Structure of 161609-84-3
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CAS No. : | 161609-84-3 |
Formula : | C14H16N2O2 |
M.W : | 244.29 |
SMILES Code : | N#CC1CCN(C(OCC2=CC=CC=C2)=O)CC1 |
MDL No. : | MFCD04115340 |
InChI Key : | UGKXZMBTBFELAS-UHFFFAOYSA-N |
Pubchem ID : | 22028286 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 18 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.43 |
Num. rotatable bonds | 4 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 71.18 |
TPSA ? Topological Polar Surface Area: Calculated from |
53.33 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.52 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.83 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.03 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.59 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.86 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.97 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.49 |
Solubility | 0.79 mg/ml ; 0.00323 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.57 |
Solubility | 0.657 mg/ml ; 0.00269 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.08 |
Solubility | 0.205 mg/ml ; 0.000838 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) |
Yes |
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 |
-6.49 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) |
2.59 |
* 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 |
---|---|---|
86% | With lithium hexamethyldisilazane; In tetrahydrofuran; at -78 - 20℃; for 5h; | Benzyl 4-((2-chloroethoxy)methyl)-4-cyanopiperidine-1-carboxylate. A solution of <strong>[161609-84-3]benzyl 4-cyanopiperidine-1-carboxylate</strong> (10.0 g, 410 mmol) and 2-chloroethyl chloromethyl ether (6.3 mL, 49.2 mmol) in THF (80 mL) was cooled to -78 C. To this solution was added drop wise LiHMDS (50 mL, 50 mmol, 1N in THF) and the resulting mixture was gradually warmed to room temp over 5 h. The reaction was quenched with water and the organic phase was washed with brine, dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (1:1 EtOAc/hexane) to give the title compound as yellow oil (11.9 g, 86% yield). 1H NMR (300 MHz, CDCl3) delta: 7.33-7.31 (5H, m), 5.10 (2H, d, J=5.9 Hz), 4.21 (2H, bs), 3.79-3.76 (2H, m), 3.63-3.60 (2H, m), 3.52-3.51 (2H, m), 3.09 (2H, bs), 1.96-1.92 (2H, m), 1.55-1.51 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With lithium hexamethyldisilazane; In tetrahydrofuran; at -78 - 20℃; for 18.5h; | Benzyl 4-(4-(tert-butyldimethylsilyloxy)butyl)-4-cyanopiperidine-1-carboxylate. To a stirred solution of <strong>[161609-84-3]benzyl 4-cyanopiperidine-1-carboxylate</strong> (10 g, 410 mmol) and iodo-tert-butyldimethylsilane butane (12.6 mL, 49 mmol) in THF (80 mL) cooled to -78 C. was added LiHMDS (50 mL, 50 mmol, 1M in THF) dropwise over 30 min. The resulting mixture was stirred while gradually warming to room temperature for 18 h. After quenching with water, the organic phase was diluted with EtOAc and washed with water, brine and dried (Na2SO4). After concentration, the residue was purified by flash chromatography (1% to 20% EtOAc/hexane) to give the title compound as yellow oil (11.88 g, 67% yield). 1H NMR (300 MHz, CDCl3) delta: 7.34-7.28 (5H, m), 5.09 (2H, s), 4.17 (2H, bs), 3.59 (2H, t, J=5.3 Hz), 3.07 (2H, bs), 1.89 (2H, d, J=13.2 Hz), 1.53 (6H, bs), 1.43-1.34 (2H, m), 0.85 (9H, s), 0.01 (6H, s). LCMS (M+H): 431.20. