Process for preparing nitrogen-substituted aminotetralins

Details Process for preparing nitrogen-substituted aminotetralins Process for preparing nitrogen-substituted aminotetralins

2000-11-16

2002-04-16

Owens, Amelia (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06372920

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a process for preparing nitrogen-substituted aminotetralins. Particularly, the invention relates to the alkylation of 2-aminotetralins wherein the alkylation is performed in the presence of a base selected from the group consisting of alkali metal carbonate or alkali metal bicarbonate, and wherein the amount of the base is less than about a 1.9-fold molar excess with respect to the starting material.
2. Related Art
A variety of conventional synthetic methods have been used to prepare nitrogen-substituted 2-aminotetralins included in the following Formula (I):
wherein R
1
is OA; R
2
is selected from the group consisting of H and OA; A is H or is selected from the group consisting of hydrocarbyl radicals comprising between 1 and 3 carbon atoms, as well as one of the following radicals
wherein R
5
is selected from the group consisting of alkyl and aromatic residues having from 1 to 20 carbon atoms; R
3
is selected from the group consisting of alkoxy, cycloalkoxy, optionally substituted phenyl, 3-pyridyl, 4-pyridyl,
where X is S, O or NH; R
4
is an unbranched alkyl chain having from 1 to 3 carbon atoms; and n is an integer from 1 to 5.
For example, Horn, A. S., et al.,
Pharmaceutisch Weekblad Sci. Ed.
7:208-211 (1985) describes a reductive amination wherein 2-(N-n-propylamino)-5-methoxytetralin and 2-thiopheneacetic acid are reacted in the presence of trimethylaminoborohydride to produce 2-(N-n-propyl-N-2-thienylethylamino)-5-methoxytetralin. The product is further reacted with a solution of BBr
3
to produce 2-(N-n-propyl-N-2-thienylethylamino)-5-hydroxytetralin. The reaction scheme can be presented as follows, wherein n is 2, R
4
is n-propyl and R
3
is thienyl:
U.S. Pat. No. 5,382,596 describes an alkylation reaction of the following scheme wherein R
4
is an unbranched alkyl chain comprising from 1 to 3 carbon atoms or a cyclopropylmethyl radical and R
6
is —(CH
2
)
n
—R
3
, wherein n is an integer from 1 to 4 and R
3
is alkoxy, cycloalkoxy or a cyclic ether:
U.S. Pat. No. 4,410,519 describes the following alkylation reaction, wherein R
4
is alkyl of 1 to 4 carbon atoms, A is —(CH
2
)
n
—, wherein n is 1 to 5 and Z is a leaving group, preferably chlorine, bromine, iodine, alkylsulfonyloxy or arylsulfonyloxy:
In the above reaction, the presence of the base is optional and it may be, e.g., a tertiary amine or an alkali metal carbonate or bicarbonate.
Conventional alkylation reactions produce acidic by-products from the leaving groups within the alkylating agents employed. If these acidic by-products are not neutralized, the progress of the reaction is frequently harmed either by: (a) the starting material, i.e., the amine, serving as an acid scavenger and precipitating from solution, thereby terminating the reaction, or (b) the acidic by-products degrading the starting material and/or alkylating agent, thereby terminating the reaction or producing increased amounts of impurities. In order to avoid these problems, such alkylations typically employ a large excess of base, commonly greater than two-fold molar excess with respect to the starting material.
The conventional alkylation methods described above suffer from limited product yields resulting from incomplete reactions and inefficient purification procedures required to reduce the levels of impurities. Nitrogen-substituted 2-aminotetralins are useful as pharmaceutical agents that treat a number of diseases and, therefore, product purity is a major concern. Attempts are being made to improve yields and to efficiently produce more pure products. Manufacturing problems are particularly acute when very expensive chiral starting materials are used. It can be readily seen that even minor improvements in process efficiency will result in economic benefits. This is particularly true upon scaleup manufacture of chirally pure products. A need therefore exists for processes of synthesis having improved yields, shorter reaction times and purer products.
SUMMARY OF THE INVENTION
Alkali metal carbonates and alkali metal bicarbonates are used as acid scavengers in alkylation reactions that attach substituents on the nitrogen atom in 2-aminotetralins. It has now been discovered that the amount of alkali metal carbonate or alkali metal bicarbonate used in these alkylation reactions is a critically important factor in the course of the reaction. Applicants found that the amount of alkali metal carbonate or alkali metal bicarbonate should be less than about a 1.9-fold molar excess with respect to the 2-aminotetralin starting material.
It has been discovered that the use of limited amounts of alkali metal carbonate or alkali metal bicarbonate in these reactions gives a more efficient process for preparing N-substituted 2-aminotetralins than the prior art processes used for preparing these compounds, allowing the production of more pure products and, thus, avoiding extensive purification procedures. Accordingly, the present invention provides a process for preparing 2-aminotetralins of the Formula (I):
wherein R
1
is OA; R
2
is selected from the group consisting of H and OA; A is H or is selected from the group consisting of a straight or a branched alkyl chain having from 1 to 3 carbon atoms,
wherein R
5
is selected from the group consisting of C
1
-C
20
alkyl, C
6
-C
10
aryl and C
7
-C
20
arylalkyl; R
3
is selected from the group consisting of alkoxy, cycloalkoxy, optionally substituted phenyl, 3-pyridyl, 4-pyridyl,
where X is S, O or NH; R
4
is an unbranched alkyl chain having from 1 to 3 carbon atoms; and n is an integer from 1 to 5.
The process comprises allowing a 2-aminotetralin of Formula (II):
wherein R
1
, R
2
and R
4
are as defined above, to react with a reactant of Formula (III):
Z—(CH
2
)
n
—R
3
  (III)
wherein R
3
and n are as defined above and Z is a leaving group, in the presence of a base, wherein the base is selected from the group consisting of alkali metal carbonate and alkali metal bicarbonate, and wherein the amount of the base is less than about a 1.9-fold molar excess with respect to the amount of the 2-aminotetralin.
Preferably, from about 0.2 to about 1.8 mole ratio, more preferably from about 0.2 to about 1.5 mole ratio, more preferably from about 0.3 to about 1.3 mole ratio of alkali metal carbonate or alkali metal bicarbonate with respect to the 2-aminotetralin starting material is used. Especially, from about 0.3 to about 1.0 mole ratio, more especially from about 0.4 to 0.8 mole ratio, specifically from about 0.4 to about 0.7 mole ratio, of alkali metal carbonate or alkali metal bicarbonate with respect to the 2-aminotetralin starting material is used as an acid scavenger.
Further, the present invention provides an improvement in a method of alkylating 2-aminotetralin of Formula (II), wherein R
1
, R
2
and R
4
are as defined above, with a reactant of Formula (III), wherein R
3
and n are as defined above and Z is a leaving group, in the presence of a base, the improvement comprising employing abase selected from the group consisting of alkali metal carbonate and alkali metal bicarbonate, wherein the amount of the base is less than about a 1.9-fold molar excess with respect to the amount of the 2-aminotetralin.
Additional embodiments and advantages of the invention will be set forth in part in the description as follows, and in part will be obvious from the description, or may be learned by practice of the invention. The embodiments and advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Applicants found that by reducing the amount of base in a process for preparing nitrogen-substituted 2-aminotetralins of Formula (I) the amount of by-products was essen

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