Preparation of tetrahydroisoquinolines from dihydroisoquinolines
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 process for the preparation of a 1,2,3,4-tetrahydroisoquinoline corresponding to Formula 700, the process comprising treating a 3,4-dihydroisoquinoline corresponding to Formula 600 with an asymmetric catalyst in the presence of silver tetrafluoroborate, and a hydrogen source
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, substituted 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, —(O)R 212 , —(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, —(O)R 312 , —(O)NHR 313 , or —SO 2 R 314 , R 312 , R 313 , and R 314 are independently hydrocarbyl or substituted hydrocarbyl;
R 411 is hydrogen, hydrocarbyl, —(O)R 412 , —(O)NHR 413 , or —SO 2 R 414 , R 412 , R 413 , and R 414 are independently hydrocarbyl or substituted hydrocarbyl;
R 511 is hydrogen, hydrocarbyl, or substituted hydrocarbyl; and
R 121 is hydrogen, hydrocarbyl, or substituted hydrocarbyl.
2. The process 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 process of claim 1 , wherein:
R 3 is —OR 311 ;
R 311 is hydrogen, alkyl, —C(O)R 312 , —C(O)NHR 313 , or —SO 2 R 314 ; and
R 312 , R 313 , and R 314 are independently alkyl or aryl.
4. The process 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 412 , R 413 , and R 414 are independently alkyl or aryl.
5. The process of claim 1 , wherein R 12 is alkyl, allyl, benzyl, or halo.
6. The process of claim 1 , wherein R 212 , R 213 , R 214 , R 312 , R 313 , R 314 , R 412 , R 413 , and R 414 are methyl.
7. The process of claim 1 , wherein R 3 is methoxy, R4 is hydroxyl, —OC(O)CH 3 , —OC(O)Ph, or —OSO 2 CH 3 , R 6 is methoxy, and R 1 , R 2 , R 5 , R 7 , R 12 , and R 13 are hydrogen.
8. The process of claim 1 , wherein:
R 2 is —OR 211 ;
R 211 is hydrogen, alkyl, —C(O)R 212 , —(O)NHR 213 , or —SO 2 R 214 ;
R 212 , R 213 , and R 214 are independently alkyl or aryl;
R 3 is —OR 311 ;
R 311 is hydrogen, alkyl, —C(O)R 312 , —(O)NHR 313 , or —SO 2 R 314 ;
R 312 , R 313 , and R 314 are independently alkyl or aryl;
R 4 is —OR 411 ;
R 411 is hydrogen, alkyl, —C(O)R 412 , —(O)NHR 413 , or —SO 2 R 414 ; and
R 412 , R 413 , and R 414 are independently alkyl or aryl.
9. The process of claim 8 , wherein R 212 , R 213 , R 214 , R 312 , R 313 , R 314 , R 412 , R 413 , and R 414 are methyl; R 3 is methoxy, R 4 is hydroxyl, —OC(O)CH 3 , —OC(O)Ph, or —OSO 2 CH 3 , R 6 is methoxy, and R 1 , R 2 , R 5 , R 7 , R 12 , and R 13 are hydrogen.
10. The process of claim 1 , wherein about 0.005 g to about 0.015 g of silver tetrafluoroborate per equivalent of 3,4-dihydroisoquinoline is used.
11. The process of claim 1 , wherein the temperature of the reaction mixture is from about 20° C. to about 30° C.
12. The process of claim 1 , wherein the asymmetric catalyst comprises a metal or a metal source and a chiral ligand.
13. The process of claim 12 , wherein the metal or metal source is chosen from ruthenium, a ruthenium complex, osmium, an osmium complex, rhodium, a rhodium complex, iridium, iridium complex, and combinations thereof.
14. The process of claim 12 , wherein the chiral ligand has the structure of formulae 670 or 680
wherein
R 671 , R 672 , and R 673 are independently alkyl or aryl;
R 681 is alkyl or aryl.
15. The process of claim 12 , wherein the chiral ligand is (1S,2S)-(+)-N-4-tolylsulfonyl-1,2-diphenylethylene-1,2-diamine.
16. The process of claim 1 , wherein the hydrogen source is a formic acid-triethylamine salt mixture.
17. The process of claim 16 , wherein the ratio of formic acid to triethylamine is 5 to 2.