Hydrochloric Acid → HCID 178492165, compound

HRID 1621461Notes

Reaction equation

[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:17]([C:18]3[N:26]=[C:25]([CH3:27])[N:24]=[C:23]4[C:19]=3[N:20]=[CH:21][N:22]4C3CCCCO3)=[CH:16][C:13]([CH:14]=O)=[CH:12][N:11]=2)=[CH:5][CH:4]=1.[NH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1.[BH4-].[Na+].Cl>ClCCl.CO.C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C.C(O)C>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:17]([C:18]3[N:26]=[C:25]([CH3:27])[N:24]=[C:23]4[C:19]=3[N:20]=[CH:21][NH:22]4)=[CH:16][C:13]([CH2:14][NH:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=3)=[CH:12][N:11]=2)=[CH:5][CH:4]=1

Participants

Conditions

Temperature: 70 °C

Procedure

6-(6-Methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)nicotinaldehyde (121.8 mg, 0.2734 mmol) and 2-aminopyridine (72.0 mg, 0.765 mmol) were suspended in dichloromethane (1.5 mL) and ethanol (1.5 mL) and tetraisopropoxytitanium (0.16 mL, 0.54 mmol) was added. The flask was fit with a reflux condenser and put in a preheated oil bath (70° C.) and stirred under nitrogen. After 5 hours, the reaction was diluted with DCM, and stirring was continued overnight. Then, more 2-aminopyridine (63.6 mg, 0.676 mmol) and Ti(OiPr)4 (0.18 mL, 0.61 mmol), and DCM were added, and stirring was continued at 70° C. for about 6 hours. Then, the reaction was cooled to room temperature, and sodium borohydride (38.9 mg, 1.028 mmol) was added. The reaction was stirred at room temperature for 25 minutes, and then aqueous 5N HCl (0.55 mL) was added. The flask was put in a preheated oil bath (50° C.) and stirring was continued overnight. Then, the reaction was cooled to room temperature, diluted with DCM and MeOH, and filtered through a Celite® (diatomaceous earth) pad, which was washed with a 1:1 mixture of DCM and MeOH. The filtrate was concentrated, treated with water, and filtered. The solid was washed with water, collected, treated with DMSO (about 1 mL), diluted with DCM, and filtered. The solid was washed with DCM, collected, and purified by prep HPLC (10% to 100% MeCN/water with 0.1% TFA over 30 minutes with a total flow rate of 100 mL/min) to give N-(6-methoxypyridin-3-yl)-3-(2-methyl-9H-purin-6-yl)-5-((pyridin-2-ylamino)methyl)pyridin-2-amine (62.7 mg, 52% yield). MS (ESI pos. ion) m/z 440 (M+H)+. 1H NMR (d6-DMSO, 400 MHz) δ 13.60 (br s, 1H), 12.63 (s, 1H), 9.80 (s, 1H), 9.01 (br s, 1H), 8.56 (s, 1H), 8.55 (d, J=2.54 Hz, 1H), 8.36 (d, J=2.35 Hz, 1H), 8.15 (dd, J=8.80 Hz, 2.74 Hz, 1H), 7.98 (d, J=6.26 Hz, 1H), 7.92 (t, J=7.43 Hz, 1H), 7.11 (d, J=9.0 Hz, 1H), 6.90 (t, J=6.46 Hz, 1H), 6.86 (d, J=9.0 Hz, 1H), 4.61 (s, 2H), 3.85 (s, 3H), 2.85 (s, 3H).

Workup

customThe flask was fit with a reflux condenser
customput in a preheated oil bath
stirringstirring
waitwas continued overnight
stirringstirring
waitwas continued at 70° C. for about 6 hours
temperatureThen, the reaction was cooled to room temperature
stirringThe reaction was stirred at room temperature for 25 minutes
customThe flask was put in a preheated oil bath
stirring(50° C.) and stirring
waitwas continued overnight
temperatureThen, the reaction was cooled to room temperature
filtrationfiltered through a Celite® (diatomaceous earth) pad, which
washwas washed with a 1:1 mixture of DCM and MeOH
concentrationThe filtrate was concentrated
additiontreated with water
filtrationfiltered
washThe solid was washed with water
customcollected
additiontreated with DMSO (about 1 mL)
additiondiluted with DCM
filtrationfiltered
washThe solid was washed with DCM
customcollected
custompurified by prep HPLC (10% to 100% MeCN/water with 0.1% TFA over 30 minutes with a total flow rate of 100 mL/min)

Sources & evidence

ORD record: ord-32a3f9c3ec8f4e8987db6ecd720d325d
Source dataset: uspto-grants-2014_07
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08772480B2

Reaction notes

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