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1-Hydroxybenzotriazole → Dapitant

HRID 2211412
Notes
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Reaction equation

HRID 2211412 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.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[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
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 5

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 11137716(S)-2-(2-Methoxyphenyl)propanoic acidHCID 70218598(3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)perhydroisoindol-4-ol hydrochloride

Product 1

HCID 132961
Dapitant
Yield 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 methylene chloride, this solution is then cooled to +5° C. and a suspension of 0.43 g of 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride in 10 cm3 of dry methylene chloride is added rapidly. The reaction mixture is stirred at +5° C. for 2 hours and at room temperature for 2 hours, washed with 20 cm3 of water, subsequently washed with 20 cm3 of an aqueous saturated solution of sodium chloride (twice), dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed over a Merck silica gel column (particle size 0.04-0.06 mm, diameter 2.8 cm, height 20 cm) by eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (80/20 by volume) and collecting fractions of 25 cm3. Fractions 9 to 15 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallised in a mixture of acetonitrile and diisopropyl ether. 0.17 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[2-(2-methoxyphenyl)-(S)-propionyl]-perhydroisoindol-4-ol is obtained in the form of white crystals which melt at 244° C.

Workup

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

Sources & evidence

ORD record
ord-ef967c78245b4b9db86d25313f10d712
Source dataset
uspto-grants-1995_10
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US05463077

Reaction notes

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