Phosgene → 3-Cyanobenzyl 3-(5-(2-((4-morpholin-4-ylphenyl)amino)pyrimidin-4-yl)imidazo[2,1-b][1,3]thiazol-6-yl)phenylcarbamate

HRID 562798Notes

Reaction equation

HRID 562798 reaction equation
[C:1](N1C=CN=C1)([N:3]1C=CN=C1)=O.ClC1C=CC=C(Cl)C=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[N:26]=[C:27]3[N:31]([C:32]=2[C:33]2[CH:38]=[CH:37][N:36]=[C:35]([NH:39][C:40]4[CH:45]=[CH:44][C:43]([N:46]5[CH2:51][CH2:50]N(CC)[CH2:48][CH2:47]5)=[CH:42][CH:41]=4)[N:34]=2)[CH:30]=[CH:29][S:28]3)[CH:20]=1)=[O:17].F[C:60]1[CH:61]=[C:62]([CH2:67][OH:68])[CH:63]=[C:64](F)[CH:65]=1.C(Cl)(Cl)=[O:70]>CN(C)C1C=CN=CC=1.CN1CCCC1=O.C1(C)C=CC=CC=1.C(#N)C.CO>[N:46]1([C:43]2[CH:44]=[CH:45][C:40]([NH:39][C:35]3[N:34]=[C:33]([C:32]4[N:31]5[C:27]([S:28][CH:29]=[CH:30]5)=[N:26][C:25]=4[C:21]4[CH:20]=[C:19]([NH:18][C:16](=[O:17])[O:68][CH2:67][C:62]5[CH:63]=[CH:64][CH:65]=[C:60]([C:1]#[N:3])[CH:61]=5)[CH:24]=[CH:23][CH:22]=4)[CH:38]=[CH:37][N:36]=3)=[CH:41][CH:42]=2)[CH2:51][CH2:50][O:70][CH2:48][CH2:47]1

Participants

10

Reactant 4

HCID 6371PhosgeneHCID 682631,1'-Carbonyldiimidazole2×HCID 5227213,5-Difluorobenzyl alcoholHCID 670059352,6-dichloro-N-(3-(5-(2-((4-(4-ethylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)imidazo[2,1-b][1,3]thiazol-6-yl)phenyl)benzamide

Product 1

HCID 670055663-Cyanobenzyl 3-(5-(2-((4-morpholin-4-ylphenyl)amino)pyrimidin-4-yl)imidazo[2,1-b][1,3]thiazol-6-yl)phenylcarbamate

Reagents, catalysts & solvents 5

HCID 142844-(Dimethylamino)pyridineCatalystHCID 887MethanolSolventHCID 1140TolueneSolventHCID 6342AcetonitrileSolventHCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
70 °C

Procedure

Into a 2 ml microwave vial was added EXAMPLE 3C (50 mg), 3,5-difluorophenyl)methanol (30.7 mg), 1,1′-carbonyldiimidazole (34.5 mg), 4-(dimethylamino)pyridine (2 mg), and acetonitrile (1065 μl). The mixture was heated in a Biotage Initiator 2 monomode microwave reactor at 150° C. for 25 minutes. Into the vial was added another portion of 1,1′-carbonyldiimidazole (34.5 mg) and the mixture was diluted with 1-methyl-2-pyrrolidinone (900 μl) then heated in an oil bath at 70° C. for 5 hours. To the vial was added (3,5-difluorophenyl)methanol (30.7 mg) and the mixture was heated at 70° C. for 18 hours. The mixture was cooled and phosgene (112 μl) in toluene was added and reaction was stirred at room temperature for 1 week. The mixture was filtered and purified using reverse phase HPLC with 0.1% ammonium hydroxide dissolved in the acetonitrile/water as the mobile phase. MS (ESI(+)) m/e 629 (M+H)+; 1H-NMR (500 MHz, methanol-d4) □ 8.62 (bs, 1H), 7.98 (d, 1H), 7.72-7.76 (m, 1H), 7.67-7.72 (m, 3H), 7.56 (td, 3H), 7.52 (d, 2H), 7.45 (t, 1H), 7.32 (d, 1H), 7.30 (dt, 1H), 7.20 (d, 1H), 6.69 (d, 1H), 5.19 (s, 2H), 3.87-3.94 (m, 4H), 3.33 (s, 4H).

Workup

  1. temperaturethe mixture was heated at 70° C. for 18 hours
  2. temperatureThe mixture was cooled
  3. customreaction
  4. filtrationThe mixture was filtered
  5. custompurified
  6. dissolutiondissolved in the acetonitrile/water as the mobile phase

Sources & evidence

ORD record
ord-2521b386593d4793b8fe616d3ef3494a
Source dataset
uspto-grants-2011_11
Patent number
US08067409B2

Reaction notes

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