Process for the preparation of ketimines

Details Process for the preparation of ketimines Process for the preparation of ketimines

2002-09-20

2004-02-17

O'Sullivan, Peter (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

C564S308000

Reexamination Certificate

active

06693218

ABSTRACT:

The present invention relates to a process for the preparation of ketimines, which are suitable as starting materials for the preparation of pharmaceutical active ingredients having antidepressant properties, for example sertraline.
Processes for the preparation of ketimines are described, for example, in U.S. Pat. No. 4,536,518 and U.S. Pat. No. 4,855,500.
The process for the preparation of ketimines disclosed in U.S. Pat. No. 4,536,518 (columns 9/10, Example 1(F)) comprises reaction of the ketone in an aprotic solvent, for example tetrahydrofuran, with methylamine in the presence of titanium tetrachloride, with cooling. A disadvantage of that process is the need to work with tetrahydrofuran, which is readily combustible, and with titanium tetrachloride, which is not innocuous from an ecological standpoint. In addition, the procedure is expensive, because the reaction is carried out with cooling. A further disadvantage of the process concerns the working up. The product has to be precipitated with additional hexane.
The process for the preparation of ketimines disclosed in U.S. Pat. No. 4,855,500 (columns 5/6, claim 1) comprises reaction of the ketone in an aprotic solvent, for example methylene chloride, toluene or tetrahydrofuran, with anhydrous methylamine in the presence of molecular sieve, with cooling.
That process, too, has the disadvantage of the need to work, under anhydrous conditions, with solvents that are not innocuous from an ecological standpoint, such as methylene chloride, or with readily combustible solvents, such as tetrahydrofuran. The molecular sieve used is expensive and has to be recycled in an additional step. A further disadvantage of the process is that the molecular sieve needs to be removed and the product has to be precipitated with additional hexane.
U.S. Pat. No. 5,019,655 describes a one-step process for the preparation of 4-dichlorophenyl-1-tetralones having a degree of purity of from 98 to 99%. It is disclosed that a plurality of recrystallisation operations are required at the ketone stage, using large amounts of solvents, in order to achieve a degree of purity >99.5%.
The need therefore exists for the discovery of an efficient process for the preparation of ketimines that does not have the above-listed disadvantages, especially in relation to the solvents and recrystallisation steps used.
Surprisingly, it has now been found that the desired degree of purity of ketimines can be achieved by carrying out the recrystallisation at the imine stage and using sertralone, precipitated in crude form, in the imine synthesis. At the same time high yields are achieved, and substantially smaller amounts of solvents are sufficient for the recrystallisation.
The present invention accordingly relates to a process for the preparation of compounds of formula
reacting an isomeric mixture consisting of from 75 to 95% of a compound of formula (2a) and from 5 to 25% of a compound of formula (2b) with methylamine, in a suitable solvent, using suitable methods of isolation to form an enriched sertraline-imine isomeric mixture, consisting of >99% of a compound of formula (1a) and <1% of a compound of formula (1b) (A
2
);
and then subjecting the sertraline-imine isomeric mixture obtained according to reaction route (A
1
) or (A
2
), in a suitable solvent, to recrystallisation (B), in accordance with the following scheme:
 wherein in formulae (1a), (1b), (2a) and (2b)
R
1
, R
2
and R
3
are each independently of the others hydrogen, halogen, trifluoromethyl or C
1
-C
4
alkoxy.
The solvents preferably used for reaction routes (A
1
), (A
2
) and (B) are selected from
(a) C
1
-C
24
amines,
(b) C
1
-C
12
nitriles,
(c) C
2
-C
24
carboxylic acid esters,
(d) C
3
-C
24
ortho esters,
(e) C
2
-C
24
ethers,
(f) C
1
-C
24
alkanes,
(g) aromatic solvents,
(h) amides,
(i) sulfoxides,
(k) halogenated solvents,
(l) supercritical CO
2
, and
