Home Cart 0 Sign in  

[ CAS No. 141699-59-4 ] {[proInfo.proName]}

,{[proInfo.pro_purity]}
Cat. No.: {[proInfo.prAm]}
Chemical Structure| 141699-59-4
Chemical Structure| 141699-59-4
Structure of 141699-59-4 * Storage: {[proInfo.prStorage]}
Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Quality Control of [ 141699-59-4 ]

Related Doc. of [ 141699-59-4 ]

Alternatived Products of [ 141699-59-4 ]

Product Details of [ 141699-59-4 ]

CAS No. :141699-59-4 MDL No. :MFCD04116220
Formula : C11H21NO5S Boiling Point : -
Linear Structure Formula :- InChI Key :WOEQSXAIPTXOPY-UHFFFAOYSA-N
M.W : 279.35 Pubchem ID :4184869
Synonyms :

Calculated chemistry of [ 141699-59-4 ]

Physicochemical Properties

Num. heavy atoms : 18
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.91
Num. rotatable bonds : 5
Num. H-bond acceptors : 5.0
Num. H-bond donors : 0.0
Molar Refractivity : 71.45
TPSA : 81.29 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -7.23 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.72
Log Po/w (XLOGP3) : 1.09
Log Po/w (WLOGP) : 2.06
Log Po/w (MLOGP) : 0.93
Log Po/w (SILICOS-IT) : 0.0
Consensus Log Po/w : 1.36

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -1.93
Solubility : 3.29 mg/ml ; 0.0118 mol/l
Class : Very soluble
Log S (Ali) : -2.39
Solubility : 1.14 mg/ml ; 0.00408 mol/l
Class : Soluble
Log S (SILICOS-IT) : -1.32
Solubility : 13.2 mg/ml ; 0.0474 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 0.0
Synthetic accessibility : 2.8

Safety of [ 141699-59-4 ]

Signal Word:Warning Class:
Precautionary Statements:P261-P301+P312-P302+P352-P304+P340-P305+P351+P338 UN#:
Hazard Statements:H302-H315-H319-H335 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 141699-59-4 ]

* 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.

  • Downstream synthetic route of [ 141699-59-4 ]

[ 141699-59-4 ] Synthesis Path-Downstream   1~93

  • 1
  • [ 13788-84-6 ]
  • [ 141699-59-4 ]
  • [ 180695-75-4 ]
  • [ 180695-76-5 ]
  • 2
  • [ 106-53-6 ]
  • [ 141699-59-4 ]
  • [ 188527-03-9 ]
YieldReaction ConditionsOperation in experiment
96% With potassium carbonate In acetonitrile for 18h; Heating;
79% With potassium carbonate In acetonitrile at 20℃; for 24h; Heating / reflux; 37 Intermediate 23 (82.0 g, 0.29 mol), 4-bromothiophenol (50.0 g, 0.27 mol) and K2CO3 (80.0 g, 0.58 mol) were mixed in CH3CN (5000 mL) at room temperature. The mixture was heated to reflux and stirred for 24 h. Upon completion, the reaction mixture was filtered and the filtrate was concentrated. The residue was dissolved in EtOAc and washed with IN NaOH. The organic layer was concentrated to give crude product, which was purified by column chromatography (silica, elute; petroleum: EtOAc=10:0, 10:1) to give the title intermediate (62 g, 79%) as a white solid.
With triethylamine In acetonitrile at 80℃; for 17.5h; Synthesis of N-Boc-4-(4-bromophenylthio)piperidine (10) Compound 9 (16.4 g, 0.06 mol), 4 -bromothiophenol (10.0 g, 0.054 mol) and Et3 N (40.8 g, 0.4 mol) were mixed at room temperature in CH3 CN (1000 mL) and maintained 17.5 h at 80°C. The reaction mixture was filtered and filtrate was dissolved in EtOAc and washed with 1N NaOH. Subsequently, the organic layer was separated and further purified by a silica gel column chromatography (PE:EtOAc =10:l) obtaining the crude product as a white solid (12.4 g, yield 78.5%).[2] 1 H NMR (500 MHz, CDCl3 ) δ 7.417 (d, 2H), 7.269 (d, 2H), 3.956 (m, 4H), 3.172 (m, 1H), 1.905 (dt, 4H), 1.488 (s, 9H). m/z [M+2]+ 373.06 C16H22BrNO2 S.
  • 3
  • [ 60463-12-9 ]
  • [ 141699-59-4 ]
  • [ 233281-74-8 ]
  • 4
  • [ 106984-91-2 ]
  • [ 141699-59-4 ]
  • [ 918535-59-8 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 75℃; Step 2:To the solution of hydroxypyridine 24 (0.29 g, 2.36 mmol) in DMF (20 ml) was added mesylate 23 (0.92 g, 3.30 mmol) and K2CO3 (0.71 g, 5.0 mmol). The mixture was stirred overnight at 750C, at which point additional mesylate 23 (0.18 g, 0.65 mmol) was added, and stirring at 750C was continued for another 8 h. DMF was removed under vacuum, the residue was subjected to aqueous work-up - CH2CI2 extraction. Organic phase was separated, dried over Na2SO4 and concentrated, and the residue was purified by flash chromatography (1-2% acetone/ CH2CI2) to produce 0.26 g of 25 as a white solid.
  • 5
  • [ 461-84-7 ]
  • [ 141699-59-4 ]
  • [ 474711-20-1 ]
YieldReaction ConditionsOperation in experiment
100% With sodium hydroxide; In diethyl ether; diethylene glycol dimethyl ether; ethyl acetate; Part A. Preparation of 4-(4-trifluoromethylsulfanyl-phenoxy)-piperidine-1-carboxylic Acid tert-butyl Ester A clear, colorless solution of 4-(trifluoromethylthio)phenol (10.0 g, 51.5 mmol) in diglyme (26.9 ml) was treated with 50% (w/w) NaOH (26.9 mL, 515 mmol). This resulted in an exotherm to about 35 C., and the mixture became a clear yellow solution. After 5 min, the mixture was treated with 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (17.3 g, 61.8 mmol, prepared in accordance with the method described in PCT Appl. No. PCT/US00/03061 (Publ. No. WO 00/46221, pp. 544-545, Ex. 51, Pt. D, incorporated by reference into this patent)), and then heated to 80 C. for 3 days. Subsequently, the mixture was cooled to ambient temperature, neutralized with 6 N HCl(aq) to a pH of 7, and partitioned with 1:1 ethyl acetate/diethyl ether (200 mL). The aqueous layer was separated, and the organic layer was washed with 1:1 brine/deionized H2O (2*50 mL), washed with brine (2*50 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford the desired product as a clear yellow oil (23.05 g, >100% mass recovery-the product mixture included residual EtOAc and trace amounts of 3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester [observed in HPLC, LC/MS, and 1H-NMR]). The structure of the product was confirmed by 1H-NMR, 19FNMR. LC/MS m/z=400 [M+Na]. The product was used in the next step without further purification.
  • 6
  • [ 610-81-1 ]
  • [ 141699-59-4 ]
  • [ 1018895-41-4 ]
YieldReaction ConditionsOperation in experiment
64% With caesium carbonate; In N,N-dimethyl acetamide; at 90℃; for 22h; Synthesis of tert-butyl 4-(4-amino-3-nitrophenoxy)piperidine-l-carboxylate; [00318] Cesium carbonate (14.19 g, 43.56 mmoles, 2 equivalents) was added to a stirred solution of <strong>[610-81-1]4-amino-3-nitrophenol</strong> (3.35 g, 21.78 mmoles, 1 equivalent) and tert-butyl 4-(methylsulfonyloxy)piperidine-l-carboxylate (6.69 g, 23.96 mmoles, 1.1 equivalent) in anhydrous DMA (30 ml). The stirred reaction mixture was then heated to 90 0C (thermostatically controlled heating mantle) for 22 hours. The reaction mixture was then allowed to cool to room temperature and was filtered through a plug of Celite. The reaction flask and the Celite were then washed with ethyl acetate (250 ml). The organic solution was then transferred to a separatory funnel and extracted with additional ethyl acetate (3 x 200 ml). The combined ethyl acetate solution was then washed with water (2 x 100 ml), saturated sodium chloride (2 x 100 ml), dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. This material was triturated with diethyl ether which was filtered off and washed with diethyl ether to give 4.76 g of tert-butyl 4-(4-amino-3-nitrophenoxy)piperidine-l- carboxylate (yield = 64%). 1H-NMR (400 MHz, OMSO-d6) delta 7.42 (s, IH), 7.22 (d, IH), 7.01 (d, IH), 4.18 (m, IH), 3.79 (m, 2H), 3.10 (m, 2H), 1.80 (m, 2H), 1.43 (m, 2H), 1.29 (s, 9H). MS (EI): 338 (MH+).
  • 7
  • [ 17325-26-7 ]
  • [ 141699-59-4 ]
  • [ 189695-72-5 ]
YieldReaction ConditionsOperation in experiment
With sodium hydride; In DMF (N,N-dimethyl-formamide); at 0 - 50℃; for 179h; Step B: Sodium hydride (519mg, 21. 6MMOL) was added to a cooled (0C) solution of the compound prepared Step A (4.03g, 14. 4mmol) and methyl 4-imidazolecarboxylate (2. 0g, 16mmol) in 100mL of DMF. The reaction mixture was allowed to warm to rt. After 16h at rt no desired product was observed, and the reaction mixture was heated to 50C for 163h. Although a significant amount of the starting material (the mesyl intermediate) remained, the reaction mixture was diluted with 150ML of diethyl ether, washed with water (5 x 150mL) and brine (1 x 150ML), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by MPLC (silica gel, 0-60% EtOAc/hexanes) afforded the desired product and recovered starting material. ESI-MS calculated for CISH23N304 : 309.36, found 310 (M + H).
With sodium hydride; In N,N-dimethyl-formamide; at 0 - 50℃; for 179h; Step B: Sodium hydride (519 mg, 21.6 mmol) was added to a cooled (0 C.) solution of the compound prepared in Step A (4.03 g, 14.4 mmol) and methyl 4-imidazolecarboxylate (2.0 g, 16 mmol) in 100 mL of DMF. The reaction mixture was allowed to warm to rt. After 16 h at rt no desired product was observed, and the reaction mixture was heated to 50 C. for 163 h. Although a significant amount of the starting material (the mesyl intermediate) remained, the reaction mixture was diluted with 150 mL of diethyl ether, washed with water (5×150 mL) and brine (1×150 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by MPLC (silica gel, 0-60% EtOAc/hexanes) afforded the desired product and recovered starting material. ESI-MS calculated for C15H23N3O4: 309.36. found 310 (M+H).
  • 8
  • [ 612501-52-7 ]
  • [ 141699-59-4 ]
  • [ 612501-81-2 ]
YieldReaction ConditionsOperation in experiment
95% Step 2: Preparation OF TERT-BUTVL 4-R4- 3-CHLORO-2-FLUOROANILINO)-7-METHOXVQUINAZOLIN-6- YLOXVLPIPERIDINE-1-CARBOXYLATE; 4- (3-CHLORO-2-FLUOROANILINO)-6-HYDROXY-7-METHOXYQUINAZOLINE (116.7 g), tert-butyl 4-methylsulfonyloxypiperidine 1-carboxylate (153.1 g), potassium carbonate (75.7 g) and NMP (700 ml), were stirred at 100C to 105C, under nitrogen, for 24 hours. The mixture was cooled to 75C to 80C before water (1080 ml) was added whilst maintaining the temperature above 70C. The mixture was stirred at 70C to 75C for 90 minutes then cooled to 20C to 25C. The resulting solid was filtered, washed with water (2 x 175 ml), and then dried in the vacuum oven between 50C and 55C to give tert-butyl 4- [4- (3-CHLORO-2- FLUOROANILINO) -7-METHOXYQUINAZOLIN-6-YLOXY] PIPERIDINE-1-CARBOXYLATE ; (174.4 G; 95% YIELD); Melting point: 192-193. 5C ; NMR Spectrum: (DMSO d6) 1.40-1. 42 (d, 9H); 1.62-1. 72 (m, 2H); 1.99-2. 08 (m, 2H); 3.24-3. 33 (m, 2H); 3.65-7. 73 (m, 2H); 4.00 (s, 3H); 4.76 (m 1H) ; 7.28 (s; 1H); 7.37 (t, 3H); 7.56 (t, 1H) ; 7.63 (t, 1H); 8.01 (s, 1H); 8.72 (s 1H); Mass Spectrum: (M+H) + 503.
84% With potassium carbonate; In ethanol; water; for 16.5h;Reflux;Product distribution / selectivity; Step 1: 6-[(1-tert-Butoxycarbonyl)piperidin-4-yl]oxy}-4-(3-chloro-2-fluoroanilino)-7-methoxy quinazoline4-(3-Chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinazoline (prepared as described in Step 2 of Example A; 60.00 g, 0.1828 mol), tert-Butyl(4-methanesulfonyloxy)piperidine-1-carboxylate (88.04 g, 0.3107 mol) and potassium carbonate (30.31 g, 0.2193 mol) were suspended in ethanol (584 ml) and water (58 ml), and the mixture was heated to reflux with stirring. Heating was continued at reflux for 16.5 hours. The mixture was then cooled to 70 C. and water (234 ml) was added over 60 minutes.The batch was stirred at 65 C. for a further 2 hours to establish crystallisation. The slurry was cooled to 20 C. over 6 hours. The product was isolated by filtration. The filter cake was slurried with aqueous ethanol (ethanol 117 ml, water 58 ml) and then displacement washed with aqueous ethanol (ethanol 117 ml, water 58 ml). The filter cake was then slurried with water (175 ml) and then displacement washed with water (175 ml). The product was dried in vacuo at 40 C. to give the title compound (81.5 g, 84%); 1H NMR (500 MHz, DMSO-d6) delta ppm 1.42 (s, 9H) 1.60-1.70 (m, 2H) 1.96-2.04 (m, 2H) 3.23-3.30 (m, 2H) 3.65-3.75 (m, 2H) 3.95 (s, 3H) 4.68-4.75 (m, 1H) 7.24 (s, 1H) 7.29 (t, J=8.06 Hz, 1H) 7.49 (t, J=7.50 Hz, 1H) 7.54 (t, J=7.19 Hz, 1H) 7.88 (s, 1H) 8.39 (s, 1H) 9.57 (s, 1H); Mass Spectrum: 503.5, 505.5.
60% With cesium fluoride; In N,N-dimethyl acetamide; at 85℃; for 12h; To a solution of compound 7 (1.44 g, 4.51 mmol) in DMA (15 mL) was added compound 8 (378 mg, 1.35 mmol) and CsF (685 mg, 4.51 mmol). The reaction mixture was heated to 85 C and stirred. At intervals of 2 h, 4 h and 6 h, each time compound 8 (378 mg, 1.35 mmol) and CsF (685 mg, 4.51 mmol) were added. After the final addition,the reaction mixture was stirred at 85 C for further 6 h. The solvent was removed under vacuum and the residual was partitioned between CH2Cl2 and water. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product was purified by column chromatography with MeOH/CH2Cl2 (1:25) to afford 9 (1.37 g, 60%) as a pale yellow solid, mp 200-201 C. 1H NMR (DMSO-d6): d 9.59 (s, 1H), 8.39 (s, 1H), 7.88 (s, 1H), 7.55-7.48 (m, 2H), 7.29 (t, J = 8.0 Hz, 1H), 7.24 (s, 1H), 4.71 (s, 1H), 3.95 (s, 3H), 3.71-3.69 (m, 2H), 3.29-3.26 (m, 2H), 2.01-1.99 (m, 2H), 1.68-1.62 (m, 2H), 1.42 (s, 9H). LC-MS (ESI, m/z): calcd for C25H29ClFN4O4 ([M+H]+) 503.2, found 503.1.
58% With cesium fluoride; In N,N-dimethyl acetamide; at 85℃; for 18h; 4- (3-CHLORO-2-FLUOROANILINO)-6-HYDROXY-7-METHOXYQUINAZOLINE from Step 2 (1870 mg, 5.85 mmol) was dissolved in DMA (50 ml). tert-Butyl (4-methanesulfonyloxy) piperidine-1- carboxylate (prepared as in Chemical & Pharmaceutical Bulletin 2001,49 (7), 822-829; 490 mg, 1.76 mmol) and cesium fluoride (890 mg, 5.85 mmol) were added, and the mixture was heated to 85C with stirring. At intervals of 2 hours, 4 hours and 6 hours, tert-butyl 4- METHANESULFONYLOXYPIPERIDINE-1-CARBOXYLATE and cesium fluoride were added in the above quantities to the reaction mixture. Heating was continued at 85C for a further 6 hours after the final addition. The solvent was evaporated, and the residue was partitioned between DCM (150 ml) and H20 (150 ML). The aqueous layer was extracted with DCM (4x 100 ml), and the extractions combined with the DCM layer. The combined DCM fractions were dried over MGS04 and evaporated. The residue was purified by chromatography, eluting with 0 to 2.5% (7: 1 MEOH/CONCENTRATED aqueous NH4OH) in DCM. The appropriate fractions were combined and evaporated, giving the product as a light brown foam (2.40 g, 58%, allowing for 2.3 equivalents of residual DMA).'H NMR : 1.40 (s, 9H), 1.60-1. 65 (m, 2H), 1.95-2. 00 (m, 2H), 3.20-3. 25 (m, 2H), 3.65-3. 70 (m, 2H), 3.92 (s, 3H), 4.68 (m, 1H), 7.21 (s, 1H), 7.27 (dd, 1H), 7.47 (ddd, 1H), 7.51 (dd, 1H), 7.85 (s, 1H), 8.36 (s, 1H), 9.53 (s, 1H) ; Mass Spectrum: 503.5, 505.5.
58% With cesium fluoride; In N,N-dimethyl acetamide; at 85℃; for 18h; 4- (3-CHLORO-2-FLUOROANILINO)-6-HYDROXY-7-METHOXYQUINAZOLINE from Step 2 (1870 mg, 5.85 mmol) was dissolved in DMA (50 ml). tert-Butyl (4-methanesulfonyloxy) PIPERIDINE-1-CARBOXYLATE (prepared as in Chemical & Pharmaceutical Bulletin 2001,49 (7), 822-829; 490 mg, 1.76 mmol) and cesium fluoride (890 mg, 5.85 mmol) were added, and the mixture was heated to 85C with stirring. At intervals of 2 hours, 4 hours and 6 hours, tert-butyl 4-METHANESULFONYLOXYPIPERIDINE-1-CARBOXYLATE and cesium fluoride were added in the above quantities to the reaction mixture. Heating was continued at 85C for a further 6 hours after the final addition. The solvent was evaporated, and the residue was partitioned between DCM (150 ml) and H20 (150 ml). The aqueous layer was extracted with DCM (4x 100 ml), and the extractions combined with the DCM layer. The combined DCM fractions were dried over MGS04 and evaporated. The residue was purified by chromatography, eluting with 0 to 2.5% (7: 1 MEOH/CONCENTRATED aqueous NH40H) in DCM. The appropriate fractions were combined and evaporated, giving the product as a light brown foam (2.40 g, 58%, allowing for 2.3 equivalents of residual DMA); HNMR : 1.40 (s, 9H), 1.60-1. 65 (m, 2H), 1.95-2. 00 (m, 2H), 3.20-3. 25 (m, 2H), 3.65-3. 70 (m, 2H), 3.92 (s, 3H), 4.68 (m, 1H), 7.21 (s, 1H), 7.27 (dd, 1H), 7.47 (ddd, 1H), 7.51 (dd, 1H), 7.85 (s, 1H), 8.36 (s, 1H), 9.53 (s, 1H) ; Mass Spectrum: 503.5, 505.5.
58% With cesium fluoride; In N,N-dimethyl acetamide; at 85℃; for 12h; Reference Example 3; 6-[(1-tert-Butoxycarbonyl) piperidin-4-yl] oxy}-4-(3-chloro-2-fluoroanilino)-7- methoxyquinazoline; 4- (3-Chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinazoline (Reference Example 2,1870 mg, 5.85 mmol) was dissolved in DMA (50 ml). tert-Butyl (4- methanesulfonyloxy) piperidine-l-carboxylate (prepared as in Chemical & Pharmaceutical Bulletin 2001,49 (7), 822-829; 490 mg, 1.76 mmol) and cesium fluoride (890 mg, 5.85 mmol) were added, and the mixture was heated to 85C with stirring. At intervals of 2 hours, 4 hours and 6 hours, tert-butyl 4-methanesulfonyloxypiperidine-1-carboxylate and cesium fluoride were added in the above quantities to the reaction mixture. Heating was continued at 85C for a further 6 hours after the final addition. The solvent was evaporated, and the residue was partitioned between DCM (150 ml) and H20 (150 ml). The aqueous layer was extracted with DCM (4x 100 ml), and the extractions combined with the DCM layer. The combined DCM fractions were dried over MgS04 and evaporated. The residue was purified by chromatography, eluting with 0 to 2.5% (7: 1 MeOH/concentrated aqueous NH40H) in DCM. The appropriate fractions were combined and evaporated, giving the product as a light brown foam (2.40 g, 58%, allowing for 2.3 equivalents of residual DMA) ; 1H NMR : 1.40 (s, 9H), 1.60-1. 65 (m, 2H), 1.95-2. 00 (m, 2H), 3.20-3. 25 (m, 2H), 3.65-3. 70 (m, 2H), 3.92 (s, 3H), 4. 68 (m, 1H), 7.21 (s, 1H), 7.27 (dd, 1H), 7.47 (ddd, 1H), 7.51 (dd, 1H), 7.85 (s, 1H), 8.36 (s, 1H), 9.53 (s, 1H) ; Mass Spectrum : 503.5, 505.5

