Process for preparing N6-substituted adenosine derivatives

Details Process for preparing N6-substituted adenosine derivatives Process for preparing N6-substituted adenosine derivatives

2000-01-12

2001-02-06

Dentz, Bernard (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S118000, C546S281100, C546S307000

Reexamination Certificate

active

06184382

ABSTRACT:

TECHNICAL FIELD
This invention is directed to a process for preparing N6-substituted adenosine derivatives, to intermediates useful therefor and to methods of preparing these intermediates.
BACKGROUND OF THE INVENTION
N6-substituted adenosine derivatives, as exemplified by [1S-[1&agr;,2&bgr;,3&bgr;,4&agr;(S*)]]-4-[7-[[1-[(3-chlorothien-2-yl)methyl]propyl]amino]-3H-imidazo[4,5-b]pyrid-3-yl] N-ethyl-2,3-dihydroxycyclopentanecarboxamide are useful as cardiovascular agents, more particularly as antihypertensive and anti-ischemic agents, as cardioprotective agents which ameliorate ischemic injury or myocardial infarct size consequent to myocardial ischemia, and as an antilipolytic agents which reduce plasma lipid levels, serum triglyceride levels, and plasma cholesterol levels. See U.S. Pat. Nos. 5,364,862 and 5,561,134.
Methods of preparing these N6 adenosine derivatives and intermediates thereto are disclosed in U.S. Pat. Nos. 5,364,862 and 5,561,134 and International Patent Application Nos. PCT/US97/11320, PCT/US97/15729 and PCT/US97/21439.
SUMMARY OF THE INVENTION
This invention is directed to a process for preparing a 2-halo-3-nitro-4-aminopyridine compound of formula
in which a 2,4-dihalo-3-nitropyridine compound of formula
wherein X
1
and X
2
are independently Cl or F, is reacted with an amine of formula H
2
N—X—(Y)
a
-Z; wherein X is a straight or branched chain alkylene, cycloalkylene or cycloalkenylene group; Y is NR
4
, O or S; a=0 or 1; and Z is of the formula:
where
Z
1
is N, CR
5
, (CH)
m
-CR
5
or (CH)
m
-N, m being 1 or 2; Z
2
is N, NR
6
, O or S, n being 0 or 1;
R
4
, R
5
and R
6
are independently H, alkyl, aryl or heterocyclyl; and
R
a
and R
b
are independently H, OH, alkyl, hydroxyalkyl, alkyl mercaptyl, thioalkyl, alkoxy, alkoxyalkyl, amino, alkyl amino, carboxyl, acyl, halogen, carbamoyl, alkyl carbamoyl, aryl or heterocyclyl.
In another aspect, this invention is directed to a process for preparing (R)-N-[1-[(3-chlorothien-2-yl)methyl]propyl]-2-halo-3-nitro-4-pyridinamine, by reacting a 2,4-dihalo-3-nitropyridine, wherein halo is Cl or F with (R)-1-(3-chlorothien-2-yl)-2-aminobutane, hydrochloride.
The reaction products are process intermediate useful in the preparation of 2,3,4-triaminopyridine compounds. The processes of this invention offers improved yields, purity, ease of preparation and/or isolation of intermediates and final product, and more industrially useful reaction conditions and workability over previously disclosed methods of preparation.
DETAILED DESCRIPTION OF THE INVENTION
Definitions of Terms
As used above and throughout the description of the invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings:
“Acyl” means a straight or branched alkyl-C═O group. “Thioacyl” means a straight or branched alkyl-C═S group. Preferred acyl and thioacyl groups are lower alkanoyl and lower thioalkanoyl having from 1 to about 6 carbon atoms in the alkyl group.
“Alkyl” means a saturated aliphatic hydrocarbon group which may be straight or branched and having about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups may be straight or branched and have about 1 to about 10 carbon atoms in the chain. Branched means that a lower alkyl group such as methyl, ethyl or propyl is attached to a linear alkyl chain.
“Lower alkyl” means an alkyl group having 1 to about 6 carbons.
“Cycloalkyl” means an aliphatic ring having 3 to about 10 carbon atoms in the ring. Preferred cycloalkyl groups have 4 to about 7 carbon atoms in the ring.
“Carbamoyl” means an
group. Alkylcarbamoyl and dialkylcarbamoyl means that the nitrogen of the carbamoyl is substituted by one or two alkyl groups, respectively.
“Carboxyl” means a COOH group.
“Alkoxy” means an alkyl-O group in which “alkyl” is as previously described. Lower alkoxy groups are preferred. Exemplary groups include methoxy, ethoxy, n-propoxy, i-propoxy and n-butoxy.
“Alkoxyalkyl” means an alkyl group, as previously described, substituted by an alkoxy group, as previously described.
