Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
2002-10-08
2004-11-23
Killos, Paul J. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C562S848000, C562S840000, C568S630000, C568S631000
Reexamination Certificate
active
06822114
ABSTRACT:
BACKGROUND
Roflumilast (CAS 162401-32-3) is a member of a class of fluoroalkoxy-substituted benzamides developed by BYK Gulden Lomberg Chemische Fabrik GmbH. See U.S. Pat. No. 5,712,298 to Hermann Amschler. The compounds are indicated to be useful as phosphodiesterase inhibitors. Roflumilast itself is an once-daily oral phosphodiesterase inhibitor in phase III trials to treat asthma and pulmonary obstructive disease. Another indication of dermatitis is still in preclinical stage. The chemical name of roflumilast is 3-(cyclopropylmethoxy)-N-(3,5-dichloro4-pyridiny)-4-(difluoromethoxy)benzamide.
The best known published route to roflumilast and its congeners is a six-step process with an overall yield of only 4 percent. Another previously-known synthetic route is a five-step procedure involving a Reimer-Tiemann reaction. Attempts to carry out this synthetic route failed; the particular Reimer-Tiemann reaction could not be reproduced.
A need exists for a practical process for production of roflumilast and its congeners capable of forming the products in good overall yields using available starting materials.
This invention is deemed to fulfill this need in an efficient manner.
BRIEF SUMMARY OF THE INVENTION
3,4-Disubstituted benzoic acid esters, 3,4-disubstituted benzoic acids, and 3,4-disubstituted benzoyl chlorides or bromides, in which the substituent in the 3-position, R
1
, is a C
1-6
alkoxy, C
3-7
cycloalkoxy, C
3-7
cycloalkylmethoxy, or benzyloxy group, or a C
1-4
alkoxy group which is completely or partially substituted by fluorine, and in which the substituent in the 4-position, R
2
, is a C
1-4
alkoxy group which is completely or partially substituted by fluorine, are useful intermediates for the preparation of many of the fluoroalkoxy-substituted benzamides described in U.S. Pat. No. 5,712,298 to Hermann Amschler. This invention thus provides, inter alia, processes for the preparation of such 3,4-disubstituted benzoic acid esters, 3,4-disubstituted benzoic acids, and 3,4-disubstituted benzoyl chlorides or bromides.
This invention provides a process for the preparation of a 3,4-disubstituted benzoyl compound in which the substituent in the 3-position, R
1
, is a C
1-6
alkoxy, C
3-7
cycloalkoxy, C
3-7
cycloalkylmethoxy, or benzyloxy group, or a C
1-4
alkoxy group which is completely or partially substituted by fluorine, and in which the substituent in the 4-position, R
2
, is a C
1-4
alkoxy group which is completely or partially substituted by fluorine, which process comprises:
A) alkylating an ortho-R
1
-substituted para-halophenol in which the para-halo substituent is a chloro, bromo, or iodo substituent with an alkylating agent which is a C
1-4
monobaloalkane in which the halo substituent is chloro, bromo, or iodo, and in which said monohaloalkane is otherwise completely or partially substituted by fluorine, to form a product comprised of a 1-halo-3,4-disubstituted benzene in which the substituent in the 3-position is R
1
, and in which the substituent in the 4-position is R
2
;
B) carbonylating 1 -halo-3,4-disubstituted benzene from A) with carbon monoxide to form a product comprised of a 3,4-disubstituted benzoyl compound in which the substituent in the 3-position is R
1
, and in which the substituent in the 4-position is R
2
.
In further embodiments, 3,4-disubstituted benzoyl compound from B) is converted using aniline, 4-aminopyridine, aniline which is substituted by R
31
, R
32
, and R
33
, or 4-aminopyridine which is substituted by R
34
, R
35
, R
36
, and R
37
wherein:
R
31
, is hydroxyl, halogen, cyano, carboxyl, trifluoromethyl, C
1-4
alkyl, C
1-4
alkoxy, C
1-4
alkoxycarbonyl, C
1-4
alkylcarbonyl, C
1-4
alkylcarbonyloxy, amino, mono- or di-C
1-4
alkylamino or C
1-4
alkylcarbonylarmino;
R
32
is hydrogen, hydroxyl, halogen, amino, trifluororethyl, C
1-4
alkyl, or C
1-4
alkoxy;
R
33
is hydrogen, halogen, amino, C
1-4
alkyl, or C
1-4
alkoxy;
R
34
is hydroxyl, halogen, cyano, carboxyl, C
1-4
alkyl, C
1-4
alkoxy, C
1-4
alkoxycarbonyl, or amino;
R
35
is hydrogen, halogen, amino, or C
1-4
alkyl;
R
36
is hydrogen or halogen; and
R
37
is hydrogen or halogen;
into a product comprised of the resultant 3,4-disubstituted benzamide.
