Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
2002-08-15
2003-09-16
Ford, John M. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
C544S318000
Reexamination Certificate
active
06620932
ABSTRACT:
The present invention relates to 2-alkoxy-5-methoxy-pyrimidines, tautomeric forms thereof and processes for preparing them.
5-Methoxypyrimidines are important intermediates in preparing active pharmaceutical and agrochemical ingredients. In many cases, the active ingredient, as well as other substituents, additionally contains a 2-alkoxy group. Such applications are mentioned, for example, in the documents U.S. Pat. No. 5,163,955, DE-OS 40 29 648, FR-A 1 33 318 and in Collect. Czech. Chem. Commun. 59(2), 482 (1994).
These 5-methoxypyrimidines which, as well as other substituents, contain a 2-alkoxy group can be prepared by various routes. For example, Z. Budezinski et al., Cesk. Farm. 10, 241 (1961) describe the synthesis of this type of active ingredient which comprises first preparing a 2-methylmercapto-4-hydroxy-5-methoxy-pyrimidine, then converting it to the corresponding 2,4-dihydroxypyrimidine derivative, subsequently carrying out a chlorination to give the 2,4-dichloropyrimidine derivative and finally reacting it in a plurality of steps to give the 2-methoxy-4-amino-5-methoxypyrimidine.
A disadvantage of this preparation process is the extremely long reaction sequence which additionally, owing to the lack of regioselectivity between the 2 and 4 positions on the pyrimidine ring, is prone to isomer formation and, besides, only delivers low overall yields.
It is accordingly an object of the present invention to provide novel 2-alkoxy-5-methoxypyrimidines and tautomeric forms thereof which are industrially relatively simple to prepare in high yields. According to the invention, this object is achieved by the 2-alkoxy-5-methoxypyrimidines according to claim 1.
It has been found that, surprisingly, the 2-alkoxy group may be introduced into the appropriate pyrimidine derivatives even at the start of the reaction sequence and that the 4 substituent can be converted and exchanged in a simple manner without isomeric by-products resulting.
The 2-alkoxy-5-methoxypyrimidines according to the invention conform to the general formula (I)
and include their tautomeric forms. In the formula (I)
R
1
is a linear or branched and optionally unsaturated aliphatic hydrocarbon radical having from 1 to 5 carbon atoms and
R
2
═OH, F, Cl, Br or —SO
x
R
3
where R
3
═C
1
-C
4
-alkyl and x=0, 1 or 2.
Particular preference is given to 2-alkoxy-5-methoxy-pyrimidines where R
1
═CH
3
and R
2
═OH or R
1
═CH
3
and R
2
═Cl.
The 2-alkoxy-5-methoxypyrimidines according to the invention can be synthesized in few reaction steps and in high yields from simple precursors. For example, 2-alkoxy-4-hydroxy-5-methoxypyrimidines can be prepared by reacting an alkyl ester of 3-hydroxy-2-methoxyacrylic acid or of its tautomeric forms or an alkali metal salt of the ester with an O-alkylisourea or a corresponding salt.
Preferred alkyl esters of 3-hydroxy-2-methoxyacrylic acid (or of its tautomeric forms or alkali metal salts) are the corresponding methyl and ethyl esters. Preference is given to preparing these compounds from methoxyacetic esters in a known manner and reacting them without isolation and further purification.
Preferred alkali metal salts of the alkyl 3-hydroxy-2-methoxyacrylate ester are the sodium or potassium salt thereof. The O-alkylisourea compounds used are in particular those of O-methylisourea and O-ethylisourea or salts thereof. In particular, O-methylisourea sulfate, O-methylisourea hydrogensulfate, the free O-methylisourea base, O-ethylisourea hydrochloride, O-ethylisourea hydrogensulfate and the free O-ethylisourea base are used.
The 3-hydroxy-2-methoxyacrylic ester is reacted with the O-alkylisourea derivative in aqueous and/or alcoholic solution in the presence of a base.
The alcohols used are preferably C
1
-C
4
-alcohols, in particular methanol or ethanol. The bases used are preferably the free O-alkylisourea, sodium hydroxide, sodium methoxide or sodium ethoxide.