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetyl chloride; In chloroform; at 0 - 20℃; for 1h; | (1) To a mixed solution of ethanol (76 g) and chloroform (110 mL) was added dropwise acetyl chloride (107 mL) under ice-cooling. After stirring for 30 min, a solution of <strong>[161609-84-3]1-benzyloxycarbonyl-4-cyanopiperidine</strong> (12.2 g) in chloroforml (10 mL) was added under ice-cooling. The mixture was stirred at room temperature for 1 hr. The reaction solution was concentrated under reduced pressure to give 1-benzyloxycarbonyl-4-(ethoxycarbimidyl)piperidine hydrochloride (15.4 g) as a white solid.(2) The above-mentioned compound (3.07 g) and 2-amino-5-fluorophenol (1.64 g) were dissolved in ethanol (60 mL) and the mixture was heated under reflux for 10 hr. The reaction solution was concentrated under reduced pressure, and 1.0 mol/L hydrochloric acid was added to the residue. The mixture was extracted with ethyl acetate. The extract solution was washed successively with a saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to give 1-benzyloxycarbonyl-4-(6-fluoro-2-benzoxazolyl)piperidine (2.51 g) as a brown solid.(3) In the same manner as in Example 33(3) and using the above-mentioned compound (2.50 g), 4-(6-fluoro-2-benzoxazolyl)piperidine (1.46 g) was obtained as a brown solid.(4) In the same manner as in Example 29(1) and using the above-mentioned compound (529 mg) and the title compound (601 mg) of Reference Example 3, 3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(6-fluoro-2-benzoxazolyl)piperidino]-2-pyrrolizinylcarbonyl}-1,3-thiazolidine (879 mg) was obtained as a white solid.(5) The above-mentioned compound (874 mg) was dissolved in ethanol (3 mL) in a 7.4 mol/L hydrochloric acid - ethanol solution (1.5 mL) and the mixture was stirred at room temperature for 14 hr. The reaction solution was concentrated under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution was added to the residue. The mixture was extracted with chloroform and the extract solution was dried and concentrated under reduced pressure. The residue was purified by silica gel chromatography and crystallized from diethyl ether to give the title compound (213 mg) as a white powder.1H-NMR(DMSO-d6)delta 1.52-1.63(1H,m), 1.70-1.87(2H,m), 2.02-2.23(4H,m), 2.25-2.36(1H,m), 2.68-3.12(8H,m), 3.57-3.98(3H,m), 4.40-4.71(2H,m), 7.71-7.27(1H,m), 7.66-7.76(2H,m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With n-butyllithium; diethylamine; In tetrahydrofuran; hexane; at -78 - 0℃; for 25h; | Diethylamine (1.4 ml) was dissolved in tetrahydrofuran (26 ml), and a solution (1.59 M, 42 ml) of n-butyllithium in hexane was added dropwise at -78C. The mixture was stirred at 0C for 30 min and cooled to -78C. A solution (26 ml) of 2-methylbenzoic acid (4.1 g) in tetrahydrofuran was added dropwise to the reaction solution. The mixture was stirred at 0C for 30 min and cooled to -78C. A solution (26 ml) of <strong>[161609-84-3]1-benzyloxycarbonyl-4-cyanopiperidine</strong> (7.2 g) in tetrahydrofuran was added dropwise to the reaction solution, and the mixture was stirred at -78C for one day. After the completion of the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, and the solvent was concentrated. The obtained residue was subjected to silica gel column chromatography. A chloroform:methanol=30:1 effluent fraction was concentrated, and diisopropyl ether was added to the precipitated crystals. The crystals were collected by filtration. Recrystallization from isopropanol gave 3-(1-benzyloxycarbonylpiperidin-4-yl)-2H-isoquinolin-1-one (1.2 g) as white crystals. melting point: 179-181C. 3-(1-Benzyloxycarbonylpiperidin-4-yl)-2H-isoquinolin-1-one (1.2 g) was suspended in chloroform (10 ml), and a solution (5 ml) of hydrobromic acid in acetic acid was added dropwise. After the completion of the reaction, the solvent was concentrated, and acetone was added to the obtained residue. The precipitated crystals were collected by filtration to give 3-(piperidin-4-yl)-2H-isoquinolin-1-one