Preparation of amides from an acid and amine for intermediates in the synthesis of morphinans
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
C07C-231/02
C07C-233/05
출원번호
US-0481993
(2009-06-10)
등록번호
US-8461384
(2013-06-11)
발명자
/ 주소
Wang, Peter X.
Moser, Frank W.
Grote, Christopher W.
Cantrell, Gary L.
출원인 / 주소
Mallinckrodt LLC
인용정보
피인용 횟수 :
0인용 특허 :
3
초록▼
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
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.
대표청구항▼
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 correspon
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 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, or SO2R214;R212, R213, and R214 are independently hydrocarbyl or substituted hydrocarbyl;R311 is hydrogen, hydrocarbyl, —C(O)R312, —C(O)NHR313, or —SO2R314:R312 is alkyl or aryl, provided, R312 is other than methyl or phenyl;R313 is hydrocarbyl or substituted hydrocarbyl;R314 is alkyl or aryl, provided, R314 is other than methyl;R411 is hydrogen, hydrocarbyl, —C(O)R412, —C(O)NHR413, or —SO2R414;R412 is alkyl or aryl, provided, R412 is other than methyl or phenyl;R413 and R414 are independently hydrocarbyl or substituted hydrocarbyl;R511 is hydrogen, hydrocarbyl, or substituted hydrocarbyl; andR121 is hydrogen, hydrocarbyl, or substituted hydrocarbyl;wherein at least one of R2, R3, or R4 is —OC(O)R212, —OC(O)NHR213, —OSO2R214, —OC(O)R312, —OC(O)NHR313, —OSO2R314, —OC(O)R412, —OC(O)NHR413, or —OSO2R414. 2. The process of claim 1, wherein: R2 is —OR211;R211 is hydrogen, alkyl, —C(O)R212, —C(O)NHR213, or —SO2R214; andR212, R213, and R214 are independently hydrocarbyl or substituted hydrocarbyl. 3. The process of claim 1, wherein: R3 is —OR311;R311 is hydrogen, alkyl, —C(O)R312, —C(O)NHR313, or —SO2R314;R312 is alkyl or aryl, provided, R312 is other than methyl or phenyl;R313 is hydrocarbyl or substituted hydrocarbyl; andR314 is alkyl or aryl, provided, R314 is other than methyl. 4. The process of claim 1, wherein: R4 is —OR411;R411 is hydrogen, alkyl, —C(O)R412, —C(O)NHR413, or —SO2R414;R412 is alkyl or aryl, provided, R412 is other than methyl or phenyl; andR413 and R414 are independently alkyl or aryl. 5. The process of claim 1, wherein R12 is alkyl, allyl, benzyl, or halo. 6. The process of claim 1, wherein R3 is methoxy, R4 is hydroxyl, —OC(O)CH2CH3, or —OSO2CH3, R6 is methoxy, and R1, R2, R5, R7, R12, and R13 are hydrogen. 7. The process of claim 1, wherein: R2 is —OR211;R211 is hydrogen, alkyl, —C(O)R212, —C(O)NHR213, or —SO2R214;R212, R213, and R214 are independently hydrocarbyl or substituted hydrocarbyl;R3 is —OR311;R311 is hydrogen, alkyl, —C(O)R312, —C(O)NHR313, or —SO2R314;R312 is alkyl or aryl, provided, R312 is other than methyl or phenyl;R313 is hydrocarbyl or substituted hydrocarbyl;R314 is alkyl or aryl, provided, R314 is other than methyl;R4 is —OR411,R411 is hydrogen, alkyl, —C(O)R412, —C(O)NHR413, or —SO2R414;R412 is alkyl or aryl, provided, R412 is other than methyl or phenyl; andR413 and R414 are independently alkyl or aryl. 8. The process of claim 7, wherein R12 is alkyl, allyl, benzyl, or halo. 9. The process of claim 7, wherein R212, R213, R214, R313, R413, and R414 are methyl. 10. The process of claim 7, wherein R12 is alkyl, allyl, benzyl, or halo; and R212, R213, R214, R313, R413, and R414 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 R1 and R7 are hydrogen,R2 is hydrogen;R3 is methoxy;R4 is —OC(O)CH3 or—OSO2CH3;R5 is hydrogen;R6 is methoxy;R12 is hydrogen; andR13 is hydrogen.
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이 특허에 인용된 특허 (3)
Rice Kenner C. (Rockville MD), Practical total synthesis unnatural enantiomers of opium-derived morphinans.
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