Preparation of 3,4-dihydroisoquinolines from an acid and an amine
View Patent ↗The present invention is directed to processes for the synthesis of morphinans. In particular, a process for coupling a carboxylic acid compound with an amine compound to form an amide product that can then be isolated or the crude amide product can be cyclized to form a 3,4-dihydroisoquinoline. In one embodiment, the carboxylic acid contains a phenol moiety protected with a labile protecting group. The protected phenol reduces reaction times, simplifies work-up of the product, and reduces the amount of cyclizing agent, POCl 3 that is necessary to form the 3,4-dihydroisoquinoline.
1. A process for the preparation of a 3,4-dihydroisoquinoline corresponding to Formula 600, the process comprising treating an acid corresponding to Formula 300 with an amine corresponding to Formula 400 in the presence of POCl 3 , the 3,4-dihydroisoquinoline being produced under anhydrous conditions and without isolation or purification of reaction intermediates:
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 311 :
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 111 is hydrogen, hydrocarbyl, or substituted hydrocarbyl;
R 211 is hydrogen, hydrocarbyl, —C(O)R 212 , —C(O)NHR 213 , —SO 2 R 214 ;
R 212 , R 213 , and R 214 are independently hydrocarbyl or substituted hydrocarbyl;
R 311 is hydrogen, hydrocarbyl, —C(O)R 312 , —C(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, —C(O)R 412 , —C(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, 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.
8. The process of claim 1 , wherein:
R 2 is —OR 211 ;
R 211 is hydrogen, alkyl, —C(O)R 212 , —C(O)NHR 213 , —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 , —C(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 , —C(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 12 is alkyl, allyl, benzyl, or halo.
10. 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.
11. The process of claim 8 , wherein R 12 is alkyl, allyl, benzyl, or halo; and R 212 , R 213 , R 214 , R 312 , R 313 , R 314 , R 412 , R 413 , and R 414 are methyl.
12. The process of claim 1 , wherein the reaction mixture comprises an amide intermediate and the amount of POCl 3 used is up to 1 equivalent of POCl 3 per equivalent of amide intermediate.
13. The process of claim 12 , wherein the amide intermediate corresponds to Formula 500:
14. The process of claim 1 , wherein the temperature of the reaction mixture is from about 40° C. to about 90° C.
15. The process of claim 1 , wherein the yield 3,4-dihydroisoquinoline corresponding to Formula 600 is at least 50%.
16. The process of claim 1 , wherein the yield 3,4-dihydroisoquinoline corresponding to Formula 600 is at least 60%.
17. The process of claim 1 , wherein the yield 3,4-dihydroisoquinoline corresponding to Formula 600 is at least 70%.
18. The process of claim 1 , wherein anhydrous conditions are obtained by removal of water from the reaction mixture by distillation.
19. The process of claim 1 , wherein anhydrous conditions are obtained by addition of a water scavenging agent to the reaction mixture.
20. The process of claim 1 , wherein the reaction is conducted in the presence of an aprotic solvent.