IE44823B1 - Preparation of a 4,6-diamino-5-arylazopyrimidine - Google Patents

Description

Adenine/or 6-aminopurine, is a naturally occurring product which is well known as .an intermediate in the formation of various final products Csee U.S. Patent Ko 3,846,426). It is known In the art that adenine may be prepared from 4,6-diamino-5-arylazopyrimidine /see Baddiley et al., Jour. of the Chem. Soc. Part II (1943) pg. 386-387 and Cavalier! et al., Jour, of the Am. Chem. Soc. Vol. DCXI (Jan.-April 1949) pg. 533-536/. It is taught in Japanese Patent Publication.28497/73 that adenine may be prepared by a catalytic reduction of an arylazomalononitrile In formamide in the presence of ammonia to obtain adenine in a single step. It has been found, however, that the resulting product leaves much to be desired in purity and yields. It has now been found that when a similar process is carried out in two stages, the yield and purity of the final product is substantially improved.

The present invention provides a method of preparing 4,6diamino-5-arylazopyrimidine that comprises the reaction of arylazomalpnonitrile with formamide and ammonia in the presence of an ammonium salt as a catalyst.

The reaction of the present invention may be carried out . I in a solvent such as methanol, ethanol, isopropanol, cyclic and acyclic ethers, methylene chloride, ethylene dichloride, hexane, octane or decane, Tlife nature of the solvent is not critical but formamide is preferably usfed as the solvent in considerable excess, i.e. 10-20 moles per mole of arylazomalononitrile. Since only 1 mole is needed ί for the reaction, the excess is utilized merely as a solvent. The ammonium salt used in the practice of this invention may be the ammonium ‘salt of any inorganic or organic acid. For example, it may be ammonium acetate, sulfate, iodide, chloride, ammonium carbonate, ammonium propionate, ammonium benzoate or ammonium nitrate, preferably, the salt is an ammonium halide since such salts ate inexpensive and 4 4 8^3 readily available. The amount of ammonium salt is usually at least 0.1% by weight based on the weight of the arylazomalononitrile, preferably from 5% to 1007. and particularly 107. to 607..

The temperature to be employed for the reaction is usually from 50°C to 400°C, but this may be varied as desired. For example, if an unusually long reaction time is not a disadvantage, room temperature may be used but it may require many days for the reaction to go to completion. Under ordinary circumstances the temperature is of from 90°C to 250°C, preferably 140°C to 160°C.

In carrying out the reaction, at least 1 mole of ammonia is used per mole of arylazomalononitrile if optimum yields are deeired. While lesser amounts can be used, the reaction requires 1 mole and any lesser amount will result in reduced yields. Based on the weight of the arylazomalononitrile, the amount of ammonia should be from 10% to 3007., preferably 25% to 100% by weight, and particularly 507. to 907..

The term aryl as used herein signifies any organic radical derived from an aromatic hydrocarbon. It also includes such radicals containing substituent groups such as amino, halo, alkyl, nitro, hydroxy, alkoxy, aryloxy, carboxyl and cyano. In the preparation of adenine, the aryl group is removed in the final reaction and the nature of this substituent is therefore not critical. Substituent groups may even enter into the reaction since these only result in impurities being formed when the aryl group is removed, but preferably the aryl group is unsubstituted.

The. preient invention also provides a process for preparing adenine which comprises reacting an arylazomalononitrile with formamide Λ and ammonia in the presence of an ammonium salt to form a 4,6diamino-5-arylazopyri.midine and thereafter hydrogenating the 4,6diamino-5-arylazopyrimidine in the presence of formic acid or a 4 823 derivative of formic acid, such as the ester or amide, to form adenine. ι The term thereafter signifies that the reaction of the arylazomalonpnitrile to form the 4,6-dianino-5-arylatopyrimidine is allowed to go to substantial completion before the pyrimidine compound is hydrogenated to form ^denine. In other words, the hydrogenation reaction is not carried out at the same time as the formation of the pyrimidine compound. This gives better yields and purity.