hydrobromide (1.1 g). melting point: >270C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With n-butyllithium; diisopropylamine; In tetrahydrofuran; hexane; water; at -78 - 0℃; for 25h; | Diisopropylamine (6.2 ml) was dissolved in tetrahydrofuran (50 ml), and a solution (1.59 M, 28 ml) of n-butyllithium in hexane was added dropwise at -78C. The mixture was stirred at 0C for 30 min and cooled to -78C. A solution (20 ml) of 2-benzylbenzoic acid (4.2 g) in tetrahydrofuran was added dropwise to the reaction solution, and the mixture was stirred at 0C for 30 min and cooled to - 78C. A solution (20 ml) of <strong>[161609-84-3]1-benzyloxycarbonyl-4-cyanopiperidine</strong> (5.3 g) in tetrahydrofuran was added dropwise to the reaction solution, and the mixture was stirred at -78C for one day. After the completion of the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, and the solvent was concentrated. The obtained residue was subjected to silica gel column chromatography. A chloroform:methanol=40:1 effluent fraction was concentrated, and diisopropyl ether was added to the precipitated crystals. The crystals were collected by filtration to give 3-(1-benzyloxycarbonylpiperidin-4-yl)-4-phenyl-2H-isoquinolin-1-one (2.1 g) as white crystals (melting point: 276-278C). 3- (1-Benzyloxycarbonylpiperidin-4-yl)-4-phenyl-2H-isoquinolin-1-one (2.0 g) was suspended in chloroform (10 ml), and a solution (5 ml) of hydrobromic acid in acetic acid was added dropwise. After the completion of the reaction, the solvent was concentrated, and acetone was added to the obtained residue. The precipitated crystals were collected by filtration to give 4-phenyl-3-(piperidin-4-yl)-2H-isoquinolin-1-one hydrobromide (1.5 g) . melting point: >270C.1H-NMR(DMSO-d6) d: 1.71-1.75(2H,m), 2.05-2.15(2H,m), 2.54-2.68(2H,m), 3.23-3.29(2H,m), 6.84(1H,d,J=8Hz), 7.26(2H,d,J=6Hz), 7.42-7.58(5H,m), 8.20-8.22(1H,m), 8.69(1H,brS), 11. 09 (1H,brS). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydroxylamine hydrochloride; sodium carbonate; In ethanol; dichloromethane; water; | b. 1-Benzyloxycarbonyl-4-piperidinecarboxamideoxime A solution of hydroxylamine hydrochloride (0.340 g) in water (5 mL) was treated with sodium carbonate (0.26 g), followed by a solution of <strong>[161609-84-3]1-benzyloxycarbonyl-4-cyanopiperidine</strong> (1.00 g) in ethanol (10 mL). The resulting mixture was heated under reflux for 3 hours. Additional hydroxylamine hydrochloride (0.340 g) and sodium carbonate (0.26 g) were added, and the mixture was heated at reflux for an additional 14 hours. The mixture was cooled and evaporated. The semisolid residue was suspended in dichloromethane, filtered and the solid product dried to afford the carboxamideoxime as a white solid (0.70 g); mp 111-113 C.; NMR: 8.83 (s,1), 7.35 (m, 5), 5.33 (broad s, 2), 5.07 (s,2), 4.02 (broad d, 2, J=13.1), 2.80 (broad, 2), 2.19 (m, 1), 1.69 (broad d, 2, J=11.0), 1.55-1.42 (m, 2); MS: m/z=278(M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In sodium carbonate; | a. 1-Benzyloxycarbonyl-4-cyanopiperidine A solution of 4-cyanopiperidine (5.00 g) in 10% aqueous sodium carbonate solution (100 mL) was cooled to 0 C. and treated dropwise with benzyl chloroformate (9.30 g). The resulting mixture was warmed to room temperature and stirred for 16 hours. The biphasic mixture was extracted with ethyl acetate. The organic extracts were washed with water and brine, combined, dried, filtered and evaporated. The resulting oil was purified by chromatography, with ethyl acetate:hexane (gradient 1:4, 1:2) as eluent, to give the protected piperidine as a clear oil (9.64 g); MS: m/z=245(M+1); NMR (CDCl3): 7.35 (m, 5), 5.13 (s,2), 3.71 (m, 2), 3.44 (m, 2), 2.81 (m, 1), 1.88-1.60 (m, 4). