DK142875B - Process for the preparation of adenine. - Google Patents

Description

.S '(11) PUBLICATION WRITING 1 U2S7 5 DENMARK (51) Int. Cl.3 C 07 D 473/34 _ ± _ (21) Application No. 1717/77 (22) Filed on 19 * & per. 1977 f (24) Race day 19 Apr. 1977 (44) The application submitted and the petition published on 1 O · f © b. 1 9 ° 1

DIRECTORATE OF

PATENT AND TRADEMARKET SYSTEM (30) Priority requested from mm (71) MERCK & CO. INC., Rahway, New Jersey, US.

(72) Inventor: Michael Cornells Vander Zwan, 30 Shelley Drive, Somerset, New Jersey, US: Donald Floyd Reinhold, 564 Parkview Avenue, North Plainfield,

New Jersey, US.

(74) Plenipotentiary in the proceedings:

Hofman-Bang & Boutard Engineering Company.

(54) Process for the preparation of adenine.

The present invention relates to a particular process for the preparation of adenine from arylazomalononitrile and formamide in the presence of ammonia.

Adenine and β-aminopurine are a naturally occurring product that is well known as an intermediate in the preparation of various end products (see U.S. Patent No. 3,846,426). It is known that adenine can be prepared from 4,6-diamino-5-arylazopyrimidine (see Baddi-ley et al., "Jour. Of the Chem. Soc." Part II (1943) pages 386-387 and Cavalieri et al. al., "Jour. of the Am.Chem.Soc." Vol. LXXI (Jan.-April 1949) pages 533-536). Japanese Patent Publication 2 142875 28497/73 discloses that adenine can be prepared in one step by reaction of arylazomalononitrile with formamide in the presence of ammonia under simultaneous catalytic reduction. However, it has been found that the product produced by this process is extremely unclean and is not obtained in satisfactory yield. This is probably due to premature removal of the aryl group in arylazomalononitrile by hydrogenation. The resulting aminomalononitrile is believed to be relatively unstable and decompose under the reaction conditions. Further, Japanese Patent Publication No. 81394 discloses that adenine can be prepared by treating arylazomalononitrile with formamide in the presence of ammonia followed by treatment of the pyrimidine obtained with formic acid or a derivative thereof under reducing conditions. This method also yields a rather poor yield of less pure adenine.

The process according to the invention, which is characterized by the characterizing part of claim 11, provides extremely pure adenine in high yield.

The process of the invention can be carried out in a solvent such as methanol, ethanol, isopropanol, cyclic and acylic ethers, methylene chloride, ethylene dichloride, hexane, oxane or decane. The nature of the solvent is not critical, but according to a preferred embodiment, formamide is used as a solvent in considerable excess, such as 10-20 moles per liter. mole of arylazomalononitrile. Since only one mole is required for the reaction, the excess is utilized only as solvent. The ammonium salts used include ammonium salts of any inorganic or organic acid. Examples are ammonium acetate, sulfate, iodide, chloride, carbonate, propionate and nitrate. The salt is preferably an ammonium halide which is cheap and readily available. The ammonium salts are usually recognized in amounts of at least 0.1% by weight, based on the weight of arylazomalononitrile, however preferably 5 - 100%, especially 10 - 60%.

The temperature used in the reaction is usually between 50 ° C and 400 ° C, but the temperature can be varied if desired. If a particularly long reaction time is no disadvantage, e.g.

At room temperature, however, many days are required to complete the reaction. Under normal circumstances, a temperature between 90 ° C and 250 ° C is used, and the preferred range is 100 - 200 ° C, preferably 140 - 160 ° C.

In carrying out the reaction, at least 1 mole of ammonia is used per day. moles of arylazomalononitrile whose optimum yields are desired. Although smaller amounts can be used, the reaction requires 1 mole and any smaller amount will result in diminished yield. Based on the weight of arylazomalononitrile, ammonia should be present in amounts from 10 to 300%, preferably 25 to 100% by weight. Usually 50 to 90% is used.

The term "aryl" as used herein is used for any organic radical derived from an aromatic hydrocarbon. Also included are such radicals which contain substituents such as amino, halogen, alkyl, nitro, hydroxy, alkoxy, aryloxy, carboxyl or cyano.

