U.S. patent application number 09/888067 was filed with the patent office on 2002-02-14 for method for the preparation of 5-cyanophthalide.
This patent application is currently assigned to H. Lundbeck A/S. Invention is credited to Dahlberg Nielsen, Poul, Petersen, Hans.
Application Number | 20020019546 09/888067 |
Document ID | / |
Family ID | 8107494 |
Filed Date | 2002-02-14 |
United States Patent
Application |
20020019546 |
Kind Code |
A1 |
Petersen, Hans ; et
al. |
February 14, 2002 |
Method for the preparation of 5-cyanophthalide
Abstract
A method for the preparation of 5-cyanophthalide in which
5-carboxyphthalide is converted to the corresponding amide of
Formula (IV) 1 in which R is hydrogen or C.sub.1-6 alkyl, which is
then reacted with a dehydrating agent thereby obtaining
5-cyanophthalide. The conversion of 5-carboxyphthalide to the
corresponding amide of Formula (IV) may be carried out via the
corresponding C.sub.1-6 alkyl or phenyl ester or the acid chloride,
which is converted to the amide of Formula (IV) by amidation with
ammonia or a C.sub.1-6 alkylamine. By the process 5-cyanophthalide,
an important intermediate used in the preparation of the
antidepressant citalopram, is prepared in high yields by a
convenient, cost effective procedure.
Inventors: |
Petersen, Hans; (Vanlose,
DK) ; Dahlberg Nielsen, Poul; (Vig, DK) |
Correspondence
Address: |
DARBY & DARBY P.C.
805 Third Avenue
new York
NY
10022
US
|
Assignee: |
H. Lundbeck A/S
Valby-Copenhagen
DK
|
Family ID: |
8107494 |
Appl. No.: |
09/888067 |
Filed: |
June 22, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
09888067 |
Jun 22, 2001 |
|
|
|
PCT/DK99/00728 |
Dec 22, 1999 |
|
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Current U.S.
Class: |
549/307 |
Current CPC
Class: |
C07D 307/88
20130101 |
Class at
Publication: |
549/307 |
International
Class: |
C07D 307/87 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 23, 1998 |
DK |
PA 1998 01718 |
Claims
1. A method for the preparation of 5-cyanophthalide comprising a)
conversion of a 5-carboxyphthalide to an amide of Formula IV 7in
which R is hydrogen or C.sub.1-6alkyl, and b) then reacting the
amide of Formula IV with a dehydrating agent thereby obtaining
5-cyanophthalide 8
2. The method of claim 1, wherein the conversion of
5-carboxyphthalide to the amide of Formula IV is carried out via an
ester of Formula VI: 9wherein R.sub.1is C.sub.1-6 alkyl or phenyl,
by treatment of 5-carboxyphthalide with an alcohol R.sub.1OH in the
presence of an acid and subsequent amidation of the ester of
formula VI with ammonia or a C.sub.1-6 alkylamine.
3. The method of claim 1, wherein the conversion of
5-carboxyphthalide to the amide of Formula IV is carried out via an
acid chloride of Formula VII: 10by treatment of 5-carboxyphthalide
with POCl.sub.3, PCl.sub.5 or SOCl.sub.2 and subsequent amidation
of the acid chloride of Formula VII with ammonia or a C.sub.1-6
alkylamine.
4. The method of claim 1, wherein the conversion of
5-carboxyphthalide to the amide of Formula IV is carried out via an
acid chloride of Formula VII and an ester of Formula VI: 11wherein
R.sub.1 is C.sub.1-6 alkyl or phenyl, by treatment of
5-carboxyphthalide with POCl.sub.3, PCl.sub.5 or SOCl.sub.2,
reacting the acid chloride of Formula VII thus formed with an
alcohol R.sub.1OH and performing amidation of the ester of Formula
VI with ammonia or a C.sub.1-6 alkylamine.
5. The method of claim 2, wherein the acid used is a mineral acid
or Lewis acid.