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; chloroform; | (1) Acetyl chloride (180 mL) was dropwise added to a mixture of ethanol (160 mL) and chloroform (180 mL) under ice-cooling. After the mixture was stirred for 30 min, a solution of <strong>[161609-84-3]1-benzyloxycarbonyl-4-cyanopiperidine</strong> [product of Example 298 (2), 20.6 g] in chloroform (180 mL) was added thereto under ice-cooling. The mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure to give 1-benzyloxycarbonyl-4-(ethoxycarbonimidoyl)piperidine hydrochloride (28.7 g) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trichlorophosphate; In pyridine; | (2) The above-mentioned compound (33.3 g) and imidazole (17.3 g) were dissolved in pyridine (350 mL), and phosphorus oxychloride (47 mL) was added thereto under ice-cooling. The mixture was stirred at room temperature for 3 hr. The saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture under ice-cooling, and the mixture wasextracted with chloroform. The extract was washed with brine, dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to give 1-benzyloxycarbonyl-4-cyanopiperidine (20.6 g) as a slightly yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; sodium hydroxide; sulfuric acid; triethylamine hydrochloride; trifluoroacetic acid; In 1-methyl-pyrrolidin-2-one; water; tert-butyl alcohol; | (3) The above-mentioned compound (1.42 g) was dissolved in N-methyl-2-pyrrolidone (60 mL), and sodium azide (1.13 g) and triethylamine hydrochloride (1.24 g) were added thereto. The mixture was stirred at 150C for 6 hr. 1 mol/L Hydrochloric acid was added to the reaction mixture to adjust its pH to 1, and the mixture was extracted with ethyl acetate. 10% Aqueous sodium hydroxide solution was added to the extract, and the mixture was washed with diethyl ether. The aqueous layer was adjusted to pH 1 with concentrated hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was dried and concentrated under reduced pressure. Trifluoroacetic acid (6 mL), tert-butanol (0.900 g) and concentrated sulfuric acid (0.16 mL) were added to the residue, and the mixture was stirred at room temperature for 3 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with 2.5 mol/L aqueous sodium hydroxide solution and brine, dried, and concentrated under reduced pressure. The residue was purified by HPLC to give 1-benzyloxycarbonyl-4-(2-tert-butyl-2H-tetrazol-5-yl)piperidine (140 mg) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of <strong>[161609-84-3]benzyl 4-cyanopiperidine-1-carboxylate</strong> (20 g, 82 mmol) in methanol (150 mL) was added a solution of sodium methoxide in methanol (25wt%, 5.6 mL, 25 mmol) at room temperature. After 30 minutes, a solution of formic hydrazide (4.9 g, 82 mmol) in methanol (20 mL) was added and the reaction was heated to reflux for 24 hours, at which time sodium methoxide in methanol (25wt%, 5.6 mL, 25 mmol) and formic hydrazide (4.9 g, 82 mmol) was added. After 72 hours, the reaction was cooled to room temperature and quenched with acetic acid (3.0 mL, 49 mmol) and concentrated. The resulting residue was dissolved in ethyl acetate, washed with water, saturated sodium bicarbonate, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography eluting with 1-35% IPA/DCM. The appropriate fractions were combined and the solvent removed in vacuo to give benzyl 4-(lH-1,2,4-triazol-3-yl)piperidine-1-carboxylate as a solid. MS (M+Eta1"): 287.2; 1H-NMR (400 MHz, CDCl3): delta 11.13 (s, IH), 8.06 (s, IH), 7.36-7.31 (m, 5H), 5.15 (s, 2H), 4.24 (br.s, 2H), 3.06-2.98 (m, 3H), 2.07-2.04 (m, 2H), 1.84-1.78 (m, 2H). | ||
