CS201657B1 - Method of preparing 1-/5-oxohexyl/theobromine - Google Patents
Method of preparing 1-/5-oxohexyl/theobromine Download PDFInfo
- Publication number
- CS201657B1 CS201657B1 CS863177A CS863177A CS201657B1 CS 201657 B1 CS201657 B1 CS 201657B1 CS 863177 A CS863177 A CS 863177A CS 863177 A CS863177 A CS 863177A CS 201657 B1 CS201657 B1 CS 201657B1
- Authority
- CS
- Czechoslovakia
- Prior art keywords
- theobromine
- oxohexyl
- bromo
- reaction mixture
- hexanone
- Prior art date
Links
- YAPQBXQYLJRXSA-UHFFFAOYSA-N theobromine Chemical compound CN1C(=O)NC(=O)C2=C1N=CN2C YAPQBXQYLJRXSA-UHFFFAOYSA-N 0.000 title claims description 15
- 229960004559 theobromine Drugs 0.000 title claims description 7
- 238000000034 method Methods 0.000 title description 8
- BYPFEZZEUUWMEJ-UHFFFAOYSA-N Pentoxifylline Chemical compound O=C1N(CCCCC(=O)C)C(=O)N(C)C2=C1N(C)C=N2 BYPFEZZEUUWMEJ-UHFFFAOYSA-N 0.000 claims description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- CZGOECYPTLSLNI-UHFFFAOYSA-N 6-bromohexan-2-one Chemical compound CC(=O)CCCCBr CZGOECYPTLSLNI-UHFFFAOYSA-N 0.000 claims description 9
- 239000011541 reaction mixture Substances 0.000 claims description 8
- CORZNQNMOFOBGZ-UHFFFAOYSA-N 3,7-dimethylpurine-2,6-dione;potassium Chemical compound [K].CN1C(=O)NC(=O)C2=C1N=CN2C CORZNQNMOFOBGZ-UHFFFAOYSA-N 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 2
- 230000002152 alkylating effect Effects 0.000 claims description 2
- 239000003880 polar aprotic solvent Substances 0.000 claims description 2
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims 1
- 239000000047 product Substances 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
(54) Sposob přípravy l-(5-oxohexyI) teobromínu(54) Process for preparing 1- (5-oxohexyl) theobromine
Vynález rieši sposob pripravy l-(5-oxohexyl) teobromínu, liečiva s periférnym vazodilatačným účinkom.The present invention provides a process for the preparation of 1- (5-oxohexyl) theobromine, a drug having a peripheral vasodilatory effect.
l-(5-oxohexyl) teobromín (pentoxifilín) možno připravit alkyláciou draselnej soli teobromínu l-bróm-5-hexahónom v prostředí polárného aprotického rozpúšťadla:1- (5-oxohexyl) theobromine (pentoxifilin) can be prepared by alkylating the potassium salt of theobromine with 1-bromo-5-hexahone in a polar aprotic solvent medium:
selnej soli teobromínu, pričom sa reakčný produkt izoluje z reakčnej zmesi tak, že po oddestilování rozpúšťadla sa reakčná zmes (zahuštěná) vymieša s chloroformom, nerozpustný bromid draselný sa odfiltruje a z filtrátu sa po zahuštění produkt vyzráža n-hexánom. Týmto sposobom sa prebytočná časťof theobromine salt, whereby the reaction product is isolated from the reaction mixture by stirring the solvent (concentrated) with chloroform, insoluble potassium bromide is filtered off and the product is precipitated with n-hexane after concentration. This way the surplus part
Sposob přípravy podlá čsl. autorského osvedčenia č. 164 643 z roku 1975 používá na jeden mól l-bróm-5-hexanónu 0,8 molu dra(0,2 molu) l-bróm-5-hexanónu nevyužije, preto výťažok produktu vzhladom na l-bróm-5hexanón je poměrně nízký (cca 70 %). Nevý201657 hodou tohto spósobu je tiež poměrně obtiažna izolácia produktu ž reakčnej zmesi.Method of preparation according to Czechoslovak. of the author's certificate no. 164 643 of 1975 uses 0.8 moles (0.2 mol) of 1-bromo-5-hexanone per mole of 1-bromo-5-hexanone, so the yield of the product relative to 1-bromo-5-hexanone is relatively low ( 70%). The disadvantage of this method is also the relatively difficult isolation of the product from the reaction mixture.