In carrying out the hydrogenation reaction, any solvent may be used as given above but again it is preferred that formamide be used as the solvent. Since 2 moles of formamide are required in the reaction for each mole of pyrimidine compound, it is preferred to use from 4 to 20 moles of formamide as both reactant and solvent. With the solvent the same for both reactions, this means that the intermediate product need not be isolated. Preferably a hydrogenation catalyst is used in the reaction, the amount of it being from 0.1 to 10%, preferably 0.5 to 2.5% and particularly about 1%, based on the weight of the pyrimidine compound. The hydrogenatiop catalyst can be any of the well known catalysts, e.g. platinum, nickel, Raney nickel, copper, rhodium, ruthenium, and all other metals in Groups VIII, IB, 1IB, VB, VIB and VIIB of the periodic Table.

Other hydrogenation catalysts may be selected as desired.

The following Examples are given to illustrate the invention and are not intended to limit it in any manner. All parts are expressed ( in part by weight unless otherwise indicated. Examples 3 and 13 are comparative. .

EXAMPLE 1 Preparation of 4j6-Diamin0-5-phenylazopyrimidine A 300-ml autoclave is sequentially charged with 2.12 g of ammonium chloride (0.04 mole), 17.0 g of phenylazomalononitrile (0.10 mole), and 92 ml of formamide. The system is flushed with ammonia, sealed, and then saturated, with ammonia to 10 psi. The system is then heated with 44833 stirring at 1000 rpm to 150°C for five hours with occasional venting to maintain 40-50 psi. After cooling to room temperature, excess of ammoni is sparged with nitrogen, the.orange solids are filtered (mother liquors are used for all transfers and saved for recycling), and the cake is displaced first with 12 ml of fresh formamide and then with ml of water. The cake is vacuum-oven-dricd (100DC, 20 mm Hg, three hours) and gives 19.55 g of 4,6-diamino-5-phenylazopyri)midine (91.4% yield); U.V. (0.1M HCl in methanol) 488¾ ‘Tsnax 370 = 893, m.p. 295-300°C.f eg. wt. (SCloj 216.3 (98.6% pure), tic '(silica gel, CHCl3:MeOH:6;l by vol.): single spot.

EXAMPLE 2 Preparation of Adenine from Phenylazomalononitrile A·glass liner is charged with 20 ml. of ethyl alcohol, 4.5 g. of formamide, 0.53 of ammonium chloride, .4.25 g. of phenylazomalononitrile, 4 g. of ammonia and 0.15 g. of Raney nickel. The system is sealed and heated to 150°C. and aged at that temperature with rocking for 4 hours. After this point a charge of 1300-1400 psi of 52 is applied to the system and the reaction is continued (at 150 °C. with rocking) for an additional 8 hours. After cooling to room temperature, the volatile material is distilled off and the residue is dissolved in water containing 0.40 g. Of sodium hydroxide. After swirling for 20 minutes, the insoluble catalyst is'filtered off. The filtrate is worked up in the usual fashion (i.e., acidifying to pH 7.0 with HCl and filtering off solids) to give material which after vacuum-oven drying at 80°C. amounts to 3.0 g.

This material has an identical Rf as adenine on tic and is single spot material. The U.V. (N/10 HCl)z-max 263, E% 822 indicates 85% purity. Liquid chromatography (L.C.) compared to analytical adenine indicates 73.8% purity. L.C. also indicates that the filtrate contains an additional 0.25 g. of adenine. Total yield corrected for purity (3.0) (0.738) + 0.25 g. equals 2.47 g. or 73%. -644823 EXAMPLE 3 Preparation of 4,6-Diamino-5-phenylazopyrimidine Example 1 is repeated exactly as described except that no anmonium chloride is added. After an identical work-up 5 there is obtained 19.5 g. (yield 91.16%) of lower quality 4,6-diamino-5-phenylazopyrimidine, U.V. (0.1N HCl)max = 365, E% = 786; m.p. 280-297°C.; eq. wt. (HC104) 224.8 (7% off calculated); tic, silica gel (CHCl^MeOH: :6:1, by vol.): trace two impurities. This example shows that without the ammonium salt a lower yield is obtained and the product is impure.

