Preparation of 3,4-dihydroisoquinolines 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 compound corresponding to Formula 602:
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 is hydrogen, hydrocarbyl, substituted hydrocarbyl, or —OR 511 ;
R 6 is hydrogen, hydrocarbyl, substituted hydrocarbyl, or —OR 611 ;
R 12 is hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, or —OR 121 ;
R 13 is hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, or —OR 131 ;
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 is alkyl;
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;
R 611 is hydrogen, hydrocarbyl, or substituted hydrocarbyl;
R 121 is hydrogen, hydrocarbyl, or substituted hydrocarbyl; and
R 131 is hydrogen, hydrocarbyl, or substituted hydrocarbyl;
wherein at least one of the R 2 , R 3 , or R 4 substituents 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 ; and
wherein at least one of the remaining R 2 , R 3 , or R 4 substituents is defined as follows:
(i) 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 is alkyl and R 213 , and R 214 are independently alkyl or aryl,
(ii) 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 alkyl or aryl; and
R 314 is alkyl or aryl, provided, R 314 is other than methyl, or
(iii) 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.
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 ;
R 212 is alkyl; and
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)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 alkyl or aryl; and
R 314 is alkyl or aryl, provided, R 314 is other than methyl.
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 ;
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 compound of claim 1 , wherein R 12 is alkyl, allyl, benzyl, or halo.
6. The compound of claim 1 , wherein R 213 , R 214 , R 313 , R 413 , and R 414 are independently methyl or phenyl.