  • 9
  • [ 124-63-0 ]
  • [ 109384-19-2 ]
  • [ 554-68-7 ]
  • [ 141699-59-4 ]
YieldReaction ConditionsOperation in experiment
With triethylamine; In dichloromethane; at 0℃; for 1h; To a stirred solution of tert-butyl 4-hydroxypiperidine-l-carboxylate (21.1 g, 100 mmol) and triethyl amine (22 ML) in dichloromethane (250 mL) at 0 C was slowly added methanesulfonyl chloride (9.0 ML, 1.1 equiv. ). The resulting mixture was stirred for an additional 1 h and during this time white solid was formed. The mixture was then washed with 3 N HC1, dried over NA2SO4 and evaporated to give: tert-butyl 4- [ (methylsulfonyl) oxy] piperidine-1-carboxylate as a white solid (29.2 g). 1H NMR (400 MHz, CDC13) : 8 4.92-4. 87 (m, 1H), 3.75-3. 69 (m, 2H), 3.34-3. 28 (m, 2H), 3.05 (s, 3H), 2.01-1. 94 (m, 2H), 1.87-1. 78 (m, 2H).
  • 10
  • [ 828-27-3 ]
  • [ 141699-59-4 ]
  • [ 131667-57-7 ]
  • [ 287952-66-3 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate In water at 20 - 101℃; Heating / reflux; 2 Production of 4- (4-trifluoromethoxyphenoxy) piperidine 40.74 g of 1-t-butoxycarbonyl-4- mesyloxypiperidine obtained in the above Reference Example 1,14. 43 g of 4-trifluoromethoxyphenol and 4.50 g of tetra-n-butyl ammonium chloride were suspended in 72 ml of water. Next, after adding 33.59 g of potassium carbonate to the suspension, the suspension was subjected to reflux for 8 hours (inner temperature: 101°C). After leaving the suspension at room temperature overnight, 216 ml of n-hexane was added thereto and stirring was conducted for 5 minutes. Thereto was added 72 ml of 10% aqueous sodium hydroxide solution and after stirring, the mixture was separated. After washing with water (72 mlx2), the organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and 39.02 g of a mixture of 1-t-butoxycarbonyl-4- (4- trifluoromethoxyphenoxy) piperidine and 1-t- butoxycarbonyl-3, 4-dehydropiperidine was obtained. From 1H-NMR (CDCl3) analysis, the mixture was regarded to contain 28.48 g of 1-t-butoxycarbonyl-4- (4- trifluoromethoxyphenoxy) piperidine and 10.54 g of 1-t- butoxy-3,4-dehydropiperidine. The above mixture was dissolved in 117 ml of ethyl acetate, and 51 ml of 4N-hydrochloric acid-ethyl acetate solution was added thereto dropwise at room temperature over 10 minutes. After stirring the mixture at the room temperature for an hour, thin layer chromatography analysis revealed that the raw materials were not completely consumed, and so further 51 ml of 4N-hydrochloric acid-ethyl acetate solution was added thereto. The mixture was further stirred at room temperature for 3 hours and left overnight at the room temperature. The reaction solution was cooled with ice and 163 ml of 10% aqueous sodium hydroxide solution was carefully poured thereto. The temperature increased to 23°C due to heat generation. The mixture was separated and the ethyl acetate phase was washed with saturated saline (80 ml) and water (80 ml), and then dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure and 19.45 g of pale yellow solid of 4- (4-trifluoromethoxyphenoxy) piperidine was obtained. H-NMR (300 MHz, CDCl3) bppm : 1.54 (1H, br. s), 1.58-1. 73 (2H, m), 1. 94-2. 06 (2H, m), 2.72 (2H, ddd, J = 12.5 Hz, J = 9.4 Hz, J = 3.1 Hz), 3.14 (2H, ddd, J = 12.5 Hz, J = 4.8 Hz, J = 4.8 Hz), 4.33 (1H, ddd, J = 12.3 Hz, J = 8.4 Hz, J = 4.0 Hz), 6.89 (2H, d, J = 9. 1 Hz), 7.12 (2H, d, J = 9.1 Hz). Reference Data 1-t-butoxycarbonyl-4- (4- trifluoromethoxyphenoxy) piperidine: 1H-NMR (300 MHz, CDC13) 8ppm : 1.47 (9H, s), 1.68-1. 82 (2H, m), 1.82-2. 00 (2H, m), 3.29-3. 40 (2H, m), 3.63-3. 78 (2H, m), 4.39-4. 49 (1H, m), 6.90 (2H, d, J = 8.6 Hz), 7.13 (2H, d, J = 8. 6 Hz). 1-t-butoxycarbonyl-3, 4-dehydropiperidine: 1H-NMR (300 MHz, CDC13) 8ppm : 1.46 (9H, s), 2.13 (2H, br. s), 3.49 (2H, t, J = 5. 7 Hz), 3.88 (2H, br, t, J = 2.5 Hz), 5.58-5. 74 (1H, m), 5.74-5. 91 (1H, m).
  • 11
  • [ 930-62-1 ]
  • [ 141699-59-4 ]
  • 4-(2,4-dimethyl-imidazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
6% With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 100℃; for 72h; A suspension of 2,4-dimethylimidazole (5.16 g), tert-butyl 4-[(methylsulfonyl)oxy]piperidine-1-carboxylate (10 g) and potassium carbonate (4.95 g) in DMF (80 mL) was stirred at 100C for 72 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water and ethyl acetate. An organic layer was separated, washed with saturated sodium hydrogencarbonate, and then dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The residue was purified with a silica gel column (dichloromethane/methanol/aqueous ammonia = 100/3.5/0.5 to 100/10/1) to obtain the title compound (0.58 g, 6%) as a yellow oil. NMR (300 MHz, CDCl3) delta: 1.43 (9H, s), 1.66-1.92 (3H, m), 2.16 (3H, s), 2.37 (3H, s), 2.77-2.85 (2H, m), 3.79-3.91 (2H, m), 4.26 (2H, m), 6.55 (1H, s).
  • 12
  • [ 374063-92-0 ]
  • [ 141699-59-4 ]
  • [ 832735-47-4 ]
YieldReaction ConditionsOperation in experiment
With caesium carbonate; In N,N-dimethyl-formamide; at 90℃; for 14h; 1) Production of 2-(1-t-butoxycabonylpiperidin-4-yloxy)-5-bromopyrazine: Cesium carbonate (372 mg) was added to a DMF solution (2 ml) of <strong>[374063-92-0]2-bromo-5-hydroxypyrazine</strong> (100 mg) and 1-t-butoxycarbonyl-4-(methanesulfonyloxy)piperidine (192 mg), and stirred at 90C for 14 hours. The reaction mixture was cooled to room temperature, water was added thereto and extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (C-300, hexane:ethyl acetate = 1:11) to obtain the entitled compound (198 mg).
With 18-crown-6 ether; potassium carbonate; In butanone; at 130℃; for 0.25h;Microwave irradiation; Example B4; 5-((4-(5-(4-(Methylsulfonyl)piperazin-l-yl)pyrazin-2-yloxy)piperidin-l-yl)methyl)-3-(trifluoromethyl)- 1 ,2,4-oxadiazole[0045] Step A: A mixture of <strong>[374063-92-0]5-bromopyrazin-2-ol</strong> B4a (525 mg, 3mmol), tert- butyl 4-(methylsulfonyloxy)piperidine-l-carboxylate (1.117 g, 4 mmol), 18-crown-6 (79 mg, 0.3 mmol), K2C03 (829 mg, 6 mmol) in butan-2-one (19 mL) is subjected to microwave irradiation at 130C for 15 min. The solids are filtered off, washed with ethyl acetate and purified by flash chromatography (hexanes/ethyl acetate gradient) to afford tert-butyl 4-(5-bromopyrazin-2-yloxy)piperidine-l-carboxylate B4b as a white solid: MS calcd. For C14H2iBrN303 ([M+H]+): 358.1, found: 358.1.
  • 13
  • [ 5858-17-3 ]
  • [ 141699-59-4 ]
  • [ 367500-89-8 ]
YieldReaction ConditionsOperation in experiment
80% With potassium carbonate; In acetonitrile; at 90℃; for 16h; Step 7B: tert-butyl 4-[(3,4-dichlorophenyl)thio]piperidine-l-carboxylate; A suspension of the mesylate from Step 2 (3.8 g, 7.1 mmol), <strong>[5858-17-3]3,4-dichlorothiophenol</strong> (2.9 g, 2.1 mL), and K2CO3 (3.0 g, 11.4 mmol) in CH3CN (30 mL) was heated in a 90 0C bath for 16 h. The resulting mixture was diluted with H2O (100 mL) and EtOAc (100 mL). The aqueous phase was extracted with EtOAc (50 mL). The combined organic phases were washed with H2O and brine, dried (MgSO4) and concentrated to afford a yellow oil which was purified by SiO2 chromatography (elution with 5 to 10% EtOAc-hex) to afford the thioether (3.97 g), a pale yellow oil, in 80% yield.1H NMR (400 MHz3 CDCl3) delta L35 - 1.59 (m, 11 H), 1.92 (d, J=I 3.1 Hz, 2 H), 2.93 (t, J=I 1.7 Hz, 2 H), 3.13 - 3.32 (m, 1 H), 3.96 (s, 2 H), 7.23 (d, J=8.3 Hz, 1 H), 7.37 (d, J=8.3 Hz, 1 H), 7.49 (s, 1 H).
With potassium carbonate; In water; acetonitrile; Step 1 4-(3,4-dichloro-phenylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester 4-Methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (11.18 g) and <strong>[5858-17-3]3,4-dichlorothiophenol</strong> (6.15 ml) were stirred together in acetonitrile (200 ml) and potassium carbonate (8.86 g) was added. The mixture was heated at reflux for 18 hours after which water was added and the resulting mixture extracted with dichloromethane. The organic extracts were combined, washed with water, dried (MgSO4) and evaporated to give the sub-title compound (14.58 g). 1H NMR (299.944 MHz, CDCl3) delta 1.45 (9H, s), 1.49-1.62 (2H, m), 1.87-1.96 (2H, m), 2.89-2.98 (2H, m), 3.16-3.26 (1H, m), 3.91-4.01 (2H, m), 7.21-7.57 (3H, m).
  • 14
  • [ 4556-23-4 ]
  • [ 141699-59-4 ]
  • 4-[4-(t-butoxycarbonyl)piperidylthio]pyridine [ No CAS ]
YieldReaction ConditionsOperation in experiment
82.4% With sodium hydroxide; sodium methylate In methanol; water; ethyl acetate 11.ii ii) ii) Synthesis of 4-[4-(t-butoxycarbonyl)piperidylthio]pyridine 4-Mercaptopyridine (362 mg, 3.26 mmol) was dissolved in 30 ml of anhydrous methanol and 4.1M sodium methylate solution in methanol (0.80 ml, 3.26 mmol) was added. The mixture was stirred for 30 minutes. N-t-Butoxycarbonyl-4-methanesulfonyloxypiperidine (760 mg, 2.72 mmol) was added and the mixture was refluxed for 18 hours. After cooling, the solvent was distilled off. The residue was dissolved in ethyl acetate and was washed with 1N aqueous solution of sodium hydroxide and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: hexane/ethyl acetate=1:1) to obtain 660 mg of the desired compound (82.4%, colorless powder), mp: 71.0°-72.0° C. Anal. for C15 H22 N2 O2 S. Calcd.: C; 61.19, H; 7.53, N; 9.51. Found: C; 61.28, H; 7.64, N; 9.39. NMR (200 MHz, CDCl3) δ:1.46 (9 H, s), 1.50-1.80 (2 H, m), 2.03 (2 H, ddd, J=14, 9, 4 Hz), 3.61 (2 H, ddd, J=14, 10, 4 Hz), 3.56 (1 H, tt, J=10, 4 Hz), 3.96 (2 H, dt, J=14, 4 Hz), 7.14 (2 H, dd, J=5, 2 Hz), 8.42 (2 H, dd, J=5, 2 Hz). IR (KBr)cm-1: 2960, 2930, 2850, 1690, 1580.
  • 15
  • 1-(t-Butoxycaronyl)-4-(hydroxymethyl)piperidine [ No CAS ]
  • [ 123855-51-6 ]
  • [ 141699-59-4 ]
  • [ 145508-94-7 ]
YieldReaction ConditionsOperation in experiment
With sodium iodide; triethanolamine; In dichloromethane; acetone; Step B 1-(t-Butoxycarbonyl)-4-(iodomethyl)piperidine Methanesulfonyl chloride (4. 10 mL, 6.07 g, 52.9 mmol) was added dropwise to a solution of 1-(t-butoxycarbonyl)-4-(hydroxymethyl)piperidine (10.0 g, 46.4 mmol, from EXAMPLE 155, Step A) and TEA (9.80 mL, 7.11 g, 70.3 mmol) in CH2Cl2 (140 mL) at 5-8 C. After 1 h, the mixture was diluted with EtOAc (400 mL) and washed with H2O (200 mL). The aqueous layer was extracted with EtOAc (2*150 mL) and the combined organic layers were washed with 1 N HCl (200 mL), saturated aq. NaHCO3 (200 mL), and saturated aq. NaCl (200 mL). The organic layer was dried (Na2SO4), decanted, and evaporated to give 13.58 g of 1-(t-butoxycarbonyl)piperidin-4-yl methanesulfonate as a pale yellow solid. A mixture of 1-(t-butoxycarbonyl)piperidin-4-yl methanesulfonate (13.58 g, 46.4 mmol) and sodium iodide (34.68 g, 232 mmol) in acetone (80 mL) was heated to reflux for 3 h. The mixture was partitioned between ether (350 mL) and H2O (350 mL). The organic layer was washed with saturated aq. NaCl (250 mL), and the aqueous layers were extracted in succession with ether (250 mL). The combined organic layers were dried (Na2SO4), decanted, and evaporated to give 14.8 g of 1-(t-butoxycarbonyl)-4-(iodomethyl)piperidine as a pale yellow oil. 1H NMR (500 MHz) delta 4.25-4.00 (m, 2H), 3.12 (d, J=4, 2H), 2.78-2.52 (m, 2H), 1.85 (d, J=13, 2H), 1.68-1.56 (m, 1H), 1.48 (s, 9H), 1.15 (qd, J=12, 4, 2H).
  • 16
  • [ 2458-26-6 ]
  • [ 141699-59-4 ]
  • [ 936214-99-2 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 3-phenylpyrazole With sodium hydride In N,N-dimethyl-formamide at 20℃; for 1.5h; Stage #2: 1-(tert-butoxycarbonyl)piperidin-4-yl methanesulfonate In N,N-dimethyl-formamide at 50 - 100℃; for 6.5h; 6.2 1.57 g of 3-phenylpyrazole was dissolved in 11 ml of N,N-dimethylformamide. To the resulting solution was added 0.50 g of 60% sodium hydride, and the entire mixture was stirred for 1.5 hours at room temperature. To this mixture was added a solution containing 2.90 g of the 1-tert-butoxycarbonylpiperidin-4-yl methanesulfonate dissolved in 2 ml of N,N-dimethylformamide, and the entire mixture was stirred for two hours at 50°C, one hour at 70°C, and then 3.5 hours at 100°C. The reaction liquid was then poured into water, and extracted twice with ether. The organic layer was washed three times with water and dried over anhydrous magnesium sulfate, and the solvent was then removed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate = 4/1 (volume ratio)), yielding 1.54 g of the target compound.
  • 17
  • [ 3469-69-0 ]
  • [ 141699-59-4 ]
  • [ 877399-73-0 ]
YieldReaction ConditionsOperation in experiment
70.2% To a stirred solution of 4-iodo-lH-pyrazole (8.98 g, 46.28 mmol) in DCM (160 mL) was added NaH (1.67 g, 55.53 mmol, 80% NaH/mineral oil) portion-wise at 0 C. The mixture was stirred at 0 C for 1 hour, then tert-butyl 4-((methylsulfonyl)oxy)piperidine-l- carboxylate (14.22 g, 50.90 mmol) was added. The resulted mixture was stirred at 100 C for 15 hours, then cooled to rt, quenched with H20 (30 mL) and concentrated in vacuo. The residue was diluted with H20 (150 mL), and the mixture was extracted with EtOAc (100 mL x 5). The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 5/1) to give the title compound as a white solid (12.25 g, 70.2%>). MS (ESI, pos. ion) m/z: 322.0 (M-56+1).
70.2% The compound 4-iodo-1H-pyrazole (8.98 g, 46.28 mmol)Dissolve in DCM (160 mL), cool to 0 C, thenAfter the reaction was added NaH (1.67 g, 55.53 mmol, 80% NaH / mineral oil) in portions,After stirring for 1 hour,To the reaction solution was further added tert-butyl 4 - ((methylsulfonyl) oxy) nicardine-1-carboxylate(14.22 g, 50.90 mmol),Heated to 100 C, the reaction was stirred for 15 hours,The reaction mixture was cooled to room temperature, quenched by adding water (30 mL), concentrated under reduced pressure and the residue washed with water (150 mL). The resulting mixture was extracted with EtOAc (100 mL × 5). The combined organic phases were dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 5/1) to give the title compound as a white solid (12.25 g, 70.2%
68.7% With sodium hydride; In N,N-dimethyl-formamide; at 100℃; for 14h;Cooling with ice; Step 2: 1-(1-tert-butoxycarbonyl-4-piperidinyl)-4-iodopyrazole 4-iodopyrazole (5.54 g) and anhydrous N,N-dimethylformamide (90 mL) were added in a round bottomed flask (250 mL) and 1.371 g of sodium hydride (60%) was further added with agitating in an ice-water bath. Then, 8.776 g of 1-tert-butoxycarbonyl-4-methylsulfonyloxy piperidine was added in the mixture when it was agitated in an ice-water bath for another 2h, and it was warmed to 100C, agitated for 12h and cooled in an ice-water bath. The resulted mixture was quenched by adding 300 mL of water. The reaction solution was extracted by ethyl acetate (3x100 mL), the parts of ethyl acetate were combined, washed by saturated saline solution, dried over anhydrous sodium sulfate, and purified by column chromatography (ethyl acetate:petroleum ether=1:5) to produce 1-(1-tert-butoxycarbonyl-4-piperidinyl)-4-iodopyrazole as white solid (7.43 g, yield: 68.7%). 1H-NMR (300Hz, CDCl3) delta: 7.51 (s, 1H), 7.46 (s, 1H), 4.30 (m, 3H), 2.87 (m, 2H), 2.12 (m, 2H), 1.89 (m, 2H), 1.47 (s, 9H).
66% With NaH; In N,N-dimethyl-formamide; pentane; tert-butyl 4-(4-iodo-1H-pyrazol-1-yl)piperidine-1-carboxylate (3) NaH (1.2 eq., 0.68 mmol) was added portionwise to a stirred solution of 4-iodopyrazole (0.57 mmol) in DMF (2 L) at 4 C. The resulting mixture was stirred for 1 hour at 4 C. and 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester, compound 2 (1.1 eq., 0.63 mmol) was then added. The resulting mixture was heated to 100 C. for 12 h. The reaction was quenched with H2O and extracted with EtOAc several times. The combined organic layers were dried, filtered, and concentrated to afford an orange oil. The residue was purified by silica gel chromatography (eluding with 5% EtOAc in pentane) to give compound 3 as a white solid (140 g, 66%).
66% NaH (1.2 eq., 0.68 mmol) was added portionwise to a stirred solution of 4-iodopyrazole (0.57 mmol) in DMF (2 L) at 4 C. The resulting mixture was stirred for 1 hour at 4 C. and 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester, compound 2 (1.1 eq., 0.63 mmol) was then added. The resulting mixture was heated to 100 C. for 12 h. The reaction was quenched with H2O and extracted with EtOAc several times. The combined organic layers were dried, filtered, and concentrated to afford an orange oil. The residue was purified by silica gel chromatography (eluting with 5% EtOAc in pentane) to give compound 3 as a white solid (140 g, 66%).
66% tert-butyl 4-(4-iodo-1H-pyrazol-1-yl)piperidine-1-carboxylate (23-1a) NaH (1.2 eq., 0.68 mmol) was added portionwise to a stirred solution of 4-iodopyrazole (0.57 mmol) in DMF (2 L) at 4 C. The resulting mixture was stirred for 1 hour at 4 C. and compound 23-4 (1.1 eq., 0.63 mmol) was then added. The resulting mixture was heated to 100 C. for 12 h. The reaction was quenched with H2O and extracted with EtOAc several times. The combined organic layers were dried, filtered, and concentrated to afford an orange oil. The residue was purified by silica gel chromatography (eluding with 5% EtOAc in pentane) to give compound 23-1a as a white solid (140 g, 66%).
66% NaH (1.2 eq., 0.68 mmol) was added portionwise to a stirred solution of 4-iodopyrazole (0.57 mmol) in DMF (2 L) at 4C. The resulting mixture was stirred for 1 hour at 4C and compound 23-4 (1.1 eq., 0.63 mmol) was then added. The resulting mixture was heated to 100C for 12 h. The reaction was quenched with H2O and extracted with EtOAc several times. The combined organic layers were dried, filtered, and concentrated to afford an orange oil. The residue was purified by silica gel chromatography (eluting with 5% EtOAc in pentane) to give compound 23-1 a as a white solid (140 g, 66%).
66% tert-butyl 4-(4-iodo-1 H-yrazoI- 1 -yI)i eridine-1 -carboxylate (3)NaH (1 .2 eq., 0.68 mmol) was added portionwise to a stirred solution of 4- iodopyrazole (0.57 mmol) in DMF (2 L) at 4C. The resulting mixture was stirred for 1 hour at 4C and 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester, compound (1.1 eq., 0.63 mmol) was then added. The resulting mixture was heated to 100C for 12 h. The reaction was quenched with H20 and extracted with EtOAc several times. The combined organic layers were dried, filtered, and concentrated to afford an orange oil. The residue was purified by silica gel chromatography (eluting with 5% EtOAc in pentane) to give compound 3 as a white solid (140 g, 66%).
66% tert-butyl 4-(4-iodo-1 H-pyrazol-1-yl)piperidine-1-carboxylate (3): NaH (1.2 eq., 0.68 mmol) was added portionwise to a stirred solution of 4-iodopyrazole (0.57 mmol) in DMF (2 L) at 4C. The resulting mixture was stirred for 1 hour at 4C and 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester, compound 2 (1.1 eq., 0.63 mmol) was then added. The resulting mixture was heated to 100C for 12 h. The reaction was quenched with H2O and extracted with EtOAc several times. The combined organic layers were dried, filtered, and concentrated to afford an orange oil. The residue was purified by silica gel chromatography (eluting with 5% EtOAc in pentane) to give compound 3 as a white solid (140 g, 66%).
66% tert-butyl 4-(4-iodo-1H-pyrazol-1-yl)piperidine-1-carboxylate (3) NaH (1.2 eq., 0.68 mmol) was added portionwise to a stirred solution of 4-iodopyrazole (0.57 mmol) in DMF (2 L) at 4 C. The resulting mixture was stirred for 1 hour at 4 C. and 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester, compound 2 (1.1 eq., 0.63 mmol) was then added. The resulting mixture was heated to 100 C. for 12 h. The reaction was quenched with H2O and extracted with EtOAc several times. The combined organic layers were dried, filtered, and concentrated to afford an orange oil. The residue was purified by silica gel chromatography (eluting with 5% EtOAc in pentane) to give compound 3 as a white solid (140 g, 66%).
60.67% With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; Step-1: Tert-butyl4-( 4-iodo-lH-pyrazol-1-yl)piperidine-1-carboxylate 4-Iodo-lH-pyrazole (1.4 g, 7.2 mmol) and tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (1.19 g, 8.6 mmol) were dissolved in dry DMF (25 ml) and added potassiumcarbonate (1.6 g, 21.6 mmol). The resulting mixture was heated to 60 oc overnight. The reactionwas monitored by TLC (30% ethyl acetate in hexane). The reaction mixture was diluted with icewater (150 ml) and extracted with ethyl acetate (2x50 ml). The organic layer was dried over Na2S04, and concentrated under reduced pressure to afford 1.64 g (60.67% yield) of the pureproduct which was taken as such for next reaction.1H NMR (CDCh, 300MHz): 8 7.51 (s, lH), 7.45 (s, lH), 4.30-4.21 (m, 2H), 3.87 (s, lH), 3.48(t, lH), 2.95-2.80 (m, 2H), 2.12-2.03 (m, 2H), 1.88 (m, 2H), 1.48-1.47 (s, 9H).
60.67% With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; 4-Iodo-1H-pyrazole (1.4 g, 7.2 mmol) and tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (1.19 g, 8.6 mmol) were dissolved in dry DMF (25 ml) and added potassium carbonate (1.6 g, 21.6 mmol). The resulting mixture was heated to 60 C. overnight. The reaction was monitored by TLC (30% ethyl acetate in hexane). The reaction mixture was diluted with ice water (150 ml) and extracted with ethyl acetate (2×50 ml). The organic layer was dried over Na2SO4, and concentrated under reduced pressure to afford 1.64 g (60.67% yield) of the pure product which was taken as such for next reaction. [0159] 1H NMR (CDCl3, 300 MHz): delta 7.51 (s, 1H), 7.45 (s, 1H), 4.30-4.21 (m, 2H), 3.87 (s, 1H), 3.48 (t, 1H), 2.95-2.80 (m, 2H), 2.12-2.03 (m, 2H), 1.88 (m, 2H), 1.48-1.47 (s, 9H).
57.9% With caesium carbonate; at 80℃; for 8h;Inert atmosphere; 4-Iodo-1H-pyrazole (7.0 g, 0.036 mol) and barium carbonate(15.3 g, 0.047 mol) were dissolved in nitromethylpyrrolidone (100 ml)under an atmosphere of nitrogen at 80 C. A solution of tert-butyl-4-((methylsulfonyl)oxy)cyclohexane-1-carboxylate 1 (15.3 g, 0.047 mol)in nitromethylpyrrolidone (100 ml) was added dropwise and the mixture was stirred for 8 h. Then, the mixture was cooled to roomtemperature and poured into a mixed solvent of methyl tert-butyl ether(100 ml) and water (100 ml). After stirred for 10 min, the organic layerwas poured into N-heptane (300 ml). The precipitates was collected byfiltration to give a white solid 2 (7.88 g, 57.9%). MS (ESI) m/z: 400.3[M+Na]+.
51% With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; A mixture of tert-butyl 4- [(methylsulfonyl)oxy]rhoiperidine-l-carboxylate: (75.5 g, 0.271 mol), 4-iodopyrazole (52.5 g, 0.271 mol), and K2CO3 (11.3 g, 0.8 mol) in 1.5 L of N, N-dimethylformamide (DMF) was stirred at 1000C overnight. After cooled to r.t., the solvent was evaporated. The residue was dissolved in DCM, filtered, and washed with water and brine. The organic layer was dried and evaporated to an oil. The crude product was purified by chromatography (MeOH/DCM 1 :40) and (EtOH/MeOH 10%-20%) to give 52 g of the product as a white solid after standing, in 51% yield.
41% Step-I: tert-butyl 4-(4-iodopyrazol-1-yl)piperidine-1-carboxylate (Va-1-I) NaH (60% suspension, 1.13 g, 28.4 mmol) was added portion wise to a solution of 4-iodopyrazole (5 g, 25.7 mmol) in anhydrous DMF (30 mL) at 0 C.; and it was stirred for 1 h. Finally, tert-butyl 4-mesylpiperidine-1-carboxylate (CAS: 141699-59-4) (6.5 g, 32.7 mmol) was added to the reaction mixture and it was stirred at 100 C. for 16 h. It was, then, cooled and quenched with saturated solution of NH4Cl (100 mL). Extraction was carried out using EtOAc (50 mL*2); the combined organic layers were washed with water (100 mL); brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide crude product, which was further purified by silica gel column chromatography (20% EtOAc in hexanes) to give title compound Va-1-I (4 g, 41%). LCMS: m/z 378.1 (M+1)+.
620 mg To a solution of 4-iodo-lH-pyrazole (467.5 mg, 2.41 mmol) was added NaH (60%, 193 mg, 4.82 mmol) in dry DMF (8 mL) at 0 C portion-wise, then warmed to rt and continued to stirred for 2 hours, followed by adding of a solution of the above product in DMF (4 mL). The mixture was heated at 100 C for 12 hours, then quenched with NH4C1 (aq, 20 mL) and extracted with EtOAc (40 mL x 2). The combined organic phases were washed with brine (25 mL), dried over Na2S04, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 4/1) to give the title compound as a yellow solid (620 mg, 68 %). MS (ESI, pos. ion) m/z: 322.0 (M+l-56).
With caesium carbonate; In 1-methyl-pyrrolidin-2-one; at 70℃; for 5h; Take 1 mol of 4-iodopyrazole andBarium carbonate 0.6mol,Dissolve in NMP solvent after mixingHeat to 70C,Take 1.2mol A1 into the mixture, keep warm for 5h,A 9:1 water/ethanol solution was added to the filtrate to precipitate the product.Obtain 4-(4-iodo-1H-pyrazol-1-yl)-1-piperidinecarboxylic acid tert-butyl ester, denoted as B1.
Weigh 9.7g of 4-iodopyrazole in the reaction flask, add 100mL of DMF to dissolve, add 2.4g of sodium hydrogen in batches at 0 C, and after 1h of reaction at 0 C, add 15.3g of the product of step 2 and react for 12h at 100 C At the end of the reaction, quench with water, extract with ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, spin dry, and purify by column chromatography to obtain the title compound.
900 mg With caesium carbonate; In 1-methyl-pyrrolidin-2-one; at 80℃; for 16h; To a mixture of 4-iodo- 1 //-pyrazolc (750 mg, 3.86 mmol) and tert- butyl 4- ((methylsulfonyl)oxy)piperidine-l-carboxylate (1.2 g, 4.30 mmol) in NMP (10 mL) was added cesium carbonate (1.51 g, 4.64 mmol) at RT and the mixture was heated at 80 C for 16 h. The reaction mixture was cooled to RT and diluted with water. The aqueous mixture was extracted twice with ethyl acetate and the combined organic extracts were washed with water followed by brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to yield 900 mg of the desired product. NMR (400 MHz, CDCb) d 1.48 (s, 9H), 1.84-1.95 (m, 2H), 2.09-2.15 (m, 2H), 2.85-2.93 (m, 2H), 4.23-4.34 (m, 3H), 7.47 (s, 1H), 7.53 (s, 1H).

