Hydrochloric Acid → HCID 178436721, compound

HRID 1192721Notes

Reaction equation

HRID 1192721 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([C:24](O)=[O:25])[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:6](/[N:10]=[N:11]/[N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:7]=1[C:8]#[CH:9].Cl.[CH3:28][NH:29][O:30][CH3:31].O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CCN=C=NCCCN(C)C.Cl.Cl.O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:24]([N:29]([O:30][CH3:31])[CH3:28])=[O:25])[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:6](/[N:10]=[N:11]/[N:12]2[CH2:13][CH2:14][CH2:15][CH2:16]2)[C:7]=1[C:8]#[CH:9]

Participants

9

Reactant 7

HCID 313Hydrochloric AcidHCID 962WaterHCID 81138Methanamine, N-methoxy-, hydrochloride (1:1)HCID 81531DiisopropylethylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 27960291-Hydroxybenzotriazole hydrateHCID 178436723HCID 178436723, compound

Product 1

HCID 178436721HCID 178436721, compoundYield 101.9%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A solution of 4-chloro-5-ethynyl-3′-fluoro-6-[(E)-pyrrolidin-1-yldiazenyl]biphenyl-2-carboxylic acid (830 g, 2.2 mol), N,O-dimethylhydroxylamine hydrochloride (280 g, 2.9 mol), 1-hydroxybenzotriazole hydrate (360 g, 2.4 mol), and N,N-diisopropylethylamine (1.4 L, 7.8 mol) in tetrahydrofuran (5 L) was treated with EDCI HCl (520 g, 2.7 mol) and stirred at room temperature for 36 hours. The reaction mixture was cooled to approximately 5° C. and treated with 2.0 M hydrogen chloride in water (3.4 L, 6.7 mol) in portions while maintaining the internal temperature lower than 10° C. The organic layer was separated and the aqueous layer was extracted with tetrahydrofuran (2 L). The combined organic layers (˜6 L, pH ˜5) were washed with 2.0 M hydrogen chloride in water (2 L), 0.5 M sodium carbonate in water (2 L), and brine, dried over sodium sulfate, filtered, and concentrated to give a crude oil. This material was azeotroped with toluene to give the desired product (theoretical yield 930 g) as a brown oil. This material was used in the next step without further purification. A small sample was purified for spectroscopic analysis. LCMS for C21H21ClFN4O2 (M+H)+: m/z=415.1; Found: 415.0; 1H NMR (400 MHz, DMSO-d6): δ 7.44 (s, 1H), 7.35-7.29 (m, 1H), 7.12-7.06 (m, 1H), 6.93-6.84 (m, 2H), 4.48 (s, 1H), 3.62-3.58 (m, 2H), 3.29 (s, 3H), 3.25-3.17 (m, 2H), 2.93 (s, 15 H), 2.85 (s, 1.5H), 1.89-1.77 (m, 4H).

Workup

  1. temperatureThe reaction mixture was cooled to approximately 5° C.
  2. temperaturewhile maintaining the internal temperature lower than 10° C
  3. customThe organic layer was separated
  4. extractionthe aqueous layer was extracted with tetrahydrofuran (2 L)
  5. washThe combined organic layers (˜6 L, pH ˜5) were washed with 2.0 M hydrogen chloride in water (2 L), 0.5 M sodium carbonate in water (2 L)
  6. dry with materialbrine, dried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customto give a crude oil
  10. customThis material was azeotroped with toluene

Sources & evidence

ORD record
ord-c8e493d7dd76412ca197af489f47b24f
Source dataset
uspto-grants-2014_03
Patent number
US08680108B2

Reaction notes

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