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Water → Tak-778

HRID 1699349
Notes
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Reaction equation

HRID 1699349 reaction equation
[CH3:1][C@@H:2]1[S:8][C@@H:7]([C:9]([OH:11])=O)[CH2:6][C:5]2[CH:12]=[C:13]3[O:18][CH2:17][O:16][C:14]3=[CH:15][C:4]=2[C:3]1=[O:19].[NH2:20][C:21]1[CH:35]=[CH:34][C:24]([CH2:25][P:26](=[O:33])([O:30][CH2:31][CH3:32])[O:27][CH2:28][CH3:29])=[CH:23][CH:22]=1.ON1C2C=CC=CC=2N=N1.O>ClCCl.CN(C)C=O>[CH2:31]([O:30][P:26]([CH2:25][C:24]1[CH:23]=[CH:22][C:21]([NH:20][C:9]([C@H:7]2[CH2:6][C:5]3[CH:12]=[C:13]4[O:18][CH2:17][O:16][C:14]4=[CH:15][C:4]=3[C:3](=[O:19])[C@H:2]([CH3:1])[S:8]2)=[O:11])=[CH:35][CH:34]=1)([O:27][CH2:28][CH3:29])=[O:33])[CH3:32]
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 4

HCID 962WaterHCID 757711-HydroxybenzotriazoleHCID 88358Diethyl p-aminobenzylphosphonateHCID 9845635(+/-)-trans-1,2,4,5-Tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepin-2-carboxylic acid

Product 1

HCID 9806177Tak-778Yield 44%

Reagents, catalysts & solvents 2

HCID 6228
Dimethylformamide
Solvent
HCID 6344DichloromethaneSolvent

Conditions

Temperature
25 °C

Procedure

A solution of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidee hydrochloride (0.39 g) in dichloromethane (7 ml) was added to a solution of (2R,4S)-(−)-1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepin-2-carboxylic acid (0.47 g) and diethyl 4-aminobenzylphosphonate (0.41 g) in N,N-dimethylformamide (DMF) (7 ml) at 0° C., followed by the addition of 1-hydroxybenzo-triazole (HOBt) (0.28 g). This mixture was stirred at 0° C. for 1 hour and at room temperature (25° C.) for 15 hours, after which it was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (using MgSO4), after which the solvent was distilled off; the residual crystals were collected by filtration, followed by recrystallization from ethyl acetate-hexane and then recrystalized from methanolhexane to yield (2R,4S)-(−)-N-[4-(diethoxyphosphorylmethyl)phenyl]-1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzo-thiepin-2-carboxamide (0.37 g, 44%). Colorless Prisms. Melting point 181-182° C. Optical rotation [α]D (23° C.) −187.4° (c=0.50, CHCl3).

Workup

  1. extractionextracted with ethyl acetate
  2. washThe ethyl acetate layer was washed with water
  3. dry with materialdried (using MgSO4)
  4. distillationafter which the solvent was distilled off
  5. filtrationthe residual crystals were collected by filtration
  6. customfollowed by recrystallization from ethyl acetate-hexane
  7. customrecrystalized from methanolhexane

Sources & evidence

ORD record
ord-8fb65fff95284094a98dd64a8155887b
Source dataset
uspto-grants-2002_02
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US06346521B1

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes