1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → Dapitant

HRID 567144Notes

Reaction equation

HRID 567144 reaction equation
ON1C2C=CC=CC=2N=N1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C@H:19]([CH3:23])[C:20]([OH:22])=O.C(N(C(C)C)CC)(C)C.Cl.[C:34]1([C:40]2([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)[C@@H:48]3[C@@H:44]([CH2:45][NH:46][CH2:47]3)[C@@:43]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=3[O:56][CH3:57])([OH:49])[CH2:42][CH2:41]2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CN(C)CCCN=C=NCC>ClCCl>[C:58]1([C:40]2([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C@@H:48]3[C@@H:44]([CH2:45][N:46]([C:20](=[O:22])[C@H:19]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[O:12][CH3:11])[CH3:23])[CH2:47]3)[C@@:43]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=3[O:56][CH3:57])([OH:49])[CH2:42][CH2:41]2)[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1

Participants

7

Reactant 5

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 11137716(S)-2-(2-Methoxyphenyl)propanoic acidHCID 70218598(3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)perhydroisoindol-4-ol hydrochloride

Product 1

HCID 132961DapitantYield 16.5%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

0.025 g of 1-hydroxybenzotriazole, 0.38 g of (S)-2-(2-methoxyphenyl)propionic acid and 0.32 cm3 of diisopropylethylamine are added to a suspension of 0.8 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)perhydroisoindol-4-ol hydrochloride in 60 cm3 of dry dichloromethane, this solution is then cooled to +5° C. and a suspension of 0.43 g of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide in 10 cm3 of dry dichloromethane is rapidly added. The reaction mixture is stirred for 2 hours at +5° C. and for 2 hours at room temperature, washed with 20 cm3 of water, then washed with 20 cm3 of a saturated aqueous sodium chloride solution (twice), dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of Merck silica gel (particle size 0.04-0.06 mm, diameter 2.8 cm, height 20 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (80/20 by volume) and collecting 25 cm3 fractions. Fractions 9 to 15 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from a mixture of acetonitrile and diisopropyl ether. There is obtained 0.17 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[(S)-2-(2-methoxyphenyl)propionyl]perhydroisoindol-4-ol in the form of white crystals melting at 244° C.

Workup

  1. temperaturethis solution is then cooled to +5° C.
  2. additionis rapidly added
  3. washwashed with 20 cm3 of water
  4. washwashed with 20 cm3 of a saturated aqueous sodium chloride solution (twice),
  5. dry with materialdried over magnesium sulphate
  6. concentrationconcentrated to dryness under reduced pressure (2.7 kPa)
  7. customThe residue is chromatographed on a column of Merck silica gel (particle size 0.04-0.06 mm, diameter 2.8 cm, height 20 cm)
  8. washeluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (80/20 by volume)
  9. customcollecting 25 cm3 fractions
  10. concentrationconcentrated to dryness under reduced pressure (2.7 kPa)
  11. customThe residue is crystallized from a mixture of acetonitrile and diisopropyl ether

Sources & evidence

ORD record
ord-f8c0ab5e504e4defbe861e6e202d0f9d
Source dataset
uspto-grants-2001_01
Patent number
US06177450B1

Reaction notes

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