Process for the preparation of cycloheptapyridine CGRP receptor antagonists

Abstract

The disclosure generally relates to a process for the preparation of compounds of formula I, including synthetic intermediates which are useful in the process. ##STR00001##

Claims

1. A compound of formula II, or a salt thereof, where Ar.sup.1 is phenyl substituted with 0-3 substituents selected from the group consisting of cyano, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, and alkylSO.sub.2 and R.sup.1 is hydrogen or trialkylsilyl, alkoxy, alkylcarbonyl, benzyl, benzoyl, and pivaloyl ##STR00019##

2. The compound of claim 1 where Ar.sup.1 is 2,3-difluorophenyl.

3. The compound of claim 2 which is the dihydrochloride salt.

4. The compound of claim 1 where R.sup.1 is triisopropylsilyl.

5. The compound of claim 4 which is the dihydrochloride salt.

6. The compound of claim 1 where R.sup.1 is hydrogen.

7. The compound of claim 6 which is the dihydrochloride salt.

8. A compound of formula II, or a salt thereof, having the following formula: ##STR00020##

9. The compound of claim 8 which is the dihydrochloride salt.

Description

DESCRIPTION OF SPECIFIC EMBODIMENTS

Example 1

(1) ##STR00014##

(6S,9R)-6-(2,3-difluorophenyl)-9-(triisopropylsilyloxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-amine

(2) To a 100 mL hastelloy autoclave reactor was charged (6S,9R)-6-(2,3-difluorophenyl)-9-(triisopropylsilyloxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-one (5.00 g, 11.22 mmol), 1,4-dioxane (50 mL) and titanium tetra(isopropoxide) (8.33 mL, 28.11 mmol). The reactor was purged three times with nitrogen and three times with ammonia. After the purge cycle was completed, the reactor was pressurized with ammonia to 100 psig. The reaction mixture was heated to 50° C. (jacket temperature) and stirred at a speed to ensure good mixing. The reaction mixture was aged at 100 psig ammonia and 50° C. for 20 h. The mixture was then cooled to 20° C. then 5% Pd/Alumina (1.0 g, 20 wt %) was charged to the autoclave reactor. The reactor was purged three times with nitrogen and three times with hydrogen. After the purged cycle completed, the reactor was pressurized with hydrogen to 100 psig and mixture was heated to 50° C. (jacket temperature) and stirred at a speed to ensure good mixing. The reaction mixture was aged at 100 psig H.sub.2 and 50° C. for 23 h (reactor pressure jumped to ˜200 psig due to soluble ammonia in the mixture). The mixture was then cooled to 20° C. then filtered then transferred to a 100 ml 3-necked flask. To the mixture water (0.55 mL) was added drop wise, which resulted in yellow slurry. The resulting slurry was stirred for 30 min then filtered, then the titanium dioxide cake was washed with 1,4-dioxane (30 mL). The filtrate was collected and the solvent was removed. The resulting oil was dissolved in isopropanol (40 mL). To the solution ˜5N HCl in isopropanol (9.0 ml) was added drop wise resulting in a thick slurry. To the slurry isopropyl acetate (60 ml) was added and heated to 45° C. for 10 min and then cooled to 22° C. over approximately 3 h to afford a white solid (3.0 g, 51.5%). .sup.1H NMR (500 MHz, CD.sub.3OD) δ ppm 8.89 (d, J=5.3, 1H), 8.42 (bs, 1H), 8.05 (bs, 1H), 7.35 (dd, J=8.19, 16.71), 7.2 (bs, 2H), 7.22 (m, 1H) 7.15 (m, 1H), 5.7 (dd, J=1.89, J=8.51), 5.4 (m, 1H), 3.5 (m, 1H), 1.9-2.5 (B, 4 h) 1.4 (sept, J=15.13, 3H), 1.2 (t, J=7.57 18H); .sup.13C NMR (125 MHz, CD.sub.3OD) δ 153.5, 151.6, 151.5, 151.3, 149.4, 143.4, 135.03, 129.8, 129.8, 127.8, 126.8, 126.4, 118.6, 72.4, 54.1, 41.4, 34.3, 32.3, 25.4, 18.6, 18.5, 13.7, 13.6, 13.5, 13.3.

Example 2

(3) ##STR00015##

(6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ol

(4) To a 250 ml flask was charged (6S,9R)-6-(2,3-difluorophenyl)-9-(triisopropylsilyloxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-amine di HCl salt (15 g, 25.88 mmol) and a solution of isopropanol:water (45 mL:15 mL). The mixture was heated to 82° C. for 6 h then dried via azeotropic distillation at atmospheric pressure using isopropanol until the KF was less than <3%. After fresh isopropanol (25 ml) was added, the mixture was heated to 70° C. and then isopropyl acetate (45 ml) was added that resulting in a white slurry. The slurry cooled to 22° C. for 15 min to afford a white solid (9.33 g, 99%). .sup.1H NMR (500 MHz CD.sub.3OD) δ 8.77 (d, J=5.7 Hz, 1H), 8.47 (d, J=7.9 Hz, 1H), 8.11 (dd, J=6.0, 8.2 Hz, 1H), 7.21-7.32 (m, 3H), 5.53 (dd, J=3.8, 9.8 Hz, 1H) 5.33 (d, J=9.8 Hz, 1H), 3.5 (bm, 1H), 2.25-2.40 (m, 2H), 2.15 (bm, 1H), 1.90 (bm, 1H); .sup.13C NMR (125 MHz, MeOD) δ 159.4, 153.9, 151.9 and 151.8, 149.7, 143.6, 141.8, 135.7, 130.6, 127.7, 126.8, 118.9, 70.0, 54.9, 42.2, 34.5, 33.4.