In the preparation of adenine, the aryl group removes the final reaction and the nature of this substituent is not critical. Substituents which are part of the reaction can even be used, since such reactions only result in the formation of impurities when the aryl group is removed. Preferably, the aryl group is unsubstituted.

The term "then" is understood to mean that the reaction of arylazomalononitrile to form 4,6-diamino-5-arylazopyrimidine may terminate before the pyrimidine compound is hydrogenated to form adenine. , which improves yields and purity.

In carrying out the hydrogenation reaction, any solvent of the kind mentioned above may be used, but in this case also amide is preferred as the solvent. Since 2 moles of formamide are required in the reaction for each mole of pyrimidine compound, it is preferred to use an excess such as from 4 to 20 moles of formamide as a reagent and solvent. If the solvent is the same for both reaction steps, it is unnecessary to isolate the intermediate. Preferably, a hydrogenation catalyst is used in the reaction in amounts of 0.1 - 10%, based on the weight of the pyrimidine compound, preferably 0.5 - 2.5% and usually 1%. The hydrogenation catalyst can be any well-known catalyst such as platinum, lead, Raney nickel, copper, rhodium, ruthenium and all other metals of groups VIII, IB, IIB, VB, VIB and VTIB of the periodic system. Other hydrogenation catalysts may be selected if desired.

The process according to the invention will be illustrated in the following with the aid of some exemplary embodiments. All parts are expressed in parts by weight, unless otherwise stated.

EXAMPLE 1

Preparation of 4,6-diamino-5-phenyllazopyrimidine In a 500 ml autoclave, 2.12 g of ammonium chloride (0.04 mol), 17.0 g of phenylazomalononitrile (0.10 mol) and 92 ml of formamide were sequentially introduced. The apparatus was rinsed with ammonia, closed and then saturated with ammonia at a pressure of 0.7 kg / cm. The apparatus was then heated with stirring at 1000 rpm. to 160 ° C for 5 hours, the pressure being occasionally relieved to maintain 2.8 to 5.5 kg / cm. After cooling to room temperature, the ammonia was purged with nitrogen, the orange substances formed were filtered off (the mother liquor was used for recycling) and the cake was first rinsed with 12 ml of fresh formamide and then with 10 ml of water. The filter cake was dried in vacuo (100 ° C, 20 mm Hg for three hours) to give 19.55 g of 4,6-diamino-phenylazopyrimidine (91.4% yield); U.V (0.1M HCl in methanol) max max = 570, E% = 895, mp: 295-500 ° C, eq. wt (HClO) 216.5 (99.0 pure), tic (silica gel, CHCl3 in MeOH 6: 1 by vol.): single stain.

EXAMPLE 2

Preparation of adenine. from phenylazomalononitrile In a glass-clad autoclave, 20 ml of ethyl alcohol, 4.5 g of formamide, 0.55 ammonium chloride, 4.25 g of phenylazomalononitrile, 4 g of ammonia and 0.15 g of Raney nickel are introduced. The appliance is closed and heated to 5 ° C and left at this temperature without shaking for 4 hours. After this time hydrogen is introduced to obtain a pressure of 91-98 kg / cm 2 in the apparatus and the reaction is continued at 150 ° C with shaking for an additional 8 hours. After cooling to room temperature, volatiles are distilled off and the residue dissolved in water containing 0.40 g of sodium hydroxide. After shaking for 20 minutes, the insoluble catalyst is filtered off. The filtrate is worked up in the usual way (ie by adding hydrochloric acid to a pH of 7.0 and filtering off solids) to give a substance which after drying in vacuo and at 80 ° C is 3.0 g.

This substance is similar to adenine by thin layer chromatography and exhibits a single stain. U.V (N / 10 HCl) Amax 263, E% 822 shows 85% purity. Liquid chromatography (L.C.) corresponds to analytical adenine and indicates 73.8% purity. L. C. also indicates that the filtrate contains an additional 0.25 g of adenine. The total yield corrected for purity (3.0) (0.738) + 0.25 g corresponds to 2.47 g or 73%.