The molar ratio of the alkyl 3-hydroxy-2-methoxy-acrylate ester to the O-alkylisourea derivative may vary within a wide range, but it has proven particularly advantageous to set this ratio to from 1:2 to 2:1. Also, preference is given to using from 1 to 5 mol of base per mole of the desired pyrimidine compound.
It is to be regarded as essential to the invention that the reaction of the alkyl 3-hydroxymethoxyacrylate ester (or its tautomeric forms or alkali metal salts) with the O-alkylisourea (salt) be carried out at temperatures of from 20 to 100° C., in particular from 40 to 80° C. The reaction time may vary within a wide range, but for economic reasons it is preferably from 2 to 12 h.
The 2-alkoxy-4-hydroxy-5-methoxypyrimidines obtained in this way are preferably precipitated out of the reaction mixture by adjusting the pH to from 2.0 to 8.0 and removed by customary methods, for example by filtration.
These 2-alkoxy-4-hydroxy-5-methoxypyrimidines can be reacted directly with, for example, phosphorus oxy-chloride to give 2-alkoxy-4-chloro-5-methoxypyrimidines or with phosphorus oxybromide to give the corresponding 2-alkoxy-4-bromo-5-methoxypyrimidines.
This reaction is effected in particular with the addition of an excess of the appropriate phosphorus oxychloride or phosphorus oxybromide, and auxiliary bases or solvents may be used if necessary.
Preference is given to using from 2 to 8 mol of phosphorus oxychloride or phosphorus oxybromide per mole of 2-alkoxy-4-hydroxy-5-methoxypyrimidines. Examples of useful auxiliary bases include triethylamine, dimethylaniline and diethylaniline. These auxiliary bases are used in a quantity of from 0 to 1 mol of auxiliary base per mole of 2-alkoxy-4-hydroxy-5-methoxypyrimidines.
In principle, useful solvents include all organic solvents which are inert toward phosphorus oxychloride or phosphorus oxybromide, for example, toluene, xylene, hexane, cyclohexane or dichloromethane. The corresponding reaction is effected at a temperature of from 40 to 120° C., preferably from 70 to 110° C.
The 2-alkoxy-4-chloro-5-methoxypyrimidines according to the invention and the similarly preparable 2-alkoxy-4-bromo-5-methoxypyrimidines can be converted by customary subsequent reactions, for example, conversion to the corresponding 2-alkoxy-4-fluoro-5-methoxypyrimidines by reacting with potassium fluoride or sodium fluoride. Similarly, reaction with the thiols R
3
SR or its alkali metal salts thereof may be effected in an organic solvent at temperatures of from 40 to 120° C. If desired, the mercapto group SR
3
may then be oxidized using suitable oxidizing agents, for example, HOCl or peroxo compounds (in particular hydrogen peroxide) to give the desired —SOR
3
and —SO
2
R
3
radicals. Hydrocarbons, alcohols, ethers, esters, amides and nitrites are particularly useful organic solvents for this purpose.
With the aid of this processes, the 2-alkoxy-5-methoxy-pyrimidines accordy to the invention can be obtained in few reaction steps, in excellent yields and in a technically simple manner.
The invention is illustrated by the following examples:
REFERENCES:
patent: 4125720 (1978-11-01), Pesson et al.
patent: 6362335 (2002-03-01), Emonds et al.
patent: 34 41 369 (1986-05-01), None
patent: 40 29 648 (1992-03-01), None
Pyrimidines Part XI, Synthesis of 5-Hydroxypyrimidine and Related Compounds, Chesterfield, et al. J. Chem. Soc. 1960, pp. 4590-4596.
Pyrimidines X. Synthesis of bacimethrin, 2-Methoxy . . . Alkoxypyrimidines, Koppel, et al., J. Org. Chem. 1962, pp. 3614-3617.
Chem. Abstract 96, Nr. 180550 (1982).
Güthner Thomas
Neuhauser Karl-Heinz
Degussa - AG
Ford John M.
Fulbright & Jaworski L.L.P.
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