Processes to produce brivaracetam
AssigneeESTEVE QUIMlCA S.A.
InventorsPeng WANG, Pixu LI, Qiang WEI, Yuanhua LIU
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Abstract
The present invention provides a scalable synthesis of enantiomerically pure brivaracetam, and related derivatives.
Claims31
A process for the preparation of the compound of formula XII from the compound of formula IV,
- wherein, R is saturated or unsaturated C1-20 alkyl or C1alkyl-unsubstituted or substituted aryl, comprising the steps of decarboxylation of the compound of formula IV
- to produce the compound of formula VI
- ring-opening of the compound of formula VI to produce the compound of formula VII
- wherein R1 is saturated or unsaturated C1-20 alkyl or C1alkyl-unsubstituted or substituted aryl;
- and X is Cl, Br, I, OMs, OTs, ONs;
- or
- the compound of formula X
- then converting VII or X by reacting with (S)-2-aminobutanamide or its salt or alkyl (S)-2-aminobutanoate to produce the compound of formula XII, or
- reacting the compound of formula VI with (S)-2-aminobutanamide or its salt to produce the compound of formula XII in one step;
- or reacting the compound of formula VI with alkyl (S)-2-aminobutanoate to produce XII-a
- wherein R in the compound of formula XII-a is a saturated or unsaturated C1-C20 alkoxyl ;
- and
- then converting XII-a to XII by aminolysis and amide formation reaction.
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A process for the preparation of VII from VI
- comprising the step of
- a) converting the compound of the formula VI to the compound of formula VII in the presence of a solvent and TMSI, TMSBr, HBr, HCl or HI;
- or
- b) ring-opening of the compound of the formula VI and hydrolysis under basic conditions in a solvent, followed by esterification and a reaction with sulfonyl chloride, wherein the sulfonyl chloride is selected from the group consisting of MsCl, TsCl, and NsCl, to obtain the compound of formula VII;
- wherein R1 is saturated or unsaturated C1-20 alkyl or C1alkyl-unsubstituted or substituted aryl;
- and X is Cl, Br, I, OMs, OTs, or ONs.
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A process for the preparation of brivaracetam XII from VII
- wherein R1 is saturated or unsaturated C1-20 alkyl or C1alkyl-unsubstituted or substituted aryl;
- and X is Cl, Br, I, OMs, OTs, ONs.
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A process for the preparation of the compound of formula X from the compound of formula VI
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A process of making the compound of formula XII (brivaracetam) from the compound of formula X
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A process for the preparation of brivaracetam, comprising the ring-closing reaction as follows:
- in the presence of a base, wherein R is NH2, C1-C20 alkoxyl;
- X is Cl, Br, I, OMs, OTs, or ONs;
- if R is NH2 and X is Cl then XI-b is XI, and if R is NH2 XII-a is XII.
A process for preparation of the compound of formula XII (brivaracetam), which comprises the steps of:
A process for preparation of the compound of formula XII (brivaracetam), which comprises the steps of:
A process for preparation of the compound of formula XII (brivaracetam), which comprises the step of reacting the compound of formula VI with (S)-2-aminobutanamide to produce the compound of formula XII (brivaracetam).
23-28. (canceled)
A compound of formula VII:
- wherein R1 is R1 is H or saturated or unsaturated C1-20 alkyl or C1alkyl-unsubstituted or substituted aryl , and X is Cl, Br, I, OMs, OTs, ONs, with the proviso that if R1 is H, X is not I.
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A compound of formula IX:
- wherein R1 is saturated or unsaturated C1-20 alkyl or C1alkyl-unsubstituted or substituted aryl.
A compound of formula X
A compound of formula XI-b:
- wherein R is NH2 or C1-C20 alkoxyl;
- and Xis Cl, Br, I, OMs, OTs, ONs.
A substantially pure compound VII:
- wherein R1 is H, and X is I.
Dependencies are inferred from the claim text.