U.S. patent application number 11/376573 was filed with the patent office on 2006-11-30 for process for the preparation of optically active (s)-(+)-n,n-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine.
Invention is credited to Mili Abramov, Santiago Ini, Anita Liberman.
Application Number | 20060270861 11/376573 |
Document ID | / |
Family ID | 36593962 |
Filed Date | 2006-11-30 |
United States Patent
Application |
20060270861 |
Kind Code |
A1 |
Ini; Santiago ; et
al. |
November 30, 2006 |
Process for the preparation of optically active
(S)-(+)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine
Abstract
Diasteromerically enriched salts of (S)-DNTH.sup.+ EPA.sup.- and
(R)-DNTH.sup.+EPA.sup.-, methods of preparing such
diasteromerically enriched salts of (S)-DNTH.sup.+ EPA.sup.- and
(R)-DNTH.sup.+ EPA.sup.-, and methods of preparing enantiomerically
enriched (S)-DNT and enantiomerically enriched (R)-DNT are
provided.
Inventors: |
Ini; Santiago; (Haifa,
IL) ; Abramov; Mili; (Givataim, IL) ;
Liberman; Anita; (Tel-Aviv, IL) |
Correspondence
Address: |
KENYON & KENYON LLP
ONE BROADWAY
NEW YORK
NY
10004
US
|
Family ID: |
36593962 |
Appl. No.: |
11/376573 |
Filed: |
March 14, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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60726502 |
Oct 12, 2005 |
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60736746 |
Nov 14, 2005 |
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60661711 |
Mar 14, 2005 |
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60773593 |
Feb 14, 2006 |
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Current U.S.
Class: |
549/76 |
Current CPC
Class: |
C07D 333/16 20130101;
A61P 13/00 20180101; A61P 25/24 20180101; C07D 333/20 20130101;
A61K 31/38 20130101; A61P 29/00 20180101 |
Class at
Publication: |
549/076 |
International
Class: |
C07D 333/22 20060101
C07D333/22 |
Claims
1. A method of synthesizing (S)-(+)-DNT, comprising: a) treating a
solution of (R,S)-DNT with an H-EPA; b) crystallizing a
diastereomerically enriched salt of (S)-(+)-DNTH.sup.+ EPA.sup.-;
and c) separating the enriched salt.
2. A method of synthesizing (R)-(-)-DNT, comprising: a) treating a
solution of (R,S)-DNT with an H-EPA; b) crystallizing a
diastereomerically enriched salt of (R)-(-)-DNTH.sup.+ EPA.sup.-;
and c) separating the enriched salt.
3. The method of any of claims 1 or 2, wherein the H-EPA is greater
than about 75 percent pure enantiomeric acid.
4. The method of claim 3, wherein the H-EPA is greater than about
85 percent pure enantiomeric acid.
5. The method of claim 4, wherein the H-EPA is greater than about
98 percent pure enantiomeric acid.
6. The method of any of claims 1 or 2, wherein the H-EPA is
selected from the group consisting of di-R-L-sub-tartaric acid,
(R)-(-)-mandelic acid,
(-)-2,3:4,6-Di-O-isopropylidene-2-keto-L-gulonic acid, and the
opposite enantiomerically pure acids.
7. The method of claim 6, wherein the subgroup is selected from the
group consisting of toluoyl, benzoyl, and pyvaloyl.
8. The method of claim 7, wherein the subgroup is toluoyl.
9. The method of any of claims 1 or 2, wherein step a) is performed
in an organic solvent or water.
10. The method of claim 9, wherein the organic solvents is selected
from the group consisting of toluene, ethyl acetate, and
dichloromethane.
11. The method of any of claims 1 or 2, wherein step a) is
performed at a temperature of from about room temperature to about
the reflux temperature of the solvent.
12. The method of claim 11, wherein step a) is performed at a
temperature of from about 50.degree. to about 95.degree. C.
13. The method of claim 11, wherein the heating is for about 5
minutes to about 48 hours.
14. The method of claim 1, wherein step c) is followed by basic
hydrolysis, obtaining enantiomerically enriched (S)-DNT.
15. The method of claim 2, wherein step c) is followed by basic
hydrolysis, obtaining enantiomerically enriched (R)-DNT.
16. A diasteromerically enriched salt of (S)-DNTH.sup.+
EPA.sup.-.
