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United States Patent (19) 11 Patent Number: 5,677,453 Cramm Et Al

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United States Patent (19) 11 Patent Number: 5,677,453 Cramm Et Al US005677453A United States Patent (19) 11 Patent Number: 5,677,453 Cramm et al. 45 Date of Patent: Oct. 14, 1997 54 PROCESS FOR THE PREPARATION OF 46 R. Hull, A New Sythesis of 4:6-dihydroxypyrimidines-J. DCHLOROPYRIMDINES Chem. Soc. (1951) p. 2214. Contribution a la synthese de la dichloro-4-6 pyrimidine, 75 Inventors: Ginther Cramm; Wolker Kiss, both Hennart et al., Bull. de la Soc. Chim. France, (1959) pp. of Leverkusen; Guido Stefan, 741-742. Odenthal, all of Germany Experiments on the Synthesis of Purine Nucleosides. Part IV. Kenner et al., J. Chem. Soc. (1943), pp. 574-575. 73) Assignee: Bayer Aktiengesellschaft, Leverkusen, A New Synthesis of 4:6-Dihydroxpyrimidines, Hull, J. Germany Chem. Soc. (1951), p. 2214. Synthesis of 21 Appl. No.: 699,812 4-(p-Aminobenzenesulfonamido)-6-Methoxypyrimidine, 22 Filed: Aug. 19, 1996 Zasosov et al., Translated from Khimiko-Farmatsevticheskii Zhurnal, vol. 8, No. 12, pp. 28–31, Dec., 1974. Original 30 Foreign Application Priority Data article submitted Dec. 6, 1973. Aug. 25, 1995 DEl Germany ........................ 19531 299.6 Primary Examiner-John M. Ford Attorney, Agent, or Firm-Sprung Horn Kramer & Woods (51) Int. Cl. ... C07D 239/30 52 U.S. Cl. ..................... ... 544/334 57 ABSTRACT 58) Field of Search ............................................. 544/334 4,6-Dichloropyrimidines are obtained by the reaction of (56) References Cited 4,6-dihydroxypyrimidines with excess phosphoryl chloride in a particularly advantageous manner when no base is FOREIGN PATENT DOCUMENTS added, during and/or after the reaction 0.75 to 1.5 mol of O 251 246A1 1A1988 European Pat. Off.. phosphorus trichloride and 0.7 to 1.3 mol of chlorine are O 697 406A1 2/1996 European Pat. Off. added per equivalent of exchanged hydroxyl groups so that WO95/29166 11/1995 WIPO . an excess of phosphorus trichloride with respect to chlorine WO 96/23776 8/1996 WIPO . is always present, and finally phosphorus trichloride and phosphoryl chloride are separated off. This process can be OTHER PUBLICATIONS carried out in a particularly simple manner and also con Hennartet al., Contributionala synthesis dela dichloro-4-6 tinuously. pyrimidine-Societe Chimique de France No. 140, (1959) pp. 741-742. 10 Claims, No Drawings 5,677,453 1. 2 PROCESS FOR THE PREPARATION OF 46. admixed with phosphorus trichloride and the amount of DCHLOROPYRIMDINES chlorine given above so that always an excess of phosphorus trichloride with respect to chlorine is present in the reaction The present invention relates to an improved process for the preparation of 4,6-dichloropyrimidines from 4,6- mixture. The excess is preferably determined so that from dihydroxypyrimidines. 0.3 to 5% by weight, preferably from 1 to 3% by weight of 4,6-Dichloropyrimidines are intermediates, for example free phosphorus trichloride is always present. It is possible in the preparation of plant protection agents and dyes. to proceed so that phosphorus trichloride and chlorine are In known processes for the preparation of 4.6- metered in at a uniform rate, with a brief prior addition of dichloropyrimidines, 4,6-dihydroxypyrimidines are phosphorus trichloride. admixed with phosphoryl chloride and a base such as 10 Per equivalent of exchanged hydroxyl groups, for dimethylaniline or pyridine (see J. Chem. Soc. 1943,574; J. example from 0.75 to 1.5 mol of phosphorus trichloride can Chem. Soc. 1951, 2214Bull. Soc. Chim. France 1959, 741 be added, taking care that an excess thereof with respect to and Khim.-Pharm. Zhurnal 8(12), 28 (1974)-English trans chlorine is always present. lation p. 741). The addition of phosphorus trichloride and chlorine can For the work-up, the excess phosphoryl chloride is first 15 be carried out, for example, at from 60° to 110° C. Tem drawn off and the residue is either added to ice and the peratures of from 80° to 100° C. are preferred. When the product obtained by extraction and distillation or is sub addition of phosphorus trichloride and chlorine is complete, jected to a sublimation process by which the product is it can be advantageous, especially in batchwise operation, to obtained as sublimate. In this process, it is disadvantageous after-stir the mixture at from 60° to 110° C. for some time, that the bases are used in large quantities, but can only be 20 for example for 10 minutes to 3 hours. recovered and reused at considerable cost. Finally, an aque After completion of the reaction with phosphorustrichlo ous work-up is very costly because of the disposal of the ride and chlorine, the reaction mixture can be worked up, for waste water formed and the handling of extractants. A example by distillation. work-up by sublimation is also very costly on the industrial Because of the dilution effect of the phosphoryl chloride scale, for example with respect to the apparatus to be used 25 presentin the