PROCEDE POUR LA PREPARATION D'HYDROXYALKYLXANTHINES

PROCESS FOR PREPARING HYDROXYALKYLXANTHINES

Abrégé anglais

ABSTRACT OF THE DISCLOSURE
A process for the preparation of compounds of general formula
<IMG> (I)
(wherein one of the groups R1, R2 and R3 represent an (.omega.-1)-hydroxyalkyl
group containing 4 to 8 carbon atoms being unbranched in the (.omega.-1)-position
and the other of the groups R1, R2 and R3, which may be the same or differ-
ent, each represents an alkyl group containing 1 to 12 carbon atoms or a
hydrogen atom with the proviso that R2 does not represent a hydrogen atom)
which is selected from the group consisting of A) hydrating a compound of
formula
<IMG> (I')
(wherein one of the groups R1', R2' and R3' represent an (.omega.-1)-alkenyl
group containing 4 to 8 carbon atoms being unbranched in the (.omega.-1)-position
and the other of the groups R1', R2' and R3' are as hereinbefore defined
for the groups R1, R2 and R3 which do not represent an (.omega.-1)-hydroxyalkyl
group) in the presence of a dilute acid or an ion exchange resin containing
sulphonic acid groups and adding B) a hydrogen halide to a compound of
formula (I') in conventlonal manner to produce an (.omega.-1)-halogenoalkyl com-
pound and then saponifying said compound in conventional manner to yield
the (.omega.-1)-hydroxyalkyl compound and compounds of formula (I'). These com-
pounds find use in pharmacological preparations, for example to increase
the rate of blood flow.

Revendications

THE EMBODIMENT OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY
OR PRIVILEGE IS CLAIMED IS DEFINED AS FOLLOWS:
1. A process for the preparation of compounds of general formula
<IMG>
(I)
(wherein one of the groups R1, R2 and R3 represents an (.omega.-1)-hydroxyalkyl
group containing 4 to 8 carbon atoms being unbranched in the (.omega.-1)-position
and the other of the groups R1, R2 and R3, which may be the same or
different, each represents an alkyl group containing 1 to 12 carbon atoms
or a hydrogen atom with the proviso that R2 does not represent a hydrogen
atom) which is selected from the group consisting of A) hydrating a
compound of formula
<IMG> (I')
(wherein one of the groups R1', R2' and R3' represents an (.omega.-1)-alkenyl
group containing 4 to 8 carbon atoms being unbranched in the (.omega.-1)-position
and the other of the groups R1', R2' and R3' are as hereinbefore defined
for the groups R1, R2 and R3 which do not represent an (.omega.-1)-hydroxyalkyl
group) in the presence of a dilute acid or an ion exchange resin
containing sulphonic acid groups and B) adding a hydrogen halide to a
compound of formula (I') in conventional manner to produce an (.omega.-1)-halogeno-
alkyl compound and then saponifying said compound in conventional manner
to yield the (.omega.-1)-hydroxyalkyl compound.
-10-

2. A process for the preparation of compounds of general formula
I as claimed in claim 1 as groups A) wherein the alkyl group containing 1 to
12 carbon atoms is a methyl group.
3. A process for the preparation of compounds of general formula
I as claimed in claim 1 as group A) wherein one of the groups R1, R2 and R3
represents an (.omega.-1)-hydroxyalkyl group containing 4 to 8 carbon atoms being
unbranched in the (.omega.-1)-position, a second represents an alkyl group contain-
ing 2 to 12 carbon atoms and the third represents an alkyl group containing
1 to 12 carbon atoms or a hydrogen atom with the provisos that R2 does not
represent a hydrogen atom and that at least one of the groups R1, R2 and R3
contains at least 5 carbon atoms.
4. A process as claimed in claim 1 or 2 or 3 wherein the acid is
present in the reaction mixture in a concentration up to 2N.
5. A process as claimed in claim 1 or 2 or 3 wherein the hydration
is effected at a temperature from 40 to 150°C.
6. A process as claimed in claim 1 or 2 or 3 wherein the (.omega.-1)-
alkenyl compound of formula I' is present in the reaction mixture in suspen-
sion or in solution.
7. A process as claimed in claim 1 or 2 or 3 wherein the hydration
is effected in the presence of an organic solvent which is inert to the acid
catalyst and is present in an amount by volume to or less than the amount of
water present.
8. A process according to claim 1 A) wherein the starting materials
are chosen to provide a compound selected from 1-(5-hydroxyhexyl)-3-methyl-7-
propyl-xanthine; 1-propyl 3-methyl-7-(5-hydroxyhexyl)-xanthine; 1-pentyl-3-
methyl-7-(5-hydroxyhexyl)-xanthine; 1-(5-hydroxyhexyl)-3-methyl-7-ethyl-
xanthine; 1-(5-hydroxyhexyl)-3-methyl-7-butyl-xanthine; 1-(5-hydroxyhexyl)-3-
methyl-7-isobutyl-xanthine; 1-(5-hydroxyhexyl)-3-methyl-7-decyl-xanthine; 1-
isobutyl-3-methyl-7-(5-hydroxyhexyl)-xanthine; 1-hexyl-3-methyl-7-(5-hydroxy-
11

