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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
Synonyms: 3,3-Difluoroazetidine hydrochloride
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Batch number can be found on the product's label following the word 'Batch'.
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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 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
* 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.
Yield | Reaction Conditions | Operation 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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dichloromethane; | Step 1 DIEA (0.196 mL, 1.12 mmol) was added to a stirred mixture of 3,3-difluoroazetidine hydrochloride (64.8 mg, 0.50 mmol) and <strong>[50712-69-1]2-bromomethyl-5-chlorobenzonitrile</strong> (121.0 mg, 0.52 mmol) in CH2Cl2 (7 mL). After 16 h the reaction was partitioned between EtOAc and water. The organic layer was washed with water and brine, dried (Na2SO4) and evaporated. The residue was partitioned between 1N HCl and ether. The aqueous layer was made neutral with NaHCO3 and was extracted with CH2Cl2. The organic layer was dried with Na2SO4 and then evaporated to give 5-chloro-2-[(3,3-difluoroazetidin-1-yl)methyl]benzonitrile (67.8 mg) as a glass: 1H NMR (CDCl3, 400 MHz) delta 3.68 (t, J=11.9 Hz. 4H), 3.93 (s, 2H), 7.54 (m, 2H), 7.63 (d, J=2.2 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
psi-Chloro^-methyl-S-nitropyridine (1 g, 5.79 mmol) and 3,3-difluoroazetidine hydrochloride salt (0.948 g, 6.95 mmol) were dissolved in in MeOH (15 ml) followed by addition of TEA (1.22 ml 8.69 mMol) and stirred at 400C for 2h, then at 600C for 17 h. At RT, K2CO3 (0.801 g, 5.79 mmol) was added, followed by 3,3-difluoroazetidine hydrochloridride salt (0.395 g, 2.9 mmol) and the solution was stirred at 60°C for 16h. The reaction mixture was diluted with EtOAc and washed with NaHCO3 aq. sat. soP and brine. The combined organic layers were dried (Na2SO4) and after filtration, the solvent was removed under reduced pressure and the crude product was dried under high vacuum (500C) to obtain the title compound (1.256 g) as a brown solid. The product was used in the next step without further purification. (HPLC: tR 6.468 min (Method B); M+H = 230 MS-ES. ) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | To an ice-cold solution of 2-bromoisonicotinaldehyde (0.40 g, 2.15 mmol) in THF (5 mL) was added 3,3-difluoroazetidine hydrochloride (0.41 g, 3.12 mmol) and N-methyl morpholine (catalytic). The reaction was stirred at 0° C. for 15 min followed by the portion wise addition of sodium cyano borohydride (0.41 g, 6.45 mmol). The mixture was stirred at RT for 16 h. H2O (50 mL) was added followed by extraction with EtOAc (3×100 mL). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. Purification by chromatography on silica (30percent EtOAc-Hexane) gave Precursor 49 (0.18 g, 32percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68.79% | To a mixture of <strong>[204688-60-8](R)-2-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)acetic acid</strong> (690 mg, 3.01 mmol) in dichloromethane (40 mL) was sequentially added 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (693.3 mg, 3.63 mmol) and 1- hydroxybenzotriazole (593.43 mg, 4.53 mmol), and then DIPEA (1.55 g, 12.04 mmol) was added drop-wise. The mixture was stirred for 10 mm and 3,3-difluoroazetidine hydrochloride(464.4 g, 3.6 mmol) was added. The reaction was stirred at room temperature overnight. The reaction was diluted with dichloromethane (50 mL x 2) and washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 100: ito 50: ito give (R)-tert-butyl 3-(2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl)pyrrolidine-i-carboxylate (630 mg, 68.79% yield) as a colorless oil. LC-MS: m/z =249 [M+H-56j. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 20℃; for 48.0h; | General procedure: To a solution of Intermediate 7 (110 mg, 0.37 mmol), 3-methoxybenzene-1,2- diamine (50 mg, 0.34 mmol) and DIPEA (0.2 mL, 1 mmol) in DMF (2 mL) was added HATU (160 mg, 0.41 mmol). The reaction mixture was stirred at r.t. for 48 h, then partitioned between DCM and water. The organic phase was separated, then dried and concentrated in vacuo. The crude residue was purified by flash column chromatography (0-100% EtOAc/hexanes) to give the title compound (28.7 mg, 20%) as a white solid. LCMS (Method 5): [M+H]+ m/z 415, RT 1.31 minutes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tris(acetoxy)borohydride; acetic acid; In tetrahydrofuran; at 50℃; for 0.5h; | A microwave vial was charged with 1-benzylpiperidin-3-one hydrate HCl salt (100 mg, 0.4 mmol), 3,3-difluoroazetidine hydrochloride (80 mg, 0.6 mmol) and AcOH (47 muL, 0.8 mmol) in THF (1 mL). The resulting suspension was stirred at 50 C until a clear solution was obtained, then NaBH(OAc)3 (261 mg, 1.2 mmol) was added. The reaction mixture was stirred at 50 oC for 30 minutes then allowed to cool to ambient temperature and quenched by the addition of saturated aqueous NaHCO3 solution. The mixture was stirred for 10 minutes then extracted with DCM (x 3). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give 1-benzyl-3-(3,3-difluoroazetidin-1-yl)piperidine, which was used directly in the next step |
Tags: 3,3-Difluoroazetidine HCl | 3,3-Difluoroazetidine hydrochloride | Azetidines | Fluorinated Building Blocks | Inorganic Salts | Synthetic Reagents | Organic Building Blocks | Heterocyclic Building Blocks | 288315-03-7
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Total Compounds: mg
The concentration of the dissolution solution you need to prepare is mg/mL