Method for the preparation of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-l,4-dihydro-1-6-naphthyridine-3-carbox-amide and the purification thereof for use as an active pharmaceutical ingredient

Abstract

The present invention relates 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) ##STR00001##
and also the preparation and use of the crystalline polymorph I of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula (I).

Claims

1. A process for preparing a compound of formula (VI) ##STR00108## comprising reacting a compound of formula (XIV) or formula (XlVa) ##STR00109## with dimethyl sulphate to give a compound of formula (XV) or (XVa) ##STR00110## reducing the non-isolated methyl esters of the formula (XV) or (XVa) with 1.21 equivalents of REDAL (sodium bis(2-methoxyethoxy)aluminium dihydride) and 1.28 equivalents of N-methylpiperazine to give an aldehyde of formula (XVI) or (XVIa) ##STR00111## and reacting the aldehyde of formula (XVI) or (XVIa) without isolation to give the compound of formula (VI) ##STR00112##

2. A process for preparing compounds of formulae .[.(Villa+b).]. .Iadd.(VIIIa+b) .Iaddend. ##STR00113## comprising dissolving a compound of formula (VI) ##STR00114## in isopropanol .[.(3-7 fold).]. .Iadd.3-7 fold.Iaddend., 5-10 mol % of piperidine and 5-10 mol % of glacial acetic acid at 30° C. and reacting the dissolved compound of formula (VI) with a compound of formula (VII) ##STR00115## to give the compounds of formulae (VIII a+b) ##STR00116##

3. A process for preparing a compound of formula (XI) ##STR00117## comprising stirring a compound of formula (X) ##STR00118## with 2.5-5 equivalents of triethyl orthoacetate in dimethylacetamide at 100 to 120° C. for 1.5 to 3 hours to give the compound of formula (XI) ##STR00119##

4. A process for preparing a compound of formula (XII) ##STR00120## comprising saponifying a compound of formula (XI) ##STR00121## in a THF/water mixture .[.(2:1, 9-fold).]. .Iadd.2:1, 9-fold, .Iaddend.with aqueous sodium hydroxide solution to give the compound of formula (XII) ##STR00122##

5. A process for preparing a compound of formula (XIII) ##STR00123## comprising reacting a compound of formula (XII) ##STR00124## in a one-pot reaction in THF by first admixing with carbodiimidazole and catalytic amounts of 4-(dimethylamino)pyridine to form an admixture, heating the admixture under reflux together with hexamethyldisilazane for 16 to 24 hours and then in a third step hydrolysing in water with THF or water to give the compound of formula (XIII) ##STR00125##

6. A process for preparing compounds of formulae (VIII a+b): ##STR00126## comprising preparing the compound of formula (VI) ##STR00127## according to the process of claim 1, dissolving the compound of formula (VI) in isopropanol .[.(3-7 fold).]..Iadd., 3-7 fold.Iaddend., 5-10 mol % of piperidine and 5-10 mol % of glacial acetic acid at 30° C. and reacting the dissolved compound of formula (VI) with a compound of formula (VII) ##STR00128## to give the compounds of formulae (VIII a+b): ##STR00129##

7. A process for preparing a compound of formula (XI) ##STR00130## comprising preparing the compounds of formulae (VIII a+b) according to claim 2, reacting the compounds of formulae (VIII a+b) with a compound of formula (IX) ##STR00131## to give a compound of formula (X) ##STR00132## stirring the compound of formula (X) with 2.5-5 eq of triethyl orthoacetate in dimethylacetamide at 100 to 120° C. for 1.5 to 3 hours to give the compound of the formula (XI) ##STR00133##

8. A process for preparing a compound of formula (XII) ##STR00134## comprising preparing the compound of formula (XI) according to claim 3, saponifying the compound of formula (XI) in a THF/water mixture .[.(2:1, 9-fold).]. .Iadd.2:1, 9-fold, .Iaddend.with aqueous sodium hydroxide solution to give the compound of formula (XII) ##STR00135##

9. A process for preparing a compound of formula (XIII) ##STR00136## comprising preparing the compound of formula (XII) ##STR00137## according to the process of claim 4, reacting the compound of formula (XII) in a one-pot reaction in THF by first admixing with carbodiimidazole and catalytic amounts of 4-(dimethylamino)pyridine to form an admixture, heating the admixture under reflux together with hexamethyldisilazane for 16 to 24 hours and then in a third step hydrolysing in water with THF or water to give the compound of formula (XIII) ##STR00138##

10. A process for preparing a compound of formula (XI) ##STR00139## comprising preparing compounds of formulae (VIII a+b) ##STR00140## according to the process of claim 6 reacting the compounds of formulae (VIII a+b) with a compound of formula (IX) ##STR00141## to give a compound of formula (X) ##STR00142## stirring the compound of formula (X) with 2.5-5 eq of triethyl orthoacetate in dimethylacetamide at 100 to 120° C. for 1.5 to 3 hours to give a compound of formula (XI) ##STR00143##

