Methyl chloroformate → HCID 57495361, compound

HRID 242345Notes

Reaction equation

HRID 242345 reaction equation
[CH3:1][O:2][C:3]1[N:10]=[CH:9][C:8]([N:11]2[CH2:26][CH2:25][C:14]3[N:15]=[CH:16][N:17]=[C:18]([O:19][C@H:20]4[CH2:24][CH2:23][NH:22][CH2:21]4)[C:13]=3[CH2:12]2)=[CH:7][C:4]=1[C:5]#[N:6].C(N(CC)CC)C.[C:34](Cl)(=[O:37])[O:35][CH3:36]>C(Cl)Cl>[CH3:36][O:35][C:34]([N:22]1[CH2:23][CH2:24][C@H:20]([O:19][C:18]2[C:13]3[CH2:12][N:11]([C:8]4[CH:9]=[N:10][C:3]([O:2][CH3:1])=[C:4]([C:5]#[N:6])[CH:7]=4)[CH2:26][CH2:25][C:14]=3[N:15]=[CH:16][N:17]=2)[CH2:21]1)=[O:37]

Participants

5

Reactant 3

HCID 6586Methyl chloroformateHCID 8471TriethylamineHCID 66653749HCID 66653749, compound2×

Product 1

HCID 57495361HCID 57495361, compoundYield 35%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

To a solution of 2-methoxy-5-[4-((S)-pyrrolidin-3-yloxy)-7,8-dihydro-5H-pyrido[4,3-d]py rimidin-6-yl]-nicotinonitrile (prepared using intermediate 11 and method 1b, process step 2, example 1) (25.0 mg, 0.071 mmol) and triethylamine (0.04 mL, 0.29 mmol) in CH2Cl2 (2 mL) was added methyl carbonochloridate (0.006 mL, 0.078 mmol) and the mixture stirred at room temperature for 18 h. Diluted with CH2Cl2 (2 mL) and washed with sat. NaHCO3(aq) (1 mL). The organic layer was filtered through a phase separation tube and evaporated in vacuo. Purification was performed by reverse phase Gilson HPLC (Method A) and subsequent neutralization of the combined fractions by elution through an Isolute® SCX-2 cartridge, eluting with methanol, then with 2M ammonia in methanol. Basic fractions were concentrated in vacuo gave (S)-3-[6-(5-cyano-6-methoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carboxylic acid methyl ester (10 mg, 35% yield) as a yellow powder. 1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 2.09-2.31 (m, 2H) 2.91 (t, 2H) 3.45-3.75 (m, 9H) 3.93 (s, 3H) 4.17 (s, 2H) 5.58-5.65 (m, 1H) 8.09 (d, 1H) 8.27 (d, 1H) 8.61 (s, 1H) LCMS: [M+H]+=411.1, Rt(1)=1.58 min.

Workup

  1. washwashed with sat. NaHCO3(aq) (1 mL)
  2. filtrationThe organic layer was filtered through a phase separation tube
  3. customevaporated in vacuo
  4. customPurification
  5. washwas performed by reverse phase Gilson HPLC (Method A) and subsequent neutralization of the combined fractions by elution through an Isolute® SCX-2 cartridge
  6. washeluting with methanol
  7. concentrationBasic fractions were concentrated in vacuo

Sources & evidence

ORD record
ord-c8229cf595024196b98ea02a12b35d7c
Source dataset
uspto-grants-2014_02
Patent number
US08653092B2

Reaction notes

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