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Chemical Structure| 288315-03-7 Chemical Structure| 288315-03-7
Chemical Structure| 288315-03-7

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Synonyms: 3,3-Difluoroazetidine hydrochloride

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Product Details of 3,3-Difluoroazetidine HCl

CAS No. :288315-03-7
Formula : C3H6ClF2N
M.W : 129.54
SMILES Code : Cl.FC1(CNC1)F
Synonyms :
3,3-Difluoroazetidine hydrochloride
MDL No. :MFCD05663714
InChI Key :CDBAEFXTCRKJPZ-UHFFFAOYSA-N
Pubchem ID :2758247

Safety of 3,3-Difluoroazetidine HCl

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Application In Synthesis of 3,3-Difluoroazetidine HCl

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Upstream synthesis route of [ 288315-03-7 ]
  • Downstream synthetic route of [ 288315-03-7 ]

[ 288315-03-7 ] Synthesis Path-Upstream   1~1

  • 1
  • [ 288315-03-7 ]
  • [ 79099-07-3 ]
  • [ 1093066-74-0 ]
YieldReaction ConditionsOperation in experiment
88%
Stage #1: at 20℃; for 0.25 h;
Stage #2: With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane for 17 h;
To a solution of 4-oxo-piperidine-l-carboxylic acid tert-butyl ester (1.0 g, 5.0 mmol) in DCE (50 mL) was added 3,3-difluoroazetidine hydrochloride (712 mg, 5.5 mmol). The mixture was stirred at RT for 15 min, then sodium triacetoxyborohydride (1.59 g, 7.5 mmol) was added and stirring was continued for 17 h. The reaction mixture was diluted with brine and extracted with DCM. The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by column chromatography to give 4-(3,3- difluoroazetidin-l-yl)-piperidine-l-carboxylic acid tert-butyl ester as a pale yellow solid (1.2 g, 88 percent). To a solution of 4-(3,3-difluoro-azetidin-l-yl)-piperidine-l-carboxylic acid tert- butyl ester (552 mg, 2.0 mmol) in DCM (4 mL) was added TFA (2 mL) and the resulting mixture was stirred at RT for 45 min. The reaction mixture was loaded onto an Isolute.(R). SCX- 2 cartridge. The cartridge was washed with MeOH then eluted with 2 M NH3 in MeOH to give the title compound as a pale yellow solid (271 mg, 77 percent). <n="94"/>1H NMR (400 MHz, CDCl3): δ 1.16-1.27 (m, 2 H), 1.63-1.72 (m, 2 H), 2.14-2.23 (m, 1 H), 2.54-2.62 (m, 2 H), 3.09 (dt, J = 12.7, 3.9 Hz, 2 H) and 3.46-3.57 (m, 4 H).
88%
Stage #1: at 20℃; for 0.25 h;
Stage #2: With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane for 17 h;
Reference Example 254-(3,3-Difluoro-azetidin-l-yl)-piperidineTo a solution of 4-oxo-piperidine-l-carboxylic acid tert-butyl ester (1.0 g, 5.0 mmol) in DCE (50 mL) was added 3,3-difluoroazetidine hydrochloride (712 mg, 5.5 mmol). The mixture was stirred at RT for 15 min, then sodium triacetoxyborohydride (1.59 g, 7.5 mmol) was added and stirring was continued for 17 h. The reaction mixture was diluted with brine and extracted with DCM. The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by column chromatography to give 4-(3,3- difluoro-azetidin-l-yl)-piperidine-l-carboxylic acid tert-butyl ester as a pale yellow solid (1.2 g, 88 percent). To a solution of 4-(3,3-difluoro-azetidin-l-yl)-piperidine-l-carboxylic acid tert- butyl ester (552 mg, 2.0 mmol) in DCM (4 mL) was added TFA (2 mL) and the resulting <n="69"/>mixture was stirred at RT for 45 min. The reaction mixture was loaded onto an Isolute.(R). SCX- 2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH to give the title compound as a pale yellow solid (271 mg, 77 percent).1H NMR (400 MHz, CDCl3): δ 1.16-1.27 (m, 2 H), 1.63-1.72 (m, 2 H), 2.14-2.23 (m, 1 H), 2.54-2.62 (m, 2 H), 3.09 (dt, J = 12.7, 3.9 Hz, 2 H) and 3.46-3.57 (m, 4 H).
88% at 20℃; for 17 h; To a solution of 4-oxo-piperidine-l-carboxylic acid tert-butyl ester (1.0 g, 5.0 mmol) in DCE (50 mL) was added 3,3-difluoroazetidine hydrochloride (712 mg, 5.5 mmol). The mixture was stirred at RT for 15 min, then sodium triacetoxyborohydride (1.59 g, 7.5 mmol) was added and stirring was continued for 17 h. The reaction mixture was diluted with brine and extracted with DCM. The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by column chromatography to give 4-(3,3- difluoroazetidin-l-yl)piperidine-l-carboxylic acid tert-butyl ester as a pale yellow solid (1.2 g, 88 percent). To a solution of 4-(3,3-difluoroazetidin-l-yl)piperidine-l-carboxylic acid tert-butyl ester (552 mg, 2.0 mmol) in DCM (4 mL) was added TFA (2 mL) and the resulting mixture was stirred at RT for 45 min. The reaction mixture was loaded onto an Isolute.(R). SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH to give the title compound as a pale yellow solid (271 mg, 77 percent). 61H NMR (400 MHz, CDCl3): 5 1.16-1.27 (m, 2 H), 1.63-1.72 (m, 2 H), 2.14-2.23 (m, 1 H), 2.54-2.62 (m, 2 H), 3.09 (dt, J = 12.7, 3.9 Hz, 2 H) and 3.46-3.57 (m, 4 H).
43%
Stage #1: With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 50℃; for 16 h;
Stage #2: With sodium tris(acetoxy)borohydride; acetic acid In N,N-dimethyl-formamide at 40℃; for 16 h;
A solution of 3,3-difluoroazetidine hydrochloride (300 mg, 2.3 mmol), te/f-butyl 4-oxopiperidine- 1 -carboxylate (461 mg, 2.3 mmol) and DIPEA (0.40 ml_, 2.3 mmol) in DMF (6 mL) was heated to 50 °C for 16 h before cooling to rt, addition of sodium triacetoxyborohydride (1 .23 g, 5.8 mmol) and AcOH (0.13 mL, 2.3 mmol) and further heating at 40 °C for 16 h. The mixture was cooled to rt, quenched by addition of sat. aq. NaHC03 (3 mL) and concentrated in vacuo. The residue was diluted with DCM (15 mL) and washed with sat. aq. NaHC03 (15 mL) and brine (15 mL). Organics were dried (Biotage phase separator) and concentrated in vacuo. The crude residue was purified on silica (Biotage Isolera, SNAP 25 g cartridge, 0 - 10 percent MeOH / DCM and subsequently SNAP 25 g cartridge, 0 - 5 percent MeOH / DCM) to yield te/f-butyl 4-(3,3- difluoroazetidin-1 -yl)piperidine-1 -carboxylate (273 mg, 43 percent) as a white crystalline solid, which was used directly in the next step.

References: [1] Patent: WO2009/53715, 2009, A1, . Location in patent: Page/Page column 92-93.
[2] Patent: WO2009/53716, 2009, A1, . Location in patent: Page/Page column 67-68.
[3] Patent: WO2008/152394, 2008, A1, . Location in patent: Page/Page column 45.
[4] Patent: WO2017/21729, 2017, A1, . Location in patent: Page/Page column 41.
 

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