17. The diasteromerically enriched salt of claim 16, wherein the
salt is enriched with greater than about 60 percent of
(S)-DNTH.sup.+ EPA.sup.-.
18. The diasteromerically enriched salt of claim 17, wherein the
salt is enriched with greater than about 75 percent of
(S)-DNTH.sup.+ EPA.sup.-.
19. The diasteromerically enriched salt of claim 18, wherein the
salt is enriched with greater than about 90 percent of
(S)-DNTH.sup.+ EPA.sup.-.
20. The diasteromerically enriched salt of claim 19, wherein the
salt is enriched with greater than about 95 percent of
(S)-DNTH.sup.+ EPA.sup.-.
21. A diasteromerically enriched salt of (R)-DNTH.sup.+
EPA.sup.-.
22. The diasteromerically enriched salt of claim 21, wherein the
salt is enriched with greater than about 60 percent of
(R)-DNTH.sup.+ EPA.sup.-.
23. The diasteromerically enriched salt of claim 22, wherein the
salt is enriched with greater than about 75 percent of
(R)-DNTH.sup.+ EPA.sup.-.
24. The diasteromerically enriched salt of claim 23, wherein the
salt is enriched with greater than about 90 percent of
(R)-DNTH.sup.+ EPA.sup.-.
25. The diasteromerically enriched salt of claim 24, wherein the
salt is enriched with greater than about 98 percent of
(R)-DNTH.sup.+ EPA.sup.-.
26. A process for the racemization of DNT, comprising: a) providing
a mixture of DNT, a polar aprotic solvent, and an alkaline metal
base; b) heating the mixture to a temperature of from about room
temperature to about the reflux temperature of the solvent; and c)
recovering substantially racemic (R,S)-DNT.
27. The process of claim 26, wherein the DNT is enantiomerically
pure or enantiomerically rich.
28. The process of claim 26, wherein the polar aprotic solvent is
selected from the group consisting of dimethyl sulfoxide (DMSO),
dimethyl formamide (DMF), dimethylacetamide (DMA),
1-methyl-2-pyrolidinone (NMP) and hexamethylphosphoramide
(HMPA).
29. The process of claim 28, wherein the polar aprotic solvent is
DMSO.
30. The process of claim 26, wherein the alkaline metal base is
selected from the group consisting of lithium hydride, lithium
N,N-diisopropylamide, sodium hydride, potassium hydride, sodium
hydroxide, potassium hydroxide, sodium amide, potassium amide,
sodium tert-butoxide, sodium methoxide, sodium ethoxide, potassium
tert-butoxide, potassium methoxide, potassium ethoxide. More
preferably, the alkaline metal base is potassium hydroxide or
potassium tert-butoxide.
31. The process of claim 30, wherein the alkaline metal base is
potassium hydroxide or potassium tert-butoxide.
32. The process of claim 26, wherein the mixture is heated to a
temperature of from about 50.degree. to about 140.degree. C.
33. The process of claim 32, wherein the mixture is heated to a
temperature of about 80.degree..
34. The process of claim 26, wherein, after step b), the mixture is
maintained for about fifteen minutes to about 48 hours.
35. The process of claim 34, wherein the mixture is maintained for
about 18 hours.
36. A pharmaceutically acceptable salt of duloxetine prepared by
obtaining the (S)-(+)-DNT in accordance with the method of claim 1,
and converting the (S)-(+)-DNT to a pharmaceutically acceptable
salt of duloxetine.
37. The process of claim 36, wherein the (S)-(+)-DNT is converted
to duloxetine hydrochloride.
Description
RELATED APPLICATIONS
[0001] This application claims benefit of U.S. Provisional
Application Nos. 60/726,502, filed Oct. 12, 2005, 60/736,746, filed
Nov. 14, 2005, 60/661,711, filed Mar. 14, 2005, and 60/773,593,
filed Feb. 14, 2006.
FIELD OF THE INVENTION
[0002] The present invention provides processes for synthesis of
duloxetine intermediate. The present invention also provides
processes for converting these duloxetine intermediate into
pharmaceutically acceptable salts of duloxetine.
BACKGROUND
[0003] Duloxetine is a dual reuptake inhibitor of the
neurotransmitters serotonin and norepinephrine. It is used for the
treatment of stress urinary incontinence (SUI), depression, and
pain management. Duloxetine hydrochloride, CAS Registry No.
