Morpholine → HCID 68709776, compound

HRID 645516Notes

Reaction equation

HRID 645516 reaction equation
C(OC(C1C(OCCC2CCN(C(OC(C)(C)C)=O)CC2)=NC(C#N)=NC=1Cl)=O)C=C.C1C2(CCC(CN)CC2)CC1.C(N(CC)CC)C.C([O:53][C:54]([C:56]1[C:57]([O:75][CH2:76][CH2:77][CH:78]2[CH2:83][CH2:82][N:81]([C:84]([O:86][C:87]([CH3:90])([CH3:89])[CH3:88])=[O:85])[CH2:80][CH2:79]2)=[N:58][C:59]([C:73]#[N:74])=[N:60][C:61]=1[NH:62][CH2:63][CH:64]1[CH2:72][CH2:71][C:67]2([CH2:70][CH2:69][CH2:68]2)[CH2:66][CH2:65]1)=[O:55])C=C.N1CCOCC1>C(C#N)C.CCOC(C)=O.C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:87]([O:86][C:84]([N:81]1[CH2:82][CH2:83][CH:78]([CH2:77][CH2:76][O:75][C:57]2[C:56]([C:54]([OH:55])=[O:53])=[C:61]([NH:62][CH2:63][CH:64]3[CH2:72][CH2:71][C:67]4([CH2:70][CH2:69][CH2:68]4)[CH2:66][CH2:65]3)[N:60]=[C:59]([C:73]#[N:74])[N:58]=2)[CH2:79][CH2:80]1)=[O:85])([CH3:90])([CH3:88])[CH3:89]

Participants

10

Reactant 5

HCID 8083MorpholineHCID 8471TriethylamineHCID 509989941-(Spiro[3.5]nonan-7-yl)methanamineHCID 68708275HCID 68708275, compoundHCID 86627799HCID 86627799, compound

Product 1

HCID 68709776HCID 68709776, compound

Reagents, catalysts & solvents 4

HCID 178418397HCID 178418397, compoundCatalystHCID 7854PropionitrileSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent2×

Conditions

Temperature
80 °C

Procedure

To a solution of 4-[2-(1-tert-butoxycarbonylpiperidin-4-yl)ethoxy]-6-chloro-2-cyanopyrimidine-5-carboxylic acid allyl ester (1.1 mmol) and C-Spiro[3.5]non-7-yl-methylamine (1.4 mmol) in C2H5CN (10 mL) is added triethylamine (2.8 mmol) at room temperature. After stirring at 80° C. for 1 h, the reaction mixture is cooled to room temperature and diluted with AcOEt. The organic layer is washed with H2O and aq. KHSO4 and brine. The organic layer is dried over MgSO4 and evaporated in vacuo, which is directly used for the next reaction without further purification. To a solution of the crude 4-[2-(1-tert-butoxy carbonylpiperidin-4-yl)ethoxy]-2-cyano-6-[(spiro[3.5]non-7-ylmethyl)amino]pyrimidine-5-carboxylic acid allyl ester (1.1 mmol) in THF (5 mL) are added morpholine (3.4 mmol) and Pd(PPh3)4 (0.06 mmol) successively. After stirring at the same temperature for 0.5 h, the reaction mixture is diluted with AcOEt. The organic layer is washed with H2O and evaporated in vacuo. The residue is purified by silica gel column chromatography to give a 4-[2-(1-tert-butoxycarbonylpiperidin-4-yl)ethoxy]2-cyano-6-[(spiro[3.5]non-7-ylmethyl)amino]pyrimidine-5-carboxylic acid as yellow pale solid; 1H-NMR (CDCl3), δ: 0.97-1.08 (2H, m), 1.15-1.29 (5H, m), 1.48 (9H, s), 1.48-1.86 (15H, m), 2.69 (2H, t), 3.39 (2H, t), 4.11 (2H, m), 4.66 (2H, t), 9.42 (1H, br t).

Workup

  1. temperaturethe reaction mixture is cooled to room temperature
  2. washThe organic layer is washed with H2O and aq. KHSO4 and brine
  3. dry with materialThe organic layer is dried over MgSO4
  4. customevaporated in vacuo, which
  5. customis directly used for the next reaction without further purification
  6. stirringAfter stirring at the same temperature for 0.5 h
  7. washThe organic layer is washed with H2O
  8. customevaporated in vacuo
  9. customThe residue is purified by silica gel column chromatography

Sources & evidence

ORD record
ord-525104e030a2494b9b2e86fd3a85c8e1
Source dataset
uspto-grants-2010_04
Patent number
US07704996B2

Reaction notes

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