Reference: [1]Patent: WO2014/193647,2014,A2 .Location in patent: Paragraph 0184
[2]Patent: CN104119331,2018,B .Location in patent: Paragraph 0382; 0387; 0388
[3]Patent: EP2650293,2013,A1 .Location in patent: Paragraph 0195; 0196
[4]Patent: US2008/300273,2008,A1
[5]Patent: US2008/293769,2008,A1 .Location in patent: Page/Page column 6
[6]Patent: US2006/46991,2006,A1 .Location in patent: Page/Page column 69-70
[7]Patent: WO2006/21881,2006,A2 .Location in patent: Page/Page column 81; 82
[8]Journal of Medicinal Chemistry,2011,vol. 54,p. 6342 - 6363
[9]Patent: WO2013/17989,2013,A1 .Location in patent: Page/Page column 67
[10]Patent: EP2764866,2014,A1 .Location in patent: Paragraph 0053
[11]Patent: US2016/206608,2016,A1 .Location in patent: Paragraph 0264; 0265
[12]Patent: WO2014/24077,2014,A1 .Location in patent: Page/Page column 36
[13]Patent: US2015/183781,2015,A1 .Location in patent: Paragraph 0158
[14]Organic process research and development,2011,vol. 15,p. 1018 - 1026
[15]Bioorganic and Medicinal Chemistry,2019,vol. 27,p. 4089 - 4100
[16]Journal of Medicinal Chemistry,2011,vol. 54,p. 4092 - 4108
[17]Journal of Medicinal Chemistry,2013,vol. 56,p. 2294 - 2310
[18]Patent: WO2010/68292,2010,A1 .Location in patent: Page/Page column 85
[19]Patent: US2015/64196,2015,A1 .Location in patent: Paragraph 0183
[20]Patent: WO2014/89280,2014,A1 .Location in patent: Page/Page column 50
[21]Patent: CN107417603,2017,A .Location in patent: Paragraph 0021
[22]Patent: CN106831720,2017,A .Location in patent: Paragraph 0016; 0018; 0019
[23]Patent: CN108047231,2020,B .Location in patent: Paragraph 0049-0050; 0059-0063
[24]Patent: WO2020/70331,2020,A1 .Location in patent: Page/Page column 54-55
  • 18
  • [ 2075-45-8 ]
  • [ 141699-59-4 ]
  • [ 877399-50-3 ]
YieldReaction ConditionsOperation in experiment
77% With 1-methyl-pyrrolidin-2-one; caesium carbonate; at 80℃; for 12h;Large scale; 2.08 kg of cesium carbonate,0.78 kg of 4-bromopyrazole was dissolved in 4 liters of N-methylpyrrolidone,Heated to 80 degrees,A 5 liter solution of N-methylpyrrolidone was added to 1.8 kg of compound (CZT-7)Reaction for 12 hours.Cooled to room temperature,Add 50 litersMethyl tert-butyl etherwith50 liters of water,Stir for 1 hour.After dispensing,The organic phase was washed with 20 liters of * 4 water and dried 50percentLiter of hexane and stirred at room temperature for 2 hours. Filtered and dried to give 1.35 kg of compound (CZT-8) in a yield of 77percent
58% B. To a cold solution (0 °C) of 4-bromo-lH-pyrazole (14.9 g, 0.10 mol) in 80 mL of dichloromethane was added sodium hydride (8.13 g, 0.20 mol) portion wise. The mixture was stirred at 0 °C for 1 hour, followed by the addition of a solution of tert-butyl 4-((methylsulfonyl)oxy)piperidine-l-carboxylate (34.0 g, 0.12 mol) in 30 mL of N,N-dimethylformamide. The resulting mixture was heated at 110 °C overnight. Purification by column chromatography afforded tert-butyl 4-(4-bromo-lH- pyrazol-l-yl)piperidine-l-carboxylate as a yellow oil in 58percent yield (19.5 g). 1H NMR (400 MHz, CDC13) delta 7.48 (s, 1H), 7.44 (s 1H), 4.35-4.20 (m, 3H), 2.95-2.85 (m, 2H), 2.15-2.05 (m, 2H), 1.92-1.81 (m, 2H), 1.48 (s, 9H).
45% To a stirred solution of 4-bromo-pyrazole (10.44 g, 71.03 mmol) in anhydrous DMF (96 mL), cooled to 0° C., was slowly added NaH (60percent in mineral oil) (3.13 g, 78.133 mmol). The solution was stirred for 1 hour at 0° C. 4-Methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (19.82 g, 71.03 mmol) was added slowly and the reaction was heated to 100° C. overnight or until consumption of the pyrazole by NMR. The reaction was cooled to room temperature and water added (20 mL) followed by extraction with EtOAc. The combined extracts were washed with saturated aqueous NaCl (4*20 mL), dried with Na2SO4 and concentrated to afford 4-(4-bromo-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester as an orange oil. The oil was purified using silica gel chromatography eluding with 10percent EtOAc/hexanes to 25percent EtOAc/hexanes to provide 4-(4-bromo-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester as a white solid (10.55 g, 45percent yield) with a Rf=0.4 (25percent EtOAc/hexanes, using iodine as the stain). 1H NMR (CDCl3, 400 MHz) delta 7.46 (s, 1H), 7.43 (s, 1H), 4.23 (m, 3H), 2.88 (m, 2H), 2.10 (m, 2H), 1.88 (m, 2H), 1.47 (s, 9H).
45% To a stirred solution of 4-bromo-pyrazole (10.44 g, 71.03 mmol) in anhydrous DMF (96 mL), cooled to 0°C, was slowly added NaH (60percent in mineral oil) (3.13 g, 78.133 mmol). The solution was stirred for 1 hour at 0°C. 4-Methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (19.82 g , 71.03 mmol) was added slowly and the reaction was heated to 100°C overnight or until consumption of the pyrazole by NMR. The reaction was cooled to room temperature and water added (20 mL) followed by extraction with EtOAc. The combined extracts were washed with saturated aqueous NaCI (4 x 20 mL), dried with Na2SO4 and concentrated to afford 4-(4-bromo-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester as an orange oil. The oil was purified using silica gel chromatography eluting with 10percent EtOAc/hexanes to 25percent EtOAc/hexanes to provide 4-(4-bromo-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester as a white solid (10.55 g, 45percent yield) with a R^= 0.4 (25percent EtOAc/hexanes, using iodine as the stain). 1H NMR (CDCI3, 400 MHz) 8 7.46 (s, 1H), 7.43 (s, 1H), 4.23 (m, 3H), 2.88 (m, 2H), 2.10 (m, 2H), 1.88(m, 2H), 1.47(s, 9H).
NaH (60percent in mineral oil, 1.36 g, 34 mmol) is added portionwise to a stirred solution of 4- bromopyrazole (4.58 g, 30.9 mmol) in DMF (20 ml). The resulting mixture is stirred for 1h at O0C and 4-Methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (as obtained in preparation 61 , 8.62 g, 30.9 mmol) is added. The resulting pale suspension is heated at 1000C for 1h. The reaction is quenched with water and extracted with EtOAc several times. The combined organic layers are washed with brine, dried over Na2SO4, filtered and the filtrate is concentrated in vacuo. The residue is purified by chromatography on a 120 g silica gel column on a Combiflash Companion.(TM). (Isco Inc.) apparatus ( gradient hexanes: TBDME from 1 :0 => 0:1) to afford the title compound as a colorless solid, Rt = 1.213 min (Acquity UPLC BEH C18, 2.1x50mm, 1.7 micron, detection 215nM, 0.1 min 2percent CH3CN in H2O , 2percent to 100percent CH3CN in H2O in 1.5min, 0.4 min 100percent CH3CN + 0.1 percent TFA, flow rate 1.0ml/min); MS: 330 (M+1, 79Br)+.
As shown in step 3-ii of Scheme 3, to a solution of 4-bromopyrazole (4.68 g, 31.83 mmol) in DMF (300 mL) at 00C was added sodium hydride (60percent on mineral oil, 1.27 g, 31.83 mmol). The solution was stirred at 00C for one hour, at which point a solution of Compound 1013 (9.78 g, 31.83 mmol) in DMF (50 mL) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour and then refluxed for 16 hours. Disappearance of both starting materials was observed by TLC (1 : 1 EtOAc/hexanes). The reaction was cooled to room temperature, quenched by the addition of brine (300 mL), and extracted with ethyl acetate (3 x 200 mL). The combined organics were washed with 1percent aqueous LiCl (3 x 200 mL), dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude bromide was purified by silica gel chromatography (0 - 25percent EtOAc/hexanes) to give Compound 1014.
With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 80℃; for 12h; c) tert-Butyl 4-(4-bromo- 1 H-pyrazol- 1 -yl)piperidine- 1 -carboxylateTo a cooled solution of the compound of Intermediate Example 5(b) (6.7 g, 23.9 mmol) in DMF (50 ml) was added NaH (2.8 g, 1 19 mmol, 5 eq.) and 4-bromo-lH-pyra- zole (2.8 g, 19.1 mmol, 0.8 eq.) and stirred at 80 °C for 12 h. The mixture was quenched and extracted with ethyl acetate (3 chi 100 ml). The combined organic layer was washed with water, brine and dried over sodium sulphate. The solvent was distilled off to afford the crude product (8.0 g).
General procedure: To an ice-cooled solution of 4-bromo-1H-pyrazole (1.19 g, 8.07 mmol) in 10 mL of DMF was added portionwise sodium hydride (355 mg, 8.88 mmol, 60percent in oil). The resulting mixture was stirred for additional 1 h. Then to the mixture was added oxan-4-yl methanesulfonate (1.60 g, 8.88 mmol), which was prepared in a similar manner as described for 12. The resulting mixture was gradually heated to 100 °C and stirred for 10 h. After cooled to room temperature, the reaction was quenched with water. The mixture was extracted with EA. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by silica gel column chromatography (EA/PE, 1:6) to afford 26a as a white solid in 61percent yield.
With sodium hydride; In N,N-dimethyl-formamide; at 80℃; for 12h; To a cooled solution of the compound of Intermediate Example 5(b) (6.7 g, 23.9 mmol) in DMF (50 ml) was added NaH (2.8 g, 119 mmol, 5 eq.) and 4-bromo-1H-pyrazole (2.8 g, 19.1 mmol, 0.8 eq.) and stirred at 80° C. for 12 h. The mixture was quenched and extracted with ethyl acetate (3*100 ml). The combined organic layer was washed with water, brine and dried over sodium sulphate. The solvent was distilled off to afford the crude product (8.0 g).
With sodium hydride; In N,N-dimethyl-formamide; at 20 - 110℃;Inert atmosphere; Sodium hydride (400 mg, 60percent dispersion, 10 mmol) was added to a stirred solution of the bromopyrazole (1.47g, lOmmol) and 4-Methanesulfonyloxy-pipehdine-1-carboxylic acid tert-butyl ester (2.4 g, 8.6 mmol) in dry DMF (10 ml) at room temperature. After gas evolution had ceased, the reaction was stirred and heated at 110 0C under N2 for 4 h. The reaction mixture was allowed to cool to room temperature and stand at for 18 h before being partitioned between EtOAc and H2O. The organic layer was separated, washed with water H2O (x2), brine (x1 ), then dried (Na2SO4), filtered and the solvent removed in vacuo.The residue was purified using silica column chromatography running a 10-25percentEtOAc/petrol gradient to give a colourless oil (1.7 g, 5.15 mmol). 1 H NMR (400 MHz,CDCI3): 7.48 (1 H, s), 7.45 (1 H, s), 4.45-4.07 (3H, m), 2.90 (2H, t), 2.12 (2H, d), 1.97-1.79(2H, m), 1.50 (9H, s).

