Triethylamine → HCID 53373215, compound

HRID 515839Notes

Reaction equation

HRID 515839 reaction equation
CS(O[CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:40])[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:24](=[S:25])[N:23]([C:26]3[CH:27]=[N:28][C:29]([C:36]#[N:37])=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=3)[C:22](=[O:38])[C:18]32[CH2:21][CH2:20][CH2:19]3)=[CH:13][C:12]=1[F:39])(=O)=O.Cl.[F:42][C:43]1([F:48])[CH2:47][CH2:46][NH:45][CH2:44]1.C(N(CC)CC)C.CCOC(C)=O>C1COCC1.[Cl-].[Na+].O>[C:36]([C:29]1[N:28]=[CH:27][C:26]([N:23]2[C:22](=[O:38])[C:18]3([CH2:21][CH2:20][CH2:19]3)[N:17]([C:14]3[CH:15]=[CH:16][C:11]([C:10]([NH:9][CH2:8][CH2:7][CH2:6][N:45]4[CH2:46][CH2:47][C:43]([F:48])([F:42])[CH2:44]4)=[O:40])=[C:12]([F:39])[CH:13]=3)[C:24]2=[S:25])=[CH:31][C:30]=1[C:32]([F:33])([F:35])[F:34])#[N:37]

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 8857Ethyl AcetateHCID 249034823,3-Difluoropyrrolidine hydrochlorideHCID 86683492HCID 86683492, compound

Product 1

HCID 53373215HCID 53373215, compoundYield 9.2%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
70 °C

Procedure

A mixture of 3-(4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluorobenzamido)propyl methanesulfonate (45 mg, 0.075 mmol), 3,3-difluoropyrrolidine hydrochloride (54 mg, 0.37 mmol), and triethylamine (0.14 mL, 1.05 mmol) in THF (2 mL) was heated to 70° C. overnight. Brine and EtOAc were added to a cooled reaction mixture and the aqueous layer was extracted with EtOAc (2×), the organics were combined, dried over sodium sulfate, and evaporated to dryness. The residue obtained was purified by reverse phase HPLC (acetonitrile/water:TFA) to obtain 4.2 mg of 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-N-(3-(3,3-difluoropyrrolidin-1-yl)propyl)-2-fluorobenzamide. 1H NMR (300 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.68 (d, 1H), 8.51 (t, 1H), 7.72 (t, 1H), 7.39 (dd, 1H), 7.30 (dd, 1H), 3.25 (m, 4H), 2.80 (t, 2H), 2.64-2.58 (m, 4H), 2.44-2.40 (m, 2H), 2.16 (m, 2H), 1.91 (m, 1H), 1.64-1.45 (m, 3H). LCMS [M+1]+ 611.1.

Workup

  1. extractionthe aqueous layer was extracted with EtOAc (2×)
  2. dry with materialdried over sodium sulfate
  3. customevaporated to dryness
  4. customThe residue obtained
  5. customwas purified by reverse phase HPLC (acetonitrile/water:TFA)

Sources & evidence

ORD record
ord-9bbd803daeb64579a4f79791bc315b58
Source dataset
uspto-grants-2015_08
Patent number
US09108944B2

Reaction notes

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