Water → (S)-isopropyl (1-(3-(5-fluoro-2-methoxyphenyl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-yl)(methyl)carbamate

HRID 870777Notes

Reaction equation

HRID 870777 reaction equation
[CH:1]([O:4][C:5](=[O:23])[N:6]([C@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:19](Br)=[CH:20][N:21]=3)[N:18]=2)[CH2:9]1)[CH3:7])([CH3:3])[CH3:2].[F:24][C:25]1[CH:26]=[CH:27][C:28]([O:34][CH3:35])=[C:29](B(O)O)[CH:30]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[CH:1]([O:4][C:5](=[O:23])[N:6]([C@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:19]([C:27]4[CH:26]=[C:25]([F:24])[CH:30]=[CH:29][C:28]=4[O:34][CH3:35])=[CH:20][N:21]=3)[N:18]=2)[CH2:9]1)[CH3:7])([CH3:3])[CH3:2]

Participants

7

Reactant 4

HCID 962WaterHCID 11430Potassium CarbonateHCID 27826735-Fluoro-2-methoxyphenylboronic acidHCID 86696483(S)-isopropyl (1-(3-bromoimidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-yl)(methyl)carbamate

Product 1

HCID 86696487(S)-isopropyl (1-(3-(5-fluoro-2-methoxyphenyl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-yl)(methyl)carbamateYield 40.5%

Reagents, catalysts & solvents 2

HCID 178418807HCID 178418807, compoundCatalystHCID 6342AcetonitrileSolvent

Procedure

[(S)-1-(3-Bromo-imidazo[1,2-b]pyridazin-6-yl)-pyrrolidin-3-yl]-methyl-carbamic acid isopropyl ester (120 mg, 0.3 mmol), 5-fluoro-2-methoxy phenyl boronic acid (107 mg, 0.6 mmol), potassium carbonate (65 mg, 0.45 mmol), and Pd(dppf)Cl2 dichloromethane (26 mg, 0.03 mmol) were taken up in 2 mL acetonitrile and 1 mL water and microwaved in a sealed tube at 140° C. for 15 minutes. Reaction was then filtered through celite with acetonitrile reduced in vacuo, then purified on shimadzu neutral phase prep and product fractions lyophilized to get 52 mg (S)-isopropyl(1-(3-(5-fluoro-2-methoxyphenyl)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-yl)(methyl)carbamate. 1H NMR (400 MHz, DMSO-d6) δ 8.33-8.38 (m, 1H), 7.99 (s, 1H), 7.91 (d, J=9.85 Hz, 1H), 7.13-7.18 (m, 2H), 6.92 (d, J=9.85 Hz, 1H), 4.76-4.86 (m, 2H), 3.87 (s, 3H), 3.63-3.70 (m, 2H), 3.36-3.50 (m, 2H), 2.80 (s, 3H), 2.10-2.22 (m, 2H), 1.21 (d, J=6.32 Hz, 6H). (ESI) m/z 428 [(M+H)]+, calc'd for C22H26FN5O3: 427.4.

Workup

  1. customReaction
  2. filtrationwas then filtered through celite with acetonitrile
  3. custompurified on shimadzu neutral phase prep and product fractions

Sources & evidence

ORD record
ord-a035d8e17abe4f94a5cab5f1f0db9663
Source dataset
uspto-grants-2015_03
Patent number
US08969565B2

Reaction notes

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