  • 19
  • [ 13808-64-5 ]
  • [ 141699-59-4 ]
  • [ 1076223-99-8 ]
  • [ 1092500-89-4 ]
YieldReaction ConditionsOperation in experiment
NaH (60% in mineral oil, 410 mg, 10.2 mmol) is added portionwise to a stirred solution of 4- bromo-3-methylpyrazole (1.69 g, 10.2 mmol) in DMF (20 ml). The resulting mixture is stirred for 1 h at 00C and 4-Methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (as obtained in preparation 61 , 2.839 g, 10.16 mmol) is added. The resulting pale suspension is heated at 950C for 1h. The reaction is quenched with water and extracted with EtOAc several times. The combined organic layers are washed with brine, dried over Na2SO4, filtered and the filtrate is concentrated in vacuo. The residue is purified by chromatography on a 120 g silica gel column on a Combiflash Companion (Isco Inc.) apparatus ( gradient hexanes: TBDME from 1 :0 => 1 :1) to afford the two regioisomers identified by preparation 92 and preparation 93.
  • 20
  • [ 50995-95-4 ]
  • [ 141699-59-4 ]
  • tert-butyl 4-(2-propyl-1H-imidazol-1-yl)piperidine-1-carboxylate [ No CAS ]
  • 21
  • [ 64922-04-9 ]
  • [ 141699-59-4 ]
  • [ 1108164-12-0 ]
YieldReaction ConditionsOperation in experiment
Preparation of Intermediate 1: 4-(3-Methanesulfonyloxymethyl-[l,2,4]triazol-l- yl)-piperidine-l-carboxylic acid tert-butyl esterStep 1: 4-(3-Methoxycarbonyl-[l,2,4]triazol-l-yl)-piperidine-l-carboxylic acid tert-butyl ester; <n="65"/>To a solution of IH-[1, 2,4]triazole-3-carboxylic acid ethyl ester (1.05 g, 8.23 mmol) in dimethylformamide (50 rnL) was added sodium hydride (60%, 0.395 g, 9.88 mmol). The solution was stirred at room temperature for 20 minutes followed by 1 hour at 70 0C. 4-methanesulfonyloxy-piperidine-l-carboxylic acid tert-butyl ester (2.3 g, 8.23 mmol) was then added in a single portion and heated at 70 0C for 40 hours. The solution was cooled to 0 0C and the salt precipitate was removed by filtration. The filtrate was diluted with dichloromethane and washed with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatograph on silica gel with Hexanes and EtOAc to afford the desired product. 1H NMR (CDCl3): 5 8.18 (IH, s), 4.40 (IH, m), 4.22 (2H, m), 3.96 (3H, s), 2.82 (2H, m), 2.12 (2H, m), 1.94 (2H, m), 1.41 (9H, s).
  • 22
  • C4H4BrN2(1-)*Na(1+) [ No CAS ]
  • [ 141699-59-4 ]
  • [ 1076223-99-8 ]
  • [ 1092500-89-4 ]
YieldReaction ConditionsOperation in experiment
In N,N-dimethyl-formamide; at 20 - 90℃; Sodium hydride (11.53 g) was added portionwise to a stirred solution of 4-bromo-3- methyl-lH-pyrazole (42.2 g) dissolved in DMF (600 ml) over a period of 15 minutes at <n="164"/>00C under nitrogen. The resulting slurry was stirred at 00C for 1 hour. Then tert-butyl 4- methylsulfonyloxypiperidine-1-carboxylate (73.2 g) was added and the mixture was stirred 1 hour at room temperature then heated to 900C overnight. The reaction mixture was then allowed to stir at room temperature over a period of 2 days, quenched with water (2 ml), concentrated to dryness, diluted with ethyl acetate (1500 ml), washed with water (2x1000 ml), brine (1000 ml), dried over magnesium sulfate and concentrated to afford the crude product. A purification by flash chromatography on silica gel eluting with 20 % ethyl acetate in petroleum ether afforded tert-butyl 4-(4-bromo-5-methyl-pyrazol-l- yl)piperidine-l-carboxylate (22.5 g) (NMR Spectrum: (DMSOd) 1.42 (s, 9H), 1.72-1.86 (m, 4H), 2.28 (s, 3H), 2.91 (bs, 2H), 3.96-4.13 (m, 2H), 4.34-4.43 (m, IH), 7.50 (s, IH); Mass spectrum: M-tBu: 288), and tert-butyl 4-(4-bromo-3-methyl-pyrazol-l-yl)piperidine- 1-carboxylate (28.7 g) (NMR Spectrum (DMSOd): 1.44 (s, 9H), 1.70 (dd, IH), 1.75 (dd, IH), 1.91-1.99 (m, 2H), 2.11 (s, 3H), 2.87 (bs, 2H), 4.95-4.10 (m, 2H), 4.21-4.30 (m, IH), 7.95 (s, IH); Mass spectrum: M-tBu: 288).
  • 23
  • [ 15366-34-4 ]
  • [ 141699-59-4 ]
  • [ 922516-36-7 ]
  • [ 922516-37-8 ]
YieldReaction ConditionsOperation in experiment
A suspension of 60 % dispersion of sodium hydride in mineral oil (192 mg, 4.8 mmol) in 20 mL of N,N-dimethylformamide was cooled to 0 0C, and methyl 3- pyrazolecarboxylate (605.37 mg, 4.8 mmol) was gradually added with stirring in nitrogen atmosphere. The reaction mixture was stirred at room temperature for 0.5 h and cooled again to 0 C. A solution of 1,1-dimethylethyl 4-[(methylsulfonyl)oxy]-l-piperidine-carboxylate(1.18 g, 4 mmol) (i.e. the product of Example 18, Step A) in 5 mL of N,N- dimethylformamide was gradually added to the reaction mixture. The resulting mixture was stirred for 5 days at 60 C. The reaction mixture was poured in ice water and extracted with ethyl acetate. The organic layer was dried (MgSC^), evaporated in vacuo, and purified by <n="99"/>medium-pressure liquid chromatography on silica gel eluting with 0-10 % methanol in ethyl acetate as eluant to give 290 mg of the title compound as a white solid.1H NMR (CDCl3) delta 1.46 (s, 9H), 1.88-2.00 (m, 2H), 2.12-2.20 (m, 2H), 2.80-2.92 (m, 2H),3.92 (s, 3H), 4.24-4.33 (m, 2H), 4.34-4.37 (m, IH), 6.82 (s, IH), 7.44 (s, IH). Additionally, 370 mg of 1,1-dimethylethyl 4-[5-(methoxycarbonyl)-lH-pyrazol-l-yl]-l- piperidinecarboxylate was isolated eluting before the title compound.1H NMR (CDCl3) 6 1.46 (s, 9H), 1.92-2.00 (m, 2H), 2.08-2.15 (m, 2H), 2.85-2.95 (m, 2H), 3.89 (s, 3H), 4.20-4.31 (m, 2H), 5.24-5.32 (m, IH), 6.85 (s, IH), 7.51 (s, IH).
  • 24
  • [ 13808-64-5 ]
  • [ 141699-59-4 ]
  • [ 1092500-89-4 ]
YieldReaction ConditionsOperation in experiment
In N,N-dimethyl-formamide; mineral oil; The tert-butyl 4-(4-bromo-3-methyl-pyrazol-1-yl)piperidine-1-carboxylate used as a reagent was prepared as follows: Sodium hydride (60% dispersion in mineral oil, 11.53 g) was added portionwise to a stirred solution of <strong>[13808-64-5]4-bromo-3-methyl-1H-pyrazole</strong> (42.2 g) dissolved in DMF (600 ml) over a period of 15 minutes at 0 C. under nitrogen. The resulting slurry was stirred at 0 C. for 1 hour. Then tert-butyl 4-methylsulphonyloxypiperidine-1-carboxylate (73.2 g) was added and the mixture was stirred 1 hour at room temperature then heated to 90 C. overnight. The reaction mixture was then allowed to stir at room temperature over a period of 2 days, quenched with water (2 ml), concentrated to dryness, diluted with ethyl acetate (1500 ml), washed with water (2*1000 ml), brine (1000 ml), dried over magnesium sulfate and concentrated to afford the crude product.
  • 25
  • [ 1146951-57-6 ]
  • [ 141699-59-4 ]
  • [ 1146951-56-5 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate In ethyl acetate; acetonitrile; Petroleum ether 62 EXAMPLE 62 4-bromo-1H-pyrazole-3-carboxamide (673 mg), potassium carbonate (636 mg) and tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate (1187 mg) in acetonitrile (20 ml) were stirred at 90° C. overnight. The mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water, brine, dried over magnesium sulfate and concentrated. The crude product was purified by flash chromatography on silica gel eluding with 55 to 100% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford tert-butyl 4-(4-bromo-3-carbamoyl-pyrazol-1-yl)piperidine-1-carboxylate (489 mg) as a solid. NMR Spectrum: (DMSOd6): 1.41 (s, 9H), 1.78 (dd, 1H), 1.83 (dd, 1H), 1.96-2.04 (m, 2H), 2.90 (bs, 2H), 4.03 (m, 2H), 4.33-4.41 (m, 1H), 7.30 (s, 1H), 7.44 (s, 1H), 8.14 (s, 1H)
  • 26
  • [ 141699-59-4 ]
  • [ 85838-94-4 ]
YieldReaction ConditionsOperation in experiment
92% With 1,8-diazabicyclo[5.4.0]undec-7-ene; at 80℃; for 16h; PREPARATION 72 3,6-Dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester Heat a solution of 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (0.69 mol, 193g) in DBU (400 mL) at 80 C. for 16 h. Dilute the reaction mixture with water, extract with diethyl ether, and wash the organic layer with 1 N hydrochloric acid and saturated sodium bicarbonate solution. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to obtain the title compound (116 g, 92%) as a brown oil. 1H NMR (400 MHz, CDCl3) delta 1.46 (s, 9H), 2.12 (br s, 2H), 3.47 (t, 2H), 3.87 (s, 2H), 5.65 (br s, 1H), 5.81 (br s, 1H).
92% With 1,8-diazabicyclo[5.4.0]undec-7-ene; at 80℃; for 16h; Step 2: 4-Methanesulfonyloxy-piperidine-1-carboxylic acid fert-butyl ester (25.0 g, 89mmol) in DBU (50 muL) was heated at 80C for 16 h. The reaction mixture was diluted with water, extracted with diethyl ether, and washed the organic layer with 1 N hydrochloric acid and saturated sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the reduced compound (15.0 g, 92%) as a brown oil. 1HNMR (400 MHz, CDCl3): delta 5.81 (brs, 1H),5.65 (br s, 1H), 3.87 (s, 2H), 3.47 (t, J= 7.84 Hz, 2H), 2.12 (br s, 2H), 1.46 (s, 9H).
90% With 1,8-diazabicyclo[5.4.0]undec-7-ene; In tetrahydrofuran;Reflux; A solution of compound mt 4-5 (312 g, 1.12 mol) and DBU (400 g, 2.24 mol) in THF (4.5 L) was heated to reflux overnight. TLC (petroleum ether: EtOAc = 3:1, Rf = 0.8) showed the reaction was complete. The mixture was poured into ice-water (2 L) and then extracted with EtOAc (2 L), the combined organic phase was washed with 1 M HC1 solution (4L2), aq. NaHCO3 (4 L), and dried over anhydrous Na2504, then the mixture was concentrated in vacuo to provide compound mt 4-6 (185 g, 90 %) which was used in the next step without further purification. ?H NMR: (CDC13) oe 5.8 (m, 1H), 5.65 (m, 1H), 3.85 (t, J=7Hz, 2H), 3.46 (t, J=l4Hz, 2H), 2.1 (bs, 2H), 1.45 (s, 9H).
8 g With 1,8-diazabicyclo[5.4.0]undec-7-ene; at 80℃; for 16h; Step 2) l-(tert-butoxycarboxyl)-L2,3,6-tetrahvdropyridine [0242] A solution ofl-(tert-butoxycarbonyl)piperidin-4-yl methanesulfonate(14 g, 48 mmol) in DBU (80 mL) was heated to 80 C and stirred for 16 h. Then the mixture was cooled to rt, diluted with H20 (200 mL) and extracted with EtOAc(150 mL x 3). The combined organic phases were washed with 1 M HC1 (450 mL x 3), followed by saturated aqueous a2CO3(450 mL x 2). The solution was dried over anhydrous a2S04, and concentrated in vacuo to obtain the title compound as brown oil (8 g, 100 %), which was used forthe next step without further purification. LC-MS (ESI, pos. ion) m/z: 128[(M + H)+ - C4H8]; NMR (400 MHz, CDC13) delta (ppm): 5.83-5.80 (m, 1H), 5.66 (m, 1H), 3.87 (m, 2H), 3.49-3.47 (t, J= 5.2 Hz, 2H), 2.13 (m, 2H), 1.47 (s, 9H).
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In tetrahydrofuran;Reflux; Step 2: A solution of tert-butyl 4-[(methylsulfonyl)oxy]piperidine-1-carboxylate (312 g, 1.12 mol) and DBU (400 g, 2.24 mol) in THF (4.5 L) was heated to reflux overnight. The mixture was poured into ice-water (2 L) and then extracted with EtOAc (2 L). The combined organic phase was washed with 1 M HCl solution (4L*2), aq. NaHCO3 (4 L), and dried over anhydrous sodium sulfate. The residue was concentrated to afford tert-butyl 3,6-dihydropyridine-1(2H)-carboxylate, which was used in the next step without further purification.
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In tetrahydrofuran;Reflux; Step F- Preparation of Int 4-6 Int 4-5 Int 4-6 A solution of compound Int 4-5 (312 g, 1.12 mol) and DBU (400 g, 2.24 mol) in THF (4.5 L) was heated to reflux overnight. TLC (petroleum ether: EtOAc = 3: 1, Rf = 0.8) showed the reaction was complete. The mixture was poured into ice-water (2 L) and then extracted with EtOAc (2 L), the combined organic phase was washed with 1 M HCl solution (4L x 2), aq. NaHC03 (4 L), and dried over anhydrous Na2S04, then the mixture was concentrated in vacuo to provide compound Int 4-6 (185 g, 90 %) which was used in the next step without further purification. 1H NMR: (CDC13) delta 5.8 (m, 1H), 5.65 (m, 1H), 3.85 (t, J=7Hz, 2H), 3.46 (t, J=14Hz, 2H), 2.1 (bs, 2H), 1.45 (s, 9H).

