Toluene → 3-Hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, (2S,3S)-

HRID 377444Notes

Reaction equation

HRID 377444 reaction equation
C(N(CC)[C@H]1C2C(=CC=CC=2)C[C@H]1O[C:14]([C@H:16]1[C@H:18]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[O:17]1)=[O:15])C.C(OC([C@H]1[C@H](C2C=CC(OC)=CC=2)O1)=O)(C)(C)C.[NH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[SH:54].CC1C=CC=CC=1>C1(C)C(C)=CC=CC=1.CO>[OH:17][C@H:16]1[C:14](=[O:15])[NH:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=2[S:54][C@H:18]1[C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1

Participants

7

Reactant 4

HCID 1140Toluene2×HCID 87132-AminothiophenolHCID 9856318(2R,3S)-3-(4-methoxyphenyl)oxirane-2-carboxylic tert-butyl esterHCID 10861851HCID 10861851, compound

Product 1

HCID 27336733-Hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, (2S,3S)-

Reagents, catalysts & solvents 2

HCID 887MethanolSolvent2×HCID 7237O-XyleneSolvent

Conditions

Temperature
120 °C

Procedure

2.0 grams (4.8 mmol) of the mixture of (2R,3S)-3-(4-methoxyphenyl)oxirane-2-carboxylic (1S,2R)-1-(diethylamino)-2-indanyl ester (diastereomeric ratio 89:11) and (2R,3S)-3-(4-methoxyphenyl)oxirane-2-carboxylic tert-butyl ester (enantiomeric excess 80%) of Example V was dissolved in 20 ml of xylene+1 ml of methanol. This solution was heated to 120° C. and 600 mg (5.0 mmol) of 2-aminothiophenol was added drop by drop in 5 min. After 6 hours' heating at 120° C. the solution was cooled to 20° C. and 1.1 grams (6,0 mmol) of p-toluene sulphonic monohydrate was added. This was followed by 6 hours' heating at reflux temperature, during which 1-2 ml of a xylene/methanol mixture was removed through distillation. After cooling, the brown solution was dissolved in dichloromethane and washed with a 5% Na2CO3 solution in water and a 0.5M KH2PO4 solution in water. After drying with the aid of Na2SO4 and evaporation, the chemically pure product was obtained after chromatography using silica gel (eluant:toluene/ethyl acetate 2:1). 85% enantiomeric excess (determined with the aid of anisochrony in 1H NMR, see C. Giordano et al.; J. Org. Chem. 1991, (59), 2270). The enantiomeric excess was increased to >95% through one recrystallisation from toluene. White needles. Melting point: 200-202° C. [α]20D +109 (c=0.4, methanol). 1H NMR (200 MHz, CDCl3): 2.93 (d, 1H), 3.71 (s, 3H), 4.41 (dd, 1H), 5.02 (d, 1H), 6.74 (d, 2H), 7.03-7.21 (m, 2H), 7.29-7.44 (d+m, 3H), 7.61 (d, 1H) and 8.47 (br s, 1H). The (1S,2R)-1-(diethylamino)-2-indanol was recovered from the 0.5M KH2PO4 extraction solution.

Workup

  1. temperatureAfter 6 hours' heating at 120° C. the solution
  2. temperaturewas cooled to 20° C.
  3. temperature' heating
  4. temperatureat reflux temperature
  5. customduring which 1-2 ml of a xylene/methanol mixture was removed through distillation
  6. temperatureAfter cooling
  7. dissolutionthe brown solution was dissolved in dichloromethane
  8. washwashed with a 5% Na2CO3 solution in water
  9. dry with materialAfter drying with the aid of Na2SO4 and evaporation
  10. customthe chemically pure product was obtained after chromatography
  11. customThe (1S,2R)-1-(diethylamino)-2-indanol was recovered from the 0.5M KH2PO4 extraction solution

Sources & evidence

ORD record
ord-51b43e0b70d94e9e8bc4f779a57e3901
Source dataset
uspto-grants-2000_02
Patent number
US06025506

Reaction notes

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