Diisopropylethylamine → N-((1S,2R)-1-(3,5-Difluorobenzyl)-3-{[1-(3-ethylphenyl)cyclopropyl]amino}-2-hydroxypropyl)-3-{[isopentyl(methyl)amino]methyl}-5-methylbenzamide Dihydrochloride

HRID 14155Notes

Reaction equation

HRID 14155 reaction equation
[CH2:1]([N:6]([CH2:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([CH3:19])[CH:18]=1)[C:12]([O:14]C)=O)[CH3:7])[CH2:2][CH:3]([CH3:5])[CH3:4].CC[C@@H]([C@H](NC([C@H]1N(C([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](N)C(C)C)=O)CO)=O)CCC(N)=O)=O)CC(N)=O)=O)CC2C=CC(O)=CC=2)=O)CCC1)=O)C(N[C@H](C(N[C@H](C(N)=O)CCC(N)=O)=O)C(C)C)=O)C.O.[OH-].[Li+].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[ClH:130].Cl.[NH2:132][C@@:133](C)([CH2:149][C:150]1[CH:155]=[C:154]([F:156])[CH:153]=[C:152]([F:157])[CH:151]=1)[C@H:134]([OH:148])[CH2:135][NH:136][C:137]1([C:140]2[CH:145]=[CH:144][CH:143]=[C:142]([CH2:146][CH3:147])[CH:141]=2)[CH2:139][CH2:138]1>O1CCCC1.CO.O.C(OCC)(=O)C>[ClH:130].[ClH:130].[F:156][C:154]1[CH:155]=[C:150]([CH:151]=[C:152]([F:157])[CH:153]=1)[CH2:149][C@H:133]([NH:132][C:12](=[O:14])[C:11]1[CH:16]=[C:17]([CH3:19])[CH:18]=[C:9]([CH2:8][N:6]([CH2:1][CH2:2][CH:3]([CH3:4])[CH3:5])[CH3:7])[CH:10]=1)[C@H:134]([OH:148])[CH2:135][NH:136][C:137]1([C:140]2[CH:145]=[CH:144][CH:143]=[C:142]([CH2:146][CH3:147])[CH:141]=2)[CH2:139][CH2:138]1

Participants

9

Reactant 6

HCID 81531DiisopropylethylamineHCID 168937Lithium hydroxide, monohydrateHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 21086187Methyl 3-{[isopentyl(methyl)amino]methyl}-5-methylbenzoateHCID 57487378(2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-{[1-(3-ethylphenyl)cyclopropyl]amino}-3-methylbutan-2-ol dihydrochlorideHCID 101685186Val-ser-gln-asn-tyr-pro-ile-val-gln-NH2

Product 1

HCID 68609447N-((1S,2R)-1-(3,5-Difluorobenzyl)-3-{[1-(3-ethylphenyl)cyclopropyl]amino}-2-hydroxypropyl)-3-{[isopentyl(methyl)amino]methyl}-5-methylbenzamide Dihydrochloride

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 21892291Methanol tetrahydrofuran waterSolvent

Procedure

To methyl 3-{[isopentyl(methyl)amino]methyl}-5-methylbenzoate prepared by the method in Example SP-211, Step 1 (160 mg, 0.61 mmol) in tetrahydrofuran/methanol/water (2:1:1, 8 mL) is added lithium hydroxide monohydrate (51 mg, 1.2 mmol), and the reaction is stirred at room temperature 16 h. The solution is concentrated under reduced pressure, redissolved in DMF (5 mL), and diisopropylethylamine (424 μL, 2.4 mmol), HATU (290 mg, 0.8 mmol), and (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-{[1-(3-ethylphenyl)cyclopropyl]amino}-3-methylbutan-2-ol dihydrochloride prepared by the method in Example SP-272 (291 mg, 0.7 mmol) are added. The reaction stirred at room temperature 2 h. The reaction mixture is diluted with ethyl acetate, washed with water, saturated sodium bicarbonate, brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 8% methanol/methylene chloride) provides the title compound as the free base. The residue is dissolved in diethyl ether (3 mL) and 1N hydrochloric acid in diethyl ether (2 mL) is added. The mixture is concentrated under reduced pressure to yield the title compound. ESI MS m/z 592.3 [M+H]+.

Workup

  1. concentrationThe solution is concentrated under reduced pressure
  2. dissolutionredissolved in DMF (5 mL)
  3. additionare added
  4. stirringThe reaction stirred at room temperature 2 h
  5. washwashed with water, saturated sodium bicarbonate, brine
  6. dry with materialdried (sodium sulfate)
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure
  9. customPurification by flash column chromatography (silica, 8% methanol/methylene chloride)

Sources & evidence

ORD record
ord-74c93b8375d742d28c51b344cab2c887
Source dataset
uspto-grants-2010_06
Patent number
US07727997B2

Reaction notes

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