Diisopropylethylamine → 3-[3-tert-Butyl-5-(3-{(1S,4R)-4-[3-((S)-1-methyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureido)-pyrazol-1-yl]-benzoic acid ethyl ester

HRID 630740Notes

Reaction equation

HRID 630740 reaction equation
[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]1[N:11]2[CH:12]=[C:13]([O:16][C@H:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C@@H:20]([NH2:27])[CH2:19][CH2:18]3)[CH:14]=[CH:15][C:10]2=[N:9][N:8]=1.[CH2:28]([O:30][C:31](=[O:56])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[C:42]([NH:43][C:44](OCC(Cl)(Cl)Cl)=[O:45])=[CH:41][C:40]([C:52]([CH3:55])([CH3:54])[CH3:53])=[N:39]2)[CH:33]=1)[CH3:29].CCN(C(C)C)C(C)C>O1CCOCC1>[CH2:28]([O:30][C:31](=[O:56])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[C:42]([NH:43][C:44]([NH:27][C@@H:20]3[C:21]4[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=4)[C@H:17]([O:16][C:13]4[CH:14]=[CH:15][C:10]5[N:11]([C:7]([C@@H:3]6[CH2:4][CH2:5][CH2:6][N:2]6[CH3:1])=[N:8][N:9]=5)[CH:12]=4)[CH2:18][CH2:19]3)=[O:45])=[CH:41][C:40]([C:52]([CH3:55])([CH3:54])[CH3:53])=[N:39]2)[CH:33]=1)[CH3:29]

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 866870083-[3-tert-Butyl-5-(2,2,2-trichloro-ethoxycarbonylamino)-pyrazol-1-yl]-benzoic acid ethyl esterHCID 117666105(1S,4R)-4-[3-((S)-1-Methyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-ylamine

Product 1

HCID 896122263-[3-tert-Butyl-5-(3-{(1S,4R)-4-[3-((S)-1-methyl-pyrrolidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureido)-pyrazol-1-yl]-benzoic acid ethyl esterYield 96%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
90 °C

Procedure

A mixture of Intermediate 5c (163 mg, 0.45 mmol), Intermediate 30a (208 mg, 0.45 mmol) in 1,4-dioxane (3 mL) and DIPEA (119 μL, 0.68 mmol) was stirred at 90° C. for 3 h. The cooled mixture was concentrated in vacuo. The residue was purified by FCC, using 0-12% MeOH in DCM, to give the product (291 mg, 96%). A 64 mg portion of this was further purified by HPLC (C18 X-select column, 30-98% MeCN in H2O, 0.1% HCO2H) to give the title compound as a white powder after freeze-drying powder (38 mg). LCMS (Method 5): Rt 3.85 min, m/z 677.3 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.26-1.33 (12H, m), 1.80-2.27 (11H, m), 2.30-2.39 (1H, m), 3.09-3.16 (1H, m), 3.99 (1H, br t, J 8.2), 4.32 (2H, q, J 7.1), 4.74-4.83 (1H, m), 5.36-5.41 (1H, m), 6.33 (1H, s), 7.11 (1H, d, J 8.6), 7.19-7.37 (5H, m), 7.66 (1H, t, J 7.9), 7.75 (1H, d, J 9.9), 7.80-7.84 (1H, m), 7.93-7.98 (1H, m), 8.07-8.09 (1H, m), 8.22-8.28 (2H, m).

Workup

  1. concentrationThe cooled mixture was concentrated in vacuo
  2. customThe residue was purified by FCC

Sources & evidence

ORD record
ord-6a5a3b869e0f4a9395f811c17f0ab461
Source dataset
uspto-grants-2016_04
Patent number
US09315503B2

Reaction notes

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