1,1'-Carbonyldiimidazole → N-((R)-1-(3,4-dichlorophenyl)ethyl)-2-(1,1,1-trifluoro-3-hydroxypropan-2-ylamino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxamide

HRID 2279560Notes

Reaction equation

HRID 2279560 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH2:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].CCN(C(C)C)C(C)C.C1N=CN([C:26](N2C=NC=C2)=[O:27])C=1.[F:33][C:34]([F:50])([F:49])[CH:35]([NH:38][C:39]1[N:40]=[CH:41][C:42]2[CH2:48][CH2:47][NH:46][CH2:45][C:43]=2[N:44]=1)[CH2:36][OH:37]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:11][C:26]([N:46]2[CH2:47][CH2:48][C:42]3[CH:41]=[N:40][C:39]([NH:38][CH:35]([CH2:36][OH:37])[C:34]([F:33])([F:49])[F:50])=[N:44][C:43]=3[CH2:45]2)=[O:27])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8]

Participants

6

Reactant 4

HCID 682631,1'-CarbonyldiimidazoleHCID 81531DiisopropylethylamineHCID 793515(R)-1-(3,4-dichlorophenyl)ethanamineHCID 682952573,3,3-Trifluoro-2-(5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-ylamino)propan-1-ol

Product 1

HCID 86705547N-((R)-1-(3,4-dichlorophenyl)ethyl)-2-(1,1,1-trifluoro-3-hydroxypropan-2-ylamino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxamide

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

To a stirred solution of 185 (21.0 mg, 0.111 mmol) in DCM (1 mL) at RT under nitrogen was added sequentially DIPEA (38.5 μL, 0.221 mmol) neat by syringe followed by CDI (17.9 mg, 0.111 mmol) neat as a solid. After stirring for 30 min, the solution was added by pipet to a flask containing solid 354 (29 mg, 0.111 mmol). The reaction was stirred at RT under nitrogen overnight. The reaction was diluted to 30 mL with DCM and washed sequentially with 2 N HCl (2×30 mL) with 2N HCl and satd. aq. NaHCO3 (2×30 mL). The organics were dried (MgSO4), filtered and concentrated to a yellow foam. The crude product was purified by SiO2 chromatography (Biotage 12S) eluting with EtOAc. The product containing fractions were pooled and concentrated to afford 10 mg (19%) of I-92 as a yellow residue: 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.39 (m, 2H), 7.17 (dd, 1H), 5.57 (d, 1H), 4.97 (m, 1H), 4.91 (m, 1H), 4.75 (d, 1H), 4.36 (s, 2H), 3.96 (m, 2H), 3.65 (m, 2H), 2.69 (dd, 2H), 1.48 (d, 6H); MS m/z (APCI-pos) M+1=478.5.

Workup

  1. additionthe solution was added by pipet to a flask
  2. stirringThe reaction was stirred at RT under nitrogen overnight
  3. washwashed sequentially with 2 N HCl (2×30 mL) with 2N HCl
  4. dry with materialThe organics were dried (MgSO4)
  5. filtrationfiltered
  6. concentrationconcentrated to a yellow foam
  7. customThe crude product was purified by SiO2 chromatography (Biotage 12S)
  8. washeluting with EtOAc
  9. additionThe product containing fractions
  10. concentrationconcentrated
  11. customto afford 10 mg (19%) of I-92 as a yellow residue

Sources & evidence

ORD record
ord-aa6189d9f80a4cab8f32334d719d2960
Source dataset
uspto-grants-2015_09
Patent number
US09133187B2

Reaction notes

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