6. The method of claim 5, wherein the mineral acid or Lewis acid is
selected from the group consisting of HCI, H.sub.2SO.sub.4,
POCl.sub.3, PCl.sub.5 and SOCl.sub.2.
7. The method of claim 2, 4 or 5, wherein R.sub.1 is methyl or
ethyl.
8. The method of claim 1, in which the dehydrating agent used in
step b) is SOCl.sub.2, POCl.sub.3 or PCl.sub.5.
9. The method of claim 8, in which the dehydrating agent is
SOCl.sub.2.
10. The method of claim 1, wherein the reaction in step b) is
carried out neat or in a suitable solvent.
11. The method of claim 10, wherein the reaction is carried out in
a solvent selected from the group consisting of toluene, sulfolan
or acetonitrile.
12. The method of claim 11, wherein the solvent is toluene.
13. The method of claim 10, wherein the dehydrating agent used in
step b) is SOCl.sub.2 and the reaction is carried out in toluene
comprising a catalytic amount of N,N-dimethylformamide.
14. The method of claim 1, wherein R is H or tert-butyl.
15. The method of claim 2, wherein the 5-carboxyphthalide of
Formula III is reacted with an alcohol R.sub.1OH, in the presence
of POCl.sub.3,in order to obtain an ester of Formula VI, which is
then reacted with ammonia, thereby giving 5-carbamoyl-phthalide,
which in turn is reacted with SOCl.sub.2 to 5-cyanophthalide.
16. The method of claim 15, wherein the alcohol R.sub.1OH is
ethanol or methanol.
17. The method of claim 15, wherein the 5-carboxyphthalide of
Formula III is reacted with ethanol in the presence of POCl.sub.3,
in order to obtain the ethyl ester of Formula VI, which is then
reacted with ammonia in methanol, thereby giving
5-carbamoylphthalide, which in turn is reacted with SOCl.sub.2 to
5-cyanophthalide.
Description
[0001] The present invention relates to a novel process for the
preparation of 5-cyanophthalide which is an intermediate used in
the manufacture of the well known antidepressant drug citalopram, 1
-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuran-
carbonitrile.
Background of the Invention.
[0002] Citalopram is a well known antidepressant drug that has now
been on the market for some years and has the following structure:
2
[0003] It is a selective, centrally active serotonin
(5-hydroxytryptamine; 5-HT) reuptake inhibitor, accordingly having
antidepressant activities. The antidepressant activity of the
compound has been reported in several publications, eg. J. Hyttel,
Prog. Neuro-PsychopharmacoL. & Biol. Psychiat., 1982, 6,
277-295 and A. Gravem, Acta Psychiatr. Scand., 1987, 75,
478-486.
[0004] Citalopram is prepared by the process described in U.S. Pat.
No. 4,650,884, according to which 5-cyanophthalide is subjected to
two successive Grignard reactions, i.e. with 4-fluoro-phenyl
magnesium halogenide and N,N-dimethylaminopropyl magnesium
halogenide, respectively, and the resulting compound of the formula
3
[0005] is subjected to a ring closure reaction by dehydration with
strong sulfuric acid.
[0006] Enantiomers of citalopram may be prepared by the method
described in U.S. Pat. No. 4,943,590, i.e. by separating the
enantiomers of the intermediate of Formula II and performing
enantioselective ring closure in order to obtain the desired
enantiomer.
[0007] Thus, 5-cyanophthalide is an important intermediate for the
manufacture of citalopram and it is important to produce this
material in an adequate quality, by a convenient process and in a
cost-effective way.
[0008] A method for the preparation of 5-cyanophthalide has
previously been described in Bull. Soc. Sci. Bretagne, 26, 1951, 35
and in Levy and Stephen, J. Chem. Soc., 1931, 867. By this method,
5-aminophthalide is converted to the corresponding 5-cyanophthalide
by diazotation followed by reaction with CuCN. 5-Aminophthalide was
obtained from 4-aminophthalimide by a two step reduction
procedure.
