Triethylamine → N-(2-(cyanomethylamino)-2-oxoethyl)-3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide

HRID 336994Notes

Reaction equation

HRID 336994 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:30]([F:33])([F:32])[F:31])[O:13][N:12]=[C:11]([C:14]3[S:18][C:17]([C:19]([NH:21][CH2:22][C:23]([OH:25])=O)=[O:20])=[C:16]4[CH2:26][CH2:27][CH2:28][CH2:29][C:15]=34)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CN(C(O[N:42]1N=[N:49][C:44]2C=CC=N[C:43]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.Cl.NCC#N>C(Cl)Cl.O>[C:43]([CH2:44][NH:49][C:23](=[O:25])[CH2:22][NH:21][C:19]([C:17]1[S:18][C:14]([C:11]2[CH2:10][C:9]([C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)([C:30]([F:33])([F:32])[F:31])[O:13][N:12]=2)=[C:15]2[CH2:29][CH2:28][CH2:27][CH2:26][C:16]=12)=[O:20])#[N:42]

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 11491918Aminoacetonitrile hydrochlorideHCID 714688182-(3-(5-(3,5-Dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamido)acetic acid

Product 1

HCID 71468820N-(2-(cyanomethylamino)-2-oxoethyl)-3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamideYield 44.7%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

Stir a mixture of 2-(3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamido)acetic acid (230 mg, 0.44 mmol), HATU (251 mg, 0.66 mmol) and NEt3 (133 mg, 1.32 mmol) in DCM (5 mL) at room temperature for 15 min, followed by addition of 2-aminoacetonitrile hydrochloride (61 mg, 0.65 mmol). Stir the reaction mixture at room temperature for additional 1.5 hour. Dilute the reaction mixture with water (20 mL) and extract with DCM (20 mL×3). The combined organic layers are washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum. Purify the residue by preparative HPLC to afford N-(2-(cyanomethylamino)-2-oxoethyl)-3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide as a white solid (110 mg, 44.7%). MS (m/z): 559.1 (M+1). 1H NMR (DMSO-d6, 400 MHz) δ 8.64 (t, J=5.6 Hz, 1H), 8.22 (t, J=5.6 Hz, 1H), 7.81-7.80 (m 1H), 7.68 (s, 2H), 4.35-4.22 (m, 2H), 4.16-4.15 (m, 2H), 3.88-3.86 (m, 2H), 2.94-2.86 (m, 4H), 1.70-1.69 (m, 4H).

Workup

  1. stirringStir the reaction mixture at room temperature for additional 1.5 hour
  2. extractionextract with DCM (20 mL×3)
  3. washThe combined organic layers are washed with brine
  4. dry with materialdried over anhydrous Na2SO4
  5. concentrationconcentrated under vacuum
  6. customPurify the residue by preparative HPLC

Sources & evidence

ORD record
ord-bcd83086221c4beaa03547ebd642a572
Source dataset
uspto-grants-2014_11
Patent number
US08889710B2

Reaction notes

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