U.S. patent application number 11/376574 was filed with the patent office on 2006-11-16 for (s)-n,n-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl) propanamine-di-p-toluoyl-l-tartarate and methods of preparation thereof.
Invention is credited to Mili Abramov, Santiago Ini, Tamas Koltai.
Application Number | 20060258871 11/376574 |
Document ID | / |
Family ID | 36593962 |
Filed Date | 2006-11-16 |
United States Patent
Application |
20060258871 |
Kind Code |
A1 |
Ini; Santiago ; et
al. |
November 16, 2006 |
(S)-n,n-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)
propanamine-di-p-toluoyl-l-tartarate and methods of preparation
thereof
Abstract
The invention provides
(S)-N,N-Dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine-Di-p-tolu-
oyl-L-tartarate (DNT-L-pTTA), which can be used as an intermediate
in the preparation of duloxetine hydrochloride, processes for the
preparation of DNT-L-pTTA, a crystalline form of DNT-L-pTTA, and
processes for the preparation of duloxetine hydrochloride form
DNT-L-pTTA.
Inventors: |
Ini; Santiago; (Haifa,
IL) ; Koltai; Tamas; (Netanya, IL) ; Abramov;
Mili; (Givataim, IL) |
Correspondence
Address: |
KENYON & KENYON LLP
ONE BROADWAY
NEW YORK
NY
10004
US
|
Family ID: |
36593962 |
Appl. No.: |
11/376574 |
Filed: |
March 14, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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60661711 |
Mar 14, 2005 |
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60761905 |
Jan 24, 2006 |
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60771071 |
Feb 6, 2006 |
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60773593 |
Feb 14, 2006 |
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Current U.S.
Class: |
549/76 |
Current CPC
Class: |
A61K 31/38 20130101;
A61P 29/00 20180101; A61P 25/24 20180101; A61P 13/00 20180101; C07D
333/20 20130101; C07D 333/16 20130101 |
Class at
Publication: |
549/076 |
International
Class: |
C07D 333/22 20060101
C07D333/22 |
Claims
1.
(S)-N,N-Dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine-Di-p-t-
oluoyl-L-tartarate (DNT-L-pTTA).
2. The DNT-L-pTTA of claim 1, characterized by data selected from:
.sup.1H NMR (400 MHz, CDCl3 d6) .delta.(ppm): 8.26 (m, 1H), 7.99
(d, J=8.2 Hz, 4H), 7.81 (m, 1H), 7.51 (m, 2H), 7.42 (d, J=8.3 Hz,
1H), 7.26 (t, J=8.0 Hz, 1H), 7.17 (m, 1H), 7.07 (d, J=3.2 Hz, 1H),
6.89 (t, J=3.9 Hz, 1H), 6.84 (d, J=7.7 Hz, 1H), 5.88 (s, 2H), 5.79
(m, 1H), 3.20 (m, 2H), 2.75 (s, 6H), 2.58 (m, 2H), 2.37 (s, 6H);
13C {1H}NMR (100 MHz): .delta. 170.5, 165.7, 152.3, 143.6, 142.7,
134.5, 130.0, 128.9, 127.5, 126.9, 126.8, 126.3, 125.7, 125.5,
125.3, 125.0, 121.6, 121.0, 107.2, 73.3, 72.6, 54.6, 43.0, 38.6,
33.0, 21.5; and FAB MS: m/z 312 ([M-H]+, 100%).
3. A crystalline form of DNT-L-pTTA, characterized by a powder XRD
pattern having peaks at about 5.5.degree., 13.9.degree.,
17.7.degree., 19.9.degree., and 22.8.degree.
2.theta..+-.0.2.degree. 2.theta..
4. The crystalline form of claim 3, further characterized by a
powder XRD pattern having peaks at about 10.2.degree.,
15.1.degree., 16.9.degree., 18.9.degree., and 24.2.degree.
2.theta..+-.0.2.degree. 2.theta..
5. The crystalline form of claim 4, characterized by an X-ray
powder diffraction pattern substantially as depicted in FIG. 1.
6. A process for preparing the DNT-L-pTTA of claim 1, comprising a.
providing a mixture of Di-p-toluoyl-L-tartaric acid and a solution
of DNT in a solvent selected from a group consisting of C.sub.1-8
alcohols, C.sub.3-8 esters, C.sub.2-8 ethers, C.sub.3-8 ketones,
C.sub.6-12 aromatics hydrocarbons and acetonitrile; b. maintaining
the mixture until a precipitate is formed; and c. recovering the
DNT-L-pTTA.