To a solution of benzyl 4-cyanopiperidine-l-carboxylate (20 g, 82 mmol) in methanol (150 mL) was added a solution of sodium methoxide in methanol (25wt%, 5.6 mL, 25 mmol) at room temperature. After 30 minutes, a solution of formic hydrazide (4.9 g, 82 mmol) in methanol (20 mL) was added and the reaction was heated to reflux for 24 hours, at which time sodium methoxide in methanol (25wt%, 5.6 mL, 25 mmol) and formic hydrazide (4.9 g, 82 mmol) was added. After 72 hours, the EPO <DP n="138"/>reaction was cooled to room temperature and quenched with acetic acid (3.0 mL, 49 mmol) and concentrated. The resulting residue was dissolved in ethyl acetate, washed with water, saturated sodium bicarbonate, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography eluting with 1-35% IPA/DCM. The appropriate fractions were combined and the solvent removed in vacuo to give benzyl 4-(lH-l,2,4-triazol-3-yl)piperidine-l-carboxylate as a solid. MS (M+Eta+): 287.2; 1H-NMR (400 MHz, CDCl3): delta 11.13 (s, IH), 8.06 (s, IH), 7.36-7.31 (m, 5H), 5.15 (s, 2H), 4.24 (br.s, 2H), 3.06-2.98 (m, 3H), 2.07-2.04 (m, 2H), 1.84-1.78 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With sodium azide; zinc dibromide; In water; isopropyl alcohol; at 120℃; for 72h; | A mixture of <strong>[161609-84-3]4-cyano-piperidine-1-carboxylic acid benzyl ester</strong> (0.73 g, 3.0 mmol), sodium azide (0.39 g, 6.0 mmol) and zinc bromide (0.33 g, 1.5 mmol) in 2-propanol (5 mL) and water (10 mL) was stirred at 120 C. for 3 days into a pressure tube. The reaction mixture was then partitioned between aqueous 3.0N HCl (1.5 mL) and ethyl acetate and then stirred vigorously until 2 clear phases were obtained. Aqueous layer was then extracted with ethyl acetate and combined ethyl acetate layers dried over Na2SO4, filtered, and the solvent evaporated in vacuo to yield a crude residue. The residue was dissolved in ethyl acetate (10 mL) and washed with 0.25N aqueous sodium hydroxide. Aqueous layer was acidified to pH=1 with aqueous 3.0N HCl and extracted with ethyl acetate. Ethyl acetate layer was dried over Na2SO4, filtered, and the solvent evaporated in vacuo to yield a crude gum. The gum was purified via flash chromatography (4% methanol in dichloromethane) to yield 4-(1H-Tetrazol-5-yl)-piperidine-1-carboxylic acid benzyl ester as a gum (1.14 g, 66%).1H NMR (400 MHz, CDCl3) delta 7.36-7.29 (m, 5H), 5.16 (br s, 2H), 4.27-4.24 (m, 2H), 3.34-3.27 (m, 1H), 3.06-2.98 (m, 2H), 2.16-2.06 (m, 2H), 1.82-1.77 (m, 2H)LC/MS (m/z) [M+1]+ 288.3 (calculated for C14H17N5O2, 287.32). |
1.45 g | With sodium azide; ammonium chloride; In N,N-dimethyl-formamide; at 90℃; for 24h; | NaN3 (1.7 g, 26.14 mmol) and NH4Cl (1.75 g, 32.7 mmol) were added to the solution of <strong>[161609-84-3]benzyl 4-cyanopiperidine-1-carboxylate</strong> (1.6 g, 26.14 mmol) in DMF (16 mL) and stirring was continued at 90 C. for 24 h. The reaction mixture was quenched with 10% aqueous citric acid solution, extracted with EtOAc, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 1.45 g of the title compound. MS (ESI): m/z 288.5 (M+H). |
4.6 g | With sodium azide; ammonium chloride; In N,N-dimethyl-formamide; at 100℃; for 15h; | NH4Cl (3.28 g, 61.41 mmol, 3.00 equiv.)and NaN3 (3.99 g, 61.41 mmol, 3.00 equiv.) were added toa solution of compound 1(5.00 g, 20.47 mmol, 1.00 equiv.)in DMF (50.00 mE) and the resulting mixture was stirred at 1000 C. for 15 hrs. The reaction mixture was poured into H20 (300 mE), and extracted with EtOAc (200 mL*3). Combined the organic phases were washed with brine (100 mL*5), dried over Na2504, filtered. Concentration under reduced pressure resulted in 4.6 g of 2 as light yellow oil which was submitted to the next step with out further purification. ?H NMR (400 MHz, CDC13): oe ppm 7.34-7.28 (m, 5H), 5.15 (s, 1H), 4.25-4.21 (m, 2H), 3.32-3.30 (m, 1H), 3.29-3.26 (m, 2H), 2.13-2.04 (m, 2H), 1.88-1.79 (m, 2H). LCMS (ESI): mlz: [M+Na] calcd for C,4H,7N5O2Na; 310. 