Hydrochloric Acid → Bms-973013

HRID 1666141Notes

Reaction equation

HRID 1666141 reaction equation
FC1C(F)=CC=CC=1[C@@H]1CC[C@@H](CC([N:23]2[CH2:28][CH2:27][CH:26]([N:29]3[C:37]4[C:32](=[N:33][CH:34]=[CH:35][CH:36]=4)[NH:31][C:30]3=[O:38])[CH2:25][CH2:24]2)=O)C2=NC=CC=C2C1.FC1C(F)=CC=CC=1[C@H]1CC[C@H](CC(N2CCC(N3C4C(=NC=CC=4)NC3=O)CC2)=O)C2=NC=CC=C2C1.Cl>C(Cl)Cl>[NH:23]1[CH2:24][CH2:25][CH:26]([N:29]2[C:37]3[C:32](=[N:33][CH:34]=[CH:35][CH:36]=3)[NH:31][C:30]2=[O:38])[CH2:27][CH2:28]1

Participants

5

Reactant 3

HCID 313Hydrochloric AcidHCID 46174835HCID 46174835, compoundHCID 46174836HCID 46174836, compound

Product 1

HCID 22293182Bms-973013

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

1-(1-(2-((6R,9S)-6-(2,3-Difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)acetyl)piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 1-(1-(2-((6S,9R)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)acetyl)piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one. In a 100 mL round-bottomed flask was 2-((6,9-trans)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)acetic acid (46.0 mg, 0.145 mmol) and 1-(piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (95 mg, 0.435 mmol) (bis-HCl salt) in CH2Cl2 (4 ml) to give a colorless suspension. Hunig'sBase (0.127 ml, 0.725 mmol) and 3-(DIETHOXYPHOSPHORYLOXY)-1,2,3-BENZO-TRIAZIN-4(3H)-ONE (87 mg, 0.290 mmol) were added. The reaction mixture was diluted with DMF (1 ml). Most solids were dissolved. It was stirred at rt overnight. 44 h: LCMS indicated complete conversion. It was diluted with EtOAc and washed with water. The layers were separated. The organic layer was washed with brine, dried with Na2SO4, and concentrated to a tan oil/gel. Purification by FCC (ISCO) up to 8% MeOH in CH2Cl2 afforded the desired product as a tan foam (68 mg, 86% for 2 steps). MS(ESI)[M+H+]=518.27; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 11.44 (br.s., 1 H) 8.25-8.42 (m, 1 H) 8.05 (d, J=5.29 Hz, 1 H) 7.38 (t, J=8.44 Hz, 1 H) 7.20-7.31 (m, 1 H) 6.83-7.10 (m, 5 H) 4.87 (d, J=12.34 Hz, 1 H) 4.53-4.73 (m, 1 H) 4.43 (t, J=15.36 Hz, 1 H) 3.81-4.00 (m, 1 H) 3.36-3.60 (m, 2 H) 3.24 (t, J=12.97 Hz, 1 H) 2.94 (t, J=11.21 Hz, 1 H) 2.33-2.80 (m, 4 H) 2.05-2.31 (m, 3 H) 1.80-2.05 (m, 3 H) 1.38-1.63 (m, 1 H). The racemic product was resolved by chiral HPLC (Chiralpak AD-H analytical column, 4.6×250 mm, 5 μm; Mobile Phase: 40% MeOH in CO2; Temp: 35° C.; Flow rate: 2.0 mL/min. for 26 min; Injection: 5 uL of ˜2 mg/mL in MeOH). Compound (6R, 9S) was the first peak with tR=13.88 min while compound (6S, 9R) was the second peak with tR=19.19 min).

Workup

  1. customIn a 100 mL round-bottomed flask was

Sources & evidence

ORD record
ord-3dc15722a8964492b6e3ba7c6b97ccc6
Source dataset
uspto-grants-2011_10
Patent number
US08044043B2

Reaction notes

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