136434-34-9, has the chemical structure Formula I. ##STR1##
[0004] An intermediate in the synthesis of duloxetine is
(S)-(+)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine.
The intermediate is also known as (S)-(+)-DNT, has been assigned
the CAS Registry No. 132335-46-7, and has the chemical structure
Formula II. ##STR2##
[0005] U.S. Pat. Nos. 4,956,388 ("the '388 patent") and 5,023,269
("the '269 patent"), incorporated herein by reference in their
entirety, disclose 3-aryloxy-3-substituted propanamines capable of
inhibiting the uptake of serotonin and norepinephrine. The '269
patent describes the preparation of duloxetine by reacting
(S)-(-)-N,N-Dimethyl-3-(2-thienyl)-3-hydroxypropanamine with
fluoronaphtalene (Stage a) to produce
N,N-Dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine (DNT),
followed by demethylation with phenyl chloroformate or
trichloroethyl chloroformate (Stage b) and basic hydrolysis (Stage
c) in accordance with the following Scheme 1. ##STR3##
[0006] U.S. Pat. No. 5,491,243, incorporated herein by reference in
its entirety, discloses a stereospecific process for the synthesis
of (S)-(+)-DNT.
[0007] U.S. Pat. No. 6,541,668, incorporated herein by reference in
its entirety, discloses the preparation of
3-aryloxy-3-arylpropylamines and intermediates thereof using a
nucleophilic aromatic displacement in
1,3-dimethyl-2-imidazolidinone or N-methylpyrrolidinone.
[0008] EP 273,658, which corresponds to the '388 and '269 patents,
and is incorporated herein by reference in its entirety, discloses
3-aryloxy-3-substituted propanamines capable of inhibiting the
uptake of serotonin and norepinephrine.
[0009] Wheeler W. J., et al, J. Label. Cpds. Radiopharm, 1995, 36,
312, incorporated herein by reference in its entirety, discloses
the conversion of duloxetine to its hydrochloride salt.
[0010] The prior art discloses that enantiomerically pure
duloxetine may be prepared by different routes than those shown in
Scheme 1. These prior art routes for preparing enantiomerically
pure duloxetine may be summarized as follows: [0011] a. Chiral
resolution of 3-(Dimethylamino)-1-(2-thienyl)-1-propanol (alcohol a
in Scheme 2), Path A, followed by Path C or D; [0012] b. Asymmetric
reduction of 3-(Dimethylamino)-1-(2-thienyl)-1-propanone (amino
ketone b in Scheme 2), Path B, followed by Path C or D; [0013] c.
Chiral resolution of 3-methylarmino-1-(2-thienyl)-1-propanol
(alcohol c in Scheme 2); and, [0014] d. Chiral resolution of the
racemic duloxetine. ##STR4##
[0015] The drawback of the processes described in Scheme 2 is the
lack of processes for synthesizing an enantiomerically pure DNT and
a racemization process for the reprocessing of the undesirable
enantiomer.
SUMMARY OF THE INVENTION
[0016] The present invention is directed to a method of
synthesizing (S)-(+)-DNT of Formula II. ##STR5## The method of the
invention comprises: (a) treating a solution of (R,S)-DNT with an
enantiomerically pure acid (H-EPA); (b) crystallizing a
diastereomerically enriched salt of (S)-(+)-DNTH.sup.+ EPA.sup.-;
and, (c) separating the enriched salt.
[0017] The present invention also provides a method of synthesizing
(R)-(-)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine
((R)-(-)-DNT) of formula III. ##STR6## The method of the invention
comprises: (a) treating a solution of (R,S)-DNT with an H-EPA; (b)
crystallizing a diastereomerically enriched salt of
(R)-(-)-DNTH.sup.+ EPA.sup.-; and, (c) separating the enriched
crystalline diastereomeric salt.
[0018] In alternative embodiments the invention provides a
diasteromerically enriched salt of (S)-DNTH.sup.+ EPA.sup.- and a
diasteromerically enriched salt of (R)-DNTH.sup.+ EPA.sup.-.
[0019] In a further embodiment, the invention provides a process
for the racemization of DNT. The process comprises providing a
mixture of DNT, a polar aprotic solvent, and an alkaline metal
base, heating the mixture to a temperature of from about room
temperature to the reflux temperature of the solvent, and
recovering substantially racemic (R,S)-DNT.
