Chloroacetyl chloride → HCID 78318876, compound

HRID 527424Notes

Reaction equation

HRID 527424 reaction equation
FC(F)(F)C(O)=O.[NH2:8][C:9]1[CH:10]=[C:11]([N:15]2[C:20]3[N:21]=[C:22]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([N:32]5[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]5)=[CH:28][C:27]=4[O:39][CH3:40])[N:23]=[CH:24][C:19]=3[CH:18]=[CH:17][C:16]2=[O:41])[CH:12]=[CH:13][CH:14]=1.CCN(C(C)C)C(C)C.[Cl:51][CH2:52][C:53](Cl)=[O:54]>C(Cl)Cl>[Cl:51][CH2:52][C:53]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:15]2[C:20]3[N:21]=[C:22]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([N:32]5[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]5)=[CH:28][C:27]=4[O:39][CH3:40])[N:23]=[CH:24][C:19]=3[CH:18]=[CH:17][C:16]2=[O:41])[CH:10]=1)=[O:54]

Participants

5

Reactant 3

HCID 6577Chloroacetyl chlorideHCID 81531DiisopropylethylamineHCID 86732023HCID 86732023, compound

Product 1

HCID 78318876HCID 78318876, compound

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

8-(3-Aminophenyl)-24(2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (1b, 131 mg, 0.29 mmol) in DCM (5 mL) at 0° C. was treated with DIEA (0.13 mL, 0.72 mmol) and cooled in an ice bath at 0° C. The solution was then treated with 2-chloroacetyl chloride (Sigma Aldrich; 0.027 mL, 0.344 mmol) slowly dropwise over 10 min and stirred at 0° C. for 30 min. LC-MS indicated only trace amounts of the desired product. The reaction mixture was sonicated for 10 min to help dissolve the substrate and another 2 drops of 2-chloroacetyl chloride was added. After 30 min, LC-MS indicated 74% conversion to the desired product m/z (ESI, +ve ion) 533.9 (M+H)+ along with unreacted starting material. 2 more drops of 2-chloroacetyl chloride was added and the solution stirred for another 75 min resulting in clean conversion to the desired product. The reaction mixture was concentrated, treated with DMSO (8 mL) and purified on a Gilson preparatory HPLC (Gemini Phenomenex; 30×150 mm, 5μ, 10-95% 0.1% TFA/CH3CN in 0.1% TFA/water). The product containing fractions were concentrated under reduced pressure (rotary evaporator) and the resulting aqueous solution treated with a 10% aqueous solution of Na2CO3 and extracted with DCM (4×30 mL), dried over sodium sulfate and dried under vacuum overnight affording 2-chloro-N-(3-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acetamide (53.4 mg, 0.100 mmol, 35% yield) as a yellow solid. m/z (ESI, +ve ion) 533.9 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.50 (1H, s), 8.75 (1H, s), 8.17 (1H, s), 7.91 (1H, d, J=9.4 Hz), 7.75 (1H, d, J=8.2 Hz), 7.49-7.57 (2H, m), 7.25 (1H, d, J=9.0 Hz), 7.04 (1H, d, J=7.8 Hz), 6.53 (1H, d, J=2.2 Hz), 6.44 (1H, d, J=9.4 Hz), 6.04 (1H, br. s.), 4.25 (2H, s), 3.78 (3H, s), 3.06 (4H, br. s.), 2.40-2.48 (4H, m), 2.23 (3H, s).

Sources & evidence

ORD record
ord-be4f0fd77cd146f4a958aa07c44c76ae
Source dataset
uspto-grants-2016_05
Patent number
US09346801B2

Reaction notes

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