Process for the preparation of ketimines

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

2002-05-14

2004-10-19

O'Sullivan, Peter (Department: 1621)

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

Organic compounds

Amino nitrogen containing

C564S304000, C564S308000

Reexamination Certificate

active

06806386

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 compounds having antidepressant properties, for example sertraline.
Processes for the preparation of ketimines are described, for example, in U.S. Pat. No. 4,536,518 or U.S. Pat. No. 4,855,600.
The process for the preparation of ketimines disclosed in U.S. Pat No. 4,536,518 (columns 9/10, Example 1(F)) is characterized in that the ketone is reacted with methylamine with cooling in the presence of titanium tetrachloride in an aprotic solvent, for example tetrahydrofuran. This process has the disadvantage that it has to be carried out using titanium tetrachloride, which is ecologically hazardous. The process procedure is additionally expensive, because the reaction is carried out with cooling. A further disadvantage of this process relates to the work-up. The product must be precipitated using additional hexane.
The process for the preparation of ketimines disclosed in U.S. Pat No. 4,855,500 (columns 5/6, claim
1
) comprises reacting the ketone with anhydrous methylamine with cooling in an aprotic solvent, such as, for example, methylene chloride, toluene or tetrahydrofuran in the presence of a molecular sieve.
This process has the disadvantage that the molecular sieve employed is expensive and has to be recycled again in an additional step. A further disadvantage of this process is that the molecular sieve has to be separated off and the product precipitated using additional hexane.
There is therefore furthermore the need to find an efficient process for the preparation of ketimines, which does not have the abovementioned disadvantages.
The present invention therefore relates to a process for the preparation of compounds of the formula
in which
R
1
, R
2
and R
3
independently of one another are hydrogen, halogen, trifluoromethyl or C
1
-C
4
alkoxy, wherein a compound of the formula
in which
R
1
, R
2
and R
3
are as defined in formula (1) is reacted with methylamine in the presence of a C
1
-C
24
amine or C
1
-C
12
nitrile as solvent to give the compound of the formula (1), or
is reacted with methylamine in the presence of a sulfonic acid catalyst and of a non-alcoholic solvent to give the compound of the formula (1).
Halogen is, for example, chlorine, bromine or iodine. Chlorine is preferred.
C
1
-C
4
alkoxy is a branched or unbranched hydrocarbon radical, for example methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy. Methoxy is preferred.
The non-alcoholic solvent preferred for the process according to the invention is preferably 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
orthoesters,
(e) C
2
-C
24
ethers,
(f) C
6
-C
24
alkanes,
(g) aromatic solvents,
(h) amides,
(i) sulfoxides,
(k) halogenated solvents, and
(j) supercritical CO
2
.
Particularly preferred solvents (a) are selected from aliphatic monoamines, in particular methylamine, nitrogen heterocycles, aliphatic di- and triamines, non-substituted or substituted aromatic monoamines or aromatic diamines.
Further preferred solvents (a) are those of the formula
in which
R
3
is hydrogen; C
1
-C
5
alkyl; hydroxy-C
1
-C
5
alkyl; C
5
-C
7
cycloalkyl; phenyl which is not substituted or is substituted by one or more C
1
-C
5
alkyl groups, halogen or nitro; phenyl-C
1
-C
3
alkyl which is not substituted or is substituted by one or more C
1
-C
5
alkyl groups, halogen or nitro;
R
4
and R
5
, independently of one another, are C
1
-C
5
alkyl; hydroxy-C
1
-C
5
alkyl; C
5
-C
7
cycloalkyl; phenyl which is not substituted or is substituted by one or more C
1
-C
5
alkyl groups, halogen or nitro; phenyl-C
1
-C
3
alkyl which is not substituted or is substituted by one or more C
1
-C
5
alkyl groups, halogen or nitro; or
R
4
and R
5
together with the nitrogen atom form a three- to 6-membered heterocyclic radical.
