Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2001-09-12
2003-04-01
Davis, Brian J. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C564S413000, C549S075000
Reexamination Certificate
active
06541668
ABSTRACT:
Certain 3-aryloxy-3-arylpropylamines are known to possess central nervous system activity. See U.S. Pat. Nos. 5,744,474; 5,023,269; 4,956,388; 4,194,009; 4,314,081 and 5,658,590. The present application relates to processes for preparing 3-aryloxy-3-arylpropylamines, including duloxetine and tomoxetine.
Syntheses of 3-aryloxy-3-arylpropylamines utilizing nucleophilic aromatic displacement are known in the art. For example U.S. Pat. Nos. 5,225,585; 5,166,437; 5,023,269; 4,956,388; 5,362,886; and 5,023,269
; Tetrahedron Letters
, 31(49), 7101-7104 (1990); and PCT Publication No. WO 94/00416.
The nucleophilic aromatic displacement reaction with 3-hydroxy-3-arylpropylamines is facile for activated aryl halides. A variety of dipolar solvents, for example, dimethylsulfoxide (WO 94/00416) and 1,3-dimethyl-2-imidazolidinone and N-methylpyrrolodinone (U.S. Pat. No. 5,847,214) have been reported for the reaction of N-methyl-3-phenyl-3-hydroxypropylamine with 4-trifluoromethyl-1-chlorobenzene to give N-methyl-(4-trifluoromethylphenoxy)-3-phenylpropylamine (fluoxetine).
Nucleophilic aromatic displacement of alkoxides in 1,3-dimethyl-2-imidazolidinone are described in Japanese Kokoku Patent Publication Sho 60-23656, published Jun. 8, 1985. However, the description is limited to lower order alcohols and the exemplified preparations using unactivated aromatics are carried out at temperatures of from 160° to 190° C. in a pressure vessel reactor. See Japanese Kokoku Patent Publication Sho 60-23656, published Jun. 8, 1985, examples 7-9, 11, and 14. Thus, it does not appear that 1,3-dimethyl-2-imidazolidinone would a be useful solvent in a safe and convenient nucleophilic aromatic displacement with complex alcohols using unactivated aromatics. This is especially so for aromatics such as 2-fluorotoluene which has a boiling point of 113-114° C.
In addition, the reported reaction of unactivated substrate, 2-fluorotoluene, with the alkoxide of (S)-N-methyl-3-phenyl-3-hydroxypropylamine in dimethylsulfoxide gave a modest yield.
Tet. Let
., 35, 1339-1342 (1994).
In spite of the difficulties with using unactivated aryl halides, a method for preparing 3-aryloxy-3-arylpropylamines using nucleophilic aromatic displacement is desirable. In contrast to methods utilizing other displacements, such as the Mitsunobu reaction or displacement of a halide by a phenol, the nucleophilic aromatic displacement method allows for cost efficient assembly of the required substituents directly from a 3-hydroxy-3-arylpropylamine.
Surprisingly, we have discovered that nucleophilic aromatic displacement using complex benzylic alcohols, such as N-methyl-3-phenyl-3-hydroxypropylamine and N,N-dimethyl-3-(2-thienyl)-3-hydroxypropylamine can be carried out with unactivated aromatics, such as 1-fluoronaphthylene and 2-fluorotoluene in 1,3-dimethyl-2-imidazolidinone or N-methylpyrrolidinone at temperatures of less than about 140° C.
The present processes provide safe and convenient methods for a high yield preparation of 3-aryloxy-3-arylpropylamines utilizing nucleophilic aromatic displacement on unactivated aromatics in 1,3-dimethyl-2-imidazolidinone or N-methylpyrrolidinone.
