Process for the preparation of hexahydroisoquinolines from 1,2,3,4-tetrahydroisoquinolines
View Patent ↗The present invention is directed to processes for the synthesis of morphinans. In particular, a process for the asymmetric reduction of an imine moiety in a 3,4-dihydroisoquinoline to produce a tetrahydroisoquinoline, followed by a Birch reduction to produce a hexahydroisoquinoline. In various embodiments, the 3,4-dihydroisoquinoline contains a phenol moiety protected with a labile protecting group. In other embodiments, the imine reduction reaction mixture contains silver tetrafluoroborate.
1. A compound corresponding to Formula 703:
wherein
R 1 and R 7 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, or —OR 111 ;
R 2 is hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, or —OR 211 ;
R 3 is hydrogen, hydrocarbyl, or —OR 311 ;
R 4 is hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, or —OR 411 ;
R 5 and R 6 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, or —OR 511 ;
R 12 is hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, or —OR 121;
R 13 is hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, or —OR 511 ;
R 17 is hydrogen, or acyl;
R 111 is hydrogen, hydrocarbyl, or substituted hydrocarbyl;
R 211 is hydrogen, hydrocarbyl, —C(O)R 212 , —C(O)NHR 213 , or —SO 2 R 214 ;
R 212 , R 213 and R 214 are independently hydrocarbyl or substituted hydrocarbyl;
R 311 is hydrogen, hydrocarbyl, —C(O)NHR 313 , or —SO 2 R 314 ;
R 313 , or R 314 are independently hydrocarbyl or substituted hydrocarbyl;
R 411 is hydrogen, hydrocarbyl, —C(O)R 412 , —C(O)NHR 413 , or —SO 2 R 414 ;
R 412 is hydrogen, alkyl or aryl, provided, R 412 is other than phenyl;
R 413 , and R 414 are independently hydrocarbyl or substituted hydrocarbyl;
R 511 is hydrogen, hydrocarbyl, or substituted hydrocarbyl;
R 121 is hydrogen, hydrocarbyl, or substituted hydrocarbyl; and
wherein at least one of R 2 , R 3 , or R 4 is —OC(O)R 212 , —OC(O)NHR 213 ,—OSO 2 R 214 , —OC(O)R 313 , —OSO 2 R 314 , —OC(O)R 412 , —OC(O)NHR 413 , or —OSO 2 R 414 .
2. The compound of claim 1 , wherein:
R 2 is —OR 211 ;
R 211 is hydrogen, alkyl, —C(O)R 212 , —C(O)NHR 213 , or —SO 2 R 214 ; and
R 212 , R 213 , and R 214 are independently alkyl or aryl.
3. The compound of claim 1 , wherein:
R 3 is —OR 311 ;
R 311 is hydrogen, alkyl,—C(O)NHR 313 , or —SO 2 R 314; and
R 313 , and R 314 are independently alkyl or aryl.
4. The compound of claim 1 , wherein:
R 4 is —OR 411 ;
R 411 is hydrogen, alkyl, —C(O)R 412 , —C(O)NHR 413 , or —SO 2 R 414; and
R 413 , and R 414 are independently alkyl or aryl.
5. The compound of claim 1 , wherein R 12 is alkyl, allyl, benzyl, or halo.
6. The compound of claim 1 , wherein R 212 , R 213 , R 214, R 313 , R 314 , R 412 , R 413 , and R 414 are methyl.
7. The compound of claim 1 , wherein R 3 is methoxy, R 4 is —OC(O)CH 2 CH 3 , or —OSO 2 CH 3 , R 6 is methoxy, and R 1 , R 2, R 5 , R 7 , R 12 , R 13 are hydrogen.
8. The compound of claim 1 , wherein:
R 2 is —OR 211 ;
R 211 is hydrogen, alkyl, —C(O)R 212 , —C(O)NHR 213 , or —SO 2 R 214 ; and
R 212 , R 213 , and R 214 are independently alkyl or aryl;
R 3 is —OR 311 , R 311 is hydrogen, alkyl, —C(O)NHR 313 , or —SO 2 R 314 ; and
R 313 , and R 314 are independently alkyl or aryl;
R 4 is —OR 411 ;
R 411 is hydrogen, alkyl, —C(O)R 412 , —C(O)NHR 413 , or —SO 2 R 414 ; and
R 413 , and R 414 are independently alkyl or aryl.
9. The compound of claim 8 , wherein R 212 ,R 213 , R 214 ,R 313 , R 314 , R 412 , R 413 , and R 414 are methyl; R 3 is methoxy, R 4 is —OC(O)CH 2 CH 3 , or OSO 2 CH 3 , R 6 is methoxy, and R 1 , R 2 , R 5 , R 7 , R 12 , R 13 are hydrogen.