NO143224B - PROCEDURE FOR THE PREPARATION OF HYDROXYALKYLXANTHINES - Google Patents
PROCEDURE FOR THE PREPARATION OF HYDROXYALKYLXANTHINES Download PDFInfo
- Publication number
- NO143224B NO143224B NO752423A NO752423A NO143224B NO 143224 B NO143224 B NO 143224B NO 752423 A NO752423 A NO 752423A NO 752423 A NO752423 A NO 752423A NO 143224 B NO143224 B NO 143224B
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- Prior art keywords
- water
- acid
- residues
- hydroxyalkylxanthines
- preparation
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 5
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical compound OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 claims description 5
- 238000010471 Markovnikov's rule Methods 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 3
- 239000011707 mineral Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 230000008018 melting Effects 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- -1 halogen ketones Chemical class 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- LZRTZRBKFZHHQT-UHFFFAOYSA-N 1-hex-5-enyl-3,7-dimethylpurine-2,6-dione Chemical compound CN1C(=O)N(CCCCC=C)C(=O)C2=C1N=CN2C LZRTZRBKFZHHQT-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- ZGIBYCLLIMGXEZ-UHFFFAOYSA-N 1,3-dimethyl-7-prop-2-enylpurine-2,6-dione Chemical compound O=C1N(C)C(=O)N(C)C2=C1N(CC=C)C=N2 ZGIBYCLLIMGXEZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 230000008021 deposition Effects 0.000 description 3
- 229940075420 xanthine Drugs 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- NSMXQKNUPPXBRG-UHFFFAOYSA-N 1-(5-hydroxyhexyl)-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione Chemical compound O=C1N(CCCCC(O)C)C(=O)N(C)C2=C1N(C)C=N2 NSMXQKNUPPXBRG-UHFFFAOYSA-N 0.000 description 2
- BTFHIKZOEZREBX-UHFFFAOYSA-N 3,7-dimethyl-1-prop-2-enylpurine-2,6-dione Chemical compound CN1C(=O)N(CC=C)C(=O)C2=C1N=CN2C BTFHIKZOEZREBX-UHFFFAOYSA-N 0.000 description 2
- LMCWCVODLNWLCV-UHFFFAOYSA-N 7-but-3-enyl-1,3-dimethylpurine-2,6-dione Chemical compound O=C1N(C)C(=O)N(C)C2=C1N(CCC=C)C=N2 LMCWCVODLNWLCV-UHFFFAOYSA-N 0.000 description 2
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical compound O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 2
- 229940065721 systemic for obstructive airway disease xanthines Drugs 0.000 description 2
- 229960004559 theobromine Drugs 0.000 description 2
- NMOKEUUZNWHWOS-UHFFFAOYSA-N 3,7-dimethyl-1-(2-methylbut-3-enyl)purine-2,6-dione Chemical compound O=C1N(CC(C)C=C)C(=O)N(C)C2=C1N(C)C=N2 NMOKEUUZNWHWOS-UHFFFAOYSA-N 0.000 description 1
- NHAXKHSVJBVINX-UHFFFAOYSA-N 3,7-dimethylpurine-2,6-dione;sodium Chemical compound [Na].CN1C(=O)NC(=O)C2=C1N=CN2C NHAXKHSVJBVINX-UHFFFAOYSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- PESRCCQMYJSHAV-UHFFFAOYSA-N 7-(3-hydroxybutyl)-1,3-dimethylpurine-2,6-dione Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2CCC(O)C PESRCCQMYJSHAV-UHFFFAOYSA-N 0.000 description 1
- COCPIYBVBNOICS-UHFFFAOYSA-N 7-hex-5-enyl-3-methylpurine-2,6-dione Chemical compound O=C1NC(=O)N(C)C2=C1N(CCCCC=C)C=N2 COCPIYBVBNOICS-UHFFFAOYSA-N 0.000 description 1
- GEPVMDINFCTKRV-UHFFFAOYSA-N 8,8-dimethyl-3H-purine-2,6-dione Chemical class CC1(N=C2NC(NC(C2=N1)=O)=O)C GEPVMDINFCTKRV-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- KYHQZNGJUGFTGR-UHFFFAOYSA-N Proxyphylline Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2CC(O)C KYHQZNGJUGFTGR-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 230000008033 biological extinction Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- MXRGZXBFSKSZPH-UHFFFAOYSA-N protheobromine Chemical compound O=C1N(CC(O)C)C(=O)N(C)C2=C1N(C)C=N2 MXRGZXBFSKSZPH-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Steroid Compounds (AREA)
Description
