Sodium Hydroxide → (6-Chloro-pyridin-3-yl)-(4-cyclobutyl-[1,4]diazepan-1-yl)-methanone

HRID 474204Notes

Reaction equation

HRID 474204 reaction equation
Cl.Cl.[CH:3]1([N:7]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1.[OH-:14].[Na+].[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][N:18]=1>C(OC(C)C)(=O)C>[Cl:16][C:17]1[N:18]=[CH:19][C:20]([C:21]([N:10]2[CH2:11][CH2:12][CH2:13][N:7]([CH:3]3[CH2:6][CH2:5][CH2:4]3)[CH2:8][CH2:9]2)=[O:14])=[CH:23][CH:24]=1

Participants

5

Reactant 3

HCID 14798Sodium Hydroxide2×HCID 1554792-Chloro-5-(chloromethyl)pyridineHCID 574239521-Cyclobutyl-1,4-diazepane dihydrochloride

Product 1

HCID 58076653(6-Chloro-pyridin-3-yl)-(4-cyclobutyl-[1,4]diazepan-1-yl)-methanoneYield 91%

Reagents, catalysts & solvents 1

HCID 7915Isopropyl AcetateSolvent2×

Conditions

Temperature
0 °C

Procedure

A 5-L, 3-necked, round-bottomed flask was equipped with a mechanical stirrer and a thermocouple and charged with 1-cyclobutyl-[1,4]diazepane dihydrochloride (110.0 g, 484.6 mmol), 1 N NaOH (1400 mL) and isopropyl acetate (600 mL). A pre-cooled (0° C.). solution of 6-chloronicotinyl chloride (82.7 g, 470.0 mmol) in isopropyl acetate (800 mL) was added via an addition funnel at a rate such that the reaction temperature was maintained between 5-10° C. After the addition was complete, the reaction mixture was warmed to rt and stirred for 2 h (pH of reaction mixture ca. 5.6). The reaction mixture was basified with 2 N NaOH(aq) (to pH ca. 13). The phases were separated and the aqueous layer was extracted with isopropyl acetate (2×300 mL). Some reddish-brown flocculent material was observed during the extractions. The organic layers were pooled and filtered through a pad of diatomaceous earth. The filtrate was washed with satd. aq. NaCl (1×300 mL) and dried over anhydrous Na2SO4. Filtration and removal of the solvent by rotary evaporation under reduced pressure afforded the crude product as a reddish brown oil (126.0 g, 91%). 1H-NMR (400 MHz, CDCl3) δ ppm: 8.45 (m, 1H), 7.74 (m, 1H), 7.39 (m, 1H), 3.86-3.76 (m, 2H), 3.53-3.45 (m, 2H), 3.05-2.80 (m, 1H), 2.70 (br s, 1H), 2.62-2.45 (m 3H), 2.10-1.56 (m, 8H). MS m/z (ESI+): 294.1 (M+H+). HPLC (Method B): Rt=6.06 min.

Workup

  1. temperaturewas maintained between 5-10° C
  2. additionAfter the addition
  3. temperaturethe reaction mixture was warmed to rt
  4. custom(pH of reaction mixture ca. 5.6)
  5. customThe phases were separated
  6. extractionthe aqueous layer was extracted with isopropyl acetate (2×300 mL)
  7. extractionSome reddish-brown flocculent material was observed during the extractions
  8. filtrationfiltered through a pad of diatomaceous earth
  9. washThe filtrate was washed with satd
  10. dry with materialaq. NaCl (1×300 mL) and dried over anhydrous Na2SO4
  11. filtrationFiltration and removal of the solvent
  12. customby rotary evaporation under reduced pressure

Sources & evidence

ORD record
ord-9b7df78c89444f6d8a9de01af58de8ff
Source dataset
uspto-grants-2014_01
Patent number
US08637520B2

Reaction notes

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