Purine derivatives having cyclopropane ring

Details Purine derivatives having cyclopropane ring Purine derivatives having cyclopropane ring

2000-04-03

2002-01-29

Berch, Mark L. (Department: 1624)

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

Organic compounds

Pteroyl per se or having -c-, wherein x is chalcogen, bonded...

C544S265000, C544S276000, C544S277000

Reexamination Certificate

active

06342603

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a purine derivative having a cyclopropane ring, a process for preparing the same, and a process for preparing a cyclopropane ring-cleaved purine derivative from the purine derivative having a cyclopropane ring. The present invention also relates to a process for preparing a cyclopropane ring-cleaved compound.
2. Discussion of the Related Art
Conventionally, as to preparation process for purine derivatives useful for preparation intermediates for antiviral agents, there can be cited, for instance, a process disclosed in Japanese Patent Laid-Open No. Hei 3-120279. However, when the purine derivative is prepared from the preparation intermediates in the above preparation processes, its yield is as low as about 20 to about 40%. In addition, since extremely complicated procedures are necessitated in order to prepare the above preparation intermediates, there is a defect that the purine derivatives cannot be readily prepared as a consequence.
Therefore, recently, a development of a preparation intermediate which can be used in a process which can readily prepare a cyclopropane ring-cleaved purine derivative in a high yield and at high purity has been in demand.
In addition, there has been known to prepare a cyclopropane ring-cleaved compound by a process comprising hydrogenating a compound having a cyclopropane ring in the presence of a metal catalyst by the action of hydrogen gas as a hydrogen source; and cleaving the cyclopropane ring by reduction.
However, in this process, since it has been necessitated to pressurize the reaction system with hydrogen gas to a pressure of 3 to 5 kgf/cm
2
upon hydrogenation, there arise such defects that the desired cyclopropane ring-cleaved compound has a low yield owing to the presence of large amounts of by-products in addition to the lack of operability and safety.
In view of the problems in the prior art, an object of the present invention is to provide a process for readily preparing a cyclopropane ring-cleaved purine derivative in a high yield and at high purity, a purine derivative having a cyclopropane ring which can be suitably used in the above process, and a process for preparing the purine derivative having a cyclopropane ring.
Another object of the present invention is to provide a process for preparing a cyclopropane ring-cleaved compound with excellent operability and safety in a high yield.
These and other objects of the present invention will be apparent from the following description.
SUMMARY OF THE INVENTION
The present invention pertains to the following:
(1) a purine derivative having a cyclopropane ring represented by the formula (I):
 wherein A is —CH
2
— group or —CO— group; X
1
is hydrogen atom, a halogen atom, an alkoxy group having 1 to 10 carbon atoms, or hydroxyl group; each of X
2
, X
3
, and X
4
is independently hydrogen atom or a halogen atom; R
1
is hydrogen atom, a halogen atom, or a protected or unprotected amino group; and each of R
2
and R
3
is independently hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 7 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 11 carbon atoms, or a substituted or unsubstituted acyl group having 1 to 7 carbon atoms, with proviso that in a case where A is —CO— group, neither R
2
nor R
3
is a substituted or unsubstituted acyl group having 1 to 7 carbon atoms, and each of X
3
and X
4
is independently a halogen atom;
(2) the purine derivative having a cyclopropane ring according to item (1) above, wherein the purine derivative having a cyclopropane ring represented by the formula (I) is a compound represented by the formula (II):
 wherein each of X
13
and X
14
is independently a halogen atom; each of R
4
and R
5
is independently hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 7 carbon atoms, or a substituted or unsubstituted aralkyl group having 7 to 11 carbon atoms; and X
1
, X
2
, and R
1
are the same as defined above;
(3) the purine derivative having a cyclopropane ring according to item (1) above, wherein the purine derivative having a cyclopropane ring represented by the formula (I) is a compound represented by the formula (III):
 wherein X
1
, X
2
, X
3
, X
4
, R
1
, R
2
, and R
3
are the same as defined above;
(4) the purine derivative having a cyclopropane ring according to item (3) above, wherein the purine derivative having a cyclopropane ring represented by the formula (III) is a compound represented by the formula (IV):
 wherein each of X
5
and X
6
is independently a halogen atom; and X
1
, X
2
, R
1
, R
2
, and R
3
are the same as defined above;
(5) the purine derivative having a cyclopropane ring according to item (3) or (4) above, wherein X
1
is chlorine atom;
(6) the purine derivative having a cyclopropane ring according to any one of items (3) to (5) above, wherein each of R
2
and R
3
is hydrogen atom;
(7) the purine derivative having a cyclopropane ring according to any one of items (3) to (5) above, wherein each of R
2
and R
3
is acetyl group;
(8) a process for preparing a purine derivative having a cyclopropane ring represented by the formula (II):
 wherein X
1
is hydrogen atom, a halogen atom, an alkoxy group having 1 to 10 carbon atoms, or hydroxyl group; X
2
is hydrogen atom or a halogen atom; each of X
13
and X
14
is independently a halogen atom; R
1
is hydrogen atom, a halogen atom, or a protected or unprotected amino group; and each of R
4
and R
5
is independently hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 7 carbon atoms, or a substituted or unsubstituted aralkyl group having 7 to 11 carbon atoms,
comprising reacting a malonic acid derivative represented by the formula (V):
 wherein each of X
7
, X
13
, and X
14
is independently a halogen atom; and R
4
and R
5
are the same as defined above, with a purine compound represented by the formula (VI):
 wherein X
1
, X
2
, and R
1
are the same as defined above;
(9) a process for preparing a purine derivative having a cyclopropane ring represented by the formula (IIIa):
 wherein X
1
is hydrogen atom, a halogen atom, an alkoxy group having 1 to 10 carbon atoms, or hydroxyl group; X
2
is hydrogen atom or a halogen atom; each of X
13
and X
14
is independently a halogen atom; and R
1
is hydrogen atom, a halogen atom, or a protected or unprotected amino group,
comprising reacting a dicarboxylic acid-based compound represented by the formula (VII):
 wherein each of R
6
and R
7
is independently a substituted or unsubstituted alkyl group having 1 to 7 carbon atoms; and X
1
, X
2
, X
13
, X
14
and R
1
are the same as defined above, with a metal hydride;
(10) a process for preparing a purine derivative having a cyclopropane ring represented by the formula (IIIc):
 wherein X
1
is hydrogen atom, a halogen atom, an alkoxy group having 1 to 10 carbon atoms, or hydroxyl group; each of X
2
, X
3
, and X
4
is independently hydrogen atom or a halogen atom; R
1
is hydrogen atom, a halogen atom, or a protected or unprotected amino group; and each of R
8
's is independently a substituted or unsubstituted alkyl group having 1 to 7 carbon atoms or a substituted or unsubstituted aralkyl group having 7 to 11 carbon atoms,
comprising reacting a purine derivative having a cyclopropane ring represented by the formula (IIIb):
 wherein X
1
, X
2
, X
3
, X
4
, and R
1
are the same as defined above,
with an alkylating agent represented by the formula (VIII):
R
8
—X
8
  (VIII)
wherein X
8
is chlorine atom, bromine atom, or iodine atom; and R
8
is the same as defined above;
(11) a process for preparing a purine derivative having a cyclopropane ring represented by the formula (IIId):
 wherein X
1
is hydrogen atom, a halogen atom, an alkoxy group having 1 to 10 carbon atoms, or hydroxyl group; each of X
2
, X
3
, and X
4
is independently hydrogen atom or a halogen atom; R
1
is hydrogen atom, a halogen atom, or a protected or unprotected ami

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