HU187592B - Process for preparing purine derivatives - Google Patents

Abstract

A process of prepg a cpd of general formula 1 wherein R3 is hydrogen or lower alkyl and n is an integer from 1 to 5, comprising reacting a cpd of the general formula 2 with a lower alkyl orthoester of a lower fatty acid or with formic acid in the presence of acetic anhydride. - (12pp)

Description

The present invention relates to a process for the preparation of partially novel purine derivatives of the formula I; in the formula

R is hydrogen or lower alkyl, and n is an integer from 1 to 5.

Compounds of formula (I) wherein R is hydrogen are known, but the process for their preparation described herein is novel.

Simon (U.S. Patent Nos. 4,221,909 and 4,211,794), Giner-Sorolla (U.S. Patent 4,221,910), Faanes, International Journal of Immunopharmacology, Volume 2, Volume 3, 197 p. (1980)], Florentine (International Journal of Immunopharmacology, Vol. 2, No. 3, p. 240). (1980)], Hadden (International Journal of Immunopharmacology, Volume 2, Volume 3, page 198, 1980), Pahwa (International Journal of Immunopharmacology, Volume 2, Volume 3, p. 199). (Wybran, International Journal of Immunopharmacology, Vol. 2, No. 3, p. 201). (1980)] and Simon (4th International Congress of Immunology, Paris (1980)) have shown that erythro-9- (2-hydroxy-3-nonyl) -hypoxanthine (Ia) (NPT 15592) and The compounds disclosed in the patents cited therein are potent immunomodulatory agents and have been found to enhance suppressed immunity in all tumor animals (Sato, International Journal of Immunopharmacology, Vol. (1980)], all in different tumors (Simon, American Chemical Society Book of Abstracts, 182nd American Chemical Society Meeting (1981)). Although the synthesis of these pharmacologically useful substances has been carried out using the methods disclosed in the cited patents, their production, for example NPT 15392, using these methods has been very difficult, costly and time consuming.

Known methods for preparing erythro-9- (2-hydroxy-3-nonyl) -hypoxanthine [J. Amer. Chem. Soc. 83, 2680 (1961); U.S. Patent Nos. 4,315,920 and 4,221,910], which discloses that 3-amino-2-nonanol is reacted with 4,6-dichloro-5-amino-pyrimidine followed by 4-chloro-5-amino-6- (2). -alkyl- or -hydroxyalkylamino) -pyrimidine, for example, is cyclized with ortho-formic acid ester.

4,6-Dichloro-5-aminopyrimidine is prepared from 4,6-pyrimidinediol or 2,4,6-pyrimidine triol by a series of highly selective reaction operations. Namely, the hydroxyl groups on the pyrimidine ring are replaced with chlorine atoms after 5-nitration, then the nitro group is selectively reduced, the 2,4,6-trichloro-substituted pyrimidine is selectively dehalogenated to remove the 2-chlorine atom, and the 6-chloro are substituted with a substituted amino group. Selective reactions will inevitably result in the formation of isomers, thus requiring difficult separation operations which can only be resolved under laboratory conditions and significantly reduce the yield. 4,6-Dichloro-5-nitro- and 2,4,6-trichloro-5-nitro-pyrimidine are toxic and allergenic substances, as are 4,6-dichloro-5-aminopyrimidine.

In this procedure, the imidazole ring is first formed as shown in Scheme [B], and the resulting new erythro-4-amino-3- (2-hydroxy-3-nonyl) imidazole-5-carboxamide ring is coupled to form a pyrimidine ring. The process does not require selective reactions θ, the number of operations ^{u is} significantly less, no hazardous compounds are formed, so the process is suitable for industrial implementation.

According to the present invention are prepared ve of the formula (I) ₅ gyületeket - wherein

R is lower alkyl, i.e., C 1-4 alkyl, such as methyl, ethyl, propyl or butyl, and n is an integer from 1 to 5.

₍₀₎ According to the process of the invention, a new starting compound, erythro-4-amino-3- (2-hydroxy-3-nonyl) -imidazole-5-carboxamide (Compound Ha) (NPT 15459) can be used to prepare NPT 15392. , and homologues of Formula II can be used to prepare the corresponding homologues and analogues of NPT 15392.

