Hydrochloric Acid → 1-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)-N-(1,3-dioxoisoindolin-5-yl)piperidine-3-carboxamide hydrochloride

HRID 1755399Notes

Reaction equation

HRID 1755399 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:27]=[CH:28][N:29]=3)[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([OH:26])=O)[CH2:19]3)[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10].[NH2:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[C:36](=[O:40])[NH:35][C:34]2=[O:41].N1C=CC=CC=1.[ClH:48]>O=P(Cl)(Cl)Cl.O>[ClH:48].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:27]=[CH:28][N:29]=3)[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([NH:30][C:31]4[CH:32]=[C:33]5[C:37](=[CH:38][CH:39]=4)[C:36](=[O:40])[NH:35][C:34]5=[O:41])=[O:26])[CH2:19]3)[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10]

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 1049PyridineHCID 729154-AminophthalimideHCID 866827441-(8-(5,6-Dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)piperidine-3-carboxylic acid

Product 1

HCID 866827431-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)-N-(1,3-dioxoisoindolin-5-yl)piperidine-3-carboxamide hydrochlorideYield 2%

Reagents, catalysts & solvents 2

HCID 24813Phosphorus oxychlorideCatalystHCID 962WaterSolvent

Conditions

Temperature
0 °C

Procedure

A mixture of 1-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)piperidine-3-carboxylic acid (500 mg, 1.26 mmol), 5-aminoisoindoline-1,3-dione (250 mg, 1.51 mmol) and pyridine (10 mL) was stirred at 0° C. for 2 h. POCl3 (20 drops) was added and stirred for 10 mins, then water (5 mL) was added and the mixture extracted with ethyl acetate (10 mL). The organic layer was washed with brine (10 mL), then dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by prep-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; gradient conditions: 20% acetonitrile/80% water (0.1% TFA, v/v) initially, proceeding to 50% acetonitrile/50% water (0.1% TFA, v/v) in a linear fashion over 9 min) to give the product. HCl (1 mL) was added and then the mixture concentrated in vacuo to give 1-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)-N-(1,3-dioxoisoindolin-5-yl)piperidine-3-carboxamide hydrochloride (10 mg, 2%). 1H NMR (300 MHz, DMSO): δ 11.23 (s, 1H), 10.65 (s, 1H), 10.21 (s, 1H), 8.15 (s, 2H), 7.98 (s, 1H), 7.86 (d, 1H, J=8.4 Hz), 7.77 (d, 1H, J=7.8 Hz), 7.43 (d, 1H, J=8.1 Hz), 6.93 (d, 1H, J=8.1 Hz), 4.29 (d, 1H, J=11.7 Hz), 4.14 (d, 1H, J=12.3 Hz), 3.91 (s, 3H), 7.56 (s, 3H), 3.23-3.02 (m, 2H), 2.73 (s, 1H), 2.10-2.06 (s, 1H), 1.82-1.75 (m, 3H). LC-MS: [M+H]+, 543, tR=1.406 min, HPLC: 98.08% at 214 nm, 98.69% at 254 nm, tR=5.25 min.

Workup

  1. stirringstirred for 10 mins
  2. extractionthe mixture extracted with ethyl acetate (10 mL)
  3. washThe organic layer was washed with brine (10 mL)
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customThe crude product was purified by prep-HPLC (Gemini 5u C18 150×21.2 mm
  8. waitgradient conditions: 20% acetonitrile/80% water (0.1% TFA, v/v) initially, proceeding to 50% acetonitrile/50% water (0.1% TFA, v/v) in a linear fashion over 9 min
  9. custom) to give the product
  10. concentrationthe mixture concentrated in vacuo

Sources & evidence

ORD record
ord-c09949b304e04508a7af653863e70274
Source dataset
uspto-grants-2015_10
Patent number
US09169259B2

Reaction notes

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