7. The process of claim 6, wherein the DNT-L-pTTA obtained is a
crystalline form of DNT-L-pTTA, characterized by a powder XRD
pattern having peaks at about 5.5.degree., 13.9.degree.,
17.7.degree., 19.9.degree., and 22.8.degree.
2.theta..+-.0.2.degree. 2.theta..
8. The process of claim 6, wherein the solvent is selected from a
group consisting of C.sub.4-6 alcohols, C.sub.4-6 esters, C.sub.4-6
ethers, and C.sub.3-8 ketones.
9. The process of claim 8, wherein the solvent is selected from a
group consisting of n-BuOH, acetone, ethyl acetate, and MTBE.
10. The process of claim 6, wherein the mixture is maintained while
stirring at about room temperature for about 1 hour.
11. The process of claim 6, wherein the solution of DNT contains a
first molar amount of enantiomer R of DNT, and the precipitate
contains a second molar amount of enantiomer R of DNT-L-pTTA, and
wherein the second molar amount is less than the first molar
amount.
12. The process of claim 11, wherein the second molar amount is at
least about 60 percent less than the first molar amount.
13. The process of claim 12, wherein the second molar amount is at
least about 80 percent less than the first molar amount.
14. The process of claim 13, wherein the second molar amount is at
least about 90 percent less than the first molar amount.
15. The process of claim 14, wherein the second molar amount is at
least about 99.8 percent less than the first molar amount.
16. A process for preparing enantiomerically pure DNT, comprising:
a. combining the DNT-L-pTTA of claim 1, water, base, and toluene to
obtain a two phase system; and b. separating the organic phase
containing enantiomerically pure DNT and toluene.
17. The process of claim 16, wherein the DNT-L-pTTA is a
crystalline form of DNT-L-pTTA, characterized by a powder XRD
pattern having peaks at about 5.5.degree., 13.9.degree.,
17.7.degree., 19.9.degree., and 22.8.degree.
2.theta..+-.0.2.degree. 2.theta..
18. Pharmaceutically acceptable salts of duloxetine prepared by
obtaining the DNT-L-pTTA of claim 1, and converting the DNT-L-pTTA
to pharmaceutically acceptable salts of duloxetine.
19. The process of claim 18, wherein the DNT-L-pTTA is converted to
duloxetine hydrochloride.
Description
[0001] This application claims benefit of U.S. Provisional
Application Nos. 60/661,711 filed Mar. 14, 2005, 60/761,905 filed
Jan. 24, 2006, 60/771,071 filed Feb. 6, 2006 and 60/773,593 filed
Feb. 14, 2006, the contents of which are incorporated herein by
reference.
FIELD OF THE INVENTION
[0002] The present invention relates to
DNT-Di-p-toluoyl-L-tartarate, an intermediate for the synthesis of
Duloxetine, and the solid state chemistry of
DNT-Di-p-toluoyl-L-tartarate. The present invention also provides
processes for converting the DNT-Di-p-toluoyl-L-tartarate into
pharmaceutically acceptable salts of duloxetine.
BACKGROUND OF THE INVENTION
[0003] Duloxetine HCl 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 has the chemical name
(S)-(+)-N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine
hydrochloric acid salt and the following structure. ##STR1##
[0004] Duloxetine, as well as processes for its preparation is
disclosed in U.S. Pat. No. 5,023,269 (US '269). EP Patent No.
457559 (EP '559), and U.S. Pat. No. 5,491,243 (US '243) and U.S.
Pat. No. 6,541,668 provide synthetic routes for the preparation of
duloxetine. US '269 describes the preparation of duloxetine by
reacting (S)-(-)-N,N-Dimethyl-3-(2-thienyl)-3-hydroxypropanamine
with fluoronaphtalene (Stage a), followed by demethylation with
Phenyl chloroformate or trichloroethyl chloroformate (Stage b) and
basic hydrolysis (Stage c) according the following scheme.
##STR2##
[0005] The conversion of duloxetine to its hydrochloride salt is
described in U.S. Pat. No. 5,491,243 and in Wheeler W. J., et al,
J. Label. Cpds. Radiopharm, 1995, 36, 312. In both cases the
reactions are performed in ethyl acetate.
[0006] EP '559 discloses the conversion of DNT-Oxal to DNT-base
with sodium hydroxide. The use of oxalic acid results in the
formation of very toxic substances.
[0007] There is a need in the art for an improved synthetic process
for the preparation of duloxetine HCl.
[0008] Stereochemical purity is of importance in the field of
pharmaceuticals, where many of the most prescribed drugs exhibit
chirality, and the two isomers exhibit different potency.
