Structure of 141699-59-4
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CAS No. : | 141699-59-4 |
Formula : | C11H21NO5S |
M.W : | 279.35 |
SMILES Code : | C(=O)(OC(C)(C)C)N1CCC(CC1)O[S](=O)(=O)C |
MDL No. : | MFCD04116220 |
InChI Key : | WOEQSXAIPTXOPY-UHFFFAOYSA-N |
Pubchem ID : | 4184869 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P301+P312-P302+P352-P304+P340-P305+P351+P338 |
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 ? Topological Polar Surface Area: Calculated from |
81.29 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.72 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.09 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.06 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.93 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.0 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.36 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.93 |
Solubility | 3.29 mg/ml ; 0.0118 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.39 |
Solubility | 1.14 mg/ml ; 0.00408 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.32 |
Solubility | 13.2 mg/ml ; 0.0474 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
No |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
Yes |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-7.23 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
0.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
1.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<0.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.8 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
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 |
Yield | Reaction Conditions | Operation 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). |
Yield | Reaction Conditions | Operation 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 |
Yield | Reaction Conditions | Operation 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. |
Yield | Reaction Conditions | Operation 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 |
Yield | Reaction Conditions | Operation 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). |
Yield | Reaction Conditions | Operation 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]+. |
Yield | Reaction Conditions | Operation 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]+. |
Yield | Reaction Conditions | Operation 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). |
Tags: 141699-59-4 synthesis path| 141699-59-4 SDS| 141699-59-4 COA| 141699-59-4 purity| 141699-59-4 application| 141699-59-4 NMR| 141699-59-4 COA| 141699-59-4 structure
A110474 [129888-60-4]
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A878895 [940890-90-4]
(S)-tert-Butyl 3-((methylsulfonyl)oxy)piperidine-1-carboxylate
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A231118 [161975-39-9]
tert-Butyl 4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate
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tert-Butyl 3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate
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A110474 [129888-60-4]
tert-Butyl 3-((methylsulfonyl)oxy)piperidine-1-carboxylate
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Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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The concentration of the dissolution solution you need to prepare is mg/mL