  • 27
  • [ 141699-59-4 ]
  • [ 210039-65-9 ]
  • [ 1160656-38-1 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 1h; 111.b Preparation of intermediate 4-(2-formyl-4-trifluoromethyl-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester acid tert-butyl ester A mixture of 2-hydroxy-5-trifluoromethyl-benzaldehyde (1.36 g, 7.17 mmol), 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (2.2 g, 7.88 mmol) and K2CO3 (2.96 g, 21.5 mmol) in anhydrous N,N-dimethylformamide (15 mL) was heated at 100° C. for 1 h. After cooled to room temperature, the mixture was filtered and the filtrate was concentrated. The residue was dissolved in DCM (50 mL). The solution was washed with water, dried over anhydrous Na2SO4 and concentrated. The residue was purified by chromatography to give the title compound (1.43 g).
  • 28
  • [ 52805-46-6 ]
  • [ 141699-59-4 ]
  • [ 1196531-33-5 ]
YieldReaction ConditionsOperation in experiment
80% With potassium carbonate; In isopropyl alcohol;Reflux; Step 1. Preparation of tert-butyl 4-(5-cyano-2-methoxyphenoxy)piperidine-1-carboxylate (2)<strong>[52805-46-6]3-hydroxy-4-methoxybenzonitrile</strong> (1, 6.00 g, 39.62 mmole), tert-butyl(4-methanesulfonyloxy)piperidine-1-carboxylate (16.6 g, 59.44 mmoles) (Chemical & Pharmaceutical Bulletin 2001, 49(7), 822-829); and potassium carbonate (6.71 g, 47.55 mmoles) were suspended in isopropanol (78.98 g) and the mixture was heated at reflux with stirring. Additional tert-butyl(4-methanesulfonyloxy)piperidine-1-carboxylate (2.08 g, 7.43 mmoles) was added to push the reaction to completion. The mixture was then cooled and quenched by the addition of water (100.47 g). Seeding with tert-butyl 4-(5-cyano-2-methoxyphenoxy)piperidine-1-carboxylate (2) followed by cooling to 0 C. resulted in a crystalline product, which was isolated by filtration. The filter cake was washed with a mixture of water (8.86 g) and isopropanol (6.97 g), followed by water (23.64 g) and then dried to give the title compound (10.75 g, 80% yield); 1H NMR (400 MHz, DMSO-d6) delta ppm 1.39 (s, 9H) 1.48 (m, 2H) 1.88 (m, 2H) 3.13 (m, 2H) 3.67 (m, 2H) 3.83 (s, 3H) 4.56 (tt, J=8.1, 3.8 Hz, 1H) 7.13 (d, J=8.4 Hz, 1H) 7.42 (dd, J=8.4, 1.9 Hz, 1H) 7.51 (d, J=1.9 Hz, 1H); Mass Spectrum: m/z (M+H)+ 333.1.
80% With potassium carbonate; In isopropyl alcohol;Reflux; Step 1. Preparation of tert-butyl 4-(5-cyano-2-methoxyphenoxy)piperidine-l- carboxylate (Intermediate 2).; <strong>[52805-46-6]3-hydroxy-4-methoxybenzonitrile</strong> (Compound (X), 6.00 g, 39.62 mmole), tert-butyl (4-methanesulfonyloxy)piperidine-l-carboxylate (16.6 g, 59.44 mmoles) (Chemical &; Pharmaceutical Bulletin 2001, 49(7), 822-829); and potassium carbonate (6.71 g, 47.55 mmoles) were suspended in isopropanol (78.98 g) and the mixture was heated at reflux with stirring. Additional tert-butyl (4-methanesulfonyloxy)piperidine-l- carboxylate (2.08 g, 7.43 mmoles) was added to push the reaction to completion. The mixture was then cooled and quenched by the addition of water (100.47 g). Seeding with intermediate 2 followed by cooling to 00C resulted in a crystalline product, which was isolated by filtration. The filter cake was washed with a mixture of water (8.86 g) and isopropanol (6.97 g), followed by water (23.64 g) and then dried to give Intermediate 2 (10.75 g, 80% yield); 1H NMR (400 MHz, DMSO-d6) delta ppm 1.39 (s, 9 H) 1.48 (m, 2 H) 1.88 (m, 2 H) 3.13 (m, 2 H) 3.67 (m, 2 H) 3.83 (s, 3 H) 4.56 (tt, J=8.1, 3.8 Hz, 1 H) 7.13 (d, J=8.4 Hz, 1 H) 7.42 (dd, J=8.4, 1.9 Hz, 1 H) 7.51 (d, J=1.9 Hz, 1 H); Mass Spectrum: m/z (M + H)+ 333.1.
  • 29
  • [ 54197-66-9 ]
  • [ 141699-59-4 ]
  • [ 233281-92-0 ]
YieldReaction ConditionsOperation in experiment
65% With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 20h; A suspension of 6-hydroxy-3,4-dihydroquinolin-2(lH)-one (5.0 g), tert-butyl 4-(methanesulfonyloxy)piperidine-l-carboxylate (13 g) and potassium carbonate (5.1 g) in N,N-dimethylformamide (30 mL) was stirred at 1000C for 20 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with chloroform. The organic layer was washed with brine and concentrated under reduced pressure. The resulting residue was purified by NH-type silica gel column chromatography (eluting solvent: chloroform/hexane = 4/1) to give the titled compound (6.9 g, 65%) as a colorless solid.
  • 30
  • [ 1007351-17-8 ]
  • [ 141699-59-4 ]
  • [ 877401-19-9 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 5-iodo-1H-pyrazole With sodium hydride In N,N-dimethyl-formamide at 20 - 80℃; for 0.583333h; Stage #2: 1-(tert-butoxycarbonyl)piperidin-4-yl methanesulfonate In N,N-dimethyl-formamide at 20 - 90℃; 75 To 500 mg 5-iodo-1 H-pyrazole in 3 mL DMF was added 54 mg 95% NaH. This was stirred at room temperature for 5 minutes followed by heating for 30 minutes at 80°C . The solution was cooled to room temperature and 417 mg BOC piperidine mesylate was added. The reaction was heated to 90°C overnight. Still some iodo-pyrazole by TLC so added 100 mg more mesylate and heated another 18 hours. The reaction was cooled and someof the DMF was removed in vacuo. The solution was diluted with ethyl acetate and washed with sodium bicarbonate, brine, and dried over sodium sulfate. Removal of solvent led to a clear oil Chromatography with 5, 10, 20% EtOAc/CH2CI2 led to 180 mg of product as a clear oil. 1H NMR (400 MHz, CHLOROFORM-D) 5 ppm 7.23 (d, J=2.27 Hz, 1 H) 6.40 (d, J=2.27 Hz, 1 H) 4.24 (m, 3 H) 2.84 (s, 2 H) 2.02 - 2.12 (m, 2 H) 1.87 (m, 2 H) 1.40 -1.47 (m, 9 H).
  • 31
  • [ 16576-78-6 ]
  • [ 141699-59-4 ]
  • [ 893424-12-9 ]
YieldReaction ConditionsOperation in experiment
tert-Butyl 4-(4-pyridin-2-yl- lH-imidazol- 1 -yDpiperidine- 1 -carboxylateTo a solution of 2-(lH-imidazol-4-yl)pyridine (0.87 g, 6 mmol) in DMF (12 mL) at 0 0C was added sodium hydride (346 mg, 7.2 mmol). The reaction mixture was allowed to warm to room temperature and stirred for an additional 20 min. tert-Butyl 4-[(methylsulfonyl)oxy]piperidine-1- carboxylate (1.34 g, 4.8mmol) was added and the resulting mixture was heated at 800C for 48 h. The reaction was cooled to room temperature, diluted with CH2CI2, and washed with water and brine. The combined organic layers were dried over magnesium sulfate and the solvents removed in vacuo. The residue was purified by silica gel chromatography (0%-100% MeOH/ CH2CI2) and then by HPLC (phenomenex column, 30%-100% acetonitrile/water+0.1%TFA) to afford tert-butyl 4-(4-pyridin-2-yl- lH-imidazol-1-yl)piperidine-1-carboxylate as an oil. 1H NMR (500 MHz, CD3OD) delta 8.88 (m, IH), 8.70 EPO <DP n="67"/>(m, IH), 8.40 (m, IH), 8.10 (m, IH), 8.00 (m, IH), 7.55 (m, IH), 4.58 (m, IH), 4.32 (m, 2H), 3.01 (m,2H), 2.24 (m, 2H), 2.00 (m, 2H), 1.49 (s, 9H).
  • 32
  • [ 670-95-1 ]
  • [ 141699-59-4 ]
  • [ 863257-51-6 ]
YieldReaction ConditionsOperation in experiment
A solution of 4.0 g (27.9 mmol) of 4-phenyl-imidazole in 40 ml of N,N-dimethylformamide is added dropwise to a suspension, cooled with an ice bath, of 1.1 g (27.9 mmol) of sodium hydride (60% suspension in oil) in 30 ml of N,N-dimethylformamide. The mixture is subsequently stirred at ambient temperature for one hour, is then cooled to 0 C. and 2.6 g (9.3 mmol) of 1,1-dimethylethyl 4-[(methylsulphonyl)oxy]piperidine-1-carboxylate, obtained in stage 1.1., in solution in 20 ml of N,N-dimethylformamide, are added dropwise. The reaction mixture is subsequently heated at 80 C. for 2 hours. It is cooled to ambient temperature and diluted with 150 ml of water and 150 ml of ethyl acetate. Separation by settling is carried out and the aqueous phase is extracted twice with 100 ml of ethyl acetate. The organic phases are washed with two times 100 ml of water and then with 100 ml of a saturated aqueous sodium chloride solution. They are dried over sodium sulphate and evaporated to dryness. The residue is purified by chromatography on silica gel, elution being carried out with a 98/2 mixture of dichloromethane and of methanol, to produce 1.0 g of product in the form of a yellow oil.
  • 33
  • [ 15366-34-4 ]
  • [ 141699-59-4 ]
  • [ 922516-36-7 ]
YieldReaction ConditionsOperation in experiment
Step B: Preparation of 1,1-dimethylethyl 4-[3-(methoxycarbonyl)-1H-pyrazol-1-yl]-1-piperidinecarboxylate. A suspension of 60 % dispersion of sodium hydride in mineral oil (192 mg, 4.8 mmol) in 20 mL of N,N-dimethylformamide was cooled to 0 C, and methyl 3-pyrazolecarboxylate (605.37 mg, 4.8 mmol) was gradually added with stirring in nitrogen atmosphere. The reaction mixture was stirred at room temperature for 0.5 h and cooled again to 0 0C. A solution of 1,1-dimethylethyl 4-[(methylsulfonyl)oxy]-1-piperidine-carboxylate (1.18 g, 4 mmol) (i.e. the product of Example 18, Step A) in 5 mL of N,N- dimethylformamide was gradually added to the reaction mixture. The resulting mixture was stirred for 5 days at 60 0C. The reaction mixture was poured in ice water and extracted with ethyl acetate. The organic layer was dried (MgSO4), evaporated in vacuo, and purified by medium-pressure liquid chromatography on silica gel eluting with 0-10 % methanol in ethyl acetate as eluant to give 290 mg of the title compound as a white solid. 1H NMR (CDCl3) 6 1.46 (s, 9H), 1.88-2.00 (m, 2H), 2.12-2.20 (m, 2H), 2.80-2.92 (m, 2H), 3.92 (s, 3H), 4.24-4.33 (m, 2H), 4.34-4.31 (m, IH), 6.82 (s, IH), 7.44 (s, IH).Additionally, 370 mg of 1,1-dimethylethyl 4-[5-(methoxycarbonyl)-1H-pyrazol-1-yl]-1-piperidinecarboxylate was isolated eluting before the title compound. 1H NMR (CDCl3) 5 1.46 (s, 9H), 1.92-2.00 (m, 2H), 2.08-2.15 (m, 2H), 2.85-2.95 (m, 2H), 3.89 (s, 3H), 4.20-4.31 (m, 2H), 5.24-5.32 (m, IH), 6.85 (s, IH), 7.51 (s, IH).
  • 34
  • [ 1547-29-1 ]
  • [ 141699-59-4 ]
  • [ 1189550-34-2 ]
YieldReaction ConditionsOperation in experiment
62% With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 75℃; t-Butyl 4-(methanesulfonyloxy)piperidine-1-carboxylate (2.96 g, 10.6 mmol) and potassium carbonate (2.69 g, 19.5 mmol) were added to a N,N-dimethylformamide solution (45 ml) of <strong>[1547-29-1]3-fluoro-2-hydroxypyridine</strong> (1.00 g, 8.84 mmol), at room temperature, and stirring was carried out at 75C overnight. The reaction solution was cooled to room temperature, and water was added to the residue resulting from concentration, followed by extraction with methylene chloride. After the resulting organic layer was dried over anhydrous sodium sulfate, the residue resulting from concentration was purified by silica gel column chromatography to afford t-butyl 4-[(3-fluoropyridin-2-yl)oxy]piperidine-1-carboxylate (1.63 g, yield 62%) as a colorless oil. 1H-NMR (CDCl3, 400 MHz) delta: 7.88 (1H, d, J=3.9 Hz), 7.33-7.29 (1H, m), 6.84-6.81 (1H, m), 5.32-5.27 (1H, m), 3.81-3.77 (2H, m), 3.33-3.28 (2H, m), 2.02-1.98 (2H, m), 1.82-1.75 (2H, m), 1.47 (9H, s). MS (ESI, m/z): 241 (M-tBu+H)+.
  • 35
  • [ 4214-79-3 ]
  • [ 141699-59-4 ]
  • [ 442199-12-4 ]
YieldReaction ConditionsOperation in experiment
65% With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 75℃; t-Butyl 4-(methanesulfonyloxy)piperidine-1-carboxylate (3.02 g, 10.8 mmol) and potassium carbonate (2.35 g, 17.0 mmol) were added to a N,N-dimethylformamide solution (77 ml) of <strong>[4214-79-3]5-chloro-2-hydroxypyridine</strong> (1.00 g, 7.72 mmol), at room temperature, and stirring was carried out at 75°C overnight. After the reaction solution was cooled to room temperature, water was added to the residue resulting from concentration, followed by extraction with methylene chloride. The resulting organic layer was dried over anhydrous sodium sulfate, and the residue resulting from concentration was purified by silica gel column chromatography to afford t-butyl 4-[(5-chloropyridin-2-yl)oxy]piperidine-1-carboxylate (1.57 g, yield 65percent) as a colorless oil. 1H-NMR (CDCl3, 400 MHz) delta: 8.06 (1H, d, J=2.7 Hz), 7.51 (1H, dd, J=8.8 Hz, 2.7 Hz), 6.67 (1H, d, J=8.8 Hz), 5.18-5.13 (1H, m), 3.79-3.73 (2H, m), 3.31-3.24 (2H, m), 1.99-1.93 (2H, m), 1.74-1.66 (2H, m), 1.47 (9H, s) .
32% With potassium carbonate; In N,N-dimethyl-formamide; at 75℃;Sealed tube; Potassium carbonate (0.352 g, 2.55 mmol) was added to a solution of tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate from step (i) (0.453 g, 1.621 mmol) and <strong>[4214-79-3]5-chloropyridin-2-ol</strong> (0.15 g, 1.158 mmol) in N,N-dimethylformamide (10 ml) in a sealed tube. The reaction was stirred at 75° C. overnight. The reaction was quenched with water and extracted with DCM three times. The combined organics were washed with water, dried (phase separator) and concentrated. The crude product was freeze-dried to remove the remaining DMF. The crude product was purified by 10 g KP-silica Biotage SNAP cartridge eluted with 0-50percent ethyl acetate/petrol to give tert-butyl 4-(5-chloropyridin-2-yloxy)piperidine-1-carboxylate (0.116 g, 0.371 mmol, 32.0percent yield). [0608] 1H NMR (400 MHz, Dichloromethane-d2) delta ppm 1.48 (s, 9H) 1.64-1.81 (m, 2H) 1.90-2.03 (m, 2H) 3.19-3.35 (m, 2H) 3.70-3.85 (m, 2H) 5.13-5.25 (m, 1H) 6.73 (s, 1H) 7.52-7.62 (m, 1H) 8.05-8.14 (m, 1H) [0609] MS ES+: 257
0.116 g With potassium carbonate; In N,N-dimethyl-formamide; at 75℃;Sealed tube; Step (ii): Potassium carbonate (0.352 g, 2.55 mmol) was added to a solution of tert-butyl 4- (methylsulfonyloxy)piperidine-l-carboxylate from step (i) (0.453 g, 1.621 mmol) and <strong>[4214-79-3]5-chloropyridin-2-ol</strong> (0.15 g, 1.158 mmol) in N,N-dimethylformamide (10 ml) in a sealed tube. The reaction was stirred at 75°C overnight. The reaction was quenched with water and extracted with DCM three times. The combined organics were washed with water, dried (phase separator) and concentrated. The crude product was freeze-dried to remove the remaining DMF. The crude product was purified by 10 g KP-silica Biotage SNAP cartridge eluted with 0-50percent ethyl acetate / petrol to give tert-butyl 4-(5-chloropyridin-2- yloxy)piperidine-l-carboxylate (0.116 g, 0.371 mmol, 32.0 percent yield). H NMR (400 MHz, Dichloromethane-i) delta ppm 1.48 (s, 9 H) 1.64 - 1.81 (m, 2 H) 1.90 - 2.03 (m, 2 H) 3.19 - 3.35 (m, 2 H) 3.70 - 3.85 (m, 2 H) 5.13 - 5.25 (m, 1 H) 6.73 (s, 1 H) 7.52 - 7.62 (m, 1 H) 8.05 - 8.14 (m, 1 H) MS ES+: 257
  • 36
  • [ 141699-59-4 ]
  • [ 252061-78-2 ]
  • C19H24N2O4 [ No CAS ]
  • 37
  • [ 1849-36-1 ]
  • [ 141699-59-4 ]
  • [ 333986-94-0 ]
YieldReaction ConditionsOperation in experiment
68% With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 7h; L.L-1 4-(4-Nitro-phenylsulfanyl)-piperidine-1 -carboxylic acid tert-butyl ester[00528] Potassium carbonate (0.45g, 3.5mmol) was added in one portion to a stirred solution of 4-methanesulfonyloxy-piperidine-1 -carboxylic acid te/t-butyl ester (0.75g, 2.5mmol) and 4-nitrothiophenol (0.5g, 3.2mmol) in DMF (25ml) and the mixture heated to 70°C for 7 hours. After this time, the reaction mixture was concentrated under vacuum and re-dissolved in ethyl acetate (25ml) and washed with NaOH (1 M solution, 20ml) and brine (20ml). The organic layer was separated, dried (MgSO4), filtered and concentrated under vaccum. The resulting residue was purified by column chromatography (elution: 60% heptane, 40% ethyl acetate) to afford the title compound (0.74g, 68% yield) as an off-white solid. δΗ (250 MHz, DMSO) 8.14 (2H, d), 7.55 (2H, d), 3.89-3.69 (3H, m), 3.07-2.90 (2H, m), 2.04-1 .89 (2H, m), 1 .51 -1 .33 (10H, m).
31% With potassium carbonate In N,N-dimethyl-formamide at 100℃; 488.3 Step 3 To a mixture of 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (5 g, 32 mmol) in DIVIF (25 mL) was added 4-nitro-benzenethiol (13.4 g, 48 mmol) and K2C03 (8.8 g, 64 mmol).The mixture was stirred at 100 °C overnight. The mixture was washed H20 (100 mLx5) and extracted with EA (100 mLx5). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography (PE/EA = 20/1) to give 4-(4-nitro-phenylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester (3.38 g, yield 31%) as a yellow liquid. MS: m/z 339.0 (M+H).
Stage #1: para-nitrobenzenethiol With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Stage #2: 1-(tert-butoxycarbonyl)piperidin-4-yl methanesulfonate In tetrahydrofuran at 60℃; 18.A 4-Nitrobenzenethiol (23.99mmol, 4.653g) and sodium hydride (32.9mmol, 1.314g) were combined in tetrahydrofuran and stirred at 0°C for 30 minutes. tert-Butyl 4- (methylsulfonyloxy)piperidine-l-carboxylate (36.0mmol, 10.05g) was added and the reaction mixture stirred and heated overnight at 60°C. The reaction mixture was concentrated under vacuum and the residue partitioned between dichloromethane and water, the organic layer was separated, dried, and concentrated under vacuum. The residue was purified by silica column chromatography (eluting with a 0-10% methanol / dichloromethane gradient) to afford the title compound (2.90g).1H NM (CDCIs, 400 MHz): 58.14 (d, 2H), 7.40 (d, 2H), 3.97 (d, 2H), 3.48 (m, 1 H), 3.04 (t, 2H), 2.01 (dd, 2H), 1 .62 (qd, 2H), 1.47 (s, 9H)
Stage #1: para-nitrobenzenethiol With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Stage #2: 1-(tert-butoxycarbonyl)piperidin-4-yl methanesulfonate In tetrahydrofuran at 60℃; 20.A 4-Nitrobenzenethiol (5.93mmol, 1.15g), and sodium hydride (8.12mmol, 0.325g) were combined in tetrahydrofuran and stirred at 0°C for 30 minutes. tert-Butyl 4-(methyl- sulfonyloxy)piperidine-1 -carboxylate (8.89mmol, 2.484g) was added and the reaction mixture heated at 60°C overnight. The reaction mixture was concentrated under vacuum and residue dissolved in dichloromethane and washed with water. The organic layer was separated, dried and concentrated under vacuum. The residue was purified by silica column chromatography (eluent: dichloromethane) to afford the title compound (1.45g). MS (ESI) m/z 339.5 [M+H]+
With triethylamine In N,N-dimethyl-formamide at 100℃; 6.A Step A: tert-Butyl 4-r(4-nitrophenyl)sulfanyl1piperidine-l-carboxylate Step A: tert-Butyl 4-r(4-nitrophenyl)sulfanyl1piperidine-l-carboxylate To a solution of tert-butyl 4-hydroxypiperidine-l-carboxylate (8.0 g, 40 mmol) in 100 mL of DCM was added triethylamine (8.0 g, 80 mmol) and the mixture was cooled to 0 °C. Methanesulfonyl chloride (5.0 g, 44 mmol) was added dropwise, and the reaction mixture was stirred at r.t. for 12 h. The mixture was concentrated in vacuo and the resulting residue redissolved in DMF (150 mL). 4-Nitrobenzenethiol (2.5 g, 16 mmol) was added, followed by triethylamine (4.9 g, 36 mmol) and the mixture was heated at 100 °C overnight. The mixture was cooled to r.t., diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2S04 and concentrated. The residue was purified by via chromatography (PE/EtOAc 10: 1) to provide tert-butyl 4-[(4-nitrophenyl)sulfanyl]piperidine-l- carboxylate. 1H-NMR (400 MHz, CDC13) δ ppm 8.13 (d, J= 9.1 Hz, 2H), 7.39 (d, J= 9.1 Hz, 2H), 3.95-4.0 (m, 2H), 3.45-3.52 (m, 1H), 3.01-3.06 (m, 2H), 1.99-2.03 (m, 2H), 1.56-1.63 (m, 2H), 1.45 (s, 9H).

  • 38
  • [ 220239-66-7 ]
  • [ 141699-59-4 ]
  • [ 1304787-68-5 ]
  • 39
  • [ 220239-66-7 ]
  • [ 141699-59-4 ]
  • [ 1304787-69-6 ]
  • 40
  • [ 141699-59-4 ]
  • [ 23612-36-4 ]
  • [ 1334712-92-3 ]
YieldReaction ConditionsOperation in experiment
34% With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; Intermediate 1 (394 mg, 1.99 mmol), tert-bxxtyl 4-[(methylsulfonyl)oxy]piperidine-l- carboxylate (614 mg, 2.20 mmol) and Cs2C03 (1.30 g, 4.00 mmol) in DMF (10 mL) was heated at 80 C overnight. Most of the solvent was evaporated and the residue was purified by flash chromatography (3% MeOH in CHCI3) to give the title compound as an off-white solid (260 mg, 34%). MS (ESI+) m/z = 380, 382 (M+H)+.
34% With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; Intermediate 1 (394 mg, 1.99 mmol), tert-butyl 4-[(methylsulfonyl)oxy]piperidine-1-carboxylate (614 mg, 2.20 mmol) and Cs2CO3 (1.30 g, 4.00 mmol) in DMF (10 mL) was heated at 80 C. overnight. Most of the solvent was evaporated and the residue was purified by flash chromatography (3% MeOH in CHCl3) to give the title compound as an off-white solid (260 mg, 34%). MS (ESI+) m/z=380, 382 (M+H)+.
  • 41
  • [ 141699-59-4 ]
  • [ 189205-49-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: methanol / 15 h / Reflux 2: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 15 h / 0 - 20 °C
  • 42
  • [ 53857-57-1 ]
  • [ 141699-59-4 ]
  • [ 1383968-69-1 ]
YieldReaction ConditionsOperation in experiment
58% With sodium hydride In N,N-dimethyl-formamide at 0 - 100℃; for 14h; 16.2 Step 2: tert-butyl 4-(5-bromo-lH-indazol-l-yl)piperidine-l-carboxylateAt 0 °C, to a mixture of 5-bromo-lH-indazole (197 mg, 1.0 mmol) and NaH (44 mg, 1.1 mmol, 60 %) in dry DMF (20 mL) was added tert-butyl 4-(methylsulfonyloxy)piperidine-l-carboxylate (307 mg, 1.1 mmol), then the reaction mixture was heated at 100 °C for 14 hours. After removal of the solvent under reduced pressure, the residue was separated between CH2C12 and water. The organic phase was washed with brine, dried over anhydrous Na2S04, concentrated under reduced pressure and purified with flash column chromatography (EtOAc : petrol ether = 1 : 4) to give tert-butyl 4-(5-bromo-lH-indazol-l-yl)piperidine-l-carboxylate (220 mg, 58 %).1H NMR (CDCI3): δ 7.93 (1H, d, / = 0.8 Hz), 7.88 (1H, dd, / = 0.8 Hz, / = 1.6 Hz), 7.45 (1H, dd, / = 1.6 Hz, / = 8.8 Hz), 7.33 (1H, d, / = 8.8 Hz), 4.53-4.55 (1H, m), 4.29-4.32 (2H, m), 2.93-2.97 (2H, m), 2.18-2.23 (2H, m), 2.00-2.05 (2H, m), 1.48 (9H, s).
53% With sodium hydride In N,N-dimethyl-formamide; mineral oil at 90℃; for 2h; 4.9 5.4.9 tert-Butyl 4-(5-bromo-1H-indazol-1-yl)piperidine-1-carboxylate (7) To a solution of 13 6 (6.81g, 34.6mmol) in 75 N,N-dimethylformamide (DMF) (200mL) was added 76 NaH (60% in oil, 2.12g, 53.0mmol). After the mixture being stirred at room temperature for 10min, 14 tert-butyl 4-[(methanesulfonyl)oxy]piperidine-1-carboxylate (14.8g, 53.0mmol) was added to the mixture. After stirring at 90°C for 2h, the reaction was quenched with 72 water at 0°C and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (20-50% 73 EtOAc in hexanes) to afford 16 7 as a pale yellow solid (6.97g, 53% yield). 1H NMR (600MHz, CDCl3) δ ppm 1.48 (s, 9H), 1.95-2.03 (m, 2H), 2.15-2.25 (m, 2H), 2.88-3.02 (m, 2H), 4.21-4.38 (m, 2H), 4.48-4.55 (m, 1H), 7.33 (d, J=8.8Hz, 1H), 7.44 (dd, J=8.8, 1.7Hz, 1H), 7.87 (d, J=1.7Hz, 1H), 7.93 (s, 1H).
45.68 g With potassium <i>tert</i>-butylate In tetrahydrofuran for 24h; Reflux; 6.a Preparation of tert-butyl 4-(5-bromo-1H-indazol-1-yl)piperidine-1-carboxylate (Compound Q17) To a suspension of potassium tert-butoxide (37.25 g) in tetrahydrofuran (1000 mL) was added 5-bromoindazole (54.52 g), and the mixture was stirred at room temperature for 15 minutes. To the reaction solution was added tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (98.74 g), and the reaction solution was heated at reflux for 1 day. Then, the mixture was partitioned between ethyl acetate and water, and the organic layer was washed with brine and dried over Na2SO4. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:3 as the eluting solvent) to give Compound Q17 (45.68 g). [0271] 1H-NMR (400 MHz, CDCl3): 1.49 (9H, s), 2.00 (2H, m), 2.21 (2H, m), 2.96 (2H, m), 4.31 (2H, m), 4.52 (1H, m), 7.34 (1H, d, J=8.8 Hz), 7.45 (1H, d, J=1.7 Hz, 8.8 Hz), 7.88 (1H, d, J=1.7 Hz), 7.94 (1H, s)
45.68 g Stage #1: 5-bromo-1H-indazole With potassium <i>tert</i>-butylate In tetrahydrofuran at 20℃; for 0.25h; Stage #2: 1-(tert-butoxycarbonyl)piperidin-4-yl methanesulfonate In tetrahydrofuran for 24h; Reflux; 6.a tert-butyl 4- (5-bromo -1H- indazole-1-yl) piperidine-1-carboxylate in tetrahydrofuran suspension of tert-butoxy potassium (37.25 g) (1000mL) It was added 5-bromo-indazole (54.52g), and stirred at room temperature for15 minutes. After addition of butyl tert 4- (methylsulfonyloxy)piperidine-1-carboxylate (98.74g) to the reaction solution, the reactionsolution was heated to reflux for 1 day. After completion of the reaction,ethyl acetate - to separatory extraction with water, after which the resultingorganic layer was washed with saturated brine, and dried over sodiumsulfate. The resulting residue was purified by silica gel columnchromatography (elution solvent; ethyl acetate: hexane = 1: 3) to give compoundQ17 (45.68g) purified by

