Hydrochloric Acid → 4-(7-(6-cyano-5-methylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluoro-N-methylbenzamide

HRID 515809Notes

Reaction equation

HRID 515809 reaction equation
[N:1]([C:4]1[CH:5]=[C:6]([CH3:12])[C:7]([C:10]#[N:11])=[N:8][CH:9]=1)=[C:2]=[S:3].[C:13]([C:15]1([NH:19][C:20]2[CH:29]=[CH:28][C:23]([C:24]([NH:26][CH3:27])=[O:25])=[C:22]([F:30])[CH:21]=2)[CH2:18][CH2:17][CH2:16]1)#N.C[OH:32].Cl>CC(N(C)C)=O.O>[C:10]([C:7]1[N:8]=[CH:9][C:4]([N:1]2[C:13](=[O:32])[C:15]3([CH2:18][CH2:17][CH2:16]3)[N:19]([C:20]3[CH:29]=[CH:28][C:23]([C:24]([NH:26][CH3:27])=[O:25])=[C:22]([F:30])[CH:21]=3)[C:2]2=[S:3])=[CH:5][C:6]=1[CH3:12])#[N:11]

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 887MethanolHCID 441395204-[(1-Cyanocyclobutyl)amino]-2-fluoro-N-methylbenzamide2×HCID 580972105-Isothiocyanato-3-methylpicolinonitrile2×

Product 1

HCID 533547634-(7-(6-cyano-5-methylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluoro-N-methylbenzamideYield 29%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 31374DimethylacetamideSolvent

Conditions

Temperature
65 °C

Procedure

A mixture of 5-isothiocyanato-3-methylpicolinonitrile (Intermediate 6, 2.9 g, 16.57 mmol) and 4-((1-cyanocyclobutyl)amino)-2-fluoro-N-methylbenzamide (Intermediate 21, 2.7 g, 11.05 mmol) in DMA was heated to 65° C. overnight. MeOH (50 mL) and HCl (2M, 70 mL) were added and the mixture was heated to 105° C. for 1 h then cooled to room temperature. Water was slowly added until a yellow solid precipitated and the mixture was stirred at room temperature for 3 h. The solid was filtered, washed with water, dissolved in DCM, dried over sodium sulfate, and absorbed on silica gel. Purification by column chromatography on silica gel eluting with 0 to 100% EtOAc/hexanes afforded a pale yellow solid. This solid was triturated in MeOH, filtered, and dried to afford 1.39 g (29%) of 4-(7-(6-cyano-5-methylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluoro-N-methylbenzamide as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.64 (d, 1H), 8.40 (m, 1H), 8.06 (d, 1H), 7.75 (t, 1H), 7.43 (dd, 1H), 7.32 (dd, 1H), 2.73 (d, 3H), 2.59-2.53 (m, 2H), 2.52 (s, 3H), 2.44-2.23 (m, 2H), 1.91-1.88 (m, 1H), 1.52-1.48 (m, 1H). LCMS [M+1]+ 424.0.

Workup

  1. temperaturethe mixture was heated to 105° C. for 1 h
  2. temperaturethen cooled to room temperature
  3. customprecipitated
  4. filtrationThe solid was filtered
  5. washwashed with water
  6. dissolutiondissolved in DCM
  7. dry with materialdried over sodium sulfate
  8. customabsorbed on silica gel
  9. customPurification by column chromatography on silica gel eluting with 0 to 100% EtOAc/hexanes
  10. customafforded a pale yellow solid
  11. customThis solid was triturated in MeOH
  12. filtrationfiltered
  13. customdried

Sources & evidence

ORD record
ord-13542170ce5f46988729f7c7c06ab680
Source dataset
uspto-grants-2015_08
Patent number
US09108944B2

Reaction notes

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