Der er tidligere kjent legemidler hvilke som aktiv be-standdel inneholder dimethylxanthinderivater som i 1- eller 7-stilling oppviser en (co-l)-hydroxyalkylrest. Disse er tilgjen-gelige ved reduksjon av de tilsvarende ketoforbindelser, hvis fremstilling blant annet skjer over halogenketoner og som redu-seres f.eks. med hjelp av metallhydrider. Halogenketoner og hy-drider er tildels lite bestandige, hvilket særlig er uheldig Medicines have previously been known which as active ingredient contain dimethylxanthine derivatives which have a (co-1)-hydroxyalkyl residue in the 1- or 7-position. These are available by reduction of the corresponding keto compounds, the production of which, among other things, takes place via halogen ketones and which are reduced, e.g. with the help of metal hydrides. Halogen ketones and hydrides are partly not stable, which is particularly unfortunate
ved fremstilling i større målestokk. Ennvidere er der fra DT-BP 1.067.025 kj.ent en fremgangsmåte ved fremstilling av l-((3-hydr-oxypropyl)-3, 7-dimethylxanthin (= 1-((3-hydroxypropyl)-theobro-min) ved hvilken der under anvendelse av vanntilleiringskataly-satorer,siik som konsentrert svovelsyre, tilleires vann til 1-ally1-3,7-dimethylxanthin. IfSlge dette patentskrift er den kjente omsetning bare spesifikk for 1-ally1-theobromin, da alle-rede 7-allyl-theofyllin ikke er mulig ved denne reaksjon. when manufacturing on a larger scale. Furthermore, from DT-BP 1,067,025 a method is known for the production of 1-((3-hydroxypropyl)-3,7-dimethylxanthine (= 1-((3-hydroxypropyl)-theobromine)) by which, using water addition catalysts, such as concentrated sulfuric acid, water is added to 1-ally1-3,7-dimethylxanthine. According to this patent, the known reaction is only specific for 1-ally1-theobromine, since all 7-allyl -theophylline is not possible with this reaction.
Det har nu vist seg at denne vanskelighet kan overvin-nes når man omsetter det tilsvarende (u-l)-alkenylxanthin uav-hengig av alkenylgruppen ved tilleiring av vann i nærvær av visse fortynnede syrer til det onskede (to-1)-hydroxyalkylxanthin. Denne omsetning er mulig i nesten kvantitativt utbytte. It has now been shown that this difficulty can be overcome when the corresponding (u-1)-alkenylxanthine is converted independently of the alkenyl group by addition of water in the presence of certain dilute acids to the desired (two-1)-hydroxyalkylxanthine. This turnover is possible in almost quantitative yield.
Foreliggende oppfinnelse angår følgelig en fremgangsmåte ved fremstilling av hydroxyalkylxanthiner av den generelle formel (I) hvor en av restene R 1, R 2 og R er en (CJ -1)-hydroxyalkylrest med 4-8 carbonatomer, som i (CJ -1)-stilling ikke bærer noen forgrening, og hvor de øvrige rester er alkylrester med 1-12 carbonatomer, idet R<1> og/eller R<3> også kan være hydrogen, og fremgangsmåten er særpreget ved at der til tilsvarende (CJ-1)-alkenyixanthiner tilleires vann etter Markownikoffs regel i nærvær av en fortynnet mineralsyre eller sulfonsyre eller en i hydrogenform foreliggende sulfonsyregruppeholdig ionebytter som katalysator. The present invention therefore relates to a process for the production of hydroxyalkylxanthines of the general formula (I) where one of the residues R 1 , R 2 and R is a (CJ -1)-hydroxyalkyl residue with 4-8 carbon atoms, as in (CJ -1) -position does not bear any branching, and where the other residues are alkyl residues with 1-12 carbon atoms, since R<1> and/or R<3> can also be hydrogen, and the method is characterized by the fact that to the corresponding (CJ-1 )-alkenyxanthines precipitate water according to Markownikoff's rule in the presence of a dilute mineral acid or sulphonic acid or an ion exchanger containing a sulphonic acid group present in hydrogen form as a catalyst.