14. found 310.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | General procedure AF: Alkylation a to a nitrileA base such as LiHMDS, NaHMDS, KHMDS, LDA, NaH (1 to 5 equiv, preferably 1.5 equiv) is added to a nitrile compound in a suitable organic solvent such as THF, 1,4-dioxane, Et20, hexane, DMF, DMA (preferably THF) at about -78 C to rt (preferably about -78 C to 0 C) and stirred for 0.5 to 2 h (preferably about 1 h). An alkylating agent (1 to 5 equiv, preferably 1.5 equiv) is added and the mixture stirred for 30 min to 24 h (preferably about 16 h). To the mixture is is added an aqueous salt solution (preferably saturated NH4C1) and the mixture is extracted with a suitable organic solvent such as EtOAc, DCM, Et20 (preferably DCM). The organic layer is isolated and may be optionally washed in no particular order with water and/or aqueous solutions containing an acid (such as HC1, AcOH or NH4C1) and/or aqueous solutions containing a base (such as NaHC03, Na2C03, NaOH, KOH or NH4OH) and/or aqueous solutions containing an inorganic salt (such as NaCl Na2S03 or Na2S2C>3). The organic solution may then be optionally dried with a drying agent (such as anhydrous MgS04 or Na2S0 ), filtered and concentrated in vacuo to give the targeted compound. Alternatively, the residue obtained by concentration of the organic extracts may be purified by HPLC or column chromatography to provide the target compound.Illustration of General Procedure AF:Preparation No.AF.l: Benz l 4-cyano-4-methylpiperidine-l-carboxylateLiHMDS (47.6 mL, 47.6 mmol) was added dropwise via syringe to the mixture of benzyl 4- cyanopiperidine-l-carboxylate (8.00 g, 31.8 mmol, [Oakwood]) in THF (50 mL) at about -78 C and stirred for about 1 h. Mel (6.76 g, 47.6 mmol) was added dropwise via syringe at about -78 C and the mixture was stirred overnight at rt. The solution was cooled to 0 C and saturated aqueous NH4C1 (200 mL) was added. The mixture was extracted with DCM (3x300 mL). The combined organic extracts were dried over anhydrous Na2S04, filtered and concentrated in vacuo. The sample was deposited onto silica gel and purified by column chromatography eluting with 10: 1 pet ether/EtOAc to give benzyl 4-cyano-4-methylpiperidine-l-carboxylate (6.6 g, 74%): LC/MS (Table 2, Method i) Rt = 2.03 min; MS m/z: 259 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | Preparation No. -(aminomethyl)-4-cyanopiperidine-l-carboxylateTo a mixture of benzyl 4-cyanopiperidine-l-carboxylate (1.0 g, 4.0 mmol, Oakwood) in THF (50 mL) at about -78 C was added LiHMDS (1.0 M solution in THF, 6.14 mL, 6.14 mmol) dropwise via syringe. The mixture was stirred for about 1 h. Paraformaldehyde (0.25 g, 8.2 mmol) was added in one portion and the mixture was stirred overnight at rt. The mixture was concentrated in vacuo and the residue was purified by preparative TLC (1 :1 EtO Ac/pet ether) to give benzyl 4- cyano-4-(hydroxymethyl)piperidine-l-carboxylate (0.45 g, 35%): LC/MS (Table 2, Method k) Rt = 0.60 min; MS mix: 21 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | General procedure: To a solution of the nitrile / sulfone (1.2 mmol) in THF (5 ml) at -78 oC (under an N2atmosphere) was added LiHMDS (1.2 mL of 1 M in THF, 1.2 mmol) dropwise and thereaction mixture was stirred at this temperature for 5 minutes. The heterocycle (1 mmol,1 eq.) was added at while the reaction mixture was at -78oC, the cooling bath wasremoved and the reaction mixture was stirred until the reaction was judged complete byLCMS