Carbamoylglycine derivatives
The present invention relates to carbamoylglycine derivatives, a process for the preparation of carbamoylglycine derivatives and the use of carbamoylglycine derivatives in the preparation of enantiomerically enriched α-amino acids. Furthermore, the present invention relates to the preparation of pharmaceutically active products such as perindopril and ramipril using the novel carbamoylglycine derivatives.
1. A compound of formula [1]
wherein R is
m and n are 0, 1, 2, 3 or 4 and m+n≧1 or a salt thereof.
2. The compound according to claim 1 that is 3-(2-oxocyclopentyl)-2-ureidopropanoic acid or 3-(2-oxocyclohexyl)-2-ureidopropanoic acid or a salt thereof.
3. A method for the preparation of the compound of claim 1 comprising treating a compound of formula [4] with an acid followed by a cyanate,
wherein R is
m and n are 0, 1, 2, 3 or 4, m+n≧1 and R 2 and R 3 are independently chosen from the list consisting of —CH 3 , —CH 2 X, —CHX 2 , —CX 3 , —C 6 H 6 , —C 6 H 5 X 2 , —C 6 H 4 X 2 , —SiY′Y′Y′″, lower alkyl and aryl, wherein X represents Br, CH 3 , C 2 H 5 , NO 2 , Cl, F or I and Y′, Y″ and Y′″ independently represent lower alkyl or aryl.
4. The method according to claim 3 , wherein said cyanate is potassium cyanate or sodium cyanate or a mixture thereof.
5. A method for the preparation of a compound of the formula [5]
wherein p is 1 or 2, which method comprises contacting a compound according to formula [1] with a carbamoylase,
wherein R is
m is 3 or 4 and n is 0, or salt thereof.
6. The method according to claim 5 , wherein said compound of formula [1] is also contacted with a racemase and a hydantoinase.
7. A method for the preparation of a compound of the formula [6]
wherein p is 1 or 2, which method comprises contacting a compound according to formula [1] with a carbamoylase,
wherein R is
m is 3 or 4 and n is 0, or a salt thereof, to obtain a compound of formula [5],
wherein p is 1 or 2, and then subjecting the compound of formula [5] to hydrogenation to provide the compound of formula [6].
8. A method for the preparation of a compound according to formula [9]:
wherein p is 1 or 2, which method comprises contacting a compound of the formula [1] with a carbamoylase,
wherein R is
m is 3 or 4 and n is 0, or a salt thereof, to obtain a compound of formula [5],
wherein p is 1 or 2,
subjecting the compound of formula [5] to hydrogenation to provide the compound of formula [6],
wherein p is 1 or 2, and
contacting the compound of the formula [6] with a compound of formula [7] or a compound of formula [8]:
wherein R 4 is —CH 3 or phenyl to provide the compound of the formula [9].
9. The method according to claim 8 , wherein R 4 is —CH 3 and p has the value 2 or wherein R 4 is phenyl and p has the value 1.
10. The method according to claim 8 , wherein the compound of formula [9] is ramipril and the compound of formula [1] is 3-(2-oxycyclopentyl)-2-ureidopropanoic acid.
11. The method according to claim 8 , wherein the compound of formula [9] is perindopril and the compound of formula [1] is 3-(2-oxocyclohexyl)-2-ureidopropanoic acid.
12. The method according to claim 8 , wherein the compound of formula [9] is trandolapril and the compound of formula [1] is 3-(2-oxocyclohexyl)-2-ureidopropanoic acid.