Acryloyl chloride → HCID 86677242, compound

HRID 1842621Notes

Reaction equation

HRID 1842621 reaction equation
[C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[NH2:6][C:7]1[CH:12]=[C:11]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[CH:21]=[N:22][N:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=34)[C:17]([Cl:29])=[CH:16][N:15]=2)[C:10]([O:30][CH3:31])=[CH:9][C:8]=1[N:32]1[CH2:37][CH2:36][N:35]([C:38](=[O:49])[C@@H:39]([NH:41]C(=O)OC(C)(C)C)[CH3:40])[CH2:34][CH2:33]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH2:41][C@@H:39]([CH3:40])[C:38]([N:35]1[CH2:36][CH2:37][N:32]([C:8]2[CH:9]=[C:10]([O:30][CH3:31])[C:11]([NH:13][C:14]3[N:19]=[C:18]([C:20]4[CH:21]=[N:22][N:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=45)[C:17]([Cl:29])=[CH:16][N:15]=3)=[CH:12][C:7]=2[NH:6][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:33][CH2:34]1)=[O:49]

Participants

5

Reactant 3

HCID 13140Acryloyl chlorideHCID 81531DiisopropylethylamineHCID 86677243HCID 86677243, compound2×

Product 1

HCID 86677242HCID 86677242, compoundYield 28.2%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

A solution of acryloyl chloride (10.2 μL, 0.13 mmol) in CH2Cl2 (3 mL) was added dropwise to a stirred solution of (S)-tert-butyl N-[1-(4-{2-amino-4-[(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]-5-methoxyphenyl}piperazin-1-yl)-1-oxopropan-2-yl]carbamate (Intermediate 59, 65 mg) and DIPEA (0.75 mL) in CH2Cl2 (10 mL), which was cooled in an ice/water bath. The mixture was stirred for 0.75 h. then quenched with water (10 mL) and 2M Na2CO3 (5 mL). The phases were separated and the organic solution was dried (MgSO4) and concentrated in vacuo. The resulting residue was dissolved in CH2Cl2 (3 mL) and was then treated with TFA (0.1 mL). After standing for 0.25 h a second portion of TFA (0.2 mL) was added. After a further 0.25 h the solution was concentrated in vacuo and purified by preparative HPLC (Waters SunFire column, 5μ silica, 19 mm diameter, 100 mm length), eluting with decreasingly polar mixtures of water (containing 0.1% formic acid) and CH3CN. Fractions containing the desired compound were concentrated in vacuo to give the title compound (17 mg, 6% from 5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine) as a white solid; 1H NMR: 1.25 (3H, s), 2.83-2.96 (4H, m), 3.65-3.82 (7H, m), 4.14-4.23 (1H, m), 5.73 (1H, d), 61.9 (1H, d), 6.64-6.70 (1H, m), 6.69 (1H, s), 7.08-7.12 (1H, m) 7.30-7.37 (1H, m), 8.20-8.28 (2H, m), 8.35-8.41 (2H, m), 8.68 (1H, s), 8.80-8.84 (1H, m), 8.95 (1H, s), 9.11-9.15 (1H, m); m/z: ES+ MH+ 576.60.

Workup

  1. temperaturewas cooled in an ice/water bath
  2. customthen quenched with water (10 mL) and 2M Na2CO3 (5 mL)
  3. customThe phases were separated
  4. dry with materialthe organic solution was dried (MgSO4)
  5. concentrationconcentrated in vacuo
  6. dissolutionThe resulting residue was dissolved in CH2Cl2 (3 mL)
  7. additionwas then treated with TFA (0.1 mL)
  8. waitAfter standing for 0.25 h
  9. additiona second portion of TFA (0.2 mL) was added
  10. concentrationAfter a further 0.25 h the solution was concentrated in vacuo
  11. custompurified by preparative HPLC (Waters SunFire column, 5μ silica, 19 mm diameter, 100 mm length)
  12. washeluting with decreasingly polar mixtures of water (containing 0.1% formic acid) and CH3CN
  13. additionFractions containing the desired compound
  14. concentrationwere concentrated in vacuo

Sources & evidence

ORD record
ord-40b25f61baeb4b489a534c02769318ee
Source dataset
uspto-grants-2015_02
Patent number
US08946235B2

Reaction notes

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