Furthermore, optical purity is important since certain isomers may
actually be deleterious rather than simply inert. Therefore, there
is a need to obtain the desired enantiomer of duloxetine HCl in
high enantiomeric purity.
[0009] Polymorphism, the occurrence of different crystal forms, is
a property of some molecules and molecular complexes. A single
molecule of a compound, such as DNT-Di-p-toluoyl-L-tartarate, may
give rise to a variety of crystalline forms, having distinct
crystal structures and physical properties, such as melting point,
X-ray diffraction pattern, infrared absorption fingerprint, and
solid state NMR spectrum. One crystalline form may give rise to
thermal behavior different from that of another crystalline form.
Thermal behavior can be measured in the laboratory by such
techniques as capillary melting point, thermogravimetric analysis
("TGA"), and differential scanning calorimetry ("DSC"), which have
been used to distinguish polymorphic forms.
[0010] The difference in the physical properties of different
crystalline forms results from the orientation and intermolecular
interactions of adjacent molecules or complexes in the bulk solid.
Accordingly, polymorphs are distinct solids sharing the same
molecular formula yet having distinct advantageous physical
properties compared to other crystalline forms of the same compound
or complex.
SUMMARY OF THE INVENTION
[0011] In one embodiment, the present invention provides
(S)-N,N-Dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine-Di-p-tolu-
oyl-L-tartarate (DNT-L-pTTA) represented by the formula
C.sub.39H.sub.39NO.sub.9S and the structure ##STR3##
[0012] DNT-L-pTTA may also exist in a crystalline form. The
crystalline form is characterized by data selected from: .sup.1H
NMR (400 MHz, CDCl3 d6) .delta.(ppm): 8.26 (m, 1H), 7.99 (d, J=8.2
Hz, 4H), 7.81 (m, 1H), 7.51 (m, 2H), 7.42 (d, J=8.3 Hz, 1H), 7.26
(t, J=8.0 Hz, 1H), 7.17 (m, 1H), 7.07 (d, J=3.2 Hz, 1H), 6.89 (t,
J=3.9 Hz, 1H), 6.84 (d, J=7.7 Hz, 1H), 5.88 (s, 2H), 5.79 (m, 1H),
3.20 (m, 2H), 2.75 (s, 6H), 2.58 (m, 2H), 2.37 (s, 6H); 13C {1H}NMR
(100 MHz): .delta. 170.5, 165.7, 152.3, 143.6, 142.7, 134.5, 130.0,
128.9, 127.5, 126.9, 126.8, 126.3, 125.7, 125.5, 125.3, 125.0,
121.6, 121.0, 107.2, 73.3, 72.6, 54.6, 43.0, 38.6, 33.0, 21.5; and
FAB MS: m/z 312 ([M-H]+, 100%).
[0013] In another embodiment, the present invention provides a
crystalline form of DNT-L-pTTA, herein defined as Form 01,
characterized by a powder XRD pattern having peaks at about
5.5.degree., 13.9.degree., 17.7.degree., 19.9.degree., and
22.8.degree. 2.theta..+-.0.2.degree. 2.theta..
[0014] In another embodiment, the present invention provides a
process for preparing DNT-L-pTTA, comprising providing a mixture of
Di-p-toluoyl-L-tartaric acid and a solution of DNT in a solvent
selected from a group consisting of C.sub.1-8 alcohols, C.sub.3-8
esters, C.sub.2-8 ethers, C.sub.3-8 ketones, C.sub.6-12 aromatics
hydrocarbons, and acetonitrile; maintaining the mixture until a
precipitate is formed, and recovering the DNT-L-pTTA.
[0015] In another embodiment, the invention provides a process for
preparing enantiomerically pure DNT, comprising combining
DNT-L-pTTA, water, base, and toluene to obtain a two phase system,
and separating the organic phase containing enantiomerically pure
DNT and toluene.
[0016] The present invention further provides pharmaceutically
acceptable salts of duloxetine prepared by obtaining DNT-L-pTTA, as
described above, and converting the DNT-L-pTTA to pharmaceutically
acceptable salts of duloxetine. Preferably, the DNT-L-pTTA is
converted to duloxetine hydrochloride.
BRIEF DESCRIPTION OF THE FIGURE
[0017] FIG. 1 illustrates the powder X-ray diffraction pattern for
DNT-L-pTTA Form 01.
DETAILED DESCRIPTION OF THE INVENTION
[0018] As used herein, the terms "DNT" or "DNT-base" refer to the
compound
(S)-N,N-Dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine,
having at least 2.3% (mol%) of the enantiomer R.
