Sodium hydride → HCID 59511480, compound

HRID 1157781Notes

Reaction equation

HRID 1157781 reaction equation
[CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([C:9]2[CH:13]=[CH:12][NH:11][N:10]=2)=[C:5]2[NH:14][CH:15]=[C:16]([C:17](=[O:37])[C:18]([N:20]3[CH2:25][CH2:24][N:23]([C:26]4[N:30]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=5)[N:29]=[N:28][N:27]=4)[CH2:22][CH2:21]3)=[O:19])[C:4]=12.[H-].[Na+].Br[CH2:41][C:42]([O:44]C)=[O:43]>CN(C=O)C>[C:42]([CH2:41][N:11]1[CH:12]=[CH:13][C:9]([C:6]2[N:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]3[C:16]([C:17](=[O:37])[C:18](=[O:19])[N:20]4[CH2:25][CH2:24][N:23]([C:26]5[N:30]([C:31]6[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=6)[N:29]=[N:28][N:27]=5)[CH2:22][CH2:21]4)=[CH:15][N:14]([CH2:41][C:42]([OH:44])=[O:43])[C:5]=23)=[N:10]1)([OH:44])=[O:43]

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 60984Methyl bromoacetate2×HCID 178493711HCID 178493711, compound

Product 1

HCID 59511480HCID 59511480, compound

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of 1-(4-methoxy-7-(1H-pyrazol-3-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (0.207 g, 0.414 mmol) in DMF (2 mL) was added NaH (0.083 g, 2.072 mmol). The mixture was stirred for 5 minutes at rt and methyl bromoacetate (0.047 mL, 0.497 mmol) was added. The mixture was stirred at rt for 30 minutes. LC/MS showed starting material still present, so an additional 0.05 mL of methyl bromoacetate was added. The mixture was stirred for 1 h at rt, and was quenched with water. The solvent was removed under reduced pressure, and the residue was partitioned with water and dichloromethane. The aqueous layer was acidified to pH=1 using 0.1N HCl. The solids that formed were collected by filtration, dissolved in DMF, and were purified by prep HPLC. The aqueous layer containing the remainder of the material was concentrated under reduced pressure, and was dissolved in DMF. The DMF solution was filtered through a plug of celite to remove solids, and the DMF solution was purified by prep HPLC. A second prep HPLC run was used to purify the product. 2-(7-(1-(carboxymethyl)-1H-pyrazol-3-yl)-4-methoxy-3-(2-oxo-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-1-yl)acetic acid was isolated as a light-yellow solid (0.032 g, 0.052 mmol, 12.5% yield). 1H NMR (500 MHz, DMSO-D6) δ ppm 8.65-8.69 (m, 1H) 8.50 (s, 1H) 8.13-8.19 (m, 2H) 7.92 (s, 1H) 7.85 (d, J=7.93 Hz, 1H) 7.64 (dd, J=7.63, 4.88 Hz, 1H) 6.65 (s, 1H) 5.17 (s, 2H) 5.05 (s, 2H) 4.01 (s, 3H) 3.72 (s, 2H) 3.45 (dd, J=11.60, 3.05 Hz, 4H) 3.29 (d, J=3.36 Hz, 2H). LCMS: m/e 616.34 (M+H)+, ret time 1.565 min (method 4). 2-(3-(4-methoxy-3-(2-oxo-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazol-1-yl)acetic acid was isolated as an off-white solid (0.132 g, 0.237 mmol, 52.1% yield). 1H NMR (500 MHz, DMSO-D6) δ ppm 1H NMR (500 MHz, DMSO-D6) d ppm 12.37 (s, 1H) 8.65-8.68 (m, 1H) 8.32 (s, 1H) 8.13-8.18 (m, 1H) 8.07 (s, 1H) 7.96 (d, J=2.44 Hz, 1H) 7.85 (d, J=7.93 Hz, 1H) 7.64 (dd, J=7.48, 4.73 Hz, 1H) 7.03 (d, J=1.83 Hz, 1H) 5.17-5.20 (m, 2H) 4.01 (s, 3H) 3.70-3.75 (m, 2H) 3.40-3.49 (m, 4H) 3.24-3.29 (m, 2H). LCMS: m/e 558.19 (M+H)+, ret time 0.955 min (method 3).

Workup

  1. stirringThe mixture was stirred at rt for 30 minutes
  2. stirringThe mixture was stirred for 1 h at rt
  3. customwas quenched with water
  4. customThe solvent was removed under reduced pressure
  5. customthe residue was partitioned with water and dichloromethane
  6. customThe solids that formed
  7. filtrationwere collected by filtration
  8. dissolutiondissolved in DMF
  9. customwere purified by prep HPLC
  10. additionThe aqueous layer containing the remainder of the material
  11. concentrationwas concentrated under reduced pressure
  12. dissolutionwas dissolved in DMF
  13. filtrationThe DMF solution was filtered through a plug of celite
  14. customto remove solids
  15. customthe DMF solution was purified by prep HPLC
  16. customto purify the product

Sources & evidence

ORD record
ord-56121fda4d7f435e952fcdaea70ef030
Source dataset
uspto-grants-2010_10
Patent number
US07807676B2

Reaction notes

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