Structure of 87120-72-7
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CAS No. : | 87120-72-7 |
Formula : | C10H20N2O2 |
M.W : | 200.28 |
SMILES Code : | NC1CCN(C(OC(C)(C)C)=O)CC1 |
MDL No. : | MFCD01076201 |
InChI Key : | LZRDHSFPLUWYAX-UHFFFAOYSA-N |
Pubchem ID : | 1268291 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319 |
Precautionary Statements: | P264-P280-P302+P352-P337+P313-P305+P351+P338-P362+P364-P332+P313 |
Num. heavy atoms | 14 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.9 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 59.3 |
TPSA ? Topological Polar Surface Area: Calculated from |
55.56 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.44 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.73 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.96 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.86 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.32 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.06 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.34 |
Solubility | 9.08 mg/ml ; 0.0453 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.48 |
Solubility | 6.7 mg/ml ; 0.0335 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-0.92 |
Solubility | 24.1 mg/ml ; 0.12 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 |
Yes |
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) |
No |
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 |
-7.0 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 |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.12 |
* 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 |
---|---|---|
91% | With pyridine In pyridine at 20℃; for 16 h; Cooling with ice | 5.00 g (25.0 mmol) of BOC-4-aminopiperidine are dissolved in pyridine (19.8 mL) and cooled in an ice bath. 2.13 mL (27.5 mmol) of methanesulfonyl chloride are added slowly. The reaction is stirred at RT for 16 h. After diluting with water, the reaction is extracted with DCM. Organic layers are washed with water, dried with MgSO4 and filtered. The solvent is removed under reduced pressure to afford 6.30 g of (1-Methanesulfonyl-piperidin-4-yl)-carbamic acid tert-butyl ester. Yield: 91percent; ESI-MS: 279 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With potassium phosphate; copper(l) iodide; N,N-diethylsalicylamide; In N,N-dimethyl-formamide; at 90℃; for 24h; | Step 2: 4-(Pyrimidin-5-ylamino)-piperidine-1-carboxylic acid tert-butyl ester A mixture of <strong>[38696-20-7]5-bromo-2-phenyl-pyrimidine</strong> (3.50 g, 14.89 mmol, 1.0 equiv), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (4.48 g, 22.33 mmol, 1.5 equiv), copper(I) iodide (0.28 g, 1.49 mmol, 0.1 equiv), N,N-diethylsalicylamide (0.58 g, 2.98 mmol, 0.2 equiv) and K3PO4 (3.16 g, 14.89 mmol, 1.0 equiv) in degassed DMF (30 mL) was heated under Ar to 90° C. for 24 h. The solvent was removed under reduced pressure and the crude reaction product extracted from water (300 mL) and 25percent NH4OH (30 mL) with ethyl acetate (3*300 mL). The combined organic phases were dried over Na2SO4, concentrated by evaporation under reduced pressure and the crude material purified by silica column chromatography eluding with a gradient of heptane/ethyl acetate (4:1-->1:1) to provide 1.98 g (38percent) of the title compound. MS (ESI): 377.1 [M+Na]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2% | With potassium tert-butylate;tetrakis(triphenylphosphine) palladium(0); XPhos; In toluene; at 100℃; for 16h; | Step 1: 