Methanol → HCID 131722700, compound

HRID 1068202Notes

Reaction equation

HRID 1068202 reaction equation
[CH3:1][CH:2]1[C@H:6]([CH2:7][O:8][Si](C(C)(C)C)(C)C)[C@@H:5]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[CH2:4][N:3]1[C:23](OC(C)(C)C)=O.C(N([CH:36]([CH3:38])[CH3:37])CC)(C)C.C([C@@H]1[C@@H](C2C=CC=CC=2)CN([C@H](C(C)C)[C:53]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][C:60](OC)=[CH:59][CH:58]=2)=[O:54])C1)=O.[CH3:68]O>Cl.C(Cl)Cl>[CH3:1][CH:2]1[C@H:6]([CH2:7][OH:8])[C@@H:5]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[CH2:4][N:3]1[C@H:23]([CH2:68][CH:36]1[CH2:38][CH2:37]1)[C:53]([O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)=[O:54]

Participants

7

Reactant 4

HCID 887MethanolHCID 81531DiisopropylethylamineHCID 20664067HCID 20664067, compoundHCID 59924622HCID 59924622, compound

Product 1

HCID 131722700HCID 131722700, compoundYield 73%

Reagents, catalysts & solvents 2

HCID 313Hydrochloric AcidSolventHCID 6344DichloromethaneSolvent2×

Conditions

Temperature
50 °C

Procedure

2-Methyl-3-(R)-((tert-butyldimethylsilyloxy)methyl)-4-(S)-(3-fluorophenyl)-1-tert-butoxycarbonylpyrrolidine (210 mg, 0.5 mmol, from Step B) was dissolved in 6 mL of a solution of 1% HCl in methanol and heated to 50° C. overnight. The solution was concentrated and converted to the free base by solid phase extraction (column: Varian SCX, loading: methanol, elution: 2M ammonia in methanol). This material (60 mg, 0.29 mmol) was dissolved in 1 mL of CH2Cl2. Diisopropylethylamine (0.061 mL, 0.35 mmol) was added, followed by hydroxy ester 9 (102 mg, 0.29 mmol). The reaction mixture was stirred under nitrogen for 1.5 h, and was then diluted with CH2Cl2, washed with 1N NaOH and dried over Na2SO4. The solution was concentrated and purified by preparative HPLC (column: YMC combiprep ODS-A 20×50 mm, gradient: 10% acetonitrile/water w/0.1% TFA to 100% acetonitrile/water w/0.1% TFA over 8 min, then ramp to 10% acetonitrile/water w/0.1% TFA over 2 min, flow: 20 mL/min) to afford 87 mg (73% yield) of the title compound. 1H NMR (400 MHz, CDCl3) δ0.00-0.08 (m, 1H), 0.15-0.21 (m, 1H), 0.36-0.43 (m, 1H), 0.43-0.55 (m, 1H), 0.62-0.75 (m, 1H), 1.55 (d, 3H), 1.74-1.81 (m, 1H), 2.09-2.17 (m, 1H), 2.30-2.40 (m, 1H), 3.39-3.58 (m, 3H), 3.60-3.64 (m, 1H), 3.64-3.73 (m, 1H), 4.18-4.22 (m, 1H), 4.24-4.32 (m, 1H), 5.23-5.38 (m, 2H), 6.94-6.98 (m, 1H), 7.05-7.10 (m, 1H), 7.16-7.20 (m, 1H), 7.26-7.35 (m, 1H), 7.38-7.46 (m, 5H); ESI-MS (M+H): 412.5; HPLC A: 1.79 min.

Workup

  1. concentrationThe solution was concentrated
  2. extractionconverted to the free base by solid phase extraction (column: Varian SCX, loading: methanol, elution: 2M ammonia in methanol)
  3. washwashed with 1N NaOH
  4. dry with materialdried over Na2SO4
  5. concentrationThe solution was concentrated
  6. custompurified by preparative HPLC (column
  7. customover 8 min
  8. customover 2 min

Sources & evidence

ORD record
ord-e577f407944d401c9f9ca13eb543f3d4
Source dataset
uspto-grants-2001_06
Patent number
US06248755B1

Reaction notes

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