1,1'-Carbonyldiimidazole → (S)-1-(7-fluorochroman-4-yl)-3-(3-(2-methylpyridin-4-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea

HRID 571420Notes

Reaction equation

HRID 571420 reaction equation
[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:12]3[CH:13]=[N:14][C:15]([NH2:17])=[CH:16][C:11]=3[N:10]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.C1N=CN([C:42]([N:44]2C=N[CH:46]=[CH:45]2)=[O:43])C=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl.[F:60][C:61]1[CH:70]=[C:69]2[C:64]([C@@H](N)C[CH2:67][O:68]2)=[CH:63][CH:62]=1>C1COCC1.C(Cl)Cl>[F:60][C:61]1[CH:70]=[C:69]2[C:64]([C@@H:45]([NH:44][C:42]([NH:17][C:15]3[N:14]=[CH:13][C:12]4[C:8]([C:6]5[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=5)=[N:9][N:10]([C:18]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)[C:11]=4[CH:16]=3)=[O:43])[CH2:46][CH2:67][O:68]2)=[CH:63][CH:62]=1

Participants

7

Reactant 4

HCID 682631,1'-CarbonyldiimidazoleHCID 2724254Sodium bis(trimethylsilyl)amideHCID 72943051(4S)-7-fluoro-3,4-dihydro-2H-1-benzopyran-4-amine hydrochlorideHCID 895258183-(2-methylpyridin-4-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-amine

Product 1

HCID 89525880(S)-1-(7-fluorochroman-4-yl)-3-(3-(2-methylpyridin-4-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)ureaYield 78%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent3×

Procedure

In a vial 3-(2-methylpyridin-4-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-amine (101.0 mg, 0.216 mmol) and CDI (77 mg, 0.475 mmol) were dissolved in THF (6.00 ml) before treatment with 1.0 M solution NaHMDS in THF (0.454 ml, 0.454 mmol). After stirring at RT for 1 h, a solution of (S)-7-fluorochroman-4-amine hydrochloride (97 mg, 0.475 mmol) and TEA (0.151 ml, 1.080 mmol) in THF (2.00 ml) were added. The resulting mixture was heated to 55° C. for 1 h. The mixture was cooled to RT and taken up in DCM. The organic phase was washed with saturated NaHCO3 and the aqueous phase was back-extracted with DCM (2×). The combined organic layers were dried (Na2SO4) and volatiles were evaporated in vacuo. Crude material was purified via reverse phase HPLC over a gradient of 10-90% MeCN in water with 0.1% TFA to yield (S)-1-(7-fluorochroman-4-yl)-3-(3-(2-methylpyridin-4-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea (111 mg, 0.168 mmol, 78% yield). MS ESI calc'd. for C41H33FN6O6 [M+1]+ 661, found 661.

Workup

  1. temperatureThe resulting mixture was heated to 55° C. for 1 h
  2. temperatureThe mixture was cooled to RT
  3. washThe organic phase was washed with saturated NaHCO3
  4. extractionthe aqueous phase was back-extracted with DCM (2×)
  5. dry with materialThe combined organic layers were dried (Na2SO4) and volatiles
  6. customwere evaporated in vacuo
  7. customCrude material was purified via reverse phase HPLC over a gradient of 10-90% MeCN in water with 0.1% TFA

Sources & evidence

ORD record
ord-3db611be531f4a5f852f35d72c5877e3
Source dataset
uspto-grants-2015_05
Patent number
US09023865B2

Reaction notes

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