The process of the present invention comprises reacting erythro-4-amino-3- (2-hydroxy-3-alkyl) -imidazole-carboxamide (II) with n-acrylic anhydride in the presence of acetic anhydride with the lower carbon orthoalkanoic acid mentioned above.

The compounds of formula (I) have immunomodulatory and immunopotentialing properties.

An immunopotentiator or immunomodulator is a substance that either restores suppressed immune function or enhances normal immune function, or both. The immune function is the development and expression of humoral (antibody-mediated) immunity, cellular (thymocyte-mediated) immunity, or macrophage and granulocyte-mediated resistance. This logically includes agents that act directly on cells involved in the expression of the immune response, or agents that act on intracellular or molecular mechanisms, which in turn affect the function of cells involved in the immune response. An increase in immune function may result from the action of an agent that removes suppressive mechanisms resulting from endogenous or exogenous negative feedback effects on the immune system. Thus, immune potentiators have different mechanisms of action. Despite differences in the site of action on the cell and the effect of immunopotentiators, their applications are essentially the same; that is, their purpose is to increase the host resistance.

Various methods for determining immunomodulatory activity are disclosed in European Patent Application Publication No. 0036077.

The preparation of the starting compound (II) is carried out using erythro-4-amino-3- (2-hydroxy-3-nonyl) -21.

The preparation of 187,592 imidazole-5-carboxamide is illustrated in Scheme [A] and [B].

2-Amino-2-cyanoacetamide is reacted with triethyl ortho formic acid in boiling in acetonitrile. The resulting 2-cyano-2 - [(ethoxymethylene) imino] acetamide is then reacted with erythro-3-amino-2-hydroxy-nonane to give NPT 15459, i.e., erythro-4-amino-3- (2- hydroxy-3-nonyl) imidazole-5-carboxamide.

Other compounds of formula II may be prepared in a similar manner using the appropriate amino alcohol such as erythro-3-amino-2-pentanol and erythro-3-amino-2-octanol in place of erythro-3-amino-2-nonanol. Other tri-lower alkyl esters of ortho formic acid, such as trimethyl ester of ortho formic acid, tripropyl ortho formic acid and tributyl ester of ortho formic acid, may be used instead of ortho formic acid triethyl ester.

Example 1

Preparation of Eritro-4-amino-3- (2-hydroxy-3-nonU) -imidazole-5-carboxamide (NPT 15459)

For better yields, the reactions shown in Schemes [A] and [B] are carried out sequentially without isolation of the intermediate 2-cyano-2 - [(ethoxymethylene) imino] acetamide. 171 g (1.71 mol) of 2-amino-2-cyanoacetamide are suspended in 2200 ml of acetonitrile. To the suspension was added 334 mL (2.0 moles) of triethyl ortho-formic acid and 2 mL of pyridine. The suspension is heated to reflux in an oil bath preheated to 100 ° C. The mixture is refluxed for 40-60 minutes. 2-Cyano-2 - [(ethoxymethylene) imino] acetamide is formed in situ. 272.5 g (1.71 moles) of erythro-3-amino-2-nonanol are added to the reaction mixture over a period of 3 to 5 minutes and reflux is continued for a further 10 to 15 minutes. The reaction mixture was quickly cooled to room temperature. Erythro-4-amino-3- (2-hydroxy-3-nonyl) -imidazole-5-carboxamide (NPT 15459) crystallized. It was filtered off, washed with a little acetonitrile and dried in vacuo at 70 ° C.

Yield: 330.4 g (72%).

Melting point (after recrystallization from acetonitrile): 154-158 ° C.

A: Using NPT 15459 to make NPT 15392:

Scheme [C] illustrates the use of NPT 15459 for the preparation of NPT 15392, i.e., erythro-9- (2-hydroxy-3-nonyl) hypoxanthine.

