Process for producing N.sub.1 -(Dihydroxyalkyl)-5-substituted uracils

Abstract

A process for producing N.sub.1 -(dihydroxyalkyl)-5-substituted uracils of the formula: ##SPC1##WhereinR.sub.1 is hydrogen, methyl, a trihalomethyl, a halogen,R.sub.2 is 1,4-dihydroxybutyl-2,1,4-dihydroxypentyl-2,2,5-dihydroxypentyl-1,Characterized by reducing N.sub.1 -(butyrolactone)uracils of the formula: ##SPC2##WhereinR.sub.1 is hydrogen, methyl, a trihalomethyl, a halogen,A is: ##SPC3##With an alkali metal boron hydride in an aqueous or aquo-alcoholic solution at a temperature ranging from 15.degree. to 50.degree.C.

Description

The present invention relates to a process for producing nucleoside analogues and, more specifically, to a process for producing N.sub.1 -(dihydroxyalkyl)-5-substituted uracils corresponding to the generic formula: ##SPC4##

Wherein R.sub.1 is hydrogen, methyl, a trihalomethyl or a halogen; R.sub.2 is 1,4-dihydroxybutyl-2, 1,4-dihydroxypentyl-2, 2,5-dihydroxypentyl-1.

Said compounds are analogues of pyrimidine-nucleosides, wherein a sugar residue is replaced by a dihydroxyalkyl group. Such compounds are particularly interesting as possible inhibitors of nucleic exchange and may be useful for the production of analogues of mono-, oligo-nucleotides and nucleic acids.

Known in the art is a process for producing N.sub.1 -(2,3-dihydroxypropyl-1)-uracil by alkylation of uracil or 4-ethoxy-2-keto-1,2-dihydropyrimidine with glycidol in a dimethylformamide medium in the presence of anhydrous potassium carbonate (cf. N. Ueda, T. Kawabata, K. Takemoto, L. Heterocyclic Chem., 1971, 8, 827).

Also known in the art is a process for producing N.sub.1 -(3',5'-dihydroxypentyl-1)-uracil (cf. B. R. Baker, T. J. Shawan, J. Med. Chem., 1966, 9, 73) by condensing uracil with 1-chloro-3,5-diacetoxypentane, followed by hydrolysis of acetyl groups with butylamine.

None of said prior-art processes can be applied for the synthesis of other N.sub.1 -dihydroxyalkyluracils.

It is an object of the present invention to provide a process for producing N.sub.1 -(dihydroxyalkyl)-5-substituted uracil derivatives which would enable the production of all the compounds corresponding to the generic formula given hereinabove.

This object is accomplished by the process for producing N.sub.1 -(dihydroxyalkyl)-5-substituted uracils of the formula: ##SPC5##

Wherein R.sub.1 is hydrogen, methyl, a trihalomethyl or a halogen, R.sub.2 is 1,4-hydroxybutyl-2, 1,4-dihydroxypentyl-2,2,5-dihydroxypentyl-1, Which, according to the present invention, comprises reducing N.sub.1 -(butyrolactone)uracils of the formula: ##SPC6## Wherein R.sub.1 is hydrogen, methyl, a trihalomethyl or a halogen, and A is ##SPC7## With an alkali metal boron hydride in an aqueous or aquo-alcoholic solution at a temperature ranging from 15.degree. to 50.degree.C. The reaction of interaction of the components proceeds according to schemes I, II, III: ##SPC8##

The process for producing said N.sub.1 -(dihydroxyalkyl)-uracils is performed in the following manner.

A suspension of a N.sub.1 -(butyrolactone)-5-substituted uracil in water is gradually added, with stirring, to an aqueous or alcoholic solution of an alkali metal boron hydride such as sodium boron hydride at room temperature. 20-30 minutes after the addition of the total amount of the N.sub.1 -(butyrolactone)-uracil, its complete dissolution in the reaction mixture is observed.

The reaction mixture is allowed to stand for 2-3 hours, whereafter it is acidified with acetic acid to pH = 5 decompose the excess of said boron hydride, passed through a column filled with a cationite "Amberlite-IR-120", and eluted with water. The eluate is passed through a column with an anionite "Dowex-3", eluted with water and then with a 0.5N aqueous ammonia solution.

The aqueous eluate, after evaporation, gives N.sub.1 -(dihydroxyalkyl)-5-substituted uracil derivatives. The ammoniacal liquor contains a by-product of the reaction, viz. an ammonium salt of a corresponding hydroxy-acid.

For better understanding of the present invention, the following Examples illustrating the production of N.sub.1 -(dihydroxyalkyl)-5-substituted uracil derivatives are given hereinbelow.

EXAMPLE 1: PRODUCTION OF N.sub.1 -(1,4-DIHYDROXYBUTYL-2)-URACIL

To a solution of 0.8 g (0.022 mol) of sodium boron hydride in 40 ml of water there is added, under stirring, a suspension of 3 g (0.015 mol) of N.sub.1 -(.alpha.-butyrolactone)uracil in 40 ml of water. The reaction mixture is stirred for 2-3 hours at room temperature. Then, the excess sodium boron hydride is decomposed with acetic acid, passed through a column with a cationite such as "Amberlite IR-120", and eluted with water. The eluate is passed through a column with "Dowex-3" anionite, eluted with water and then with a 0.5M ammonia solution. After evaporation, the aqueous eluate gives 1.7 g (57% of the theoretical amount) of N.sub.1 -(1,4-dihydroxybutyl-2)uracil in the form of white crystals which are then recrystallized from ethanol. Melting point 108.degree.-110.degree.C.