batch, it can be advantageous to use only apart and the occupational hygiene conditions for removal of the of the reaction mixture for the work-up, and to admix the product from the Sublimer. remainder, if desired after addition of phosphoryl chloride, Some attempts to improve the known processes by the so that the proportion of this in the reaction mixture does not use of Smaller amounts of bases failed because the yield of fall below a predetermined value, with fresh 46 4,6-dichloropyrimidines is greatly reduced and the forma 30 dihydroxypyrimidine and, after complete reaction of the tion of high boilers and resins greatly increases (see latter, to react again with the corresponding amount of Example 5). phosphorus trichloride and chlorine. This procedure can be A process has now been found for the preparation of repeated as often as desired. 4,6-dichloropyrimidines by the reaction of 4.6- The addition of phosphorus trichloride can also be car dihydroxypyrimidines with excess phosphoryl chloride, 35 ried out before or simultaneously with the addition of the characterized in that no base is added, after the reaction from 4,6-dihydroxypyrimidine. It can thus be advantageous for 0.7 to 1.3 mol of chlorine is added per equivalent of practical operation to add the 4,6-dihydroxypyrimidines as a exchanged hydroxyl group in the presence of phosphorus suspension in phosphorus trichloride. In this case, the addi trichloride so that an excess of phosphorus trichloride with tion of phosphorustrichloride before the addition of chlorine respect to chlorine is always present, and finally the phos can be omitted. phorustrichloride and phosphoryl oxychloride are separated It has been found to be particularly favourable to carry off. out this reaction sequence and the subsequent distillation In the process of the invention, for example 46 separation continuously. dihydroxypyrimidine or 4,6-dihydroxypyrimidines substi The removal of phosphoryl trichloride and phosphoryl tuted in position 2 and/or position 5 with, for example, 45 chloride can, according to whether the process of the inven C-Co-alkyl and/or C-Co-aryl groups can be used. The tion is carried out batchwise, semicontinuously, or alkyl and aryl groups can in turn if desired contain, for continuously, be carried out in various ways. example, halogen, nitro and/or C-C-alkoxy as substitu In batchwise operation, for example, the whole of the ents. Independently of a substitution in position 2, reaction mixture can be subjected to a distillation, preferably 5-halogen-, for example, 5-chlorine-substituted 4,6- 50 at reduced pressure, and the phosphorus trichloride and dihydroxypyrimidines can be used. Preferably, 4,6- phosphorus oxychloride can be separated off in succession. dihydroxypyrimidine is used. Where 4, 6 In semicontinuous operation, the procedure can be, for dihydroxypyrimidines or 4,6-dihydroxypyrimidines are example, first adding to a completely reacted reaction mix referred to below, the substituted types shall be regarded as ture more 4,6-dihydroxypyrimidine followed by phosphorus included. 55 trichloride and chlorine in the manner described above, in For each mole of 4,6-dihydroxypyrimidine used, for the amounts described above, and at the temperatures example 2.5 to 12 mol of phosphoryl chloride can be used. described above, and allowing the reaction to proceed. This This amount is preferably from 3.5 to 5 mol. further addition can, depending on the size of the reaction For the reaction of 4,6-dihydroxypyrimidines with phos vessel used, be repeated a number of times, for example up phoryl chloride, temperatures for example in the range 60° to 20 times. Part of the reaction mixture so produced can to 110° C. are suitable. Temperatures from 80 to 100° C. are then be removed, preferably over arange of 20% by weight preferred. It is possible to proceed so that, for example, the of the amount of the increase in weight since the first phosphoryl chloride is added first and the 46 addition of 4,6-dihydroxypyrimidine, Phosphoryl chloride, dihydroxypyrimidine is metered into it. Other working then 4,6-dihydroxypyrimidine, and then phosphorustrichlo methods are also possible. 65 ride and chlorine can then be added again to the residue as Preferably after the 4,6-dihydroxypyrimidine used has described above, and, after the reaction has subsided, a part dissolved in the phosphoryl chloride, the reaction mixture is of the reaction mixture can be removed, preferably with a 5,677,453 3 4 range of from +20% by weight of the amount that corre EXAMPLES sponds to the increase in weight since the addition of 4,6-dihydroxypyrimidine. This cycle can be repeated as Example 1 often as desired, for example up to 50 times. a) Starting phase: The portions of the reaction mixture separated off in this To 2500 g of phosphoryl chloride, 28 g of 4,6- procedure can be subjected, for example, to a distillation, dihydroxypyrimidine (referred to below as DHP) were preferably under reduced pressure, and the phosphorus added at from 85° to 90° C.
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