Diisopropylethylamine → (4-{6-Amino-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)-ethoxy]-furo[3,2-c]pyridin-3-yl}-3,6-dihydro-2H-pyridin-1-yl)-piperazin-1-ylmethanone

HRID 911958Notes

Reaction equation

HRID 911958 reaction equation
ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[Cl:13][C:14]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([Cl:21])[C:15]=1[C@H:22]([O:24][C:25]1[C:26]2[O:34][CH:33]=[C:32]([C:35]3[CH2:36][CH2:37][NH:38][CH2:39][CH:40]=3)[C:27]=2[CH:28]=[N:29][C:30]=1[NH2:31])[CH3:23].CCN(C(C)C)C(C)C.[N:50]1([C:56](OC(C)(C)C)=[O:57])[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1>C(Cl)Cl>[NH2:31][C:30]1[N:29]=[CH:28][C:27]2[C:32]([C:35]3[CH2:36][CH2:37][N:38]([C:56]([N:50]4[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]4)=[O:57])[CH2:39][CH:40]=3)=[CH:33][O:34][C:26]=2[C:25]=1[O:24][C@@H:22]([C:15]1[C:16]([Cl:21])=[CH:17][CH:18]=[C:19]([F:20])[C:14]=1[Cl:13])[CH3:23]

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 94429TriphosgeneHCID 143452tert-Butyl piperazine-1-carboxylateHCID 578124807-[(R)-1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-3-(1,2,3,6-tetrahydropyridin-4-yl)furo[3,2-c]pyridin-6-ylamine

Product 1

HCID 44181653(4-{6-Amino-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)-ethoxy]-furo[3,2-c]pyridin-3-yl}-3,6-dihydro-2H-pyridin-1-yl)-piperazin-1-ylmethanone

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent3×

Procedure

A solution of triphosgene (4 mg, 0.01 mmol) in DCM (0.8 mL) was cooled to 0° C. A solution of 7-[(R)-1-(2,6-dichloro-3-fluorophenyl)-ethoxy]-3-(1,2,3,6-tetrahydropyridin-4-yl)-furo[3,2-c]pyridin-6-ylamine (10.0 mg, 0.0237 mmol), DIPEA (0.04 mL, 0.2 mmol) and DCM was added, and the mixture was allowed to warm to rt. A solution of tert-butyl 1-piperazinecarboxylate (8.82 mg, 0.0474 mmol) in DCM was then added, and the mixture was stirred at rt for 30 min. The material was transferred to a separatory funnel and washed with sat. aq. NaHCO3. The organic layer was concentrated in vacuo, redissolved in dioxane and transferred to a sealed tube. 4 M HCl in 1,4-dioxane (0.2 mL) was added, and the solution was heated to 50° C. for 3 h. The material was concentrated in vacuo and redissolved in DMF (0.5 mL). The solution was purified by HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a brown solid. 1H NMR (CD3OD, 400 MHz): δ=1.89 (d, J=6.8 Hz, 3H), 2.56 (br, s, 2H), 3.21-3.29 (m, 4H), 3.44-3.52 (m, 4H), 3.56 (t, J=5.8 Hz, 2H), 4.08 (d, J=2.5 Hz, 2H), 6.26 (br, s, 1H), 6.50 (q, J=6.7 Hz, 1H), 7.22 (t, J=8.7 Hz, 1H), 7.40 (dd, J=9.0, 4.9 Hz, 1H), 7.66 (s, 1H), 8.19 (s, 1H). MS (ES+): m/z 534.14 [MH+]. HPLC: tR=2.16 min (ZQ2, polar—5 min).

Workup

  1. customThe material was transferred to a separatory funnel
  2. washwashed with sat. aq. NaHCO3
  3. concentrationThe organic layer was concentrated in vacuo
  4. dissolutionredissolved in dioxane
  5. customtransferred to a sealed tube
  6. addition4 M HCl in 1,4-dioxane (0.2 mL) was added
  7. temperaturethe solution was heated to 50° C. for 3 h
  8. concentrationThe material was concentrated in vacuo
  9. dissolutionredissolved in DMF (0.5 mL)
  10. customThe solution was purified by HPLC
  11. additionThe fractions containing the pure product
  12. concentrationwere concentrated in vacuo

Sources & evidence

ORD record
ord-bec30a6609c64340a6c39afaef3c40d0
Source dataset
uspto-grants-2011_09
Patent number
US08022206B2

Reaction notes

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