Preparation of 3,4-Dihydroisoquinolines from an Acid and an Amine
AssigneeMallinckrodt Inc.
InventorsChristopher W. Grote, Peter X. Wang, Frank W. Moser, Gary L. Cantrell
Life of this patent
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Abstract
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, POCl3 that is necessary to form the 3,4-dihydroisoquinoline.
Claims21
1-41. (canceled)
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 POCl3, the 3,4-dihydroisoquinoline being produced under anhydrous conditions and without isolation or purification of reaction intermediates:
- wherein:
- R1 and R7 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, or —OR111;
- R2 is hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, or —OR211;
- R3 is hydrogen, hydrocarbyl, substituted hydrocarbyl, or —OR311;
- R4 is hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, or —OR411;
- R5 and R6 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, or —OR511;
- R12 is hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, or —OR121;
- R13 is hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, or —OR511;
- R111 is hydrogen, hydrocarbyl, or substituted hydrocarbyl;
- R211 is hydrogen, hydrocarbyl, —C(O)R212, —C(O)NHR213, —SO2R214;
- R212, R213, and R214 are independently hydrocarbyl or substituted hydrocarbyl;
- R311 is hydrogen, hydrocarbyl, —C(O)R312, —C(O)NHR313, or —SO2R314;
- R312, R313, and R314 are independently hydrocarbyl or substituted hydrocarbyl;
- R411 is hydrogen, hydrocarbyl, —C(O)R412, —C(O)NHR413, or —SO2R414;
- R412, R413, and R414 are independently hydrocarbyl or substituted hydrocarbyl;
- R511 is hydrogen, hydrocarbyl, or substituted hydrocarbyl;
- and
- R121 is hydrogen, hydrocarbyl, or substituted hydrocarbyl.
Dependencies are inferred from the claim text.