Optically active 1,4-benzodioxin-2-carboxylic acid...

Details Optically active 1,4-benzodioxin-2-carboxylic acid... Optically active 1,4-benzodioxin-2-carboxylic acid...

2001-10-18

2003-01-21

Lambkin, Deborah C. (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06509482

ABSTRACT:

1. Field of The Invention
The present invention relates to optically active 1,4-benzodioxin-2-carboxylic acid derivatives which are intermediates useful for the synthesis of (RRR)-optical isomers of 1,4-benzodioxin-2-carboxylic acid derivatives which are useful as a prophylactic and therapeutic agent for diabetes, hyperglycemia and the like, and processes for the preparation thereof. The invention also relates to processes for effectively preparing (RRR)-optical isomers of 1,4-benzodioxin-2-carboxylic acid derivatives using these intermediates.
2. Background Art
WO 96/35685 discloses an (RRR)-optical isomer of 1,4-benzodioxin-2-carboxylic acid derivatives represented by the following general formula (7′) which is useful as a prophylactic and therapeutic agent for diabetes, hyperglycemia and the like, and a process for the preparation thereof.
wherein R
1
is hydroxy or (C
1
-C
4
)alkoxy, and R
2
and R
3
may be the same or different, and each is hydrogen, halogen, (C
1
-C
6
)alkyl, trifluoromethyl, (C
1
-C
6
)alkoxy, aryl, aryloxy or aryl(C
1
-C
6
)alkyloxy, the aryl, aryloxy or aryl(C
1
-C
6
)alkyloxy being optionally substituted by one or two halogens, or R
2
and R
3
may together form —OCH
2
O—.
According to a method disclosed in WO 96/35685, a compound of the above formula (7′) is prepared as shown in the following Scheme I. A compound of formula (6) is reductively condensed with a compound of formula (8) to form a mixture of diastereoisomers of formula (9), which is then converted into an N-tert-butoxy carbonyl derivative of formula (10), and the derivative is separated into diastereoisomers of formulae (11) and (12) by column chromatography, and then a compound of formula (11) is hydrolyzed to prepare an (RRR)-optical isomer of 1,4-benzodioxin-2-carboxylic acid derivatives represented by the formula (7′).
The above-mentioned process has not been accepted as an efficient method, because it forms a compound of formula (12) which is not required for the production of a desired compound [formula (7′)], which resulted in reducing a total yield of the desired compound.
Therefore, it has been demanded to efficiently produce an (RRR)-optical isomer of 1,4-benzodioxin-2-carboxylic acid derivatives represented by the formula (7′), which is useful as a prophylactic and therapeutic agent for diabetes, hyperglycemia and the like.
DISCLOSURE OF THE INVENTION
In view of the above-mentioned problems, the present inventors have zealously studied a process for producing efficiently a compound of formula (7′). As a result, the inventors have succeeded in producing the desired compound in high yield with the reduced formation of unnecessary optical isomers and not accompanied by complicated steps. The present invention is based on findings that optically active alcohols of the following formulae (1) and (2) are useful as starting materials, which can be obtained by acylating racemates of the following formula (3) in the presence of a hydrolase, followed by separation, and also that the desired 1,4-benzodioxin-2-carboxylic acid derivative represented by the above formula (7′) can be produced very efficiently and more selectively via an intermediate of the following formula (7) which can be obtained by condensing an optically active halogenated product or sulfonylated product (a compound of the following formula (5)) obtained by halogenating or sulfonylating these starting materials with an (R)-2-amino-1-phenylethanol derivative (a compound of the following formula (6)).
According to the present invention, a mixture of a compound of formula (2)
wherein R is as defined below and a compound of formula (4)
wherein R is as defined below and X is (C
1
-C
4
)acyl can be obtained by reacting a racemate of formula (3)
