Synthesis
AssigneeEisai Co., Ltd.
InventorsPiotr Graczyk, Afzal Khan, Gurpreet Bhatia
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Abstract
The present invention provides a novel substituted azaindoline intermediate of formula (I) and a method for its synthesis. The novel substitued azaindoline intermediate (I) is provided for use in the manufacture of 5-substituted 7-azaindolines and 5-substituted 7-azaindoles.
Claims36
A compound of formula (I)
- wherein X is R1S(O)2, (R1)3Si, R1C(O), R1OCH2, R12NSO2, R1OC(O)—, R1(R1O)CH—, R1CH2CH2—, R1CH2—, PhC(O)CH2—, CH2═CH—, ClCH2CH2—, Ph3C—, Ph2(4-pyridyl)C—, Me2N—, HO—CH2—, R1OCH2—, (R1)3SiOCH2—, (R1O)2CH—, t-BuOC(O)CH2—, Me2NCH2— and tetrahydropyranylamine;
- wherein R1 is C1-6 alkyl, C3-12 cycloalkyl, C1-6 haloalkyl, C6-12 heterocyclyl or C6-12 carbocyclyl;
- optionally substituted with one or more of C1-6 alkyl, Si(R3)3, OR3, NO2, CO2, CO2R3, halogen, haloalkyl, SR3, CN, NR3COR3, COR13CONR3R3,
- wherein R3 is hydrogen or C1-6 alkyl,
- with the proviso that when X is R1OC(O)—, R1 is not PhCH2.
A method for synthesising a compound of formula (I) comprising brominating a compound of formula (II);
- wherein X is (R1)3Si or R1OCH2, and R1 is C1-6 alkyl or C6-12 aryl.
A method for the production of a compound of formula (IV)
- comprising a metal-halogen exchange with a metal of formula M(R2)n, wherein each R2 is C1-6 alkyl, C6-12 aryl, C6-12 carbocyclyl, halogen, OH or a group OR20 wherein R20 is C1-6 alkyl or C6-12 aryl and wherein two or more R20 groups may together form a 4 to 7 membered ring, X is an amino-protecting group selected from R1S(O)2, (R1)3Si, R1C(O), R1OCH2, R12NSO2, R1OC(O)—, R1(R1O)CH—, R1CH2CH2—, R1CH2—, PhC(O)CH2—, CH2═CH—, ClCH2CH2—, Ph3C—, Ph2(4-pyridyl)C—, Me2N—, HO—CH2—, R1OCH2—, (R1)3SiOCH2—, (R1O)2CH—, t-BuOC(O)CH2—, Me2NCH2— and tetrahydropyranylamine;
- wherein R1 is C1-6 alkyl, C3-12 cycloalkyl, C1-6 haloalkyl, C6-12 heterocyclyl or C6-12 carbocyclyl;
- optionally substituted with one or more of C1-6 alkyl, Si(R3)3, OR3, NO2, CO2, CO2R3, halogen, haloalkyl, SR3, CN, NR3COR3, COR13CONR3R3,
- wherein R3 is hydrogen or C1-6 alkyl,
- n is 1, 2, 3 or 4, and M is Li, Sn, B, Mg, In, Cu, Zr or Pd.
A method of producing 7-azaindoline from 7-azaindole, comprising the reaction of 7-azaindole with a formic acid-triethylamine mixture in the presence of a palladium catalyst, followed by incubation with sodium or potassium hydroxide.
A compound selected from the group consisting of
Dependencies are inferred from the claim text.