Method for the preparation of aryl ethers

Details Method for the preparation of aryl ethers Method for the preparation of aryl ethers

1999-12-23

2002-04-23

Barts, Samuel (Department: 1621)

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

Organic compounds

Amino nitrogen containing

C564S351000, C544S174000

Reexamination Certificate

active

06376711

ABSTRACT:

SUMMARY
The present invention relates to an improved method for preparing certain aryl ethers that are useful as antidepressants. The invention also relates to intermediates useful in the method, and to methods for preparing such intermediates.
BACKGROUND OF THE INVENTION
U.S. Pat. No. 4,229,449, issued Oct. 21, 1980, discloses compounds of formula (A)
wherein
n and n1 are, independently, 1, 2 or 3;
each of the groups R and R
1
, which may be the same or different, is hydrogen; halogen; halo-C
1
-C
6
alkyl; hydroxy; C
1
-C
6
alkoxy; C
1
-C
6
alkyl optionally substituted; aryl-C
1
-C
6
alkyl optionally substituted; aryl-C
1
-C
6
alkoxy optionally substituted; —NO
2
; NR
5
R
6
wherein R
5
and R
6
are, independently, hydrogen or C
1
-C
6
alkyl, or two adjacent R groups or two adjacent R
1
groups, taken together, form a —O—CH
2
—O— radical;
R
2
is hydrogen; C
1
-C
12
alkyl optionally substituted, or aryl-C
1
-C
6
alkyl;
each of the groups R
3
and R
4
, which may be identical or different, is hydrogen, C
1
-C
6
alkyl optionally substituted, C
2
-C
4
alkenyl, C
2
-C
4
alkynyl, aryl-C
1
-C
4
alkyl optionally substituted, C
3
-C
7
cycloalkyl optionally substituted, or R
3
and R
4
with the nitrogen atom to which they are bounded form a pentatomic or hexatomic saturated or unsaturated, optionally substituted, heteromonocyclic radical optionally containing other heteroatoms belonging to the class of O, S and N;
or R
2
and R
4
, taken together, form a —CH
2
—CH
2
— radical;
or a pharmaceutically acceptable salt thereof.
The compounds are disclosed to possess antidepressant activity.
In particular, U.S. Pat. No. 4,229,449 discloses the compound: 2-[&agr;-(2-ethoxyphenoxy)benzyl]morpholine:
and pharmaceutically acceptable salts thereof, which possess useful antidepressant properties. This compound is also known as Reboxetine.
As illustrated in
FIG. 4
, U.S. Pat. No. 5,068,433 (issued Nov. 26, 1991) and related U.S. Pat. No. 5,391,735 (issued Feb. 21, 1995) disclose processes and intermediates useful for preparing single diastereomers of compounds of formula VIb:
wherein R is C
1
-C
6
alkoxy or tri-halomethyl. These diastereomers are disclosed to be useful intermediates for preparing compounds of formula A, including Reboxetine. The processes disclosed in these patents and in U.S. Pat. No. 4,229,449, however, are inefficient and provide a low overall yield of compounds of formula A when carried out on a commercial scale. Additionally the processes require the use of expensive reagents and require significant production times. Thus, it is not economical to prepare compounds of formula A on a commercial scale using the processes disclosed in these patents.
Accordingly, there is currently a need for improved processes for preparing compounds of formula (A), and for preparing intermediates useful for preparing compounds of formula (A). Ideally, the improved processes should utilize inexpensive reagents, be faster to carry out, or provide improved intermediate or overall yields compared to existing processes. Such improvements would facilitate the commercial scale production of compounds of formula (A).
SUMMARY OF THE INVENTION
As illustrated in
FIG. 2
, the invention provides a method for preparing an amine of formula VIIa:
comprising:
a) oxidizing an optionally substituted trans-cinnamyl alcohol to give an intermediate epoxide of formula Ia:
b) reacting the epoxide with an optionally substituted phenol to give a diol of formula IIa:
c) reacting the diol with a silylating reagent to give an alcohol of formula IIa:
 wherein P is a silyl-linked radical;
d) reacting the alcohol of formula IIIa with reactive derivative of a sulfonic acid to give a compound of formula IVa:
 wherein Ra is a residue of a sulfonic acid;
e) removing P from the compound of formula IVa to give an alcohol of formula Va:
f) displacing the sulfonyloxy group to give an epoxide of formula VIa:
 and
g) reacting the epoxide with ammonia to give the compound of formula VIIa.
As illustrated in
FIG. 3
, the invention also provides a method further comprising:
h) reacting a compound of formula VIIa:
 with a carboxylic acid of formula HOOCCH
2
L or a reactive derivative thereof, wherein L is a leaving group, to give an amide of formula VIIIa:
i) reacting the compound of formula VIIIa to give a compound of formula IXa:
 and
j) reducing the compound of formula IXa to give a corresponding compound of the following formula:
The invention also provides novel intermediates disclosed herein (e.g. compounds of formulae III, IV, V, IIIa, IVa, and Va) as well as methods for their synthesis.


REFERENCES:
patent: 4229449 (1980-10-01), Melloni et al.
patent: 5068433 (1991-11-01), Melloni et al.
patent: 5391735 (1995-02-01), Melloni et al.
Cossy, J., et al., “Silylation Selection Par L Hexamethyldisilazane”,Tetrahedron Letters,vol. 28, No. 48, XP-002136947, 6039-6040, (1987).

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