[0009] Synthesis of certain alkyl- and phenylnitriles from acid
chlorides is described in Tetrahedron Letters, 1982, 23, 14,
1505-1508, and in Tetrahedron, 1998, 54, 9281.
[0010] Though a number of other methods failed, it has been found
that 5-cyanophthalide may be prepared in high yields by a
convenient, cost-effective procedure from 5-carboxyphthalide.
DESCRIPTION OF THE INVENTION
[0011] Accordingly, the present invention provides a novel method
for the preparation of 5-cyanophthalide from 5-carboxyphthalide
comprising
[0012] a) converting 5-carboxyphthalide to an amide of Formula IV
4
[0013] in which R is hydrogen or C.sub.1-6 alkyl, and
[0014] b) then reacting the amide of Formula IV with a dehydrating
agent thereby obtaining 5-cyanophthalide 5
[0015] The conversion of 5-carboxyphthalide to the amide of Formula
IV may be carried out via an ester of Formula VI or an acid
chloride of Formula VII or via the ester and the acid chloride:
6
[0016] wherein R.sub.1 is C.sub.1-6 alkyl or phenyl. The acid
chloride is conveniently obtained by treatment of
5-carboxyphthalide with POCl.sub.3, PCl.sub.5 or SOCl.sub.2 neat or
in a suitable solvent, such as toluene or toluene comprising a
catalytic amount of N,N-dimethylformamide. The ester is obtained by
treatment of 5-carboxyphthalide with an alcohol R.sub.1OH, wherein
R.sub.1 is as defined above, in the presence of an acid, preferably
a mineral acid or a Lewis acid, such as HCI, H.sub.2SO.sub.4,
POCl.sub.3, PCl.sub.5 or SOCl.sub.2. Alternatively, the ester may
be obtained from the acid chloride by reaction with an alcohol. The
ester of Formula VI or the acid chloride of Formula VII is then
converted to the amide of Formula IV by amidation with ammonia or
an C.sub.1-6 alkylamine, preferably t-butyl amine.
[0017] Throughout the specification and Claims, C.sub.1-6 alkyl
refers to a branched or unbranched alkyl group having from one to
six carbon atoms inclusive, such as methyl, ethyl,-1-propyl,
2-pro-pyl, 1 -butyl, 2-butyl, 2-methyl-2-propyl,
2,2-dimethyl-1-ethyl and 2-methyl-1-propyl.
[0018] The dehydrating agent used in step b) may be any suitable
dehydrating agent, and the optimal agent may easily be determined
by a person skilled in the art. Examples of suitable dehydrating
agents are SOCl.sub.2, POCl.sub.3, and PCl.sub.5, preferably
SOCl.sub.2.
[0019] The reaction in step b) is carried out neat or in a suitable
solvent, such as toluene, sulfolan or conveniently acetonitrile.
When the reaction is carried out in a solvent, 1.0-1.5, preferably
1.0-1.2 equivalents of dehydrating agent is used per equivalent of
the amide of Formula V. Furthermore, when a solvent is used, a
catalytic amount of N,N-dimethylformamide may be needed, in
particular when the dehydrating agent is SOCl.sub.2. Preferably,
toluene is used as the solvent, if necessary in the presence of a
catalytic amount of N,N-dimethylformamide.
[0020] The reaction in step b) is carried out at elevated
temperature, preferably at the reflux temperature of the
solvent.
[0021] The reaction time is not important and may easily be
determined by a person skilled in the art.
[0022] 5-Cyanophthalide may be isolated in a conventional way, e.g.
by addition of water, filtration and subsequent washing of the
crystals. Further purification may, if desired, be performed by
recrystallisation.
[0023] In a preferred embodiment of the process of the invention, R
in Formula IV is H or t-butyl. When the reaction in step a) is
carried out via an ester, R.sub.1 is preferably methyl or
ethyl.