4-(2-Morpholin-4-yl-pyrimidin-5-ylamino)-piperidine-1-carboxylic acid tert-butyl ester To a degassed solution of 4-(5-bromo-pyrimidin-2-yl)-morpholine (4.70 g, 19.26 mmol, 1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (4.63 g, 23.11 mmol, 1.2 equiv; commercially available) in toluene (40 mL) was added KOtert-Bu (5.40 g, 48.15 mmol, 2.5 equiv), dicyclohexyl-(2',4',6'-triisopropyl-biphenyl-2-yl)-phosphane (0.18 g, 0.39 mmol, 0.02 equiv; X-Phos ligand [CAS RN 564483-18-7]; commercially available from Strem Chemicals, USA) and tris(dibenzylideneacetone)dipalladium(0) (1.60 g, 1.54 mmol, 0.08 equiv). The reaction mixture was stirred under nitrogen at 100 C. for 16 h, cooled to rt, filtered and the filtrate concentrated by evaporation under reduced pressure. The crude material was purified with silica column chromatography eluding with a gradient of heptane/ethyl acetate (3:2→2:3) to provide 0.14 g (2%) of the title compound in 90% purity according to 1H NMR. 1H NMR (360 MHz, DMSO): δ 1.11-1.25 (m, 2H), 1.39 (s, 9H), 1.84 (d, J=14.1 Hz, 2H), 2.88 (br s, 2H), 3.30 (br s, 1H), 3.46 (t, J=5.0 Hz, 4H), 3.64 (t, J=4.1 Hz, 4H), 3.84 (d, J=12.7 Hz, 2H), 5.03 (d, J=8.6 Hz, 1H), 7.96 (s, 2H). MS (ESI): 364.3 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With sodium tris(acetoxy)borohydride; acetic acid; In 1,2-dichloro-ethane; at 20℃; for 18h; | Add sodium triacetoxyborohydride (30. 50 g, 144 mmol) to a stirred solution of 4- amino-1-N Boc-piperidine (18.00 g, 89.9 mmol), <strong>[104146-17-0]4-chloro-thiazole-5-carbaldehyde</strong> (13.09 g, 88.7 mmol), acetic acid (5.5 mL, 96.1 mmol), and 1, 2-dichloroethane (350 mL). Stir the reaction for 18 hours at room temperature under nitrogen. Pour the reaction into 2N NaOH (400 mL) and extract with ethyl acetate (3 X 150 mL). Wash the ethyl acetate with brine (2 X 150 mL). Dry the ethyl acetate over sodium sulfate and then filter off the sodium sulfate. Concentrate on a rotary evaporator and purify the crude product by flash chromatography on silica gel eluting with 75percent ethyl acetate/hexanes then with 100 percent ethyl acetate to yield 21.78 g (74percent) of 4-f [ (4-chloro-thiazol-5-yl) methyl]-amino}- piperidine-1-carboxylic acid tert-butyl ester: mass spectrum (ion spray): m/z = 332.1 (M+1) ; IH NMR (CDC13) : 8 = 8.67 (s, 1H), 4.10-4. 02 (m, 4H), 2.88-2. 82 (m, 2H), 2.74- 2.67 (m, 1H), 1.92-1. 89 (m, 2H), 1.49 (s, 9H), 1.37-1. 28 (m, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With hydrogen;Raney nickel; In ethanol; under 2585.81 Torr; | To a solution of N-t-butoxycarbonyl-4-piperidone 1 (15 g, 75.3 mmol) in pyridine (50 mL) was added hydroxylamine ? HCl (5.23 g, 75.3 mmol). The mixture was heated in an oil bath at 65 C for 1 h. After cooling, pyridine was removed under reduced pressure and the residue was dried under high vacuum overnight to give a solid. To this solid was added water (100 mL) and the mixture was sonicated. The precipitate was filtered and washed with water then dried under high vacuum to give the oxime derivative of compound 1 (10.5 g, 65%); FAB MS [M+1]+ 215.3. The oxime (10 g, 46.67 mmol) was dissolved in absolute EtOH (100 mL) followed by the addition of Raney Ni (29 g, washed with absolute EtOH). The mixture was hydrogenated in a Parr shaker at 50 psi overnight. After reaction was complete, the Raney Ni was filtered off (caution; risk of fire) and the filtrate was concentrated to give compound 2 (9.2 g, 46 mmol,98% yield) as an oil which solidified under high vacuum drying. FAB MS [M+1]+ 201.3. To a solution of the bromoacetamide derivative 3 (3.0g,6.2 mmol) (prepared in Example 3) in CH2Cl2 (62 mL) at -10 C were added Huenig's base (1.2 mL, 6.82 mmol) and compound 2 (2.48 g, 12.39 mmol). The solution was gradually warmed to RT overnight. After reaction was complete, CH2Cl2 (300 mL) was added and the mixture was washed with brine (100 mL, 3x), dried over MgSO4 and filtered. The filtrate was evaporated to dryness to give a light yellow solid which was purified by flash chromatography on silica gel (200 g), eluting with 5% [NH4OH/MeOH (1:9)] /CH2Cl2 to give a 71% yield of the title compound 4 as a white solid (2.66 g, 4.4 mmol), m.p. 78-81 C; FAB MS [M+1]+35Cl 603.1; Calcd. for C31H40N4O4Cl2, C, 61.69; H, 6.68; N,9.28; Cl,11.74. Found: C, 61.33; H, 6.94; N, 9.17; Cl, 11.27. |
With hydrogen;5% rhodium on activated aluminium oxide; In methanol; at 50℃; | Example 2 Synthesis of Compound 191 EPO <DP n="18"/>A solution of 5.8 g (0.31 mol) of N-t-Boc-piperidone in 80 ml of ethanol was cooled to O0C on an ice bath. To this was added 5.2 ml (0.04 mol) of TEA then 2.6 g (0.37 mol) of solid hydroxylamine HCl. The mixture was warmed to room temperature and then heated to reflux temperature for 6 h. The solvent was removed and the solid was partitioned between saturated aqueous ammonium chloride and ethyl acetate (100 ml each). The aqueous layer was extracted with a second portion of ethyl acetate (100 ml) and the combined extract was dried over sodium sulfate. The solvent was removed at reduced pressure to afford 6.0 g of a white solid. The solid was dissolved in 60 ml of methanol and then hydrogenated over 5% Rhodium on Alumina (0.6 g) at 5O0C. After the uptake of hydrogen ceased, the catalyst was filtered and the solvent removed to afford 5.5 g (98%) of reactant 5. The NMR spectrum was consistent with the proposed structure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium cyanoborohydride; acetic acid; In acetonitrile; at 20℃; for 16.0h; | (i) 4-Isopropylamino-piperidine-1-carboxylic acid tert-butyl ester To a solution of 1.5 g 4-Amino-piperidine-1-carboxylic acid tert-butyl ester in 20 ml acetonitrile, 2.6 ml acetone, 0.94 g Na(CN)BH3 and 0.3 ml acetic acid were added. After stirring for 16 h at RT the solvent was removed under reduced pressure and the residue was partitioned between 30 ml of water and 30 ml of ethyl acetate. The organic layer was washed with saturated Na2CO3 solution, water and was dried over Na2SO4. Removal of the solvent under reduced pressure yields a white solid. Yield: 2.8 g MS (ES+): m/e=243. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; N,N-dimethyl-formamide; at -40 - 20℃; for 18.0h; | EXAMPLE 6D tert-butyl 4-(7-cyano-1-oxo-1,3-dihydroisoindol-2-yl)piperidine-1-carboxylate To a solution of EXAMPLE 6C (300 mg) in tetrahydrofuran (2 mL) and N,N'-dimethylformamide (2 mL) was added tert-butyl 4-aminopiperidine-1-carboxylate (320 mg,) in N,N'-dimethylformamide (2 mL) and tetrahydrofuran (2 mL) at -40 C. The solution was warmed to ambient temperature over 2 hours, and stirred for 16 hours. The solvent was removed, and the concentrate was partitioned between ethyl acetate and water. The extract was washed with brine and concentrated, and the concentrate was purified by flash chromatography on silica gel with 80% ethyl acetate in hexanes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
