Preparing amidines derived from...

Details Preparing amidines derived from... Preparing amidines derived from...

2002-04-26

2003-11-25

Shah, Mukund J. (Department: 1624)

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

Organic compounds

Unsubstituted hydrocarbyl chain between the ring and the -c-...

C544S376000, C546S196000, C548S204000, C548S214000, C548S527000, C549S060000, C549S405000, C549S407000

Reexamination Certificate

active

06653472

ABSTRACT:

This application is a 371 or PCT/FR00/02417 filed Sep. 1, 2000.
The present invention relates to a new process for the synthesis of amidine derivatives of (−)-6-hydroxy-2,5,7,8-tetramethylchromane-2-carboxylic acid.
Amidine derivatives of (−)-6-hydroxy-2,5,7,8-tetramethylchromane-2-carboxylic acid, and in particular (S)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide, are described in the PCT Patent Applications WO 98/42696 and WO 98/58934. These compounds have the advantage of inhibiting both the NO synthases (NOS) and the formation of reactive oxygen species or ROS.
An important intermediate in the synthesis of the above-mentioned amidines is (−)-6-hydroxy-2,5,7,8-tetramethylchromane-2-carboxylic acid. Processes for the preparation of this product and of (−)-6-benzyloxy-2,5,7,8-tetramethylchromane-2-carboxylic acid have been described in the following article: Scott et al.,
Journal of the American Oil Chemist's Society
, May 1974, 200-203. This product is also marketed under the name Trolox®.
The Applicant has perfected a new process for the preparation of amidine derivatives of (−)-6-hydroxy-2,5,7,8-tetramethylchromane-2-carboxylic acid, which uses new synthesis intermediates. The said process has the advantage of being able to be used on an industrial scale and offers both a very good overall yield and a very pure product.
The Applicant has also developed a new process for resolving 6-benzyloxy-2,5,7,8-tetramethylchromane-2-carboxylic acid, which makes it possible to easily obtain an enantiomeric excess of greater than 99% for any of the enantiomers.
The invention relates firstly to the new products of general formula (II)B
in racemic, enantiomeric form or any combination of these forms, general formula (II)B in which
A′ represents the
 radical,
X represents —Z
1
—CO—;
&rgr; represents a bond or a heterocycle chosen from the group constituted by the piperidine, piperazine, homopiperazine, 2-methylpiperazine, 2,5-dimethyl-piperazine, 4-aminopiperidine radicals;
Y represents a radical chosen from the —Z
2
— and —NR
3
—Z
2
radicals,
R
3
representing a hydrogen atom, a linear or branched alkyl radical having from 1 to 6 carbon atoms or a —COR
4
radical,
R
4
representing a linear or branched alkyl radical having from 1 to 6 carbon atoms;
Z
1
and Z
2
represent independently a single bond or a linear or branched alkylene radical having from 1 to 6 carbon atoms, Z
1
and Z
2
preferably representing —(CH
2
)
m
—,
m being an integer comprised between 0 and 6;
R
6
represents a hydrogen atom or an OH group.
The products of general formula (II)B are useful in the preparation of amidines of general formula (I) described hereafter.
Optically active products can be prepared by resolving 6-benzyloxy-2,5,7,8-tetramethylchromane-2-carboxylic acid, then by syntheses similar to those described in the PCT Patent Applications WO 98/42696 and WO 98/58934.
The invention therefore also relates to the use of the previously-described products of general formula (II)B in the preparation of amidines of general formula (I)
in which
A represents the
 radical,
B represents a carbocyclic aryl or heterocyclic aryl radical with 5 or 6 members containing from 1 to 4 heteroatoms chosen from O, S, N and in particular the thiophene, furane, pyrrole or thiazole radicals, the aryl radical being optionally substituted by one or more groups chosen from the linear or branched alkyl, alkenyl or alkoxy radicals having 1 to 6 carbon atoms;
X represents —Z
1
—CO—;
&rgr; represents a bond or a heterocycle chosen from the group constituted by the piperidine, piperazine, homopiperazine, 2-methylpiperazine, 2,5-dimethyl-piperazine, 4-aminopiperidine radicals;
Y represents a radical chosen from the —Z
2
— and —NR
3
—Z
2