EXAMPLE 4 Preparation of 4,6-Diamino-5-phenylazopyrimidine Example 1 is repeated exactly as described except that ammonium acetate is added. After an identical work-up there is obtained 19.92 g. of 4,6-diamino-5-phenylazopyrimidine (93.2%): U.V. (0.1N HCU'z'-max = 365, E% = 773; m.p. 298300°C.; eq. wt. (HC104) 218; tic, silica gel (CHClj:MeOH:: 6:1, by vol.): single spot. The example shows that other ammonium salts are suitable for the reaction.

EXAMPLE 5 Preparation of 4,6-Diamino-5-phenylazopyrimidine Example 1 is repeated exactly as described except that amnanium irrtids is added. After an identical work-up there is obtained 19.20 g. of 4,6-diamino-5-pher.ylazopyrimidine (89.75): U.V. (0.1N HCD/'-max = 365, E% = 817; m.p. 299302°C.; eq. wt. (HC104) 213.8; tic, silica gel (CHClg:MeOH:: 6:1, by vol.): single spot. The Example shows that other ammonium salts are suitable for the reaction. -7EXAMPLE 6 Preparation of 4,6-Diamino-5-phenylazopyrimidine Example 1 is repeated exactly as described except that aranoniun sulfate is added. After an identical work-up there is obtained 19.6 g. of 4,6-diamino-5-phenylazopyrimidine (91.4%): U.V. (Q.lN HCl)7-max = 365, E% = 808; m.p. 293-297°C.;eg. wt. (HCIO^) 217.6; tic, silica gel (CSCl^:MeOB::6:1, by vol.): single spot. The Example shows that other ammonium- salts are suitable fot the reaction.

EXAMPLES 7-10 Example 1 is repeated with the exception that μ the reaction is carried out at various temperatures as sjiown in the following table.

Example Temp. (°C.) Wt. Yield (grams) % Yield m.p. (°C.) Eq. Wt. (HC104) U.V. (0.1N HCl) CZ-max 365) 7 90 17.0 79.4 255-264 190.4 1090 8 120 18.5 86.5 252-259 206.7 863 9 250 13.2 61.8 299-305 214.8 785 . 10 25 Some material by tic.

The table shows that the reaction may be carried out over a wide range of temperature conditions. Preferably the temperature is in the range of 30°G. to 250°C. -84·4 8 23 EXAMPLE 11 Preparation of Adenine from 4,6-Diamino-5-pbenyLazopyrimidine A 300-ml. autoclave is charged sequentially with 24 ml. of formamide (27 g., 0.6 mole), 21.42 g. of 4,6diamino-5-phenylazopyrimidine (0.1 mole), SO ml. of isopropanoi alcohol, and 240 mg. of 5% Pd/C. The system is sealed and pressurized with 1200 psi of hydrogen, heated to 200°C. and rocked for eight hours. The vessel is then cooled to room temperature and the pale-yellow adenine is filtered (all transfers are done with mother liquors).

The cake is dissolved in 50 ml. of 2N sodium hydroxide solution. The reduction catalyst is filtered off and the filtrate is neutralized to pH 7.0. The white adenine is collected on a funnel and washed with 20 ml. of water.

After vacuum-oven drying (100°C., 20 mm Hg, 3 hours) there is obtained 12.75 g. of adenine (yield 94.5%); U.V. (0.1N HCl)>-max = 263, E% = 928; m.p.>358°C., liquid chromatography, wt. % adenine = 94.7% pure; tic, silica gel (CHCl^: MeOH:i6:l by vol.): single spot.

