Hydrochloric Acid → HCID 66719460, compound

HRID 879715Notes

Reaction equation

HRID 879715 reaction equation
[CH3:1][O:2][C:3](=[O:34])[C@:4]([NH2:33])(C(OC(C)(C)C)=O)[CH2:5][C:6]1[CH:25]=[CH:24][C:9]2[O:10][CH:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21](=[O:23])[CH3:22])=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1.Cl.COC(=O)[C@@H](N)CC1C=CC2[O:45][CH:46]([C:49]3[CH:54]=[CH:53][C:52](OC(=O)C)=[CH:51][CH:50]=3)COC=2C=1.C=O.[C:65](Cl)(=O)C1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C(O)(C(F)(F)F)=O.CCOC(C)=O.O>[CH3:1][O:2][C:3]([C@@H:4]1[CH2:5][C:6]2[CH:7]=[C:8]3[O:13][CH2:12][C@H:11]([C:14]4[CH:19]=[CH:18][C:17]([O:20][C:21](=[O:23])[CH3:22])=[CH:16][CH:15]=4)[O:10][C:9]3=[CH:24][C:25]=2[CH2:65][N:33]1[C:46](=[O:45])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:34]

Participants

11

Reactant 6

HCID 313Hydrochloric AcidHCID 712FormaldehydeHCID 7412Benzoyl chlorideHCID 10340Sodium CarbonateHCID 66719534HCID 66719534, compoundHCID 66719565HCID 66719565, compound

Product 1

HCID 66719460HCID 66719460, compound

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 6422Trifluoroacetic acidSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Procedure

(S)-3-[2-(4-Acetoxy-phenyl)-2,3-dihydro-benzo[1,4]dioxin-6-yl]-2-tert-butoxycarbonyl-amino-propionic acid methyl ester was converted to the HCl salt of (S)-3-[2-(4-acetoxy-phenyl)-2,3-dihydro-benzo[1,4]dioxin-6-yl]-2-amino-propionic acid methyl ester according to General Procedure C. This intermediate (450 mg) dissolved in dioxane (32 mL) and TFA (8 mL). To this solution was added paraformaldehyde (60 mg) and stirred at room temperature for 6 hours. After completion of the reaction, the mixture was poured into water (100 mL) and extracted with EtOAc. The organic layer was neutralized to a pH of 7 using NaHCO3 and washed with water and brine, and then dried to get an oil. The oil was taken up in fresh EtOAc (200 mL) and benzoyl chloride and saturated Na2CO3 (20 mL) were added. The mixture was stirred for 2-3 hours and the organic layer was separated, washed dried and concentrated and purified (silica; hexanes/EtOA, 8:2 to 7:3) to get (3S,8S)-3-(4-acetoxy-phenyl)-7-benzoyl-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid methyl ester (468 mg). This ester (215 mg) was hydrolyzed according to General Procedure B to afford (3S,8S)-7-benzoyl-3-(4-hydroxy-phenyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid (200 mg). LCMS (m/z) 431. This acid was coupled with (S)-2-amino-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester bis hydrochloride according to General Procedure L gave (S)-2-{[(3S,8S)-7-Benzoyl-3-(4-hydroxy-phenyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester (224 mg). LCMS (m/z): 699.

Workup

  1. customAfter completion of the reaction
  2. extractionextracted with EtOAc
  3. washwashed with water and brine
  4. customdried
  5. customto get an oil
  6. stirringThe mixture was stirred for 2-3 hours
  7. customthe organic layer was separated
  8. washwashed
  9. customdried
  10. concentrationconcentrated
  11. custompurified (silica; hexanes/EtOA, 8:2 to 7:3)

Sources & evidence

ORD record
ord-d9cc929445ee457e9204d00797f16c00
Source dataset
uspto-grants-2015_03
Patent number
US08987295B2

Reaction notes

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