Industrial process for the preparation of N-alkyl-N-trialkylsilylamides
The present invention relates to a process for producing N-alkyl-N-trialkylsilylamides from trialkylsilylhalides and N-alkylamides in the presence of a base and in the absence of a solvent.
1. A process for the preparation of a compound of formula
wherein R 1 , R 2 , R 3 , R 4 and R 5 independently of each other represent C 1 -C 6 alkyl,
comprising
reacting a compound of formula
wherein R 1 and R 2 are as defined above
with a compound of formula
wherein X represents a halogen and R 3 , R 4 and R 5 are as defined above,
in the presence of an organic base [OB] to form the compound of formula I and the salt of the protonated organic base [OB]H + X − , wherein X is as defined above and separating the compound of formula I from the salt of the protonated organic base [OB]H + X − , wherein the process is carried out in a reaction medium, wherein the compound of formula II, the compound of formula III, the organic base [OB] and the reaction products formed during the reaction are present in a combined amount of at least 90% of the reaction medium,
and
wherein 0.8 to 2 moles of the organic base [OB] are used per mole of the compound of formula II.
2. The process according to claim 1 , wherein about 1 mole of the organic base [OB] is used per mole of the compound of formula II.
3. The process according to claim 1 , wherein R 1 , R 2 , R 3 , R 4 and R 5 independently of each other represent C 1 -C 4 alkyl which can be identical or different.
4. The process according to claim 3 , wherein R 1 , R 2 , R 3 , R 4 and R 5 independently of each other represent C 1 or C 2 alkyl which can be identical or different.
5. The process according to claim 1 , wherein R 1 , R 2 , R 3 , R 4 and R 5 are the same.
6. The process according to claim 5 , wherein R 1 , R 2 , R 3 , R 4 and R 5 represent methyl.
7. The process according to claim 1 , wherein X represents chlorine.
8. The process according to claim 1 , wherein the organic base [OB] is a nitrogen containing organic base.
9. The process according to claim 1 , wherein the compound of formula I is separated from the salt of the organic base [OB]H + X − by adding an antisolvent for [OB]H + X − to the reaction medium so that the salt of the organic base [OB]H + X − precipitates and can be removed by filtration.
10. The process according to claim 9 , wherein the antisolvent is an alkane having a boiling point in the range from 35 to 80° C.
11. The process according to claim 1 , wherein the compound of formula II is reacted with the compound of formula III in a compound of formula II/compound of formula III molar ratio of 1/5 to 5/1.
12. The process according to claim 1 , wherein the reaction of the compound of formula II with the compound of formula III is carried out at a temperature in the range from 20 to 50° C.
13. A process for the manufacture of a peptide or peptide analogue which comprises
preparing a compound of formula I according to claim 1 ,
reacting the compound of formula I with an amino acid, a peptide or a peptide analogue to obtain a persilylated amino acid, peptide or peptide analogue, and
reacting the persilylated amino acid, peptide or peptide analogue with a compound of formula
Y-A-COOH IV
wherein Y is an amino protecting group, A is an amino acid, peptide or peptide analogue residue and COOH designates an optionally activated carboxylic group.
14. The process according to claim 1 , wherein the organic base [OB] is triethylamine.
15. The process according to claim 1 , wherein the compound of formula II is reacted with the compound of formula III in a compound of formula II/compound of formula III molar ratio of 1.5/1 to 1/1.
16. A process for the preparation of a compound of formula
wherein R 1 , R 2 , R 3 , R 4 and R 5 independently of each other represent C 1 -C 6 alkyl,
comprising
reacting a compound of formula
wherein R 1 and R 2 are as defined above
with a compound of formula
wherein X represents a halogen and R 3 , R 4 and R 5 are as defined above, in the presence of an organic base [OB] to form the compound of formula I and the salt of the protonated organic base [OB]H + X − , wherein X is as defined above and separating the compound of formula I from the salt of the protonated organic base [OB]H + X − , wherein the process is carried out in a reaction medium, wherein the compound of formula II, the compound of formula III, the organic base [OB] and the reaction products formed during the reaction are present in a combined amount of at least 90% of the reaction medium,
and
wherein about 1 mole of the organic base [OB] is used per mole of the compound of formula II, wherein about equimolar amounts of the compounds of formula III and the organic base [OB] are used and wherein compounds of formula II and III and the organic base [OB] are slowly added together.
17. The process according to claim 16 , wherein the compound III is added at a rate of 150 to 250 L/h to the mixture of compounds II and of the organic base.
18. The process according to claim 16 , wherein the compound II is added at a rate of 150 to 250 L/h to the mixture of compounds III and of the organic base.