Hydrochloric Acid → HCID 66719319, compound

HRID 391815Notes

Reaction equation

HRID 391815 reaction equation
[CH3:1][O:2][C:3](=[O:34])[C@@H:4]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[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.[CH3:36]OC(=O)[C@@H](N)CC1C=CC2OC(C3C=CC(OC(=O)C)=CC=3)COC=2C=1.C=O.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.CCN(C(C)C)C(C)C>O1CCOCC1.C(O)(C(F)(F)F)=O.C(Cl)Cl.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:15]=[CH:16][C:17]([O:20][C:21](=[O:23])[CH3:22])=[CH:18][CH:19]=4)[O:10][C:9]3=[CH:24][C:25]=2[CH2:36][N:26]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:34]

Participants

11

Reactant 6

HCID 313Hydrochloric AcidHCID 712FormaldehydeHCID 81531DiisopropylethylamineHCID 90495Di-tert-butyl dicarbonateHCID 66719534HCID 66719534, compoundHCID 66719561HCID 66719561, compound

Product 1

HCID 66719319HCID 66719319, compound

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 6422Trifluoroacetic acidSolventHCID 312751,4-DioxaneSolvent

Procedure

(S)-3-[2-(4-Acetoxy-phenyl)-2,3-dihydro-benzo[1,4]dioxin-6-yl]-2-tert-butoxycarbonylamino-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) was dissolved in dioxane (32 mL) and TFA (8 mL). To this solution was added paraformaldehyde (60 mg) and stirred at rom 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 dried to get an oil. The oil was taken in fresh DCM (200 mL) and Boc anhydride and DIEA (3 mL) were added. The mixture was stirred for 2-3 h and the organic layer was separated, washed dried and concentrated and purified (silica; hexanes/EtOAc, 8:2 to 7:3) to get (3S,8S)-3-(4-acetoxy-phenyl)-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester 8-methyl ester. This Boc ester (485 mg) was dissolved in methanol (20 mL). To this solution was added NaHCO3 (2.0 g). The mixture was stirred at room temperature for 3 h. After completion of the reaction, the mixture was poured into water (200 mL) and was extracted with EtOAc (300 mL). The organic layer was washed with water, brine, dried and concentrated to get the desired product as a white solid (380 mg). This intermediate was coupled with cyclohexane methanol according to General Procedure K furnished (3S,8S)-3-(4-cyclohexylmethoxy-phenyl)-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester 8-methyl ester. This ester upon hydrolysis according to General Procedure B furnished (3S,8S)-3-(4-cyclohexylmethoxy-phenyl)-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester (C). LCMS (m/z): 525.

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 h
  7. customthe organic layer was separated
  8. washwashed
  9. customdried
  10. concentrationconcentrated
  11. custompurified (silica; hexanes/EtOAc, 8:2 to 7:3)

Sources & evidence

ORD record
ord-39a8d9399ccd493ea5dbbab7ad17a104
Source dataset
uspto-grants-2013_02
Patent number
US08383644B2

Reaction notes

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