  • 43
  • [ 288-13-1 ]
  • [ 141699-59-4 ]
  • [ 1269429-29-9 ]
YieldReaction ConditionsOperation in experiment
55.9% With sodium hydride In N,N-dimethyl-formamide at 50℃; for 12h; 3A1 synthesis of tert-butyl 4-( lH-pyrazol- 1 -yl)piperidine- 1 -carboxylate Example 3[(2S,3aR,6aR)-2-[4-(lH-pyrazol- 1 -yl)piperidin- 1 -yl]hexahydropentalen-3a(lH)-yl] [3- (trifluoromethyl)-7,8-dihydro-l,6-naphthyridin-6(5H)-yl]methanone Example 3A1tert-butyl 4-( lH-pyrazol- 1 -yl)piperidine- 1 -carboxylate To a solution of lH-pyrazole (0.51 g, 7.46 mmol) in DMF (20 mL) was added NaH (0.43 g, 10.67 mmol) and Example 4A (2 g, 7.1 1 mmol) at room temperature. The mixture was stirred for 12 hours at 50 °C. TLC (petroleum ethenEtOAc = 1 : 1) indicated the reaction was completed. The reaction mixture was quenched with aqueous NH4CI4 (20 mL) and extracted with EtOAc (3X 50mL). The organic layer was dried over Na2S04, filtered, and concentrated in vacuum, the residue was purified by silica gelchromatography to give the title compound (1.0 g, 55.9%) as a colorless solid. NMR (400 MHz, CDCI3) δ 7.45 (d, IH), 7.35 (d, IH), 6.19 (t, IH), 4.21 (m, 3H), 2.82 (m, 2H), 2.03 (m, 2H), 1.84 (m, 2H), 1.40 (s, 9H).
55% Stage #1: NH-pyrazole With sodium hydride In N,N-dimethyl-formamide for 0.0833333h; Inert atmosphere; Stage #2: 1-(tert-butoxycarbonyl)piperidin-4-yl methanesulfonate In N,N-dimethyl-formamide at 150℃; for 0.25h; Inert atmosphere; Microwave irradiation; Step B: tert-butyl 4-(1H-pyrazol-1-yl)piperidine-1-carboxylate Step B: tert-butyl 4-(1H-pyrazol-1-yl)piperidine-1-carboxylate (0091) (0092) To a solution of pyrazole (100 mg, 1.50 mmol) in DMF (10.0 ml) under nitrogen atmosphere was added sodium hydride (60 mg, 1.65 mmol) and the solution stirred for 5 min. After bubbling ceased, the title compound from Step A (204 mg, 1.50 mmol) in 2.5 mL of DMF was added to the solution. The mixture was placed in a microwave reaction vessel and nitrogen was blown into it before closing. (0093) Microwave: The reaction was set at 150°C for 15 minutes on high absorption. After the reaction cooled, it was quenched with ammonium chloride solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated to dryness. Purification of the residue was done on silica gel preparative plate (500 µM) eluting with 70% ethyl acetate in hexane to afford the product (52.2 mg, 55%). ESI-MS calculated for C13H21N3O: Exact Mass: 251.16; Found: 252.16 (MH)+ and 274.15 (MNa)+.
  • 44
  • [ 5932-27-4 ]
  • [ 141699-59-4 ]
  • [ 1421065-44-2 ]
YieldReaction ConditionsOperation in experiment
56.5% With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 12h; Example 14A2 4-(3-Ethoxycarbonyl-pyrazol- l-yl)-piperidine-l-carboxylic acid tert-butyl ester A mixture of Example 14A1 (1 g, 3.55 mmol), Example 4A (0.498 g, 3.55 mmol) and K2CO3 (1.47 g, 10.67 mmol) in DMF (20 mL) was heated at 70 °C for 12 hours. TLC (Petroleum ether: EtOAc = 4: 1) indicated that the reaction was completed. The reaction mixture was filtered and the filtrate was concentrated in vacuum and the residue was purified by chromatography on silica to give Example 14A2 (0.65 g, 56.5 percent) as a colorless solid.
  • 45
  • [ 5932-27-4 ]
  • [ 141699-59-4 ]
  • [ 1421065-45-3 ]
  • 46
  • [ 141699-59-4 ]
  • [ 762240-09-5 ]
  • 47
  • [ 141699-59-4 ]
  • [ 134464-79-2 ]
  • 48
  • [ 261-96-1 ]
  • [ 141699-59-4 ]
  • C21H25N3O2S [ No CAS ]
  • 49
  • [ 141699-59-4 ]
  • [ 224779-27-5 ]
  • 50
  • [ 1776-37-0 ]
  • [ 141699-59-4 ]
  • [ 1469326-84-8 ]
YieldReaction ConditionsOperation in experiment
1.04 g To a solution of <strong>[1776-37-0]5-methylindazole</strong> (901 mg) in DMF (10 mL) was added sodium hydride (327 mg) at 0° C., and the mixture was stirred with heating at 40° C. for 30 minutes. To the reaction solution was added tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (2.28 g), and the mixture was stirred with heating at 90° C. for 19 hours. Then, the mixture was partitioned between ethyl acetate and water, and the organic layer was washed with brine and dried over Na2SO4. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:5 as the eluting solvent) to give Compound Q1 (1.04 g). [0225] 1H-NMR (400 MHz, CDCl3): 1.47 (9H, s), 2.00 (2H, m), 2.21 (2H, m), 2.43 (3H, s), 2.93 (2H, br), 4.28 (2H, br), 4.50 (1H, m), 7.19 (1H, d, J=8.0 Hz), 7.32 (1H, d, J=8.0 Hz), 7.48 (1H, s), 7.89 (1H, s)
1.04 g in DMF solution of 5-methyl-indazole (901mg) (10mL) at 0 It was added sodium hydride (327 mg), heatedand stirred for 30 minutes at 40 ° C.. Thereafter,by adding to the reaction solution tert- butyl 4- (methylsulfonyloxy)piperidine-1-carboxylate (2.28 g) for 19 hours under heating and stirred at 90° C.. After completion of the reaction, ethyl acetate - toseparatory extraction with water, after which the resulting organic layer waswashed with saturated brine, and dried over sodium sulfate. The resultingresidue was purified by silica gel column chromatography (elution solvent;ethyl acetate: hexane = 2: 5) to give compound Q1 (1.04g) purified by
  • 51
  • [ 15366-34-4 ]
  • [ 141699-59-4 ]
  • [ 922516-37-8 ]
YieldReaction ConditionsOperation in experiment
337 mg Sodium hydride (252 mg, 10.5 mmol) was added to a solution of methyl 1H-pyrazole-3- carboxylate (883 mg, 7.00 mmol) in NMP (17.5 mL) in a microwave vial. The reaction was stirred at room temperature for 0.5 hours. tert-Butyl 4-((methylsulphonyl)oxy)-piperidine-1-carboxylate (1955 mg, 7 mmol) was added and the vial sealed. The reaction was heated to 75C overnight. The reaction mixture was partitioned between DCM and water, dried (hydrophobic frit) and the organic phase concentrated in vacuo. The crude product was purified by reverse phase chromatography on C18 silica eluted with 5-95% water (with 0.05% ammonia)/acetonitrile to afford tert-butyl 4-(5-(methoxycarbonyl)- 1H-pyrazol-1-yl)piperidine-1-carboxylate (337 mg, 1.089 mmol, 15.6 %)?H NMR (400 MHz, DMSO-d6) & 1.41 (s, 9 H) 1.71 - 1.96 (m, 4 H) 3.19 - 3.37 (m, 2 H)3.84 (s, 3 H) 4.07 (m, J=12.60 Hz, 2 H) 5.11 - 5.30 (m, 1 H) 6.89 (d, J=2.02 Hz, 1 H) 7.61(d, J=1.77 Hz, 1 H)
  • 52
  • [ 19438-10-9 ]
  • [ 141699-59-4 ]
  • tert-butyl 4-(3-methoxycarbonylphenoxy)-piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
91.4% With potassium carbonate In acetonitrile at 80℃; Preparation of reajent KR-37: tert-butyl 4-(3-methoxycarbonylrhenoxy)- rireridine-1 -carboxylate The reagent KR-36 (2.79 g, 10 mmol) dissolved in CH3CN (30 mL) wasadded into K2003 (2.76 mg, 20 mmol) and commercially available methyl 3- hydroxybenzoate (1 .52 mg, 10 mmol), then stirred at 80°C overnight. Thereaction mixture was concentrated under vacuo, then extracted with ethylacetate and washed with water, dried over Na2SO4 and concentrated under vacuo to give KR-37 (3.05 g, 91.4%). ESI-MS (Mi-i): 336 calc. forC18H25N05: 335.17.
  • 53
  • [ 1500-85-2 ]
  • [ 141699-59-4 ]
  • tert-butyl 4-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
36% With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 4h;Inert atmosphere; Microwave irradiation; 500 mg (3.7 mmol) of 7H-pyrrolo[2,3-d]pyrimidin-4-amine were dissolved in 40 mL of dry DMF and 1.03 g (3.7 mmol) of tert-butyl 4-[(methylsulfonyl)oxy]piperidine-1-carboxylate were added, followed by 3.87 g (3.7 mmol) of caesium carbonate, under argon atmosphere. The mixture was heated in a microwave apparatus at 100 C for 4 hours, then the solvent removed under vacuum.The residue was taken up with dicholomethane and washed with brine. Theorganic layer was dried over Na2S04 and evaporated to give, after trituration with diethyleher, 420 mg of the title compound. (36%)
  • 54
  • [ 19230-71-8 ]
  • [ 141699-59-4 ]
  • tert-butyl 4-(4-methyl-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylate [ No CAS ]
  • tert-butyl 4-(4-methyl-1H-1,2,3-triazol-1-yl)-piperidine-1-carboxylate [ No CAS ]
  • tert-butyl 4-(5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
4-Methyl-iH-i,2,3-triazole (357 mg, 4.30 mmol) was placed in a flask with dry DMF (5 mL). Sodium hydride (186 mg, 4.65 mmol) was added and the reaction mixture was stirred atroom temperature for 15 minutes. tert-Butyl 4-((methylsulfonyl)oxy)piperidine- 1 -carboxylate (step 1) (1.00 g, 3.58 mmol) was added and the reaction mixture was stirred at 100C for4 hours. The resulting mixture was partitioned between EtOAc and water. The organic phase was washed with water and brine, dried over Mg504, filtered and the solvent was removedvacuo. The product was purified by chromatography on silica eluting with iso-hexane/(EtOAc:MeOH - 10:1) to afford:Product Step 2a: tert- Butyl 4-(4-methyl-2 H- 1,2, 3-triazol-2-yl)piperidine- 1 -carboxylate;1H NMR (400 MHz, DMSO-d6) O 7.52 (iH, 5), 4.60 (iH, m), 3.93 (2H, m), 2.98 (2H, m), 2.21(3H, 5), 2.03 (2H, m), 1.80 (2H, m), 1.40 (9H, 5).Product Step 2b: tert- Butyl 4-(4-methyl- 1 H- 1,2, 3-triazol- 1 -yl)piperidine- 1 -carboxylate;1H NMR (400 MHz, DMSO-d6) O 7.91 (iH, 5), 4.62 (iH, m), 4.02 (2H, m), 2.92 (2H, m), 2.21(3H, 5), 2.01 (2H, m), 1.80 (2H, m), 1.42 (9H, 5).Product Step 2c: tert-Butyl 4-(5-methyl- 1 H- 1,2, 3-triazol- 1 -yl) piperidine- 1 -carboxylate;1H NMR (400 MHz, DMSO-d6) O 7.49 (1H, s), 4.51 (1H, m), 4.08 (2H, m), 2.97 (2H, m), 2.31(3H, s), 1.95 (2H, m), 1.87 (2H, m), 1.42 (9H, s).
  • 55
  • [ 7170-01-6 ]
  • [ 141699-59-4 ]
  • tert-butyl 4-(3-methyl-1H-1,2,4-triazol-1-yl)piperidine-1-carboxylate [ No CAS ]
  • tert-butyl 4-(5-methyl-1H-1,2,4-triazol-1-yl)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
3-Methyl-iH-i,2,4-triazole (375 mg, 4.51 mmol) was placed in a flask with dry DMF (5 mL).Sodium hydride (195 mg, 4.89 mmol) was added and the RM was stirred at room temperature for 15 minutes. tert-Butyl 4-((methylsulfonyl)oxy) pi peridi ne-i -carboxylate (Intermediate C, step 1) (i.OOg, 3.S8mmol) was then added and the RM was stirred at 10000 for 4 hours. The resulting mixture was partitioned between EtOAc and water. The organic phase was washed with water and brine, dried over Mg504, filtered and the solvent wasremoved in vacuo. The product was purified by chromatography on silica eluting with isohexane/( EtOAc:MeOH - 10:1) to afford:Product Step 1 a: tert- Butyl 4-(3-methyl- 1 H- 1,2 ,4-triazol- 1 -yl)piperidine- 1 -carboxylate;1H NMR (400 MHz, DMSO-d6) O 8.40 (iH, 5), 4.48 (iH, m), 4.01 (2H, m), 2.90 (2H, m), 2.22(3H, 5), 1.99 (2H, m), 1.72 (2H, m), 1.40 (9H, 5).Product Step 1 b: tert- Butyl 4-(5-methyl- 1 H- 1,2 ,4-triazol- 1 -yl)piperidine- 1 -carboxylate;1H NMR (400 MHz, DMSO-d6) O 7.79 (iH, 5), 4.45 (iH, m), 4.02 (2H, m), 2.90 (2H, m), 2.41 (3H, 5), 1.82 (2H, m), 1.75 (2H, m), 1.41 (9H, 5).
  • 56
  • [ 141699-59-4 ]
  • [ 1201935-36-5 ]
  • 57
  • [ 288-36-8 ]
  • [ 141699-59-4 ]
  • tert-butyl 4-(2H-1,2,3-triazol-2-yl)piperidine-1-carboxylate [ No CAS ]
  • 58
  • [ 14521-80-3 ]
  • [ 141699-59-4 ]
  • [ 1621910-10-8 ]
  • tert-butyl 4-(3-bromo-1H-pyrazol-1-yl)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
15%; 25% With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 5h; Step 2. tert-butyl 4-(3-bromo-lH-pyrazol-l-yl)piperidine-l-carboxylate (Intermediate 17) and tert-butyl 4-(5-bromo-lH-pyrazol-l-yl)piperidine-l-carboxylate (Intermediate 18) [0258] A mixture of tert-butyl 4-(methylsulfonyloxy)piperidine-l -carboxylate (0.837 g, 3.00 mmol), 3-bromo-lH-pyrazole (0.441 g, 3.02 mmol), and cesium carbonate (2.94 g, 9.02 mmol) in DMF (10 mL) stirred for 5 h at 100 C. The reaction mixture was cooled to room temperature and poured ethyl acetate (50 mL). The mixture was washed with water (3 x 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue purified via column chromatography on silica gel (eluting with 10% dichloromethane/methanol to afford tert-butyl 4-(3- bromo-lH-pyrazol-l-yl)piperidine-l -carboxylate (0.25 g, 25%) as a white solid. MS (ESI, pos. ion) m/z 330,332 [M+H]+. [0259] tert-butyl 4-(5-bromo-lH-pyrazol-l-yl)piperidine-l -carboxylate (0.150 g, 15%) was also obtained as a white solid. MS (ESI, pos. ion) m/z 330,332 [M+H]+.
  • 59
  • [ 22300-52-3 ]
  • [ 141699-59-4 ]
  • tert-butyl 4-(4-bromo-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylate [ No CAS ]
  • tert-butyl 4-(4-bromo-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
33%; 20% Step 2. tert-butyl 4-(4,5-dibromo-2H-l,2,3-triazol-2-yl)piperidine-l-carboxylate and tert-butyl 4-(4,5-dibromo-lH-l,2,3-triazol-l-yl)piperidine-l-carboxylate [0261] A mixture of 4,5-dibromo-2H-l,2,3-triazole (2.27 g, 10.08 mmol), tert-butyl 4- (methylsulfonyloxy)piperidine-l -carboxylate (2.79 g, 10.00 mmol), and cesium carbonate (9.75 g, 29.91 mmol) in N,N-dimethylformamide (50 mL) stirred overnight at 100 °C. The reaction mixture was cooled to room temperature, poured into water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford a mixture of tert-butyl 4-(4,5-dibromo-2H- 1 ,2,3- triazol-2-yl)piperidine- 1 -carboxylate and tert-butyl 4-(4,5-dibromo- 1 H- 1 ,2,3-triazol- 1 -yl)piperidine- 1-carboxylate (4.00 g, 97percent) as a yellow oil. MS (ESI, pos. ion) m/z 411 , 409, 413 [M+H]+. Step 3. tert-butyl 4-(4-bromo-2H-l,2,3-triazol-2-yl)piperidine-l-carboxylate (Intermediate 19) and tert-butyl 4-(4-bromo-lH-l,2,3-triazol-l-yl)piperidine-l-carboxylate (Intermediate 20) [0262] n-Butyllithium (2.5 M in hexanes, 2.92 mL, 7.30 mmol) was added dropwise to a -78 °C solution containing a mixture of tert-butyl 4-(4,5-dibromo-2H- 1,2, 3-triazol-2-yl)piperi dine- 1- carboxylate and tert-butyl 4-(4,5-dibromo-lH-l,2,3-triazol-l-yl)piperidine-l -carboxylate (3.00 g, 7.35 mmol) in tetrahydrofuran (20 mL). The resulting solution stirred for 1 hour at -78 °C, and then the reaction mixture was poured into saturated aqueous ammonium chloride solution (20 mL). The aqueous phase was separated and extracted with ethyl acetate (3 x 20 mL), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 2: 1, ethyl acetate/petroleum ether) to afford tert-butyl 4-(4-bromo-2H-l,2,3-triazol-2-yl)piperidine-l- carboxylate (0. 800 g, 33percent) as a colorless oil. MS (ESI, pos. ion) m/z 331, 333[M+H]+. [0263] tert-Butyl 4-(4-bromo-lH-l ,2,3-triazol-l-yl)piperidine-l-carboxylate (0.500g, 20percent) was also obtained as a colorless oil. MS (ESI, pos. ion) m/z 331, 333 [M+H]+.
  • 60
  • [ 22300-52-3 ]
  • [ 141699-59-4 ]
  • tert-butyl 4-(4,5-dibromo-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylate [ No CAS ]
  • tert-butyl 4-(4,5-dibromo-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; Step 2. tert-butyl 4-(4,5-dibromo-2H-l,2,3-triazol-2-yl)piperidine-l-carboxylate and tert-butyl 4-(4,5-dibromo-lH-l,2,3-triazol-l-yl)piperidine-l-carboxylate [0261] A mixture of 4,5-dibromo-2H-l,2,3-triazole (2.27 g, 10.08 mmol), tert-butyl 4- (methylsulfonyloxy)piperidine-l -carboxylate (2.79 g, 10.00 mmol), and cesium carbonate (9.75 g, 29.91 mmol) in N,N-dimethylformamide (50 mL) stirred overnight at 100 °C. The reaction mixture was cooled to room temperature, poured into water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford a mixture of tert-butyl 4-(4,5-dibromo-2H- 1 ,2,3- triazol-2-yl)piperidine- 1 -carboxylate and tert-butyl 4-(4,5-dibromo- 1 H- 1 ,2,3-triazol- 1 -yl)piperidine- 1-carboxylate (4.00 g, 97percent) as a yellow oil. MS (ESI, pos. ion) m/z 411 , 409, 413 [M+H]+.
  • 61
  • [ 2557-78-0 ]
  • [ 141699-59-4 ]
  • tert-butyl 4-((2-fluorophenyl)thio)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
98% With potassium carbonate In acetonitrile at 80℃; 7 [0150] A mixture of 2-fluorobenzenethiol (0.764 mL, 7.15 mmol), tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (1.816 g, 6.5 mmol), and K2CO3 (1.348 g, 9.75 mmol) in ACN (16.25 mL) was heated at 80° C. overnight. The reaction mixture was poured into water and extracted twice with EtOAc. The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure gave tert-butyl 4-((2-fluorophenyl)thio)piperidine-1-carboxylate as a yellow oil (1.98 g, 98%), which was carried forward without purification
98% With potassium carbonate In acetonitrile at 80℃; 7 A mixture of 2-fluorobenzenethiol (0.764 mL, 7.15 mmol), tert-butyl 4- ((methylsulfonyl)oxy)piperidine-1-carboxylate (1.816 g, 6.5 mmol), and K2C03 (1.348 g, 9.75 mmol) in ACN (16.25 mL) was heated at 80 °C overnight. The reaction mixture was poured into water and extracted twice with EtOAc. The combined organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure gave tert-butyl 4-((2- fluorophenyl)thio)piperidine-1-carboxylate as a yellow oil (1.98 g, 98%), which was carried forward without purification.
98% With potassium carbonate In acetonitrile at 80℃; 7 j0127j A mixture of 2-fluorobenzenethiol (0.764 mL, 7.15 mmol), tert-butyl 4- ((methylsulfonyl)oxy)piperidine-1-carboxylate (1.816 g, 6.5 mmol), and K2C03 (1.348 g, 9.75 mmol) in ACN (16.25 mL) was heated at 80 °C overnight. The reaction mixture was poured into water and extracted twice with EtOAc. The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure gave tert-butyl 4-((2- fluorophenyl)thio)piperidine-1-carboxylate as a yellow oil (1.98 g, 98%), which was carried forward without purification.
  • 62
  • [ 1996-44-7 ]
  • [ 141699-59-4 ]
  • tert-butyl 4-((2,4-difluorophenyl)thio)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
2.141 g With potassium carbonate; In acetonitrile; at 80℃; [0153] A mixture of <strong>[1996-44-7]2,4-difluorobenzenethiol</strong> (0.810 mL, 7.15 mmol), tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (1.816 g, 6.5 mmol), and K2CO3 (1.348 g, 9.75 mmol) in ACN (16.25 mL) was heated at 80 C. overnight. The reaction mixture was poured into water and extracted twice with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford tert-butyl 4-((2,4-difluorophenyl)thio)piperidine-1-carboxylate (2.141 g) as a yellow oil, which was carried forward without purification
2.141 g With potassium carbonate; In acetonitrile; at 80℃; A mixture of <strong>[1996-44-7]2,4-difluorobenzenethiol</strong> (0.810 mL, 7.15 mmol), tert-butyl 4- ((methylsulfonyl)oxy)piperidine-1-carboxylate (1.816 g, 6.5 mmol), and K2C03 (1.348 g, 9.75 mmol) in ACN (16.25 mL) was heated at 80 C overnight. The reaction mixture was poured into water and extracted twice with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford tert-butyl 4-((2,4- difluorophenyl)thio)piperidine-1-carboxylate (2.141 g) as a yellow oil, which was carried forward without purification.
2.141 g With potassium carbonate; In acetonitrile; at 80℃; j0131j A mixture of <strong>[1996-44-7]2,4-difluorobenzenethiol</strong> (0.810 mL, 7.15 mmol), tert-butyl 4- ((methylsulfonyl)oxy)piperidine-1-carboxylate (1.816 g, 6.5 mmol), and K2C03 (1.348 g, 9.75 mmol) in ACN (16.25 mL) was heated at 80 C overnight. The reaction mixture was poured into water and extracted twice with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford tert-butyl 4-((2,4- difluorophenyl)thio)piperidine-1-carboxylate (2.141 g) as a yellow oil, which was carried forward without purification.
  • 63
  • [ 2557-77-9 ]
  • [ 141699-59-4 ]
  • tert-butyl 4-((3-fluorophenyl)thio)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
100% With potassium carbonate In acetonitrile at 23 - 80℃; for 17h; 9 [0156] A mixture of tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (1.0 g, 3.58 mmol), K2CO3 (0.742 g, 5.37 mmol), and 3-fluorobenzenethiol (0.363 mL, 4.30 mmol) in ACN (7.5 mL) was stirred at 23° C. for 5 min. The reaction mixture was stirred at 80° C. for 17 h, cooled to 23° C. and partitioned between EtOAc and water. The layers were separated, the organic phase was washed with brine, dried over Na2SO4, filtered, rinsed with EtOAc, and dried in vacuo gave tert-butyl 4((3-fluorophenyl)thio)piperidine-1-carboxylate (1.115 g, 100%) as a yellow oil. ESI-MS m/z [M+H]+ 255.9
100% With potassium carbonate In acetonitrile at 23 - 80℃; for 17h; 9 A mixture of tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (1.0 g, 3.58 mmol), K2C03 (0.742 g, 5.37 mmol), and 3-fluorobenzenethiol (0.363 mL, 4.30 mmol) in ACN (7.5 mL) was stirred at 23 °C for 5 mm. The reaction mixture was stirred at 80 °C for 17 h, cooled to 23 °C and partitioned between EtOAc and water. The layers were separated, the organic phase was washed with brine, dried over Na2SO4, filtered, rinsed with EtOAc, and dried in vacuo gave tert-butyl 4-((3 -fluorophenyl)thio)piperidine- 1 -carboxylate (1.115 g, 100 %) as a yellow oil. ESI-MS m/z [M+H]+ 255.9.
100% With potassium carbonate In acetonitrile at 23 - 80℃; for 17h; 9 j0135j A mixture of tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (1.0 g, 3.58 mmol), K2C03 (0.742 g, 5.37 mmol), and 3-fluorobenzenethiol (0.363 mL, 4.30 mmol) in ACN (7.5 mL) was stirred at 23 °C for 5 mm. The reaction mixture was stirred at 80 °C for 17 h, cooled to 23 °C and partitioned between EtOAc and water. The layers were separated, the organic phase was washed with brine, dried over Na2SO4, filtered, rinsed with EtOAc, and dried in vacuo gave tert-butyl 4-((3 -fluorophenyl)thio)piperidine- 1 -carboxylate (1.115 g, 100 %) as a yellow oil. ESI-MS mlz [M+H]+ 255.9.
  • 64
  • [ 1996-44-7 ]
  • [ 141699-59-4 ]
  • tert-butyl 4-((2,4-difluorophenyl)sulfonyl)piperidine-1-carboxylate [ No CAS ]
  • 65
  • [ 3034-38-6 ]
  • [ 141699-59-4 ]
  • [ 190515-50-5 ]
YieldReaction ConditionsOperation in experiment
2.4 g With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; Example 243b tert-Butyl 4-(4-Nitro-1H-imidazol-1-yl)piperidine-1-carboxylate 243b A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 243a (7.0 g, 25.1 mmol), DMF (120 mL), 4-nitro-1H-imidazole (2.80 g, 25.1 mmol), and K2CO3 (6.9 g, 50.2 mmol). The mixture was heated at 120C for overnight. After this time the reaction was cooled to room temperature and filtered. The filtrate was evaporated in vacuo. The residue was purified by silica-gel column chromatography eluting with 2:2:1 ethyl acetate/petroleum ether/dichloromethane to afford 243b (2.4 g, 32.4%) as a yellow solid. MS-ESI: [M+H]+ 297.3
  • 66
  • [ 6146-52-7 ]
  • [ 141699-59-4 ]
  • 4-(5-nitroindol-1-yl)piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
75% Stage #1: 5-nitroindole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 0.5h; Stage #2: 1-(tert-butoxycarbonyl)piperidin-4-yl methanesulfonate In N,N-dimethyl-formamide; mineral oil at 100℃; for 12h; 19.1 Step 1 5-nitroguanidine (1.0 g, 6.2 mmol)Soluble in N,N-dimethylformamide (10.0 mL),Sodium hydrogen (0.5 g, 12.4 mmol, 60%) was slowly added to the system.The reaction system was stirred at 20 ° C for 30 minutes.Next, 1-Boc-4-methanesulfonyloxypiperidine (1.72 g, 6.2 mmol) was added to the above reaction system.Stir at 100 ° C for 12 hours.then,Quenching the reaction with water,Extracted with ethyl acetate.The organic phases were combined and washed with saturated brine.The organic phase was separated and dried over anhydrous sodium sulfate.filter,concentrate,The residue was purified by silica gel column chromatography (35% ethylCompound 14.1 (0.85 g, yield: 75%) was obtained as a yellow oil.
