Process for preparing resorcinol derivatives

Details Process for preparing resorcinol derivatives Process for preparing resorcinol derivatives

2001-03-08

2003-01-07

McKane, Joseph K. (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S341000, C549S397000

Reexamination Certificate

active

06504037

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to an improved process for preparing 4-substituted resorcinol derivatives.
BACKGROUND OF THE INVENTION
Resorcinol derivatives are known to be useful for a variety of purposes. For example, in the cosmetic field, resorcinol derivatives have been used as skin lightening agents. The use of resorcinol derivatives as skin lightening agents is described in European Patent Application EP 904,774, published Mar. 31, 1999; U.S. Pat. No. 5,468,472, issued Nov. 21, 1995; U.S. Pat. No. 5,399,785, issued Mar. 21, 1995; European Patent Application EP 623,339, published Nov. 9, 1994; JP 5-4905, published Jan. 14, 1993; and European Patent Application EP 341,664, published Nov. 15, 1989.
Resorcinol derivatives have also been used as dandruff control agents (JP 4-169516, published Jun. 17, 1992); as anti-acne agents (JP 4-169511, published Jun. 17, 1992); as potentiators of anti-microbial compounds (U.S. Pat. No. 4,474,748, issued Oct. 2, 1984); as anti-browning agents for foods (U.S. Pat. No. 5,304,679, issued Apr. 19, 1994); and in the preparation of photographic dye images (U.S. Pat. No. 3,756, 818, issued Sep. 4, 1973).
The present invention provides an improved process for preparing 4-substituted resorcinol derivatives. The present invention further provides intermediate compounds useful in preparing such resorcinol derivatives, as well as processes for preparing the intermediate compounds. The improved process of the present invention is easier to use than standard methods for preparing resorcinol derivatives in large quantities. In addition, the improved process of the present invention results in a higher yield of final product than standard methods.
SUMMARY OF INVENTION
The invention provides a process for preparing a resorcinol derivative of formula I:
or a pharmaceutically acceptable salt thereof, wherein the dashed line indicates an optional double bond at that position, and wherein X and Y are each independently selected from hydrogen, (C
1
-C
12
)alkyl, (C
2
-C
12
)alkenyl, (C
2
-C
12
)alkynyl, or X and Y are taken together with the carbon to which they are attached to form a (C
4
-C
8
)cycloalkyl ring or (C
5
-C
8
)cycloalkenyl ring, provided that the (C
4
-C
8
)cycloalkyl ring or (C
5
-C
8
)cycloalkenyl ring is not aromatic; which (C
1
-C
12
)alkyl, (C
2
-C
12
)alkenyl, (C
2
-C
12
)alkynyl, (C
4
-C
8
)cycloalkyl ring or (C
5
-C
8
)cycloalkenyl ring is optionally substituted by one to three independently selected groups Z, wherein Z is any substituent capable of being substituted thereon where the process of the present invention can be used to prepare the particular substituted resorcinol derivative.
In a preferred embodiment, Z is selected from the group consisting of cyano; halo; (C
1
-C
6
)alkyl; aryl; (C
2
-C
9
)heterocycloalkyl; (C
2
-C
9
)heteroaryl; aryl(C
1
-C
6
)alkyl-; ═O; ═CHO(C
1
-C
6
)alkyl; amino; hydroxy; (C
1
-C
6
)alkoxy; aryl(C
1
-C
6
)alkoxy-; (C
1
-C
6
)acyl; (C
1
-C
6
)alkylamino-; aryl(C
1
-C
6
)alkylamino-; amino(C
1
-C
6
)alkyl-; (C
1
-C
6
)alkoxy-CO—NH—; (C
1
-C
6
)alkylamino-CO—; (C
2
-C
6
)alkenyl; (C
2
-C
6
)alkynyl; hydroxy(C
1
-C
6
)alkyl-; (C
1
-C
6
)alkoxy(C
1
-C
6
)alkyl-; (C
1
-C
6
)acyloxy(C
1
-C
6
)alkyl-; nitro; cyano(C
1
-C
6
)alkyl-; halo(C
1
-C
6
)alkyl-; nitro(C
1
-C
6
)alkyl-; trifluoromethyl; trifluoromethyl(C
1
-C
6
)alkyl-; (C
1
-C
6
)acylamino-; (C
1
-C
6
)acylamino(C
1
-C
6
)alkyl-; (C
1
-C
6
)alkoxy(C
1
-C
6
)acylamino-; amino(C
1
-C
6
)acyl-; amino(C
1
-C
6
)acyl(C
1
-C
6
)alkyl-; (C
1
-C
6
)alkylamino(C
1
-C
6
)acyl-; ((C
1
-C
6
) alkyl)
2
amino(C
1
-C
6
)acyl-; —CO
2
R
2
; —(C
1
-C
6
)alkyl-CO
2
R
2
; —C(O)N(R
2
)
2
; —(C
1
-C
6
)alkyl-C(O)N(R
2
)
2
; R
2
ON═; R
2
ON═(C
1
-C
6
)alkyl-; R
2
ON═CR
2
(C
1
-C
6
)alkyl-; —NR
2
(OR
2
); —(C
1
-C
6
)alkyl-NR
2
(OR
2
); —C(O)(NR
2
R
2
); —(C
1
-C
6
)alkyl-C(O)(NR
2
OR
2
); —S(O)
m
R
2