hexyl)-xanthine; 1-(2-methyl-3-hydroxybutyl)-3,7-dimethyl-xanthine; 1,3-
dimethyl-7-(2-methyl-3-hydroxybutyl)-xanthine.
9. A compound chosen from the group comprising 1-(5-hydroxyhexyl)-
3-methyl-7-propyl-xanthine, 1-propyl-3-methyl-7-(5-hydroxyhexyl)-xanthine,
1-pentyl-3-methyl-7-(5-hydroxyhexyl)-xanthine, 1-(5-hydroxyhexyl)-3-methyl-7-
ethyl-xanthine, 1-(5-hydroxyhexyl)-3-methyl-7-butyl-xanthine, 1-(5-hydroxy-
hexyl)-3-methyl-7-isobutyl-xanthine, 1-(5-hydroxyhexyl)-3-methyl-7-decyl-
xanthine, 1-isobutyl-3-methyl-7-(5-hydroxyhexyl)-xanthine, 1-hexyl-3-methyl-
7-(5-hydroxyhexyl)-xanthine, 1-(2-methyl-3-hydroxybutyl)-3,7-dimethyl-xanthine,
1,3-dimethyl-7-(2-methyl-3-hydroxybutyl)-xanthine whenever prepared by the
process of claim 8 or by an obvious chemical equivalent thereof.
12

Description

~L~627 ~
This invention relates to the preparation o~ hydroxy-
alkylxanthines having valuable pharmacologlcal properties and
to novel alkenylxanthines for use in the said preparation .
Dimethylxanthins having an (~ hydroxyalkyl substitu-
5 ent in the 1- or 7-position are known to have valuable pharma-
cological propertie6, for example 1 ~5-hydroxyhexyl)-3,7-di-
methylxanthine is known to increase the rate of blood flow.
It has been proposed to prepare ~ -1)-hydroxyalkyl-dimethyl-
xanthines by reduction of the corresponding keto compounds,
10 which may themselves be prepared by reduction o~ the corres- -
ponding halogenoketones, for example using metal hydrides.
However~ a disadvantage of this synthetic route i8 that the
reduction of halogenoketones with metal hydride~ is sometimes
dif~ioult to control, particularly when carried out on a
15 large scale.
In addition German (Fed. Rep.) Patent No. 1,0679025 des
cribes and claim~ a process for preparing 1~ hydroxypropyl)-
3,7-dimethylxanthine (1~ hydroxgpropyl)~theobromine)
which comprises hydrating 1-allyl-3,7-dimethylxanthine in the
20 pre~ence o~ concentrated sulphuric acid a~ hydration catalyst.
Accordin~ to the patent ~pecification however bhis process i
quite speci~ic to the preparation of 1~ hydroxypropyl)~
theobromine and i9 unsuccessful for the preparation of ~or
example 7-(~-hydroxypropyl~-theophylline.
According to the present invention we now provide a pro-
ce~s for the preparaticn of compounds of general formula
,~ '.
-, ~ -, ., ,, ... .. -, .' , '' ' ' , . '. ~ '. .. " .,: ' .. : '
, , : . ,,. . : . ,
.';." ' ' '. " ,. ~ .

o
O , - R3 (I~
(wherein one of the group~ R1~ R2 and R3 repre~ents an (~
hydroxyalkyl group containing 4 to 8 carbon atoms b~ing un-
branched in the (~ position and the other of the group~
Rl, R2 and R3, which may be the ~ame or different, each re-
5 presents an alkyl group containing 1 to 12 carbon atoms~or ahydrogen atom with the proviso that R2 does not represent a
hydrogen atom) which comprises hydrating a compound of
formula
O
R1~-N ~ ~N 3~ (I')
O l N
: ~ R2,
~wherein one of the groups R1,, R2, and R3, repre3enta an
~10 (~ alkenyl ~roup containing 4 to 8 carbon atoms being un-
branched in the (~ po~ition and the other Or the groups
R1 " R2, and R3t are as hereinbefore de~ined for the group~
R1l R2 and~R3 which do not represent an ~ hydroxyalkyl
group) in the presence o~ a dilute acid or an ion exchange
15 re~in containing sulphonic acid group~.
3 --

We have found that when the reaction i5 effected in the
presence of a dilute acid or an acid ion exchange re~in, the
addition of water iB according to Markownikoff's rule and an
~ hydroxyalkyl derivative i~ the predominant product. In
5 many case~ we have produced almost quantitative yields of
compound~ o~ general formula I (a~ h~reinbefore defined) by
mean~ o~ the proces~ according to the invention.
In general hydration of alkenyl compounds wherein the
double bond is at the end po~ition OCCUr8 at least partially
10 anti-Markownilco~f's rule and predominantly Markowniko~
addition o~ water only occurs under certaln conditions. The
~ hydroxyalkyl compound3 may be prepared al~o from the
corresponding (~ alkenyl compounds by first adding a
hydrogen halide in conventional manner to produce an (~
15 halogenoalkyl compound and then ~ap~nifying this compound
again in conventional manner to yield the (~ hydroxyalkyl
compound.
- The process according to the invention i5 particularly
u~eful ~or the preparation o~ compound~ o~ general ~ormula I
20 ~herein the hydroxyalkyl ~roup ;~ in the 1- or the 7-position
and is unbranched, and especially for the preparation o~ the
~. .
~ollowing compounds:
1-(5-hydroxyhexyl)-3,7-dimethylxant~ine and
7-(5-hydroxyhexyl)-1,3-dimethylxanthine.
25 The proce 8 may be used for the preparation o~ both hydroxy-
alkyl-methyl-~or -dimeth~ xanthine~ and their homolo~ues
wherein at lea~t one methyl group is replaced b~y an alkyl
- 4 -
~ . . . . , ,:
. . .

7~9
group containing 2 to 12 carbon atoms and pre~erably wherein
at least one of the substituents contain~ at least 5 carbon
atoms.
The hydration is effected in the presence of a dilute
5 acid or an ion exchange resin containing ~ulphonic acid groups.
The dilute acid is pre~erably a mineral acid, for example a
hydrohalic acid, nitric acid, pho~phoric acid or sulphuric
acidg or a sulphonic acid, for example trifluoro-methylsul-
phonic acid. The dilute acid is generally preRent in the
10 reackion mixture in a concentration up to 2N, pre~erably at
least 0.5N and more especially from 1 to 2N. The alkenyl-
xanthine compound Or formula I' used as starting material may
be present in solution or in suspension. In certain cases it
is advantageous to perform the reaction in the presence of
15 an organic solvent which is inert to the acid catalyst~ for
example 1,4-dioxane, benzene or toluene, the quantity by
volume of organic~solvent being generally equal to or les~ -
than the quantity of water pre~ent in the reaction mixture.
The hydration is generally effected at a temperature from
20 40 to 150C preferably 60 to 120C.
The course of the reaction and the detectlon Or the
end point may be conveniently monitored by thin layer chroma-
tography.
The reaction product of formula I prese~t in the aqueous
25 phase of the reaction mixture .nay be conveniently isolated
by extraction with a chlorinated hydrocarbon, e.g. methylene
chloride or chloro~orm. I~ a second, organic phase is present
the reaction product Or formula I may be isolated therefrom
' ' . ,' ~; .: ,

~6~6;~7~C~
~or example by evaporating the organic solvent, i~ neces~ary
under reduced pre~sure.
The (~ alkenylxanthines of general formula I' (as
hereinbefore defined) are new compounds and constltute a
5 rurther feature o~ the pre~ent invention. The following com-
pounds of general formula I' thus lie within the sco~e of
this invention and may be used a starting materials for the
process accordin~ to the invention:-
1-(3-bukenyl)-3~7-dimethyl-xanthine
1-(4-pentenyl)-3,7-dimethyl-xanthine
1-(5-hexenyl)~3j7-dimethyl-xanthine
1-(2-methyl-3-butenyl~-3,7-dimethyl-xanthine
1~(5-hexenyl)-3-methyl-7-ethyl-xanthine
1-(5-hexenyl)-3-methyl-7-propyl-xanthine
1-(5-hexenyl)-3-methyl-7-butyl-xanthine
1-(5-hexenyl)-3-methyl-7-isobutyl xanthine
.: . . ......... ., , . , :: . ,
', ,~ ' .'' ' ' .,' :, ', '' ' i '': : '

i2~
1-(5-hexenyl)-3-methyl-7-decyl-xan~hine
1,3-dimethyl-7-~2-methyl-3-butenyl)-xanthine
1,3-dimethyl-7-~3-butenyl)-xanthine
1,3-dimethyl-7-~4-pentenyl)-xanthine
1,3-dimethyl-7-(5-hexenyl)-xanthine
1,3-dimethyl-7-~6-heptenyl)-xanthine
3-methyl-7-~5-hexenyl)-xanthine
l-propyl-3-methyl-7-(5-hexenyl)-xanthine
l-isobutyl-3-methyl-7-(5-hexenyl)-xanthine
10 1-pentyl-3-methyl-7-~5-hexenyl)-xanthine and
l-hexyl-3-methyl-7-~5-hexenyl)-xanthine.
The above compounds of general formula Tl may be prepared by
reacting an appropriate halogenoalkene with an alkali metal sal~ of a xanthine
derivative.
The following Examples serve to illustrate the new process
according to the present invention:
E_ample 1
16.3 g of 1-bromohexene-(5) are reacted at 120C with 20.2 g of
sodium theobromine in 200 ml of dimethylformamide, while stirring, until the
termination of the reaction is determined from a thin layer chromatogram, i.e.
after about 6 to 8 hours. The solvent is then distilled off under reduced
pressure. The residue is dissolved at 20C in 100 ml of methylene chloride,
separated from the undissolved sodium bromide and purified in a column of
- .
~ ~ neutral alumina
,~ .
.:~ 4
. ' , ', , ' ' " ', ' ' ' , . ", . ' : ' "' ' ' ~, ' . : ,
' ' ', :' . ' . ' ' " .. . ' ' ' ' ' ' . '.' ' -

~6;~
in order to remove ~mall amounts of dark contaminations~
1-(5-hexenyl)-3,7-dimethylxanthine melts from n-hexane in
colourless needles melting at 76 to 77C. The yield iB 24 . 1 g
(92 percent of the theory). After thin layer chromatography
5 with ~ilica gel 60 F254 (Merck DC-~heets) as the ~b~orbent
and with a mixture of benzene and acetone in the volume ratio
o~ 60 : 40 as the eluting agent the sub~tance h~ a Rf-value
0~ 0 . 47, With a mixture o~ nitromethane~ benzene and pyridine
in a volume ratio of 20 : 10 : 3 a~ the eluting agent the sub-
10 ~tance ha~ a Rf-value of 0.60. In both cases it is indicated
by UV-light~ However when using the latter eluent the pyri-
dine cohtent thereof has to be removed in view Or its property
to extingui~h fluorescence by heating to 50C under reduced
pre~sure.
2.6 g of 1-(5-hexenyl)-3,7-dimethyl-xanthine are boiled
with 25 ml Or 1-normal sulfuric acid for 24 hours. A small
portion o~ the clear solution is tested ~or the degree of
addition o~ water. The deslred ~inal product doe~ extin~uish
~luorescence at a R~-value frGm 0.30 to 0.37 while u~ing the
20 nitromethane-benzene-pyridine-eluent~ Aft~r termination of
the reaction the product is neutralized and extracted with
methylene chloride from which 1~(5-hydroxyhexyl)-3~7-dimethyl-
xan~hine is obtained in colourless crystals having after re-
crystallizatlon from methanol a melting point of 126C. The
25 yield iB 2,6 g (9~ percent of the theory).
~ he following compounds have been pr~pared analo~ously
to Example 1~
-- 8 --
" '.
. . ': ' ' ,' '. ' ' . ' ' .,, . ' ' ' ' : :, . ' ' ' , ~ '

~6~27~ -
2) 1-(5-Hydroxyhexyl)-3-methyl-7-propyl-xanthine 76-77
3) 1-~ropyl-3-methyl-7-(5-hydroxyhexyl)-xanthine 53
4) 1 Pentyl-3-methyl-7-(5-hydroxyhexyl~-xanthine 65-67
5) 1-(3-Hydroxybutyl)-3~7-dimethyl-xanthine 130
6) 1-(4-Hydroxypentyl)-3,7-dimethyl-xanthine 100
7) 1-(5-Hydroxy~hexyl)-3-methyl~7-ethyl-xanthine 87
8) 1-(5-Hydroxyhexyl)-3-methyl-7-butyl-xanthine 56-57
9) 1-(5-Hydroxyhexyl)-3-methyl-7 isobutyl-xanthine 54-55
10 10) 1-(5-Hydroxyhexyl)-3-methyl-7-decyl-xanthine .37-38
11) 1-Isobutyl-3-methyl-7-(5-hydroxyhexyl?-xanthine 62-63
12) 1-Hexyl-3-methyl-7-(5~hydroxyhexyl) xanthine 68-69
13) 1-(2-Methyl-3-hydroxybutyl)-3,7-dimethyl-xanthine ~yrupy
14) 1,3~Dimethyl-7-(2-met~y~-3-hydroxybutyl)~xanthine syrupy
15 15) 1,3-Dimethyl-7-(3-hydroxybutyl)-:Kanthine 124
.
16) 1,3-Dimethyl-7t-(4-hydroxypentyl)-xanthine 84
17) 1,3-Dimethyl-7-(5-hydroxyhexyl)-:Kanthine 93-94
lB) ,~-Dimethyl-7-(6-hydroxyheptyl~-xanthine 109
, , . : . , . :
., , . : . .., . :.: ,
' '': ' '. . ' '. . : : .: . ~. :