IPC분류정보
국가/구분 |
United States(US) Patent
등록
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국제특허분류(IPC7판) |
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출원번호 |
US-0889484
(2010-09-24)
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등록번호 |
US-8431705
(2013-04-30)
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발명자
/ 주소 |
- Grote, Christopher W.
- Moser, Frank W.
- Wang, Peter X.
- Cantrell, Gary L.
- Berberich, David W.
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출원인 / 주소 |
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인용정보 |
피인용 횟수 :
2 인용 특허 :
3 |
초록
The present invention provides an efficient process for the preparation of hexahydroisoquinolines from amides. In particular, the invention provides a good yielding, one-pot process for the synthesis of hexahydroisoquinolines.
대표청구항
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1. A one-pot process for the preparation of a compound comprising Formula (IV), the process comprising: (a) contacting a compound comprising Formula (I) with POCl3 to form a compound comprising Formula (II);(b) contacting the compound comprising Formula (II) with an asymmetric catalyst and a hydroge
1. A one-pot process for the preparation of a compound comprising Formula (IV), the process comprising: (a) contacting a compound comprising Formula (I) with POCl3 to form a compound comprising Formula (II);(b) contacting the compound comprising Formula (II) with an asymmetric catalyst and a hydrogen donor comprising a formate ion to form a compound comprising Formula (III); and(c) contacting the compound comprising Formula (III) with an alkali metal and an electron source to form the compound comprising Formula (IV) according to the following reaction scheme: wherein: R1, R5, and R7 are independently chosen from hydrogen, hydrocarbyl, substituted hydrocarbyl, and —OR111;R2, R4, and R6 are independently chosen from hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, and —OR211;R3 is chosen from hydrogen, hydrocarbyl, substituted hydrocarbyl, and —OR211;R12 and R13 are independently chosen from hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, and —OR111;R111 is chosen from hydrogen, hydrocarbyl, and substituted hydrocarbyl;R211 is chosen from hydrogen, hydrocarbyl, —C(O)R212, —C(O)C(R212)3, —C(O)NHR212, and —SO2R212; andR212 is chosen from hydrocarbyl and substituted hydrocarbyl,and further wherein (i) the compound comprising Formula (II) is not isolated as a solid prior to step (b) and (ii) the compound comprising Formula (III) is not isolated as a solid prior to step (c). 2. The process of claim 1, wherein a compound comprising Formula (III′) is also formed during step (b): wherein: R1, R5, and R7 are independently chosen from hydrogen, hydrocarbyl, substituted hydrocarbyl, and —OR111;R2, R4, and R6 are independently chosen from hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, and —OR211;R3 is chosen from hydrogen, hydrocarbyl, substituted hydrocarbyl, and —OR211;R12 and R13 are independently chosen from hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, and —OR111;R111 is chosen from hydrogen, hydrocarbyl, and substituted hydrocarbyl;R211 is chosen from hydrogen, hydrocarbyl, —C(O)R212, —C(O)C(R212)3, —C(O)NHR212, and —SO2R212; andR212 is chosen from hydrocarbyl and substituted hydrocarbyl. 3. The process of claim 1, wherein a compound comprising Formula (IV′) is also formed during step (c): wherein: R1, R5, and R7 are independently chosen from hydrogen, hydrocarbyl, substituted hydrocarbyl, and —OR111;R2, R4, and R6 are independently chosen from hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, and —OR211;R3 is chosen from hydrogen, hydrocarbyl, substituted hydrocarbyl, and —OR211;R12 and R13 are independently chosen from hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, and —OR111;R111 is chosen from hydrogen, hydrocarbyl, and substituted hydrocarbyl;R211 is chosen from hydrogen, hydrocarbyl, —C(O)R212, —C(O)C(R212)3, —C(O)NHR212, and —SO2R212; andR212 is chosen from hydrocarbyl and substituted hydrocarbyl. 