Fortrinnsvis står hydroxyalkylresten i 1- eller 7-stilling og er uforgrenet. Der er nu funnet at hydroxylgruppen ved den nye fremgangsmåte alltid tilleires efter Markownikoffs regel til det hydrogenfattige carbonatom, altså i (CO -1)-stilling. Dette er forsåvidt overraskende, da Markownikoffs regel nettopp ved forbindelser med dobbeltbindinger i enden bare gjelder betinget. Preferably, the hydroxyalkyl residue is in the 1- or 7-position and is unbranched. It has now been found that the hydroxyl group in the new method is always assigned according to Markownikoff's rule to the hydrogen-poor carbon atom, i.e. in the (CO -1) position. This is of course surprising, as Markownikoff's rule only applies conditionally in the case of compounds with double bonds at the end.
Egnede utgangsmaterialer for anvendelse ved den nye fremgangsmåte for fremstilling av (u-l)-hydroxyalkylxanthin er f.eks. 1-(3-butenyl)-, 1-(4-pentenyl)-, 1-(5-hexenyl)- og 1- (2-methyl-3-butenyl)-3,7-dimethylxanthin, 1-(5-hexenyl)-3-methyl-7-alkylxanthin, slik som -7-ethyl-, -7-propyl-, -7-but-yl-, -7-isobutyl- og -7-decylxanthin, ennvidere 1,3-dimethyl-7-(2-methyl-3-butenyl)-, -7-(3-butenyl)-, -7-(4-pentenyl)-, -7-(5-hexenyl)- og -7-(6-heptenyl)-xanthin, såvel som 3-methyl-7-(5-hexenyl)-xanthin og dettes derivat med i 1-stilling foreliggende propyl-, isobutyl-, pentyl- eller hexylgrupper. Suitable starting materials for use in the new process for the production of (u-1)-hydroxyalkylxanthine are e.g. 1-(3-butenyl)-, 1-(4-pentenyl)-, 1-(5-hexenyl)- and 1-(2-methyl-3-butenyl)-3,7-dimethylxanthine, 1-(5- hexenyl)-3-methyl-7-alkylxanthine, such as -7-ethyl-, -7-propyl-, -7-but-yl-, -7-isobutyl- and -7-decylxanthine, further 1,3-dimethyl -7-(2-methyl-3-butenyl)-, -7-(3-butenyl)-, -7-(4-pentenyl)-, -7-(5-hexenyl)- and -7-(6- heptenyl)-xanthine, as well as 3-methyl-7-(5-hexenyl)-xanthine and its derivative with propyl, isobutyl, pentyl or hexyl groups present in the 1-position.
Ifolge foreliggende oppfinnelse kan såvel hydroxyl-alkylmethylxanthiner som deres homologe fremstilles, i hvilken i det minste en methylrest er erstattet med en al kylrest med 2- 12 C-atomer. Eksempelvis kan de sistnevnte forbindelser According to the present invention, both hydroxyl-alkylmethylxanthines and their homologues can be prepared, in which at least one methyl residue is replaced by an alkyl residue with 2-12 C atoms. For example, the latter compounds can
/ 12 / 12
være av en slik beskaffenhet at minst én av restene R , R og be of such a nature that at least one of the residues R , R and
3 3
R har minst 5 C-atomer. R has at least 5 carbon atoms.
