4-Methylmorpholine → HCID 58346747, compound

HRID 222046Notes

Reaction equation

HRID 222046 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:23]3[C:24]4[CH2:32][CH2:31][C:30]5[C:26](=[CH:27][N:28]([CH2:33][C:34](O)=[O:35])[N:29]=5)[C:25]=4[S:37][C:22]=3[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[CH3:38][N:39]([CH3:48])[CH2:40][CH2:41][CH2:42][N:43]=[C:44]=NCC.CN1CCOCC1.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[N:19]=[CH:20][N:21]=[C:22]3[S:37][C:25]4[C:26]5[C:30]([CH2:31][CH2:32][C:24]=4[C:23]=23)=[N:29][N:28]([CH2:33][C:34]([N:43]2[CH2:42][CH2:41][C@H:40]([N:39]([CH3:48])[CH3:38])[CH2:44]2)=[O:35])[CH:27]=5)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1

Participants

6

Reactant 4

HCID 79724-MethylmorpholineHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 58346739HCID 58346739, compound

Product 1

HCID 58346747HCID 58346747, compoundYield 42%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To DMF (3 mL) were sequentially added [6-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-4,5-dihydro-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-2-yl]acetic acid (80 mg, 0.15 mmol), 3(R)-(−)-3(Dimethylamino)pyrrolidine (23 mg, 0.20 mmol), (3-Dimethylamino-propyl)-ethyl-carbodiimide (50 mg, 0.26 mmol), 4-methylmorpholine (0.03 ml, 0.29 mmol), and 1-Hydroxybenzotriazole (39 mg, 0.29 mmol). The mixture was stirred at rt for 14 h after which time the reaction mixture was concentrated in vacuo. The residue was diluted with water and extracted with EtOAc. The combined organic layers were concentrated in vacuo and purified by prep HPLC. The combined fractions were treated with saturated Na2CO3 and dried to afford free base product (35 mg, 42%) as a white solid. 1H-NMR (CD2Cl2) δ 8.38 (s, 1H), 7.81 (d, 1H), 7.53 (s, 1H), 7.45 (dd, 1H), 7.38 (dd, 1H), 7.28-7.22 (m, 2H), 6.97-7.08 (m, 3H), 5.15 (s, 2H), 4.84 (s, 2H), 3.64-3.80 (m, 2H), 3.15-3.53 (m, 3H), 3.07 (t, 2H), 2.61-2.81 (m, 1), 2.25 (s, 3H), 2.23 (s, 3H), 1.69-2.20 (m, 3H); LCMS RT=3.80 min, [M+H]+=632.2

Workup

  1. concentrationwas concentrated in vacuo
  2. additionThe residue was diluted with water
  3. extractionextracted with EtOAc
  4. concentrationThe combined organic layers were concentrated in vacuo
  5. custompurified by prep HPLC
  6. additionThe combined fractions were treated with saturated Na2CO3
  7. customdried

Sources & evidence

ORD record
ord-34666852b35e40148287bd3099794288
Source dataset
uspto-grants-2012_06
Patent number
US08207172B2

Reaction notes

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