“Alkoxycarbonyl means an alkoxy-C═O group.
“Aralkyl” means an alkyl group subsituted by an aryl radical, wherein “aryl” means a phenyl or naphthyl. “Substituted aralkyl” and “substituted aryl” means that the aryl group, or the aryl group of the aralkyl group is substituted with one or more substituents which include alkyl, alkoxy, amino, nitro, carboxy, carbalkoxy, cyano, alkyl amino, halo, hydroxy, hydroxyalkyl, mercaptyl, alkylmercaptyl, trihaloalkyl, carboxyalkyl or carbamoyl.
“Aralkoxycarbonyl” means an aralkyl-O—C═O group.
“Aryloxycarbonyl” means an aryl-O—C═O group.
“Carbalkoxy” means a carboxyl substituent esterified with an alcohol of the formula C
n
H
2n+1
OH, wherein n is from 1 to about 6.
“Halogen” (or “halo”) means chlorine (chloro), fluorine (fluoro), bromine (bromo) or iodine (iodo).
“Heterocyclyl” means about a 4 to about a 10 membered ring structure in which one or more of the atoms in the ring is an element other than carbon, e.g., N, O or S. Heterocyclyl may be aromatic or non-aromatic, i.e., may be saturated, partially or fully unsaturated. Preferred heterocyclyl groups include pyridyl, pyridazinyl, pyrimidinyl, isoquinolinyl, quinolinyl, quinazolinyl, imidazolyl, pyrrolyll, furanyl, thienyl, thiazolyl, benzothiazolyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, and morpholinyl groups.
“Substituted heterocyclyl” means that the heterocyclyl group is substituted by one or more substituents wherein the substituents include alkoxy, alkylamino, aryl, carbalkoxy, carbamoyl, cyano, halo, heterocyclyl, trihalomethyl, hydroxy, mercaptyl, alkylmercaptyl or nitro.
“Hydroxyalkyl” means an alkyl group substituted by a hydroxy group. Hydroxy lower alkyl groups are preferred. Representative groups include hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl and 3-hydroxypropyl.
Preferred Embodiments
The preparation of N6-substituted adenosine derivatives of formula (I) is outlined in Scheme 1.
In Scheme 1, X
1
and X
2
are independently Cl or F,
Q is CH
2
O;
T is
or R
3
O—CH
2
;
X is a straight or branched chain alkylene, cycloalkylene or cycloalkenylene group;
Y is NR
4
, O or S;
a=0 or 1;
Z is of the formula
or
Z
1
is N, CR
5
, (CH)
m
-CR
5
or (CH)
m
-N, m being 1 or 2;
Z
2
is N, NR
6
, O or S, n being 0 or 1;
R
1
, R
2
, R
3
, R
4
, R
5
and R
6
are independently H, alkyl, aryl or heterocyclyl;
R
7
and R
8
are independently hydrogen, alkyl, aralkyl, carbamoyl, alkyl carbamoyl, dialkyl-carbamoyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, aryloxycarbonyl, or R
7
or R
8
together may form
where R
c
is hydrogen or alkyl,
where R
d
and R
e
are independently hydrogen, alkyl, or together with the carbon atom to which they are attached may form a 1,1-cycloalkyl group; and
R
a
and R
b
are independently H, OH, alkyl, hydroxyalkyl, alkyl mercaptyl, thioalkyl, alkoxy, alkoxyalkyl, amino, alkyl amino, carboxyl, acyl, halogen, carbamoyl, alkyl carbamoyl, aryl or heterocyclyl.
As shown in Scheme 1, the preparation of N6-substituted adenosine derivatives of formula (I), begins with the reaction of the 2,4-dihalo-3-nitropyridine compound (II) with an amine of formula H
2
N—X—(Y)
a
-Z (III) provides the 2-halo-3-nitro-4-aminopyridine compound (IV). The reaction is carried out in the presence of a tertiary amine or aromatic amine base such as triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 4-methylmorpholine, and the like or an inorganic carbonate base such as sodium carbonate, potassium carbonate, and the like. Preferred bases are 4-methylmorpholine, triethylamine and diisopropylethylamine. The reaction is carried out in a polar aprotic solvent such as 1-methyl-2-pyrrolidone or dimethylformamide, an aromatic solvent such as benzene or toluene, a higher-boiling ethereal solvent such as diglyme or a hindered alcohol such as isopropanol or 2-butanol at a temperature of from about ambient temperature to th

Affiliated with

Also associated with

Rating

Process for preparing N6-substituted adenosine derivatives does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Process for preparing N6-substituted adenosine derivatives, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for preparing N6-substituted adenosine derivatives will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2606999