Furthermore, solvents (a) are preferably used which are those of the formula
in which
R
6
and R
8
independently of one another are hydrogen; C
1
-C
5
akyl; or C
5
-C
7
cycloalkyl, R
7
and R
9
independently of one another are C
1
-C
5
alkyl; or C
5
-C
7
cycloalkyl, phenyl which is not substituted or is substituted by one or more C
1
-C
5
alkyl groups, halogen or nitro; phenyl-C
1
-C
3
alkyl which is not substituted or is substituted by one or more C
1
-C
5
alkyl groups, halogen or nitro; or
R
6
and R
7
, R
8
and R
9
or R
7
and R
9
form a three- to 6-membered heterocyclic radical; and A
2
is C
1
-C
5
alkylene.
Exemplary representatives of solvents (a) used according to the invention which may be mentioned are:
as aliphatic monoamines, for example, methylamine, dimethylamine, triethylamine, diethylamine, triethylamine, di-n-propylamine, diisopropylamine, tri-n-propylamine, or triisopropylamine;
as nitrogen heterocycles ethyleneimine, pyrrolidine, piperidine or morpholine,
as aliphatic diamines, for example, N,N-dimethylethylenediamine or hexamethylenediamine;
as aromatic monoamines, for example, N-methylaniline or N,N-dimethylaniline;
as substituted aromatic monomamines, for example, o-, m- or p-toluidine, 2-, 3- or
4-chloroaniline, 2-, 3- or 4-nitroaniline;
as aromatic diamines, for example, o-, m- or p-phenylenediamine.
Solvents (b) preferably used are those of the formula
in which
R
10
is straight-chain or branched C
1
-C
12
alkyl; C
5
-C
7
cycloalkyl; phenyl which is not substituted or is substituted by one or more C
1
-C
5
akyl groups, halogen or nitro; phenyl-C
1
-C
3
alkyl which is not substituted or is substituted by one or more C
1
-C
5
alkyl groups, halogen or nitro.
Exemplary representatives of this group are benzonitrile or in particular acetonitrile. Solvents (c) which are preferably used are compounds of the formula
in which
R
12
and R
13
independently of one another are straight-chain or branched C
1
-C
12
alkyl; C
5
-C
7
cycloalkyl; or phenyl which is not substituted or is substituted by one or more C
1
-C
5
alkyl groups, halogen or nitro; phenyl-C
1
-C
3
alkyl which is not substituted or is substituted by one or more C
1
-C
5
alkyl groups, halogen or nitro.
Exemplary representatives of these solvents are acetates, such as, for example, methyl acetate or ethyl acetate.
Solvents (d) preferably employed according to the invention are those of the formula
in which
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.
Exemplary representatives of these solvents are C
1
-C
3
alkyl orthoformates, in particular methyl or ethyl orthoformate or C
1
-C
3
alkly orthoacetates, in particular ethyl orthoacetate. Solvents (e) preferably employed according to the invention are those of the formula
R
16
—O—R
17
, in which (8)
R
16
and R
17
independently of one another are hydrogen; straight-chain or branched C
1
-C
12
alkyl; or C
5
-C
7
cycloalkyl; or R
16
and R
17
together with the oxygen atom form a 5- to 6-membered radical.
Exemplary representatives of those solvents are dimethyl ether, diethyl ether, methyl ethyl ether, methyl n-propyl ether, methyl i-propyl ether, diisopropyl ether, dibutyl ether or tert-butyl methyl ether. In addition, polyethers can also be employed.
Solvents (f) preferably employed according to the invention are saturated C
1
-C
22
hydro-carbons, such as, for example, methane, ethane, propane, butane, pentane, hexane, neohexane, heptane, octane, i-octane, nonane, decane, undecane, dodecane, tridecane, tetradecane, pentadecane, hexadecane, heptadecane, octadecane, nonadecane, eicosane, heneicosane or docosane.
Solvents (g) preferably employed according to the invention are in particular benzene, toluene, xylene and xylene isomer mixtures.
Solvents (h) preferably employed according to the invention are in particular aliphatic and aromatic amides of the formula
in which
R
18
and R
19
independently of one another are hydrogen; C
1
-C
5
alkyl; or C
5
-C
7
cycloalkyl, and
R
20
is C
1
-C
5
alkyl; C
5
-C
7
cycloalkyl; phenyl which is not substituted or is substituted by one or m

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