Dicyclohexylcarbodiimide → (S)-2-[4-[(2-Amino-3-benzyloxy-1-oxopropyl)amino]phenyl]-6-hydroxy-3-[3-methoxy-4-(1-pyrrolidinylmethyl)benzyl]benzo[b]thiophene

HRID 1595929Notes

Reaction equation

HRID 1595929 reaction equation
[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17]CC4C=CC=CC=4)[CH:15]=[CH:16][C:10]=3[C:9]=2[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[C:28]([O:38][CH3:39])[CH:27]=2)=[CH:4][CH:3]=1.C(OC([NH:50][C@H:51]([C:61]([OH:63])=O)[CH2:52][O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=O)C1C=CC=CC=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=NC2N(O)N=NC=2C=1.C([O-])=O.[NH4+]>CN(C=O)C.[Cl-].[Na+].O.C1COCC1.[Pd]>[NH2:50][C@@H:51]([CH2:52][O:53][CH2:54][C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)[C:61]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:10]=3[C:9]=2[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][N:33]3[CH2:34][CH2:35][CH2:36][CH2:37]3)=[C:28]([O:38][CH3:39])[CH:27]=2)=[CH:4][CH:3]=1)=[O:63]

Participants

10

Reactant 5

HCID 10868DicyclohexylcarbodiimideHCID 181649HOAtHCID 2723923Ammonium formateHCID 6993425N-((Phenylmethoxy)carbonyl)-O-(phenylmethyl)-L-serineHCID 155495242-(4-Aminophenyl)-6-benzyloxy-3-[3-methoxy-4-(1-pyrrolidinylmethyl)benzyl]benzo[b]thiophene

Product 1

HCID 15549525(S)-2-[4-[(2-Amino-3-benzyloxy-1-oxopropyl)amino]phenyl]-6-hydroxy-3-[3-methoxy-4-(1-pyrrolidinylmethyl)benzyl]benzo[b]thiopheneYield 39.1%

Reagents, catalysts & solvents 4

HCID 23938PalladiumCatalystHCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolventHCID 57417360Sodium chloride; waterSolvent

Procedure

2-(4-Aminophenyl)-6-benzyloxy-3-[3-methoxy-4-(1-pyrrolidinylmethyl)benzyl]benzo[b]thiophene (Preparation 7; 273 mg) and N-benzyloxycarbonyl-O-benzyl-(L)-serine (184 mg) were dissolved in DMF (5.0 mL), treated with DCC (130 mg) and HOAt (88 mg) sequentially, and allowed to stir at ambient temperature under argon for 22 h. The reaction mixture was diluted with brine (30 mL), extracted with ethyl acetate (20 mL×3). The combined organic layers were dried with sodium sulfate and concentrated. Chromatography with Et3N:EtOAc (0-3%) afforded the direct coupling product. This product was dissolved in THF (5.0 mL), treated with a solution of ammonium formate (25% in H2O, 2.0 mL) and 10% palladium on carbon (100 mg) sequentially at ambient temperature. The resulting mixture was stirred at ambient temperature under argon for 45 h before it was filtered through diatomaceous earth followed by rinsing with dichloromethane and methanol. The filtrate was extracted with dichloromethane (20 mL×3) from water (30 mL). The combined organic layers were dried with sodium sulfate and concentrated under reduced pressure. Chromatography with Et3N:MeOH:EtOAc (5:10:85) followed by NH4OH:MeOH:EtOAc (5:10:85) afforded the title compound (124 mg) along with a minor amount of the completely debenzylated product (20 mg) described below in Example 2.

Workup

  1. extractionextracted with ethyl acetate (20 mL×3)
  2. dry with materialThe combined organic layers were dried with sodium sulfate
  3. concentrationconcentrated
  4. customChromatography with Et3N:EtOAc (0-3%) afforded the direct coupling product
  5. stirringThe resulting mixture was stirred at ambient temperature under argon for 45 h before it
  6. filtrationwas filtered through diatomaceous earth
  7. washby rinsing with dichloromethane and methanol
  8. extractionThe filtrate was extracted with dichloromethane (20 mL×3) from water (30 mL)
  9. dry with materialThe combined organic layers were dried with sodium sulfate
  10. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-b5445798c3e4474f93e74ace31dc03fa
Source dataset
uspto-grants-2001_09
Patent number
US06288105B1

Reaction notes

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