Triethylamine → 3-({5-[3-Methyl-1-(4'-trifluoromethyl-biphenyl-4-yl)-butylamino]-pyrimidine-2-carbonyl}-amino)-propionic acid ethyl ester

HRID 2406992Notes

Reaction equation

HRID 2406992 reaction equation
[CH3:1][CH:2]([CH3:31])[CH2:3][CH:4]([NH:21][C:22]1[CH:23]=[N:24][C:25]([C:28](O)=[O:29])=[N:26][CH:27]=1)[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.Cl.[CH2:56]([O:58][C:59](=[O:63])[CH2:60][CH2:61][NH2:62])[CH3:57].C(N(CC)CC)C>ClCCl>[CH2:56]([O:58][C:59](=[O:63])[CH2:60][CH2:61][NH:62][C:28]([C:25]1[N:26]=[CH:27][C:22]([NH:21][CH:4]([C:5]2[CH:6]=[CH:7][C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:20])[F:19])=[CH:13][CH:12]=3)=[CH:9][CH:10]=2)[CH2:3][CH:2]([CH3:31])[CH3:1])=[CH:23][N:24]=1)=[O:29])[CH3:57]

Participants

7

Reactant 5

HCID 8471TriethylamineHCID 458475beta-Alanine, ethyl ester, hydrochlorideHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 27960291-Hydroxybenzotriazole hydrateHCID 67983293(+/-)-5-[3-Methyl-1-(4'-trifluoromet hyl-biphenyl-4-yl)-butylamino]-pyrimidine-2-carboxylic acid

Product 1

HCID 679806583-({5-[3-Methyl-1-(4'-trifluoromethyl-biphenyl-4-yl)-butylamino]-pyrimidine-2-carbonyl}-amino)-propionic acid ethyl esterYield 94%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

(+/−)-5-[3-Methyl-1-(4′-trifluoromethyl-biphenyl-4-yl)-butylamino]-pyrimidine-2-carboxylic acid (636 mg, theoretical 596 mg, 1.39 mmol) was combined with N-(3-dimethylaminopropyl)-N′-ethylcarbodimide hydrochloride (399 mg, 2.08 mmol), 1-hydroxybenzotriazole hydrate (319 mg, 2.08 mmol), and anhydrous dichloromethane (10 mL). Beta-alanine ethyl ester hydrochloride (256 mg, 1.67 mmol) was added followed by triethylamine (0.386 mL, 2.78 mmol). This was stirred at room temperature as a solution for 17 h before the reaction was partitioned between ethyl acetate and sat. NH4Cl. The aqueous layer was extracted with ethyl acetate and the combined organics dried over MgSO4. Purification by silica gel flash chromatography (ethyl acetate/heptanes followed by methanol/ethyl acetate) gave impure material. The residue was partitioned between ethyl acetate and sat. NaHCO3. The aqueous layer was extracted with ethyl acetate and the combined organics dried over MgSO4 and concentrated in vacuo to give (+/−)-3-({5-[3-methyl-1-(4′-trifluoromethyl-biphenyl-4-yl)-butylamino]-pyrimidine-2-carbonyl}-amino)-propionic acid ethyl ester (0.687 g, 94%) as a clear oil. 1H NMR (400 MHz, CDCl3, δ): 8.17 (t, J=6.2 Hz, 1 H) 8.09 (s, 2 H) 7.62-7.73 (m, 4 H) 7.56 (d, J=8.2 Hz, 2 H) 7.40 (d, J=8.2 Hz, 2 H) 4.53-4.58 (m, 1 H) 4.44-4.52 (m, 1 H) 4.11-4.19 (m, 2 H) 3.72 (q, J=6.2 Hz, 2 H) 2.61 (t, J=6.0 Hz, 2 H) 1.66-1.87 (m, 3 H) 1.21-1.29 (m, 3 H) 1.04 (d, J=6.0 Hz, 3 H) 0.99 (d, J=5.9 Hz, 3 H); MS (M+1): 529.7.

Workup

  1. customwas partitioned between ethyl acetate and sat. NH4Cl
  2. extractionThe aqueous layer was extracted with ethyl acetate
  3. dry with materialthe combined organics dried over MgSO4
  4. customPurification by silica gel flash chromatography (ethyl acetate/heptanes followed by methanol/ethyl acetate)
  5. customgave impure material
  6. customThe residue was partitioned between ethyl acetate and sat. NaHCO3
  7. extractionThe aqueous layer was extracted with ethyl acetate
  8. dry with materialthe combined organics dried over MgSO4
  9. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-0160e3aa8c4745c3a4beb3406b2aa91e
Source dataset
uspto-grants-2014_08
Patent number
US08809342B2

Reaction notes

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