[0019] Wherein the DNT has less than about 2.3% of the enantiomer
R, the DNT is "enantiomerically pure DNT". Preferably, the
enantiomerically pure DNT has less than 1.5% of the enantiomer R,
more preferably less than 0.4% of the enantiomer R.
[0020] In one embodiment, the present invention provides
(S)-N,N-Dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)
propanamine-Di-p-toluoyl-L-tartarate (DNT-L-pTTA), represented by
the formula C.sub.39H.sub.39NO.sub.9S and the structure:
##STR4##
[0021] DNT-L-pTTA may also exist in a crystalline form. The
crystalline form is characterized by data selected from: .sup.1H
NMR (400 MHz, CDCl3 d6) .delta.(ppm): 8.26 (m, 1H), 7.99 (d, J=8.2
Hz, 4H), 7.81 (m, 1H), 7.51 (m, 2H), 7.42 (d, J=8.3 Hz, 1H), 7.26
(t, J=8.0 Hz, 1H), 7.17 (m, 1H), 7.07 (d, J=3.2 Hz, 1H), 6.89 (t,
J=3.9 Hz, 1H), 6.84 (d, J=7.7 Hz, 1H), 5.88 (s, 2H), 5.79 (m, 1H),
3.20 (m, 2H), 2.75 (s, 6H), 2.58 (m, 2H), 2.37 (s, 6H); 13C {1H}NMR
(100 MHz): .delta. 170.5, 165.7, 152.3, 143.6, 142.7, 134.5, 130.0,
128.9, 127.5, 126.9, 126.8, 126.3, 125.7, 125.5, 125.3, 125.0,
121.6, 121.0, 107.2, 73.3, 72.6, 54.6, 43.0, 38.6, 33.0, 21.5; and
FAB MS: m/z 312 ([M-H]+, 100%).
[0022] In another embodiment, the present invention provides a
crystalline form of DNT-L-pTTA, herein defined as Form 01,
characterized by a powder XRD pattern having peaks at about
5.5.degree., 13.9.degree., 17.7.degree., 19.9.degree., and
22.8.degree.2.nu..+-.0.2.degree. 2.theta.. The crystalline form may
be further characterized by an X-ray powder diffraction pattern
having peaks at about 10.2.degree., 15.1.degree., 16.9.degree.,
18.9.degree., and 24.2.degree. 2.theta..+-.0.2.degree. 2.theta..
The crystalline form may be further characterized by an X-ray
powder diffraction pattern substantially as depicted in FIG. 1.
[0023] Preferably, the crystalline form 01 of DNT-L-pTTA has a
maximum particle size of less than about 500 .mu.m, more
preferably, less than about 300 .mu.m, more preferably, less than
about 200 .mu.m, more preferably, less than about 100 .mu.m, and,
most preferably, less than about 50 .mu.m.
[0024] The particle size of DNT-L-pTTA crystalline forms may be
measured by methods, including, but not limited to, sieves,
sedimentation, electrozone sensing (coulter counter), microscopy,
and Low Angle Laser Light Scattering (LALLS).
[0025] In another embodiment, the present invention provides a
process for preparing DNT-L-pTTA, comprising providing a mixture of
Di-p-toluoyl-L-tartaric acid and a solution of DNT in a solvent
selected from the group consisting of C.sub.1-8 alcohols, C.sub.3-8
esters, C.sub.2-8 ethers, C.sub.3-8 ketones, C.sub.6-12 aromatics
hydrocarbons and, acetonitrile; maintaining the mixture until a
precipitate is formed, and recovering the DNT-L-pTTA.
[0026] Preferably, the obtained DNT-L-pTTA is crystalline Form
01.
[0027] Preferably, the solvent is selected from a group consisting
of C.sub.4-6 alcohols, C.sub.4-6 esters, C.sub.4-6 ethers, and
C.sub.3-8 ketones, more preferably, the solvent is selected from a
group consisting of n-BuOH, acetone, ethyl acetate, and MTBE.
[0028] Preferably, the mixture is maintained while stirring. More
preferably, the mixture is maintained while stirring at about room
temperature for about 1 hour.
[0029] DNT-L-pTTA may then be recovered by any method known in art,
such as filtration and drying the precipitate, preferably at a
temperature of from about room temperature to about 70.degree. C.,
at a pressure below about 100 mmHg in a vacuum oven.
[0030] The process described above also decreases the level of the
undesired R-enantiomer of DNT-L-pTTA, relative to the amount of DNT
R-enantiomer in the original DNT, such that, where the solution of
DNT contains a first molar amount of enantiomer R of DNT, and the
precipitate contains a second molar amount of enantiomer R of
DNT-L-pTTA, the second molar amount is less than the first molar
amount.