(m) protic solvents.
Especially preferred solvents (a) are selected from aliphatic monoamines, especially methylamine, nitrogen heterocycles, and aliphatic and aromatic, non-substituted or substituted secondary and tertiary mono-, di- and tri-amines.
Further preferred solvents (a) correspond to formula
R
3
is hydrogen; C
1
-C
5
alkyl; hydroxy-C
1
-C
5
alkyl; C
5
-C
7
cycloalkyl; non-substituted phenyl or phenyl substituted by one or more C
1
-C
5
alkyl groups, by halogen or by nitro; non-substituted phenyl-C
1
-C
3
alkyl or phenyl-C
1
-C
3
alkyl substituted by one or more C
1
-C
5
alkyl groups, by halogen or by nitro;
R
4
and R
5
are each independently of the other C
1
-C
5
alkyl; C
5
-C
7
cycloalkyl; hydroxy-C
1
-C
5
alkyl; non-substituted phenyl or phenyl substituted by one or more C
1
-C
5
alkyl groups, by halogen or by nitro; non-substituted phenyl-C
1
-C
3
alkyl or phenyl-C
1
-C
3
alkyl substituted by one or more C
1
-C
5
alkyl groups, by halogen or by nitro; or R
4
and R
5
together with the nitrogen atom form a 3- to 6-membered heterocyclic radical.
There are furthermore preferably used solvents (a) that correspond to formula
R
6
and R
8
are each independently of the other hydrogen; C
1
-C
5
alkyl; or C
5
-C
7
cycloalkyl,
R
7
and R
9
are each independently of the other C
1
-C
5
alkyl; C
5
-C
7
cycloalkyl; non-substituted phenyl or phenyl substituted by one or more C
1
-C
5
alkyl groups, by halogen or by nitro; non-substituted phenyl-C
1
-C
3
alkyl or phenyl-C
1
-C
3
alkyl substituted by one or more C
1
-C
5
alkyl groups, by halogen or by nitro, or
R
6
and R
7
, R
8
and R
9
, or R
7
and R
9
, as the case may be, form a 3- to 6-membered heterocyclic radical; and
A
2
is C
1
-C
5
alkylene.
The following may be mentioned as representative examples of solvents (a) for use in accordance with the invention:
as aliphatic monoamines, e.g. methylamine, dimethylamine, triethylamine, diethylamine, triethylamine, di-n-propylamine and tri-n-propylamine;
as nitrogen heterocycles, ethylene-imine, pyrrolidine, piperidine and morpholine,
as aliphatic diamines, e.g. N,N-dimethylethylenediamine and hexamethylenediamine;
as aromatic monoamines, e.g. N-methylaniline and N,N-dimethylaniline;
as substituted aromatic monoamines, e.g. o-, m- and p-toluidine, 2-, 3- and 4-chloroaniline, 2-, 3- and 4-nitroaniline;
as aromatic diamines, e.g. o-, m- and p-phenylenediamine.
Preferably used solvents (b) correspond to formula
R
10
—C≡N,  (5) wherein
R
10
is straight-chain or branched C
1
-C
1
2alkyl; C
5
-C
7
cycloalkyl; non-substituted phenyl or phenyl substituted by one or more C
1
-C
5
alkyl groups, by halogen or by nitro; non-substituted phenyl-C
1
-C
3
alkyl or phenyl-C
1
-C
3
alkyl substituted by one or more C
1
-C
5
alkyl groups, by halogen or by nitro.
Representative examples of that group of solvents include acetonitrile and benzonitrile.
As solvents (c) there are preferably used compounds of formula
R
12
and R
13
are each independently of the other straight-chain or branched C
1
-C
12
alkyl;
C
5
-C
7
cycloalkyl; non-substituted phenyl or phenyl substituted by one or more C
1
-C
5
alkyl groups, by halogen or by nitro; non-substituted phenyl-C
1
-C
3
alkyl or phenyl-C
1
-C
3
alkyl substituted by one or more C
1
-C
5
alkyl groups, by halogen or by nitro.
Representative examples of such solvents include acetates, e.g. methyl acetate and ethyl acetate.
Solvents (d) preferably used according to the invention correspond to formula
R
14
is hydrogen; straight-chain or branched C
1
-C
5
alkyl; or C
5
-C
7
cycloalkyl; and
R
15
is C
1
-C
5
alkyl.
Representative examples of such solvents include orthoformic acid C
1
-C
3
alkyl esters, especially orthoformic acid methyl or ethyl ester, and orthoacetic acid C
1
-C
3
alkyl esters, especially orthoacetic acid ethyl ester.
Solvents (e) preferably used according to the invention correspond to formula
R
16
—O—R
17
,  (8) wherein
R
16
and R
17
are each independently of the other straight-chain or branched C
1
-C
12
alkyl; or C
5
-C
7
cycloalkyl.
Representative examples of such solvents include dimethyl ether, diethyl ether, methyl ethyl ether, methyl n-propyl ether, meth

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