Example 3

(5) ##STR00016##

(5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate

(6) To a round bottom flask was charged (5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ol dihydrochloride (1.00 g, 2.73 mmol) and dichloromethane (15 mL). A solution of sodium carbonate (0.58 g, 5.47 mmol), 20 wt % aqueous sodium chloride (5 mL), and water (10 mL) was added and the biphasic mixture was aged for 30 min. The phases were allowed to separate and the organic stream was retained. The dichloromethane solvent was then switched with azeotropic drying to tetrahydrofuran, with a final volume of (15 mL). At 20° C. was added, 1-(1-(1H-imidazole-1-carbonyl)piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (0.95 g, 3.01 mmol), followed by a 20 wt % potassium tert-butoxide solution in THF (4 mL, 6.20 mmol). The thin slurry was aged for 1 h, and then the reaction was quenched with the addition of 20 wt % aqueous sodium chloride (5 mL) and 20 wt % aqueous citric acid (2.5 mL). The layers were allowed to separate and the organic rich layer was retained. The organic layer was washed with 20 wt % aqueous sodium chloride (15 mL). The organic tetrahydrofuran stream was then concentrated in vacuo to afford an oil which was resuspended in dichloromethane (20 mL) and dried with MgSO.sub.4. The dichloromethane stream was concentrated in vacuo to afford an oil, which was crystallized from ethanol:heptane to afford a white solid (1.14 g, 78.3%). LCMS: [M+H]=535: .sup.1H NMR (600 MHz, d.sub.6-DMSO) δ 11.58 (1H, bs), 8.45 (1H, bd), 8.03 (1H, d, J=7.3 Hz), 7.91 (1H, bs), 7.54 (1H, bd), 7.36 (1H, bm), 7.34 (1H, bm), 7.28 (1H, m), 7.21 (1H, m), 7.01 (1H, bs), 6.01 (1H, dd, J=3.2, 9.8 Hz), 4.48 (1H, d, J=9.5 Hz), 4.43 (1H, bm), 4.38 (1H, bm), 4.11 (1H, bm), 3.08 (1H, bm), 2.93 (1H, bm), 2.84 (1H, m), 2.62 (1H, bm), 2.20 (2H, bm), 2.13 (1H, bm), 2.12 (1H, bm), 1.75 (1H, bm), 1.72 (1H, bm), 1.66 (1H, bm); .sup.13C NMR (125 MHz, d.sub.6-DMSO) δ 156.6, 154.2, 153.0, 149.8, 148.1, 146.4, 143.5, 139.6, 137.4, 134.0, 132.8, 124.7, 124.5, 123.3, 122.2, 116.3, 115.0, 114.3, 73.7, 52.8, 50.0, 43.8, 43.3, 32.0, 30.3, 28.6; mp 255° C.

Example 4

(7) ##STR00017##

1-(1-(1H-imidazole-1-carbonyl)piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one

(8) To a round bottom flask was added, 1,1′-carbonyldiimidazole (8.59 g, 51.4 mmol), diisopropylethylamine (12.6 mL, 72.2 mmol) and tetrahydrofuran (100 mL). This mixture was warmed to 40° C. and aged for 10 min, after which 1-(piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one dihydrochloride (10 g, 34.3 mmol) was added. The slurry was aged at 40° C. for 3 h, and then upon reaction completion, the solvent was swapped to acetonitrile which afforded an off white solid (9.19 g, 85.9%). LCMS: [M+H]=313; .sup.1H NMR (400 MHz, d.sub.6-DMSO) δ 11.58 (1H, s), 8.09 (1H, s), 7.97 (1H, d, J=8.0 Hz), 7.73 (1H, d, J=4.0 Hz), 7.53 (1H, s), 7.05 (1H, s), 7.00 (1H, dd, J=4.0, 8.0 Hz), 4.52, (1H, dd, J=8.0, 12.0 Hz), 4.05 (2H, bd, J=8.0 Hz), 3.31 (2H, m), 2.34 (2H, m), 1.82 (2H, bd, J=12.0 Hz); .sup.13C NMR (100 MHz, d.sub.6-DMSO) δ 153.0, 150.4, 143.4, 139.8, 137.2, 128.9, 123.0, 118.7, 116.4, 115.2, 49.3, 45.1, 28.5; mp 226° C.

Example 5

(9) ##STR00018##

1-(1-(1H-imidazole-1-carbonyl)piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one

(10) To a 250 ml round bottom flask was added 3-N-piperidin-4-ylpyridine-2,3-diamine dihydrochloride (10 g, 52 mmol) and acetonitrile (100 mL). Triethyl amine (11.44 g, 113 mmol) and 1,1′-Carbonyldiimidazole (18.34 g, 113 mmol) were added at ambient temperature and the mixture was stirred for 2 h. The solvent was evaporated under vacuum to ˜30 ml reaction volume and isopropyl acetate (50 mL) was added into the resulting slurry at 40° C. The slurry was cooled to 10-15° C. and then stirred for 1 h to afford an off white solid (10 g, 85%).

(11) It will be evident to one skilled in the art that the present disclosure is not limited to the foregoing illustrative examples, and that it can be embodied in other specific forms without departing from the essential attributes thereof. It is therefore desired that the examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing examples, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.