11. A process for preparing the compound of formula (XII) ##STR00144## comprising preparing the compound of formula (XI) according to claim 7, and saponifying the compound of formula (XI) in a THF/water mixture .[.(2:1, 9-fold).]. .Iadd.2:1, 9-fold, .Iaddend.with aqueous sodium hydroxide solution to give the compound of formula (XII) ##STR00145##

12. A process for preparing a compound of formula (XIII) ##STR00146## comprising preparing the compound of formula (XII) ##STR00147## according to the process of claim 8, reacting the compound of formula (XII) in a one-pot reaction in THF by first admixing with carbodiimidazole and catalytic amounts of 4-(dimethylamino)pyridine to form an admixture, heating the admixture under reflux together with hexamethyldisilazane for 16 to 24 hours and then in a third step hydrolysing in water with THF or water to give the compound of formula (XIII) ##STR00148##

13. A process for preparing a compound of formula (XII) ##STR00149## comprising preparing the compound of formula (XI) ##STR00150## according to the process of claim 10, saponifying the compound of formula (XI) in a THF/water mixture .[.(2:1, 9-fold).]. .Iadd.2:1, 9-fold, .Iaddend.with aqueous sodium hydroxide solution to give a compound of formula (XII) ##STR00151##

14. A process for preparing a compound of formula (XIII) ##STR00152## comprising preparing the compound of formula (XII) ##STR00153## according to the process of claim 11, reacting the compound of formula (XII) in a one-pot reaction in THF by first admixing with carbodiimidazole and catalytic amounts of 4-(dimethylamino)pyridine to form an admixture, heating the admixture under reflux together with hexamethyldisilazane for 16 to 24 hours and then in a third step hydrolysing in water with THF or water to give the compound of formula (XIII) ##STR00154##

15. A process for preparing a compound of formula (XIII) ##STR00155## comprising preparing the compound of formula (XII) ##STR00156## according to the process of claim 13, reacting the compound of formula (XII) in a one-pot reaction in THF by first admixing with carbodiimidazole and catalytic amounts of 4-(dimethylamino)pyridine to form an admixture, heating the admixture under reflux together with hexamethyldisilazane for 16 to 24 hours and then in a third step hydrolysing in water with THF or water to give the compound of formula (XIII) ##STR00157##

16. A process for preparing a compound of formula (I) ##STR00158## comprising preparing the compound of formula (XIII) in a mixture of enantiomers according to the process of claim 5 and isolating the compound of formula (I) from the mixture.

17. A process for preparing a compound of formula (I) ##STR00159## comprising preparing the compound of formula (XIII) in a mixture of enantiomers according to the process of claim 9 and isolating the compound of formula (I) from the mixture.

18. A process for preparing a compound of formula (I) ##STR00160## comprising preparing the compound of formula (XIII) in a mixture of enantiomers according to the process of claim 12 and isolating the compound of formula (I) from the mixture.

19. A process for preparing a compound of formula (I) ##STR00161## comprising preparing the compound of formula (XIII) in a mixture of enantiomers according to the process of claim 14 and isolating the compound of formula (I) from the mixture.

20. A process for preparing a compound of formula (I) ##STR00162## comprising preparing the compound of formula (XIII) in a mixture of enantiomers according to the process of claim 15 and isolating the compound of formula (I) from the mixture.

21. The process of claim 17, wherein the isolated compound of the formula (I) is present in one or more polymorphs or as a solvate in an inert solvent, further comprising stirring the inert solvent containing the isolated compound of formula (I) at a temperature of 20° C.-120° C. and isolating the compound of the formula (I) as crystalline polymorph I.

22. The process of claim 18, wherein the isolated compound of the formula (I) is present in one or more polymorphs or as a solvate in an inert solvent, further comprising stirring the inert solvent containing the isolated compound of formula (I) at a temperature of 20° C.-120° C. and isolating the compound of the formula (I) as crystalline polymorph I.

23. The process of claim 19, wherein the isolated compound of the formula (I) is present in one or more polymorphs or as a solvate in an inert solvent, further comprising stirring the inert solvent containing the isolated compound of formula (I) at a temperature of 20° C.-120° C. and isolating the compound of the formula (I) as crystalline polymorph I.

24. The process of claim 20, wherein the isolated compound of the formula (I) is present in one or more polymorphs or as a solvate in an inert solvent, further comprising stirring the inert solvent containing the isolated compound of formula (I) at a temperature of 20° C.-120° C. and isolating the compound of the formula (I) as crystalline polymorph I.

