4-Hydroxymethyl-4-methylpiperidine

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 55A (5.03 g, 13.3 mmol) in DCM (250 mL) was added (4-methylpiperidin-4-yl)methanol hydrochloride (2.4 g, 14.6 mmol) followed by DIPEA (2.5 mL, 14.6 mmol). The mixture was stirred at RT for 20 min before the addition of sodium triacetoxyborohydride (5.6 g, 26.5 mmol) and MeOH (5 mL). The reaction mixture was stirred at RT overnight. Further (4-methylpiperidin-4-yl)methanol (360 mg, 2.7 mmol), DIPEA (0.5 ml) and sodium triacetoxyborohydride (1.1 g, 5.2 mmol) were added and the mixture was stirred at RT for 3 days. Even more sodium triacetoxyborohydride (2 g, 9.5 mmol) was added and the mixture was stirred for another 2 h. Yet another portion of sodium triacetoxyborohydride (4 g, 19 mmol) was added and the mixture was left at RT overnight. The mixture was then washed with a saturated aqueous solution of Na2CO3. The organic layer was filtered through a phase separator and the solvent was removed by evaporation. The crude product was purified by flash chromatography starting with EtOAc and then eluting the product with 5% methanol in DCM where the methanol contained ammonia (2 M). The pure fractions were combined and evaporated. The residue was triturated with diethyl ether and there was obtained 3.55 g (54%) of the product as a crystalline solid, m. p. 102° C. and 146° C. 1H NMR (500 MHz, CDCl3): δ 0.94 (s, 3H), 1.33 (m, 2H), 1.55 (m, 2H), 2.28 (m, 2H), 2.53 (m, 2H), 3.37 (m, 2H), 3.47 (s, 2H), 3.88 (s, 3H), 4.33 (m, 1H), 4.62 (m, 1H), 4.72 (m, 1H), 5.06 (m, 1H), 5.11 (m, 1H), 6.71 (d, 2H), 7.00 (d, 2H), 7.26 (m, 2H), 8.08 (d, 2H), MS (APCI+) m/z 493 [M+H]+, LC purity: 97%. the mixture was stirred at RT for 3 days the mixture was stirred for another 2 h the mixture was left at RT overnight The mixture was then washed with a saturated aqueous solution of Na2CO3 The organic layer was filtered through a phase separator the solvent was removed by evaporation The crude product was purified by flash chromatography eluting the product with 5% methanol in DCM where the methanol evaporated The residue was triturated with diethyl ether

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 69A (3.00 g, 10.3 mmol) in DCM (50 mL) was added (4-methylpiperidin-4-yl)methanol (2.56 g, 15.5 mmol) followed by DIPEA (3.60 mL, 20.6 mmol). The reaction mixture was stirred at RT for 20 min and then sodium triacetoxyborohydride (6.55 g, 30.9 mmol) was added. The mixture was stirred at RT overnight and then washed with a saturated aqueous solution of Na2CO3. The aqueous layer was extracted several times with DCM. The organic layers were filtered through a phase separator and then evaporated. There was obtained 3.1 g (74%) of the product as an oil. 1H NMR (500 MHz, CDCl3): δ 0.95 (s, 3H), 1.33 (m, 2H), 1.45 (s, 9H), 1.51 (m, 2H), 2.26 (m, 2H), 2.30 (s, 3H), 2.51 (m, 2H), 3.38 (s, 2H), 3.39 (s, 2H), 3.99 (m, 2H), 4.27 (m, 2H), 4.84 (m, 1H), 6.48 (dd, 1H), 6.56 (d, 1H), 7.16 (d, 1H), MS (APCI+) m/z 405 [M+H]+. The mixture was stirred at RT overnight washed with a saturated aqueous solution of Na2CO3 The aqueous layer was extracted several times with DCM The organic layers were filtered through a phase separator evaporated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 69A (3.00 g, 10.3 mmol) in DCM (50 mL) was added (4-methylpiperidin-4-yl)methanol (2.56 g, 15.5 mmol) followed by DIPEA (3.60 mL, 20.6 mmol). The reaction mixture was stirred at RT for 20 min and then sodium triacetoxyborohydride (6.55 g, 30.9 mmol) was added. The mixture was stirred at RT overnight and then washed with a saturated aqueous solution of Na2CO3. The aqueous layer was extracted several times with DCM. The organic layers were filtered through a phase separator and then evaporated. There was obtained 3.1 g (74%) of the product as an oil. 1H NMR (500 MHz, CDCl3): δ 0.95 (s, 3H), 1.33 (m, 2H), 1.45 (s, 9H), 1.51 (m, 2H), 2.26 (m, 2H), 2.30 (s, 3H), 2.51 (m, 2H), 3.38 (s, 2H), 3.39 (s, 2H), 3.99 (m, 2H), 4.27 (m, 2H), 4.84 (m, 1H), 6.48 (dd, 1H), 6.56 (d, 1H), 7.16 (d, 1H), MS (APCI+) m/z 405 [M+H]+. The mixture was stirred at RT overnight washed with a saturated aqueous solution of Na2CO3 The aqueous layer was extracted several times with DCM The organic layers were filtered through a phase separator evaporated

