Triethylamine → HCID 87402161, compound

HRID 1400952Notes

Reaction equation

HRID 1400952 reaction equation
[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:22])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:21])=[CH:17]/[C:18]([OH:20])=O.C(Cl)(=O)C(Cl)=O.[CH:29]1([NH:32][C:33]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][C:43]3[CH:48]=[CH:47][N:46]=[C:45]4[CH:49]=[C:50]([C:52]5[CH:57]=[CH:56][C:55]([CH2:58][N:59]6[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]6)=[CH:54][N:53]=5)[S:51][C:44]=34)=[C:38]([F:65])[CH:37]=2)=[O:34])[CH2:31][CH2:30]1.C(N(CC)CC)C>CN(C=O)C.C(Cl)Cl>[CH:29]1([NH:32][C:33]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][C:43]3[CH:48]=[CH:47][N:46]=[C:45]4[CH:49]=[C:50]([C:52]5[CH:57]=[CH:56][C:55]([CH2:58][N:59]6[CH2:60][CH2:61][N:62]([C:18](=[O:20])/[CH:17]=[C:16](\[CH3:21])/[CH:15]=[CH:14]/[CH:13]=[C:12](\[CH3:22])/[CH:11]=[CH:10]/[C:3]7[C:4]([CH3:8])([CH3:9])[CH2:5][CH2:6][CH2:7][C:2]=7[CH3:1])[CH2:63][CH2:64]6)=[CH:54][N:53]=5)[S:51][C:44]=34)=[C:38]([F:65])[CH:37]=2)=[O:34])[CH2:31][CH2:30]1

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 65578Oxalyl chlorideHCID 444795Retinoic AcidHCID 674423881-Cyclopropyl-3-(3-fluoro-4-(2-(5-(piperazin-1-ylmethyl)pyridin-2-yl)thieno[3,2-b]-pyridin-7-yloxy)phenyl)urea

Product 1

HCID 87402161HCID 87402161, compoundYield 24.1%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 6344DichloromethaneSolvent

Procedure

To a stirred solution of all-trans retinoic acid (ATRA) (130 mg, 0.43 mmol) in a mixture of DMF (1 ml) and DCM (6.5 ml) at 0° C. under nitrogen was added dropwise oxalyl chloride (76 μl, 0.87 mmol). The reaction mixture was stirred at rt for 50 min. DCM was removed under reduced pressure (no heat!) and the remaining solution was diluted with DMF (2 ml). To a stirred solution of 49 (150 mg, 0.29 mmol) and triethylamine (120 μl, 0.87 mmol) in DMF (5 ml) at 0° C. under nitrogen was slowly added the solution of the acyl chloride intermediate. After one hour, the reaction mixture at 0° C. was quenched by addition of water. The resulting suspension was shaken then the solid was collected by filtration, rinsed with water and air-dried. The crude material was purified twice by Biotage (Snap 25 g cartridge; MeOH/DCM: 0/100 to 5/95 over 30 CV, then 05/95 to 10/90 over 10 CV; Snap 25 g cartridge; MeOH/DCM: 1/99 to 10/90 over 30 CV). The desired fractions were combined and concentrated. The residue was dissolved in MeOH, concentrated until precipitation was occurred. The solid was collected by filtration, rinsed with MeOH and dried to afford the desired product 548 (56 mg, 0.07 mmol, 24% yield) as a bright yellow fluffy solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.72 (s, 1H), 8.57 (bd, J=1.8 Hz, 1H), 8.52 (d, J=5.5 Hz, 1H), 8.34 (s, 1H), 8.26 (d, J=8.2 Hz, 1H), 7.88 (dd, J=8.2, 1.9 Hz, 1H), 7.73 (dd, J=13.6, 2.4 Hz, 1H), 7.38 (t, J=9.1 Hz, 1H), 7.19 (dd, J=9.0, 1.4 Hz, 1H), 6.82 (dd, J=15.3, 11.3 Hz, 1H), 6.65 (dd, J=5.5, 0.8 Hz, 1H), 6.59 (bd, J=2.5 Hz, 1H), 6.39 (d, J=15.1 Hz, 1H), 6.25-6.10 (m, 4H), 3.60 (s, 2H), 3.57-3.43 (m, 4H), 2.59-2.51 (m, 1H), 2.45-2.34 (m, 4H), 2.04-1.96 (m, 5H), 1.95 (s, 3H), 1.68 (s, 3H), 1.61-1.52 (m, 2H), 1.46-1.40 (m, 2H), 1.00 (s, 6H), 0.72-0.58 (m, 2H), 0.49-0.36 (m, 2H). MS (m/z): 801.8 (M+H).

Workup

  1. customDCM was removed under reduced pressure (no heat
  2. addition) and the remaining solution was diluted with DMF (2 ml)
  3. waitAfter one hour
  4. customthe reaction mixture at 0° C. was quenched by addition of water
  5. stirringThe resulting suspension was shaken
  6. filtrationthe solid was collected by filtration
  7. washrinsed with water
  8. customair-dried
  9. customThe crude material was purified twice by Biotage (Snap 25 g cartridge
  10. concentrationconcentrated
  11. dissolutionThe residue was dissolved in MeOH
  12. concentrationconcentrated until precipitation
  13. filtrationThe solid was collected by filtration
  14. washrinsed with MeOH
  15. customdried

Sources & evidence

ORD record
ord-5c6a1c5a5bf043fa9066489788ccfbbc
Source dataset
uspto-grants-2014_12
Patent number
US08906852B2

Reaction notes

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