Description

EXAMPLES

Example 1

Methyl 4-bromo-2-methoxybenzoate (XV)

(1) 3.06 kg (22.12 mol) of potassium carbonate are initially charged in 3.6 l of acetone and heated to reflux. To this suspension are added 1.2 kg of 4-bromo-2-hydroxybenzoic acid (5.53 mol), suspended in 7.8 l of acetone and is further rinsed with 0.6 l of acetone. The suspension is heated under reflux for 1 hour (vigorous evolution of gas!). 2.65 kg (21.01 mol) of dimethyl sulphate are then added over 4 hours while boiling. The mixture is subsequently stirred under reflux for 2.5 hours. The solvent is largely distilled off (to the point of stirrability) and 12 l of toluene are added and the residual acetone is then distilled off at 110° C. About 3 l of distillate are distilled off, this being supplemented by addition of a further 3 l of toluene to the mixture. The mixture is allowed to cool to 20° C. and 10.8 l of water are added and vigorously stirred in. The organic phase is separated off and the aqueous phase is extracted once more with 6.1 l of toluene. The combined organic phases are washed with 3 l of saturated sodium chloride solution and the toluene phase is concentrated to ca. 4 l. Determination of the content by evaporation of a portion results in a converted yield of 1.306 kg (96.4% of theory). The solution is used directly in the subsequent stage.

(2) HPLC method A: RT ca. 11.9 min.

(3) MS (EIpos): m/z=245 [M+H].sup.+

(4) .sup.1H NMR (400 MHz, CD.sub.2Cl.sub.2): δ=3.84 (s, 3H), 3.90 (s, 3H), 7.12-7.20 (m, 2H), 7.62 (d, 1H).

Example 2

4-Bromo-2-methoxybenzaldehyde (XVI)

(5) 1.936 kg (6.22 mol) of a 65% Red-A1 solution in toluene is charged with 1.25 l of toluene at −5° C. To this solution is added 0.66 kg (6.59 mol) of 1-methylpiperazine, which is rinsed with 150 ml of toluene, keeping the temperature between −7 and −5° C. The mixture is then allowed to stir at 0° C. for 30 minutes. This solution is then added to a solution of 1.261 kg (5.147 mol) of methyl 4-bromo-2-methoxybenzoate (XV), dissolved in 4 l of toluene, keeping the temperature at −8 to 0° C. After further rinsing twice with 0.7 l of toluene, the mixture is then stirred at 0° C. for 1.5 hours. For the work-up, the solution is added to cold aqueous sulphuric acid at 0° C. (12.5 l of water+1.4 kg of conc. sulphuric acid). The temperature should increase at maximum to 10° C. (slow addition). The pH is adjusted to pH 1, if necessary, by addition of further sulphuric acid. The organic phase is separated off and the aqueous phase is extracted with 7.61 of toluene. The combined organic phases are washed with 5.1 l of water and then substantially concentrated and the residue taken up in 10 l of DMF. The solution is again concentrated to a volume of ca. 5 l. Determination of the content by evaporation of a portion results in a converted yield of 1.041 kg (94.1% of theory). The solution is used directly in the subsequent stage.

(6) HPLC method A: RT ca. 12.1 min.

(7) MS (EIpos): m/z=162 [M+H].sup.+

(8) .sup.1H-NMR (CDC.sub.3, 400 MHz): δ=3.93 (3H, s), 7.17 (2H, m), 7.68 (1H, d), 10.40 (1H, s)

Example 3

4-Formyl-3-methoxybenzonitrile (VI)

(9) 719 g (3.34 mol) of 4-bromo-2-methoxybenzaldehyde (XVI) as a solution in 4.5 l of DMF are charged with 313 g (0.74 mol) of potassium hexacyanoferrate (K.sub.4[Fe(CN).sub.6]) and 354 g (3.34 mol) of sodium carbonate and a further 1.2 l of DMF and 3.8 g (0.017 mol) of palladium acetate are added. The mixture is stirred at 120° C. for 3 hours. The mixture is allowed to cool to 20° C. and 5.7 l of water is added to the mixture. The mixture is extracted with 17 l of ethyl acetate and the aqueous phase washed once more with 17 l of ethyl acetate. The organic phases are combined and substantially concentrated, taken up in 5 l of isopropanol and concentrated to ca. 2 l. The mixture is heated to boiling and 2 l of water added dropwise. The mixture is allowed to cool to 50° C. and 2 l of water added anew. The mixture is cooled to 3° C. and stirred at this temperature for one hour. The product is filtered off and washed with water (2 times 1.2 l). The product is dried at 40° C. under vacuum.

(10) Yield: 469 g (87% of theory) of a beige solid.

(11) HPLC method A: RT ca. 8.3 min.

(12) MS (EIpos): m/z=162 [M+H]+

(13) 1H-NMR (300 MHz, DMSO-d6): δ=3.98 (s, 3H), 7.53 (d, 1H), 7.80 (s, 1H), 7.81 (d, 1H), 10.37 (s, 1H).

