Diisopropylethylamine → (3aR, 7R,7aR)-2-{{[3-(1-pyrrolidinyl)-2-propoxy]phenyl}acetyl}-4,4-diphenyl-7-fluoroperhydroisoindole

HRID 1721205Notes

Reaction equation

HRID 1721205 reaction equation
O.OC1C2N=NNC=2C=CC=1.Cl.[C:13]1([C:19]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:27][CH2:26][C@@H:25]([F:28])[C@@H:24]3[C@H:20]2[CH2:21][NH:22][CH2:23]3)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[N:35]1([CH2:40][CH:41]([O:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[CH2:50][C:51](O)=[O:52])[CH3:42])[CH2:39][CH2:38][CH2:37][CH2:36]1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>ClCCl>[N:35]1([CH2:40][CH:41]([O:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[CH2:50][C:51]([N:22]2[CH2:21][C@@H:20]3[C@@H:24]([C@H:25]([F:28])[CH2:26][CH2:27][C:19]3([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:23]2)=[O:52])[CH3:42])[CH2:36][CH2:37][CH2:38][CH2:39]1

Participants

7

Reactant 5

HCID 81531DiisopropylethylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 54259613{[3-(1-Pyrrolidinyl)-2-propoxy]phenyl}acetic acidHCID 67746156(3aR, 7R,7aR)-4,4-diphenyl-7-fluoroperhydroisoindole hydrochlorideHCID 178526939HCID 178526939, compound

Product 1

HCID 22856108(3aR, 7R,7aR)-2-{{[3-(1-pyrrolidinyl)-2-propoxy]phenyl}acetyl}-4,4-diphenyl-7-fluoroperhydroisoindoleYield 41.7%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
20 °C

Procedure

0.04 g of hydroxybenzotriazole hydrate is added to a solution, cooled to +5° C., of 1 g of (3aR, 7R,7aR)-4,4-diphenyl-7-fluoroperhydroisoindole hydrochloride and 0.924 g of 2-{[3-(1-pyrrolidinyl)-2-propoxy]phenyl}acetic acid in 40 cm3 of dry dichloromethane, followed by 0.79 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 0.51 cm3 of diisopropylethylamine. After stirring for 2.5 hours at +5° C. and for 20 hours at 20° C., the reaction mixture is washed twice with 50 cm3 of water, dried over magnesium sulphate and then concentrated to dryness at 40° C. under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 2.4 cm, height 31 cm), eluting under a nitrogen pressure of 0.5 bar with an ethyl acetate, acetic acid and water mixture (60/10/10 by volume) and collecting fractions of 25 cm3. Fractions 11 to 31 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 20 cm3 of dichloromethane, the solution is washed with 20 cm3 of a 1N aqueous solution of sodium hydroxide and then dried over magnesium sulphate and concentrated to dryness. This wash with a basic solution is repeated again. 0.68 g of (3aR, 7R,7aR)-2-{{[3-(1-pyrrolidinyl)-2-propoxy]phenyl}acetyl}-4,4-diphenyl-7-fluoroperhydroisoindole is obtained in the form of a white solid.

Workup

  1. washthe reaction mixture is washed twice with 50 cm3 of water
  2. dry with materialdried over magnesium sulphate
  3. concentrationconcentrated to dryness at 40° C. under reduced pressure (2.7 kPa)
  4. customThe residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 2.4 cm, height 31 cm)
  5. washeluting under a nitrogen pressure of 0.5 bar with an ethyl acetate, acetic acid and water mixture (60/10/10 by volume)
  6. customcollecting fractions of 25 cm3
  7. concentrationconcentrated to dryness under reduced pressure (2.7 kPa)
  8. washthe solution is washed with 20 cm3 of a 1N aqueous solution of sodium hydroxide
  9. dry with materialdried over magnesium sulphate
  10. concentrationconcentrated to dryness
  11. washThis wash with a basic solution

Sources & evidence

ORD record
ord-784ce18633154086bb6b50ecd83dce09
Source dataset
uspto-grants-1996_04
Patent number
US05508433

Reaction notes

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