EXAMPLE 12 Preparation of Adenine without Isolation of 4,6-Diamino5-phenylazopyrimidine A 300-ml. autoclave is sequentially charged with 2.13 g. of ammonium chloride (0.04 mole), 17.0 g. of phenylazomalononitrile (0.10 mole), 240 mg. of 5% Pd/C and 92 ml. of formamide which contains 12% ammonia by'weight. The system is rocked at 150°C. for five hours and then charged with H2 to 1200 psi. After aging (with -944® 33 rocking) at this temperature for an additional 5 hours, the system is cooled to room temperature. Identical work-up as described for adenine in Example 11 affords 10.8 g. of adenine (yield 80%) U.V. (0.1N HCl)T-max = 263, E% = 900, m.p. y>355oC., L.C. wt. % adenine = 92% pure, tic single spot.

This Example illustrates that when the reaction of the pheiiylazomalononitrile to form the 4,6-diamino-5-phepylazopyrimidine is allowed to go to substantial completion before the introduction of H2 pure adenine in high yield is obtained. When the reaction is carried out with H2 present ' from the start of the reaction the yield of adenine is substantially reduced as illustrated in Example 13.

EXAMPLE 13 Preparation of Adenine from Pheiiylazomalononitrile When Example 12 is repeated except that the hydrogen is present from the start of the reaction, there is obtained (by an identical work-up) 13.5 g. of crude material which contains 11.4% adenine by high pressure liquid chromatography assay (or 1.53 g. of adenine) representing a 45%-yield. This material is too impure for a melting point and tic reveals the presence of several contaminants.

Claims (15)

1. A method of preparing a 4,6-diamino-5-arylazopyriinidine that comprises reaction of an aiylazomalononitrile with formamide and ammonia in the presence of an ammonium salt,

2. A method as claimed in Claim 1, in which at least 1 mole of 5 ammonia is used per mole of aiylazomalononitrile.

3. A method as claimed in Claim 1 or 2, in which the weight of ammonium salt is at least 0.1 JS of the weight of the aiylazomalononitrile. 4. -4883 , / ’ ·

4. A method as claimed in Claim J, in which the weight of ammonium salt is from 5 to 100)1 of the weight of the aiylazomalononitrile.

5. From the reaction mixture in which- it is formed.

6. A method as claimed in any one of Claims 1 to 5, in which the reaction is carried out at a temperature in the range JO to 400°C.

7. A method as claimed in Claim 6, in which tho temperature is in 15 the range 90 to 2'30°C.

8. A. method ns claimed is Claim 7, in which the temperature is in the range 140 to l6o°C.

9. A method of preparing adenine, that comprises fonning- a 4,6diamino~5-axylazoryrimidine hy a method as claimed in any one of Claims 1 20 to 8 and hydrogenating the 4,6~diamino-5-niylazopyrimidine in the presence of formic acid or a derivative thereof.

10. - A method as claimed in claim 9, in which the hydrogenation is carried out in the presence of a hydrogenation catalyst. 10 5. A method as claimed in Claim 4, in which the weight of ammonium salt is from 10 to 60# of the weight of the aiylazomalononitrile.

11. . A method as claimed in claim 9 or 10, in which the 4,6diamino-5-ary|azopyrimidine is hydrogenated without being separated

12. • 12. A-.inethijd as claimed in claim 1, carried out substantially as hereinbefore described in any one of Examples 1 and 4 to 10.

13. · A method as claimed in claim 9, in which the hydrogenation is carried out substantially as hereinbefore described in any one of 10 Examples 2 and 11.

14. Ι A method as claimed in claim 11, carried out substantially as hereinbefore described in Example 12, 15. A 4,6-.diaraino-5~arylazopyrimidine, when prepared by a method as claimed in any one of claims 1 to 8 and 12.

15. 16 i Adenine, when prepared by a method as claimed in any one of claims 9, 10, 11, 13 and 14.