IPC분류정보
국가/구분 |
United States(US) Patent
등록
|
국제특허분류(IPC7판) |
|
출원번호 |
US-0518430
(2007-12-10)
|
등록번호 |
US-8242277
(2012-08-14)
|
국제출원번호 |
PCT/US2007/025262
(2007-12-10)
|
§371/§102 date |
20090610
(20090610)
|
국제공개번호 |
WO2008/073389
(2008-06-19)
|
발명자
/ 주소 |
- Cantrell, Gary L.
- Magparangalan, Dan P.
- Moser, Frank W.
- Bao, Jian
- Grote, Christopher W.
- Wang, Peter X.
|
출원인 / 주소 |
|
인용정보 |
피인용 횟수 :
0 인용 특허 :
3 |
초록
▼
The present invention is directed to processes for the synthesis of morphinans. In particular, a process for the asymmetric reduction of an imine moiety in a 3,4-dihydroisoquinoline to produce a tetrahydroisoquinoline, followed by a Birch reduction to produce a hexahydroisoquinoline. In various embo
The present invention is directed to processes for the synthesis of morphinans. In particular, a process for the asymmetric reduction of an imine moiety in a 3,4-dihydroisoquinoline to produce a tetrahydroisoquinoline, followed by a Birch reduction to produce a hexahydroisoquinoline. In various embodiments, the 3,4-dihydroisoquinoline contains a phenol moiety protected with a labile protecting group. In other embodiments, the imine reduction reaction mixture contains silver tetrafluoroborate.
대표청구항
▼
1. A process for the preparation of a 1,2,3,4-tetrahydroisoquinoline corresponding to Formula 700, the process comprising treating a 3,4-dihydroisoquinoline corresponding to Formula 600 with an asymmetric catalyst in the presence of silver tetrafluoroborate, and a hydrogen source wherein R1 and R7
1. A process for the preparation of a 1,2,3,4-tetrahydroisoquinoline corresponding to Formula 700, the process comprising treating a 3,4-dihydroisoquinoline corresponding to Formula 600 with an asymmetric catalyst in the presence of silver tetrafluoroborate, and a hydrogen source 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;R17 is hydrogen, or acyl;R111 is hydrogen, hydrocarbyl, or substituted hydrocarbyl;R211 is hydrogen, hydrocarbyl, —(O)R212, —(O)NHR213, or —SO2R214, R212, R213, and R214 are independently hydrocarbyl or substituted hydrocarbyl;R311 is hydrogen, hydrocarbyl, —(O)R312, —(O)NHR313, or —SO2R314, R312, R313, and R314 are independently hydrocarbyl or substituted hydrocarbyl;R411 is hydrogen, hydrocarbyl, —(O)R412, —(O)NHR413, or —SO2R414, R412, R413, and R414 are independently hydrocarbyl or substituted hydrocarbyl;R511 is hydrogen, hydrocarbyl, or substituted hydrocarbyl; andR121 is hydrogen, hydrocarbyl, or substituted hydrocarbyl. 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 alkyl or aryl. 3. The process of claim 1, wherein: R3 is —OR311;R311 is hydrogen, alkyl, —C(O)R312, —C(O)NHR313, or —SO2R314; andR312, R313, and R314 are independently alkyl or aryl. 4. The process of claim 1, wherein: R4 is —OR411;R411 is hydrogen, alkyl, —C(O)R412, —C(O)NHR413, or —SO2R414; andR412, R413, 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 R212, R213, R214, R312, R313, R314, R412, R413, and R414 are methyl. 7. The process of claim 1, wherein R3 is methoxy, R4 is hydroxyl, —OC(O)CH3, —OC(O)Ph, or —OSO2CH3, R6 is methoxy, and R1, R2, R5, R7, R12, and R13 are hydrogen. 8. The process of claim 1, wherein: R2 is —OR211;R211 is hydrogen, alkyl, —C(O)R212, —(O)NHR213, or —SO2R214;R212, R213, and R214 are independently alkyl or aryl;R3 is —OR311;R311 is hydrogen, alkyl, —C(O)R312, —(O)NHR313, or —SO2R314;R312, R313, and R314 are independently alkyl or aryl;R4 is —OR411;R411 is hydrogen, alkyl, —C(O)R412, —(O)NHR413, or —SO2R414; andR412, R413, and R414 are independently alkyl or aryl. 9. The process of claim 8, wherein R212, R213, R214, R312, R313, R314, R412, R413, and R414 are methyl; R3 is methoxy, R4 is hydroxyl, —OC(O)CH3, —OC(O)Ph, or —OSO2CH3, R6 is methoxy, and R1, R2, R5, R7, R12, and R13 are hydrogen. 10. The process of claim 1, wherein about 0.005 g to about 0.015 g of silver tetrafluoroborate per equivalent of 3,4-dihydroisoquinoline is used. 11. The process of claim 1, wherein the temperature of the reaction mixture is from about 20° C. to about 30° C. 12. The process of claim 1, wherein the asymmetric catalyst comprises a metal or a metal source and a chiral ligand. 13. The process of claim 12, wherein the metal or metal source is chosen from ruthenium, a ruthenium complex, osmium, an osmium complex, rhodium, a rhodium complex, iridium, iridium complex, and combinations thereof. 14. The process of claim 12, wherein the chiral ligand has the structure of formulae 670 or 680 wherein R671, R672, and R673 are independently alkyl or aryl;R681 is alkyl or aryl. 15. The process of claim 12, wherein the chiral ligand is (1S,2S)-(+)-N-4-tolylsulfonyl-1,2-diphenylethylene-1,2-diamine. 16. The process of claim 1, wherein the hydrogen source is a formic acid-triethylamine salt mixture. 17. The process of claim 16, wherein the ratio of formic acid to triethylamine is 5 to 2.
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