Example 4

2-Cyanoethyl 4-(4-cyano-2-methoxyphenol)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridin-3-carboxylate (X)

(14) Variant A

(15) 1.035 kg (6.422 mol) of 4-formyl-3-methoxybenzonitrile (VI), 1.246 kg (8.028 mol) of 2-cyanoethyl 3-oxobutanoate, 54.6 g (0.642 mol) of piperidine and 38.5 g (0.642 mol) of glacial acetic acid are heated under reflux in 10 l of dichloromethane for 6.5 hours on a water separator. The mixture is allowed to cool to room temperature and the organic phase is washed twice with 5 l of water each time. The dichloromethane phase is then concentrated at atmospheric pressure and the still stirrable residue is taken up in 15.47 kg of 2-butanol and 0.717 kg (5.78 mol) of 4-amino-5-methylpyridone is added. The residual dichloromethane is distilled off until an internal temperature of 98° C. is reached. The mixture is subsequently heated under reflux for 20 hours. The mixture is cooled to 0° C., allowed to stir at this temperature for 4 hours and the product is filtered off. The product is dried at 40° C. under vacuum under entraining gas.

(16) Yield: 2.049 kg (87.6% of theory based on 4-amino-5-methylpyridone, since this component is used substoichiometrically) of a pale yellow solid.

(17) HPLC method A: RT ca. 9.7 min.

(18) MS (EIpos): m/z=405 [M+H].sup.+

(19) .sup.1H-NMR (300 MHz, DMSO-d.sub.6): δ=2.03 (s, 3H), 2.35 (s, 3H), 2.80 (m, 2H), 3.74 (s, 3H), 4.04 (m, 1H), 4.11 (m, 1H), 5.20 (s, 1H), 6.95 (s, 1H), 7.23 (dd, 1H), 7.28-7.33 (m, 2H), 8.18 (s, 1H), 10.76 (s, 1H).

(20) Variant B

(21) 1.344 kg (8.34 mol) of 4-formyl-3-methoxybenzonitrile (VI), 71 g (0.834 mol) of piperidine and 50.1 g (0.834 mol) of glacial acetic acid are charged in 6 l of isopropanol and at 30° C. a solution of 1.747 kg (11.26 mol) of 2-cyanoethyl 3-oxobutanoate in 670 ml of isopropanol is added over 3 hours. The mixture is then stirred at 30° C. for one hour. The mixture is cooled to 0-3° C. and stirred for 0.5 hours. The product is filtered off and washed twice with 450 ml of cold isopropanol each time. To determine the yield, the product is dried at 50° C. under vacuum (2.413 kg, 97% of theory); however, due to the high yield, the isopropanol-moist product is generally further processed directly. For this purpose, the product is taken up in 29 l of isopropanol and 1.277 kg (7.92 mol) of 4-amino-5-methylpyridone are added and then the mixture is heated to an internal temperature of 100° C. under a positive pressure of ca. 1.4 bar for 24 h in a closed vessel. The mixture is then cooled to 0° C. by means of a gradient over a period of 5 h and then stirred at 0° C. for 3 hours. The product is then filtered off and washed with 2.1 l of cold isopropanol. The product is dried at 60° C. under vacuum.

(22) Yield: 2.819 kg (88% of theory based on 4-amino-5-methylpyridone, since this component is used substoichiometrically) of a pale yellow solid.

(23) HPLC method A: RT ca. 9.7 min.

(24) MS (EIpos): m/z=405 [M+H].sup.+

(25) .sup.1H-NMR (300 MHz, DMSO-d.sub.6): δ=2.03 (s, 3H), 2.35 (s, 3H), 2.80 (m, 2H), 3.74 (s, 3H), 4.04 (m, 1H), 4.11 (m, 1H), 5.20 (s, 1H), 6.95 (s, 1H), 7.23 (dd, 1H), 7.28-7.33 (m, 2H), 8.18 (s, 1H), 10.76 (s, 1H).

Example 5

2-Cyanoethyl 4-(4-cyano-2-methoxyphenol)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (XI)

(26) 2.142 kg (5.3 mol) of 2-cyanoethyl 4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylate (X) and 4.70 kg (29 mol) of triethyl orthoacetate are dissolved in 12.15 l of dimethylacetamide and 157.5 g of concentrated sulphuric acid are added. The mixture is heated at 115° C. for 1.5 hours and then cooled to 50° C. At 50° C., 12.15 l of water are added dropwise over 30 minutes. After completion of the addition, the mixture is seeded with 10 g of the title compound (XI) and a further 12.15 l of water are added dropwise over 30 minutes at 50° C. The mixture is cooled to 0° C. (gradient, 2 hours) and stirred at 0° C. for two hours. The product is filtered off, washed twice with 7.7 l each time of water and dried at 50° C. under vacuum.

(27) Yield: 2114.2 g (92.2% of theory) of a pale yellow solid.

(28) HPLC method B: RT ca. 10.2 min.

(29) MS (EIpos): m/z=433 [M+H].sup.+

(30) .sup.1H-NMR (300 MHz, DMSO-d.sub.6): δ=1.11 (t, 3H), 2.16 (s, 3H), 2.42 (s, 3H), 2.78 (m, 2H), 3.77 (s, 3H), 4.01-4.13 (m, 4H), 5.37 (s, 1H), 7.25 (d, 1H), 7.28-7.33 (m, 2H), 7.60 (s, 1H), 8.35 (s, 1H).

