CS267379B1 - Process for the preparation of 3-methyl-7-n-propyl-3,7-dihydro-1H-purine-2,6-dione - Google Patents
Process for the preparation of 3-methyl-7-n-propyl-3,7-dihydro-1H-purine-2,6-dione Download PDFInfo
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- CS267379B1 CS267379B1 CS883550A CS355088A CS267379B1 CS 267379 B1 CS267379 B1 CS 267379B1 CS 883550 A CS883550 A CS 883550A CS 355088 A CS355088 A CS 355088A CS 267379 B1 CS267379 B1 CS 267379B1
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Abstract
Zlúčenina vzorca I sa používá vo farmaceutickej chémii ako medziprodukt pri výrobě periférneho vazodilatans a hemoreologika propantofylínu. Jej výroba spočívá v tom, že sa 5- n-propylamíno-6-amíno-l-metyl-lH-pyrimidín- * 2,4-dion vzorca II formyluje pósobením formamidu a in šitu vznikajúci 5-N-(n-propyl)-formylamíno-6-amíno-l-metyl-lH-pyrimidín-2,6-dion vzorca III sa termicky cyklizuje v prostředí formamidu pri teplote 100 až 195 °C za přítomnosti kyseliny s hodnotou pKa max. 4,8, s výhodou kyseliny mravčej.The compound of formula I is used in pharmaceutical chemistry as an intermediate in the production of the peripheral vasodilator and haemorheologic propantofylline. Its production consists in the fact that 5-n-propylamino-6-amino-1-methyl-1H-pyrimidine-2,4-dione of formula II is formylated by treatment with formamide, and the resulting 5-N-(n-propyl)-formylamino-6-amino-1-methyl-1H-pyrimidine-2,6-dione of formula III is thermally cyclized in a formamide environment at a temperature of 100 to 195 °C in the presence of an acid with a pKa value of max. 4.8, preferably formic acid.
Description
Vynález sa týká spósobu přípravy 3-metyl-7n-propyl-3,7-dihydro-1H-purin-2,6-dionu vzorca I
ktorý sa používá vo farmaceutickej chémii ako medziprodukt pri výrobě periférneho vazodilatancia a hemoreologika propentofylínu.
Doposial’ sa zlúčenina vzorca I připravovala alkyláciou 3-metyl-3,7-dihydro-lH-purin-2,6dionu s n-propylhalogenidom za přítomnosti uhličitanu alkalického kovu v aprotickom rozpúšťadle A. Rybář a spol.: CS AO 263 595 alebo alkyláciou alkalickej soli 3-metyl-3,7-dihydro-lH-purin-2,6-dionu s n-propylhalogenidom v aprotickom rozpúšťadle A. Rybář a spol.: CS AO 263 595. Nevýhodou týchto postupov je, že pri nich móže vznikať ako vedfajší produkt 3-metyl-l,7-di-n-propyl-3,7-dihydro-lH-purin-2,6-dion, ktorý třeba odstraňovať.
Túto nevýhodu odstraňuje spósob přípravy zlúčeniny vzorca I podía vynálezu, podstatou ktorého je formylácia 5-n-propyIamíno-6-amíno-1-metyl-lH-pyrimidín-2,6-díonu vzorca II
pósobením formamidu a termická cyklizácia in šitu vznikajúceho 5-N-(n-propyl)-formyIamíno6-amíno-1 -metyl-1 H-pyrimidín-2,6-dionu vzorca III
v prostředí formamidu za přítomnosti kyseliny s hodnotou pKa max. 4,8.
Postup podía vynálezu sa uskutočňuje tak, že sa zlúčenina vzorca II zahrieva s prebytkom formamidu pri teplote 100 °C až 195 °C za přítomnosti kyseliny octovej, chlorovodíkovej, alebo s výhodou kyseliny mravčej. Zlúčenina vzorca I sa už počas reakcie vylučuje z reakčnej zmesi, úplné sa vylúči jej ochladenie na teplotu miestnosti. Izoluje sa odfiltrováním alebo odstředěním, premytím vodou a vysušením pri zvýšenej teplote, s výhodou vo vákuu.
