Diisopropylethylamine → 2-(3-{methyl-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-amino}-propyl)-thiazole-4-carboxylic acid methyl-(R)-1,2,3,4-tetrahydro-naphthalen-1-yl-amide

HRID 470723

Reaction equation

HRID 470723 reaction equation
[CH3:1][C:2]1[N:6]([CH2:7][C:8]([OH:10])=O)[N:5]=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.C(N(C(C)C)CC)(C)C.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.Cl.[CH3:58][N:59]([C@H:72]1[C:81]2[C:76](=[CH:77][CH:78]=[CH:79][CH:80]=2)[CH2:75][CH2:74][CH2:73]1)[C:60]([C:62]1[N:63]=[C:64]([CH2:67][CH2:68][CH2:69][NH:70][CH3:71])[S:65][CH:66]=1)=[O:61]>C(#N)C>[CH3:58][N:59]([C@H:72]1[C:81]2[C:76](=[CH:77][CH:78]=[CH:79][CH:80]=2)[CH2:75][CH2:74][CH2:73]1)[C:60]([C:62]1[N:63]=[C:64]([CH2:67][CH2:68][CH2:69][N:70]([CH3:71])[C:8](=[O:10])[CH2:7][N:6]2[C:2]([CH3:1])=[CH:3][C:4]([C:11]([F:14])([F:13])[F:12])=[N:5]2)[S:65][CH:66]=1)=[O:61]

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 5961182-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acidHCID 672534412-(3-methylamino-propyl)-thiazole-4-carboxylic acid methyl-(R)-1,2,3,4-tetrahydro-naphthalen-1-yl-amide hydrochloride saltHCID 866211442-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate Methanaminium

Product 1

HCID 532422142-(3-{methyl-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-amino}-propyl)-thiazole-4-carboxylic acid methyl-(R)-1,2,3,4-tetrahydro-naphthalen-1-yl-amideYield 62.2%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

To a solution of (5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid (0.053 g, 0.25 mmol) in acetonitrile (3 mL) was added diisopropylethylamine (0.17 mL, 1.01 mmol), followed by 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (0.11 g, 0.3 mmol). After stirring 15 min at RT, 2-(3-methylamino-propyl)-thiazole-4-carboxylic acid methyl-(R)-1,2,3,4-tetrahydro-naphthalen-1-yl-amide hydrochloride salt (0.096 g, 0.25 mmol) was added to the reaction mixture. After stirring overnight at RT, solvent was evaporated and the resulting yellow oil was dissolved in ethylacetate (20 mL), washed with saturated aqueous sodium bicarbonate solution (30 mL), 1M HCl solution (10 mL), and brine (10 mL). The organic layer was dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude mixture was purified by column chromatography on silica gel (ethylacetate/cyclohexane 7:3) to give 2-(3-{methyl-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-amino}-propyl)-thiazole-4-carboxylic acid methyl-(R)-1,2,3,4-tetrahydro-naphthalen-1-yl-amide (Compound No. 1.d.55, 83 mg, 61%). 1H-NMR (400 MHz, CDCl3): δ=7.75-7.80 (s, 1H (conformers)), 7.31-7.29 (m, 1H), 7.20-7.06 (m, 3H), 6.35-6.25 (s, 1H (conformers)), 6.05-5.55 (m, 1H (conformers)), 5.05-4.75 (s, 2H (conformers)), 3.55-3.46 (m, 2H), 3.10-2.90 (s, 3H (conformers)), 3.08-3.05 (m, 1H), 2.90-2.75 (s, 3H (conformers)+m, 3H), 2.30-2.20 (s, 3H (conformers)), 2.15-1.61 (m, 6H). MS: m/z=534 (M+1).

Workup

  1. stirringAfter stirring overnight at RT
  2. customsolvent was evaporated
  3. dissolutionthe resulting yellow oil was dissolved in ethylacetate (20 mL)
  4. washwashed with saturated aqueous sodium bicarbonate solution (30 mL), 1M HCl solution (10 mL), and brine (10 mL)
  5. dry with materialThe organic layer was dried over sodium sulfate
  6. filtrationfiltered
  7. customevaporated under reduced pressure
  8. customThe crude mixture was purified by column chromatography on silica gel (ethylacetate/cyclohexane 7:3)

Sources & evidence

ORD record
ord-bfea0fdff62e42aabeabf8750de5a5cb
Source dataset
uspto-grants-2014_01
Patent number
US08629286B2

Linked notes

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