(31) Alternatively, the reaction may be carried out in NMP (1-methyl-2-pyrrolidone)

2-Cyanoethyl 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (XI)

(32) 2.142 kg (5.3 mol) of 2-cyanoethyl 4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylate (X) and 2.35 kg (14.5 mol) of triethyl orthoacetate are dissolved in 3.21 kg of NMP (1-methyl-2-pyrrolidone) and 157.5 g of concentrated sulphuric acid are added. The mixture is heated at 115° C. for 1.5 hours and then cooled to 50° C. At 50° C., 2.2 l of water are added dropwise over 30 minutes. After completion of the addition, the mixture is seeded with 10 g of the title compound (XI) and a further 4.4 l of water are added dropwise over 30 minutes at 50° C. The mixture is cooled to 0° C. (gradient, 2 hours) and then stirred at 0° C. for two hours. The product is filtered off, washed twice with 4 l each time of water and dried at 50° C. under vacuum.

(33) Yield: 2180.7 g (95.1% of theory) of a pale yellow solid.

(34) HPLC method B: RT ca. 10.2 min.

Example 6

4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (XII)

(35) 2.00 kg (4.624 mol) of 2-cyanoethyl 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (XI) are dissolved in a mixture of 12 l of THF and 6 l of water and cooled to 0° C. To this solution at 0° C. is added dropwise over 15 minutes an aqueous sodium hydroxide solution (prepared from 0.82 kg of 45% aq. NaOH (9.248 mol) and 4.23 l of water and the mixture is then stirred at 0° C. for 1.5 hours. The mixture is extracted twice with 4.8 l of methyl tert-butyl ether each time and once with 4.8 l of ethyl acetate. The aqueous solution at 0° C. is adjusted to pH 7 with dilute hydrochloric acid (prepared from 0.371 kg of 37% HCl and 1.51 l of water). The solution is allowed to warm to 20° C. and an aqueous solution of 2.05 kg of ammonium chloride in 5.54 l of water is added. The solution is stirred at 20° C. for 1 hour, the product filtered and washed twice with 1.5 l of water each time and once with 4 l of acetonitrile. The product is dried at 40° C. under entraining gas.

(36) Yield: 1736.9 g (99% of theory) of an almost colourless powder (very light yellow tint).

(37) HPLC method C: RT: ca. 6.8 min.

(38) MS (EIpos): m/z=380 [M+H].sup.+

(39) .sup.1H-NMR (300 MHz, DMSO-d.sub.6): δ=1.14 (t, 3H), 2.14 (s, 3H), 2.37 (s, 3H), 3.73 (s, 3H), 4.04 (m, 2H), 5.33 (s, 1H), 7.26 (m, 2H), 7.32 (s, 1H), 7.57 (s, 1H), 8.16 (s, 1H), 11.43 (br. s, 1H).

(40) Alternative work-up using toluene for the extraction:

4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (XII)

(41) 2.00 kg (4.624 mol) of 2-cyanoethyl 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (XI) are dissolved in a mixture of 12 l of THF and 6 l of water and cooled to 0° C. To this solution at 0° C. is added dropwise over 15 minutes an aqueous sodium hydroxide solution (prepared from 0.82 kg of 45% aq. NaOH (9.248 mol) and 4.23 l of water and the mixture is then stirred at 0° C. for 1.5 hours. 5 L of toluene and 381.3 g of sodium acetate are added and stirred in vigorously. The phases are allowed to settle and the organic phase is separated. The aqueous phase is adjusted to pH 6.9 with 10% hydrochloric acid (at ca. pH 9.5 the solution is seeded with 10 g of the title compound). After precipitation of the product is complete, the mixture is stirred at 0° C. for one hour and is then filtered and washed twice with 4 l of water each time and twice with 153 ml of toluene each time. The product is dried at 40° C. under vacuum under entraining gas (nitrogen, 200 mbar. Yield: 1719.5 g (98% of theory) of an almost colourless powder (very slight yellow tint).

(42) HPLC method C: RT: ca. 6.8 min.)

Example 7

4-(4-Cyano-2-methoxyphenol)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (XIII)

(43) 1.60 kg (4.22 mol) of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (XII) and 958 g (5.91 mol) of 1,1-carbodiimidazole are charged in 8 l of THF and 51 g (0.417 mol) of DMAP is added at 20° C. The mixture is stirred at 20° C. (evolution of gas!) for one hour and then heated to 50° C. for 2.5 hours. 2.973 kg (18.42 mol) of hexamethyldisilazane is added to this solution and is boiled under reflux for 22 hours. A further 1.8 l of THF is added and the mixture cooled to 5° C. A mixture of 1.17 l of THF and 835 g of water is added over 3 hours such that the temperature remains between 5 and 20° C. The mixture is subsequently boiled under relux for one hour, then cooled via a gradient (3 hours) to 0° C. and stirred at this temperature for one hour. The product is filtered off and washed twice with 2.4 l of THF each time and twice with 3.2 l of water each time. The product is dried at 70° C. under vacuum under entraining gas.

(44) Yield: 1.501 kg (94% of theory) of an almost colourless powder (very slight yellow tint).

