Preparation of amides from an acid and amine for intermediates in the synthesis of morphinans
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 an amide corresponding to Formula 502, the process comprising treating an acid corresponding to Formula 301 with an amine corresponding to Formula 400 under anhydrous conditions and at a temperature of from about 25° C. to about 100° C. to form the amide corresponding to Formula 502:
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 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)R 312 , —C(O)NHR 313 , or —SO 2 R 314 :
R 312 is alkyl or aryl, provided, R 312 is other than methyl or phenyl;
R 313 is hydrocarbyl or substituted hydrocarbyl;
R 314 is alkyl or aryl, provided, R 314 is other than methyl;
R 411 is hydrogen, hydrocarbyl, —C(O)R 412 , —C(O)NHR 413 , or —SO 2 R 414 ;
R 412 is alkyl or aryl, provided, R 412 is other than methyl or phenyl;
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;
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 312 , —OC(O)NHR 313 , —OSO 2 R 314 , —OC(O)R 412 , —OC(O)NHR 413 , or —OSO 2 R 414 .
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 hydrocarbyl or substituted hydrocarbyl.
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 ;
R 312 is alkyl or aryl, provided, R 312 is other than methyl or phenyl;
R 313 is hydrocarbyl or substituted hydrocarbyl; and
R 314 is alkyl or aryl, provided, R 314 is other than methyl.
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 ;
R 412 is alkyl or aryl, provided, R 412 is other than methyl or phenyl; and
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 3 is methoxy, R 4 is hydroxyl, —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 , and R 13 are hydrogen.
7. 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 ;
R 212 , R 213 , and R 214 are independently hydrocarbyl or substituted hydrocarbyl;
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 is alkyl or aryl, provided, R 312 is other than methyl or phenyl;
R 313 is hydrocarbyl or substituted hydrocarbyl;
R 314 is alkyl or aryl, provided, R 314 is other than methyl;
R 4 is —OR 411 ,
R 411 is hydrogen, alkyl, —C(O)R 412 , —C(O)NHR 413 , or —SO 2 R 414 ;
R 412 is alkyl or aryl, provided, R 412 is other than methyl or phenyl; and
R 413 and R 414 are independently alkyl or aryl.
8. The process of claim 7 , wherein R 12 is alkyl, allyl, benzyl, or halo.
9. The process of claim 7 , wherein R 212 , R 213 , R 214 , R 313 , R 413 , and R 414 are methyl.
10. The process of claim 7 , wherein R 12 is alkyl, allyl, benzyl, or halo; and R 212 , R 213 , R 214 , R 313 , R 413 , and R 414 are methyl.
11. The process of claim 1 , wherein anhydrous conditions are obtained by removal of water from the reaction mixture by distillation.
12. The process of claim 1 , wherein anhydrous conditions are obtained by addition of a water scavenging agent to the reaction mixture.
13. The process of claim 1 , wherein the temperature of the reaction mixture is from about 40° C. to about 90° C.
14. A compound corresponding to Formula 502:
wherein
R 1 and R 7 are hydrogen,
R 2 is hydrogen;
R 3 is methoxy;
R 4 is —OC(O)CH 3 or—OSO 2 CH 3 ;
R 5 is hydrogen;
R 6 is methoxy;
R 12 is hydrogen; and
R 13 is hydrogen.