1-Boc-4-cyanopiperidine

Yellowish Oil

General procedure: To a solution of the aldoxime or the amide (1.0 mmol) and Et3N (1.5mmol) in EtOAc (1 mL, 1 M) at r.t. was added XtalFluor-E8 (1.1 mmol)portionwise over ca. 2 min. The resulting solution was stirred at r.t.for 1 h. The reaction mixture was quenched with sat. aq Na2CO3 and extracted with CH2Cl2 (2 × 10 mL). The combined organic layers were washed with H2O and brine, dried (MgSO4), and concentrated under vacuum to afford the crude nitrile, which was purified by flash chromatography, if required.Dehydration was achieved by reaction of 2 with POC13 in DCM at rt overnight in yields of 70-90percent. Reduction of the cyano group to the aminomethyl group by LAH in THF or diethylether at rt gave template 4 in 50-60percent yield after column chromatography. b) 4-Carbamoyl-piperidine-1-carboxylic acid tert-butyl ester (46.0 g) was dissolved in DCM (500 ml) and cooled to 0°C. TEA (57 mi) was added followed by slow addition of a solution of POC13 (20.7 mi) in DCM (100 ml) at 0°C to 5°C. The reaction mixture was stirred at rt for lh. Then a saturated sodium hydrogen carbonate solution (-300 ml) was carefully added until no more gas formation was observed. The organic layer was separated in a separation funnel and the water phase was extracted once more with DCM. The combined organic layers were subsequently washed with a 10percent citric acid solution and brine, dried with magnesium sulfate, filtered and concentrated in vacuo to give 4-cyano-piperidine-1- carboxylic acid tert-butyl ester (41.73 g). The crude material crystallized while drying at HV and was used without further purification.To a solution of piperidine-4-carbonitrile (0.5 g, 4.54 mmol) in 25 mL of distilled dichloromethane under argon, distilled triethylamine (1.3 mL, 9.08 mmol) was added. While stirring, the solution was cooled to 0 °C and di-tert-butyl dicarbonate (1.19 g, 5.4 mmol) was added in several portions over 15 mm (bubbling observed). The resulting mixture was stirred at rt for 12 h, then solvent was evaporated and the residue was purified by column chromatography on silica gel using a mixture of CH2C12 and MeOH (30:1) as an eluant to give tert-butyl 4-cyanopiperidine-1-carboxylate, 0.95 g (100percent yield) as a colorless thick oil, that solidifies on standing.9a. 4-Cyano-piperidine-1 -carboxylic acid tert-butyl ester 4-Cyanopiperidine (5.00 g, 0.044 mol) was dissolved in 1, 4-dioxane (50 mL)and di-tert-butyl dicarbonate (10.4 mL, 0.049 mol) was added dropwise to the reaction mixture at RT. The mixture was stirred overnight at sameo temperature. The reaction mixture was diluted with DCM, washed withNaHCO3 solution and NaCI solution, dried over sodium sulfate, filtered and evaporated to dryness to give the title compound (9.00 g , 97 percent) as a light yellow oil, which was usedwithout further purification. LC/MS (Method B): Rt 2.00 mm, (M+Na) 233.To a solution of piperidine-4-carbonitrile (44.4 g, 403 mmol) in CHEXAMPLE 214-(aminomethyl)-N-((5-bromothiophen-2-yl)methyl)-l-(7H-pyrrolor2, 3-dlpyrimidin-4- yl)piperidine-4-carboxamide2 IA. tert-Butyl 4-cyanopiperidine-l-carboxylate; Piperidine-4-carbonitrile (98g, 889.64 mmol) was dissolved in DCM (1200 ml), to this was added di-tert-butyl dicarbonate (204 g, 934.12 mmol) portionwise. The reaction was stirred at 25 Intermediate V:- l'-(tert-butoxycarbonyl)-1-oxo-2, 3-dihydro-1H-spiro[1, 4- diazepino[1, 2-a]indole-4, 4'-piperidine]-8-carboxylic acid Step 1: Synthesis of tert-butyl 4-cyanopiperidine-1-carboxylate Di-tert-butyl dicarbonate (26.4 mL, 109.0 mmol) is added dropwise to a solution of piperidine-4-carbonitrile (10 g, 90.9 mmol) in CHEXAMPLE 8 In a 100-ml flask, 30 mL of acetonitrile, 10 mmol of HMDS, 0.4 mmol of TEMPO, 0.4 mmol of KPF6 and 0.6 mmol of TBN were charged. The air was replaced with oxygen. The mixture was heated to 30 ° C in a preheated water bath and 4 mmol of N-Boc-4-piperidinecarboxaldehyde (as shown in formula (1-8)) was added slowly for 8 h. The reaction mixture was stirred with sodium thiosulfate solution and extracted with ether. The organic layer was separated, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography. The mixture was stirred at a volume ratio of ethyl acetate / petroleum ether of 1: 100 The eluent containing the title compound was collected and the solvent was evaporated to give N-Boc-4-piperidinecarbonitrile in an isolation yield of 70percent.; The reaction procedure was the same as in Example 20, except that the amount of acetonitrile used was 80 mL, and the isolated yield of N-Boc-4-piperidinecarbonitrile was 73percent.General procedure: To a solution of the aldoxime or the amide (1.0 mmol) and Et3N (1.5mmol) in EtOAc (1 mL, 1 M) at r.t. was added XtalFluor-E8 (1.1 mmol)portionwise over ca. 2 min. The resulting solution was stirred at r.t.for 1 h. The reaction mixture was quenched with sat. aq Na2CO3 and extracted with CH2Cl2 (2 × 10 mL). The combined organic layers were washed with H2O and brine, dried (MgSO4), and concentrated under vacuum to afford the crude nitrile, which was purified by flash chromatography, if required.EXAMPLE 8

Molecular Weight:210.27
XLogP3:1.3
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:210.136827821
Monoisotopic Mass:210.136827821
Topological Polar Surface Area:53.3
Heavy Atom Count:15
Complexity:277
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes