CA1062710A - Process for preparing hydroxyalkylxanthines - Google Patents
Process for preparing hydroxyalkylxanthinesInfo
- Publication number
- CA1062710A CA1062710A CA230,790A CA230790A CA1062710A CA 1062710 A CA1062710 A CA 1062710A CA 230790 A CA230790 A CA 230790A CA 1062710 A CA1062710 A CA 1062710A
- Authority
- CA
- Canada
- Prior art keywords
- xanthine
- methyl
- hydroxyhexyl
- omega
- groups
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
- C07D473/10—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 3 and 7, e.g. theobromine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
- C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline
Abstract
ABSTRACT OF THE DISCLOSURE
A process for the preparation of compounds of general formula (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
A process for the preparation of compounds of general formula (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
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~.
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 ~ . . . . , ,:
. . .
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.
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~.
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 ~ . . . . , ,:
. . .
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~
" '.
. . ': ' ' ,' '. ' ' . ' ' .,, . ' ' ' ' : :, . ' ' ' , ~ ' ~6~27~ -2) 1-(5-Hydroxyhexyl)-3-methyl-7-propyl-xanthine 76-77
~ he following compounds have been pr~pared analo~ously to Example 1~
" '.
. . ': ' ' ,' '. ' ' . ' ' .,, . ' ' ' ' : :, . ' ' ' , ~ ' ~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 , , . : . , . :
., , . : . .., . :.: , ' '': ' '. . ' '. . : : .: . ~. :
., , . : . .., . :.: , ' '': ' '. . ' '. . : : .: . ~. :
Claims (9)
OR PRIVILEGE IS CLAIMED IS DEFINED AS FOLLOWS:
1. A process for the preparation of compounds of general formula (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 (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.
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-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.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US48587074A | 1974-07-05 | 1974-07-05 | |
| US05/485,869 US4108995A (en) | 1973-07-11 | 1974-07-05 | Hydroxyhexyl-alkylxanthines and pharmaceutical compositions containing hydroxyhexyl-alkylxanthines |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1062710A true CA1062710A (en) | 1979-09-18 |
Family
ID=27048497
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA230,790A Expired CA1062710A (en) | 1974-07-05 | 1975-07-04 | Process for preparing hydroxyalkylxanthines |
Country Status (14)
| Country | Link |
|---|---|
| JP (1) | JPS5250800B2 (en) |
| AR (1) | AR210330A1 (en) |
| AT (1) | AT339917B (en) |
| CA (1) | CA1062710A (en) |
| CH (2) | CH622519A5 (en) |
| DK (1) | DK140214B (en) |
| ES (1) | ES439141A1 (en) |
| FI (1) | FI59249C (en) |
| FR (1) | FR2277089A1 (en) |
| GB (1) | GB1500039A (en) |
| LU (1) | LU72897A1 (en) |
| NL (1) | NL166476C (en) |
| NO (1) | NO143224C (en) |
| SE (2) | SE420097B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4833146A (en) * | 1985-07-19 | 1989-05-23 | Hoechst Aktiengesellschaft | Tertiary hydroxyalkylxanthines, medicaments containing them and their use |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH664568A5 (en) * | 1984-01-12 | 1988-03-15 | Sandoz Ag | 8-ALPHA ACYLAMINE OERGOLINE. |
| EP0570831A2 (en) * | 1992-05-20 | 1993-11-24 | Hoechst Aktiengesellschaft | Use of Xanthinderivatives for treatment of cerebral nerve dammages after disruption of the blood circulation |
-
1975
- 1975-07-02 CH CH859275A patent/CH622519A5/en not_active IP Right Cessation
- 1975-07-03 JP JP50081475A patent/JPS5250800B2/ja not_active Expired
- 1975-07-03 LU LU72897A patent/LU72897A1/xx unknown
- 1975-07-03 DK DK301775AA patent/DK140214B/en not_active IP Right Cessation
- 1975-07-04 FI FI751958A patent/FI59249C/en not_active IP Right Cessation
- 1975-07-04 AR AR258487A patent/AR210330A1/en active
- 1975-07-04 ES ES439141A patent/ES439141A1/en not_active Expired
- 1975-07-04 CA CA230,790A patent/CA1062710A/en not_active Expired
- 1975-07-04 FR FR7521043A patent/FR2277089A1/en active Granted
- 1975-07-04 NO NO752423A patent/NO143224C/en unknown
- 1975-07-04 AT AT517275A patent/AT339917B/en not_active IP Right Cessation
- 1975-07-04 SE SE7507726A patent/SE420097B/en not_active IP Right Cessation
- 1975-07-04 NL NL7507976.A patent/NL166476C/en not_active IP Right Cessation
- 1975-07-04 GB GB28341/75A patent/GB1500039A/en not_active Expired
-
1978
- 1978-07-14 SE SE7807853A patent/SE427183B/en not_active IP Right Cessation
-
1980
- 1980-04-29 CH CH331680A patent/CH622018A5/en not_active IP Right Cessation
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4833146A (en) * | 1985-07-19 | 1989-05-23 | Hoechst Aktiengesellschaft | Tertiary hydroxyalkylxanthines, medicaments containing them and their use |
Also Published As
| Publication number | Publication date |
|---|---|
| GB1500039A (en) | 1978-02-08 |
| DK140214B (en) | 1979-07-09 |
| DK301775A (en) | 1976-01-06 |
| NL7507976A (en) | 1976-01-07 |
| NL166476C (en) | 1981-08-17 |
| ATA517275A (en) | 1977-03-15 |
| AT339917B (en) | 1977-11-10 |
| FR2277089B1 (en) | 1978-03-17 |
| AU8275575A (en) | 1977-01-06 |
| DK140214C (en) | 1979-12-03 |
| JPS5134194A (en) | 1976-03-23 |
| NO752423L (en) | 1976-01-06 |
| SE427183B (en) | 1983-03-14 |
| SE7807853L (en) | 1978-07-14 |
| NO143224B (en) | 1980-09-22 |
| AR210330A1 (en) | 1977-07-29 |
| CH622519A5 (en) | 1981-04-15 |
| CH622018A5 (en) | 1981-03-13 |
| FR2277089A1 (en) | 1976-01-30 |
| LU72897A1 (en) | 1976-05-31 |
| FI751958A (en) | 1976-01-06 |
| SE7507726L (en) | 1976-01-06 |
| FI59249B (en) | 1981-03-31 |
| FI59249C (en) | 1981-07-10 |
| NO143224C (en) | 1981-01-02 |
| ES439141A1 (en) | 1977-02-16 |
| NL166476B (en) | 1981-03-16 |
| JPS5250800B2 (en) | 1977-12-27 |
| SE420097B (en) | 1981-09-14 |
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