(45) HPLC method B: RT ca. 6.7 min.

(46) MS (EIpos): m/z=379 [M+H].sup.+

(47) .sup.1H-NMR (300 MHz, DMSO-d.sub.6): δ=1.05 (t, 3H), 2.12 (s, 3H), 2.18 (s, 3H), 3.82 (s, 3H), 3.99-4.07 (m, 2H), 5.37 (s, 1H), 6.60-6.84 (m, 2H), 7.14 (d, 1H), 7.28 (dd, 1H), 7.37 (d, 1H), 7.55 (s, 1H), 7.69 (s, 1H).

Example 8

(4S)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (I) as a solution in acetonitrile/methanol 40:60

(48) Enantiomer Separation on an SMB System

(49) The feed solution is a solution corresponding to a concentration consisting of 50 g of racemic 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (XIII), dissolved in 1 liter of a mixture of methanol/acetonitrile 60:40.

(50) The solution is chromatographed by means of an SMB system on a stationary phase: Chiralpak AS-V, 20 μm. The pressure is 30 bar and a mixture of methanol/acetonitrile 60:40 is used as eluent.

(51) 9.00 kg of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (XII) are dissolved in 180 l of a mixture consisting of methanol/acetonitrile 60:40 and chromatographed by means of SMB. After concentrating the product-containing fractions, 69.68 liters of a 6.2% solution (corresponding to 4.32 kg of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (I) is obtained as a solution in acetonitrile/methanol 40:60).

(52) Yield: 4.32 kg (48% of theory), as a colourless fraction dissolved in 69.68 liters of acetonitrile/methanol 40:60.

(53) Enantiomeric purity: >98.5% e.e. (HPLC, method D)

(54) A sample is concentrated under vacuum and gives: MS (EIpos): m/z=379 [M+H].sup.+

(55) .sup.1H-NMR (300 MHz, DMSO-d.sub.6): δ=1.05 (t, 3H), 2.12 (s, 3H), 2.18 (s, 3H), 3.82 (s, 3H), 3.99-4.07 (m, 2H), 5.37 (s, 1H), 6.60-6.84 (m, 2H), 7.14 (d, 1H), 7.28 (dd, 1H), 7.37 (d, 1H), 7.55 (s, 1H), 7.69 (s, 1H).

Example 9

(4S)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthridine-3-carboxamide (I)

(56) Crystallization and Polymorph Adjustment

(57) 64.52 liters of a 6.2% solution from Example 8 in a mixture of acetonitrile/methanol 40:60 (corresponding to 4.00 kg of compound 1) were filtered through a filter cartridge (1.2 um) and subsequently sufficiently concentrated at 250 mbar such that the solution is still stirrable. 48 l of ethanol, denatured with toluene, was added and distilled again at 250 mbar up to the limit of stirrability (redistillation in ethanol). A further 48 l of ethanol, denatured with toluene, was added and then distilled off at atmospheric pressure down to a total volume of ca. 14 l (jacket temperature 98° C.). The mixture was cooled via a gradient (4 hours) to 0° C., stirred at 0° C. for 2 hours and the product filtered off. The product was washed twice with 4 l of cold ethanol each time and then dried at 50° C. under vacuum.

(58) Yield: 3.64 kg (91% of theory) of a colourless crystalline powder.

(59) Enantiomeric purity: >>99% e.e. (HPLC method D); Retention times/RRT: (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-16-naphthyridine-3-carboxamide (1) ca. 11 min. RRT: 1.00; (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (I) ca. 9 min. RRT: 0.82

(60) Purity: >99.8% (HPLC method B), RT: ca. 6.7 min.

(61) Content: 99.9% (relative to external standard)

(62) specific rotation (chloroform, 589 nm, 19.7° C., c=0.38600 g/100 ml): −148.8°.

(63) MS (EIpos): m/z=379 [M+H].sup.+

(64) .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ=1.05 (t, 3H), 2.12 (s, 3H), 2.18 (s, 3H), 3.82 (s, 3H), 3.99-4.07 (m, 2H), 5.37 (s, 1H), 6.60-6.84 (m, 2H), 7.14 (d, 1H), 7.28 (dd, 1H), 7.37 (d, 1H), 7.55 (s, 1H), 7.69 (s, 1H).

(65) Melting point: 252° C. (compound of the formula (I) in crystalline form of polymorph I)

(66) Physicochemical Characterization of Compound of the Formula (I) in Crystalline Form of Polymorph I

(67) Compound of the formula (I) in crystalline form of polymorph I melts at 252° C., ΔH=95-113 Jg.sup.−1 (heating rate 20 Kmin.sup.−1, FIG. 1).

(68) A depression of the melting point was observed depending on the heating rate.

(69) The melting point decreases at a lower heating rate (e.g. 2 Kmin.sup.−1) since decomposition occurs.

(70) No other phase transitions were observed. A loss of mass of ca. 0.1% was observed up to a temperature of 175° C.