A preferred embodiment of this invention is a process for the preparation of a 3,4-disubstituted benzoic acid ester in which the substituent in the 3-position, R
1
,is a C
1-6
alkoxy, C
3-7
cycloalkoxy, C
3-7
cycloalkylmethoxy, or benzyloxy group, or a C
1-4
alkoxy group which is completely or partially substituted by fluorine, and in which the substituent in the 4-position, R
2
, is a C
1-4
alkoxy group which is completely or partially substituted by fluorine, which process comprises:
A) alkylating an ortho-R
1
-substituted para-halophenol in which the para-halo substituent is a chloro, brormo, oriodo substituent with an alkylating agent which is a C
1-4
monohaloalkane in which the halo substituent is chloro, bromo, or iodo, and in which said monohaloalkane is otherwise completely or partially substituted by fluorine, to form a product comprised of a 1-halo-3,4-disubstituted benzene in which the substituent in the 3-position is R
1
, and in which the substituent in the 4-position is R
2
;
B) carbonylating 1-halo-3,4-disubstituted benzene from A) with carbon monoxide under alkaline conditions and in the presence of an alcohol to form a product comprised of a 3,4-disubstituted benzoic acid ester in which the substituent in the 3-position is R
1
, and in which the substituent in the 4-position is R
2
.
A preferred way of converting the 3,4-disubstituted benzoyl compound formed in B)—in this particular case a 3,4-disubstituted benzoic acid ester—to the desired 3,4-disubstituted benzamide comprises hydrolyzing 3,4-disubstituted benzoic acid ester from B) to the corresponding 3,4-disubstituted benzoic acid. 3,4-Disubstituted benzoic acid formed by the hydrolysis can be readily converted to the corresponding 3,4-disubstituted benzoyl chloride or bromide, for example by reaction with SOCl
2
or SOBr
2
. Such 3,4-disubstituted benzoyl chloride or bromide can then be amidated with aniline, 4-aminopyridine, aniline which is substituted by R
31
, R
32
, and R
33
, or 4-aminopyridine which is substituted by R
34
, R
35
, R
36
, and R
37
, wherein R
31
, R
32
, R
33
, R
34
, R
35
, R
36
, and R
37
are as described above, to form a product comprised of the resultant 3,4-disubstituted benzamide.
Another of the preferred embodiments of this invention is a process for the preparation of a 3,4-disubstituted benzoic acid ester in which the substituent in the 3-position, R
1
,is a C
1-6
alkoxy, C
3-7
cycloalkoxy, C
3-7
cycloalkylmethoxy, or benzyloxy group, or a C
1-4
alkoxy group which is completely or partially substituted by fluorine, and in which the substituent in the 4-position, R
2
, is a C
1-4
alkoxy group which is completely or partially substituted by fluorine, which process comprises:
a) halogenating (i) an ortho-R
1
-substituted phenol to form a product comprised of (ii) an ortho-R
1
-substituted para-halophenol in which the para-halo substituent of (ii) is a chloro, bromo, or iodo substituent;
b) alkylating ortho-R
1
-substituted para-halophenol from a) with an alkylating agent which is a C
1-4
monohaloalkane in which the halo substituent is chloro, bromo, or iodo, and in which said monohaloalkane is otherwise completely or partially substituted by fluorine, to form a product comprised of (iii) a 1-halo-3,4-disubstituted benzene in which the substituent in the 3-position is R
1
, and in which the substituent in the 4-position is R
2
;
c) carbonylating 1-halo-3,4-disubstituted benzene from b) with carbon monoxide under alkaline conditions and in the presence of an alcohol to form a product comprised of (iv) an 3,4-disubstituted benzoic acid ester in which the substituent in the 3 -position is R
1
, and in which the substituent in the 4-position is R
2
.
As noted above, 3,4-disubstituted benzoic acid ester formed in the carbonylation reaction can readily be hydrolyzed to the corresponding 3,4-disubstituted b
Williams Eric L.
Wu Tse-Chong
Albemarle Corporation
Killos Paul J.
Spielman, Jr. Edgar E.
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