Triethylamine → Cyclopentyl-{4-[2-methyl-4-(6-pyrrolidin-1-yl-pyrido[3,4-d]pyrimidin-4-ylamino)-phenoxy]-piperidin-1-yl}-methanone

HRID 731909Notes

Reaction equation

HRID 731909 reaction equation
C(OC(N1CCCCC1[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]2[C:23]3[CH:31]=[C:30](F)[N:29]=[CH:28][C:24]=3[N:25]=[CH:26][N:27]=2)=[CH:17][C:16]=1[CH3:33])=O)(C)(C)C.F[C:35]1[N:45]=[CH:44][C:38]2N=CNC(=O)[C:37]=2[CH:36]=1.O=S(Cl)Cl.CC[N:52]([CH2:55][CH3:56])[CH2:53][CH3:54].C(OC(N1CCC([O:70][C:71]2[CH:76]=[CH:75][C:74](N)=[CH:73][C:72]=2C)CC1)=O)(C)(C)C>ClCCCl.CN(C=O)C>[CH:76]1([C:71]([N:45]2[CH2:35][CH2:36][CH:37]([O:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]4[C:23]5[CH:31]=[C:30]([N:52]6[CH2:53][CH2:54][CH2:56][CH2:55]6)[N:29]=[CH:28][C:24]=5[N:25]=[CH:26][N:27]=4)=[CH:17][C:16]=3[CH3:33])[CH2:38][CH2:44]2)=[O:70])[CH2:75][CH2:74][CH2:73][CH2:72]1

Participants

8

Reactant 5

HCID 8471TriethylamineHCID 24386Thionyl ChlorideHCID 22181171Tert-butyl 4-(4-amino-2-methylphenoxy)piperidine-1-carboxylateHCID 865952384-(6-Fluoro-pyrido[3,4-d]pyrimidin-4-ylamino)-2-methyl-phenoxyl-piperidine-1-carboxylic acid tert-butyl esterHCID 1354173706-fluoropyrido[3,4-d]pyrimidin-4-ol

Product 1

HCID 11202845Cyclopentyl-{4-[2-methyl-4-(6-pyrrolidin-1-yl-pyrido[3,4-d]pyrimidin-4-ylamino)-phenoxy]-piperidin-1-yl}-methanoneYield 56%

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolventHCID 6228DimethylformamideSolvent

Procedure

4-[4-(6-Fluoro-pyrido[3,4-d]pyrimidin-4-ylamino)-2-methyl-phenoxyl-piperidine-1-carboxylic acid tert-butyl ester: A solution of 6-Fluoro-3H-pyrido[3,4-d]pyrimidin-4-one (2.0 g, 12.11 mmol), SOCl2 (14.4 g, 121.1 mmol), and DMF (0.4 mL) in DCE (40 mL) was heated to reflux for 4 h. The reaction was then concentrated and the resulting dark residue was dissolved in t-BuOH/DCE 1:1 (40 mL), NEt3 (2.45 g, 24.22 mmol) and 4-(4-Amino-2-methyl-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (3.7 g, 12.11 mmol) were added, the resulting solution was heated to reflux for 2 h. The reaction was concentrated, the residue was dissolved in EtOAc and washed 2× water then the organic layer was dried over Na2SO4. Purification by flash column chromatography (CH2Cl2/MeOH 98:2) gave the title compound as a yellow solid (3.08 g, 56%). LRMS: 454.2; 398.2; 354.2 (MH+); 1H NMR (DMSO-d6, 400 MHz): δ 9.88 (s, 1H), δ 8.84 (s, 1H), δ 8.56 (s, 1H), δ 8.17 (s, 1H), δ 7.53-7.55 (m, 2H), δ 7.00-7.02 (m, 1H), δ 4.50-4.55 (m, 1H), δ 3.21-3.26 (m, 2H), δ 2.16 (s, 3H), δ 1.83-1.89 (m, 2H), δ 1.51-1.59 (m, 1H), δ 1.37 (s, 9H).

Workup

  1. temperatureto reflux for 4 h
  2. concentrationThe reaction was then concentrated
  3. dissolutionthe resulting dark residue was dissolved in t-BuOH/DCE 1:1 (40 mL)
  4. temperaturethe resulting solution was heated
  5. temperatureto reflux for 2 h
  6. concentrationThe reaction was concentrated
  7. dissolutionthe residue was dissolved in EtOAc
  8. washwashed 2× water
  9. dry with materialthe organic layer was dried over Na2SO4
  10. customPurification by flash column chromatography (CH2Cl2/MeOH 98:2)

Sources & evidence

ORD record
ord-c7d2ace3d9fb49e7b6537dbe22840e0e
Source dataset
uspto-grants-2009_09
Patent number
US07585869B2

Reaction notes

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