Ethanol → HCID 16006725, compound

HRID 2389953Notes

Reaction equation

HRID 2389953 reaction equation
[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)[CH2:9][N:10]2[CH:14](OCC)[CH2:13][CH2:12][C:11]2=O)=[CH:4][CH:3]=1.[CH2:27](O)[CH3:28]>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C:19]3[C:24](=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH2:12][CH2:11][N:10]4[CH2:28][CH2:27][CH2:5][CH2:8][CH2:9]4)[CH:20]=3)[C@H:11]3[CH2:12][CH2:13][CH2:14][N:10]3[CH2:9]2)=[CH:6][CH:7]=1

Participants

4

Reactant 2

HCID 702EthanolHCID 67542885HCID 67542885, compound

Product 1

HCID 16006725HCID 16006725, compoundYield 78%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Procedure

A mixture of 1-[2-(4-bromo-phenyl)-2-(3-methoxy-phenyl)-ethyl]-5-ethoxy-pyrrolidin-2-one (472.2 mg, 1.13 mmol) and MSA (2 N in ethanol, 10 mL) was stirred for 2 h at rt. The mixture was diluted with EtOAc, washed with satd. aq. NaHCO3 and brine, dried (MgSO4), and concentrated to give a colorless oil. Chromatographic purification (EtOAc/hexanes) yielded 325.4 mg (78%) of the desired product as a mixture of cis and trans diastereomers. The diastereomers were separated by normal-phase HPLC. Trans-6-(4-Bromo-phenyl)-8-methoxy-1,5,6,10b-tetrahydro-2H-pyrrolo[2,1-a]isoquinolin-3-one. MS: exact mass calcd for C19H18BrNO2, 371.1; m/z found, 372.0 [M+H]+, 374.0 [M+H]+. 1H NMR (CDCl3): 7.45 (m, 2H), 7.07 (m, 3H), 6.82 (m, 1H), 6.29 (d, J=1.9, 1H), 4.87 (m, 1H), 4.41 (m, 1H), 4.10 (m, 1H), 3.62 (s, 3H), 3.00 (m, 1H), 2.55 (m, 1H), 2.47 (m, 1H), 2.42 (m, 1H). Cis-6-(4-Bromo-phenyl)-8-methoxy-1,5,6,10b-tetrahydro-2H-pyrrolo[2,1-a]isoquinolin-3-one. The cis isomer was processed as described in Example 43 below. MS: exact mass calcd for C19H18BrNO2, 371.1; m/z found, 372.3 [M+H]+, 374.3 [M+H]+. 1H NMR (acetone-d6): 7.36 (m, 2H), 6.98 (m, 3H), 6.70 (d, J=8.0, 1H), 6.24 (d, J=7.5, 1H), 4.89 (m, 1H), 4.34 (dd, J=6.0, 12.8, 1H), 3.98 (dd, J=5.5, 11.2, 1H), 3.79 (s, 3H), 2.89 (m, 1H), 2.83 (m, 1H), 2.48 (m, 1H), 2.33 (m, 1H), 1.64 (m, 1H). Step 11. Trans-6-(4-Bromo-phenyl)-8-hydroxy-1,5,6,10b-tetrahydro-2H-pyrrolo[2,1-a]isoquinolin-3-one. A solution of the product from Step 10 (2.56 mmol, 1.0 equiv.) in CH2Cl2 (0.1 M) was treated with BBr3 (1.0 M in CH2Cl2, 5 equiv.). The mixture was stirred overnight and then poured onto a mixture of crushed ice and CH2Cl2. The mixture was diluted with water and the layers were separated. The organic layer was washed with water (×2) and brine, dried (MgSO4), and concentrated to give the crude product (776.0 mg) as a mixture of the desired product and the corresponding des-bromo material (trans-6-phenyl-8-hydroxy-1,5,6,10b-tetrahydro-2H-pyrrolo[2,1-a]isoquinolin-3-one). The crude product was taken on to the next step without purification. Brominated product: MS (ESI, negative ionization): exact mass calcd for C18H16BrNO2, 357.0; m/z found, 355.9 [M−H]−, 357.9 [M−H]−. Des-bromo product: MS: exact mass calcd for C18H17NO2, 279.1; m/z found, 278.0 [M−H]−. Step 12. Trans-6-(4-Bromo-phenyl)-8-(3-chloro-propoxy)-1,5,6,10b-tetrahydro-2H-pyrrolo[2,1-a]isoquinolin-3-one. A mixture of the crude material from Step 11 (2.43 mmol, 1.0 equiv.), K2CO3(5 equiv.), and 1,3-bromochloropropane (5.12 mmol, 3 equiv.) in acetone (0.1 M) was heated at 60° C. overnight. The reaction mixture was diluted with CH2Cl2, filtered and concentrated. The crude product was purified by chromatography (EtOAc/hexanes) to provide a mixture of the desired product and trans-6-phenyl-8-methoxy-1,5,6,10b-tetrahydro-2H-pyrrolo[2,1-a]isoquinolin-3-one (637.6 mg). Brominated product: MS: exact mass calcd for C21H21BrClNO2, 433.0; m/z found, 434.0 [M+H]+, 436.0 [M+H]+. Des-bromo product: MS: exact mass calcd for C21H22ClNO2, 355.1; m/z found, 356.1 [M+H]+. Step 13. Trans-6-(4-Bromo-phenyl)-8-(3-piperidin-1-yl-propoxy)-1,5,6,10b-tetrahydro-2H-pyrrolo[2,1-a]isoquinolin-3-one. Prepared from the product mixture from Step 12 (est. 1.61 mmol), as described in Example 39, Step 7. The reaction was performed in a glass pressure tube. Chromatographic purification (NH3 in MeOH/CH2Cl2) gave a mixture of the desired product and trans-6-phenyl-8-(3-piperidin-1-yl-propoxy)-1,5,6,10b-tetrahydro-2H-pyrrolo[2,1-a]isoquinolin-3-one (683.9 mg). The product mixture was taken on to the next step without characterization. Step 14. Prepared as described in Example 39, Step 8, on a 1.54 mmol scale (est.). Purification of the crude mixture of bromo and des-bromo compounds by reverse-phase HPLC gave the desired product (25.6 mg, 2%) as the TFA salt as well as 45.4 mg (4%) of the des-brominated product (Example 49). MS: exact mass calcd for C26H33N2OBr, 468.2; m/z found, 469.1 [M+H]+, 471.1 [M+H]+. 1H NMR (MeOH-d4): 7.51 (d, J=8.2, 2H), 7.29 (br d, J=7.8, 1H), 7.11 (br s, 2H), 6.98 (br d, J=6.9, 1H), 6.52 (br s, 1H), 4.57 (br s, 1H), 3.99 (m, 2H), 3.75 (br d, 2H), 3.53 (d, J=11.7, 2H), 4.45 (br m, 1H), 3.22 (t, J=7.8, 2H), 2.72 (br s, 1H), 2.15 (m, 5H), 1.91 (m, 2H), 1.79 (m, 3H), 1.50 (m, 1H).

Workup

  1. washwashed with satd
  2. dry with materialaq. NaHCO3 and brine, dried (MgSO4)
  3. concentrationconcentrated
  4. customto give a colorless oil
  5. customChromatographic purification (EtOAc/hexanes)

Sources & evidence

ORD record
ord-7b1a08bcc0e24655924de749a71bac7d
Source dataset
uspto-grants-2012_09
Patent number
US08273762B2

Reaction notes

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