UV-spectrum, pH = 2,.lambda..sub.max 266(.epsilon.9.630); pH =12.lambda..sub.max 265(.epsilon.7.100);

IR-spectrum 1,060 cm.sup.-.sup.1 (.sup..fwdarw..sub.C-OH), 3,300-3,450 cm.sup.-.sup.1 ; (.nu..sub.OH) 1,680, 1,720 cm.sup.-.sup.1 (.nu..sub.CO).

Analysis. Found, %: C, 48.25; H, 6.20; N, 14.12. C.sub.8 H.sub.12 N.sub.2 O.sub.4. Calculated, %: C, 47.99; H, 6.04; N, 13.99.

EXAMPLE 2: PRODUCTION OF N.sub.1 -(1,4-DIHYDROXYBUTYL-2)-5-FLUOROURACIL

The reaction is conducted as described in Example 1. Using 3 g (0.014 mol) of N.sub.1 -(.alpha.-butyrolactone)-5-fluorouracil and 0.8 g (0.022 mol) of sodium boron hydride, there is obtained 1 g (33% of the theoretical amount) of N.sub.1 -(1,4-dihydroxybutyl-2)-5-fluorouracil in the form of a white crystalline substance. The desired product is recrystallized from ethanol. Melting point 181.degree.-182.degree.C.

UV-spectrum pH = 2.lambda..sub.max 276(.epsilon.8,540), pH = 12.lambda..sub.max 276(.epsilon.6,420)

IR-spectrum 1,670; 1,720 cm.sup.-.sup.1 (.nu..sub.CO), 3,200-3,400 (.nu..sub.OH), 1,050 (.nu..sub.C-OH).

Analysis. Found, %: C, 44.49; H, 5.10; N, 12.93; F, 8.16. C.sub.8 H.sub.11 N.sub.2 O.sub.4 F. Calculated, %: C, 44.04; H, 5.08; N, 12.84; F, 8.70.

EXAMPLE 3: PRODUCTION OF N.sub.1 -(1,4-DIHYDROXYPENTYL-2)-5-METHYLURACIL

The reaction is conducted as described in Example 1. Using 3.3 g (0.015 mol) of N.sub.1 -(.gamma.-methyl-.alpha.-butyrolactone)-5-methyluracil and 0.8 g (0.022 mol) of sodium boron hydride, there is obtained 1.2 g (53% of the theoretical amount) of N.sub.1 -(1,4-dihydroxypentyl-2)-5-methyluracil which is then recrystallized from ethanol. Melting point 166.degree.-168.degree.C.

UV-spectrum pH = 2.lambda..sub.max 273(.epsilon.9.200), pH = 12.lambda..sub.max 273(.epsilon.7,100).

IR-spectrum 1,680; 1,700 cm.sup.-.sup.1 (.nu..sub.CO); 3,230-3,420 cm.sup.-.sup.1 (.nu..sub.OH); 1,050 cm.sup.-.sup.1 (.nu..sub.C-OH).

Analysis. Found, %: C, 52.05; H, 7.28; N, 12.42. C.sub.10 H.sub.16 N.sub.2 O.sub.4. Calculated, %: C, 52.19; H, 7.02; N, 12.28.

EXAMPLE 4: PRODUCTION OF N.sub.1 -(2,5-DIHYDROXYPENTYL-1)-5-TRIFLUOROMETHYLURACIL

The reaction is conducted as described in Example 1. Using 4.2 g (0.015 mol) of N.sub.1 -(butyrolactone-.gamma.-methylene)-5-trifluoromethyluracil and 0.8 g (0.022 mol) of sodium boron hydride, there is obtained 0.8 g (28% of the theoretical amount) of N.sub.1 -(2,5-dihydroxypentyl-1)-5-trifluoromethyluracil. The product is recrystallized from ethanol. Melting point is 195.degree.-197.degree.C.

UV-spectrum pH = 2 .lambda..sub.max 262(.epsilon.9.940) pH = 12.lambda..sub.max 261(.epsilon.6.720);

IR-spectrum 1,680; 1,700 cm.sup.-.sup.1 (.nu..sub.CO); 3,200-3,400 cm.sup.-.sup.1 (.nu..sub.OH), 1,050; 1,090 cm.sup.-.sup.1 (.nu..sub.C-OH).

Analysis. Found, %: C, 42.85; H, 4.60; N, 9.99; F, 19.73. C.sub.10 H.sub.13 N.sub.2 O.sub.4 F.sub.3. Calculated, %: C, 42.55; H, 4.64; N, 9.79; F, 20.20.

Claims

1. A process for producing N.sub.1 -(dihydroxyalkyl)-5-substituted uracils of the formula: ##SPC9##

where R.sub.1 is selected from the group consisting of hydrogen, methyl, trifluoromethyl and fluorine; R.sub.2 is selected from the group consisting of 1,4-dihydroxybutyl-2,1,4-dihydroxypentyl-2, and 2,5-dihydroxypentyl-1, comprising reducing N.sub.1 -(butyrolactone) uracils of the formula: ##SPC10##

wherein R.sub.1 is selected from the group consisting of hydrogen, methyl, trifluoromethyl and fluorine; and A is selected from the group consisting of ##SPC11##

with an alkali metal boron hydride in an aqueous or aqua-alcoholic solution at a temperature ranging from 15.degree. to 50.degree.C.

2. A process according to claim 1 wherein R.sub.1 is hydrogen and A is ##SPC12##

3. A process according to claim 1 wherein R.sub.1 is fluorine and A is ##SPC13##

4. A process according to claim 1 wherein R.sub.1 is methyl, and A is ##SPC14##

5. A process according to claim 1 wherein R.sub.1 is trifluoromethyl and A is ##SPC15##