Process for the preparation of new antidiabetic agents

Details Process for the preparation of new antidiabetic agents Process for the preparation of new antidiabetic agents

2001-05-30

2003-03-11

Raymond, Richard L. (Department: 1624)

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

Organic compounds

Chalcogen in the nitrogen containing substituent

C560S060000

Reexamination Certificate

active

06531596

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of novel antidiabetic compounds having the formula (1).
where R
1
represents hydrogen or lower alkyl group, and X represents hydrogen or halogen
U.S. patent application Ser. No. 09/012,585, now U.S. Pat. No. 6,054,453, describes a process for the preparation of a novel antidiabetic compound having the formula (1). The process described therein comprises converting aldehyde of formula (2) where X is as defined above to a compound of formula (3) where all symbols are as defined above and R
2
represents lower alkyl group, reducing the compound of formula (3) to produce a compound of formula (4), hydrolysing the compound of formula (4) to obtain an acid of formula (5), converting the acid of formula (5) to an amide of the formula (6) and hydrolysing the amide to produce the compound of formula (1), where X and R
1
are as defined above. The process is shown in the scheme-1 given below
OBJECTIVES OF THE PRESENT INVENTION
The main objective of the present invention is therefore to provide a convergent synthesis of the compounds of the formula (1).
Another objective of the present invention is to provide a convergent and stereoselective synthesis of the compounds of the formula (1) and a commercial viable process.
Another objective of the present invention is to provide a process for the preparation of the compounds of the formula (1) by preparing chiral amine addition salts followed by hydrolysis to afford the uni-isomer of an intermediate which can later be converted into the required isomers having the formula (1). In the event of a small amount of racemization, if any, during the course of converting the intermediate to the final compounds of the formula (1), resolution can easily be done by employing chiral amines without losing much of the compounds of the formula (1).
Accordingly, the present invention provides a process for the preparation of compounds of the formula (1) where R
1
represents hydrogen atom or lower alkyl group such as C
1
-C
6
group preferably methyl, ethyl, propyl and the like, X represents hydrogen atom or halogen atom such as chlorine, bromine or iodine which comprises:
(i) benzylamino p-hydroxybenzldehyde of the formula (7) by conventional methods to yield a compound of the formula (8),
(ii) reacting the compound of the formula (8) with alkyl haloacetates in the presence of a base at a temperature in the range of −10° C. to 60° C. (Darzen's condensation) to yield the glycedic ester of the formula (9) where R represents lower alkyl group,
(iii) opening up the epoxide group of the glycedic ester of the compound of the formula (9) by conventional methods to yield a compound of the formula (10) where R is as defined above,
(iv) hydrolyzing the compound of the formula (10) by conventional methods followed by the resolution of the resultant compound to yield (S)-hydroxy compound of the formula (11),
(v) converting the compound of the formula (11) to the corresponding alkylated compound of the formula (12) where R
1
represents hydrogen or lower alkyl, R
2
represents lower alkyl group in one pot reaction by treating it with an alkylating agent in the presence of base,
(vi) debenzylating the compound of the formula (12) by conventional methods to produce the compound of the formula (13) where R
1
and R
2
are as defined above, if desired,
(vii) converting the compound of the formula (13) to a compound of formula (14) where X represents halogen atom and all other symbols are as defined above by conventional methods,
(viii) reacting either the compound of the formula (13) or the compound of the formula (14) with phenoxazinyl mesylate of the formula (15) to give the ester of the formula (16) where X represents hydrogen or halogen atom, and R
1
and R
2
are as defined above,
(ix) hydrolysing the compound of the formula (16) by conventional methods to yield the compound of the formula (1) defined above, and if desired,
(x) chemically resolving the compound of formula (1) by employing chiral amines, in case there is any racemization during the course of converting the (S)-hydroxy compound of the formula (11) to the final compound of formula (1).
The process explained above is shown in scheme-2 below:
Benzyl protection of p-hydroxybenzaldehyde having the formula (7) affords the protected aldehyde of the formula (8). Reaction of the compound of the formula (8) with alkylhaloacetates such as methyl chloroacetate, methylbromoacetate, ethylchloroacetate, ethylbromoacetate, and the like in the presence of a base such as sodium methoxide, sodium ethoxide, sodium carbonate, potassium carbonate, potassium sec. Butoxide, t-BuOK and the like gives the glycedic ester of the formula (9) where R represents lower alkyl group such as C
1
-C
6
alkyl preferably methyl, ethyl and the like. The glycedic ester of the formula (9) is opened up with reagents such as Raney. Ni, H
2
/Pd—C, borane reagents, and the like to give the racemic hydroxy ester having the formula (10). Hydrolysis of the ester of the formula (10) followed by its resolution using chiral amines such as R(+)&agr;-methylbenzylamine, S(+)-phenylglycinol, cinchonidine, ephedrine, n-octylglucosamine and the like gives the optically active hydroxy acid having the formula (11), which on alkylation using alkylating agents such as diethylsuphate, ethyliodide, methyliodide, dimethylsuphate and the like, in the presence of a base such as NaH, NaOH, KOH, t-BuOK, K
2
CO
3
, NaHCO
3
, and the like, affords the compound of the formula (12) where R
1
represents hydrogen or lower alkyl group such as C
1
-C
6
group preferably methyl, ethyl, propyl and the like, R
2
represents lower alkyl group such as C
1
-C
6
group preferably methyl, ethyl, propyl and the like. The compound of the formula (12) upon debenzylation using reagents such as H
2
/Pd—C, HCl/AcOH, and the like in the presence of solvents such as THF, ethylacetate, 1,4-dioxane, AcOH and the like gives the substituted phenol of the formula (13). The compound of the formula (13) is converted to a compound of formula (14) using suitable halogenating agents such as ICl/HCl, I
2
/KI, Cl
2
/H
+
, Br
2
/AcOH and the like. The optically active compound of the formula (13) or the compound of the formula (14) reacts with the phenoxazinyl mesylate having the formula (15) to give the ester of the formula (16) which on hydrolysis employing conventional methods yields the required compound of the formula (1) in an optically pure form. However, in the event of a small amount of racemization, if any, during the course of converting the intermediate of the formula (11) to the final compound of the formula (1), resolution can easily be done employing chiral amines such as those described above without losing much of the compound of the formula (1).
The present invention also provides another improved process for the preparation of compounds of the formula (1) described above which comprises:
(i) benzylamino p-hydroxybenzaldehyde of the formula (7) by conventional methods to yield a compound of the formula (8),
(ii) reacting the compound of the formula (8) with alkyl haloacetates in the presence of a base at a temperature in the range of −10° C. to 60° C. (Darzen's condensation) to yield the glycedic ester of the formula (9) where R represents lower alkyl group,
(iii) opening up the epoxide group of the glycedic ester of the compound of the formula (9) by conventional methods to yield a compound of the formula (10) where R has the meaning given above,
(iv) alkylating the compound of the formula (10) using alkylating agent in the presence of a base to obtain a compound of the formula (12a) where R
1
represents hydrogen or lower alkyl, R
2
represents lower alkyl group,
(v) debenzylating the compound of the formula (12a) by conventional methods to produce the compound of the formula (13a) where R
1
and R
2
are as defined above, if desired,
(vi) converting the compound of the formula (13a) to a compound of formula (14a) where X represents halogen atom R
1

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