Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2002-04-08
2004-03-23
Davis, Brian (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C564S376000, C564S384000, C564S386000, C564S446000, C564S447000, C564S448000
Reexamination Certificate
active
06710210
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a novel N-substituted-aminomethyl cyclopropyl ketone derivative or a salt thereof and a production process therefor, as well as to production processes for an aminomethyl cyclopropyl ketone derivative or a salt thereof, for an 2-amino-1-cyclopropylethanol derivative or a salt thereof and for a N-substituted-2-amino-1-cyclopropylethanol derivative or a salt thereof, using the N-substituted-aminomethyl cyclopropyl ketone derivative or a salt thereof as a starting material.
2. Description of the Related Art
Aminomethyl cyclopropyl ketone derivatives, hydrohalide salts thereof, 2-amino-1-cyclopropylethanol derivatives and hydrohalide salts thereof are useful as, for example, pharmaceutical intermediates (e.g., Chem. Pharm. Bull. 36, 11, 4435 (1988)).
Aminomethyl cyclopropyl ketone may be produced by a process, in which an isocyanoacetic ester is allowed to react with an acid chloride to thereby yield an &agr;-C-acylglycine ester, and the &agr;-C-acylglycine ester is then hydrolyzed. However, such an acid chloride used in the process is difficult to handle. The material isocyanoacetic ester is not easily available, since it must be synthetically obtained from a precursor N-formylglycine ester, and the production procedure of the precursor requires highly toxic phosgene. In addition, this process does not provide a sufficient overall yield of aminomethyl cyclopropyl ketone.
Conventionally, 2-amino-1-cyclopropylethanol is produced by a process in which cyclopropanecarboxaldehyde is nitrated and is then reduced. However, this process requires dangerous nitromethane in the nitration step and an expensive reducing agent in the reduction step. In addition, the resulting yield is not satisfactory.
PCT International Publication Number WO 00/09481 describes a synthesis example of a N-benzylaminomethyl cyclopropyl ketone derivative using 2-(3,5-dichlorophenyl)-2-propylamine having two substituents at the benzylic position. However, the resulting N-benzylaminomethyl cyclopropyl ketone derivative obtained by this process cannot yield, through a simple and easy reaction, 2-amino-1-cyclopropylethanol that is practically used as a pharmaceutical intermediate.
SUMMARY OF THE INVENTION
Accordingly, an object of the present invention is to provide a novel N-substituted-aminomethyl cyclopropyl ketone derivative or a salt thereof which are useful for the preparation of aminomethyl cyclopropyl ketone derivatives, 2-amino-1-cyclopropylethanol derivatives, or salts thereof, as well as to provide a production process for the N-substituted-aminomethyl cyclopropyl ketone derivative or a salt thereof.
Another object of the present invention is to provide production processes for an aminomethyl cyclopropyl ketone derivative or a salt thereof and for a N-substituted-2-amino-1-cyclopropylethanol derivative or a salt thereof, which are useful for the preparation of 2-amino-1-cyclopropylethanol derivatives or salts thereof.
A further object of the present invention is to provide a process for efficiently producing an 2-amino-1-cyclopropylethanol derivative or a salt thereof from an easily available material through a simple and easy reaction.
After intensive investigations to achieve the above objects, the present inventors have found that such an aminomethyl cyclopropyl ketone derivative or a salt thereof and an 2-amino-1-cyclopropylethanol derivative or a salt thereof can easily be obtained from a novel N-substituted-aminomethyl cyclopropyl ketone derivative or a salt thereof. The present invention has been accomplished based on these findings.
Specifically, the present invention provides, in one aspect, a N-substituted-aminomethyl cyclopropyl ketone derivative represented by following Formula (1):
wherein R
1
, R
2
and R
3
are the same or different and are each a hydrogen atom or an aliphatic hydrocarbon group; and R
4
and R
5
are the same or different and are each a hydrogen atom or an arylmethyl group which may have a substituent, where at least one hydrogen atom or aryl group as a substituent is combined with a carbon atom in the methyl moiety-of the arylmethyl group, and at least one of R
4
and R
5
is an arylmethyl group which may have a substituent, or a salt thereof.