[[00187]] To an oven dried 250 mL round bottom flask with a stir bar was added 3.00 g (12.4 mmol) of 4-hydroxy-6- bromocoumarin and 25.0 mL of dry [CH2C12. TO] this was added 2.25 mL (16.1 mmol) of triethylamine, and the resultant solution cooled to-10 [C] in an ice/sat NaCl bath. Triflic anhydride was then added dropwise (2.80 mL, 16.6 mmol) and the reaction. stirred at this temp under N2 for 2 h. After this time, the reaction solution was allowed to warm to rt, and was then diluted with 120 mL of 1: 1 [ETHER/HEXANE.] The mixture was then poured over a bed of silica gel to remove the fine white precipitate and the cake rinsed with 1: 1 ether/hexane. Evaporation of the filtrate afforded 4.30 g of a yellow solid. This material was then added to a 500 mL rb flask with a stir bar and 100 mL THF was added. To this was added 2.40 g (12.0 mmol) of [4-AMINO-PIPERIDINE-1-CARBOXYLIC] acid tert-butyl ester and the reaction mixture allowed to stir for 5 h. After this time the solvent was evaporated down and the resultant material taken up in 1: 1 EtOAc/hexanes and loaded onto a plug of silica gel. Elution with the same mixture afforded the title product as a white [SOLID. 1H] NMR (300 MHz, [DMSO-D6)] ppm 1.42 (m, 11 H) 1.89 (s, 2 H) 2.89 (m, 2 H) 3.75 (m, [1] H) 3.99 (m, 2 H) 5.37 (m, [1] H) 7.29 (m, 2 H) 7.74 (m, [1] H) 8.40 (m, 1 H); MS (DCI/NH3) m/z 425 [M+H] [+.] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.2% | With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; for 18h;Reflux; | <strong>[19064-24-5]1,3-difluoro-2-nitrobenzene</strong> (3.000 g, 18.857 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (3.777 g, 18.857 mmol), potassium carbonate (3.127 g, 22.629 mmol) and potassium iodide (0.031 g, 0.189 mmol) were dissolved in N,N-dimethylformamide (150 mL) at room temperature, after which the resulting solution was heated under reflux for 18 hours, and then a reaction was finished bylowering a temperature to room temperature. Solvent was removed from the reaction mixture under reduced pressure, after which water was poured into the resulting concentrate, and then an extraction was performed with ethyl acetate. An organic layer was washed with saturated sodium chloride aqueous solution, then dehydrated with anhydrous magnesium sulfate, then filtered, and then concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (SiO2, 40 g cartridge; ethyl acetate/hexane = 0 to 40%) and concentrated to obtain a title compound (4.300 g, 67.2%) in a red solid form. |
With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 6h; | 5: 4-(3-Fluoro-2-nitro-phenylamino)-piperidine-l-carboxylic acid tert-butyl ester l,3-Difluoro-2-nitro-benzene (31 mmol) and 4-amino-l-Boc piperidine (31 mmol) were dissolved in DMF (50 rnL) and K2CO3 (50 mmol) was added. The mixture was stirred at 70 C for 6h, then it was cooled and poured into brine and extracted x3 with ethyl acetate. The combined organic phases were washed x3 with brine, dried on MgSO4, filtered and evaporated. The crude product was used without further purification. | |
With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 6h; | 5: 4-(3-Fluoro-2-nitro-phenylamino)-piperidine-l-carboxylic acid tert-butyl ester l,3-Difluoro-2-nitro-benzene (31 mmol) and 4-amino-l-Boc piperidine (31 mmol) were dissolved in DMF (50 rnL) and K2CO3 (50 mmol) was added. The mixture was stirred at 70 C for 6h, then it was cooled and poured into brine and extracted x3 with ethyl acetate. The combined organic phases were washed x3 with brine, dried on MgSO4, filtered and evaporated. The crude product was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
