Semi-continuous process for preparing bis-silyl carboxamides

Details Semi-continuous process for preparing bis-silyl carboxamides Semi-continuous process for preparing bis-silyl carboxamides

2001-03-29

2002-01-01

Shaver, Paul F. (Department: 1621)

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

Organic compounds

Silicon containing

C544S069000, C548S110000

Reexamination Certificate

active

06335456

ABSTRACT:

The present invention relates to a semi-continuous process for preparing bis-silyl carboxamides of formula R—C[═NSi(CH
3
)
3
]OSi(CH
3
)
3
(I) in which R represents a linear or branched alkyl radical containing a number of carbon atoms ranging from 1 to 4; —CH═CH
2
, —C(CH
3
)═CH
2
, —CH
2
F, —CHF
2
, —CF
3
.
Bis-silyl carboxamides are used as agents for silylating organic compounds such as amino acids, carboxylic acids, alcohols and amides during the synthesis of pharmaceutical products or for analytical purposes.
Thus, N,O-bis trimethylsilyl)acetamide (BSA) of formula CH
3
C[═NSi(CH
3
)
3
]OSi(CH
3
)
3
is used in the synthesis of antibiotics such as cephalosporins.
There are many routes of access to the bis-silyl carboxamides of formula (I).
The conventional route is that which was used by Birkofer L. et al. (Angew. Chem. 1963, 75, pages 93 and 94) which consists in reacting acetamide in the presence of two equivalents of trimethylchlorosilane (TMCS) in the presence of tertiary amines as hydrochloric acid acceptors. Triethylamine is the usual solvent. This route has two major drawbacks. Firstly, the amine hydrochloride tends to sublime during the reaction and, secondly, the step of filtering off the amine hydrochloride is difficult in particular on account of the very high sensitivity of BSA to water.
French patent application FR-A-2 574 079 proposes a process for preparing BSA which consists in reacting acetic anhydride first with hexamethyldisilazane and then with trimethylchlorosilane and a tertiary amine.
Although this process produces only half as much amine hydrochloride as the process using acetamide and TMCS, it has the drawback of producing trimethylsilyl acetate as a byproduct, which is difficult to upgrade.
Processes which do not co-produce amine hydrochloride have also been proposed.
These processes involve reacting acetamide or the N-trimethylsilyl derivative thereof with trimethylsilylimidazole or alkyl or aryl derivatives thereof as disclosed in patent application JP 63-79889.
Similarly, U.S. Pat. No. 4,276,423 discloses a batchwise process for preparing BSA, which consists in placing acetamide or N-(trimethylsilyl)acetamide (mono-BSA) in contact with 1-(trimethylsilyl)imidazole (TMSIm) and then in reacting them under reduced pressure and heating them gradually to a temperature of not more than 180° C. and removing the BSA from the reaction medium during the synthesis.
The advantage of this process is that it does not co-produce amine hydrochloride.
However, in this process, it is necessary to heat the reaction medium to a sufficiently high temperature in order to displace the reaction equilibrium (A):
towards the formation of BSA and imidazole (Im) and to extract the said BSA by distillation.
Working in this way has the drawback of involving an appreciable residence time of the BSA in the reaction medium, resulting in a partial decomposition of the BSA, this unstable product thermally decomposing into hexamethyldisiloxane and acetonitrile.
A semi-continuous process has now been found for preparing bis-silyl carboxamides of formula (I):
in which R represents a linear or branched alkyl radical containing a number of carbon atoms ranging from 1 to 4; preferably unsubstituted or fluorosubstituted alkyl, especially —CH═CH
2
, —C(CH
3
)═CH
2
, —CH
2
F, —CHF
2
, —CF
3
by reacting an amide RCONH
2
(2) or the N-trimethylsilyl derivative thereof RCONHSi(CH
3
)
3
(3) with a silylating agent R
1
Si(CH
3
)
3
(4) according to the reactions:
in which R
1
is chosen from pyrazolyl, imidazolyl, 1,2,4-triazolyl, pyrrolidinyl, morpholinyl and benzotriazolyl radicals, optionally substituted with one or more linear or branched alkyl residues containing a number of carbon atoms ranging from 1 to 4; characterized in that the following steps are simultaneously carried out:
