U.S. patent application number 11/249331 was filed with the patent office on 2006-02-23 for process for the production of optically active 3-phenylisoserine.
This patent application is currently assigned to ALTANA PHARMA AG. Invention is credited to Wijnand Faber, Jan Koek, Jorg Senn-Bilfinger, Ton Vries.
Application Number | 20060041163 11/249331 |
Document ID | / |
Family ID | 8177924 |
Filed Date | 2006-02-23 |
United States Patent
Application |
20060041163 |
Kind Code |
A1 |
Faber; Wijnand ; et
al. |
February 23, 2006 |
Process for the production of optically active
3-phenylisoserine
Abstract
The invention relates to a process for preparation of (R,
R)-3-phenylisoserine and its derivates.
Inventors: |
Faber; Wijnand; (Groningen,
NL) ; Koek; Jan; (Sauwerd, NL) ;
Senn-Bilfinger; Jorg; (Konstanz, DE) ; Vries;
Ton; (Groningen, NL) |
Correspondence
Address: |
Gary M. Nath;NATH & ASSOCIATES PLLC
6th Fl.
1030 15th St. N.W.
Washington
DC
20005-1503
US
|
Assignee: |
ALTANA PHARMA AG
|
Family ID: |
8177924 |
Appl. No.: |
11/249331 |
Filed: |
October 14, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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10482483 |
Dec 31, 2003 |
|
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PCT/EP02/07092 |
Jun 27, 2002 |
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11249331 |
Oct 14, 2005 |
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Current U.S.
Class: |
560/129 ;
562/401 |
Current CPC
Class: |
C07C 227/06 20130101;
C07C 227/34 20130101; C07C 229/36 20130101; C07C 227/06
20130101 |
Class at
Publication: |
560/129 ;
562/401 |
International
Class: |
C07C 227/34 20060101
C07C227/34 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 3, 2001 |
EP |
01116083.5 |
Claims
1-8. (canceled)
9. A process for the production of 3-phenylisoserine or a salt or a
1-4C-alkyl ester thereof, which comprises a. reacting a
3-phenylglycidic acid salt with ammonia, b. obtaining a
3-phenylisoserine salt, and c. optionally converting the
3-phenylisoserine salt into 3-phenylisoserine or into
3-phenylisoserine 1-4C-alkyl ester.
10. The process according to claim 9, wherein the 3-phenylglycidic
acid salt is the sodium salt.
11. The process according to claim 9, wherein the reaction with
ammonia is carried out in a protic solvent, with an ammonia
concentration of about 15 to 33% and at a temperature between 25
and 75.degree. C.
Description
TECHNICAL FIELD
[0001] The invention relates to a process for the production of
3-phenylisoserine and its derivatives in high optical purity.
3-Phenylisoserine is a valuable intermediate in the production of
pharmaceuticals.
PRIOR ART
[0002] Known processes for the production of 3-phenylisoserine and
its derivatives in high optical purity are not suited for the
production of these compounds on an industrial scale.
SUMMARY OF THE INVENTION
[0003] It has been found, surprisingly, that the process described
in more detail below is suited to produce 3-phenylisoserine and its
derivatives in high optical purity on an industrial scale.
[0004] The process according to the invention includes mainly two
steps: (a) The production of racemic 3-phenylisoserine or a
derivative thereof and (b) its separation into the enantiomers. The
inventive process is contained in--and can be summarised exemplary
by--the following reaction scheme: ##STR1##
[0005] The reaction scheme shall serve as a brief description of
the invention without restricting it to the details given eg on the
reaction arrows. In the scheme, it is understood that the phenyl
ring and the carboxylic group attached to the oxirane ring are in
trans position to each other. In the last formula of the scheme,
(R, R)-3-phenylisoserine ethyl ester is shown as reaction product
when using L-(+)-tartaric acid as optical resolution agent.
Likewise, D-(-)-tartaric acid can be used in order to obtain (S,
S)-3-phenylisoserine ethyl ester in high optical purity.
