tert-Butylimino-tri(pyrrolidino)phosphorane → Methyl 7-(2-methoxyphenyl)-2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxylate

HRID 518890Notes

Reaction equation

HRID 518890 reaction equation
[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH:15]=O)=[C:10]([O:17][CH:18]([CH3:20])[CH3:19])[CH:9]=2)[CH2:4][CH2:3]1.CC(N=P(N1CCCC1)(N1CCCC1)N1CCCC1)(C)C.[CH3:42][O:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[C:50]1[C:54]2[N:55]=C(S(C)(=O)=O)[N:57]=[CH:58][C:53]=2[S:52][C:51]=1[C:63]([O:65][CH3:66])=[O:64]>CN(C=O)C.C(OCC)(=O)C>[CH3:42][O:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[C:50]1[C:54]2[N:55]=[C:15]([NH:14][C:11]3[CH:12]=[CH:13][C:8]([CH:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:9][C:10]=3[O:17][CH:18]([CH3:20])[CH3:19])[N:57]=[CH:58][C:53]=2[S:52][C:51]=1[C:63]([O:65][CH3:66])=[O:64]

Participants

6

Reactant 3

HCID 3856267tert-Butylimino-tri(pyrrolidino)phosphoraneHCID 86698039HCID 86698039, compoundHCID 86698041Methyl 7-(2-methoxyphenyl)-2-(methylsulfonyl)thieno[3,2-d]pyrimidine-6-carboxylate

Product 1

HCID 86698040Methyl 7-(2-methoxyphenyl)-2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxylateYield 73.8%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

A mixture of 527 mg of N-[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]formamide and 953 mg of 1-[N-(2-methylpropan-2-yl)-P,P-di(pyrrolidin-1-yl)phosphorimidoyl]-pyrrolidine (BTPP) in 10 ml of anhydrous DMF is stirred at ambient temperature for 30 min, and then a solution of 577 mg of methyl 7-(2-methoxyphenyl)-2-(methylsulfonyl)thieno[3,2-d]pyrimidine-6-carboxylate in 15 ml of anhydrous DMF is slowly added. The mixture is stirred at ambient temperature for 48 h, and then diluted with ethyl acetate and washed three times with water. The organic phase is dried over magnesium sulfate, filtered and concentrated under vacuum. The crude product is purified on 80 g of silica, elution being carried out with 5-10% of methanol in dichloromethane, so as to obtain 615 mg of methyl 7-(2-methoxyphenyl)-2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxylate in the form of a yellow solid. The crude product is diluted with 600 ml of 7N ammoniacal methanol and the solution is stirred at ambient temperature for 48 h, and then concentrated under vacuum. The residue is solubilized with 100 ml of hot ethyl acetate and the solution is left to cool in order to obtain a suspension. The suspension is cooled in an ice bath and filtered. The solid is washed with ethyl ether and dried under vacuum, so as to obtain 477 mg of 7-(2-methoxyphenyl)-2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide in the form of a yellow solid.

Workup

  1. stirringThe mixture is stirred at ambient temperature for 48 h
  2. washwashed three times with water
  3. dry with materialThe organic phase is dried over magnesium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated under vacuum
  6. customThe crude product is purified on 80 g of silica, elution

Sources & evidence

ORD record
ord-09e6653e56b04194919b022d43bb1013
Source dataset
uspto-grants-2015_08
Patent number
US09115140B2

Reaction notes

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