4. The process of claim 1, wherein: R3 is —OR211;R211 is chosen from hydrogen, alkyl, —C(O)R212, —C(O)C(R212)3, —C(O)NHR212, and —SO2R212; andR212 is chosen from alkyl and aryl. 5. The process of claim 1, wherein: R4 is —OR211;R211 is chosen from hydrogen, alkyl, —C(O)R212, —C(O)C(R212)3, —C(O)NHR212, and —SO2R212; andR212 is chosen from alkyl and aryl. 6. The process of claim 1, wherein: R6 is —OR211;R211 is chosen from hydrogen, alkyl, —C(O)R212, —C(O)C(R212)3, —C(O)NHR212, and —SO2R212; andR212 is chosen from alkyl and aryl. 7. The process of claim 1, wherein R1, R2, R5, R7, R12, and R13 are hydrogen; R3 and R6 are methoxy; R4 is chosen from hydroxyl, —OC(O)CH3, —C(O)C(CH3)3, —OC(O)Ph, and —OSO2CH3; R12 is chosen from alkyl, allyl, benzyl, and halo; and R212 is methyl. 8. The process of claim 1, wherein: R3, R4, and R6 are —OR211;R211 is chosen from hydrogen, alkyl, —C(O)R212, —C(O)C(R212)3, —C(O)NHR212, and —SO2R212; andR212 is chosen from alkyl and aryl. 9. The process of claim 1, wherein the molar ratio of the compound comprising Formula (I) to POCl3 is from about 1:0.5 to about 1:5. 10. The process of claim 1, wherein the asymmetric catalyst comprises a metal or a metal source and a chiral ligand. 11. The process of claim 10, wherein the metal or metal source is chosen from ruthenium, a ruthenium complex, osmium, an osmium complex, rhodium, a rhodium complex, iridium, an iridium complex, palladium, a palladium complex, platinum, a platinum complex, and combinations thereof; and the chiral ligand is a compound chosen from Formula 670, Formula 680, Formula 690, and Formula 700: wherein: R671, R672, R673, R681, R691, R692, R701, and R702 are independently alkyl or aryl; and R671, R672, and R673 are independently alkyl or aryl; andR691 and R692 of Formula 690 and R701 and R702 of Formula 700, and the carbon atoms to which they are attached, may optionally form a cyclic or bicyclic compound. 12. The process of claim 10, wherein the metal source is dichloro(p-cymene) ruthenium(II) dimer and the chiral ligand is (1S,2S)-(+)-N-4-tolylsulfonyl-1,2-diphenylethylene-1,2-diamine. 13. The process of claim 1, wherein the weight ratio of the asymmetric catalyst to the compound comprising Formula (II) is about 0.001:1 to about 0.1:1; the molar ratio of the compound comprising Formula (II) to the hydrogen donor is about 1:1 to about 1:20. 14. The process of claim 1, wherein the hydrogen donor is chosen from formic acid, a salt of formic acid, and a mixture of formic acid and an organic base. 15. The process of claim 1, wherein the hydrogen donor comprises formic acid and triethylamine. 16. The process of claim 1, wherein the alkali metal is chosen from lithium, sodium, and potassium; and the electron source is chosen from liquid ammonia, methylamine, ethylamine, ethylenediamine, and combinations thereof. 17. The process of claim 1, wherein the alkali metal is lithium and the electron source is liquid ammonia. 18. The process of claim 1, wherein the molar ratio of the compound comprising Formula (III) to the alkali metal is from about 1:2 to about 1:20; and the weight to volume ratio of the compound comprising Formula (III) to the electron source is from about 1:2 to about 1:50 (g/mL). 19. The process of claim 1, wherein steps (a) and (b) are conducted at a temperature from about 20° C. to about 100° C., and step (c) is conducted at a temperature from about −80° C. to about 10° C.; and the compound comprising Formula (IV) has a yield of at least about 60%. 20. The process of claim 1, wherein the molar ratio of the compound comprising Formula (I) to POCl3 is about 1:1; the asymmetric catalyst comprises dichloro(p-cymene) ruthenium(II) dimer and either (1S,2S)-(+)-N-4-tolylsulfonyl-1,2-diphenylethylene-1,2-diamine or (1R,2R)-(+)-N-4-tolylsulfonyl-1,2-diphenylethylene-1,2-diamine; the weight ratio of the asymmetric catalyst to the compound comprising Formula (II) is about 0.01:1; the hydrogen donor comprises formic acid and triethylamine; the molar ratio of the compound comprising Formula (II) to formic acid to triethylamine is from about 1:4:2 to about 1:6:3; the alkali metal is lithium and the electron source is liquid ammonia; the molar ratio of the compound comprising Formula (III) to lithium is from about 1:3 to about 1:10; the weight to volume ratio of the compound comprising Formula (III) to liquid ammonia is from about 1:3 to about 1:10 (g/mL); steps (a) and (b) are conducted at a temperature from about 22° C. to about 25° C.; step (c) is conducted at a temperature from about −70° C. to about −60° C.; and the compound comprising Formula (IV) has a yield of at least about 60%.
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