The present invention provides, in another aspect, a process for producing the N-substituted-aminomethyl cyclopropyl ketone derivative represented by Formula (1) or a salt thereof. The process includes the step of aminating a cyclopropyl halomethyl ketone derivative represented by following Formula (2):
wherein X is a halogen atom; and R
1
, R
2
and R
3
are the same or different and are each a hydrogen atom or an aliphatic hydrocarbon group, by a reaction with a primary or secondary amine represented by following Formula (3):
wherein R
4
and R
5
are the same or different and are each a hydrogen atom or an arylmethyl group which may have a substituent, where at least one hydrogen atom or aryl group as a substituent is combined with a carbon atom in the methyl moiety of the arylmethyl group, and at least one of R
4
and R
5
is an arylmethyl group which may have a substituent.
In a further aspect, the present invention provides a process for producing an aminomethyl cyclopropyl ketone derivative represented by following Formula (4):
wherein R
1
, R
2
and R
3
have the same meanings as defined above, or a salt thereof. The process includes the step of hydrogenolyzing the N-substituted-aminomethyl cyclopropyl ketone derivative represented by Formula (1) or a salt thereof.
In yet another aspect, the present invention provide a process for producing an 2-amino-1-cyclopropylethanol derivative represented by following Formula (5):
wherein R
1
, R
2
and R
3
have the same meanings as defined above, or a salt thereof. The process includes the steps of hydrogenolyzing the N-substituted-aminomethyl cyclopropyl ketone derivative represented by Formula (1) or a salt thereof to thereby yield the aminomethyl cyclopropyl ketone derivative represented by Formula (4) or a salt thereof, and reducing the resulting compound.
The present invention provides, in another aspect, a process for producing a N-substituted-2-amino-1-cyclopropylethanol derivative represented by following Formula (6):
wherein R
1
, R
2
, R
3
, R
4
and R
5
have the same meanings as defined above, or a salt thereof. The process includes the step of reducing the N-substituted-aminomethyl cyclopropyl ketone derivative represented by Formula (1) or a salt thereof.
The present invention further provides, in yet another aspect, a process for producing the 2-amino-1-cyclopropylethanol derivative represented by Formula (5) or a salt thereof. The process includes the steps of reducing the N-substituted-aminomethyl cyclopropyl ketone derivative represented by Formula (1) or a salt thereof to thereby yield the N-substituted-2-amino-1-cyclopropylethanol derivative represented by Formula (6) or a salt thereof, and hydrogenolyzing the resulting compound.
In addition and advantageously, the present invention provides a process for producing an aminomethyl cyclopropyl ketone derivative represented by following Formula (8):
wherein R
1
, R
2
, R
3
and R
6
have the same meanings as defined above, or a salt thereof. This process includes the step of partially hydrogenolyzing a N-substituted-aminomethyl cyclopropyl ketone derivative represented by following Formula (7):
wherein R
1
, R
2
and R
3
have the same meanings as defined above; and R
6
and R
7
are the same or different and are each an arylmethyl group which may have a substituent, where at least one hydrogen atom or aryl group as a substituent is combined with a carbon atom in the methyl moiety of the arylmethyl group, or a salt thereof.
By these configurations, the present invention can easily yield the novel N-substituted-aminomethyl cyclopropyl ketone derivative or a salt thereof which are useful for the preparation of aminomethyl cyclopropyl ketone derivatives or salts thereof, and 2-amino-1-cyclopropylethanol derivatives or salts ther
Ikura Kiyoshi
Pan Li Rui
Tanaka Hiroki
Daicel Chemical Industries Ltd.
Davis Brian
LandOfFree
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