Process for preparation of sulfonylurea salts

Details Process for preparation of sulfonylurea salts Process for preparation of sulfonylurea salts

1998-08-25

2001-04-24

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...

Reexamination Certificate

active

06222037

ABSTRACT:

The present invention relates to a process for the preparation of potassium and sodium salts of N-pyridylsulfonyl-N′-pyrimidinylureas.
It is known how to prepare N-pyridylsulfonyl-N′-pyrimidinylureas in a manner such that a pyridylsulfonamide is reacted with a pyrimidinyl isocyanate in the presence of a base. Such reactions are described, for example, in EP-A-0 232 067, EP-A-0 459 949 or EP-A-0 540 697. The corresponding sulfonylurea salts are obtained by reacting the sulfonylureas thus prepared in a second reaction step with suitable salt-forming substances. Such salt-forming substances are bases which are able to abstract the acidic hydrogen atom in the SO
2
—NH—CO group, for example hydrides, hydroxides, alcoholates, hydrogen carbonates, and carbonates of alkali metals and alkaline earth metals. Such reactions are described, for example, in EP-A-0 521 500. This two-step synthesis, however, has a major disadvantage. The sulfonylureas thus obtained generally possess only a weak crystalline structure and can therefore only be filtered off from the reaction mixture with difficulty and in very insufficient quantities. This especially hinders the economic manufacture of such compounds on a large scale. Moreover, the yields obtained by means of the known processes are as a rule unsatisfactory.
It is therefore the purpose of the present invention to make available a process for the preparation of N-pyridylsulfonyl-N′-pyrimidinylurea sodium and potassium salts which is characterised by a simple reaction procedure and which avoids the disadvantages of the known processes.
It has now been found that N-pyridylsulfonyl-N′-pyrimidinylurea salts can be prepared in a simple manner and with high yields by either reacting a pyridylsulfonamide salt with a pyrimidinyl isocyanate or a pyridylsulfochloride with a pyrimidinylurea salt.
According to the invention, it is therefore proposed that compounds of formula I
wherein R
1
is CO
2
CH
3
, CON(CH
3
)
2
, OCH
2
CF
3
, N(CH
3
)COCH
3
, N(CH
3
)SO
2
CH
3
, CF
3
or SO
2
C
2
H
5
; R
2
is hydrogen or CF
3
; and M is sodium or potassium, are prepared in a manner such that a compound of formula IV
is reacted in an aprotic, organic solvent either with a compound of formula V
wherein R
1
, R
2
and M are as defined under formula I, or is reacted with NH
3
in an aprotic, organic solvent to form a compound of formula III
reacting this with a hydride, hydroxide, alcoholate, hydrogen carbonate or carbonate of sodium or potassium in an aprotic, organic solvent to form a compound of formula II
wherein M is as defined under formula I, and then reacting this with a compound of formula VI
wherein R
1
and R
2
are as defined under formula I.
Aprotic, organic solvents suitable for reacting a compound of formula IV with a compound of formula V are, for example, ethyl acetate, acetonitrile, dimethylsulfoxide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, acetone, butanone, halogenated solvents such as dichloromethane, trichloromethane or trichlorethane, ethers such as tetrahydrofuran, diethylether, 1,2-dimethoxyethane, dioxane, methyl-tert-butylether, and also aromatic solvents such as chlorobenzene, toluene and xylene. Dioxane and tetrahydrofuran are especially preferred. The reaction of a compound of formula IV with a compound of formula V is carried out at temperatures of from −20° C. to 180° C., a temperature range of from 30 to 80° C. being preferred. The compounds of formulae IV and V can be used in equivalent stoichiometric quantities, although a slight excess of isocyanate may be of advantage.