[0020] The present invention further provides pharmaceutically
acceptable salts of duloxetine, prepared by obtaining (S)-(+)-DNT
as described above, and converting the (S)-(+)-DNT to
pharmaceutically acceptable salts of duloxetine. Preferably the
(S)-(+)-DNT is converted to duloxetine hydrochloride.
DETAILED DESCRIPTION OF THE INVENTION
[0021] Unless stated otherwise, as used herein, the term "percent"
refers to percent by weight.
[0022] The present invention provides a method of synthesizing
(S)-(+)-DNT of formula II. ##STR7## The method comprises: (a)
treating a solution of (R,S)-DNT with an H-EPA; (b) crystallizing a
diastereomerically enriched salt of (S)-(+)-DNTH.sup.+ EPA.sup.-;
and, (c) separating the enriched salt.
[0023] The present invention provides a method of synthesizing
(R)-(-)-DNT of formula III. ##STR8## The method comprises: (a)
treating a solution of racemic DNT with an H-EPA; (b) crystallizing
a diastereomerically enriched salt of (R)-(-)-DNTH.sup.+ EPA.sup.-;
and, (c) separating the enriched crystalline diastereomeric
salt.
[0024] As used herein, "H-EPA" refers to an enantiomerically pure
acid. Preferably, the H-EPA is greater than about 75 percent pure
enantiomeric acid; i.e., the H-EPA comprises greater than about 75
percent of one enantiomer of the enantiomerically pure acid. More
preferably, the H-EPA is greater than about 85 percent pure
enantiomeric acid; i.e., the H-EPA comprises greater than about 85
percent of one enantiomer of the enantiomerically pure acid. Most
preferably, the H-EPA is greater than about 95 percent pure
enantiomeric acid; i.e., the H-EPA comprises greater than about 95
percent of one enantiomer of the enantiomerically pure acid.
[0025] As used herein, "EPA-" refers to the anion of the
corresponding H-EPA. A salt of (S)-(+)-DNT and H-EPA is referred to
as (S)-(+)-DNTH.sup.+ EPA.sup.-. A salt of (R)-(-)-DNT and H-EPA is
referred to as (R)-(-)-DNTH.sup.+ EPA.sup.-.
[0026] Preferred enantiomerically pure acids may be selected from
the group consisting of di-R-L-sub-tartaric acid, (R)-(-)-mandelic
acid and (-)-2,3:4,6-Di-O-isopropylidene-2-keto-L-gulonic acid, and
the opposite enantiomerically pure acids. Preferred subgroups
include, but are not limited to, toluoyl, benzoyl, and pyvaloyl.
Most preferably, the subgroup is toluoyl.
[0027] As used herein, a diasteromerically enriched salt of
(S)-DNTH.sup.+ EPA.sup.- is preferably a salt which is greater than
about 60 percent enriched (S)-DNTH.sup.+ EPA.sup.-. More
preferably, the diasteromerically enriched salt is greater than
about 75 percent enriched (S)-DNTH.sup.+ EPA.sup.-. Even more
preferably, the diasteromerically enriched salt is greater than
about 90 percent enriched (S)-DNTH.sup.+ EPA.sup.-. Most
preferably, the diasteromerically enriched salt is greater than
about 95 percent enriched (S)-DNTH.sup.+ EPA.sup.-.
[0028] As used herein, a diasteromerically enriched salt of
(R)-DNTH.sup.+ EPA.sup.- is preferably a salt which is greater than
about 60 percent enriched (R)-DNTH.sup.+ EPA.sup.-. More
preferably, the diasteromerically enriched salt is greater than
about 75 percent enriched (R)-DNTH.sup.+ EPA.sup.-. Even more
preferably, the diasteromerically enriched salt is greater than
about 90 percent enriched (R)-DNTH.sup.+ EPA.sup.-. Most
preferably, the diasteromerically enriched salt is greater than
about 98 percent enriched (R)-DNTH.sup.+ EPA.sup.-.
[0029] In further embodiments the invention provides a
diasteromerically enriched salt of (S)-DNTH.sup.+ EPA.sup.- and a
diasteromerically enriched salt of (R)-DNTH.sup.+ EPA.sup.-.
