiment of the invention, a suitable base of step
(d) may be an organic or inorganic base such as sodium hydroxide or
ammonium hydroxide. In a specific embodiment of the invention, a
suitable base of step (d) is sodium hydroxide.
[0035] In one embodiment, the addition of a suitable base in step
(d) effects an adjustment in the pH of the solution to a pH range
between about 5.0 and about 9.0 to precipitate a crude L-DOPA ethyl
ester free base.
[0036] In a specific embodiment, the addition of a suitable base in
step (d) effects an adjustment in the pH of the solution to a pH
range between 6.5-8.0 to precipitate a crude L-DOPA ethyl ester
free base.
[0037] In one embodiment of the invention, the controlled
conditions for step (d) are conditions in which addition of the
base solution is slowly performed in a nitrogen atmosphere, and a
trace amount of L-DOPA ethyl ester is added to induce formation of
precipitate.
[0038] In one embodiment of the invention, the drying process in
step (e) of the precipitated crude L-DOPA ethyl ester base from
step (d) is effected by azeotropic distillation.
[0039] In one embodiment of the invention, a suitable solvent of
step (f) is selected from a group consisting of ethyl acetate,
methylene chloride, or toluene. In a specific embodiment, the
suitable solvent of step (f) is ethyl acetate.
[0040] In one embodiment of the invention, an antioxidant of step
(f) is selected from a group consisting of ascorbic acid,
2,6-Di-tert-butyl-4-methylphenol (BHT), butylated hydroxy anisol
(BHA), propyl gallate, and vitamin E. In a specific embodiment, an
antioxidant for step (f) is 2,6-Di-tert-butyl-4-methylphenol
(BHT).
[0041] This invention also provides a process for preparing a
composition comprising pharmaceutically acceptable, crystalline,
non-hygroscopic L-DOPA ethyl ester as free base in an amount which
is at least 95% by weight of the composition and L-DOPA in an
amount which is less than 2% by weight of the composition, which
process consists essentially of:
[0042] (a) reacting L-DOPA with ethanol in the presence of hydrogen
chloride (HCl) to produce a solution of crude L-DOPA ethyl ester
hydrochloride;
[0043] (b) removing ethanol and excess HCl from the solution of
crude L-DOPA ethyl ester hydrochloride produced in step (a);
[0044] (c) diluting the solution from step (b) with water, toluene,
and sodium metabisulfite;
[0045] (d) adding a suitable base to the solution from step (c)
under controlled conditions to precipitate a crude L-DOPA ethyl
ester free base;
[0046] (e) drying the precipitated crude L-DOPA ethyl ester free
base from step (d); and
[0047] (f) recrystallizing the dried, precipitated crude L-DOPA
ethyl ester free base from step (e) in the presence of a suitable
solvent containing an antioxidant at a temperature of less than
10.degree. C. to produce the composition of pharmaceutically
acceptable, crystalline, non-hygroscopic L-DOPA ethyl ester free
base.
[0048] In one embodiment of the process, the amount of hydrogen
chloride gas of step (a) is between 1-3 equivalents.
[0049] In another embodiment of the process, the amount of hydrogen
chloride gas of step (a) is between 1.75-2 equivalents.
[0050] In one embodiment of the process, the base solution in step
(c) is sodium hydroxide (NaOH) solution or ammonium hydroxide
(NH.sub.4OH).
[0051] In another embodiment of the process, the base solution in
step (c) is sodium hydroxide (NaOH) solution.
[0052] In another embodiment of the process, the controlled
conditions from step (d) are conditions in which addition of the
sodium hydroxide solution is slowly performed in a nitrogen
atmosphere, at a reaction temperature between 10-30.degree. C. and
a trace amount of L-DOPA ethyl ester is added to induce formation
of precipitate.
[0053] In a further embodiment of the process, the controlled
conditions from step (d) are conditions in which addition of the
sodium hydroxide solution is slowly performed in a nitrogen
atmosphere, at a reaction temperature between 25-30.degree. C. and
a trace amount of L-DOPA ethyl ester is added to induce formation
of precipitate.
