Triethylamine → 6-(2-{2-[(1R)-5-(2-methylpyrimidin-4-yl)-2,3-dihydro-1H-inden-1-yl]-2,7-diazaspiro[3.5]non-7-yl}-2-oxoethyl)-2,3-dihydro[1,4]dioxino[2,3-b]pyridine

HRID 1913474Notes

Reaction equation

HRID 1913474 reaction equation
[O:1]1[C:10]2[C:5](=[N:6][C:7]([CH2:11][C:12]([OH:14])=O)=[CH:8][CH:9]=2)[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.Cl.[CH3:36][C:37]1[N:42]=[C:41]([C:43]2[CH:44]=[C:45]3[C:49](=[CH:50][CH:51]=2)[C@H:48]([N:52]2[CH2:55][C:54]4([CH2:60][CH2:59][NH:58][CH2:57][CH2:56]4)[CH2:53]2)[CH2:47][CH2:46]3)[CH:40]=[CH:39][N:38]=1>CCOC(C)=O.ClCCl>[CH3:36][C:37]1[N:42]=[C:41]([C:43]2[CH:44]=[C:45]3[C:49](=[CH:50][CH:51]=2)[C@H:48]([N:52]2[CH2:55][C:54]4([CH2:60][CH2:59][N:58]([C:12](=[O:14])[CH2:11][C:7]5[N:6]=[C:5]6[O:4][CH2:3][CH2:2][O:1][C:10]6=[CH:9][CH:8]=5)[CH2:57][CH2:56]4)[CH2:53]2)[CH2:47][CH2:46]3)[CH:40]=[CH:39][N:38]=1

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 682631,1'-CarbonyldiimidazoleHCID 584384832-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)acetic acidHCID 674059332-[(R)-5-(2-methylpyrimidin-4-yl)-indan-1-yl]-2,7-diazaspiro[3.5]nonane dihydrochloride

Product 1

HCID 584384766-(2-{2-[(1R)-5-(2-methylpyrimidin-4-yl)-2,3-dihydro-1H-inden-1-yl]-2,7-diazaspiro[3.5]non-7-yl}-2-oxoethyl)-2,3-dihydro[1,4]dioxino[2,3-b]pyridineYield 35.1%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
40 °C

Procedure

To a mixture of 2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl) acetic acid (SM-1aj, 27.27 g, 139.73 mmol), dichloromethane (495 mL), and triethylamine (67.74 mL, 468.03 mmol) was added 1,1′-carbonyldiimidazole (22.66 g, 139.73 mmol) at 20° C. and the resulting mixture was heated to 40° C. and stirred for 2 hours. The reaction was charged with 2-[(R)-5-(2-methylpyrimidin-4-yl)-indan-1-yl]-2,7-diazaspiro[3.5]nonane dihydrochloride (3-1 h, 49.50 g, 121.51 mmol). The resulting mixture was stirred at 40° C. for 2 hours, monitoring by HPLC for consumption of amine starting material. The reaction temperature was adjusted below 25° C. and charged with water (1500 mL) and stirred for 5 min. The layers were separated and the organic layer was concentrated to dryness and backfilled with EtOAc (1000 mL) and further concentrated to approximately 300 mL. The resulting thick solution was cooled to 20° C. and stirred until crystals formed. The very thick mixture was diluted with EtOAc (1000 mL) and stirred for 5 min, filtered and dried under vacuum at 45° C. to afford the title compound (21.8 g, 35%). MS (ES+) 512.5 (M+H)+. 1H NMR (CDCl3) δ 1.64-1.75 (m, 4H), 1.90-2.00 (m, 1H), 2.14-2.23 (m, 1H), 2.81 (s, 3H), 2.85-2.94 (m, 1H), 3.08-3.20 (m, 5H), 3.45-3.57 (m, 4H), 3.77 (s, 2H), 3.98 (dd, 1H), 4.22-4.28 (m, 2H), 4.41-4.46 (m, 2H), 6.91 (d, 1H), 7.15 (d, 1H), 7.38 (d, 1H), 7.48 (d, 1H), 7.86 (d, 1H), 7.96 (s, 1H), 8.65 (d, 1H).

Workup

  1. stirringThe resulting mixture was stirred at 40° C. for 2 hours
  2. custommonitoring by HPLC for consumption of amine starting material
  3. customwas adjusted below 25° C.
  4. additioncharged with water (1500 mL)
  5. stirringstirred for 5 min
  6. customThe layers were separated
  7. concentrationthe organic layer was concentrated to dryness
  8. concentrationfurther concentrated to approximately 300 mL
  9. temperatureThe resulting thick solution was cooled to 20° C.
  10. stirringstirred until crystals
  11. customformed
  12. stirringstirred for 5 min
  13. filtrationfiltered
  14. customdried under vacuum at 45° C.

Sources & evidence

ORD record
ord-a6bbaf24e4ae4c94a4b3fbf949484a60
Source dataset
uspto-grants-2013_12
Patent number
US08609680B2

Reaction notes

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