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (4-methylpiperidin-4-yl)methanol (989 mg, 7.7 mmol) in 1,4-dioxane (18 mL) and N,N-dimethylformamide (12 mL) was added sodium hydride as 60% dispersion in mineral oil (670 mg, 28 mmol). The reaction mixture was stirred at ambient temperature for 5 minutes before 4-chloro-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (428 mg, 1.2 mmol) was added in one portion and the reaction mixture was heated at 40° C. for 18 hours. The cooled reaction mixture was diluted with water (20 mL) and ethyl acetate (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified flash chromatography (silica, 40 g, ISCO, 1-20% methanol in methylene chloride) to afford the title compound as an off-white solid, which was used in the next step without any further purification (300 mg, 56%). was added in one portion The cooled reaction mixture The organic layer was separated dried over sodium sulfate filtered concentrated in vacuo purified flash chromatography (silica, 40 g, ISCO, 1-20% methanol in methylene chloride)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (1-benzyl-4-methylpiperidin-4-yl)methanol (2.7 g, 12 mmol) in methanol (34 mL) was added ammonium formate (8.6 g, 135 mmol) followed by palladium on carbon (10% w/w, 3.6 g, 1.7 mmol). The reaction mixture was stirred for 18 hours under a balloon of hydrogen, then degassed, flushed with nitrogen, and filtered over a pad of celite. The solvent was removed in vacuo and the resulting residue was purified by flash chromatography (silica, 40 g, ISCO, 0-20% methanol in methylene chloride) to afford the title compound as a colorless oil, which was used in the next step without any further purification (1.2 g, 76%). degassed flushed with nitrogen filtered over a pad of celite The solvent was removed in vacuo the resulting residue was purified by flash chromatography (silica, 40 g, ISCO, 0-20% methanol in methylene chloride)

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (4-methylpiperidin-4-yl)methanol (989 mg, 7.7 mmol) in 1,4-dioxane (18 mL) and N,N-dimethylformamide (12 mL) was added sodium hydride as 60% dispersion in mineral oil (670 mg, 28 mmol). The reaction mixture was stirred at ambient temperature for 5 minutes before 4-chloro-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (428 mg, 1.2 mmol) was added in one portion and the reaction mixture was heated at 40° C. for 18 hours. The cooled reaction mixture was diluted with water (20 mL) and ethyl acetate (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified flash chromatography (silica, 40 g, ISCO, 1-20% methanol in methylene chloride) to afford the title compound as an off-white solid, which was used in the next step without any further purification (300 mg, 56%). was added in one portion The cooled reaction mixture The organic layer was separated dried over sodium sulfate filtered concentrated in vacuo purified flash chromatography (silica, 40 g, ISCO, 1-20% methanol in methylene chloride)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (1-benzyl-4-methylpiperidin-4-yl)methanol (2.7 g, 12 mmol) in methanol (34 mL) was added ammonium formate (8.6 g, 135 mmol) followed by palladium on carbon (10% w/w, 3.6 g, 1.7 mmol). The reaction mixture was stirred for 18 hours under a balloon of hydrogen, then degassed, flushed with nitrogen, and filtered over a pad of celite. The solvent was removed in vacuo and the resulting residue was purified by flash chromatography (silica, 40 g, ISCO, 0-20% methanol in methylene chloride) to afford the title compound as a colorless oil, which was used in the next step without any further purification (1.2 g, 76%). degassed flushed with nitrogen filtered over a pad of celite The solvent was removed in vacuo the resulting residue was purified by flash chromatography (silica, 40 g, ISCO, 0-20% methanol in methylene chloride)

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Using 7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-ylamine, phenyl chloroformate and 4-hydroxymethyl-4-methyl-piperidine, the title compound was prepared as light brown powder. MS: m/e=436(M+H+).

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Using 7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-ylamine, phenyl chloroformate and 4-hydroxymethyl-4-methyl-piperidine, the title compound was prepared as light brown powder. MS: m/e=436(M+H+).