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1-Hydroxybenzotriazole → Dapitant

HRID 375419
Notes
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Reaction equation

HRID 375419 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>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
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 dichloromethane, this solution is then cooled to +5° C. and a suspension of 0.43 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 10 cm3 of dry dichloromethane is quickly added. The reaction mixture is stirred at +5° C. for 2 hours and at room temperature for 2 hours, washed with 20 cm3 of water and then 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 on 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 crystallized in a mixture of acetonitrile and diisopropyl ether. 0.17 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[(S)-2-(2methoxyphenyl)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 quickly added
  3. washwashed with 20 cm3 of water
  4. washwashed 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 on 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 crystallized in a mixture of acetonitrile and diisopropyl ether

Sources & evidence

ORD record
ord-0f54be5af04a406e8dd0f13795364ec2
Source dataset
uspto-grants-1996_01
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US05484804

Reaction notes

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