Nedostatky uvedeného spósobu odstraňuje předložený spósob přípravy l-(5-oxohexyl) teobromínu, ktorého podstata spočívá v tom, že sa na 1 mól l-bróm-5- hexanónu použije prebytok až do 1,5 molu draselnej soli teobromínu, pričom sa výsledný produkt izoluje z reakčnej zmesi tak, že po oddestilovaní rozpúšťadla sa k zahustenej reakčnej zmesi přidá vodný roztok hydroxidu alkalického kovu, zmes sa extrahuje chloroformom a po zahuštění extraktu sa l-(5-oxohexyl) teobromín vykrystalizuje z alkoholu o 2 až 4 atómoch uhlíka. Z vodnej alkalickej fázy možno prebytočnú časť draselnej soli teobromínu jednoduchým spósobom regenerovat vo formě teobromínu.The drawbacks of this process are overcome by the present process for the preparation of 1- (5-oxohexyl) theobromine, which consists in using an excess of up to 1.5 moles of theobromine potassium salt per mole of 1-bromo-5-hexanone, whereby the resulting product The reaction mixture is isolated from the reaction mixture by adding an aqueous alkali metal hydroxide solution to the concentrated reaction mixture, extracting with chloroform, and then concentrating the extract to crystallize 1- (5-oxohexyl) theobromine from a C 2 -C 4 alcohol. From the aqueous alkaline phase, the excess portion of theobromine potassium salt can be easily regenerated in the form of theobromine.
Alkyláciou draselnej soli teobromínu 1bróm-5-hexanónom podía předloženého spósobu sa dosiahne úplné využitie tohto drahého alkylačného činidla připravovaného náročnou dvojstupňovou syntézou z dovázaných surovin (KS). Dósledkom toho je podstatné zvýšenie výtažku l-(5-oxohexyl) teobromínu vzhladom na l-bróm-5-hexanón (88 až 95 %). Navýše izolácia produktu podía předloženého spósobu je technologicky jednoduchšia, z hl’adiska surovin ovel’a lacnejšia a bezpečnejšia, pričom připravený l-(5-oxohexyl) teobromín je kvalitativně lepší.Alkylation of theobromine potassium salt with 1-bromo-5-hexanone according to the present method achieves full utilization of this expensive alkylating agent prepared by a complex two-step synthesis from imported raw materials (KS). As a result, the yield of 1- (5-oxohexyl) theobromine was substantially increased relative to 1-bromo-5-hexanone (88-95%). Moreover, the isolation of the product according to the present method is technologically simpler, much cheaper and safer in terms of raw materials, and the prepared 1- (5-oxohexyl) theobromine is qualitatively better.