B1. Tert -butyl 4-([2-(methoxycarbonyl)-5-phenylthiophen-3-yl]carbamoyl}amino)piperidine- 1 -carboxylateTo a solution of triphosgene (421 mg) in THF (15 ml) under nitrogen atmosphere was added at 0C a solution of 3-amino-5-phenylthiophene-2-carboxylate (1.00 g) in THF (10 ml) within 2 h. The mixture was stirred at 0C for 1 h and at RT for additional 14 h. The resulting suspension was cooled to 0C and a solution of tert-butyl 4-aminopiperidine-1 -carboxylate (867 mg) in THF (10 ml) was added drop- wise. After 15 min at 0C DIPEA (1.75 ml) was slowly added. The reaction mixture was stirred for 15 min at 0C and for 2.5 h at RT and then washed with an aqueous sodium chloride solution (5 % w/w, three times with 20 ml each) and with brine (20 ml). The organic layer was dried over magnesium sulfate. All volatile materials were removed in vacuo to give the title compound as a solid. MS: calc: C23H29N3O5S (459.56) found: [MH+] = 459.98; [MNa+] = 482.22 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With benzotriazol-1-ol; dicyclohexyl-carbodiimide; In tetrahydrofuran; dichloromethane; | To a flask containing 6.4 g (32.1 mmol) of <strong>[4385-77-7]3-pyrid-3-ylbenzoic acid</strong> (Maybridge), 4.6 g (34 mmol) HOBt-hydrate, was added dry THF (40mL) and methylene chloride (400mL). To the heterogeneous mixture was added 6.88 g (33.4 mmol) Dicyclohexylcarbodiimide (DCC), followed by 6.75 g (33.7 mmol) of 4-Amino- 1-Boc-piperidine (Aldrich). The reaction mixture became nearly homogeneous before a fine white precipitate is observed. The reaction was followed by TLC (5%MeOH/CH2C12) until complete. Upon completion, the reaction mixture was filtered and the filtrate concentrated to dryness. The residue was triturated with hot EtOAc (180mL), filtered and the solids washed with cold EtOAc. The filtrate was then concentrated to dryness, and re-dissolved in 30-40mL CH2C12 before adding 21 g of Si02 and concentrating the mixture to dryness. The solids were eluted on 220 g of Si02 starting with 1 :1 Et0Ac/CH2C12 and increasing to 100% EtOAc. The desired fractions were combined, heptane was added, and the solution concentrated to give 10.4 g (85%) of the Boc-piperidine Amide A as a white solid. 'HNMR (300 MHz, CDC13) = 8.85 (s, 1H), 8.61 (dd, J-4.7, 3.1 Hz, 1H), 7.98 (s, 1H), 7.90 (m, 1H), 7.72 (m, 2H), 7.54 (t, J-8Hz, 1H), 7.38 (m, 1H), 6.17 (d, J=8 Hz, 1H), 4,14 (br m, 3H), 2.91 (t, J=7Hz, 2H), 2.05 (d, J=7Hz, 2H), 1.49 (s,9H). MS(ESI+) - 382 (M+l), 282 (M- Boc+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With dmap; benzotriazol-1-ol; 1,2-dichloro-ethane; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;Inert atmosphere; | <strong>[1570-05-4]3,4-bis(benzyloxy)benzoic acid</strong> (12) (50.0 mg, 0.14 mmol) was dissolved in dry DMF (2 mL), and then treated with 4-amino-1-Boc-piperidine (34.0 mg, 0.17 mmol), HOBT (22.9 mg, 0.17 mmol), EDC (0.030 mL, 0.17 mmol), TEA (0.058 mL, 0.42 mmol), and DMAP (1.2 mg, 0.01 mmol). The reaction mixture was stirred at room temperature for 16 h under an argon atmosphere and the solvent was removed. The crude compound was purified by column chromatography on silica gel using hexane/AcOEt 40:60 as eluent. Yield 55percent. Mp 158?160 °C. 1H NMR (CDCl3), (delta) 1.46?1.58 (m, 2H), 1.50 (s, 9H, CH3), 1.94?1.99 (d, 2H, CH2, J = 10.63), 2.82?2.94 (t, 2H, J = 11.91), 4.02?4.08 (d, 3H, J = 11.90), 5.18 (s, 4H, CH2O) 5.78?5.82 (br s, NH), 6.86?7.46 (m, 13H, ArH). 