Vanntilleiringen ifølge oppfinnelsen utføres i vandige oppløsninger eller suspensjoner i nærvær av fortynnede mineral-syrer, slik som svovelsyre, halogenhydrogensyrer, salpetersyre eller fosforsyre,eller sulfonsyrer, slik som trifluormethyl-sulfonsyre, eller en i hydrogenform foreliggende sulfonsyregruppeholdig ionebytter, hvorved syremengden ikke skal over-skride den tilsvarende konsentrasjon av en 2-normal syre, fortrinnsvis mer enn 0,5-normal, og fortrinnsvis 1 .- 2-normal. Eventuelt er anvendelse av et overfor fortynnet syre inert opp-løsningsmiddel, slik som 1,4-dioxan, benzen eller toluen for-delaktig, hvorved volumandelen av oppløsningsmiddel fortrinnsvis er lik eller mindre enn vannmengden. The water deposition according to the invention is carried out in aqueous solutions or suspensions in the presence of dilute mineral acids, such as sulfuric acid, hydrohalogenic acids, nitric acid or phosphoric acid, or sulphonic acids, such as trifluoromethyl sulphonic acid, or an ion exchanger containing sulphonic acid groups present in hydrogen form, whereby the amount of acid must not exceed step the corresponding concentration of a 2-normal acid, preferably more than 0.5-normal, and preferably 1.-2-normal. Optionally, the use of a solvent inert to diluted acid, such as 1,4-dioxane, benzene or toluene, is advantageous, whereby the volume fraction of solvent is preferably equal to or less than the amount of water.
Vanntilleiringen skjer vanligvis ved temperaturer fra 40 til 150°C, fortrinnsvis fra 60 til 120°C. Forlopet av reaksjonen såvel som tidspunktet for fullstendig omsetning lar seg meget lett folge ved tynnskiktkromatografiske metoder. Det i den vandige fase foreliggende reaksjonsprodukt lar seg isolere fweks. ved ekstraksjon med klorhydrocarboner, slik som methylenklorid eller kloroform. Hvis en andre, organisk fase forelig-ger, kan eventuelt ytterligere deler av fremgangsmåteproduktet isoleres ved avdampning av oppldsningsmidlet, f.eks. under redusert trykk. The water deposition usually takes place at temperatures from 40 to 150°C, preferably from 60 to 120°C. The progress of the reaction as well as the time of complete reaction can be very easily followed by thin-layer chromatographic methods. The reaction product present in the aqueous phase can be isolated fweks. by extraction with chlorohydrocarbons, such as methylene chloride or chloroform. If a second, organic phase is present, possibly further parts of the process product can be isolated by evaporation of the solvent, e.g. under reduced pressure.
De ifolge fremgangsmåten fremstLlte hydroxylalkyl-xanthiner er kjente og terapeutisk anvendbare. Således er eksempelvis 1-(5-hydroxyhexyl)-3,7-dimethylxanthin kjennetegnet ved at det fremmer gjennomblddning. The hydroxylalkyl-xanthines produced according to the method are known and can be used therapeutically. Thus, for example, 1-(5-hydroxyhexyl)-3,7-dimethylxanthine is characterized by the fact that it promotes blood circulation.
Eksempel 1 Example 1
1) 1-( 5- hydroxyhexyl)- 3, 7- dimetnyl~ xanthin 1) 1-(5- hydroxyhexyl)- 3, 7- dimethnyl~xanthine
a) 1-( 5- hexenyl)- 3, 7- dimethyl- xanthin IO,3 g 1-brom-hexen-(5) ble omsatt med 20,2 g theobro-min-natrium i 200 ml dimethylformamid ved 120°C under omrbring inntil reaksjonen ved tynnskiktkromatografi var fullfort efter ca. 6 - 8 timer, hvorefter oppldsningsmidlet ble fjernet under redusert trykk. Residuet ble opplost i lOO ml methylenklorid ved 20°C, fraskilt opploselig natriumbromid og renset over en sbyle med noytralt aluminiumoxyd for å fjerne små mengder av morkfarvede ledsagende stoff er. Fra n-hexan ble der utkrystalli-sert farveldse nåler forenet til druser med smeltepunkt på 76-77°C. Utbytte: 24,1 g (92 % av teoretisk). Efter tynnskikts-kromatografi på Merck DC-Fertigplatten Kieselgel 60 F~ 254 med benzen/aceton (volumforhold 6:4) som flytemiddel hadde produktet en Rf-verdi på 0,47, og med nitromethan/benzen/pyridin (volumforhold 20:10:3) som flytemiddel, en Rf-verdi pi 0,60. Som indikator ble anvendt UV-lys, hvorved pyridinet i flyte-midlet