Process for preparing chiral...

Details Process for preparing chiral... Process for preparing chiral...

2000-12-07

2002-07-09

Davis, Brian J. (Department: 1621)

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

Organic compounds

Amino nitrogen containing

C564S486000, C564S488000

Reexamination Certificate

active

06417403

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a process for preparing chiral (S)-2,3-disubstituted-1-propylamine derivatives and more particularly, to the process for preparing chiral (S)-2,3-disubstituted-1-propylamine derivatives expressed in the following formula 1, performed in such a manner that a carbonyl group of chiral (S)-3,4-disubstituted-1-butanecarbonyl derivatives expressed in the following formula 2 is converted to an amine group through decarbonylation without influence on chirality, whereby preparing amine compound whose carbon backbone number is decreased bad one:
wherein,
R
1
represents hydrochloric acid salt (H.HCl), sulfuric acid salt (H.H
2
SO
4
) or —C(O)OR
2
;
R
2
represents linear or branched alkyl chain having carbon atoms of 1-10, benzyl or phenyl group;
X and Y which are same or different, represents a halogen atom, hydroxy group, acetate group, sulfonate group, or in which X and Y are combined to form epoxy group, acetonide group; and
Z represents NH
2
, NHNH
2
or hydroxy group.
2. Description of the Related Art
A chiral (S)-2,3-disubstituted-1-propylamine derivatives expressed in the formula 1 has been well known as key intermediates for preparing &bgr;-blocker used as anti-hypertensive drug. &bgr;-Blocker drugs employing (S)-3-amino-1,2-propanediol or salt thereof as raw material include (S)-atenolol, (S)-metoprolol, (S)-nadolol, (S)-timolol. A numerous study has been conducted on a process for synthesizing a compound expressed in the formula 2 or derivatives thereof as follows:
In the case of a compound having 3 carbon atoms in backbone and chiral hydroxy group at C-2, an introduction of oxygen functional group with chirality to C-2 position may be achieved from a racemic compound having 3 carbon atoms in backbone by biologically selective hydrolysis employing microorganism or enzyme.
Tetrahedron Lett.
27, 2061(1992) discloses the process for preparing chiral 1-amino-2-propanol derivatives through selective hydrolysis of racemic 2-hydroxy-1-propylamide protected by N-phenylacetyl using benzylpenicillinacylase. However, the theoretical yield of hydrolysis using the above enzyme is no more than 50%; thus optical purity is extremely low as optical isomeric ratio is 65:35.
Agric. Biol. Chem.,
48, 2055(1984) and
Agric. Biol. Chem.,
49, 1669(1985) discloses a process for preparing (S)-ester through selective hydrolysis of racemic 2-oxazolidoneester using lipase; however, the yield thereof is 35%, that is to say, very low; and additional 5 steps are required to convert prepared (R)-alcohol to desired (S)-alcohol.
A process for preparing chiral (S)-2,3-dichloro-1-propylacetate through selective hydrolysis of racemic 2,3-dichloro-1-propylacetate using lipase is described in
Agric. Biol. Chem.,
46, 1593(1982); however, the yield thereof is 9-25% which is too low to be commercialized; and on top of that, 4 steps are required to manufacture racemic 2,3-dichloro-1-propylacetate from propene.
U.S. Pat. No. 4,900,847(1990) discloses a process for preparing chiral (S)-2,3-epoxypropanol through catalytic asymmetric epoxidation of allylic alcohol. The process shows higher yield than the above-described, biological selective hydrolysis, while it shows low optical isomeric efficiency, 89%ee. The conventional methods as described above exhibit yield no more than 50%, performed in such a way that racemic compound having 3 carbon atoms in backbone is prepared and then chiral hydroxy group is introduced into it so as to prepare optical active intermediates having 3 carbon atoms in backbone.
SUMMARY OF THE INVENTION
Accordingly, an object of this invention is to provide a novel process for the preparation of chiral (S)-2,3-disubstituted-1-propylamine derivatives using chiral (S)-3,4-disubstituted-1-butanecarbonyl derivatives with high purity as starting material that may be economically obtained from natural product, whereby decreasing the production cost and solving the problems of the conventional methods, i.e. lower optical purity and yield, performed in such a way that chiral center is introduced.
