Process for manufacturing bis-silyl ureas

Details Process for manufacturing bis-silyl ureas Process for manufacturing bis-silyl ureas

2000-06-08

2001-10-16

Shaver, Paul F. (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Silicon containing

C252S182300, C252S182340, C252S183110

Reexamination Certificate

active

06303810

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a process for manufacturing bis-silyl ureas.
BACKGROUND OF THE INVENTION
Bis-silyl ureas are used as intermediates in the synthesis of pharmaceutical products. Thus, 1,3-bis(trimethylsilyl)urea (BSU) is used in the synthesis of antibiotics such as ampicillin and cephalexin.
The main routes of access to the bis-silyl ureas (I) comprise processes which consist in reacting a disilazane (II) and urea according to equation (1):
R
1
, R
2
, R
3
, R
4
, R
5
and R
6
in formulae I and II, which may be identical or different, represent a linear or branched aliphatic hydrocarbon-based radical containing from 1 to 5, a phenyl radical, a benzyl radical or a phenethyl radical.
The processes using this synthetic route are very similar and differ only in the use of different catalysts, variable urea/(II) molar ratios, different solvents and in the use of more or less pure reagents, in particular in the use of a urea which has very different particle sizes.
It is necessary to use a catalyst; otherwise reaction (1) is slow or does not take place. The reaction temperature can be increased in order to accelerate the reaction, but this increase in temperature is liable to bring about the more or less substantial degradation of the products obtained, with formation of impurities that are difficult to remove. Thus, all the processes of which we are aware use catalysts.
Most of the catalysts used are ammonium salts such as ammonium chloride or ammonium sulphate, mentioned in U.S. Pat. No. 3 992 428, Lewis acids such as BCl
3
, TiCl
4
or AlCl
3
, or inorganic acids such as HBr or H
3
PO
4
, also mentioned in U.S. Pat. No. 3 992 428, chlorosilanes such as trimethylchlorosilane mentioned in Patent Application FR 2 333 805, nitrogenous compounds containing electron-withdrawing groups, such as saccharin mentioned in Patent Application EP 43630. Thus, in this patent application, 1,3-bis(trimethylsilyl)urea (BSU) is obtained in a yield of 99% after reaction for 20 minutes between hexamethyldisilazane (HMDZ) and urea, used in an HMDZ/urea molar ratio equal to 1.187 in ethyl acetate in the presence of saccharin used in a proportion of 1 mol % relative to the urea used.
Although these catalysts reduce the reaction time, they have the major drawback of remaining in the compounds (I) and consequently result in instability of the products (I) on storage, a reduction in their resistance to hydrolysis and colorations. All these drawbacks are prohibitive for certain industrial applications such as, in particular, the manufacture of antibiotics.
In addition, the removal of the said catalysts, which are generally in very small amounts in the products (I), would entail long and expensive purification operations, which would be prohibitive as regards the production efficiency of an industrial process.
In most of the processes for manufacturing the products (I) mentioned in the literature, a solvent (or a mixture of solvents) is used. Among the solvents used, mention will be made of aromatic carbides such as benzene or toluene (U.S. Pat. No. 3,992,428), alkyl acetates such as ethyl acetate (EP 43630), ethers such as di-n-butyl ether, dioxane or THF, ketones such as acetone, chlorinated hydrocarbons such as CH
2
Cl
2
or 1,2-dichloroethane (Ts. Gueorguieva et al. Farmatsiya, 31(2) 1981 pages 1 to 5), siloxanes such as hexamethyldisiloxane mentioned in U.S. Pat. No. 3,992,428 and the disilazanes (II) which are also reagents.
Thus, Patent Application DE 4 041 651 describes a process for preparing BSU using hexamethyldisilazane (HMDZ) as reagent and solvent.
The process consists in heating, at the reflux point of the HMDZ, 10 g of urea (having a water content of 0.3% by weight), i.e. 0.151 mol. in 180 ml of HMDZ, i.e. 0.853 mol, in the presence of 1 g of cation exchanger and 0.1 g of water. After cooling, 30 g of BSU precipitates, which corresponds to a yield of 86%.
After reprocessing the filtrate, a further 4.5 g of BSU are recovered, which brings the final yield to 99%.
Although it is attractive to use HMDZ as reagent and as solvent, it is nevertheless found that this way of working has the drawback in that it is necessary to process the filtrate in order to recover an appreciable portion of BSU which has dissolved.
In addition, the said BSU recovered is liable to contain impurities and, consequently, requires a purification operation.
Given also the high price of HMDZ, its use in large amounts is prohibitive as regards the production efficiency of an industrial process.
Thus, an attempt was made to improve the process mentioned above by reducing the amounts of HMDZ, eliminating the water and the cation exchanger and using trimethylchlorosilane (TMCS) as catalyst. It was observed that such a process could only work with an HMDZ/urea molar ratio in the region of 3, since a lower ratio gave a thick reaction medium which is difficult to stir with the usual devices. Furthermore, it is difficult to remove all of the HMDZ from the BSU obtained.
During these tests, the importance was also noted of the particle size of the urea, which is virtually insoluble in HMDZ at reflux. This product is only commercially available in the form of coarse grains or beads ranging from 1 to 2 mm in diameter. The use of such course grains of urea entails a long and incomplete reaction and gives a final product which contains unconverted urea which is very difficult to remove.
In order to increase its conversion, the urea can be ground and used in the form of a fine powder. Working in this way, however, burdens the process with an expensive grinding operation, and the conversion of the urea is also not totally complete.
SUMMARY OF THE INVENTION
A process has now been found for preparing bis-silyl ureas (I), which comprises reacting in a solvent, urea and a disilazane (II) according to equation (1), said process comprising as a preferred comprehensive embodiment, conducting the following steps:
a) placing in contact, with stirring, a solvent, a disilazane and urea,
b) bringing the medium obtained in a) to a temperature equal to or less than the boiling point of the said solvent,
c) maintaining, from the start of evolution of the ammonia, a temperature equal to or different from that used in b) and preferably less than the boiling point of the solvent,
d) maintaining this temperature until virtually all of the ammonia has been evolved, optionally followed by stripping off the residual ammonia with an inert gas,
e) cooling the reaction medium, and
f) recovering the precipitated bis-silyl urea (I) by filtration, optionally washing it with a solvent identical to or different from the one used in a), and then drying it under reduced pressure;
the said process being characterized in that the solvent used in a) for the reaction and optionally in f) to wash the bis-silyl urea (I) is an aliphatic nitrile RCN in which R represents a linear or branched aliphatic hydrocarbon-based radical containing a number of carbon atoms ranging from 1 to 5 and preferably ranging from 1 to 3.
As illustrations of such aliphatic nitrites which can be used according to the present invention, mention will be made of: acetonitrile, propionitrile, butyronitrile. Acetonitrile will preferably be used.
According to the present invention, the solvent for washing the bis-silyl urea I is preferably identical to the reaction solvent used in a).
According to one particularly preferred variant of the process according to the invention, the reaction solvent used in a) can consist totally or partially of the filtrates arising from the filtration and optionally of the condensates arising from the drying of the bis-silyl urea (I) from a previous operation. In the event that the filtrates arising from the filtration and optionally the condensates arising from the drying of the bis-silyl urea (I) are partially recycled, the remainder is provided by fresh solvent.
The reaction solvent used in a) preferably all consists of filtrates arising from the filtration of a previous operation.
According to the present invention, the starting urea

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