; wherein each R
2
is independently selected from hydrogen, (C
1
-C
6
)alkyl, aryl, or aryl(C
1
-C
6
)alkyl-; R
3
C(O)O—, wherein R
3
is (C
1
-C
6
)alkyl, aryl, or aryl(C
1
-C
6
)alkyl-; R
3
C(O)O—(C
1
-C
6
)alkyl-; R
4
R
5
N—C(O)—O—; R
4
R
5
NS(O)
2
—; R
4
R
5
NS(O)
2
(C
1
-C
6
)alkyl-; R
4
S(O)
2
R
5
N—; R
4
S(O)
2
R
5
N(C
1
-C
6
)alkyl-; wherein m is 0, 1 or 2, and R
4
and R
5
are each independently selected from hydrogen or (C
1
-C
6
)alkyl; —C(═NR
6
)(N(R
4
)
2
); —(C
1
-C
6
)alkyl-C(═NR
6
)(N(R
4
)
2
) wherein R
6
represents OR
2
or R
2
wherein R
2
is defined as above; —OC(O)aryl(C
1
-C
6
)alkyl; —NH(C
1
-C
6
)alkyl; aryl(C
1
-C
6
)alkyl-HN—; and a ketal.
The present invention also provides various intermediate compounds useful in this process, and methods for making them. Specifically, this invention relates to a process for preparing a compound of formula (6)
wherein W is hydrogen or a protecting group;
wherein X and Y are each independently selected from hydrogen, (C
1
-C
12
)alkyl, (C
2
-C
12
)alkenyl, (C
2
-C
12
)alkynyl, or X and Y are taken together with the carbon to which they are attached to form a (C
4
-C
8
)cycloalkyl ring or (C
5
-C
8
)cycloalkenyl ring, provided that the (C
4
-C
8
)cycloalkyl ring or (C
5
-C
8
)cycloalkenyl ring is not aromatic; and wherein the (C
1
-C
12
)alkyl, (C
2
-C
12
)alkenyl, (C
2
-C
12
)alkynyl, (C
4
-C
8
)cycloalkyl ring or (C
5
-C
8
)cycloalkenyl ring is optionally further substituted by one to three independently selected groups Z, where Z is as defined above;
comprising reacting a compound of formula (5)
wherein Q is halo, with a base to form the compound of formula (6). In a preferred embodiment, Q is bromo, iodo or chloro; more preferably Q is bromo or iodo; and most preferably Q is bromo.
The present invention further provides a process for preparing a compound of formula
wherein W, X and Y are as defined above;
comprising reacting a compound of formula (5)
wherein Q is as defined above, with a base to form the compound of formula (7).
In a preferred embodiment, the compound of formula (5) is prepared by reacting the compound of formula (4)
wherein W, X and Y are as defined above, with a halogenating agent, wherein the halogen corresponds to Q in the compound of formula (5). In a preferred embodiment, Q is bromo, and the compound of formula (5) is prepared by reacting the compound of formula (4) with a brominating agent such as, e.g., N-bromosuccinimide.
In a further preferred embodiment, the compound of formula (4) is prepared by reacting a compound of formula (2)
with a compound of formula (3)
wherein W, X and Y are as defined above, in the presence of a base to form the compound of formula (4).
The present invention further provides a process for preparing a compound of formula
wherein Q, W, X and Y are as defined above, comprising reacting the compound of formula (4)
with a halogenating agent, as described above, to form the compound of formula (5).
In a preferred embodiment, the compound of formula (4) is prepared by reacting a compound of formula (2)
with a compound of formula (3)
wherein W, X and Y are as defined above, in the presence of a base to form the compound of formula (4).
The present invention further provides a process for preparing a compound of formula
wherein W, X and Y are as defined above; comprising reacting a compound of formula (2)
with a compound of formula (3)
in the presence of a base to form the compound of formula (4).
The present invention further provides a process for preparing a compound of formula I(a)
wherein X and Y are defined as above, comprising:
(a) reacting a compound of formula (5)
wherein Q is halo, W is hydrogen or a protecting group, and X and Y are as defined above, with a base to form a compound of formula (6); and
(b) where W is H, reducing the compound of formula (6) so formed to form the compound of formula I(a); or
(c) where W is a protecting group, reducing the compound of formula (6) so formed and removing the protecting group to form the compound of formula I(a).
In a preferred embodiment, the compound of formula (6) is reduced to form the compound of formula I(a) by reaction with trie

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