Aprotic, organic solvents suitable for the transformation of a compound of formula IV to a compound of formula III are, for example, ethyl acetate, acetonitrile, dimethylsulfoxide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, acetone, butanone, halogenated solvents such as dichloromethane, trichloromethane or trichlorethane, ethers such as tetrahydrofuran, diethylether, 1,2-dimethoxyethane, dioxane, methyl-tert-butylether, and also aromatic solvents such as chlorobenzene, toluene and xylene. Dioxane and tetrahydrofuran are especially preferred. The reaction is carried out at temperatures of −20° C. to 180° C., a temperature range of 0-80° C. being preferred. The stochiometric ratio of the compound of formula IV to the NH
3
used is 1:1 to 1:3, preferably 1:1.5.
Aprotic, organic solvents suitable for converting a compound of formula III to a compound of formula II are, for example, ethyl acetate, acetonitrile, dimethylsulfoxide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, acetone, butanone, halogenated solvents such as dichloromethane, trichloromethane or trichlorethane, ethers such as tetrahydrofuran, diethylether, 1,2-dimethoxyethane, dioxane, methyl-tert-butylether, and in the broader sense also aromatic solvents such as chlorobenzene, toluene and xylene, as well as alcohols such as C
1
-C
5
alcohols, typically methanol or ethanol. Tetrahydrofuran is especially preferred.
Aprotic, organic solvents suitable for reacting a compound of formula II with a compound of formula VI are, for example, ethyl acetate, acetonitrile, dimethylsulfoxide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone, acetone, butanone, halogenated solvents such as dichloromethane, trichloromethane or trichlorethane, ethers such as tetrahydrofuran, diethylether, 1,2-dimethoxyethane, dioxane, methyl-tert-butylether, and in the broader sense also aromatic solvents such as chlorobenzene, toluene and xylene. Tetrahydrofuran is especially preferred. The reaction is carried out at temperatures of −20° C. to 180° C., a temperature range of 0-40° C. being preferred. The stoichiometric ratio between the compound of formula III, the base, and the compound of formula VI is 1:2:1 to 1:3:2, preferably
1:2:1.1. Bases suitable for salt formation are, for example, the hydrides, carbonates, hydrogen carbonates and alcoholates of sodium and potassium, preferably the hydrides and alcoholates, such as sodium hydride, potassium hydride, sodium methylate, potassium methylate or potassium ethylate, special preference being for sodium hydride and sodium methylate.
In the process according to the invention, a compound of formula IV
is preferably reacted in an aprotic, organic solvent with a compound of formula V
wherein R
1
, R
2
and M are as defined under formula I. Special attention is drawn to the surprisingly high yield with this variant.
Especially preferred are those compounds of formula I which are prepared using the process according to the invention, wherein R
1
OCH
2
CF
3
and R
2
are hydrogen. In a further group of preferred compounds of formula I, M is sodium.
In a preferred variant of the process according to the invention, 3-(2-trifluoroethoxy)pyridin-2-ylsulfonamide sodium salt is reacted at a temperature of 30 to 80° C. in dioxane or tetrahydrofurane with 4,6-dimethoxypyrimidin-2-isocyanate.
The intermediate products of formula II
wherein M is as defined under formula I, and the intermediate product of formula III
are new, have been especially developed for the process according to the invention, and therefore constitute a subject of the present invention.
The compounds of formula I or the corresponding sulfonylureas are known and described, for example, in EP-A-0 459 949, EP-A-0 540 697, EP-A-0 103 543, EP-A-0 600 836, and EP-A-0 521 500. The sulfonylurea salts of formula I may be present in amorphous form and as solvates, for example with dioxane, or as hydrates, for example as monohydrates and dihydrates.
The preparation of the starting compound of formula IV is described, for example, in EP-A-0 232 067, page 29. The compounds of formula V may be prepared, for example, by converting the compound of formula VII
wherein R
1
and R
2
are as defined under formula I and R
3
is —CH
2
-phenyl or isopropyl, to the compound of formula VI through aqueous chlorination. This compound is treated with ammonia, and the resulting sulfonamide is then reacted with 30% sodium methylate. Such reactio

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