13C NMR (CDCl3), 166.2, 154.7, 151.6, 148.7, 136.8, 136.6, 128.6, 128.0, 127.6, 127.5, 127.2, 119.9, 114.0, 113.6, 79.7, 71.3, 71.0, 47.2, 42.7, 32.2,28.5; Anal. C31H36N2O5 (C, H, N). HPLC-GS 100percent. MS m/z 517 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.43 g | To a stirred solution of 4-amino-piperidine-l-carboxylic acid tert-butyl ester (0.3g,1.5mmol) and 4-methoxy-3-nitro-benzaldehyde (0.27g,1.5mmol) in ethanol (6ml) was added titanium isopropoxide (0.3ml) at 0C and stirred. The reaction was gradually brought to RT and stirred for 16h. Then sodiumborohydride (0.057g, 1.5mmol) was added followed by catalytic amount of acetic acid and stirred for 3h at ambient temperature. Upon completion, the solvents in the reaction were distilled out. The crude was diluted with 10% MeOH-CH2Cl2 solution and washed with water. The organic layer was then dried over sodium sulfate and concentrated under reduced pressure. The obtained crude was taken was purified by (100-200mesh) silicagel column chromatography eluting the required compound with 70% EtOAc-petether as an yellow solid (0.43g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; N-ethyl-N,N-diisopropylamine; bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate; In dichloromethane; at 20℃; for 24h;Molecular sieve; | To 2 g, 10 mmol (1 equiv.)of 4-amino-1-boc-piperidine (3) dissolved in 30 mL DCM was added 2.47 g, 10 mmol (1 equiv.) of <strong>[17794-48-8]N-(3-(trifluoromethyl)benzoyl)glycine</strong>, 4.66 g, 10 mmol (1 equiv.) of PyBroP, 1 g, 8 mmol (0.8 equiv.) of 4-dimethylaminopyridine, 5.10 mL, 30 mmol (3 equiv.) of N,N-diisopropylethylamine and molecular sieves 4 . The reaction mixture was stirred for 24 h at room temperature. The product was partitioned between DCM/1M NaOH. The organic layer was washed with brine, dried over MgSO4 and evaporated. The intermediate was purified by column chromatography (50/50 EtOAc in DCM). 1H NMR (400 MHz, CDCl3) delta: 8.11 (s, 1H), 8.00 (d, J = 8.0 Hz, 2H), 7.76 (d, J = 7.6 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.14 (d, J = 7.6 Hz, 1H), 4.17 (d, J = 4.8 Hz, 2H), 4.00-3.92 (m, 3H), 2.89 (t, J = 11.6 Hz, 2H), 1.91 (d, J = 2.8 Hz, 2H), 1.45-1.37 (m, 11H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 80℃; for 16h; | To a stirred solution of 1 -chloro-2-fluoro-3-nitrobenzene (3.64 g, 20.72 mmol, 1 eq) in DMF (42.0 mL) was added DIPEA (8.7 mL, 49.93 mmol, 2.4 eq) followed by addition of tert-butyl 4- aminopiperidine-1-carboxylate (5.0 g, 24.96 mmol, 1.2 eq). The resulting reaction mixture was stirred at 80 00 for 16 h, then poured into 10% aq. citric acid solution and the organic components were extracted into EtOAc. The organic layer was washed with water and brine. The combined organic layers were dried over anhyd. Na2504 and concentrated under reduced pressure to afford the desired compound 3 (4.2 g, 47%) as a solid. MS (ES+) 356.2 [M+H]. |
With potassium carbonate; | Step 1. Synthesis of tert-butyl 4-((2-chloro-6-nitrophenyl)amino)piperidin-1-carboxylate (GEN1-291-1) Tert-butyl 4-aminopiperidine-1-carboxylate (661 mg, 3.3 mmol) was added to a suspension of <strong>[2106-49-2]1-chloro-2-fluoro-3-nitrobenzene</strong> (526.62 mg, 3 mmol), K2CO3 (828 mg, 6 mmol) and KI (50 mg, 0.3 mmol) in DMF (20 ml) at room temperature. The resulting mixture was then stirred at 80C for 3 hours. The reaction mixture was quenched by the addition of brine (100 mL). It was extracted with EtOAc (30 mL*3). The combined organic phase was washed with brine (30 mL*2), dried over anhydrous Na2SO4, and it was concentrated to obtain the desired compound (900 mg). The crude product was used directly in the next step. MS (ESI): Rt = 1.81 min, m/z 378.0 [M+Na]+; Purity: 97.23% 254 nm, 96.42% 214 nm. | |