[0054] In a specific embodiment, the addition of a suitable base in
step (d) effects an adjustment in the pH of the solution to a pH
range between 6.5-8.0 to precipitate a crude L-DOPA ethyl ester
free base. In another specific embodiment, the addition of a
suitable base in step (d) effects an adjustment in the pH of the
solution to a pH range between 7.6 and 7.8 to precipitate a crude
L-DOPA ethyl ester base.
[0055] This invention will be better understood from the
Experimental Details which follow. However, one skilled in the art
will readily appreciate that the specific methods and results
discussed are merely illustrative of the invention as described
more fully in the claims which follow thereafter.
[0056] Experimental Details
[0057] Description of the Process
[0058] A process for preparing a composition comprising
pharmaceutically acceptable, crystalline, non-hygroscopic L-DOPA
ethyl ester as free base in an amount which is at least 95%, and
preferably 97% and more preferably 98% by weight of the composition
and L-DOPA in an amount which is less than 2% by weight of the
composition, which process comprises detailed steps A-H:
[0059] A. Reacting L-DOPA with ethanol in the presence of 1.75-2
equivalents HCl gas. The amount of HCl gas is not catalytic since
one equivalent reacts with the amino group of L-DOPA.
[0060] B. Removing the volatiles (ethanol and excess HCl) from the
crude L-DOPA ethyl ester hydrochloride.
[0061] C. Diluting the solution with water, adjusting the pH to 2-3
most preferably with 5N NaOH solution (at this pH range L-DOPA
ethyl ester is stable in the solution and will not decompose back
to L-DOPA during the distillation of the reaction mixture). 13%
NH.sub.4OH solution can also be used for the precipitation of
L-DOPA ethyl ester base.
[0062] D. Adding toluene as a cosolvent (prevents the sticking of
the L-DOPA ethyl ester crude at the walls of the reactor during the
precipitation), adjusting pH to 4-5, adding a suitable antioxidant
such as sodium metabisulfite and purging out the air from the
reactor by using a continuous stream of nitrogen gas.
[0063] E. Adjusting the reaction temperature to 10-30.degree. C.
(most preferably to 25-30.degree. C.) correcting the pH to 6.5-6.7
and seeding with L-DOPA ethyl ester to induce crystallization.
[0064] F. Precipitating L-DOPA ethyl ester base by controlled
(slow) addition of the base solution until pH 7.4-8.0 (most
preferably 7.6-7.8) and collecting the precipitate at 5.degree.
C.
[0065] G. Drying the water from the wet precipitate by azeotropic
distillation with toluene. If wet L-DOPA ethyl ester is dried in a
stainless steel vacuum oven, decomposition of the material
results.
[0066] H. Recrystallizing the dried precipitate in the presence of
ethyl acetate containing BHT as antioxidant.
[0067] Synthesis of Crude L-DOPA Ethyl Ester
[0068] Absolute ethanol (395 g, 500 ml, 8.58 moles, 17 eq.) and
L-DOPA (100 g, 0.507 moles, 1 eq.) are introduced into 1L reactor.
The batch is cooled to 15.degree. C. and HCl (g) (37.01 g, 1.014
mole, 2 eq.) is bubbled into the reaction mixture at 15-30.degree.
