5 substituted hydantoins
The present invention relates to 5-substituted hydantoins, a process for the preparation of 5-substituted hydantoins and the use of 5-substituted hydantoins 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 5-substituted hydantoins.
1. A compound of formula [1]
wherein R 1 is —Z—R 11 with Z is O or S or S(O) or S(O) 2 and R 11 is —C(O)R 111 or —S(O)R 111 or —S(O) 2 R 111 or
wherein R 1 is
and wherein
p has the value 1, 2, 3, 4, 5 or 6 and wherein R 4 and R 5 are independently chosen from the list consisting of —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —C 6 H 6 , lower alkyl, aryl or wherein R 4 and R 5 are connected to each other to form a ring chosen from the list consisting of —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 CH 2 — and —CH 2 ACH 2 — wherein A is —(CH 2 ) q O—, —(CH 2 ) q S—, —(CH 2 ) q S(O)—, —(CH 2 ) q S(O) 2 — with q is 0, 1, 2, 3 or 4; and
R 2 is —H or —C(O)R 22 or —S(O)R 22 or —S(O) 2 R 22 ; and
R 3 is —H or —C(O)R 33 or —S(O)R 33 or —S(O) 2 R 33 ; and wherein
R 111 , R 22 and R 33 are independently chosen from the list consisting of —H, —CH 3 , —CH 2 X, —CHX 2 , —CX 3 , —C 6 H 6 , —C 6 H 5 X, —C 6 H 4 X 2 lower alkyl and aryl, wherein X represents Br, CH 3 , C 2 H 5 , Cl, F or I, with the proviso that R 2 and R 3 are not —H when Z is S and R 11 is —C(O)CH 3 ; and wherein
R 7 is chosen from the list consisting of —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —C 6 H 6 , lower alkyl, aryl and substituted derivatives thereof.
2. Compound according to claim 1 wherein R 1 is —Z—R 11 with Z is O or S or S(O) or S(O) 2 and R 11 is —C(O)R 111 or —S(O)R 111 or —S(O) 2 R 111 .
3. Compound according to claim 2 wherein R 1 is —Z—R 11 and Z is O and R 11 is —C(O)H or —C(O)CH 3 and R 2 and R 3 are both —H or both the same as R 11 .
4. Compound according to claim 2 wherein R 1 is —Z—R 11 and Z is S and R 11 , R 2 and R 3 are —C(O)CH 3 .
5. Method for the preparation of a compound according to claim 2 comprising contacting a compound of formula [2]
wherein Z is O or S
(a) with a compound of formula R 111 C(O)Y
wherein R 111 is chosen from the list consisting of —H, —CH 3 , —CH 2 X, —CHX 2 , —CX 3 , —C 6 H 6 , —C 6 H 5 X, —C 6 H 4 X 2 lower alkyl and aryl,
wherein X represents Br, CH 3 , C 2 H 5 , Cl, F or I and Y represents Br, Cl, F, I, OH or OC(O)R 111 , or
(b) with a compound of formula R 111 S(O) n Y
wherein n is 1 or 2,
wherein R 111 is chosen from the list consisting of —H, —CH 3 , —CH 2 X, —CHX 2 , —CX 3 , —C 6 H 6 , —C 6 H 5 X, —C 6 H 4 X 2 lower alkyl and aryl,
wherein X represents Br, CH 3 , C 2 H 5 , Cl, F or I and Y represents Br, Cl, F, I, OH or OS(O) n R 111 .
6. Method according to claim 5 further comprising contacting the product obtained in (a) or (b) with an enamine of the general formula [3] or a ketoester of general formula [3a]
wherein p has the value 1, 2, 3, 4, 5 or 6 and wherein R 4 and R 5 are independently chosen from the list consisting of —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —C 6 H 6 , lower alkyl, aryl or wherein R 4 and R 5 are connected to each other to form a ring chosen from the list consisting of —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 CH 2 — and —CH 2 ACH 2 — wherein A is —(CH 2 ) q O—, —(CH 2 ) q S—, —(CH 2 ) q S(O)—, —(CH 2 ) q S(O) 2 — with q is 0, 1, 2, 3 or 4, and R 7 is chosen from the list consisting of —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —C 6 H 6 , lower alkyl, aryl and substituted derivatives thereof, followed by hydrolysis to give a compound of the general formula [4]
wherein p has the meaning as defined above.
7. Method according to claim 6 further comprising contacting said compound of general formula [4] with a hydantoinase, a carbamoylase and a hydantoin racemase to give a compound of the general formula [5]
wherein p has the value 1, 2, 3, 4, 5 or 6.
8. Method according to claim 7 further comprising subjecting said compound of general formula [5] to hydrogenation to give a compound of the general formula [6]
wherein p has the value 1, 2, 3, 4, 5 or 6.
9. Method according to claim 8 further comprising contacting said compound of general formula [6] with a compound of general formula [7] or a compound of general formula [8]
wherein R 6 is —CH 3 or phenyl, to give a compound of the general formula [9]
wherein p has the value 1, 2, 3, 4, 5 or 6.
10. Method according to claim 9 wherein R 6 is —CH 3 and p has the value 4 or wherein R 6 is phenyl and p has the value 3.