With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 80℃; for 3h; | Tert-butyl 4-aminopiperidine-1-carboxylate (661 mg, 3.3 mmol) was added to a suspension of <strong>[2106-49-2]1-chloro-2-fluoro-3-nitrobenzene</strong> (526.62 mg, 3 mmol), K2CO3 (828 mg, 6 mmol) and KI (50 mg, 0.3 mmol) in DMF (20 ml) at room temperature. The resulting mixture was then stirred at 80C for 3 hours. The reaction mixture was quenched by the addition of brine (100 mL). It was extracted with EtOAc (30 mL*3). The combined organic phase was washed with brine (30 mL*2), dried over anhydrous Na2SO4, and it was concentrated to obtain the desired compound (900 mg). The crude product was used directly in the next step. MS (ESI): Rt = 1.81 min, m/z 378.0 [M+Na]+; Purity: 97.23% 254 nm, 96.42% 214 nm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | To a stirred solution of tert-butyl 4-aminopiperazine-l-carboxylate (578 mg, 2.8 mmol, 1.0 equiv) in DMF (05 mL) was added HATU (2128 mg, 5.6 mmol, 2.0 equiv) at RT and stirred for 10 minutes. Then <strong>[1174321-06-2]5-(difluoromethyl)pyrazine-2-carboxylic acid</strong> (500 mg, 2.8 mmol, 1.0 equiv) was added followed by the addition of DIPEA (1.5 mL, 8.4 mmol, 3.0 equiv). The resulting reaction mixture was allowed to stir at RT for ovemigiit. Product formation was confirmed by LCMS. the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL c 2). The combined organic layer was washed with water (30mL), brine solution (30 mL x 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure, to obtain tert-butyl 4-(5-(difluoromethyl)pyrazine-2-carboxamido)piperazine-l -carboxylate (400 mg, 39 % Yield) as a brown solid. LCMS 358.2 [ M i l : NMR (400 MHz, DMSCWe) d 10.13 (s, 1 H), 9.24 (s, 1 H), 8.99 is. 1 H), 3.34 - 3.49 (m, 4 H), 2.84 (t, .7=5.04 Hz, 4 H), 1.41 (s, 9H). |
Tags: 87120-72-7 synthesis path| 87120-72-7 SDS| 87120-72-7 COA| 87120-72-7 purity| 87120-72-7 application| 87120-72-7 NMR| 87120-72-7 COA| 87120-72-7 structure
A105977 [189819-75-8]
tert-Butyl 4-aminopiperidine-1-carboxylate hydrochloride
Similarity: 0.98
A168393 [147539-41-1]
tert-Butyl 4-(methylamino)piperidine-1-carboxylate
Similarity: 0.98
A172639 [301225-58-1]
tert-Butyl 4-(propylamino)piperidine-1-carboxylate
Similarity: 0.98
A191686 [108612-54-0]
tert-Butyl methyl(piperidin-4-yl)carbamate
Similarity: 0.98
A915900 [534595-51-2]
1-Boc-4-(isopropylamino)piperidine
Similarity: 0.98
A105977 [189819-75-8]
tert-Butyl 4-aminopiperidine-1-carboxylate hydrochloride
Similarity: 0.98
A168393 [147539-41-1]
tert-Butyl 4-(methylamino)piperidine-1-carboxylate
Similarity: 0.98
A172639 [301225-58-1]
tert-Butyl 4-(propylamino)piperidine-1-carboxylate
Similarity: 0.98
A191686 [108612-54-0]
tert-Butyl methyl(piperidin-4-yl)carbamate
Similarity: 0.98
A915900 [534595-51-2]
1-Boc-4-(isopropylamino)piperidine
Similarity: 0.98
A105977 [189819-75-8]
tert-Butyl 4-aminopiperidine-1-carboxylate hydrochloride
Similarity: 0.98
A168393 [147539-41-1]
tert-Butyl 4-(methylamino)piperidine-1-carboxylate
Similarity: 0.98
A172639 [301225-58-1]
tert-Butyl 4-(propylamino)piperidine-1-carboxylate
Similarity: 0.98
A191686 [108612-54-0]
tert-Butyl methyl(piperidin-4-yl)carbamate
Similarity: 0.98
A915900 [534595-51-2]
1-Boc-4-(isopropylamino)piperidine
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