DETAILED DESCRIPTION OF THE INVENTION
This invention is characterized by a process for preparing chiral (S)-2,3-disubstituted-1-propylamine derivatives expressed in the following formula 1, in which a carbonyl group of chiral (S)-3,4-disubstituted-1-butanecarbonyl derivatives expressed in the following formula 2 is converted to an amine group:
wherein,
R
1
represents hydrochloric acid salt (H.HCl), sulfuric acid salt (H.H
2
SO
4
) or —C(O)OR
2
;
R
2
represents linear or branched alkyl chain having carbon atoms of 1-10, benzyl or phenyl group;
X and Y which are same or different, represents a halogen atom, hydroxy group, acetate group, sulfonate group, or in which X and Y are combined to form epoxy group, acetonide; and
Z represents NH
2
, NHNH
2
or hydroxy group.
This invention is explained in more detail as follows:
This invention relates to a process for preparing amine compound whose carbon backbone number is decreased by one, performed in such a manner that a carbonyl group is converted to an amine group without influence on chirality of starting material. The principle mechanism of this invention is explained by Curtius Rearrangement or Hofmann Rearrangement. As reported thus far; there have not been preparative examples that propyl amine derivatives with chiral oxygen substituents at C-2 are prepared simultaneously with decreasing of carbon backbone number from 4 to 3 by Curtius Rearrangement or Hofmann Rearrangement.
This fact may be described as follows:
The following scheme 1 shows a preparing example of a compound of formula 1 through Hofmann Rearrangement using a compound of formula 2 (where, Z is NH
2
).
wherein, X, Y and R
1
are the same as the above-specified.
According to the scheme 1, a chiral (S)-3,4-disubstituted-1-butylamide represented in formula 2a is oxidized to induce Hofmann Rearrangement, which generates isocyanate intermediate and then converted to amino group, finally producing a compound of this invention. If the final product whose R
1
is inorganic acid salt (eg., hydrochloric acid salt (H.HCl), sulfuric acid salt (H.H
2
SO
4
)) is desired, hydrochloric acid or sulfuric acid should be added to a reaction mixture containing an intermediate represented in formula 3; if the final product whose R
1
is carbamate is desired, alcohols should be added to.
According to this invention, it is preferred that the Hofmann Rearrangement is performed in the presence of alkaline metal hydroxide and halogen, or MOX (where, M is alkaline metal atom and X is halogen atom) which is generated in reaction of alkaline metal hydroxide and halogen, such as sodium hypochlorite, sodium hypobromite and potassium hypochlorite.
In the Hofmann Rearrangement, it is preferred that water or polar organic solvent is employed as solvent; more preferably, C
1
-C
10
alcohol. The reaction temperature is preferably in the range of 0-100° C.; more preferably 0-60° C. If the temperature is lower than 0° C., the reaction is scarcely proceeded; but in case of exceeding 100° C., the racemization on chiral center is occurred.
The chiral (S)-3,4-disubstituted-1-butylamide used as starting material in scheme 1 is prepared with optical purity of at least 99%ee by very inexpensive and simple method (Japanese Unexamined Publication No. Sho64-13069), from (S)-3-hydroxybutyrolactone obtained through known method (U.S. Pat. Nos. 5,374,773; 5,319,110; and 5,292,939).
The following scheme 2 represents a preparing example of a compound of formula 1 through Curtius Rearrangement using a compound of formula 2 (where, Z is NHNH
2
).
wherein, X, Y and R
1
are the same as the above-specified; and M is alkaline metal atom such as Na and K.
As shown in the scheme 2, (S)-3,4-disubstituted-1-butylhydrazide represented in formula 2b is reacted with metallic nitrite or alkylnitrite to convert hydrazide group to acylazide group and then is subjected to reflux under reaction solvent, thereby releasing nitrogen gas, finally converting acylnitrene group o

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