Příklad prevedeniaExecution example
V 500 ml Ν,Ν-dimetylformamidu sa suspenduje 262,5 g (1,2 molu) draselnej soli teobromínu a do suspenzie sa přidá 179,1 g (1 mól) l-bróm-5-hexanónu. Zmes sa vyhrieva za miešania na 80 až 100 °C po dobu 4 hodin. Z reakčnej zmesi sa vákuovo oddestiluje dimetylformamid a destilačný zvyšok sa vymieša s 1000 až 1500 ml cca 5 % vodným roztokom KOH a zmes sa extrahuje dvakrát 600 až 700 ml chloroformu. Extrakt sa vymieša s 200 až 300 ml vody a po oddělení vodnej fázy sa zahustí. Zahuštěný extrakt sa rozpustí v 1000 až 1200 ml izopropanolu. Z roztoku sa za miešania a chladenia nechá vykrystalizovat l-(5-oxohexyl) teobromín, ktorý sa odsaje a premyje 200 ml vychladeného izopropanolu. Produkt sa suší vo vákuu pri 60 až 80 °C. Získá sa 245 až 265 g l-(5-oxohexyl) teobromínu, čo zodpovedá výtažku 88 až 95 % (počítané na l-bróm-5-hexanón). Teplota topenia produktu 101 až 103 °C. V případe potřeby sa produkt ešte raz prekryštalizuje z izopropanolu.262.5 g (1.2 mol) of theobromine potassium salt are suspended in 500 ml of Ν, Ν-dimethylformamide and 179.1 g (1 mol) of 1-bromo-5-hexanone are added to the suspension. The mixture is heated with stirring at 80 to 100 ° C for 4 hours. Dimethylformamide was distilled off from the reaction mixture, and the residue was mixed with 1000 to 1500 ml of an approximately 5% aqueous KOH solution and extracted twice with 600 to 700 ml of chloroform. The extract is mixed with 200 to 300 ml of water and concentrated after concentration of the aqueous phase. The concentrated extract is dissolved in 1000 to 1200 ml of isopropanol. 1- (5-Oxohexyl) theobromine is crystallized from the solution with stirring and cooling, which is filtered off with suction and washed with 200 ml of cold isopropanol. The product is dried under vacuum at 60-80 ° C. 245 to 265 g of 1- (5-oxohexyl) theobromine are obtained, corresponding to a yield of 88 to 95% (calculated on 1-bromo-5-hexanone). Mp 101-103 ° C. If necessary, the product is recrystallized again from isopropanol.
Alkalická vodná fáza po extrakcii chloroformom sa neutralizuje kyselinou solnou a upraví pH na hodnotu 3 až 5 pH a za miešania a chladenia sa nechá vykrystalizovat teobromín, ktorý sa odsaje a premyje 200 ml destilovanej vody. Teobromín sa vysuší pri 120 až 140 °C. Získá sa (regeneruje) 32 až 35 g teobromínu, čo zodpovedá výtažku 87 až 95 % (počítané na prebytočnú draselnú sol teobromínu).The alkaline aqueous phase after extraction with chloroform is neutralized with hydrochloric acid and adjusted to a pH of 3-5 pH and theobromine is crystallized with stirring and cooling, which is filtered off with suction and washed with 200 ml of distilled water. Theobromine is dried at 120-140 ° C. 32 to 35 g of theobromine are obtained (regenerated), corresponding to a yield of 87 to 95% (calculated on the excess theobromine potassium salt).
Tento vynález umožňuje z technologického hladiska jednoduchšiu a bezpečnejšiu a z ekonomického hladiska ovela výhodnejšiu výrobu liečiva l-(5-oxohexyl) teobromínu (pentoxifilínu).The present invention makes it possible to make the manufacture of the medicament 1- (5-oxohexyl) theobromine (pentoxifilin) simpler and safer and more economical in terms of technology.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS863177A CS201657B1 (en) | 1977-12-21 | 1977-12-21 | Method of preparing 1-/5-oxohexyl/theobromine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS863177A CS201657B1 (en) | 1977-12-21 | 1977-12-21 | Method of preparing 1-/5-oxohexyl/theobromine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CS201657B1 true CS201657B1 (en) | 1980-11-28 |
Family
ID=5437132
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS863177A CS201657B1 (en) | 1977-12-21 | 1977-12-21 | Method of preparing 1-/5-oxohexyl/theobromine |
Country Status (1)
| Country | Link |
|---|---|
| CS (1) | CS201657B1 (en) |
-
1977
- 1977-12-21 CS CS863177A patent/CS201657B1/en unknown
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