(71) Stability and Moisture Absorption

(72) Samples of compound of the formula (I) in crystalline form of polymorph I were stored at 85% and 97% rel. humidity (25° C.). The samples were evaluated after 12 months by DSC, TGA and XRPD. After 12 months, a mass change of <0.1% is observed in both cases. This means that compound of the formula (I) in crystalline form of polymorph I shows no significant absorption of water under these storage conditions. According to DSC, TGA and XRPD, no difference exists in compound of the formula (I) in crystalline form of polymorph I.

Pharmaceutical formulation of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula (I)

(73) A granular solution of the compound of the formula (I) in crystalline form of polymorph I in micronized form, hypromellose 5 cP and sodium lauryl sulphate was prepared in purified water.

(74) Microcrystalline cellulose, lactose monohydrate and croscarmellose sodium were mixed (premix) in a container or a fluidized bed granulator.

(75) The premix and the granular solution were granulated in the fluid-bed granulator.

(76) The lubricant magnesium stearate was added after which the granulate was dried and sieved. A ready to press mixture was thus prepared.

(77) The ready to press mixture was compressed to give tablets using a rotary tablet press.

(78) A homogeneous coating suspension was prepared from hypromellose, talc, titanium dioxide, yellow iron oxide, red iron oxide and purified water. The coating suspension was sprayed onto the tablets in a suitable coating device.

(79) TABLE-US-00001 Ph IIb Ph IIb Ph IIb Ph IIb Ph IIb Ph IIb Ph IIb Composition [mg] [mg] [mg] [mg] [mg] [mg] [mg] Compound 1.25 2.50 5.00 7.50 10.00 15.00 20.00 of the formula (I) in polymorph I micronized Excipients Microcrystalline 73.80 72.50 69.90 67.30 64.70 62.00 59.30 cellulose Croscarmellose 4.50 4.50 4.50 4.50 4.50 4.50 4.50 sodium Hypromellose 5 cP 4.50 4.50 4.50 4.50 4.50 4.50 4.50 Lactose monohydrate 45.00 45.00 45.00 45.00 45.00 42.50 40.00 Magnesium stearate 0.90 0.90 0.90 0.90 0.90 0.90 0.90 Sodium lauryl 0.05 0.10 0.20 0.30 0.40 0.60 0.80 sulphate Weight (uncoated 130.00 130.00 130.00 130.00 130.00 130.00 130.00 tablet) Film-coating Hypromellose 5 cP 3.0336 3.0336 3.0336 3.0336 3.0336 3.0336 3.0336 Titanium dioxide 2.3196 2.3196 2.3196 2.3196 2.3196 2.3196 2.3196 Talc 0.6072 0.6072 0.6072 0.6072 0.6072 0.6072 0.6072 Yellow iron oxide 0.0324 0.0324 0.0324 0.0324 0.0324 0.0324 0.0324 Red iron oxide 0.0072 0.0072 0.0072 0.0072 0.0072 0.0072 0.0072 Weight (film- 6.0000 6.0000 6.0000 6.0000 6.0000 6.0000 6.0000 coating) Weight (coated 136.00 136.00 136.00 136.00 136.00 136.00 136.00 tablet)
HPLC Conditions/Methods
Method A

(80) YMC Hydrosphere C18

(81) 150*4.6 mm, 3.0 μm

(82) 25° C., 1 ml/min, 270 nm, 4 nm

(83) 0′: 70% TFA 0.1%*; 30% acetonitrile

(84) 17′: 20% TFA 0.1%*; 80% acetonitrile

(85) 18′: 70% TFA 0.1%*; 30% acetonitrile

(86) *: TFA in water

(87) Method B

(88) YMC Hydrosphere C18

(89) 150*4.6 mm, 3.0 μm

(90) 25° C., 1 ml/min., 255 nm, 6 nm

(91) 0′: 90% TFA 0.1%; 10% acetonitrile

(92) 20′: 10% TFA 0.1%; 90% acetonitrile

(93) 18′: 10% TFA 0.1%; 90% acetonitrile

(94) Method C

(95) Nucleodur Gravity C18

(96) 150*2 mm, 3.0 μm

(97) 35° C.; 0.22 ml/min., 255 nm, 6 nm

(98) Solution A: 0.58 g of ammonium hydrogen phosphate and 0.66 g of ammonium dihydrogen

(99) phosphate in 1 L of water (ammonium phosphate buffer pH 7.2)

(100) Solution B: acetonitrile

(101) 0′: 30% B; 70%/A

(102) 15′: 80% B; 20% A

(103) 25′: 80% B; 20% A

(104) Method D

(105) Column length: 25 cm

(106) Internal Diameter: 4.6 mm

(107) Packing: Chiralpak IA, 5 μm

(108) Reagents: 1. Acetonitrile HPLC grade

(109) 2. Methyl tert-butyl ether (MTBE), p.a.

(110) Test solution The sample is dissolved at a concentration of 1.0 mg/mL

(111) in acetonitrile.

(112) (e.g. ca. 25 mg of sample, weighed exactly, dissolved in acetonitrile to 25.0 mL).