[0024] In a particularly preferred embodiment of the invention
5-carboxyphthalide of Formula III is reacted with an alcohol,
R.sub.1OH, preferably ethanol, in the presence of POCl.sub.3, in
order to obtain the corresponding ester of Formula VI, which is
then reacted with ammonia thereby giving 5-carbamoylphthalide,
which in turn is reacted with SOCl.sub.2 in toluene comprising a
catalytic amount of N,N-dimethylformamide.
[0025] Surprisingly, substantially no reaction takes place at the
lactone ring. Accordingly, by the process of the invention,
5-cyanophthalide is obtained in high yields and the process is much
more convenient than the known process and uses more convenient and
cheaper reactants and conditions.
[0026] The 5-carboxyphthalide used as a starting material may be
obtained by the methods described in U.S. Pat. No. 3,607,884 or
German patent No. 2630927, i.e. by reacting a concentrated solution
of terephthalic acid with formaldehyde in liquid SO.sub.3 or by
electrochemical hydrogenation of trimellithic acid.
EXAMPLES
[0027] The invention is firther illustrated by the following
examples.
Example 1 Preparation of 5-Cyanophthalid
[0028] 5-Chlorocarbonylphthalid
[0029] 5-Carboxyphthalid (53 g, 0.3 mole) was suspended toluene
(200 mL) and thionylchloride (44 g, 0.6 mole).
N,N-dimethylformamide (DMF) (1 mL) was added and the mixture was
heated at reflux temperature for 3 hours. The mixture was cooled to
room temperature and n-heptane was added (200 ml). The crystals
formed were collected and washed with heptane (100 mL). Yield 52 g,
88%. DSC onset: 131.degree. C. .sup.1H NMR (CDCl.sub.3, 500 MHz):
5.47 (2H, s), 8.06 (1H, d, J=7.5 Hz), 8.28 (1H, d, J=7.5 Hz), 8.3
(1H, s). .sup.13C NMR (CDCl.sub.3, 125 MHz): 69.4, 125.1, 126.1,
131.1, 131.6, 137.8, 146.6, 167.4, 169.0.
[0030] 5-tert.Butylcarbamylphthalid
[0031] Method A):
[0032] 5-Carboxyphthalid (36 g, 0.2 mole) was suspended in
thionylchloride (100 mL). DMF (1.5 mL) was added and the mixture
was refluxed for 1 hour. Toluene (200 mL) was added and the
solvents were evaporated in vacuo. The residue was dissolved in
tetrahydofuran (THF) (200 mL) and added to a solution of
tert.butylamine (31 g, 0.42 mole) in THF (200 mL) at 5 .degree. C.
The mixture was allowed to warm to room temperature and stirred
overnight. The reaction was then poured into ice water (400 niL)
and the precipitated crystals were filtered off. The crystals were
washed with water (100 mL)Yield: 41 g, 87%. DSC onset: 189.5
.degree. C.
[0033] Method B):
[0034] A solution of 5-chlorocarbonylphthalid (39 g, 0.2 mole) in
THF (200 mL) was added to a solution of tert-butylamine (19 g. 0.25
mole) and triethylamine (26 g, 0.25 mole) in THF (200 mL) at room
temperature. The mixture was stirred for 1 hour. The reaction
mixture was then poured into ice water (500 mL). The crystalline
material formed was collected and washed with water (100 mL).
[0035] Yield 42.5 g, 91%. DSC onset: 192 .degree. C. Purity: 99.5%
(hplc, peak area). .sup.1H NMR (DMSO-d.sub.6, 500 MHz): 1.4 (9H,
s), 5.46 (2H, s), 7.88 (1H, d, J=7.5 Hz), 7.95 (1H, d, J=7.5 Hz),
8.04 (1H, s). .sup.13C NMR (DMSO-d.sub.6, 125 MHz): 28.5, 51.2,
70.0, 122.0, 124.6, 126.6, 128.2, 141.3, 147.2, 165.5, 170.1.
