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Triethylamine → tert-butyl (3S,4R)-3-(2-tert-butylsilyloxypropan-2-yl)-4-[[[1-(3-methoxypropyl)-3-methylindole-6-carbonyl]-propan-2-ylamino]methyl]pyrrolidine-1-carboxylate

HRID 1158381
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HRID 1158381 반응식
[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][CH:15]([CH3:17])[CH3:16])[C@H:10]([C:18]([CH3:26])([CH3:25])[O:19][SiH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][O:28][CH2:29][CH2:30][CH2:31][N:32]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([C:41](O)=[O:42])[CH:39]=2)[C:34]([CH3:44])=[CH:33]1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:15]([CH3:16])[CH3:17])[C:41]([C:38]2[CH:39]=[C:40]3[C:35]([C:34]([CH3:44])=[CH:33][N:32]3[CH2:31][CH2:30][CH2:29][O:28][CH3:27])=[CH:36][CH:37]=2)=[O:42])[C@H:10]([C:18]([CH3:26])([CH3:25])[O:19][SiH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
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참가 물질

6

반응물 4

HCID 8471TriethylamineHCID 152842Bis(2-oxo-3-oxazolidinyl)phosphinic chlorideHCID 59512399HCID 59512399, 화합물HCID 131728361(3S*,4R)-3-(tert-butyl-dimethyl-silanyloxymethyl)-4-(isopropylamino-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester

생성물 1

HCID 178495140
tert-butyl (3S,4R)-3-(2-tert-butylsilyloxypropan-2-yl)-4-[[[1-(3-methoxypropyl)-3-methylindole-6-carbonyl]-propan-2-ylamino]methyl]pyrrolidine-1-carboxylate

시약·촉매·용매 1

HCID 6344Dichloromethane용매

실험 절차

A mixture of (3S,4R)-3-(tert-butyl-dimethyl-silanyloxymethyl)-4-(isopropylamino-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (8.5 g, 22 mmol), 1-(3-methoxy-propyl)-3-methyl-1H-indole-6-carboxylic acid (7.6 g, 30.8 mmol), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (7.84 g, 30.8 mmol) and triethylamine (12.3 mL, 88 mmol) in CH2Cl2 (425 mL) is refluxed overnight under a nitrogen atmosphere and then quenched by the addition of an aqueous saturated solution of NaHCO3. The organic layer is separated, and the aqueous phase is extracted 3 times with AcOEt. The combined organic extracts are concentrated in vacuo. The residual oil is taken up in a mixture of THF and MeOH, NaOH 1N is added to cleave the anhydride side product and the mixture stirred for 3 h. The solvents are concentrated, CH2Cl2 is added and the layers are separated. The aqueous one is then back extracted twice with CH2Cl2 and the combined organic extracts are washed with brine, dried over Na2SO4, filtered and concentrated. The crude product is used in the next step without further purification. TLC, Rf (AcOEt)=0.6. MS (LC-MS): 516.3 [M-Boc+H]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN an H2O containing 0.1% TFA, flow: 1.5 mL/min): 8.60 min.

후처리

  1. temperatureis refluxed overnight under a nitrogen atmosphere
  2. customquenched by the addition of an aqueous saturated solution of NaHCO3
  3. customThe organic layer is separated
  4. extractionthe aqueous phase is extracted 3 times with AcOEt
  5. concentrationThe combined organic extracts are concentrated in vacuo
  6. additionThe residual oil is taken up in a mixture of THF and MeOH, NaOH 1N
  7. additionis added
  8. concentrationThe solvents are concentrated
  9. additionCH2Cl2 is added
  10. customthe layers are separated
  11. extractionThe aqueous one is then back extracted twice with CH2Cl2
  12. washthe combined organic extracts are washed with brine
  13. dry with materialdried over Na2SO4
  14. filtrationfiltered
  15. concentrationconcentrated
  16. customThe crude product is used in the next step without further purification
  17. customHPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN
  18. custom8.60 min.

출처 및 근거

ORD 기록
ord-ab8328b0cffa4b6a80ab0cd4c6269a79
출처 데이터셋
uspto-grants-2010_10
DOI
10.6084/m9.figshare.5104873.v1
특허 번호
US07807709B2

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