Note: Descriptions are shown in the official language in which they were submitted.
~ 8 Z 6~ S
Detailed Description of ~he Invention
This invention relates to an improved process for
adellosine-5'-carboxamides.
Certain adenosine-5'-carboxamides have been ~ound
to possess excellent cardiovascular activity (See German
Patent No. 2,034~785). While there are available methods
for preparing the compounds, they are generally useful only
in small laboratory runs, and in some instances, it is
extremely di~icult to obtain the desired compound. `. . ` `
L0 The present invention provides an improved process
~or preparing compounds of the formula
> ~
Rl Nll ¦ `"
R2 l
.. 1-~
. ' ~ j ,
OH OH
- ~ . , . . . " ~
1~82~5
wherein Rl and R2 ea.ch a.re selected from the group consist-
ing of hydrogen, loweralkylJ lowerhaloalkyl, lowerhydroxyalkyl,
lowercycloalkyl, loweralkylcycloalkyl, loweralkenyl, lower-
haloalkenyl, lowerhydroxyalkenyl, loweralkynyl, lowerhalo-
alkynyl, benzylamino, phenyl, loweralkylphenyl, loweralkoxy-
loweralkyl, substituted phenyl, 2-methylfuran, di(Cl-C4)-
alkylamino(Cl-C~)alkyl~ adamantyl or Rl and R2 taken together
form a 5- or 6-membered heterocyclic moiety,
Generally speaking, the process of thls invention
comprises reacting an ester of adenosine-5'-carboxylic acid,
or an acld addition salt of an ester of adenosine-5'-
carboxylic ac d with an appropriate amine of the formula
_,Rl or HNN ~ Rl .
R2 R2
in the presence of an appropriate alcohol.
15It is preferred that the ester or ester salt be
suspended in a suitable alcohol such as methanol, ethanol,
isopropanolJetc. and the amine is added to the alcohol
suspension. The reaction proceeds best at temperatures
above 70; however, it is preferred to reflux the reaction
r~ 20 for a suitable length of time, ~ ~or at least 16
hours and usually for 16 to 18 hours. It is to be under- `
stood, however, that the reaction can be carried out for
periods longer than 18 hours.
The amide is then recovered simply by, for exampleg ~.
concentrating the reaction to dryness and taking the residue .. ~ -
-2-
` " . .
' ,. .
. , . ;' . .. ': .' ', . ` ~
1~38Z6~S
up in a minimum volume of water. The amide can then be
recrystallized from water, if desired.
It is preferred to react the ester or ester salt
with an excess of the appropriate amine. While an excess
of amine is preferred, the ra~io of reactants should be at
least 1:1 in the case of the ester plus the amine and at
least 1:2 in the case of the ester salt and the amine.
It will be understood by those skilled in the art `- -
that the particular amine, in the ester or the alcohol,
détermines the final amide. While a number of esters can
be used in the process of this invention, it is preerred
e~hy J ~ enc~i nC ~ C'~r~'y ``
r~ to employ methyl adenosine-5'-carboxylate or
late or a salt thereof~
In the preferred embodiment, e~hyl adenosine-S'- `
carboxylate hydrochloride i9 employed.
The process is represented by the following reaction
scheme:
NH2 NH2 `;
N~
O+ HN 1 alcohol ~ Rl`N
RO ~ ~ R2
'. ~ I . ~, ~
OH-OH H
(or a salt thereof)
:'`
- 3- :
~ ~ 2 ~g ~ .
wherein Rl and R2 a.re 3.S deEined above and R is a.n a.liphatic
or araliphatic group.
The preferred process ~ represented by the follow-
ing reaction scheme:
NH2~HC~ NH2
~ ROH ~ HN~ 1> ~ ~ _ ~
O NC .
CH3CH~OC l R2~ ~I ff H
0~1 ~1
The esters can be prepared by, for example, the
method of German Patent No. 2,034,784. The acld addition
salts of the esters are prepared by methods well known in : `
the art
The amides can also be converted to their a.cid
addition salt by reacting the amide with an appropriate ac~d
in an appropriate solvent such as ethanol~ methanol, iso-
propanol, etc.
The ollowing examples urther illustrate the .
15 present invention: :
Example 1 .:
Preparation of Ethyl-5'-(Adenosine Carboxyla~e)
_ Hydrochloride
Thionyl chloride (5 ml.) was added dropwise ~o a
stirred suspension of adenosine-5'-carboxylic acid (5.62 g. ~.
1 ~ 8 2 ~ 5
0.02 mole) in absolute ethanol (400 ml.) at 0C. After the
addition was complete, the mixture was stirred for 25 minutes.
The cooling bath was removed and the mixture stirred for 24
hours at room temperature. The mixture was cooled in ice-
water and filtered to yield 6.7 g. of the desired product.
