Process for preparing 2-amino malonic acid derivatives and...

Details Process for preparing 2-amino malonic acid derivatives and... Process for preparing 2-amino malonic acid derivatives and...

1999-03-03

2001-09-04

Richter, Johann (Department: 1621)

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

Organic compounds

Carboxylic acid esters

C560S040000, C568S031000, C568S331000, C568S336000

Reexamination Certificate

active

06284915

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a process for preparing 2-amino malonic acid derivatives, 2-amino-1,3-propanediol derivatives and intermediates for preparing the same, which are used for preparing 2-amino-1,3-propanediol derivatives having excellent pharmacological activity, in particular immune suppression activity, rejection suppression activity, and prevention and therapy of auto immune diseases.
BACKGROUND OF THE INVENTION
Japanese Patent No. 2579602 (U.S. Pat. No. 5,604,229) discloses 2-amino-1,3-propanediol derivatives, and their properties such as pharmacological activity. The patent is herein incorporated by reference in their entirety.
The patent discloses a process for preparing 2-amino-1,3-propanediol derivatives. However, the process has disadvantages in that it contains many complicated steps, and it produces intermediates as oily substances or various isomeric mixtures. Accordingly, it is necessary to isolate and purify the intermediate products by conventional methods such as silica gel chromatography which accompany with complicated operation and use of large quantity of organic solvent. For that reason, it is difficult to remove undesired isomers, homologues, and other impurities. Thus, there is a need to a process which makes it possible to prepare an intended product with high purity, in high yield, without complicated steps, and in a large scale. That is, there is a need to a process which makes it possible to prepare 2-amino malonic acid derivatives and 2-amino-1,3-propandiol derivatives easily in a high yield.
SUMMARY OF THE INVENTION
Accordingly, an object of the present invention is to provide a process for preparing 2-amino malonic acid derivatives and 2-amino-1,3-propanediol derivatives, which permits the production thereof in a high yield readily.
Another object of the present invention is to provide intermediates for preparing 2-amino-1,3-propanediol derivatives.
After intensive investigations, the inventors have found that the above-described objects of the present invention can be attained by preparing 2-amino-1,3-propanediol derivatives and 2-amino malonic acid derivatives via a specific synthetic route.
The present invention has been completed on the basis of the above-described finding. The present invention provides a process for preparing 2-amino malonic acid derivatives of formula (1):
wherein A is linear or branched chain alkylene having from 1 to 10 carbon atoms, R
1
is linear or branched chain alkyl having from 2 to 20 carbon atoms, R
2
and R
3
are the same or different, and are lower alkyl or aralkyl, and R
4
is a protecting group,
which process comprises the step of reducing a compound of formula (6).
wherein A is linear or branched chain alkylene having from 1 to 10 carbon atoms, R
1
is linear or branched chain alkyl having from 2 to 20 carbon atoms, R
2
and R
3
are the same or different, and are lower alkyl or aralkyl, and R
4
is a protecting group.
The present invention also provides a process for preparing the compound of the formula (6), which process comprises the step of reacting a compound of formula (7):
wherein A is linear or branched chain alkylene having from 1 to 10 carbon atoms, R
1
is linear or branched chain alkyl having from 2 to 20 carbon atoms, and Z is a leaving group, and 2-(N-substituted)amino malonic diester of formula (3):
wherein R
2
and R
3
are the same or different, and are lower alkyl or aralkyl, and R
4
is a protecting group.
The present invention also provides a process for preparing 2-amino-1,3-propanediol derivative of formula (17):
wherein A is linear or branched chain alkylene having from 1 to 10 carbon atoms, R
1
is linear or branched chain alkyl having from 2 to 20 carbon atoms, and R
4
, R
6
and R
7
are the same or different, and are hydrogen or protecting groups;
which comprises the steps of reducing a compound of formula (19).
wherein A is linear or branched chain alkylene having from 1 to 10 carbon atoms, R
1
is linear or branched chain alkyl having from 2 to 20 carbon atoms, and R
4
, R
6
, R
7
and R
8
are the same or different, and are hydrogen or protecting groups, and deprotecting the compound obtained in the reducing step.
The present invention also provides intermediates for lo preparing the 2-amino malonic acid derivatives.


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