DETAILED DESCRIPTION OF THE INVENTION
[0006] Subject matter of the invention is a process for the
production of (R, R)-3-phenylisoserine including its 1-4C-alkyl
esters which comprises [0007] reacting a 3-phenylglycidic acid salt
with ammonia to yield the salt of racemic 3-phenylisoserine, [0008]
converting the salt of racemic 3-phenylisoserine to racemic
3-phenylisoserine 1-4C-alkyl ester and [0009] separating the (R,
R)-3-phenylisoserine 1-4C-alkyl ester from the racemate by reacting
the latter with L (+)-tartaric acid and working the salt obtained
for (R, R)-phenylisoserine 1-4C-alkyl ester.
[0010] Likewise, subject matter of the invention is a process for
the production of (S, S)-3-phenylisoserine including its 1-4C-alkyl
esters which comprises the above reaction steps but using
D-(-)-tartaric add instead of L-(+)-tartaric acid.
[0011] As possible salts of the 3-phenylglycidic acid,
alkaline-earth metal salts and in particular alkali metal salts
have to be mentioned, the potassium and in particular the sodium
salt being preferred.
[0012] The reaction of the 3-phenylglycidic acid salt with ammonia
is carried out preferably in a protic solvent, in particular in
water, with an ammonia concentration of about 15 to 33%, preferably
with an ammonia concentration of about 20 to 30%, in particular
with an ammonia concentration of about 25%, at a temperature
between 25 to 75.degree. C., preferably at a temperature between 35
and 65.degree. C., in particular at a temperature between 45 and
55.degree. C. Under the noted conditions, the reaction leads
surprisingly mainly to the desired product.
[0013] The esterification can be carried out according to known
processes, e.g. with thionyl chloride or with hydrogen chloride and
the 1-4C-alkyl alcohol the ester of which is desired. The reaction
is carried out under conditions as they are known to the expert,
for example by using the 1-4C-alkyl alcohol as the solvent and by
adding thionyl chloride dropwise at temperatures of <10.degree.
C. or by passing hydrogen chloride gas through the solution.
[0014] The reaction of the L-(+)-tartaric add in an appropriate
solvent, in particular in the absolute 1-4C-alkyl alcohol
corresponding to the racemic 3-phenylisoserine 1-4C-alkyl ester,
leads to the tartrate of the racemic 3-phenylisoserine 1-4C-alkyl
ester, the (R, R)-form of which surprisingly crystallises in high
optical purity. The (R, R)-3-phenylisoserine and its derivatives
(like esters, salts, amides etc.) can thus be obtained simply and
in an optical purity which up to now was not achievable on an
industrial scale.
[0015] The following examples serve to illustrate the invention
further without restricting it. The abbreviation min stands for
minute(s), h for hour(s), ee for enantiomeric excess, m.p. for
melting point and RT for room temperature.
EXAMPLES
1. Sodium-3-phenylglycidate
[0016] a) 122.6 g (5.33 mol) of sodium are added in portions to
2620 mL of methanol. The sodium methoxide solution is then cooled
below 0.degree. C. and a mixture of 250 ml (2.47 mol) of
benzaldehyde and 233 ml (2.66 mol) of chloro-acetic add methyl
ester are added drop by drop, while temperature is kept below
0.degree. C. After addition, the reaction mixture is stirred for 30
minutes at 0.degree. C. and then for 2 h without cooling thus
allowing the temperature to rise to RT. The precipitated sodium
chloride is filtered off and discarded. To the mother liquor 49.0
ml (2.72 mol) of water are added drop by drop and the mixture is
stirred overnight. The product is filtered off, rinsed with some
methanol and dried in vacuo. 416 g (2.23 mol; 90%) of the title
compound are obtained as white solid of m.p. >275.degree. C.
(decomposition).
[0017] b) Alternatively, 382.4 g (9.57 mol) of sodium hydroxide are
added in portions to a slurry of 2000 g (9.57 mol) of commercial
available ethyl-3-phenylglycidate (92% pure) in 12 L of methanol,
while the temperature is kept below 30.degree. C. The mixture is
stirred for 2 h. The obtained precipitate is collected and rinsed
with 2 L of methanol and dried on air to give 1523 g (8.18 mol;
85%) of the title compound as white solid of m.p. >275.degree.