analysis (generally 1 h). Solid KMnO4 (316 mg, 2 mmol, 2 eq.) and acetonitrile(1 ml) were added and the reaction mixture was stirred at room temperature until thereaction was judged complete by LCMS analysis (generally 4-6 h). The reaction mixturewas poured into saturated aqueous NaHCO3 and the layers separated. The aqueous layerwas then extracted with EtOAc (3x). All organics were combined, washed with water,brine, dried (Na2SO4) and evaporated to dryness. Purification by silica gel columnchromatography (12 g Isco silica cartridge) using hexanes and EtOAc gave the desiredproducts. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.6 g | General procedure: DIPEA (71 mg, 00.1 mL, 0.55 mmol) was added to a stirred solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (75 mg, 0.22 mmol) in DMF (1.5 mL) followed by addition of EDCl (63 mg, 0.33 mmol) and HOBt (32 mg, 0.24 mmol). After 10 minutes of stirring the reaction mixture, octahydro-1H-pyrido[1,2-a]pyrazine (46 mg, 0.33 mmol) was added and the resulting mixture was stirred for 16 h at 20-35 C. The reaction mixture was diluted with cold water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine solution. The ethyl acetate portion was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the crude compound, which was refluxed in hexane, filtered, and the filtrate was concentrated under reduced pressure to afford 45 mg of the title compound as a yellow solid. MS (ESI): m/z 466.3 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With triethylamine; ethanaminium,N-(difluoro-lambda4-sulfanylidene)-N-ethyl-,tetrafluoroborate; In ethyl acetate; at 20℃; for 1h;Inert atmosphere; | General procedure: To a solution of the aldoxime or the amide (1.0 mmol) and Et3N (1.5mmol) in EtOAc (1 mL, 1 M) at r.t. was added XtalFluor-E8 (1.1 mmol)portionwise over ca. 2 min. The resulting solution was stirred at r.t.for 1 h. The reaction mixture was quenched with sat. aq Na2CO3 and extracted with CH2Cl2 (2 × 10 mL). The combined organic layers were washed with H2O and brine, dried (MgSO4), and concentrated under vacuum to afford the crude nitrile, which was purified by flash chromatography, if required. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With triethylamine; ethanaminium,N-(difluoro-lambda4-sulfanylidene)-N-ethyl-,tetrafluoroborate; In ethyl acetate; at 20℃; for 1h;Inert atmosphere; | General procedure: To a solution of the aldoxime or the amide (1.0 mmol) and Et3N (1.5mmol) in EtOAc (1 mL, 1 M) at r.t. was added XtalFluor-E8 (1.1 mmol)portionwise over ca. 2 min. The resulting solution was stirred at r.t.for 1 h. The reaction mixture was quenched with sat. aq Na2CO3 and extracted with CH2Cl2 (2 × 10 mL). The combined organic layers were washed with H2O and brine, dried (MgSO4), and concentrated under vacuum to afford the crude nitrile, which was purified by flash chromatography, if required. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | To a solution of benzyl 4-cyanopiperidine-1 -carboxylate (10 g, 40.94 mmol) and Ti(i-PrO)4(7.56 g, 26.61 mmol, 7.85 mL) in Et20 (100 mL) was added EtMgBr (3 M, 40.94 mL) dropwise at -78 C. After addition, the mixture was stirred at 20 C for 1 .5 hours, and then BF3-Et20 (1 1 .62 g, 81.88 mmol, 10.10 mL) was added dropwise at -78 C. The resulting mixture was stirred at 20 C for 16 hours. Then, the reaction mixture was poured into 100 mL saturated NaHC03aqueous solution and extracted with EtOAc. The organic layers was dried over Na2S04and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (Method 33) to afford pure reagent R-07d (5 g, 44%) as a yellow oil. ESI-MS (M+1 ): 275.2 calc. for C16H22N2O2: 274.2. |
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