[0031] Preferably the decrease is at least about 60%, more
preferably, at least about 80%, even more preferably, at least
about 90%, and, most preferably, at least about 99.8%. This process
is capable of decreasing the level of the undesired R-enantiomer to
below the detection limit.
[0032] In another embodiment, the invention provides a process for
preparing enantiomerically pure DNT, comprising combining
DNT-L-pTTA, water, base, and toluene to obtain a two phase system,
and separating the organic phase containing enantiomerically pure
DNT and toluene.
[0033] Preferably, the DNT-L-pTTA is crystalline Form 01.
[0034] In another embodiment, the invention provides
pharmaceutically acceptable salts of duloxetine prepared by
obtaining DNT-L-pTTA, as described above, and converting the
DNT-L-pTTA to pharmaceutically acceptable salts of duloxetine.
[0035] Preferably, the DNT-L-pTTA is converted to duloxetine
hydrochloride.
[0036] The DNT-L-pTTA used in this process is preferably the
DNT-L-pTTA prepared, as described above. As such, it has a low
content of the R-enantiomer, and, therefore, the duloxetine HCl
obtained via this DNT-L-pTTA also has a decreased molar content of
its R-enantiomer, relative to the molar amount found in duloxetine
hydrochloride prepared with prior art methods.
[0037] The conversion of DNT-base to duloxetine HCl may be
performed by any method known in the art, such as the one described
in U.S. Pat. No. 5,491,243 or in co-pending U.S. application Ser.
No. 11/318,365, filed Dec. 23, 2005, the contents of which are
incorporated herein in their entirety by reference. The conversion
may be performed by dissolving DNT-base in an organic solvent;
adding alkyl chloroformate at a temperature of about 5.degree. C.
to less than about 80.degree. C. to obtain duloxetine alkyl
carbamate; combining the duloxetine alkyl carbamate with an organic
solvent and a base; maintaining the reaction mixture at reflux
temperatures for at least 1 to 3 hours; cooling, and adding water
and an additional amount of an organic solvent; recovering
duloxetine; combining the duloxetine with a solvent; adding
hydrochloric acid until a pH of 3 to 4 is obtained; maintaining the
reaction mixture to obtain a solid residue; and recovering
duloxetine HCl.
[0038] Having described the invention with reference to certain
preferred embodiments, other embodiments will become apparent to
one skilled in the art from consideration of the specification. The
invention is further defined by reference to the following examples
describing in detail the analysis of the duloxetine HCl and methods
for preparing the duloxetine HCl of the invention.
[0039] It will be apparent to those skilled in the art that many
modifications, both to materials and methods, may be practiced
without departing from the scope of the invention.
EXAMPLES
Instruments
[0040] X-Ray powder diffraction (XRD) data was obtained using a
Scintag X-ray powder diffractometer model X'TRA equipped with a
Cu-tube solid state detector. A round standard aluminum sample
holder with rough zero background quartz plate with a cavity of 25
(diameter).times.0.5 mm (depth) was used. The scanning parameters
included: range: 2.degree. to 40.degree. 2.theta.; scan mode:
continuous scan; step size: 0.05 a rate of 5 deg/min.
Preparation of DNT-L-PTTA
Examples 1-4
[0041] A 6.2 g sample of di-p-toluoyl-L-tartaric acid was added to
a solution of 5 g of DNT-base (2.3% enantiomer R, mol %) dissolved
in 50 ml of an appropriate solvent, and the resulting mixture was
stirred for about 1 hour. The resulting solid was filtered and
washed with 10 ml of the appropriate solvent, and dried in a vacuum
oven at 50.degree. C. for 16 hours. The product was analyzed by
XRD, and found to be form 01. TABLE-US-00001 Example Solvent %
yield % enantiomer R 1 n-BuOH 79 1.45 2 Acetone 74 0.40 3 Ethyl
acetate 85 1.61 4 MTBE 84 1.85
Preparation of enantiomerically pure DNT
Example 5
[0042] A 2 liter reactor equipped with a mechanical stirrer is
charged with a mixture of 107 g DNT-L-pTTA, 600 ml water, 96 ml of
a 22 percent solution of ammonium hydroxide, and 1 liter toluene.
The mixture is stirred at 25.degree. C. for 20-30 mintues, and the
organic phase is separated and washed with water (3.times.300 ml).
The toluene solution of DNT-base is used directly in the conversion
to duloxetine HCl, without evaporation.
[0043] 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.
* * * * *