EXAMPLE 3

Preparation of 4,6-diamino-5-nhenylazopyridine

Example 1 is repeated as described with the change that no ammonium chloride is added. After working up in the same way, 19.5 g (yield 91.16%) less pure 4,6-diamino-5-phenylazopyri-midin, U.V. (0.1N HCl) Amax = 365, E% = 786; mp: 280-297 ° C; eq. weight. (HClO 4) 224.8 (95.3% pure); tic, silica gel (CHCl

MeOH 6: 1, by vol.): Traces of two impurities. This example shows that without 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 as described with the change that ammonium acetate is added. After work-up in the same manner, 19.92 g of 4,6-diamino-5-phenylazopyrimidine (93.2%) is obtained: U.V. (0.1N HCl) Amax = 365, E% = 773; mp: 298-300 ° C; eq. weight. (HClO) 218; tic, silica gel (CHCl3: MeOH 6: 1, by vol.): single stain. The example shows that other ammonium salts are suitable for the reaction.

EXAMPLE 5

Preparation of 4,6-diamino-5-pherryiazopyrimidine

Example 1 is repeated as described with the change that ammonium iodide is added. After work-up in the same manner, 19.20 g of 4.6-diamino-5-phenylazopyrimidine (89.7%) are obtained: U.V. (0.1 N HCl) δ max, 365, E% = 817; mp: 299-302 ° C; eq. weight. (HClO 4) 213.8; tic, silica gel (CHCl3 tMeOH 6: 1, by vol.): single stain. The example shows that other ammonium salts are suitable for the reaction.

EXAMPLE 6

Preparation of 4,6-diamino-5-phenylazopyrimidine

Example 1 is repeated as described with the change that ammonium sulfate is added. After workup similarly, 19.6 g of 4.6-diamino-5-phenylazopyrimidine (91.4%) are obtained: U.V. (0 N 1 HCl) max = 365, E% = 808; mp: 293-297 ° C; eq. weight. (HClO 4) 217.6; tic, silica gel (CHGl4: MeOH 6: 1, by vol.): single stain. The example shows that other ammonium salts are suitable for the reaction.

EXAMPLES 7-10

Example 1 is repeated with the change that the reaction is carried out at different temperatures as indicated in the following table:

Mp. Eq. U.V

Example Temp. Yield Yield (C) weight. (0.N HCl) (V) (grams) (%) (HClO 4) max 365) 7 90 17.0 17.0 255-264 190.4 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.

7 142875

The table shows that the reaction can be carried out under varying temperature conditions. Preferably, the temperature ranges from 90 ° C to 250 ° C.

EXAMPLE 11

Preparation of adenine from 4,6-diamino-5-arvlazopyrimidine In a 300 ml autoclave, 24 ml of formamide (27 g, 0.6 mol), 21.42 g of 4,6-diamino-5-phenylazopyrimidine (0, 1 mol), 80 ml of isopropanol and 240 mg of 5% Pd / C. The apparatus is closed and hydrogen is introduced to a pressure of 84 kg / cm 2, then heated to 200 ° C under shaking for 8 hours. The vessel is cooled to room temperature and the pale yellow adenine is filtered (all transfers are with the mother liquor). The filter cake is dissolved in 50 ml of 2N sodium hydroxide solution. The reduction catalyst is filtered off and the filtrate neutralized to pH 7.0. The white adenine is collected on a funnel and washed with 20 ml of water. After drying in vacuo (100 ° C, 20 mmHg, 3 hours), 12.75 g of adenine (yield 94.5%) is obtained: U.V. (0.1 N HCl) Amax = 263, E% = 928; mp: 358 ° C, liquid chroma two grams of i, wt% adenine = 94.7% pure; tic, silica gel (CHCl3 in MeOH 6: 1 by vol.): single stain.

EXAMPLE 12

Preparation of adenine without isolation of 4,6-diamino-5-phenylazo-pyrimidine In a 300 ml autoclave, 2.13 g of ammonium chloride (0.04 mol), 17.0 g of phenylazomalononitrile (0.10 mol), 240 mg 5%

Pd / C and 92 ml of formamide containing 12% by weight ammonia. The apparatus is shaken at 150 ° C for 5 hours and then filled with hydrogen at a pressure of 84 kg / cm 2. After standing under shaking at this temperature for an additional 5 hours, the apparatus is cooled to room temperature. By the same reprocessing method as described for adenine in Example 11, 10.8 g of adenine (yield 80%) is obtained U.V. (0.1 N HCl) δ max = 263, = 900, mp: 355 ° C, L.C. weight% adenine = 92% pure, tic single spot.