6-Chloropyrimidine-4-carbonyl chloride → (S)-6-chloro-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)pyrimidine-4-carboxamide

HRID 880339Notes

Reaction equation

HRID 880339 reaction equation
[NH2:1][CH2:2][C@H:3]([OH:15])[CH2:4][N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1.[Cl:16][C:17]1[N:22]=[CH:21][N:20]=[C:19]([C:23](Cl)=[O:24])[CH:18]=1>C(Cl)Cl>[Cl:16][C:17]1[N:22]=[CH:21][N:20]=[C:19]([C:23]([NH:1][CH2:2][C@H:3]([OH:15])[CH2:4][N:5]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6]2)=[O:24])[CH:18]=1

Participants

4

Reactant 2

HCID 184220986-Chloropyrimidine-4-carbonyl chlorideHCID 25312355(S)-1-Amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol

Product 1

HCID 90241529(S)-6-chloro-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)pyrimidine-4-carboxamide

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
10 °C

Procedure

To a stirred mixture of (S)-1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (247 g, 1.20 mol), and TEA (250 g, 2.5 mol) in DCM (3500 mL) was added 6-chloropyrimidine-4-carbonyl chloride (190 g in 100 mL of DCM) slowly at −60° C. over 1 h. After addition, the mixture was then allowed to warm to 10° C. Stirring was continued for 1 h, at which time TLC showed the reaction was completed. The reaction was quenched by addition of water (1.5 L). The organic phase was collected, dried (Na2SO4) and evaporated. The residue was purified by flash chromatography (EtOAc˜DCM:MeOH=10:1) to give the desired product as a pale yellow solid. Four batches were run in parallel and produced a combined crude product weight of 800 g, 49% yield. 1H NMR (400 MHz, MeOD-d4) δ 8.73 (d, J=1.0 Hz, 1H), 8.07 (d, J=1.0 Hz, 1H), 7.17-7.06 (m, 3H), 7.00 (d, J=7.0 Hz, 1H), 4.12 (q, J=6.0 Hz, 1H), 3.74 (s, 2H), 3.64-3.53 (m, 2H), 2.94 (q, J=5.5 Hz, 2H), 2.92-2.81 (m, 2H), 2.78-2.64 (m, 2H); LCMS (m/z): 347.2 [M+H]+

Workup

  1. additionAfter addition
  2. customThe reaction was quenched by addition of water (1.5 L)
  3. customThe organic phase was collected
  4. dry with materialdried (Na2SO4)
  5. customevaporated
  6. customThe residue was purified by flash chromatography (EtOAc˜DCM:MeOH=10:1)

Sources & evidence

ORD record
ord-d51e6e57de5b47539747bd50440bbace
Source dataset
uspto-grants-2015_03
Patent number
US08993555B2

Reaction notes

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