wherein R is (R)-1-phenylethylamino or (S)-1-phenylethylamino with an acylating agent in the presence of a hydrolase. Separating the resultant mixture can provide each compound with high optical purity and in high yield. Further, the compound of formula (4) obtained above can be easily converted by hydrolysis or alcoholysis into a compound of formula (1)
wherein R is as defined above.
Further, a compound of formula (7) (which is an intermediate of formula (7′)),
wherein R is as defined above, and R
2
and R
3
may be the same or different and each is hydrogen, halogen, (C
1
-C
6
)alkyl, trifluoromethyl, (C
1
-C
6
)alkoxy, aryl, aryloxy or aryl(C
1
-C
6
)alkyloxy, the aryl, aryloxy or aryl(C
1
-C
6
)alkyloxy being optionally substituted by one or two halogen atoms, or R
2
and R
3
together may form —OCH
2
O—, can be prepared from the compound of formula (1) or (2) easily and in high yield.
The present invention thus provides the compound of formula (1)
wherein R is (R)-1-phenylethylamino or (S)-1-phenylethylamino.
The invention also provides the compound of formula (2)
wherein R is (R)-1-phenylethylamino or (S)-1-phenylethylamino.
Further, the present invention provides a process for preparing the compound of formula (1)
wherein R is as defined above and the compound of formula (2)
wherein R is as defined above, which comprises the steps of: reacting the racemate of formula (3)
wherein R is (R)-1-phenylethylamino or (S)-1-phenylethylamino with an acylating agent in the presence of a hydrolase to give the compound of formula (4)
wherein R is as defined above and X is (C
1
-C
4
)acyl and the compound of formula (2)
wherein R is as defined above, followed by separation, and subjecting the compound of formula (4) to alcoholysis or hydrolysis.
Further, the invention provides a process for preparing the compound of formula (7)
wherein R, R
2
and R
3
are as defined below, which comprises the steps of:
reacting the compound of formula (1)
wherein R is (R)-1-phenylethylamino or (S)-1-phenylethylamino or the compound of formula (2)
wherein R is (R)-1-phenylethylamino or (S)-1-phenyl-ethylamino with a halogenating agent or a sulfonylating agent, and condensing the resulting compound of formula (5)
wherein R is as defined above and Y is halogen, (C
1
-C
4
)alkylsulfonyloxy or arylsulfonyloxy with the compound of formula (6)
wherein R
2
and R
3
may be the same or different, and each is hydrogen, halogen, (C
1
-C
6
)alkyl, trifluoromethyl, (C
1
-C
6
)alkoxy, aryl, aryloxy or aryl(C
1
-C
6
)alkyloxy, the aryl, aryloxy or aryl(C
1
-C
6
)alkyloxy being optionally substituted by one or two halogen atoms, or R
2
and R
3
together may form —OCH
2
O—.
The compounds of formulae (1) and (2) are very useful as starting materials for the compound of formula (7′) which is useful as medicines and the compound of formula (7) which is an intermediate for the compound of formula (7′).
Specific examples of the compounds of formulae (1) and (2) include 6-(2-(R)-hydroxypropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide, 6-(2-(R)-hydroxypropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(R)-phenylethyl))-2-(R)-carboxamide, 6-(2-(S)-hydroxypropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(R)-phenylethyl))-2-(R)-carboxamide, and 6-(2-(S)-hydroxypropyl)-2,3-dihydro-1,4-benzodioxin-(N-(1-(S)-phenylethyl))-2-(R)-carboxamide.
As shown in the following Scheme II, the racemate of formula (3) is reacted with an acylating agent in the presence of a hydrolase to produce a mixture of the compound of formula (2) and the compound of formula (4).
Such a mixture can be separated into each compound by any of known separation methods based on differences in physical and chemical properties of each compound. These separation methods include fractional crystallization, fractional distillation, chromatography, fractional extraction and the like.
In formula (4), X represents a (C
1
-C
4
)acyl group, examples of which can include acetyl, propionyl, n-butyryl and isobutyryl.
Hydrolases which can be used in the present invention include lipase or esterase, specific examples of which include Candida cylindrarea (trade name “Ald. Type III Lipase”, manufactured by Aldrich), Pseudomonas cepacia (trade name “Lipase PS”, manufactured by Amano

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