C. The reaction is heated to reflux (79.degree. C.) and kept at
reflux for 3 hours. The batch is then cooled to 40.degree. C. and
350-400 ml of solvent is distilled out under vacuum during 1.5-2
hours (50 mbar, jacket temperature 60.degree. C.). Deionized water
(220 ml) is introduced, the pH of the solution is adjusted to 2-3
with 5N NaOH solution (65 ml) and 170 ml of the reaction mixture is
distilled out during 1.5-2 hours (50 mbar, jacket temperature
50.degree. C.). Toluene (20 ml) is added to the resulting solution,
the pH of the solution is adjusted to pH 4-5 with 5N NaOH solution
and sodium metabisulfite (2 g, 2% w/w) is added. The operations
from this stage on are done at nitrogen atmosphere. The temperature
of the reaction is adjusted to 25-30.degree. C., the pH is adjusted
to 6.5-6.7 with 5N NaOH and the solution is seeded with L-DOPA
ethyl ester (1 g). The precipitation is continued by controlled
addition of 5N NaOH solution (70 ml/hr.) until pH 7.6-7.8, the
reaction mixture cooled to 520 C. and kept at this temperature for
one hour. The precipitate is collected by filtration and washed
with (2.times.40 ml) cold water. The crude wet precipitate is dried
by azeotropic distillation of the water with toluene (500 ml) under
vacuum (50 mbar, jacket temperature 25-45.degree. C.) until no more
water is distilled out. The mixture is cooled to ambient
temperature, L-DOPA ethyl ester (crude) is collected by filtration,
washed with toluene and dried in a vacuum oven at 30-35.degree. C.
until constant weight. The yield of crude material is 85%.
[0069] Synthesis of Crystalline L-DOPA Ethyl Ester
[0070] Into 500 ml reactor are introduced L-DOPA ethyl ester crude
(30 g) and ethyl acetate which contains 0.01% BHT (150 ml, 5
volumes relative to L-DOPA ethyl ester weight). The batch is heated
to 50.degree. C. during half an hour and kept at this temperature
until a slight turbidity remained in the solution. The hot solution
is filtered through a 0.2.mu. filter and returned into the reactor
(the time elapsed from the beginning of the crystallization until
the end of filtration should not exceed 2.5 hours). The clear
solution is cooled to 30.degree. C. during 30 min. (seeded at
45.degree. C. with L-DOPA ethyl ester, at 37-38.degree. C. massive
crystallization is observed) then cooled to 5.degree. C. during 1
hour and kept at this temperature for another 1 hour. L-DOPA ethyl
ester (cryst.) is collected by filtration, washed with 15 ml ethyl
acetate which contains 0.01% BHT under nitrogen and dried in a
vacuum oven at 30-35.degree. C. until constant weight. The
crystallization yield is 85%. The overall yield is 72%.
[0071] Purity of L-DOPA Ethyl Ester
[0072] The active ingredient resulting from the synthesis procedure
comprises (1) L-DOPA ethyl ester in an amount which is at least 95%
by weight of active ingredient; and (2) L-DOPA in an amount which
is less than 2% by weight of the active ingredient.
[0073] To increase the purity of the product, additional water may
be added. For example, performing the final crystallization in
ethyl acetate with 1% water will result in increased purity. The
amount of water to be added is easily determinable by one skilled
in the art. However, it is preferable to use only ethyl acetate
since the addition of water will nearly always result in loss of
yield.
[0074] Levodopa ethyl ester precipitated from water has
surprisingly higher purity than levodopa ethyl ester isolated via
the extractive process (as performed in Milman et al.). The LDEE
precipitation in water takes place at low temperatures which
prevents impurities such as levodopa-levodopa ethyl ester and
cyclic L-DOPA from evolving. Crystallization performed at higher
temperatures (50.degree. C.) tends to have a higher content of
impurities. Therefore, the Milman process which requires extractive
procedures at higher temperatures has a lower purity than the
present invention.
[0075] Moreover, crude levodopa ethyl ester produced after
precipitation in the subject invention may in fact have higher
purity than the levodopa ethyl ester produced after crystallization
for the reasons stated above. The treatment with hot (50.degree.
C.) ethyl acetate may induce increased production of impurities.
However, the crystallization process is necessary for (1)
controlling the particle size distribution (PSD) and (2) filtering
each drug substance through a micron filter system during
crystallization.
[0076] Physical Properties and Stability
[0077] L-DOPA ethyl ester as free base obtained by this process is
stable, non-hygroscopic, crystalline and has a particle size in the
range of: 18-180.mu., with an average of less than 60.mu..