I. continuously and gradually introducing at preferably a substantially constant flow rate the amide (2) or the N-trimethylsilylderivative thereof RCONHSi(CH
3
)
3
(3), or alternatively the amide (2) or the N-trimethylsilyl derivative thereof (3) and some of the silylating agent R
1
Si(CH
3
)
3
(4) as a mixture or separately into a reactor containing a stirred distillation residue, comprising all or some of the silylating agent R
1
Si(CH
3
)
3
(4) brought to a temperature ranging from 130° C. to 190° C. and preferably between 150° C. and 180° C., and
II. gradually distilling off the resultant bis-silyl carboxamide (1) as it is formed by distillation at a pressure below atmospheric pressure and preferably at a pressure of between 1×10
3
Pa (10 mbar) and 2×10
4
Pa (200 mbar).
According to the present invention, the expression “all or some” means that when the reagents (2) or (3) are irtroduced, the distillation residue comprises all of the silylating agent (4) and when the process is performed according to the variant which consists in introducing the amide (2) or the N-trimethylsilyl derivative thereof (3) and the silylating agent (4) or a mixture thereof, the distillation residue consists essentially of some of the said silylating agent (4) used, this portion representing a molar amount of not more than 40% of the total amount of (4) used. According to this variant, the introduction of the reagents is stopped when at most the working volume of the reactor is reached.
According to the present invention, the reagents introduced may be heated beforehand.
The silylating agent R
1
Si(CH
3
)
3
according to the present invention is chosen from nitrogen heterocycles containing at least one nitrogen atom bearing a hydrogen atom which may be substituted with an —Si(CH
3
)
3
group, and optionally another hetero atom such as oxygen.
As illustrations of such compounds which may be used according to the invention, mention will be made of 1-(trimethylsilyl)imidazole and the alkyl derivatives thereof, such as 1-(trimethylsilyl)-2-methylimidazole, 1-(trimethylsilyl)-2-ethyl-4-methylimidazole, 1-trimethylsilyl-4-methylimidazole; 1-trimethylsilyl-1,2,4-triazole, 1-trimethylsilyl-pyrrolidine, 4-trimethylsilylmorpholine, 1-(trimethyl-silyl)pyrazole and the alkyl derivatives thereof such as 1-(trimethylsilyl)-3-methylpyrazole, 1-(trimethyl-silyl)-4-methylpyrazole and 1-(trimethylsilyl)benzo-1,2,3-triazole.
According to the present invention, the silylating agent will be carefully selected such that the bis-silyl derivative (1) formed is the most volatile compound.
The reagents are used in the case of reaction (B) in molar ratios (4)/(2) ranging from 2 to 4 and preferably between 2.3 and 2.7, and in the case of reaction (C), in molar ratios (4)/(3) ranging from 1 to 2 and preferably between 1.3 and 1.7.
The reactions according to the invention are carried out without using any catalyst or activator and without solvent.
The crude bis-silyl carboxamide (1) obtained according to the invention is purified by fractional distillation under reduced pressure. The distillation residue consisting mainly of the N-trimethylsilyl amide (3) may advantageously be recycled during a subsequent synthesis operation.
The process according to the present invention applies most particularly to the preparation of N,O-bis(trimethylsilyl)acetamide (BSA) from acetamide or the N-trimethylsilyl derivative thereof (mono-BSA) and 1-(trimethylsilyl)imidazole as silylating agent. In this case, R1 represents an imidazolyl radical and the heterocycle R
1
H co-produced is imidazole.
According to the present invention, after all of the bis-silyl carboxamide (1) has been extracted, the heterocycle R
1
H co-produced may be converted into silylating agent (4) by reacting it with hexamethyldisilazane (HMDZ) (6) according to the reaction:
The process is preferably performed using a slight excess of HMDZ relative to the stoichiometry of the reaction (D).
The reaction is generally carried out at atmospheric pressure, under an inert and dry atmosphere.
The HMDZ is introduced into the reactor containing the stirred heterocycle R
1
H and is brought to a temperature ranging from 80° C. to 200° C. and at

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