Hlavnou výhodou poslupu podía vynálezu je 1-stupňová příprava zlúčeniny vzorca I zo zlúčeniny vzorca II. Výťažky zlúčeniny vzorca I sa pohybujú okolo 80 % teorie. V ďalšom je predmet vynálezu popísaný v príkladoch prevedenia bez toho, že by sa na tieto obmedzoval. Příklad 1
Zmes 9,9 g zlúčeniny vzorca íí, 50 ml formamidu a 2,5 ml kyseliny mravčej sa zahrieva pri teplote kúpeía 185 °C počas 4 h. Po tejto době sa nechá samovolné vychladnúť, pričom z reakčnej zmesi kryštalizuje zlúčenina vzorca I. Po premytí vodou a vysušení pri zvýšenej teplote sa získá 8,25 g (79,2 % teorie) zlúčeniny vzorca 1 s 1.1.248 °C až 251 °C. Pre C9H|2N4O2 (208,2) vypočítané: 51,91 %C, 5,81 % H. 26,91 %N; nájdené: 51,69 % C, 6,00 % H, 27,08 % N. Produkt reakcie je chromatograficky totožný so zlúčeninou vzorca I připravenou podfa CS AO 263 595. Příklad 2
Zmes 9,9 g zlúčeniny vzorca II, 50 ml formamidu a 2,5 ml kyseliny octovej sa zahrieva do varu (teplota kúpeía 185 °C) počas 4 h. Po tomto čase s nechá samovolné vychladnúť, pričom vykrystalizuje zlúčenina vzorca I. Po niekofkohodinovom dochladení na teplotu okolo 0 °C sa produkt odsaje, premyje vodou a vysuší pri zvýšenej teplote vo vákuu. Získá sa 8,4 g (80,8 % teorie) zlúčeniny vzorca I s 1.1. 248 až 250 °C.
The invention relates to a process for the preparation of 3-methyl-7n-propyl-3,7-dihydro-1H-purine-2,6-dione of the formula I
which is used in pharmaceutical chemistry as an intermediate in the production of peripheral vasodilators and hemorrhages of propentophyllin.
To date, the compound of formula I has been prepared by alkylating 3-methyl-3,7-dihydro-1H-purine-2,6-dione with n-propyl halide in the presence of an alkali metal carbonate in aprotic solvent A. Rybář et al. of the 3-methyl-3,7-dihydro-1H-purine-2,6-dione alkaline salt with n-propyl halide in aprotic solvent A. Rybář et al .: CS AO 263 595. as by-product 3-methyl-1,7-di-n-propyl-3,7-dihydro-1H-purine-2,6-dione, which is to be removed.
This drawback is overcome by the preparation of the compound of formula (I) according to the invention, the subject of which is the formylation of 5-n-propylamino-6-amino-1-methyl-1H-pyrimidine-2,6-dione of formula II
by formamide and thermal cyclization of the resulting 5-N- (n-propyl) -formylamino-6-amino-1-methyl-1H-pyrimidine-2,6-dione of formula III
in formamide in the presence of acid with a pKa value of max 4.8.
The process of the invention is carried out by heating the compound of formula II with excess formamide at 100 ° C to 195 ° C in the presence of acetic acid, hydrochloric acid, or preferably formic acid. The compound of formula (I) is already precipitated from the reaction mixture during the reaction and is completely eliminated from cooling to room temperature. It is isolated by filtration or centrifugation, washing with water and drying at elevated temperature, preferably under vacuum.
The main advantage of the sequence according to the invention is the 1-step preparation of the compound of formula I from the compound of formula II. The yields of the compound of formula I are about 80% of theory. In the following, the invention will be described in the examples without limiting it. Example 1
A mixture of 9.9 g of the compound of formula (Ii), 50 ml of formamide and 2.5 ml of formic acid is heated at a bath temperature of 185 ° C for 4 h. with water and drying at elevated temperature, 8.25 g (79.2% of theory) of the compound of formula I with 1.148 ° C to 251 ° C are obtained. For C9H12N4O2 (208.2) calculated: 51.91% C, 5.81% H 26.91% N; Found: C, 51.69; H, 6.00; N, 27.08. The product of the reaction is identical to the compound of formula (I) prepared in accordance with AO 263,595.
A mixture of 9.9 g of the compound of formula II, 50 ml of formamide and 2.5 ml of acetic acid is heated to boiling (bath temperature 185 ° C) for 4 h. After this time it is allowed to cool spontaneously, whereby the compound of formula I crystallizes. cooling to about 0 ° C, the product is filtered off with suction, washed with water and dried under vacuum at elevated temperature. 8.4 g (80.8% of theory) of the compound of formula I with 1.1 are obtained. 248-250 ° C.
Claims (2)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS883550A CS267379B1 (en) | 1988-05-25 | 1988-05-25 | Process for the preparation of 3-methyl-7-n-propyl-3,7-dihydro-1H-purine-2,6-dione |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS883550A CS267379B1 (en) | 1988-05-25 | 1988-05-25 | Process for the preparation of 3-methyl-7-n-propyl-3,7-dihydro-1H-purine-2,6-dione |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CS355088A1 CS355088A1 (en) | 1989-06-13 |
| CS267379B1 true CS267379B1 (en) | 1990-02-12 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS883550A CS267379B1 (en) | 1988-05-25 | 1988-05-25 | Process for the preparation of 3-methyl-7-n-propyl-3,7-dihydro-1H-purine-2,6-dione |
Country Status (1)
| Country | Link |
|---|---|
| CS (1) | CS267379B1 (en) |
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1988
- 1988-05-25 CS CS883550A patent/CS267379B1/en unknown
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| Publication number | Publication date |
|---|---|
| CS355088A1 (en) | 1989-06-13 |
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