15.8% Stage #1: 5-nitroindole With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.5h; Cooling with ice; Stage #2: 1-(tert-butoxycarbonyl)piperidin-4-yl methanesulfonate In N,N-dimethyl-formamide at 100℃; for 12h; 1.1 Step 1) tert-butyl 4- (5-nitro-1H-indol-1-yl) piperidine-1-carboxylate Step 1) tert-butyl 4- (5-nitro-1H-indol-1-yl) piperidine-1-carboxylate[0505]To a solution of 5-nitro-1H-indole (3.0 g, 18.3 mmol) in DMF (45 mL) was added NaH (1.5 g, 38 mmol) in an ice bath. The mixture was stirred at rt for 30 min, a solution of tert-butyl 4- ( (methylsulfonyl) oxy) piperidine-1-carboxylate (5.2 g, 19 mmol) in DMF (50 mL) was added. The resulting mixture was stirred at 100 for 12 h. The reaction mixture was cooled to rt and poured into saturated aqueous sodium bicarbonate solution (150 mL) . The mixture was extracted with EtOAc (300 mL × 3) . The combined organic layers were washed with saturated aqueous NaCl, dried over anhydrous Na2SO4and concentrated in vacuo. The residue was purified by silica gel chromatography eluted with PE/EtOAc (V/V) 10/1 to give a yellow oily product (1.1 g, 15.8 ) .[0506]LC-MS: (pos. ion) m/z: 346.4 [M+1]+
1.58 g Stage #1: 5-nitroindole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 0.5h; Cooling with ice; Inert atmosphere; Stage #2: 1-(tert-butoxycarbonyl)piperidin-4-yl methanesulfonate In N,N-dimethyl-formamide; mineral oil at 100℃; for 8.5h; 16.B B. 4-(5-Nitro-indol- 1-yl)-piperidine-1-carboxylic acid tert-butyl ester, 1 6c 5-Nitro-1H-indole (2 g, 12.3 mmol) was dissolved in DMF (30 mL) and cooled in an ice bath under a nitrogen atmosphere. Sodium hydride (60% in mineral oil, 0.543 g, 13.5 mmol) was added in one portion. The mixture was stirred for 30 mm while allowed tocome to room temperature. The solution was then heated at 100 °C before a solution of 4- Methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (4.14 g, 16.7 mmol) in DMF (40 mL) was added dropwise in two portions at 30 mm intervals. The reaction was continued for 4 h at 100 °C and then allowed to cool to room temperature. The mixture was recharged with sodium hydride (60% in mineral oil, 0.543 g, 13.5 mmol) and after 30mm, a solution of 4-Methanesulfonyloxy-piperidine- 1 -carboxylic acid tert-butyl ester (4.14 g, 16.7 mmol) in DMF (40 mL) was also added dropwise. The reaction was continued for another 4 h at room temperature and quenched with water (200 mL). The organic mixture was extracted with EA (2 x 40 mL). The combined organic extracts were dried over Mg504, filtered, and concentrated to dryness. Chromatography over silica gel (gradient of DCM in heptane from 0 to 60% and then of EA in heptane from 0 to 35%) afforded the title compound (1.58 g, 37%). ‘HNMR(300 MHz, Chloroform-cl) 1.50 (s, 9H), 1.93 (qd, J 12.4, 4.4 Hz, 2H), 2.03 -2.18 (m, 2H), 2.94 (t, J= 13.3 Hz, 2H), 4.26 -4.51 (m, 3H), 6.72 (d, J= 3.4 Hz, 1H), 7.33 (d, J= 3.4 Hz, 1H), 7.40 (d, J 9.1 Hz, 1H), 8.11 (dd, J= 9.1, 2.3 Hz, 1H), 8.59 (d, J 2.2 Hz, 1H). C,8H23N304 MS m/z 290 (M+H- tBu).
  • 67
  • [ 636-93-1 ]
  • [ 141699-59-4 ]
  • C17H24N2O6 [ No CAS ]
  • 68
  • [ 434960-42-6 ]
  • [ 141699-59-4 ]
  • [ 1392137-71-1 ]
YieldReaction ConditionsOperation in experiment
31% With potassium hydroxide; In toluene; at 100℃; for 18h;Inert atmosphere; A stirred mixture of <strong>[434960-42-6]5-bromo-6-fluoro-1H-indole</strong> (1.0 g, 4.67 mmol), powdered KOH (0.52 g, 9.34 mmol) and toluene (40 ml) under a nitrogen atmosphere at ambienttemperature was treated with 4-methanesulfonyloxy-piperidine-1-carboxylic acid tertbutyl ester (1.31 g, 4.67 mmol), and the resulting mixture was heated at 100 C 18 hours. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was partitioned between water and EtOAc. The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by columnchromatography on silica gel eluting with a mixture of DCM and cyclohexane (3:7 to1:0 by volume). Further purification by column chromatography on silica gel, eluting with a mixture of DCM and cyclohexane (1:1 to 4:1 by volume), afforded the desired product as a white solid (0.65 g, 3 1%).
  • 69
  • [ 400755-41-1 ]
  • [ 141699-59-4 ]
  • C14H22N4O5 [ No CAS ]
  • 70
  • [ 5334-39-4 ]
  • [ 141699-59-4 ]
  • [ 1536200-86-8 ]
  • tert-butyl 4-(4-amino-5-methyl-1H-pyrazol-1-yl)piperidine-1-carboxylate [ No CAS ]
  • 72
  • [ 929617-35-6 ]
  • [ 141699-59-4 ]
  • tert-butyl 4-(5-bromo-1H-pyrazolo[3,4-c]pyridin-1-yl)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
36% With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 3.5h; To a solutionof 28(7.80 g, 39.4 mmol) in N,N-dimethylformamide (DMF) (120 ml) were added tert-butyl4-[(methanesulfonyl)oxy]piperidine-1-carboxylate (16.5 g, 58.0 mmol) and Cs2CO3(25.7 g, 78.9 mmol). The mixture was stirred at 80 C for 3.5 h. The reaction mixture was concentrated and purified by silica gel column chromatography(0-80% EtOAc in hexanes) to afford 29as a yellow solid (5.38 g, 36% yield).1H NMR (300 MHz, CDCl3): delta ppm1.50 (s, 9 H), 1.96 - 2.13 (m, 2 H), 2.14 - 2.34 (m, 2 H), 2.87 - 3.09 (m, 2 H),4.19 - 4.47 (m, 2 H), 4.56 - 4.73 (m, 1 H), 7.78 - 7.85 (m, 1 H), 8.00 (s, 1 H),8.77 (s, 1 H).
  • 73
  • [ 288-36-8 ]
  • [ 141699-59-4 ]
  • [ 1415312-21-8 ]
  • tert-butyl 4-(2H-1,2,3-triazol-2-yl)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
16%; 36% The NaH (60%, 0. 4g, 10mmol) was added dropwise 4 C DMF (30mL), and thereto is added 2H-1,2,3- triazole (0. 7g, 10mmol), plus complete, the ice bath was removed. 1 hour reaction at room temperature. Then added compound 1 (3. 36g,12mmol), was heated to 60 C overnight. Water was added to the reaction system (50mL), the aqueous phase was extracted with ethyl acetate (50mL x3),The combined organic phase was washed with saturated ammonium chloride solution (lmL) once, dried over anhydrous sodium sulfate for 2 hours. Filtered, filtered and driedAgent. The filtrate was concentrated under reduced pressure using a rotary evaporator to dryness, the residue was purified by column chromatography (stationary phase: column chromatography on 200-300 mesh silicaGel, mobile phase: ethyl acetate: petroleum ether = 1: 5-1: 1) to give compound V-l (l lg, 36%) and compoundV-la (500mg, 16%)
  • 74
  • [ 22272-48-6 ]
  • [ 141699-59-4 ]
  • tert-butyl 4-(3-benzylphenoxy)piperidine-1-carboxylate [ No CAS ]
  • [ 85838-94-4 ]
  • 75
  • [ 65190-36-5 ]
  • [ 141699-59-4 ]
  • tert-butyl 4-(3-carbamoyl-4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With caesium carbonate In N,N-dimethyl-formamide at 100℃; for 3h; Step 2. Into a 25 mL round-bottom flask were placed tert-butyl 4-(methanesulfonyloxy) piperidine-1-carboxylate (1 g, 3.58 mmol) in NN-dimethylformamide (10 mL), 4-nitro-7H- pyrazole-3-carboxamide (671 mg, 4.30 mmol), and cesium carbonate (3.51 g, 10.8 mmol). The resulting solution was stirred for 3 h at 100 °C. The reaction mixture was cooled to room temperature. After removal of the solvent, the residue was purified by flash chromatography on a silica gel column, eluting with dichloromethane/methanol (100: 1-10: 1). This resulted in tert- butyl 4-(3-carbamoyl-4-nitro-7H-pyrazol-1-yl) piperidine-1-carboxylate as a crystal. MS [M+H]+ 340.
  • 76
  • [ 38767-72-5 ]
  • [ 141699-59-4 ]
  • tert-butyl-4-(4-amino-2-oxopyridine-1-yl)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
43.9% <strong>[38767-72-5]4-amino-2-hydroxypyridine</strong> (5.1 g, 46.6 mmol) was dissolved in DMF (80 mL) under ice-cooling, and sodium hydride (2.0 g, 51.3 mmol) was slowly added to the reaction system at 0 C for 15 minutes TheCompound 1-3 (13.0 g, 46.6 mmol) was added to the reaction system and heated to 45 C overnight.After cooling, it was poured into 500 mL of water, extracted with ethyl acetate, and concentrated by dryness and separated by silica gel column chromatography to give Compound 1-4 (6.0 g) in a yield of 43.9%.
  • 77
  • [ 146827-60-3 ]
  • [ 141699-59-4 ]
  • tert-butyl 4-(1-(benzyloxycarbonyl)piperidin-4-ylthio)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
71% Stage #1: 4-(acetylthio)-1-(benzyloxycarbonyl)piperidine With potassium <i>tert</i>-butylate In <i>tert</i>-butyl alcohol at 40℃; for 1h; Stage #2: 1-(tert-butoxycarbonyl)piperidin-4-yl methanesulfonate In <i>tert</i>-butyl alcohol at 70℃; 3 Step 3: tert-butyl 4-(l-(benzyloxycarbonyl)piperidin-4-ylthio)piperidine-l-carboxylate Step 3: tert-butyl 4-(l-(benzyloxycarbonyl)piperidin-4-ylthio)piperidine-l-carboxylate A mixture of benzyl 4-(acetylthio)piperidine-l-carboxylate (0.95 g, 3.2 mmol, 1 eq) and /-BuOK (537 mg, 4.8 mmol, 1.5 eq) in i-BuOH (30 mL) was stirred at 40°C for lh. Then tert-butyl 4- (methylsulfonyloxy)piperidine-l-carboxylate (1.07 g, 3.84 mmol) was added to the mixture. The resulting mixture was heated to 70°C overnight. The reaction was quenched by the addition of saturated ammonium chloride (10 mL), then extracted with EtOAc (150 mL). The organic phase was washed with water (20 mL x 3), brine (10 mL x 3) and dried over anhydrous Na2SC>4. The organic phase was concentrated and the residue was purified by column chromatography (silica gel: 300-400 mesh, PE/EtOAc = 8/1 to 3/1) to give the title compound as a colorless oil (1.0 g, 71%). LRMS m/z (M-Boc+H): Calc'd 335.2, found 335.2.
  • 78
  • [ 5932-27-4 ]
  • [ 141699-59-4 ]
  • [ 782493-64-5 ]
YieldReaction ConditionsOperation in experiment
87% With caesium carbonate; In N,N-dimethyl-formamide; at 5 - 90℃; To a stirred solution of ethyl-I-H pyrazole carboxylate (5.0 g, 3.7mmol) in DMF (50 mL),Cs2CO3 (23 g, 71.3Smmol) and tert-butyl 4-((methylsulfonyl)-oxy) piperidine-I-carboxylate(9.9 g, 35.6 mmol) were added at 5 °C and reaction mixture was stirred at 90 °C overnight.The completion of the reaction was confirmed by TLC. The reaction mixture was pouredinto ice cold water. The resulting solid was filtered, washed with water (50 mL) and driedunder reduced pressure. It was used in the next step without any further purification. Yield:87percent (10 g, off white solid). 1H NMR (400 MHz, DMSO-d6 : 6 8.39 (5, IH), 7.87 (5, IH),4.45-4.39 (m, IH), 4.21 (q, J= 7.2 Hz, 2H), 4.05-4.02 (m, 2H), 2.01-1.98 (m, 2H), 1.85-1.78 (m, 2H), 1.42 (5, 9H), 1.26 (t, J = 7.2 Hz, 3H). LCMS: (Method A) 222.0 (M-Boc), Rt. 2.77 mm, 92.86percent (Max).
  • 79
  • [ 52222-73-8 ]
  • [ 141699-59-4 ]
  • tert-butyl 4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
73% With caesium carbonate; In N,N-dimethyl-formamide; at 0 - 80℃; To a stirred suspension of 4-(trifluoromethyl)-1 H-pyrazole (0.4 g, 2.93 mmol) in dry DMF (8 mL), Cs2CO3 (1 .91 g, 5.87mmol) and tert-butyl 4-((methylsulfonyl)-oxy) piperidine-1 -carboxylate (obtained as described in Step I of Intermediate 10, 1.23 g, 5.87 mmol) were added at 0 C. The reaction mixture was stirred at 80 C overnight, and the reaction mixture was diluted with water (10 mL). The product was extracted with EtOAc (2 x 10 mL). The combined organic layer was dried over anhydrous Na2504 and concentrated under vacuum. The crude product was purified by flash chromatography on silica gel (230-400mesh) to afford the title compound. Yield: 73% (0.69 g, pale brown solid). 1H NMR (400 MHz, DMSO-d6): 6 8.71 (5, IH), 7.90 (5, IH), 4.44 (q, J = 7.6 Hz, IH), 4.04-4.06 (m, 2H), 3.10-2.69 (m, 2H), 2.02-2.08 (d, 2H), 1.84-1.75 (m, 2H), 1.42 (5, 9H). LCMS: (Method A)264.2 (M-56), Rt. 4.82 mm, 91.18% (Max).
0.69 g With caesium carbonate; In N,N-dimethyl-formamide; at 0 - 80℃; To a stirred suspension of <strong>[52222-73-8]4-(trifluoromethyl)-1H-pyrazole</strong> (0.4 g, 2.93 mmol) in dry DMF (8 mL), Cs2CO3 (1.91 g, 5.87mmol) and tert-butyl 4-((methylsulfonyl)-oxy) piperidine-1-carboxylate (obtained as described in Step 1 of Intermediate 10, 1.23 g, 5.87 mmol) were added at 0 C. The reaction mixture was stirred at 80 C overnight, and the reaction mixture was diluted with water (10 mL). The product was extracted with EtOAc (2 x 10 mL). The combined organic layer was dried over anhydrous Na2S04 and concentrated under vacuum. The crude product was purified by flash chromatography on silica gel (230-400 mesh) to afford the title compound. Yield: 73% (0.69 g, pale brown solid). 1H NMR (400 MHz, DMSO-d6): delta 8.71 (s, 1 H), 7.90 (s, 1 H), 4.44 (q, J = 7.6 Hz, 1 H), 4.04-4.06 (m, 2H), 3.10-2.69 (m, 2H), 2.02-2.08 (d, 2H), 1.84-1.75 (m, 2H), 1.42 (s, 9H). LCMS: (Method A) 264.2 (M-56), Rt. 4.82 min, 91.18% (Max).
  • 80
  • [ 571-57-3 ]
  • [ 141699-59-4 ]
  • tert-butyl 4-(5-bromoisoquinolin-8-yloxy)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With caesium carbonate In N,N-dimethyl-formamide at 80℃; for 4h; 9.b b) tert-butyl 4- 5-bromoisoquinolin-8-yloxy)piperidine-l-carboxylate To a solution of 4-bromonaphthalen-l-ol (500 mg, 2.232 mmol) in DMF (6 mL) was added tert-butyl 4-(methylsulfonyloxy)piperidine-l-carboxylate (809 mg, 2.901 mmol) and CS2CO3 (2.18 g, 6.696 mmol) and the resulting mixture was heated to 80 °C for 4 h. The reaction mixture was poured into ice water and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained crude product was purified by basic alumina column chromatography using 30% ethyl acetate in hexane to yield compound tert-butyl 4-((5-bromoisoquinolin-8-yl)oxy)piperidine-l- carboxylate. LCMS Purity: 93.416%.
  • 81
  • [ 580-20-1 ]
  • [ 141699-59-4 ]
  • tert-butyl 4-(quinolin-7-yloxy)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
100 mg With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 3h; To a solution of <strong>[580-20-1]quinolin-7-ol</strong> (100 mg, 0.69 mmol) in DMF (2 mL) was added tert-butyl 4- ((methylsulfonyl)oxy)piperidine-1-carboxylate (0.23 g, 0.83 mmol) and K2CO3 (0.29 g, 2.07 mmol). The reaction mixture was heated to 90 C and stirred at that temperature for 3 h. Water (15 mL) was added to the reaction vessel and the resulting biphasic mixture was extracted with ethyl acetate (3 x 50 mL). The organic phase was washed with saturated aqueous NaCl (5 x 25 mL). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to provide tert-butyl 4-(quinolin-7-yloxy)piperidine-1-carboxylate (100 mg) as a brown oil.
  • 82
  • [ 141699-59-4 ]
  • [ 782501-25-1 ]
  • 83
  • [ 209328-55-2 ]
  • [ 141699-59-4 ]
  • [ 1189551-57-2 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 105℃; Preparation of tert-butyl 4-((5-fluoropyridin-3-yl)oxy)piperidine-l- carboxylate. To a solution of tert-butyl 4-((methylsulfonyl)oxy)piperidine-l-carboxylate (257 mg, 0.920 mmol) and <strong>[209328-55-2]3-fluoro-5-hydroxypyridine</strong> (104 mg, 0.920 mmol) in DMF (2.3 mL) was added potassium carbonate (381 mg, 2.76 mmol) and then the reaction mixture was stirred overnight at 105C. After cooling to ambient temperature, the reaction mixture was diluted with saturated NaHCCbtaq) and extracted with EtOAc. The organic extracts were washed with water and brine. The organic extracts were dried over anhydrous Na2S04(s), filtered and concentrated in vacuo to afford the title compound (assumed theoretical yield, 273 mg) in sufficient purity for step 2. MS (apci) m/z = 297.2 (M+H).
  • 84
  • [ 91233-70-4 ]
  • [ 141699-59-4 ]
  • tert-butyl 4-((2-methoxypyrimidin-5-yl)oxy)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate In N,N-dimethyl-formamide at 95℃; 257.1 Step 1 : Preparation of tert-butyl 4-((2-methoxypyrimidin-5-yl)oxy)piperidine-l- carboxylate. To a solution of tert-butyl 4-((methylsulfonyl)oxy)piperidine-l-carboxylate (222 mg, 0.793 mmol) and 2-methoxypyrimidin-5-ol (100 mg, 0.793 mmol) in DMF (2 mL) was added potassium carbonate (219 mg, 1.59 mmol) and then the reaction mixture was stirred overnight at 95°C. After cooling to ambient temperature, the reaction mixture was diluted with DCM and washed with saturated NaHC03(aq), water, and brine. The organic extracts were dried over anhydrous Na2S04(s), filtered and concentrated in vacuo to afford the title compound (assumed theoretical yield, 245 mg) in sufficient purity for step 2. MS (apci) m/z = 254.1 (M- t-bu).
  • 85
  • [ 14521-80-3 ]
  • [ 141699-59-4 ]
  • tert-butyl 4-(3-bromo-1H-pyrazol-1-yl)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
3.43 g With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 15h; A mixture of <strong>[14521-80-3]3-bromo-1H-pyrazole</strong> (2.76 g), tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (5.25 g) and cesium carbonate (12.25 g) in DMF (50 mL) was stirred at 100 C. for 15 hr. The mixture was poured into water and extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (3.43 g). 1H NMR (300 MHz, DMSO-d6) delta1.41 (9H, s), 1.62-1.81 (2H, m), 1.88-2.04 (2H, m), 2.76-2.97 (2H, m), 3.92-4.10 (2H, m), 4.25-4.43 (1H, m), 6.35-6.40 (1H, m), 7.80-7.85 (1H, m).
  • 86
  • [ 17802-02-7 ]
  • [ 141699-59-4 ]
  • t-butyl 4-(3-chloro-2-nitrophenoxy)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
69% With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; A vial was charged with <strong>[17802-02-7]3-chloro-2-nitrophenol</strong> (0.500 g, 2.88 mmol, 1.00 equiv), t-butyl 4-((methylsulfonyl)oxy)piperidine-l-carboxylate (0.804 g, 2.88 mmol, 1.00 equiv), cesium carbonate (1.88 g, 5.77 mmol, 2.00 equiv) and DMF (15 mL). The resulting solution was stirred overnight at 80 C and quenched with water (10 mL). The mixture was extracted with DCM (3 x 20 mL) and the organic layers were combined, washed with water (3 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was (1076) chromatographed on a silica gel column to provide 0.714 g (69% yield) of t-butyl 4-(3-chloro-2- nitrophenoxy)piperidine-l-carboxylate as a white solid. LCMS (ESI, m/z): 357 [M+H]+.
  • 87
  • [ 1000342-71-1 ]
  • [ 141699-59-4 ]
  • tert-butyl 4-(6-bromo-1H-pyrrolo[3,2-c]pyridin-1-yl)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
44% With caesium carbonate; In N,N-dimethyl-formamide; at 90℃; for 12h; To a stirred solution of tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate in DMF (30 mL), CS2CO3 (3.08 g. 9.5 mmol) and <strong>[1000342-71-1]6-bromo-1H-pyrrolo[3,2-c]pyridine</strong> (372 mg, 1.9 mmol) were added at rt. The reaction mixture was stirred at 90C for 12h. The reaction mixture was quenched with ice water and extracted with DCM. The organic layer was dried over anhydrous Na2SC>4, and it was concentrated under reduced pressure. The crude compound was purified by flash column chromatography using 20% EtOAc in pet ether as an eluent to afford the title compound (0.60 g, 44%).LC-MS (method 14): Rt = 2.65 min; m/z = 380.0 (M+H+).
  • 88
  • [ 55919-82-9 ]
  • [ 141699-59-4 ]
  • tert-butyl 4-(5-iodo-1H-indazol-1-yl)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
41% To a stirred solution of <strong>[55919-82-9]5-iodo-1H-indazole</strong> (1.19 g, 4.88 mmol, 1.0 eq) in DMF (20 mL) at 0 C. was added NaH (0.26 g, 5.37 mmol, 1.1 eq.) and the reaction mixture was stirred for 15 min. Then tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (1.5 g, 5.37 mmol, 1.1 eq) dissolved in DMF (10 mL) was added dropwise at 0 C. Then the reaction mixture was heated to 100 C. for 16 h. After completion, the reaction mixture was diluted with EtOAc and washed with ice water. The combined organic layers were concentrated to get the crude product which was purified by column chromatography (100-200 mesh silica gel; 50% EtOAc/Hexane; Rf-value-0.5, isomer separation) to afford tert-butyl 4-(5-iodo-1H-indazol-1-yl)piperidine-1-carboxylate (0.82 g, 41%) as a single regioisomer.
  • 89
  • [ 7411-23-6 ]
  • [ 141699-59-4 ]
  • tert-butyl 4-(3,5-dibromo-1,2,4-triazol-1-yl)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
52% Sodium hydride (34 mg, 0.86 mmol) was slowly added to a solution of <strong>[7411-23-6]3,5-dibromo-1H-1,2,4-triazole</strong> (150 mg, 0.66 mmol) and DMF (3.9 mL) at RT and the solution was stirred at 45C for 30 min. tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate (0.15 mL, 0.79 mmol) was then added portion-wise. The reaction mixture was stirred at 85 C for 2 days. The reaction was quenched with NH4Cl (aq. sat.) and extracted with DCM. The combined organic fractions were dried via a phase separator and reduced in vacuo. The crude residue was dissolved in DCM, reduced in vacuo onto silica and purified by silica flash chromatography eluting with 10-90% EtOAc in Pet. Ether to yield tert-butyl 4-(3,5-dibromo-1,2,4-triazol-1-yl)piperidine-1-carboxylate (140 mg, 0.34 mmol, 52% yield) as a pale yellow oil. UPLC-MS (ES+, Method A): 1.82 min, m/z 411.0 [M+H]+.
  • 90
  • [ 953410-86-1 ]
  • [ 141699-59-4 ]
  • tert-butyl 4-(5-bromo-7-iodo-2H-indazol-2-yl)piperidine-1-carboxylate [ No CAS ]
  • 91
  • [ 156454-43-2 ]
  • [ 141699-59-4 ]
  • tert-butyl 4-(5-bromo-7-methyl-2H-indazol-2-yl)piperidine-1-carboxylate [ No CAS ]
  • tert-butyl 4-(5-bromo-7-methyl-1H-indazol-1-yl)piperidine-1-carboxylate [ No CAS ]
  • 92
  • [ 5334-39-4 ]
  • [ 141699-59-4 ]
  • [ 1536200-86-8 ]
YieldReaction ConditionsOperation in experiment
With tetra-(n-butyl)ammonium iodide; caesium carbonate In dimethyl sulfoxide at 80℃; S105.1 Step-1:Synthesis of tert-butyl 4-(3-methyl-4-nitro-1H-pyrazol-1-yl)piperidine-1- carboxylate To a stirred solution of tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (500 mg, 1.79 mmol, 1 equiv) in DMF (10 mL), was added Cs2CO3 (1167 mg, 3.58 mmol, 2 equiv), TBAI (133 mg, 0.36 mmol, 0.2 equiv) and 3-methyl-4-nitro-1H-pyrazole (114 mg, 0.89 mmol, 0.5 equiv). The resultant reaction mixture was allowed to stir at 80 °C for overnight. Progress of the reaction was monitored by LCMS. After completion of the reaction, diluted with water (50 mL) and extracted with EtOAc (100 mL × 2). Organic layer was washed with water (100 mL) and brine solution (100 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude, which was purified by normal phase Combi flash to obtain desired product. LCMS: 311 [M+H]+
  • 93
  • [ 141699-59-4 ]
  • [ 186407-74-9 ]
  • [ 186409-45-0 ]
YieldReaction ConditionsOperation in experiment
55.3% With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 16h; Step 1: To a solution of tert-butyl 4-((methylsµLfonyl)oxy) piperidine-1-carboxylate (6.38 g, 22.84 mmol) and 4-bromo-1H-indazole (3.0 g, 15.23 mmol) in DMF (40 mL), potassium carbonate (6.31 g, 45.68 mmol) was added. The mixture was stirred at 60°C for 16 h. The resulting mixture was cooled and added with ethyl acetate (100 mL). Then the mixture was washed with water (50 mL x 3) and brine (50 mL), dried over Na2SO4 and concentrated. The residue was purified by silica gel column to obtain compound I-19a (3.2 g, 8.41 mmol, yield 55.3%) as colorless oil. MS (ESI): m/z 380.6 (M+H) +.
55.3% With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 16h; Step 1: To a solution of tert-butyl 4-((methylsµLfonyl)oxy) piperidine-1-carboxylate (6.38 g, 22.84 mmol) and 4-bromo-1H-indazole (3.0 g, 15.23 mmol) in DMF (40 mL), potassium carbonate (6.31 g, 45.68 mmol) was added. The mixture was stirred at 60°C for 16 h. The resulting mixture was cooled and added with ethyl acetate (100 mL). Then the mixture was washed with water (50 mL x 3) and brine (50 mL), dried over Na2SO4 and concentrated. The residue was purified by silica gel column to obtain compound I-19a (3.2 g, 8.41 mmol, yield 55.3%) as colorless oil. MS (ESI): m/z 380.6 (M+H) +.
Same Skeleton Products
Historical Records