[0030] The step of treating a solution of (R,S)-DNT with an H-EPA
may be performed in an organic solvent or water. Preferred organic
solvents may be selected from the group consisting of toluene,
ethyl acetate, and dichloromethane.
[0031] The step of treating a solution of (R,S)-DNT with an H-EPA
may also comprise a step of treating a solution of (R,S)-DNT with
H-EPA at a temperature of from about room temperature to about the
reflux temperature of the solvent, preferably at a temperature of
from about 50.degree. to about 95.degree. C. Preferably, the
heating is for about 5 minutes to about 48 hours.
[0032] Preferably, the step of separating the enriched crystalline
diastereomeric salt comprises a step of filtration.
[0033] A preferred embodiment embraces a process whereby (R,S)-DNT
is reacted with an H-EPA to form a diasteromerically enriched salt.
Separation of the salt followed by basic hydrolysis results in
enantiomerically enriched (S)-DNT and enantiomerically enriched
(R)-DNT accordingly. This process is illustrated in Scheme 3.
##STR9##
[0034] In a further embodiment, the invention provides a process
for the racemization of DNT. The process comprises providing a
mixture of DNT, a polar aprotic solvent, and an alkaline metal
base, heating the mixture to a temperature of from about room
temperature to about the reflux temperature of the solvent, and
recovering substantially racemic (R,S)-DNT. The DNT used in the
process of the invention can be either enantiomerically pure or
enantiomerically rich.
[0035] Preferably, the polar aprotic solvent is selected from the
group consisting of dimethyl sulfoxide (DMSO), dimethyl formamide
(DMF), dimethylacetamide (DMA), 1-methyl-2-pyrolidinone (NMP) and
hexamethylphosphoramide (HMPA). More preferably, the polar aprotic
solvent is DMSO.
[0036] Preferably, the alkaline metal base is selected from the
group consisting of lithium hydride, lithium N,N-diisopropylamide,
sodium hydride, potassium hydride, sodium hydroxide, potassium
hydroxide, sodium amide, potassium amide, sodium tert-butoxide,
sodium methoxide, sodium ethoxide, potassium tert-butoxide,
potassium methoxide, potassium ethoxide. More preferably, the
alkaline metal base is potassium hydroxide or potassium
tert-butoxide.
[0037] Preferably, the mixture is heated to a temperature of from
about 50.degree. to about 140.degree. C., and, more preferably, to
about 80.degree.. Preferably, after heating, the mixture is
maintained for about fifteen minutes to about 48 hours, and, more
preferably, the mixture is maintained for about 18 hours. The
racemic (R,S)-DNT may be recovered by any methods known in the
art.
[0038] The present invention further provides pharmaceutically
acceptable salts of duloxetine prepared by obtaining (S)-(+)-DNT as
described above, and converting the (S)-(+)-DNT to pharmaceutically
acceptable salts of duloxetine. Preferably, the (S)-(+)-DNT is
converted to duloxetine hydrochloride.
[0039] The function and advantage of these and other embodiments of
the present invention will be more fully understood from the
examples below. These examples are intended to illustrate the
benefits of the present invention, but are not intended to limit
the scope of the invention.
EXAMPLES
Example 1
Preparation of (S)-DNT di-p-toluoyl-L-tartarate in toluene
[0040] A 1.24 g portion of di-p-toluoyl-L-tartaric acid was added
to a solution of 2 g (R,S)-DNT in 10 ml of toluene. The resulting
mixture was heated to 75.degree. C. for 10 minutes, and then cooled
to room temperature. The resulting solid was filtered, and dried in
a vacuum oven to give 1.15 g of (S)-DNT
di-p-toluoyl-L-tartarate.
Example 2
Preparation of (S)-DNT di-p-toluoyl-L-tartarate in EtOAc/Ether
[0041] A 1.24 g portion of di-p-toluoyl-L-tartaric acid was added
to a solution of 2 g (R,S)-DNT in 10 ml of ethyl acetate, and the
resulting mixture was stirred at room temperature for an hour. The
addition of 6 ml of ether resulted in a precipitate. The mixture
was then heated to reflux, and an additional 20 ml of ethyl acetate
were added. The mixture was cooled to room temperature, filtered,
washed with 10 ml of ether, and dried in a vacuum oven to give 1.41
g of (S)-DNT di-p-toluoyl-L-tartarate.