Homologues of NPT 15392 can be similarly prepared from the corresponding homologues of NPT 15459. Other tri (lower alkyl) orthoformates such as trimethyl, tripropyl and tributyl orthoformate may be used instead of triethyl orthoformate. When NPT 15392 is formed, acetic anhydride forms the acetate of NPT 15392 and is then hydrolyzed with an alkali such as sodium hydroxide.

Formic acid may be used instead of ortho-formic acid ester.

Example 2:

Use of erythro-4-amino-3- (2-hydroxy-3-nonyl) imidazole-5-carboxamide (NPT 15459) for the preparation of erythro-9- (2-hydroxy-3-nonyl) hypoxanthine (NPT 15392).

Erythro-4-amino-3- (2-hydroxy-3-nonyl) -imidazole-5-carboxamide (415 g, 1.55 mol) was suspended in triethyl orthoformate (358 ml). 220 ml of acetic anhydride are added with stirring. The resulting suspension is heated to 100-105 ° C with stirring. An exothermic reaction occurs with the release of ethanol. The ethanol liberated is separated by distillation. The temperature of the reaction mixture slowly rises to 130-140 ° C. Stirring is continued for about 3 hours while the ethanol liberated is continuously separated by distillation. The reaction mixture was concentrated to a viscous syrup which was poured into a mixture of 415 ml of 30% aqueous sodium hydroxide solution and 1.68 L of water. The brown solution was slightly acidified by slowly adding 123 ml of acetic acid / 1.5 liters of water. The erythro-9- (2-hydroxy-3-nonyl) -hypoxanthine crystallizes, is filtered off, washed with water and dried in vacuo at 60 ° C.

Yield: 350 g (81.4% of theory).

Melting point (after recrystallization from aqueous ethanol): 200-201'C.

Content by titration: 99.4%.

Threo isomer content: 0.9%.

Use of NPT 15459 to make new derivatives of NPT 15392:

NPT 15459 and its homologues have the ability to react with a range of reagents that can lead to ring closure and the production of new purine derivatives. By appropriate selection of reagents, it is possible to prepare many 2-substituted derivatives of NPT 15392 and homologues which cannot be otherwise prepared.

Example 3

Erythro-9- (2-hydroxy-3-nonyl) -2-methyl-hypoxanthine

Erythro-3- (2-hydroxy-3-nonyl) -4-aminoimidazole-5-carboxamide (26.5 g), methyl orthoacetic acid (29 ml) and acetic anhydride (14.2 ml) were stirred at 150 ° C for 6 hours. The product was extracted with 2N sodium carbonate solution and acidified to pH 5. Recrystallize from acetone. 151-152 ° C. UV spectrum: 1% solution at 252 ml on a 1 cm layer 146.

Compounds of formula (I) wherein R is ethyl can be prepared in a similar manner by reacting NPT 15459 with triethyl orthopropionic acid.

Claims (6)

A process for the preparation of the Purine Derivatives of Formula I wherein R is hydrogen or lower alkyl; 187 592 n is 1, 2, 3, 4 or 5, characterized in that the erythro-4-amino-3- (2-hydroxy-3-alkyl) -imidazole-5-carboxamide of formula (II) is equivalent to that given above with a small amount of a lower carbon orthoalkane carboxylic acid trialkyl ester or formic acid in the presence of acetic anhydride. 2. A process according to claim 1 for the preparation of a purine derivative of formula I wherein R is hydrogen and n is as defined above, characterized in that the compound of formula II is as defined above - ortho-formic acid (lower carbon) -. reaction with trialkyl ester or formic acid in the presence of acetic anhydride. 3. The process according to claim 2, wherein the (lower carbon) -trialkyl ester of ortho-formic acid is reacted in the presence of acetic anhydride. 4. A process according to claim 2, wherein the formic acid is reacted in the presence of acetic anhydride. A process for the preparation of a Purine Derivative of Formula I wherein R is methyl, n is as defined above, wherein the compound of Formula II is selected from the group consisting of orthoacetic acid (lower) with a trialkyl ester. 6. A process according to claim 5, wherein the triethyl orthoacetic acid is reacted in the presence of acetic anhydride.