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US 8,802,871 B2Granted
Methods and compounds useful in the synthesis of fused aminodihydrothiazine derivatives
AssigneeEisai R&D Management Co., Ltd.
InventorsBranko Mitasev, Dae-Shik Kim, Huiming Zhang, Matthew J. Schnaderbeck, Christopher N. Farthing
Life of this patent
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Abstract
Provided are compounds and methods useful for the preparation of compounds useful as inhibitors of beta-site amyloid precursor protein (APP)-cleaving enzyme.
Claims43
A compound of Formula II:
- wherein:
- R1 is C3-4alkyl, halo-C1-4alkyl, hydroxy-C1-4-alkyl, or —C1-4-alkyl-OR′,
- wherein R′ is an oxygen protecting group;
- and
- R2 and R3 are each independently hydrogen or halo;
- subject to the proviso that when one of R2 or R3 is ortho-fluoro and the other is hydrogen, R1 is not —CH2F;
- and
- when one of R2 or R3 is ortho-fluoro, the other is hydrogen, and R1 is —C1-4alkyl-OR′, then R′ is selected from the group consisting of methylthiomethyl, benzyloxymethyl, MPM (p-methoxybenzyloxymethyl), 2-(trimethylsilyl)ethyl), benzyl, para-methoxybenzyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, TBDMS (t-butyldimethylsilyl), tribenzylsilyl, TBDPS (t-butyldiphenyl silyl), 2-trimethylsilylprop-2-enyl, t-butyl, tetrahydropyranyl and allyl, or a salt thereof.
5 more elements
A method of making a stereochemically pure compound of Formula IIa:
- wherein:
- R1 is C1-4alkyl, halo-C1-4alkyl, hydroxy-C1-4alkyl, or —C1-4alkyl-OR′,
- wherein R′ is an oxygen protecting group;
- and
- R2 and R3 are each independently hydrogen or halo,
- or a salt thereof,
- said method comprising the steps of:
- (a) adding a mixture of stereoisomers of the compound of Formula II:
- wherein R1, R2 and R3 are as given above,
- to a solvent comprising a chiral carboxylic acid compound, to form a mixture of diastereomeric salts of the compound of Formula II;
- and then
- (b) crystallizing a single diastereomeric salt formed of the compound of Formula II, to make said stereochemically pure compound of Formula IIa, or a salt thereof.
9 more elements
A method of making a compound of Formula II
- wherein:
- R1 is C1-4alkyl;
- and
- R2 and R3 are each independently hydrogen or halo;
- or a salt thereof,
- comprising the steps of:
- (a) heating a mixture comprising:
- (i) a ketone of Formula B:
- wherein R1, R2 and R3 are as given above for Formula II;
- (ii) hydroxylamine or a salt thereof;
- (iii) a base;
- and
- (iv) a solvent selected from:
- water and an alcohol,
- to at least 90′Celsius produce a heated mixture,
- (b) cooling the heated mixture to a temperature of at or below 60′Celsius, and then,
- (c) adding an organic solvent, an acid, and zinc to the mixture, wherein said mixture is maintained at or below 60′Celsius during said adding,
- to make said compound of Formula II.
15 more elements
A compound of Formula III:
- wherein:
- R1 is C3-4alkyl, halo-C1-4alkyl, hydroxy-C1-4alkyl, or —C1-4alkyl-OR′,
- wherein R′ is an oxygen protecting group;
- and
- R2 and R3 are each independently hydrogen or halo;
- subject to the proviso that when one of R2 or R3 is ortho-fluoro, and the other is hydrogen, R1 is not —CH2F;
- and
- when one of R2 or R3 is ortho-fluoro, the other is hydrogen, and R1 is —C1-4alkyl-OR′, then R′ is selected from the group consisting of methylthiomethyl, benzyloxymethyl, MPM (p-methoxybenzyloxymethyl), 2-(trimethylsilyl)ethyl), benzyl, para-methoxybenzyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, TBDMS (t-butyldimethylsilyl), tribenzylsilyl, TBDPS (t-butyldiphenyl silyl), 2-trimethylsilylprop-2-enyl, t-butyl, tetrahydropyranyl and allyl,
- or a salt thereof.
6 more elements
Dependencies are inferred from the claim text.