Thionyl Chloride → 2-{4-[1-(3-Fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethoxymethyl}-morpholine-4-carboxylic acid tert-butyl ester

HRID 1072093Notes

Reaction equation

HRID 1072093 reaction equation
S(Cl)(Cl)=O.[F:5][C:6]1[CH:7]=[C:8]([CH:31]=[CH:32][CH:33]=1)[CH2:9][N:10]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][C:20]3[C:25]4=[C:26]([CH2:29][OH:30])[CH:27]=[CH:28][N:24]4[N:23]=[CH:22][N:21]=3)=[CH:16][CH:17]=2)[CH:12]=[N:11]1.[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][O:44][C@H:43]([CH2:47]O)[CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][O:44][CH:43]([CH2:47][O:30][CH2:29][C:26]2[CH:27]=[CH:28][N:24]3[C:25]=2[C:20]([NH:19][C:15]2[CH:14]=[C:13]4[C:18](=[CH:17][CH:16]=2)[N:10]([CH2:9][C:8]2[CH:31]=[CH:32][CH:33]=[C:6]([F:5])[CH:7]=2)[N:11]=[CH:12]4)=[N:21][CH:22]=[N:23]3)[CH2:42]1)=[O:40])([CH3:37])([CH3:35])[CH3:36]

Participants

6

Reactant 4

HCID 24386Thionyl ChlorideHCID 81531DiisopropylethylamineHCID 1512577tert-Butyl (2S)-2-(hydroxymethyl)morpholine-4-carboxylateHCID 22390542(4-[1-(3-Fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]triazin-5-yl}-methanol

Product 1

HCID 674117422-{4-[1-(3-Fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethoxymethyl}-morpholine-4-carboxylic acid tert-butyl esterYield 50%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

Thionyl chloride (18 μL, 1.1 equiv) was added to a solution of {4-[1-(3-Fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]triazin-5-yl}-methanol (80 mg, 0.205 mmole) in dry DCM (4 mL) at RT. After 12 min, (2S)-2-hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester (65.3 mg, 1.5 equiv, H. Yanagisawa et al., Heterocycles, 1993, 35, 105.) was added followed by DIPEA (39.5 μL, 1.1 equiv). After 72 hr at RT, the solvent was removed and silica gel chromatography of the residue (gradient elution with 0 to 50% EtOAc in hexane) afforded 2-{4-[1-(3-Fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethoxymethyl}-morpholine-4-carboxylic acid tert-butyl ester (60 mg, 50% yield); MS: 588 (M+H)+; HPLC Ret Time: 2.69 min (Xterra C18 S5, 3.0×50 mm, 3 min gradient, 4 mL/min. A solution of this material in DCM (2 mL) was cooled to 0° C. and treated with TFA (1 mL). After 90 min, the solvents were removed and the residue was dissolved in DCM. This was washed with saturated NaHCO3 solution and the organic phase was dried (Na2SO4) and the solvents removed. Purification by preparative HPLC and then radial chromatography (1 mm silica gel plate, gradient elution with 0 to 3% NH3 (2N in MeOH) in DCM gave the title compound (30 mg, 60% yield): 1H NMR (CDCl3) δ 2.84-2.58 (m, 4H), 3.65-3.35 (m, 4H) 3.65-3.35 (m, 4H), 4.87 (s, 2H), 5.58 (s, 2H), 6.54 (d, J=2.5 Hz, 1H), 6.83 (d, J=9.5 Hz, 1H), 6.98-6.90 (m, 2H), 7.32-7.20 (m, 3H), 7.48 (d, J=2.5 Hz, 1H), 7.58 (dd, J=1.8, 8.8 Hz, 1H), 7.94 (s, 1H), 8.19 (s, 1H), 9.58 (s, 1H); MS: 488 (M+H)+; HPLC Ret Time: 1.65 min (Xterra C18 S5, 3.0×50 mm, 3 min gradient, 4 mL/min).

Workup

  1. waitAfter 72 hr at RT
  2. customthe solvent was removed
  3. washsilica gel chromatography of the residue (gradient elution with 0 to 50% EtOAc in hexane)

Sources & evidence

ORD record
ord-564c7a86dc844ac9a66594a106a73f4a
Source dataset
uspto-grants-2005_06
Patent number
US06908916B2

Reaction notes

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