Pharmaceutical Intermediates of
[ 141699-59-4 ]

Crizotinib Related Intermediates

Chemical Structure| 7379-35-3

[ 7379-35-3 ]

4-Chloropyridine hydrochloride

Chemical Structure| 877397-70-1

[ 877397-70-1 ]

(R)-3-(1-(2,6-Dichloro-3-fluorophenyl)ethoxy)-2-nitropyridine

Chemical Structure| 877399-50-3

[ 877399-50-3 ]

tert-Butyl 4-(4-bromo-1H-pyrazol-1-yl)piperidine-1-carboxylate

Chemical Structure| 73183-34-3

[ 73183-34-3 ]

4,4,4',4',5,5,5',5'-Octamethyl-2,2'-bi(1,3,2-dioxaborolane)

Chemical Structure| 15128-82-2

[ 15128-82-2 ]

2-Nitropyridin-3-ol

Related Functional Groups of
[ 141699-59-4 ]

Amides

Chemical Structure| 129888-60-4

[ 129888-60-4 ]

tert-Butyl 3-((methylsulfonyl)oxy)piperidine-1-carboxylate

Similarity: 0.92

Chemical Structure| 404577-34-0

[ 404577-34-0 ]

(R)-1-N-Boc-3-Methanesulfonyloxypiperidine

Similarity: 0.92

Chemical Structure| 940890-90-4

[ 940890-90-4 ]

(S)-tert-Butyl 3-((methylsulfonyl)oxy)piperidine-1-carboxylate

Similarity: 0.92

Chemical Structure| 161975-39-9

[ 161975-39-9 ]

tert-Butyl 4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate

Similarity: 0.91

Chemical Structure| 141699-57-2

[ 141699-57-2 ]

tert-Butyl 3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate

Similarity: 0.90

Sulfonates

Chemical Structure| 129888-60-4

[ 129888-60-4 ]

tert-Butyl 3-((methylsulfonyl)oxy)piperidine-1-carboxylate

Similarity: 0.92

Chemical Structure| 404577-34-0

[ 404577-34-0 ]

(R)-1-N-Boc-3-Methanesulfonyloxypiperidine

Similarity: 0.92

Chemical Structure| 940890-90-4

[ 940890-90-4 ]

(S)-tert-Butyl 3-((methylsulfonyl)oxy)piperidine-1-carboxylate

Similarity: 0.92

Chemical Structure| 161975-39-9

[ 161975-39-9 ]

tert-Butyl 4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate

Similarity: 0.91

Chemical Structure| 141699-57-2

[ 141699-57-2 ]

tert-Butyl 3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate

Similarity: 0.90

Related Parent Nucleus of
[ 141699-59-4 ]

Aliphatic Heterocycles

Chemical Structure| 129888-60-4

[ 129888-60-4 ]

tert-Butyl 3-((methylsulfonyl)oxy)piperidine-1-carboxylate

Similarity: 0.92

Chemical Structure| 132945-75-6

[ 132945-75-6 ]

(S)-tert-Butyl 3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate

Similarity: 0.90

Chemical Structure| 141699-57-2

[ 141699-57-2 ]

tert-Butyl 3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate

Similarity: 0.90

Chemical Structure| 109384-19-2

[ 109384-19-2 ]

tert-Butyl 4-hydroxypiperidine-1-carboxylate

Similarity: 0.70

Chemical Structure| 1179338-62-5

[ 1179338-62-5 ]

tert-Butyl 4-(2-aminoethyl)-4-hydroxypiperidine-1-carboxylate

Similarity: 0.69

Piperidines

Chemical Structure| 129888-60-4

[ 129888-60-4 ]

tert-Butyl 3-((methylsulfonyl)oxy)piperidine-1-carboxylate

Similarity: 0.92

Chemical Structure| 404577-34-0

[ 404577-34-0 ]

(R)-1-N-Boc-3-Methanesulfonyloxypiperidine

Similarity: 0.92

Chemical Structure| 940890-90-4

[ 940890-90-4 ]

(S)-tert-Butyl 3-((methylsulfonyl)oxy)piperidine-1-carboxylate

Similarity: 0.92

Chemical Structure| 161975-39-9

[ 161975-39-9 ]

tert-Butyl 4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate

Similarity: 0.91

Chemical Structure| 109384-19-2

[ 109384-19-2 ]

tert-Butyl 4-hydroxypiperidine-1-carboxylate

Similarity: 0.70