[0078] The Novelties and Advantages of the Process
[0079] The main advantage of the process herein is the reduced
number of steps which increases efficiency and economy. Comparison
between the Milman process and the presently disclosed process
shows a significant difference in productivity. The Milman process
and the process for the subject invention have been summarized in
FIGS. 1 and 2 respectively.
[0080] The Milman process comprises reacting L-DOPA with ethanol in
the presence of thionyl chloride or an acid catalyst to yield crude
L-DOPA ethyl ester hydrochloride. Any volatiles are then removed by
vacuum distillation, the residue is then dissolved with water
containing a suitable antioxidant and the pH is then adjusted to
between 6.0 and 7.0 using a suitable base to yield a solution
containing L-DOPA ethyl ester free base. To obtain the free base in
the solvent phase, the solution is extracted with a suitable
solvent such as ethyl acetate, in the presence of a suitable
antioxidant. The solvent phase is then concentrated at a
temperature lower than 40.degree. C. to form a precipitate.
Recrystallization of the precipitate occurs in the presence of a
second suitable solvent containing a second suitable antioxidant to
yield the composition of pharmaceutically acceptable, crystalline,
non-hygroscopic L-DOPA ethyl ester free base.
[0081] The Milman process (FIG. 1) requires three-extractions and
addition of salt to the water phase at the second extraction. The
addition of salt leaves the ethyl acetate saturated with salted
water which necessitates two additional washings. In addition to
the complications of extractions and washings, the resulting ethyl
acetate contains about 7% water. Drying this ethyl acetate/L-DOPA
ethyl ester solution is an involved step in the Milman process.
Because most drying agents interact with L-DOPA ethyl ester,
azeotropic distillation is the best route. Since azeotropic mixture
of water and ethyl acetate contains a small amount of water, and
since L-DOPA ethyl ester base is very sensitive to heat (producing
two impurities, cyclic levodopa and levodopa-levodopa ethyl ester),
vacuum distillation is required. Vacuum distillation is time
consuming and the prior art process, as a whole, wastes solvent.
These complications are detrimental to the resulting yield of the
product. In fact, the Milman process results in only 50% yield,
even though the reflux of L-DOPA with ethanol/HCl produces 96%
L-DOPA ethyl ester hydrochloride in the reaction mixture. The
remaining material is in the water phase and decomposed to L-DOPA
and other byproducts during the laborious work-up.
[0082] By contrast in the process of this invention (FIG. 2), after
removal of volatiles, the next step is simply to adjust the pH of
the solution, add toluene and sodium metabisulfite, and then a
solution of sodium hydroxide in a controlled manner (temp.,
stirring speed, pH, rate of addition) to precipitate L-DOPA ethyl
ester free base from the aqueous phase. The L-DOPA ethyl ester is
then dried by azeotropic distillation with toluene and crystallized
from ethyl acetate containing BHT as antioxidant. The azeotropic
distillation step disclosed in this invention eliminates the need
to use ethyl acetate for isolation of the final product.
Elimination of the distillation step results in significant savings
in solvents, their recovery, as well as time. L-DOPA ethyl ester is
not easily extracted since it is also soluble to a certain extent
in water.
[0083] Compared to the Milman process, the presently disclosed
process is simpler and shorter because the capacity of production
in the same reactors in terms of volume of output and yield is
tripled. In the Milman process, the extraction step extracts the
product into the organic phase (ethyl acetate) in a two system
mixture (aqueous/organic), while in the presently disclosed
process, the product is precipitated from an aqueous phase since
there is no organic phase. The fact that the subject invention has
a crystallization step starting from a dry crude levodopa ethyl
ester is a great advantage since reproducibility can be achieved,
while in the Milman process, crystallization was unpredictable.
[0084] Moreover, according to the present process, the
precipitation of L-DOPA ethyl ester is in water at an ambient
temperature so that very pure compound is obtained in greater yield
than previously in prior art.
* * * * *