The present invention relates to a process for preparing a 3-aryloxy-3-arylpropylamine of the formula
wherein
Ar is phenyl or 2-thienyl,
Ar
1
is 1-naphthyl, 2-methoxyphenyl, 2-thiomethoxyphenyl, or 2-methylphenyl;
G is hydrogen or methyl,
and the pharmaceutically-acceptable addition salts thereof comprising the steps of:
(a) reacting an alkoxide of a 3-hydroxy-3-arylpropylamine of the formula
wherein
Ar and G are as defined above
with a haloaromatic of the formula
Ar
1
—X
wherein
Ar
1
—X is 2-fluorotoluene, 2-chlorotoluene, 1-fluoronaphthalene, 1-chloronaphthalene, 2-fluoroanisole, 2-chloroanisole, 2-fluorothioanisole, or 2-chlorothioanisole, in 1,3-dimethyl-2-imidazolidinone or N-methylpyrrolidinone to give the 3-aryloxy-3-arylpropylamine;
(b) optional N-demethylated of the 3-aryloxy-3-arylpropylamine wherein G is methyl to give the 3-aryloxy-3-arylpropylamine wherein G is hydrogen;
(c) optional resolution of the 3-aryloxy-3-arylpropylamine to give a specific isomer of the 3-aryloxy-3-arylpropylamine; and
(d) optional formation of an acid addition salt using a pharmaceutically-acceptable acid.
That is, the present invention provides a process for preparing a 3-aryloxy-3-arylpropylamine, as defined above and the pharmaceutically acceptable salts thereof, which comprises reacting an alkoxide of 3-hydroxy-3-arylpropylamine of the formula
wherein
Ar and G are as defined above with a haloaromatic as defined above, characterized in that, 1,3-dimethyl-2-imidazolidinone or N-methylpyrrolidinone is used as solvent.
Particularly, the present invention relates to a process for preparing tomoxetine and the pharmaceutically-acceptable addition salts thereof comprising the steps of:
(a) reacting an alkoxide of N-methyl-3-phenyl-3-hydroxypropylamine with 2-fluorotoluene in 1,3-dimethyl-2-imidazolidinone to give N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine;
(b) resolution of N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine to give (R)-N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine (tomoxetine); and
(c) optional formation of an acid addition salt using a pharmaceutically-acceptable acid.
The present invention also relates to a particular process for preparing tomoxetine and the pharmaceutically-acceptable addition salts thereof comprising the steps of:
(a) reacting an alkoxide of N,N-dimethyl-3-phenyl-3-hydroxypropylamine) with 2-fluorotoluene in 1,3-dimethyl-2-imidazolidinone to give N,N-dimethyl-3-(2-methylphenoxy)-3-phenylpropylamine;
(b) N-demethylated N,N-dimethyl-3-(2-methylphenoxy)-3-phenylpropylamine to give N-methyl-3-(2-methylphenoxy) -3-phenylpropylamine;
(c) resolution of N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine to give (R)-N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine (tomoxetine); and
(d) optional formation of an acid addition salt using a pharmaceutically-acceptable acid.
That is, the present invention relates to processes for preparing tomoxetine and the pharmaceutically-acceptable addition salts thereof, which comprises, reacting an alkoxide of N-methyl-3-phenyl-3-hydroxypropylamine, or an N-protected derivative thereof, with 2-fluorotoluene, characterized in that, 1,3-dimethyl-2-imidazolidinone is used as solvent.
As used herein, the following terms have the meanings indicated:
(a) the term “DMI” refers to 1,3-dimethyl-2-imidazolidinone;
(b) the term “NMP” refers to N-methylpyrrolidinone;
(c) the term “ee” or “enantomeric excess” refers to the percent by which one enantomeric, E
1
, is in excess in a mixture of both enantiomers (E
1
+E
2
), as calculated by the equation {(E
1
−E
2
). (E
1
+E
2
)}×100% =ee;
(d) the term “pharmaceutically-acceptable addition salt” refers to an acid addition salt using a pharamaceutically-acceptable acid.
The 3-aryloxy-3-arylpropylamines and the intermediates described herein form pharmaceutically acceptable acid addition salts with a wide variety of organic and inorganic acids and include the physiologically acceptable salts which are often used in pharmaceutical chemistry.
A pharmaceutically-acceptable addition salt is formed from a pharmaceutically-acceptable acid as is well known in the art. Such salts are also part of this invention. Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydriodic, nitric, sulfuric, phosphoric, hypophosphoric, metaphosphoric, pyrophosphoric, and the like. Salts derived from organic acids, such as aliphatic mono and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, may also be used. Such pharmaceutically acceptable salts thus include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, &agr;-hydroxybutyrate
Kjell Douglas Patton
Lorenz Kurt Thomas
Davis Brian J.
Eli Lilly and Company
Stemerick David M.
Titus Robert D.
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