C. (decomposition).
2. 3-Phenylisoserine (rac.) Sodium Salt
[0018] 1000 g (537 mol) of sodium-3-phenylglycidate are stirred in
10 L of 25% ammonia (aq.) for 18 h at 50.degree. C. The solvent is
removed under reduced pressure and the resulting slurry is
co-evaporated three times with toluene to remove the last traces of
water. 1036 g (5.1 mol; 95%) of the title compound are obtained as
white solid.
3. 3-Phenylisoserine (rac.) Ethyl Ester
[0019] a) 1036 g (5.1 mol) of 3-phenylisoserine (rac.) sodium salt
are stirred in 6000 ml of absolute ethanol. 1047 ml of thionyl
chloride are added drop by drop while keeping the temperature below
20.degree. C. The mixture is refluxed for 4 h and stirred overnight
while the temperature is allowed to cool to RT. The volatiles are
removed in vacuo and the resulting slurry is co-evaporated with
tetrahydrofuran. The obtained hydrochloride of the title compound
(white solid) is stirred in 8560 ml of tetrahydrofuran (suspension)
and 2460 ml of triethylamine are added drop by drop. The suspension
is stirred for further 5 h. The triethylamine hydrochloride is
filtered off, washed with tetrahydrofuran and discarded. The
combined solutions are concentrated in vacuo. 951 g (4.54 mol;
94.7%) of the title compound are obtained as right yellow oil.
[0020] b) Alternatively, the title compound is obtained as follows:
50 g (0.25 mol) of 3-phenylisoserine sodium salt are suspended in
500 ml of absolute ethanol. HCl gas is passed through the
suspension, which turns into milk white solution in an exothermic
reaction. The HCl gas stream is stopped and the reaction mixture is
refluxed for 3 hours. After cooling the reaction mixture to room
temperature, the excess of HCl is stripped off under vacuum. The
ethanol and water is evaporated and co-evaporated from the residue
after addition of 100 ml of THF. The obtained residue is suspended
in 450 ml of THF, and 125 ml (91 g, 0.90 mol) of triethylamine are
added dropwise to the suspension. The reaction mixture is left
overnight and filtered over a buchner funnel. Finally the filtrate
is evaporated and 48.1 g (96.9%) of yellow oil is obtained which
slowly crystallises.
[0021] 4. (R, R)-3-Phenylisoserine Ethyl Ester
[0022] 951.4 g (4.54 mol) of 3-phenylisoserine (rac.) ethyl ester
are dissolved in 8020 ml of absolute ethanol and heated at
50.degree. C. 681.4 g (4.54 mol) of L-(+)-tartaric acid are added
and a clear solution is obtained. The mixture is heated with
stirring under reflux. Before reflux temperature is reached,
crystallisation of the salt starts. The mixture is allowed to cool
to RT while stirring for 10 h and is then cooled to 10.degree. C.
The precipitate is filtered off, rinsed with 2 L of absolute
ethanol and dried to yield 38.3% of the title compound with ee of
84.8%. After re-crystallisation of the salt in 9780 ml of absolute
ethanol and 978 ml of water, 438 g (1.22 mol; 26.8%) of the
tartrate of the title compound with ee of 98.6% and m.p.
162.0-162.3.degree. C. are obtained. -844 g (2.35 mol) of the salt
obtained are stirred in 5 L of ethyl acetate. 430 mL of 25% aqueous
ammonia solution (6.3 mol) are added in thr course of 5 minutes.
The mixture is stirred for 1 h. After stopping the stirring, the
new precipitate formed (diammonium tartrate) is allowed to deposit.
The ethyl acetate layer is decanted. The ammonium salt is washed
and decanted twice with each time 800 mL of ethyl acetate. The
three ethyl acetate layers are combined and evaporated. 485 g (2.32
mol, 99%) of the title compound of m.p. 92.1-94.1.degree. C. are
obtained as white solid.
[0023] Optical rotation: [.alpha.].sub.D.sup.20=14.8.degree. (c=1,
ethanol.
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