Triethylamine → HCID 67980859, compound

HRID 2173862Notes

Reaction equation

HRID 2173862 reaction equation
[CH3:1][CH:2]([CH3:31])[CH2:3][C@H:4]([NH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][N:23]=1)[C:5]1[CH:6]=[N:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:9][CH:10]=1.Cl.CN(C)CCCN=C=NCC.Cl.[CH2:45]([O:47][C:48](=[O:52])[CH2:49][CH2:50][NH2:51])[CH3:46].C(N(CC)CC)C>ClCCl>[CH2:45]([O:47][C:48](=[O:52])[CH2:49][CH2:50][NH:51][C:26]([C:25]1[CH:24]=[N:23][C:22]([NH:21][C@H:4]([C:5]2[CH:6]=[N:7][C:8]([C:11]3[CH:12]=[CH:13][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:15][CH:16]=3)=[N:9][CH:10]=2)[CH2:3][CH:2]([CH3:31])[CH3:1])=[CH:30][CH:29]=1)=[O:28])[CH3:46]

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 458475beta-Alanine, ethyl ester, hydrochlorideHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 67980651HCID 67980651, compound

Product 1

HCID 67980859HCID 67980859, compound

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

6-{(S)-3-Methyl-1-[2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-butylamino}-nicotinic acid (31.1 g wet with ethyl acetate, theoretical 65.8 mmol) was dissolved in dichloromethane (270 mL). 1-Hydroxybenotriazole hydrate (15.1 g, 98.7 mmol) was added followed by N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (18.9 g, 98.7 mmol). beta-Alanine ethyl ester hydrochloride (12.1 g, 79.0 mmol) was added and the reaction was placed in an ice bath. When only slightly cool, triethylamine (18.3 mL, 132 mmol) was added over 3 min. The bath was then removed and the reaction was stirred at room temperature as a solution. At 16 h, most of the dichloromethane was rotovapped off. The residue was partitioned between ethyl acetate and sat. NH4Cl. The aqueous was extracted with additional ethyl acetate and the combined organics were washed with sat. NaHCO3 two times. The first aqueous was back extracted with ethyl acetate to remove a small amount of product. The combined organics were washed with brine and dried over MgSO4. The material was purified by silica gel flash chromatography (ethyl acetate/heptane) and then further purified by chiral SFC. Column: Chiralcel OJ-H. Dimensions: 21 mm×250 mm. Mobile Phase: 80/20 CO2/ethanol. Flow Rate: 65 ml/min. The purified material was taken up in ethyl acetate, filtered through a course frit and concentrated in vacuo to give 3-[(6-{(S)-3-methyl-1-[2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-butylamino}-pyridine-3-carbonyl)-amino]-propionic acid ethyl ester with ethyl acetate (29.2 g) as a white foam. 1H NMR (400 MHz, CDCl3, δ): 8.83 (s, 2H) 8.54 (d, J=8.0 Hz, 2H) 8.46 (d, J=2.0 Hz, 1H) 7.81 (dd, J=8.7, 2.2 Hz, 1H) 7.73 (d, J=8.4 Hz, 2H) 6.64 (t, J=5.8 Hz, 1H) 6.36 (d, J=8.6 Hz, 1H) 5.13 (d, J=6.7 Hz, 1H) 4.97-5.08 (m, 1H) 4.09-4.21 (m, 2H) 3.68 (q, J=5.9 Hz, 2H) 2.60 (t, J=5.9 Hz, 2H) 1.81-1.95 (m, 1H) 1.67-1.81 (m, 2H) 1.26 (t, J=7.1 Hz, 3H) 1.03 (d, J=6.1 Hz, 3H) 1.00 (d, J=6.1 Hz, 3H); MS (M+1): 530.2. Analytical chiral SFC: Column—Chiralcel OJ-H. Dimensions: 4.6 mm×25 cm. Mobile Phase: 80/20 CO2/ethanol. Flow Rate: 2.5 mL/min. Retention time: 5.18 minutes.

Workup

  1. customthe reaction was placed in an ice bath
  2. temperatureWhen only slightly cool
  3. customThe bath was then removed
  4. customThe residue was partitioned between ethyl acetate and sat. NH4Cl
  5. extractionThe aqueous was extracted with additional ethyl acetate
  6. washthe combined organics were washed with sat. NaHCO3 two times
  7. extractionThe first aqueous was back extracted with ethyl acetate
  8. customto remove a small amount of product
  9. washThe combined organics were washed with brine
  10. dry with materialdried over MgSO4
  11. customThe material was purified by silica gel flash chromatography (ethyl acetate/heptane)
  12. customfurther purified by chiral SFC
  13. filtrationfiltered through a course frit
  14. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-93927e54af6042d086b3ee50b751ecbd
Source dataset
uspto-grants-2015_06
Patent number
US09056834B2

Reaction notes

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