A Publication
of Reliable Methods
for the Preparation
of Organic Compounds
Annual Volume
Org. Synth. 1937, 17, 63
DOI: 10.15227/orgsyn.017.0063
[Uracil, 6-methyl-]
Submitted by John J. Donleavy and Mearl A. Kise.
Checked by Reynold C. Fuson and William E. Ross.
1. Procedure
Eighty grams (1.33 moles) of finely powdered urea is stirred into a mixture of 160 g. (155 cc., 1.23 moles) of ethyl acetoacetate (Note 1), 25 cc. of absolute alcohol (Note 2), and ten drops of concentrated hydrochloric acid in a 5-in. crystallizing dish. The reagents are mixed well, and the dish is covered loosely with a watch glass and placed in a vacuum desiccator over concentrated sulfuric acid. The desiccator is evacuated continuously with a water pump until the mixture has gone to dryness (Note 3), which usually requires from five to seven days (Note 4). The crude β-uraminocrotonic ester when thoroughly dry weighs 200–205 g.
The dry, finely powdered, crude β-uraminocrotonic ester is stirred into a solution of 80 g. (2 moles) of sodium hydroxide in 1.2 l. of water at 95°. The clear solution is then cooled to 65° and carefully acidified, while stirring, by the slow addition of concentrated hydrochloric acid. The 6-methyluracil precipitates almost immediately, and after the mixture is cooled the product is collected on a filter, washed with cold water, alcohol, and ether, and air-dried. The substance is obtained as a colorless powder of a high degree of purity, and the yield is 110–120 g. (71–77 per cent of the theoretical amount). For further purification the pyrimidine may be crystallized from glacial acetic acid. 6-Methyluracil decomposes above 300°.
2. Notes
1. Commercial ethyl acetoacetate can be used with satisfactory results. Directions for preparing this ester are given in Org. Syn. Coll. Vol. I, 1941, 235.
2. Larger amounts of alcohol increase the period of drying without improving the yield. When no alcohol is used, the condensation proceeds slowly and the yields are low.
3. If the condensation product is used before it is dry, a large amount of carbon dioxide is evolved later in the acidification, indicating incomplete utilization of the ethyl acetoacetate.
4. It is usually advisable to change the sulfuric acid at least daily. Any lumps should be disintegrated occasionally to aid in the drying process.
3. Discussion
The synthesis of 6-methyluracil from ethyl acetoacetate and urea was described first by Behrend.1 The substance has been obtained also by the action of lead hydroxide on methylthiouracil in an alkaline medium;2 by boiling benzal-2-(4-hydroxy-6-methyl) pyrimidylhydrazine with hydrochloric acid;3 and from urea and diketene.4

References and Notes
  1. Behrend, Ann. 229, 5 (1885); Behrend and Roosen, ibid. 251, 238 (1889) Biltz and Heyn, ibid. 413, 109 (1917).
  2. List, ibid. 236, 23 (1886).
  3. Thiele and Bihan, ibid. 302, 308 (1898).
  4. Carbide and Carbon Chemicals Corporation, U. S. pat. 2,138,756 [C. A. 33, 2152 (1939)]; Standard Oil Development Company, U. S. pat. 2,174,239 [C. A. 34, 450 (1940)]; Boese, Ind. Eng. Chem. 32, 16 (1940).

Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)

β-uraminocrotonic ester

benzal-2-(4-hydroxy-6-methyl) pyrimidylhydrazine

alcohol (64-17-5)

sulfuric acid (7664-93-9)

hydrochloric acid (7647-01-0)

acetic acid (64-19-7)

ether (60-29-7)

sodium hydroxide (1310-73-2)

lead hydroxide

carbon dioxide (124-38-9)

diketene (674-82-8)

urea (57-13-6)

Ethyl acetoacetate (141-97-9)

Uracil, 6-methyl- (626-48-2)

pyrimidine (289-95-2)