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US 9,174,930 B2Granted
Preparation of sitagliptin intermediates
AssigneeLek Pharmaceuticals D.D.
InventorsMatej Sova, Zdenko Casar, Gaj Stavber
Life of this patent
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Abstract
The invention relates to the preparation of chiral compounds, in particular to the preparation of chiral compounds which may be used as intermediates for the preparation of anti-diabetic agents, preferably sitagliptin.
Claims20
A process for the preparation of an intermediate of formula I
- wherein the stereogenic center marked with an * is either in (R)- or(S)-configuration at marked center, or it is in racemic form, and
- wherein R4 and R5 are identical or different, and are independently selected from
- (i) hydrogen;
- (ii) alkyl residues optionally chiral, having from 1 to 12 carbon atoms, wherein the alkyl residues are optionally aryl and/or aryloxy substituted;
- (iii) alkyloxy residues optionally chiral, having from 1 to 12 carbon atoms, wherein the alkyloxy residues are optionally aryl substituted;
- (iv) aryl residues optionally chiral, having from 6 to 24 carbon atoms, wherein the aryl residues are optionally alkyl and/or alkyloxy substituted;
- (v) aryloxy residues optionally chiral, having from 6 to 24 carbon atoms, wherein the aryloxy residues are optionally alkyl substituted;
- (vi) benzyl;
- (vii) alkaloyl residues optionally chiral, having from 2 to 13 carbon atoms, wherein the alkaloyl residues are optionally aryl substituted;
- (viii) aroyl residues optionally chiral, having from 7 to 25 carbon atoms, wherein the aryloxy residues are optionally alkyl substituted;
- and
- (ix) alkoxycarbonyl residues optionally chiral, having from 2 to 13 carbon atoms;
- (x) aryloxycarbonyl residues optionally chiral, having from 7 to 25 carbon atoms;
- and
- (xi) tosyl;
- wherein R3 is selected from alkyl residues having from 1 to 6 carbon atoms;
- the process comprising the steps of:
- (a) providing an intermediate of formula II,
- (b) reacting the intermediate of formula II with a borating agent in a suitable solvent to obtain an intermediate of formula III,
- wherein the stereogenic center marked with an * is either in (R)- or (S)-configuration at marked center, or it is in racemic form, and
- wherein R1 and R2 are identical or different, and are selected from (i) alkyl or alkoxy residues, each having from 1 to 12 carbon atoms, wherein each alkyl or alkoxy residue is optionally aryl substituted,
- (ii) aryl or aryloxy residues, each having from 6 to 14 carbon atoms, wherein each aryl or aryloxy residue is optionally alkyl substituted;
- (iii) halides;
- and
- (iv)wherein R1 and R2 optionally form a chiral or non-chiral 5 to 10, membered mono or bicyclic ring, wherein the ring is optionally substituted at least one position with an alkyl residue having from 1 to 12 carbon atoms and/or an aryl residue having from 6 to 14 carbon atoms, and wherein R1 and R2 optionally form an O-benzenedioxy residue;
- and wherein R3 is same as above;
- (c) converting the intermediate of formula III to the intermediate of formula I.
24 more elements
An intermediate of formula I′, and the isomers, and the isomer mixtures thereof
- wherein the stereogenic center marked with an * is either in (R)- or (S)-configuration at marked center, or it is in racemic form and
- wherein R3 is selected from alkyl residues having from 1 to 6 carbon atoms;
- and
- R7 is selected from alkyl residues having from 1 to 6 carbon atoms and aryl residues, having from 6 to 24 carbon atoms optionally substituted with the proviso that R3 or R7 is not a methyl group.
1 more element
An intermediate of formula III, and the isomers, and the isomer mixtures thereof,
- wherein R1 and R2 are identical or different, and are selected from
- (i) alkyl or alkoxy residues, each having from 1 to 12 carbon atoms, wherein each alkyl or alkoxy residue is optionally aryl substituted;
- (ii) aryl or aryloxy residues, each having from 6 to 14 carbon atoms, wherein each aryl or aryloxy residue is optionally alkyl substituted;
- (iii) halides;
- and
- (iv) wherein R1 and R2 optionally form a chiral or non-chiral 5 to 10 membered mono or bicyclic ring, wherein the ring is optionally substituted at least one position with an alkyl residue having from 1 to 12 carbon atoms and/or an aryl residue having from 6 to 14 carbon atoms, and wherein R1 and R2 optionally from a O-benzenedioxy residue;
- and wherein R3 is selected from alkyl residues having from 1 to 6 carbon atoms.
4 more elements
A process for the preparation of an intermediate of formula II
- wherein R3 is selected from alkyl residues having from 1 to 6 carbon atoms;
- the process comprises the steps of:
- (a) providing an intermediate of formula V
- (b) reacting the intermediate of formula V, wherein X is selected from Cl, Br, and I, with a magnesium-containing Grignard compound, or with magnesium in the presence of an activating agent selected from iodine, methyl iodide, 1,2-dibromoethane, and any combination thereof;
- in a suitable solvent to obtain an intermediate of formula VI
- (c) reacting the intermediate of formula VI with a compound of formula VII
- wherein X is selected from Cl, Br, and I,
- wherein R3 is same as above;
- in a metal catalyzed cross-coupling process in a suitable solvent to obtain the intermediate of formula II.
6 more elements
Dependencies are inferred from the claim text.