Example 3
Preparation of (S)-DNT
[0042] A solution of 10 percent by weight NaOH was added to a
mixture of 1 g of (S)-DNT di-p-toluoyl-L-tartarate in 30 ml of
water and 30 ml of dichloromethane to provide a pH of 14, and
stirred for an hour. After phase separation, the organic phase was
washed with water (30 ml), dried over Na.sub.2SO.sub.4, filtered,
and concentrated to dryness to give 0.4 g of brownish oil (62.17
percent ee).
Example 4
Preparation of (S)-DNT-(R)-mandelate in water
[0043] A 0.49 g portion of (R)-mandelic acid was added to a mixture
of 2 g of (R,S)-DNT in 15 ml of water, and the mixture was heated
to 95.degree. C., followed by cooling to room temperature over a
period of 2 hours. The solid was filtered out, and the mother
liquor was allowed to stand overnight. The resulting solid was
filtered out, and the resulting solution analyzed by HPLC giving 45
percent ee of (S)-DNT-(R)mandelate.
Example 5
Preparation of (S)-DNT di-p-toluoyl-L-tartarate in toluene
[0044] A 6.2 g portion of Di-p-toluoyl-L-tartaric acid was added to
a solution of 10 g (R,S)-DNT in 100 ml of toluene. The resulting
mixture was heated to 75.degree. C. for 30 minutes, and then cooled
to room temperature. The resulting solid was filtered, and dried in
a vacuum oven to give 5.13 g of (S)-DNT di-p-toluoyl-L-tartarate
(ee: 77%).
Example 6
Preparation of (S)-DNT di-p-toluoyl-L-tartarate in toluene
[0045] A 0.72 g portion of di-p-toluoyl-L-tartaric acid was added
to a solution of 1.16 g (R,S)-DNT (ee: 77%) in 11.6 ml of toluene.
The resulting mixture was heated to 75.degree. C. for 20 minutes,
and then cooled to room temperature. The resulting solid was
filtered, and dried in a vacuum oven to give 1.1 g of (S)-DNT
di-p-toluoyl-L-tartarate (ee: 98%).
Example 7
Racemization of (S)-DNT with KOH
[0046] A 5.3 g sample of KOH was added to a solution of 55 g of
enantiomerically pure DNT (ee: 99.80%) dissolved in 50 ml of DMSO,
and the resulting mixture was heated to 80.degree. C. After six
hours, the mixture was cooled to room temperature. Water was added
to the reaction mixture, followed by the addition of ethyl acetate
and AcOH in an amount sufficient to provide a pH of from 8 to 9.
After phase separation, the water phase was extracted with ethyl
acetate, and the organic extracts were combined and concentrated to
dryness to give brownish oil with an ee less than 1%.
Example 8
Racemization of (S)-DNT with potassium tert-butoxide
[0047] A 2.7 g sample of KtBuO was added to a solution of 3.74 g of
enantiomerically pure DNT (ee: 99.80%) dissolved in 37 ml of DMSO,
and the resulting mixture was heated to 60.degree. C. After
eighteen hours, the mixture was cooled to room temperature. Water
was added to the reaction mixture, followed by the addition of
ethyl acetate and AcOH in an amount sufficient to provide a pH of
from 8 to 9. After phase separation, the water phase was extracted
with ethyl acetate, and the organic extracts were combined and
concentrated to dryness to give brownish oil with an ee less than
1%.
Example 9
Racemization of (R)-DNT with KOH
[0048] An 8.4 g sample of KOH was added to a solution of 7.5 g of
enantiomerically rich DNT dissolved in 75 ml of DMSO, and the
resulting mixture was heated to 80.degree. C. After six hours, the
mixture was cooled to room temperature. Water was added to the
reaction mixture, followed by the addition of ethyl acetate and
AcOH in an amount sufficient to provide a pH of from 8 to 9. After
phase separation, the water phase was extracted with ethyl acetate,
and the organic extracts were combined and concentrated to dryness
to give brownish oil with an ee less than 1%.
[0049] While it is apparent that the invention disclosed herein is
well calculated to fulfill the objects stated above, it will be
appreciated that numerous modifications and embodiments may be
devised by those skilled in the art. Therefore, it is intended that
the appended claims cover all such modifications and embodiments as
falling within the true spirit and scope of the present
invention.
* * * * *