[0036] 5-Ethoxycarbonylphthalid
[0037] Method A):
[0038] 5-Carboxyphthalid (37 g, 0.2 mole) was suspended in ethanol
(400 mL). POCl.sub.3 (10 g, 0.07 mole) was added drop-wise and the
reaction mixture was heated to reflux temperature for 5 hours. Upon
cooling to room temperature, the title compound crystallised. The
crystals were filtered off and washed with ethanol (50 ml). Yield:
35 g, 87%. DSC onset: 151 .degree. C. .sup.1H NMR (DMSO-d.sub.6,
250 MHz): 1.36 (3H, t, J=7 Hz), 4.38 (2H, q, J=7 Hz), 5.48 (2H, s),
7.95 (1H, d, J=7.5 Hz), 8.12 (1H, d, J=7.5 Hz), . .sup.13C NMR
(DMSO-d.sub.6, 62.5 MHz): 14.5, 61.5, 70.1, 124.0, 125.2, 128.8,
129.6, 134.8, 147.6, 164.9, 169.8.
[0039] Method B):
[0040] 5-Chlorocarbonylphthalid (39 g, 0.2 mole) was suspended in
ethanol (200 mL). The mixture was heated to reflux for 15 minutes.
After cooling, the crystalline material formed was filtered of and
washed with ethanol (50 ml). Yield: 36 g, 88%. DSC onset: 151
.degree. C.
[0041] 5-Carbamylphthalid.
[0042] 5 Method A):
[0043] 5-Ethoxycarbonylphthalid (41 g, 0.2 mole) was suspended in
ammonia (10M solution in methanol, 200 mL) in a pressure reactor.
The reaction temperature was held at 80 .degree. C. for 20 hours.
After cooling, the reaction mixture was poured onto ice (250 g) and
pH was adjusted to pH =1 using concentrated hydrochloric acid. The
mixture was stirred for 2 hours. The crystals formed were filtered
off and washed with water (4.times.100 mL) and dried in vacuo.
Yield: 33 g, 93%. DSC onset: 237 .degree. C. .sup.1H NMR
(DMSO-d.sub.6, 250 MHz): 5.47 (2H, s), 7.65 (H, s (NH)), 7.92 (1H,
d, J =7.5 Hz), 8.06 (1H, d, J=7.5 Hz), 8.14 (1H, s), 8.22 (1H, s
(NH)). .sup.13C NMR (DMSO-d.sub.6, 62.5 MHz): 70.0, 122.2, 124.9,
127.2, 128.2, 139.7, 147.4, 167.1, 170.1.
[0044] Method B):
[0045] 5-Chlorocarbonylphthalid (20 g, 0.1 mole) was dissolved in
THF (100 mL) and added to ammonium hydroxide (50 mL) in ice water
(300 mL). The mixture was stirred for 30 minutes and the
precipitated crystals were filtered off. The crystals were washed
with water (100 mL) and dried in vacuo. Yield: 17.1 g, 97%. DSC
onset: 237 .degree. C.
[0046] 5-Cyanophthalid.
[0047] Method A):
[0048] Dry 5-carbamylphthalid (36 g, 0.2 mole) was suspended in
toluene (600 mL) and thionyl-chloride (36 g, 0.3 mole) was added.
DMF (2 mL) was added. The reaction mixture was heated at 75
.degree. C. for 6 hours. Toluene (100 mL) was removed by
destillation and the remaining solution was cooled to room
temperature. The crystals formed were filtered off and washed with
toluene (150 mL) and water (100 mL). The product was recrystallised
from toluene. Yield: 22 g, 80%. DSC onset:203 .degree. C.
[0049] Method B):
[0050] Tert.-Butylcabamylphthalid (23.3 g, 0.1 mole) was suspended
in thionylchloride (100 mL). The mixture was heated to reflux for
30 min. Toluene (100 mL) was added and the solvents were removed in
vacuo. The title product was crystallised from acetic acid or
toluene.
[0051] Yield 15.5 g, 93% from toluene. DSC onset: 203 .degree. C.
Purity: 98% (hplc, peak area).
* * * * *