Triethylamine → 5-[(1R)-1-{7-[(5-methoxypyridin-2-yl)acetyl]-2,7-diazaspiro[3.5]non-2-yl}-2,3-dihydro-1H-inden-5-yl]pyridine-2-carbonitrile

HRID 1913476Notes

Reaction equation

HRID 1913476 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([OH:12])=O)=[N:7][CH:8]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.Cl.Cl.[CH2:34]1[C:37]2([CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:36][N:35]1[C@H:43]1[C:51]2[C:46](=[CH:47][C:48]([C:52]3[CH:53]=[CH:54][C:55]([C:58]#[N:59])=[N:56][CH:57]=3)=[CH:49][CH:50]=2)[CH2:45][CH2:44]1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([N:40]2[CH2:41][CH2:42][C:37]3([CH2:36][N:35]([C@H:43]4[C:51]5[C:46](=[CH:47][C:48]([C:52]6[CH:53]=[CH:54][C:55]([C:58]#[N:59])=[N:56][CH:57]=6)=[CH:49][CH:50]=5)[CH2:45][CH2:44]4)[CH2:34]3)[CH2:38][CH2:39]2)=[O:12])=[N:7][CH:8]=1

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 682631,1'-CarbonyldiimidazoleHCID 584384902-(5-Methoxypyridin-2-yl)acetic acidHCID 674051815-[(R)-1-(2,7-Diaza-spiro[3.5]non-2-yl)-indan-5-yl]-pyridine-2-carbonitrile dihydrochloride

Product 1

HCID 584384545-[(1R)-1-{7-[(5-methoxypyridin-2-yl)acetyl]-2,7-diazaspiro[3.5]non-2-yl}-2,3-dihydro-1H-inden-5-yl]pyridine-2-carbonitrileYield 9%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

To a mixture of (5-methoxypyridin-2-yl)acetic acid (SM-1aa), 28 mg, 0.17 mmol) in dichloromethane (5 mL) was added 1,1′-carbonyldiimidazole (28 mg, 0.17 mmol) and the reaction was stirred for 2 hours at room temperature. In a separate flask, triethylamine (68 mg, 0.67 mmol) was added to a mixture 5-[(R)-1-(2,7-diaza-spiro[3.5]non-2-yl)-indan-5-yl]-pyridine-2-carbonitrile dihydrochloride (4-1d, 58 mg, 0.17 mmol) in dichloromethane (5 mL). The activated acid was added to the amine solution and the reaction was stirred at room temperature overnight. The reaction mixture was quenched by the addition of 10 mL of saturated NaHCO3 and diluted with 50 mL of dichloromethane. The organic solution was collected, washed with saturated brine, dried over MgSO4, filtered and concentrated. Purification by preparative HPLC (on Phenomenex Luna (2) C18 21.2×150 mm, 5% H20/95% MeOH (0.1% formic acid), 10.0 min, 28 mL/min) provided the title compound (7.5 mg, 9%) as a gum. MS (ES+) 494.1 (M+H)+ 1H NMR (CD3OD) δ 1.76-1.87 (m, 4H), 2.14-2.26 (m, 1H), 2.55 (dd, 1H), 3.00-3.12 (m, 1H), 3.18-3.27 (m, 1H), 3.54-3.60 (m, 4H), 3.81-3.85 (m, 4H), 3.86 (s, 1H), 4.04 (d, 2H), 4.18 (d, 2H), 4.94 (dd, 1H), 7.22-7.29 (m, 1H), 7.31-7.38 (m, 1H), 7.63-7.72 (m, 2H), 7.75 (s, 1H), 7.93 (dd, 1H), 8.13 (d, 1H), 8.23 (dd, 1H), 8.97 (d, 1H).

Workup

  1. stirringthe reaction was stirred at room temperature overnight
  2. customThe reaction mixture was quenched by the addition of 10 mL of saturated NaHCO3
  3. additiondiluted with 50 mL of dichloromethane
  4. customThe organic solution was collected
  5. washwashed with saturated brine
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customPurification by preparative HPLC (on Phenomenex Luna (2) C18 21.2×150 mm, 5% H20/95% MeOH (0.1% formic acid), 10.0 min, 28 mL/min)

Sources & evidence

ORD record
ord-4a130824a87341b4a69cae782b7c5431
Source dataset
uspto-grants-2013_12
Patent number
US08609680B2

Reaction notes

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