(113) Eluent A. acetonitrile

(114) B. Methyl tert-butyl ether (MTBE), p.a.

(115) Flow rate 0.8 ml/min

(116) Column oven temperature 25° C.

(117) Detection measuring wavelength: 255 nm

(118) Band width: 6 nm

(119) Injection volumes 5 μL

(120) Mix composition of eluents A and B in ratio by volume of 90:10

(121) Chromatogram run time 30 min

(122) Retention times/RRT:

(123) (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (1) ca. 11 min. RRT: 1.00

(124) (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (1) ca. 9 min. RRT: 0.82

(125) Lattice Constants of Compound of the Formula (I) in Crystalline Form of Polymorph I

(126) Polymorph I

(127) Crystal system orthorhombic

(128) Space group P2(1)2(1)2(1)

(129) Molecules per unit

(130) cell 4

(131) Length of axis a [Å] 7.8610(3)

(132) Length of axis b [Å] 11.7797(6)

(133) Length of axis c [Å] 20.1792(8)

(134) α [°] 90

(135) β [°] 90

(136) γ [°] 90

(137) Calculated density at

(138) 100 K [g cm-3] 1.345

(139) Measuring Parameters of the X-ray Diffractometry for the Measurement of Compound of the Formula (I) in Crystalline Form of Polymorph I

(140) TABLE-US-00002 Data set name 2429-08a r2 Scan axis 2Theta-Omega Start position [°2Th.] 2.0000 End position [°2Th.] 37.9900 Type of divergence screen Fixed Size of divergence screen [°] 1.0000 Measurement temperature [° C.] 25 Anode material Cu K-Alpha1 [Å] 1.54060 Generator setting 35 mA, 45 kV Diffractometer type Transmission diffractometer Goniometer radius [mm] 240.00 Focus-div. screen gap [mm] 91.00 Primary beam monochromator Yes Sample rotation Yes

(141) TABLE-US-00003 Peak maximum [2 Theta] Polymorph I 8.5 11.4 11.9 13.4 14.1 14.8 15.0 15.4 16.0 17.2 18.5 19.0 19.8 20.5 20.8 22.1 22.7 23.0 23.1 23.6 23.9 24.6 24.9 25.2 25.6 26.0 26.5 27.1 27.3 28.3 28.5 28.8 29.6 30.1 30.6 31.5 31.9 32.4 32.9 33.1 33.4 33.7 34.5 34.7 35.0 35.8 36.2 36.5 37.2 37.4
Measuring Conditions for the IR and Raman Spectroscopy for the Measurement of the Compound of the Formula (I) in Crystalline Form of Polymorph I:
IR:

(142) TABLE-US-00004 Instrument Perkin Elmer Spectrum One Number of scans 32 Resolution 4 cm.sup.−1 Technique Diamond ATR unit Raman: Instrument Bruker Raman RFS 100/S Number of scans 64 Resolution 2-4 cm.sup.−1 Laser Power 350 mW Laser wavelength 1064 nm

(143) TABLE-US-00005 Band maximum [cm.sup.−1] IR-ATR Raman Polymorph I Polymorph I 3475 3074 3416 2997 3366 2970 3074 2941 2992 2920 2952 2836 2835 2231 2230 1659 1681 1641 1658 1623 1606 1601 1572 1577 1485 1487 1464 1443 1454 1383 1431 1362 1420 1327 1407 1303 1381 1267 1355 1230 1341 1191 1325 1161 1303 1123 1285 1093 1267 1032 1255 991 1229 883 1222 827 1161 810 1136 759 1097 734 1031 708 991 671 976 613 967 528 924 505 909 471 875 442 847 346 827 320 810 297 776 186 758 155 746 114 733 723 706 697 670

DESCRIPTION OF THE FIGURES

(144) FIG. 1: DSC (20 Kmin.sup.−1) and TGA of compound of the formula (I) in crystalline form of polymorph I

(145) FIG. 2: X-ray of a single crystal of polymorph I of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (1)

(146) FIG. 3: X-ray diffractogram of compound of the formula (I) in crystalline form of polymorph I

(147) FIG. 4: Raman spectrum of compound of the formula (I) in crystalline form of polymorph I

(148) FIG. 5: FT-Infrared (IR) spectrum (KBr) of compound of the formula (I) in crystalline form of polymorph I

(149) FIG. 6: FT-Infrared (IR) spectrum (ATR) of compound of the formula (I) in crystalline form of polymorph I

(150) FIG. 7: FT-Near-infrared (NIR) spectrum of compound of the formula (I) in crystalline form of polymorph I

(151) FIG. 8: FT-Far-infrared (FIR) spectrum of compound of the formula (I) in crystalline form of polymorph I

(152) FIG. 9: Solid state .sup.13C-NMR spectrum of compound of the formula (I) in crystalline form of polymorph I

(153) FIG. 10: Stability of compound of the formula (I) in crystalline form of polymorph I in air humidity (x-axis % relative humidity/y-axis weight change in %