Hydrochloric Acid → HCID 71696589, compound

HRID 926395Notes

Reaction equation

HRID 926395 reaction equation
[C:1]1([C@H:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([C:22]([OH:24])=O)[N:16]3[CH2:21][CH2:20][O:19][CH2:18][C:17]=23)=[O:12])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[CH2:48]([O:50][C:51](=[O:56])[C@@H:52]([NH:54][CH3:55])[CH3:53])[CH3:49].CN[C@@H](C)C(O)=O.Cl.C(N(CC)CC)C>CN(C)C=O.C(O)C.O1CCOCC1>[CH2:48]([O:50][C:51](=[O:56])[C@@H:52]([N:54]([CH3:55])[C:22]([C:15]1[N:16]2[C:17]([CH2:18][O:19][CH2:20][CH2:21]2)=[C:13]([C:11](=[O:12])[NH:10][C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH3:9])[CH:14]=1)=[O:24])[CH3:53])[CH3:49]

Participants

11

Reactant 7

HCID 313Hydrochloric AcidHCID 8471TriethylamineHCID 757711-HydroxybenzotriazoleHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochloride2×HCID 5288725N-Methyl-L-AlanineHCID 86621252117856-39-02×HCID 89726203HCID 89726203, compound

Product 1

HCID 71696589HCID 71696589, compoundYield 51%

Reagents, catalysts & solvents 3

HCID 702EthanolSolventHCID 6228DimethylformamideSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
25 °C

Procedure

To a solution of 8-((R)-1-phenyl-propylcarbamoyI)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carboxylic acid (Comp. No. 11a) (100 mg, 0.335 mmol) in dimethylformamide (2.2 ml) was added 1-hydroxybenzotriazole (45 mg, 0.335 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (64 mg, 0.335 mmol). The mixture was stirred for 1 h at 25° C., then (S)-2-methylamino-propionic acid ethyl ester hydrochloride (56 mg, 0.335 mmol) (prepared from (S)-2-methylamino-propionic acid by heating in ethanol and 4 M hydrogen chloride in dioxane for 18 h and evaporation of the solvents) and triethylamine (62 mg, 0.61 mmol) were added and the mixture was stirred at 25° C. overnight. Another portion of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (13 mg, 0.067 mmol) and (S)-2-methylamino-propionic acid ethyl ester hydrochloride (12 mg, 0.067 mmol) were added and the mixture was stirred for 1 h. After filtration of the mixture through a short filter cartridge the solution was purified by reverse phase HPLC (acetonitrile/water gradient with 0.1% trifluoroacetic acid) to give 68 mg (51%) (S)-2-{Methyl-[8-((R)-1-phenyl-propylcarbamoyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carbonyl]-amino}-propionic acid ethyl ester. LC/MS (method 2): Rt=1.11 min; m/z=442.3 (M+H+). 1H-NMR: δ (ppm)=8.46 (1H, t), 8.21 (1H, d), 7.35-7.36 (3H, m), 7.30 (2H, t), 7.21 (1H, t), 4.91 (2H, dd), 4.82 (1H, q), 4.19 (2H, t), 4.11 (2H, q), 3.90-3.92 (4H, m), 1.71-1.83 (2H, m), 1.21 (3H, t), 0.88 (3H, t).

Workup

  1. additionwere added
  2. stirringthe mixture was stirred at 25° C. overnight
  3. stirringthe mixture was stirred for 1 h
  4. filtrationAfter filtration of the mixture through a short filter cartridge the solution
  5. customwas purified by reverse phase HPLC (acetonitrile/water gradient with 0.1% trifluoroacetic acid)

Sources & evidence

ORD record
ord-6daa65c51b0140c0b38f7a0270748722
Source dataset
uspto-grants-2016_03
Patent number
US09284333B2

Reaction notes

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