radicals,
R
3
representing a hydrogen atom, a linear or branched alkyl radical having from 1 to 6 carbon atoms or a —COR
4
radical,
R
4
representing a linear or branched alkyl radical having from 1 to 6 carbon atoms;
Z
1
and Z
2
represent independently a single bond or a linear or branched alkylene radical having from 1 to 6 carbon atoms, Z
1
and Z
2
preferably representing —(CH
2
)
m
—,
m being an integer comprised between 0 and 6;
R
6
represents a hydrogen atom or an OH group;
use characterized in that it consists of subjecting the product of general formula (II)B to the following successive stages:
1) catalytic reduction of the nitro compound of general formula (II)B
 in which
X, &rgr;, Y and R
6
have the same meaning as in general formula (I);
and A′ represents the
 radical,
in a lower alcohol, preferably such as methanol, ethanol or isopropyl alcohol, by the action of a hydrogen donor in the presence of Pd/C in order to produce the amino compound of general formula (III)
 in which A, X, &rgr;, Y and R
6
have the same meaning as in general formula (I);
2) reaction, in a lower alcohol, such as methanol, ethanol, isopropyl alcohol or t-butanol, preferably in isopropyl alcohol, at a temperature comprised between 20 and 90° C., for example at 50° C., and lasting one to 48 hours, preferably lasting 15 to 24 hours, optionally in the presence of DMF, of the compound of general formula (III) described previously
 with the compound of general formula (IV)
in which B has the same meaning as in general formula (I) and L represents a parting group and in particular an alkoxy, alkylthio, aralkylthio, sulphonic acid, halide, aryl alcohol or tosyl radical (other parting groups well known to a person skilled in the art and able to be optionally used for the invention are described in the following work:
Advanced Organic Chemistry
, J. March, 3rd Edition (1985), McGraw-Hill, p. 315), the compound of general formula (IV) being optionally salified by a mineral acid G. Preferably, G represents HCl, HBr or HI.
The compounds of general formula (I) contain an asymmetrical centre and present isomer forms. The process according to the invention makes it possible to obtain the racemic mixtures or the enantiomers of these compounds depending on the choice of a racemic or optically active product as starting product.
The products of general formula (I) can, if appropriate, be obtained in the form of their salts and displaced towards their free acid or free base form, if required. They can, on the contrary, be obtained in their free acid or free base form and be in this case salified, if required. Common salts for the products of general formula (I) are in particular the hydrates, hydrochlorides, dihydrochlorides, fumarates and hemifumarates.
The compounds of the invention can exist in the state of bases or addition salts in particular of organic or inorganic acids or of bases, and in particular in the state of hydrates, hydrochlorides, dihydrochlorides, fumarates or hemifumarates.
The compound of general formula (II)B is obtained according to methods similar to those described in the PCT Patent Applications WO 98/42696 and WO 98/58934. The only difference with these methods is that in every case the benzylated derivative and not the hydroxylated derivative of 6-hydroxy-2,5,7,8-tetramethylchromane-2-carboxylic acid is used. 6-benzyloxy-2,5,7,8-tetramethylchromane-2-carboxylic acid, in racemic form as well as in its two enantiomer forms, can be prepared for example according to the methods described below in the examples.
Moreover, a person skilled in the art would know, if appropriate, how to adapt the above processes by combining the procedures described in the PCT Patent Applications WO 98/42696 and WO 98/58934, to the above processes or to stages of these processes.
Stage 1) of the process described above is preferably carried out at a temperature higher than ambient temperature, and more preferentially at a temperature close to the boiling point of the alcoholic solvent used. Among the hydrogen donors which can be used, formic acid, ammonium formate, cyclohexadiene and cyclohexene can be mentioned. Preferably, t

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