på grunn av sine fluorescensopplosende egenskaper imid-lertid må fjernes ved 50°C under anvendelse av redusert trykk. b) 1-( 5- hydroxyhexyl)- 3, 7- dimethyl- xanthin 2,6 g av det under punkt a) beskrevne 1-(5-hexenyl)-3,7-dimethyl-xanthin ble oppvarmet til kokning med 25 ml 1-normal svovelsyre ca. 24 timer. En prove av den klare opplos-ning ble derefter tynnskiktkromatografisk, som ovenfor beskrevet, undersokt med hensyn til graden av vanntilleiring, hvorved det bnskede fremgangsmåteprodukt viste fluorescensutslet-telse i området fra Rf 0,30 til 0,37 (nitromethan/benzen/ pyridin). Efter endt reaksjon ble produktet nøytralisert og ekstrahert med methylenklorid. Fra ekstraktoppløsningen ble frémgangsmåteprodukt erholdt i form av farveløse krystaller som efter omkrystallisering fra methanol hadde et smeltepunkt på 126°C. Utbytte: 2,6 g (93% av teoretisk). a) 1-(5-hexenyl)-3,7-dimethylxanthine 10.3 g of 1-bromo-hexene-(5) was reacted with 20.2 g of theobromine sodium in 200 ml of dimethylformamide at 120°C under stirring until the reaction by thin-layer chromatography was complete after approx. 6 - 8 hours, after which the solvent was removed under reduced pressure. The residue was dissolved in 100 ml of methylene chloride at 20°C, separated from soluble sodium bromide and purified over a bath of neutral aluminum oxide to remove small amounts of maroon-colored accompanying substances. From n-hexane, fine needles crystallized there, united to druses with a melting point of 76-77°C. Yield: 24.1 g (92% of theoretical). After thin-layer chromatography on Merck DC-Fertigplatten Kieselgel 60 F~ 254 with benzene/acetone (volume ratio 6:4) as eluent, the product had an Rf value of 0.47, and with nitromethane/benzene/pyridine (volume ratio 20:10: 3) as a fluid, an Rf value pi 0.60. UV light was used as an indicator, whereby the pyridine in the fluid, due to its fluorescence-dissolving properties, must however be removed at 50°C using reduced pressure. b) 1-(5-hydroxyhexyl)-3,7-dimethyl-xanthine 2.6 g of the 1-(5-hexenyl)-3,7-dimethyl-xanthine described under point a) was heated to boiling with 25 ml 1-normal sulfuric acid approx. 24 hours. A sample of the clear solution was then examined by thin-layer chromatography, as described above, with regard to the degree of water deposition, whereby the desired process product showed fluorescence extinction in the range from Rf 0.30 to 0.37 (nitromethane/benzene/pyridine) . After completion of the reaction, the product was neutralized and extracted with methylene chloride. From the extract solution, the process product was obtained in the form of colorless crystals which, after recrystallization from methanol, had a melting point of 126°C. Yield: 2.6 g (93% of theoretical).
Eksempler 2- 18 Examples 2-18
Ved å folge den i eksempel 1 beskrevne fremgangsmåte ble folgende hydroxylalkyl-xanthiner fremstillet og identifi-sert på lignende måte som beskrevet i eksempel 1: By following the method described in example 1, the following hydroxylalkyl-xanthines were produced and identified in a similar way as described in example 1:
Eksempel 19 Example 19
Tilleiring av vann til 1- allyltheobromin Addition of water to 1-allyl theobromine
2,2 g 1-allyltheobromin ble kokt med 25 ml 1-normal svovelsyre i 24 timer. Blandingen ble deretter nøytralisert, og reaksjons-produktet ble ekstrahert med methylenklorid.' Etter fordampning av methylenkloridet ble 1-(2-hydroxypropyl)-theobromin tilbake i form av farveløse krystaller. Etter omkrystallisering fra isopropanol ga forbindelsen et smeltepunkt på 138°C. Utbyttet var 0,47 g (= 20 % av det teoretiske). 2.2 g of 1-allyl theobromine was boiled with 25 ml of 1-normal sulfuric acid for 24 hours. The mixture was then neutralized, and the reaction product was extracted with methylene chloride. After evaporation of the methylene chloride, 1-(2-hydroxypropyl)-theobromine remained in the form of colorless crystals. After recrystallization from isopropanol, the compound gave a melting point of 138°C. The yield was 0.47 g (= 20% of the theoretical).