Recrystallization from absolute ethanol gave the product,
m.p. 174 dec; ~726 -22.
~ ;;... .. .
. ,
.
' . .
"` .
-4a- -
:, '` ':
:
`
, .. .... .
~8269~
Analysis Calcd- for C12H15N55 ~ICl C~
Cl, 10.27; N, 20.26
Found: C, 41.91; H, 4.91;
Cl, 10.07; N, 19.81
Example 2
Preparation of Aden ine-5'- rN-allyl)carboxamide7
To 150 ml. of absolute e~hanol were added 26 g. of
ethyl-5'-(adenosine carboxylate)hydrochloride. To this mix-
ture was added 35 mi. of allyl amine. The reaction was re-
fluxed overn;ght (17-18 hours). The resulting amber colored ` `
solution was concentrated to dryness under pressure. The ~`residue was dissolved in water whereupon a solid rapidly
crystallized. The solid was collected on a filter and washed
with cold water to yield 23 g. of productJ m.p. 135-137,
resolidified at 137 and remelts at 223-224. The product
was dissol~ed in boiling water, treated with darco, iltered
twice and allowed to crystallize. The solid was collected
on a funnel, washed well with water and dried in vacuo at 84
overnight to yield 21.05 g. of product, m.p. 224-225. NMR
and TLC confirmed the identity of the product.
. . .
Example 3
Preparation of Adenosine-5'- ~N-cyclopropyl)carboxamid~7
To 60 ml. of absolute ethanol were added 5.5 g. of
ethyl-5'-(adenosine carboxylate~hydrochloride. To the alcohol
2S mixture was added 10 ml. of c~clopropylamine. The mixture was `
heated to gentle reflux~ refluxed for 24 hours and cooled to
room temperature whereupon a solid crystallized. The reaction
mixture was concentrated to a solid residue under reduced
-5
.
.
~ ~ ~ 2 ~ ~
pressure. The residue was taken up in ice-wa~er whereupon
a solid crystallized. The solid was collected on a filter
and washed with ice-water to yield the 4.9 g, of crude
product, m.p, 247-249. The crude product was dissolved
in 200 ml. of hot water~ and the hot solution was treated
with darco and filtered twice. The solution was cooled in `
an ice bath and the product was collected on a filter, washed
with cold water, dried over night in vacuo at 84 to yield
4.3 g. of the pure product, m.p. 252.5-253. NMR was consis-
tent with the proposed structure.
Example 4
Preparation of Adenosine-5'- rN-isopropyl~carboxamid~
Ten grams of ethyl-5'-(adenosine carboxylate)hydro-
chloride were added to 125 ml. of ethanol. To the ethanol
mixture was added 25 ml. of isopropylamine. The reac~ion was
heated at 50 for about 18 hours in a Parr shaker. An
additional 25 ml. of isopropylamine was added and the reac-
tion was heated at 70 for 24 hours. The reaction was then
~orked up following the procedure o~ Example 2 to yield 6.28
g. of product, m.p, 2040205. NMR confirmed the identity
of the product.
Example 5
Preparation of Adenosine-5'- ~N-propargyl~carboxamid~7
To 120 ml. of absolute ethanol were added 10 g. of
~S ethyl-5'-~adenosine carboxylate)hydrochloride~ Propargyl
amine (15 ml.) was added and the mixture refluxed for
approximately 18 hours. The resulting reddish solution wa~
--6--
Z6~5
concentrated to dryness under reduced pressure. The residue
was dissolved in a min~mum of cold water whereupon a solid
qoon crystallized. The solid was chilled and collected on
a filter to yield 7.7 g, of crude product, m.p~ 100. The
~5 crude product was dissolved in approximately 100 ml. of boil-
ing water~ treated with darco and filtered. The reaction
was then cooled in an ice bath. The solid was collected on `
a filter, washed with cold water and dried in a vacuum oven
at 65 over the weekend to yield 6.49 g. of product, m.p.
118-121. NMR confirmed the identity of the product.
Example 6
Preparation of N-~-Hydroxyethyl)adenosine-5'-Carboxamide
Ethyl adenosine-5'-carboxylate, hydrochloride (10 g.)
was added to a solution of 20 ml. of ethanol amine in 150 ml.
of absolute ethanol. The reaction was refluxed overnight,
concentrated to a solid residue under reduced pressure, and
the residue taken up in a minimum of water and basified with
NaHC03. The solution was reconcentrated to dryness and ex-
tracted twice with hot absoluteethanol. Th~ filtrates were
combined, heated to boiling and cooled to room temperature
whereupon a solid slowly formed. The solid was recrystalliæed
rom 450 ml. of ethanol whereupon the 4.75 g. of the product
formed very slowly, m.p, l99-Z00. ~MR con~irmed the identity
o~ the product.
.
