IPC분류정보
국가/구분 |
United States(US) Patent
등록
|
국제특허분류(IPC7판) |
|
출원번호 |
US-0699052
(2011-05-24)
|
등록번호 |
US-9428524
(2016-08-30)
|
우선권정보 |
EP-10382142 (2010-05-25) |
국제출원번호 |
PCT/EP2011/058466
(2011-05-24)
|
§371/§102 date |
20121120
(20121120)
|
국제공개번호 |
WO2011/147828
(2011-12-01)
|
발명자
/ 주소 |
- Martin López, Ma Jesús
- Francesch Solloso, Andrés
- Cuevas Marchante, Maria del Carmen
|
출원인 / 주소 |
|
대리인 / 주소 |
|
인용정보 |
피인용 횟수 :
0 인용 특허 :
26 |
초록
This invention relates to compounds of formula II: wherein R1, R2, ProtSH, and ProtNH are as defined, to processes for the synthesis of ecteinascidins of formula I from compounds of formula II, and to processes for the synthesis of compounds of formula II.
대표청구항
▼
1. A process comprising the step of reducing a quinone of formula II to form a hydroquinone, followed by alkylation of the resulting hydroquinone with a suitable electrophilic reagent to give a compound of formula IIa: whereinR1 is a protecting group for OH;R2 is selected from substituted or unsubst
1. A process comprising the step of reducing a quinone of formula II to form a hydroquinone, followed by alkylation of the resulting hydroquinone with a suitable electrophilic reagent to give a compound of formula IIa: whereinR1 is a protecting group for OH;R2 is selected from substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, substituted or unsubstituted C2-C12 alkynyl, C(═O)Ra, C(═O)ORb, C(═O)NRcRd, and a protecting group for amino;Ra is selected from hydrogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, substituted or unsubstituted C2-C12 alkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic group;Rb is independently selected from substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, substituted or unsubstituted C2-C12 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic group, and a protecting group for OH;Rc and Rd are independently selected from hydrogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, substituted or unsubstituted C2-C12 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic group, and a protecting group for amino;ProtNH is a protecting group for amino; andProtsH is a protecting group for SH. 2. A process according to claim 1, which further comprises the step of oxidising the compound of formula IIa to give a compound of formula IIb: 3. A process according to claim 2, which further comprises the step of forming a bridged ring system to provide a compound of formula Ia: 4. A process according to claim 1 wherein ProtSH is an S-9-fluorenylmethyl (Fm) group. 5. A process according to claim 3, which further comprises the step of deprotecting a compound of formula Ia to give a compound of formula Ib: 6. A process according to claim 1 wherein R1 is a methoxyethoxymethyl group and ProtNH is a t-butoxycarbonyl group. 7. A process according to claim 5, which further comprises the step of oxidising the α-aminolactone of formula Ib to the corresponding α-ketolactone of formula Id by transamination: wherein R3 is cyano. 8. A process according to claim 7, which further comprises the step of stereospecifically forming a spirotetrahydroisoquinoline compound of formula If from the α-ketolactone of formula Id by a Pictet-Spengler reaction with the following compound: whereinX1, and X2 are as independently selected from hydrogen and substituted or unsubstituted C1-C12 alkyl. 9. A process according to claim 8, which further comprises the step of replacement of the cyano group at R3 in the compound of formula If by a hydroxy group: 10. A process according to claim 8 wherein X1 and X2 are H. 11. A process according to claim 7, which further comprises the step of stereospecifically forming a spirotetrahydro-1H-pyrido[3,4-b]indole compound of formula Ie from the α-ketolactone of formula Id by a Pictet-Spengler reaction with the following compound: whereinY1 is selected from hydrogen, ORb, OC(═O)Ra, OC(═O)ORb, OC(═O)NRcRd, SRe, SORa, SO2Ra, C(═O)Ra, C(═O)ORb, C(═O)NRcRd, NO2, NRcRd, N(Rc)C(═O)Ra, N(Rc)—ORb, C(Ra)═NORb, N(Rc)C(═O)ORb, N(Rc)C(═O)NRcRd, CN, halogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, substituted or unsubstituted C2-C12 alkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic group;Y2, and Y3 are independently selected from hydrogen and substituted or unsubstituted C1-C12 alkyl; andRe is selected from hydrogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, substituted or unsubstituted C2-C12 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic group, and a protecting group for SH. 12. A process according to claim 11, which further comprises the step of replacement of the cyano group at R3 in the compound of formula Ie by a hydroxy group: 13. A process according to claim 11 wherein Y1 is hydrogen or methoxy, and Y2 and Y3 are hydrogen. 14. A process according to claim 1, wherein R2 is methyl. 15. A process according to claim 9 wherein the compound of formula If is ET-743: 16. A process according to claim 12, wherein the compound of formula Ie is: 17. A process according to claim 5, which further comprises the step of converting a compound of formula Ib into a compound of formula Ic by reaction with a compound of formula R8LG and a compound of formula R9LG: whereinR3 is cyano;R8 and R9 are independently selected from substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, substituted or unsubstituted C2-C12 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic group, and a protecting group for amino; andLG is a leaving group. 18. A process according to claim 17, which further comprises the step of replacement of the cyano group at R3 in the compound of formula Ic by a hydroxy group: 19. A process according to claim 7, which further comprises the step of reducing the α-ketolactone of formula Id to the corresponding α-hydroxylactone followed by reaction with a compound of formula R7LG to produce a compound of formula Ig: whereinR7 is selected from substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, substituted or unsubstituted C2-C12 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic group, and a protecting group for OH. 20. A process according to claim 19, which further comprises the step of replacement of the cyano group at R3 in the compound of formula Ig by a hydroxy group:
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