Eksempel 20 Tilleiring av vann til 7- allyltheofyllin Example 20 Addition of water to 7-allyltheophylline
2,2 g 7-allyltheofyllin ble kokt med 25 ml 1-normal svovelsyre i 24 timer. Ved at man gikk frem på tilsvarende måte som i eksempel 19 ble det erholdt 0,48 g 7-(2-hydroxypropyl)-theofyllin (= 20% av det teoretiske) med et smeltepunkt på 135 - 136°C. 2.2 g of 7-allyl theophylline was boiled with 25 ml of 1-normal sulfuric acid for 24 hours. By proceeding in a similar manner as in example 19, 0.48 g of 7-(2-hydroxypropyl)-theophylline (= 20% of the theoretical) was obtained with a melting point of 135 - 136°C.
Eksempel 21( Sammenligningseksempel) Example 21 (Comparison example)
Omsetning av 1-(5-hexenyl)-theobromin ifølge vest-tysk patentskrift 1 067 025. Conversion of 1-(5-hexenyl)-theobromine according to West German patent document 1 067 025.
2,2 g 1-(5-hexenyl)-theobromin ble oppløst i 3 ml konsentrert svovelsyre under omrøring, idet temperaturen ikke ble tillatt å stige over 30°C. Blandingen ble så, under stadig omrøring, oppvarmet gradvis til 70 - 80°C i løpet av 1 time. Reaksjonsblandin-gen ble så under omrøring satt til 30 ml vann, og den erholdte opp-løsning ble kokt i 2 timer med tilbakeløpskjøling. Etter av-kjøling ble blandingen nøytralisert med natronlut, filtrert og inndampet til tørrhet i vakuum. Residuet ble kokt med isopropanol og oppløsningen inndampet til tørrhet. Det ble erholdt harpiks-aktige polymerisasjonsprodukter og en liten mengde av en sulfon-syreester som etter flere timers koking i vann ikke lot seg hydro-lysere, hvilket ble påvist ved tynnskiktkromatografering. 2.2 g of 1-(5-hexenyl)-theobromine were dissolved in 3 ml of concentrated sulfuric acid with stirring, the temperature not being allowed to rise above 30°C. The mixture was then, with constant stirring, gradually heated to 70-80°C over the course of 1 hour. The reaction mixture was then added to 30 ml of water while stirring, and the resulting solution was boiled for 2 hours with reflux cooling. After cooling, the mixture was neutralized with caustic soda, filtered and evaporated to dryness in vacuo. The residue was boiled with isopropanol and the solution evaporated to dryness. Resinous polymerization products and a small amount of a sulphonic acid ester were obtained which, after boiling in water for several hours, did not allow itself to be hydrolysed, which was demonstrated by thin layer chromatography.
Eksempel 22 Example 22
2,3 g 1,3-dimethyl-7-(3-butenyl)-xanthin oppvarmes 2.3 g of 1,3-dimethyl-7-(3-butenyl)-xanthine are heated
i 25 ml IN saltsyre i ca. 24 timer. Deretter nøytraliseres oppløsningen og ekstraheres med methylenklorid. Fra ekstrakt-oppløsningen fås 1,3-dimethyl-7-(3-hydroxybutyl)-xanthin med et smeltepunkt av 124°C i et utbytte av 9 3% av det teoretiske. in 25 ml IN hydrochloric acid for approx. 24 hours. The solution is then neutralized and extracted with methylene chloride. From the extract solution, 1,3-dimethyl-7-(3-hydroxybutyl)-xanthine with a melting point of 124°C is obtained in a yield of 93% of the theoretical.
Eksempel 2 3 Example 2 3
2,3 g 1,3-dimethyl-7-(3-butenyl)-xanthin oppvarmes i 25 ml av en blanding av dioxan og vann i forholdet 1:1 med en suspensjon av en sulfonsyregruppeholdig kationbytter. Efter 24 timer filtreres bytteren fra, og fra oppløsningen isoleres 1, 3-dirnethyl-7-r(3-hydroxybutyl) -xanthin med et. utbytte av 91%. Smeltepunkt 124°C. 2.3 g of 1,3-dimethyl-7-(3-butenyl)-xanthine is heated in 25 ml of a mixture of dioxane and water in a 1:1 ratio with a suspension of a sulfonic acid group-containing cation exchanger. After 24 hours, the changer is filtered off, and 1, 3-dirnethyl-7-r(3-hydroxybutyl)-xanthine is isolated from the solution with a yield of 91%. Melting point 124°C.
