Method for the preparation of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1-6-naphthyridine-3-carboxamide and the purification thereof for use as an active pharmaceutical ingredient
AssigneeBayer Pharma Aktiengesellschaft
InventorJohannes Platzek
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Abstract
The present invention related to a novel and improved process for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula (I)
Claims30
A process for preparing a compound of the formula (I)
- comprising separating a racemic compound of the formula (XIII) into its enantiomers, wherein the compound of the formula (XIII)
- is prepared by reacting a compound of the formula (XVIII)
- with an orthoester (XX)
- where R may be H or methyl, wherein
- the compound of the formula (XVIII)
- is prepared by reacting compounds of the formula (XVI a,b)
- with a compound of the formula (IX)
- and wherein
- the compound of the formula (XVI a,b) is prepared by reacting a compound of the formula (VI)
- with a compound of the formula (XVII)
A process for preparing a compound of the formula (I)
- comprising separating a racemic compound of the formula (XIII) into its enantiomers, where the compound of the formula (XIII)
- is prepared by reacting a compound of the formula (XVIII)
- with an orthoester (XX)
- where R may be H or methyl, and wherein
- the compound of the formula (XVIII)
- is prepared by reacting compounds of the formula (XVI a,b)
- with a compound of the formula (IX)
A process for preparing a compound of the formula (I)
- comprising separating a racemic compound of the formula (XIII) into its enantiomers, where the compound of the formula (XIII)
- is prepared by reacting a compound of the formula (XVIII)
- with an orthoester (XX)
- where R may be H or methyl.
A process for preparing a compound of the formula (I)
- comprising using the compound of the formula (XVIII)
A process for preparing a compound of the formula (I)
- comprising using the compounds of the formula (XVI a,b)
A process for preparing a compound of the formula (I)
- comprising using a compound of the formula (XVIII)
- and
- compounds of the formula (XVI a,b)
A compound of the formula (XVIII)
- and the salts, solvates and solvates of the salts thereof.
A compound of the formula (XVI a,b) as an E/Z mixture
- and the salts, solvates and solvates of the salts thereof.
A process for preparing a compound of the formula (XVIII)
- comprising reacting compounds of the formula (XVI a,b)
- with a compound of the formula (IX)
A process for preparing compounds of the formula (XVI a,b)
- comprising reacting a compound of the formula (VI)
- with a compound of the formula (XVII)
A process for preparing a compound of the formula (XIII)
- comprising reacting a compound of the formula (XVIII)
- with an orthoester (XX)
- where R may be H or methyl.
A process for preparing a compound of the formula (XIII)
- comprising reacting a compound of the formula (XVIII)
- with an orthoester (XX)
- where R may be H or methyl, and wherein
- the compound of the formula (XVIII) is prepared by reacting compounds of the formula (XVI a,b)
- with a compound of the formula (IX)
A compound of the formula (I) in crystalline form of polymorph I
- wherein the x-ray diffractogram of the compound exhibits peak maxima of the 2 theta angle at 8.5, 14.1, and 19.0.
A compound of the formula (I) in crystalline form of polymorph I
- wherein the IR spectrum of the compound exhibits band maxima at 3475, 2230, 1681, 1658, 1606, 1572, 1485, 1255, 1136 and 1031 cm−1.
A compound of the formula (I) in crystalline form of polymorph I
- wherein the Raman spectrum of the compound exhibits band maxima at 3074, 2920, 2231, 1601, 1577, 1443, 1327, 1267, 827 and 155 cm−1.
A compound of the formula (I) in crystalline form of polymorph I
- prepared by a process comprising obtaining the compound of formula XIII
- separating the compound of formula XIII by chiral separation to obtain the compound of formula I,
- dissolving the compound of formula I in an inert solvent,
- stirring at a temperature of 20° C.-120° C. and
- isolating the compound of the formula (I) in crystalline form of polymorph I.
A compound of the formula (I) in crystalline form of polymorph I
- wherein the compound is isolated in crystalline form by a process comprising:
- filtering a solution of the compound of the formula (XIII)
- in a mixture of acetonitrile and methanol or a mixture of acetonitrile and ethanol;
- performing a solvent exchange with ethanol;
- concentrating the solution until the compound crystallizes;
- cooling the solution to 0° C.;
- and
- isolating the compound in crystalline form.
A compound of the formula (I) in crystalline form of polymorph I
- wherein the compound is crystallized from a solvent selected from the group consisting of methanol, ethanol, tetrahydrofuran, acetonitrile, and mixtures thereof with water.
Dependencies are inferred from the claim text.