Claims (1)
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 (3)
Publication Number | Publication Date |
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NO752423L NO752423L (en) | 1976-01-06 |
NO143224B true NO143224B (en) | 1980-09-22 |
NO143224C NO143224C (en) | 1981-01-02 |
Family
ID=27048497
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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NO752423A NO143224C (en) | 1974-07-05 | 1975-07-04 | PROCEDURE FOR THE PREPARATION OF HYDROXYALKYLXANTHINES |
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Country | Link |
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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) |
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HU197569B (en) * | 1984-01-12 | 1989-04-28 | Sandoz Ag | Process for producing 8alpha-acylaminoergoline derivatives and pharmaceuticals comprising such compounds |
DE3525801A1 (en) * | 1985-07-19 | 1987-01-22 | Hoechst Ag | TERTIA HYDROXYALKYLXANTHINE, METHOD FOR THE PRODUCTION THEREOF, THE MEDICINAL PRODUCT CONTAINING IT AND THEIR USE |
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 DK DK301775AA patent/DK140214B/en not_active IP Right Cessation
- 1975-07-03 LU LU72897A patent/LU72897A1/xx unknown
- 1975-07-04 FI FI751958A patent/FI59249C/en not_active IP Right Cessation
- 1975-07-04 ES ES439141A patent/ES439141A1/en not_active Expired
- 1975-07-04 AT AT517275A patent/AT339917B/en not_active IP Right Cessation
- 1975-07-04 GB GB28341/75A patent/GB1500039A/en not_active Expired
- 1975-07-04 CA CA230,790A patent/CA1062710A/en not_active Expired
- 1975-07-04 SE SE7507726A patent/SE420097B/en not_active IP Right Cessation
- 1975-07-04 FR FR7521043A patent/FR2277089A1/en active Granted
- 1975-07-04 AR AR258487A patent/AR210330A1/en active
- 1975-07-04 NO NO752423A patent/NO143224C/en unknown
- 1975-07-04 NL NL7507976.A patent/NL166476C/en not_active IP Right Cessation
-
1978
- 1978-07-14 SE SE7807853A patent/SE427183B/en not_active IP Right Cessation
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1980
- 1980-04-29 CH CH331680A patent/CH622018A5/en not_active IP Right Cessation
Also Published As
Publication number | Publication date |
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CA1062710A (en) | 1979-09-18 |
SE427183B (en) | 1983-03-14 |
GB1500039A (en) | 1978-02-08 |
NO752423L (en) | 1976-01-06 |
SE7507726L (en) | 1976-01-07 |
FI59249C (en) | 1981-07-10 |
FR2277089A1 (en) | 1976-01-30 |
JPS5134194A (en) | 1976-03-23 |
ES439141A1 (en) | 1977-02-16 |
ATA517275A (en) | 1977-03-15 |
SE420097B (en) | 1981-09-14 |
LU72897A1 (en) | 1976-05-31 |
FR2277089B1 (en) | 1978-03-17 |
NL7507976A (en) | 1976-01-07 |
AU8275575A (en) | 1977-01-06 |
NL166476B (en) | 1981-03-16 |
JPS5250800B2 (en) | 1977-12-27 |
DK140214B (en) | 1979-07-09 |
DK301775A (en) | 1976-01-06 |
FI59249B (en) | 1981-03-31 |
AT339917B (en) | 1977-11-10 |
NL166476C (en) | 1981-08-17 |
AR210330A1 (en) | 1977-07-29 |
CH622519A5 (en) | 1981-04-15 |
DK140214C (en) | 1979-12-03 |
CH622018A5 (en) | 1981-03-13 |
SE7807853L (en) | 1978-07-14 |
FI751958A (en) | 1976-01-06 |
NO143224C (en) | 1981-01-02 |
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