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CAS No. : | 160357-94-8 | MDL No. : | MFCD03412449 |
Formula : | C7H14N2O | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | NLHBHVGPMMXWIM-UHFFFAOYSA-N |
M.W : | 142.20 | Pubchem ID : | 4962477 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.86 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 43.37 |
TPSA : | 46.33 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.64 cm/s |
Log Po/w (iLOGP) : | 1.56 |
Log Po/w (XLOGP3) : | -0.66 |
Log Po/w (WLOGP) : | -0.42 |
Log Po/w (MLOGP) : | -0.05 |
Log Po/w (SILICOS-IT) : | 0.07 |
Consensus Log Po/w : | 0.1 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.24 |
Solubility : | 81.9 mg/ml ; 0.576 mol/l |
Class : | Very soluble |
Log S (Ali) : | 0.16 |
Solubility : | 206.0 mg/ml ; 1.45 mol/l |
Class : | Highly soluble |
Log S (SILICOS-IT) : | -0.33 |
Solubility : | 67.1 mg/ml ; 0.472 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.09 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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 |
---|---|---|
10% | With hydrogen In ethanol for 16 h; | Example 307; 1 -(4-Amino-piperidin-1 -vl)-ethanone:; 1-Acetyl-piperidin-4-one (10 gm (70 mmol)) was dissolved in 200 ml ethanol and treated with 10 gm (143 mmol) hydroxylamine hydrochloride and 10 ml pyridine. The reaction mixture was heated to 70 °Cfor 1.5 hr. The solvent was removed and the residue was treated with water and cooled to 0 °C. The resulting slurry was filtered and dried under vacuum to afford 6.5 gm 1-Acetyl-piperidin-4-one oxime as a white solid (59 percent). The oxime (2.0 gm (12 mmol)) in a Parr bottle was dissolved in 50 ml of ethanol and treated with 0.2 gm of Raney nickel which had been washed several times with water. The reaction was placed in to Parr apparatus and hydrogenated under 50 psi hydrogen pressure for 16 hours. The mixture was carefully filtered and the filtrate was evaporated in vacuo to afford 1.7 gm (100 percent) of the desired amine as a green solid. GC Mass spectrum m/z =142 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.2 g | With hydrogenchloride In 1,4-dioxane at 20℃; for 5 h; | To a stirred suspension of ie f-butyl (1 -acetylpiperidin-4-yl) carbamate (6.61 g, 27.310 mmol) in dioxane (10 ml) was added 2.5 N HCI in dioxane (20 ml) at room temperature and the resulting reaction mixture was stirred at room temperature for 5 h. The resulting reaction mixture was concentrated under reduced pressure yielding 1 -(4-aminopiperidin-1 -yl) ethanone (2.20 g, 15.490 mmol) which was used in the next step without further purification. LCMS: Method B, 0.624 min, MS: ES+ 143.4 (M+1 ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | With hydrogen;nickel; In ethanol; under 2585.81 Torr; for 16h; | Example 307; 1 -(4-Amino-piperidin-1 -vl)-ethanone:; 1-Acetyl-piperidin-4-one (10 gm (70 mmol)) was dissolved in 200 ml ethanol and treated with 10 gm (143 mmol) hydroxylamine hydrochloride and 10 ml pyridine. The reaction mixture was heated to 70 Cfor 1.5 hr. The solvent was removed and the residue was treated with water and cooled to 0 C. The resulting slurry was filtered and dried under vacuum to afford 6.5 gm 1-Acetyl-piperidin-4-one oxime as a white solid (59 %). The oxime (2.0 gm (12 mmol)) in a Parr bottle was dissolved in 50 ml of ethanol and treated with 0.2 gm of Raney nickel which had been washed several times with water. The reaction was placed in to Parr apparatus and hydrogenated under 50 psi hydrogen pressure for 16 hours. The mixture was carefully filtered and the filtrate was evaporated in vacuo to afford 1.7 gm (100 %) of the desired amine as a green solid. GC Mass spectrum m/z =142 |
With hydrogen;Raney Ni (RaNi); In methanol; at 20℃; under 3102.97 Torr; for 4h;Product distribution / selectivity; | To compound 9 (13 g, 0.09 mol) in ethanol (100 mL) was added NH2OH.HCl (10 g, 0.14 mol) followed by pyridine (10 mL). The reaction mixture was heated to 60 C. for 3 h. Excess solvent as well as pyridine was distilled off under reduced pressure, and the crude oxime was dissolved in methanol. Raney Ni (3 g) was added under N2 and the mixture hydrogenated at 60 psi at room temperature for 4 hours. After completion of the reaction, the reaction mixture was filtered through celite, washed with methanol and the solvent was evaporated to obtain the crude product. The crude product was purified by chromatography on silica gel using (5%) DCM in methanol to obtain 10 as a brown syrup (11 g, 86%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In toluene; for 18h;Heating / reflux; | Example 308; 3-(1 -Acetyl-piperidin-4-vlamino)-2-benzyl-piperidine-1 -carboxvlic acid tert-butvl ester:; A solution of 0.53 gm (3.72 mmol) 1-(4-Amino-piperidin-1-yl)-ethanone and 1.07 gm (3.72 mmol) 2-Benzyl-3-oxopiperidine-1-carboxylic acid terf-butyl ester in toluene was heated under reflux over a Dean-Stark water separator for 18 hours. The reaction mixture was cooled to room temperature and was treated with 2.37 gm (11.2 mmol) sodium triacetoxyborohydride. The reaction mixture was then stirred for 20 hours at ambient temperature. The reaction mixture was quenched by adding saturated bicarbonate solution and then extracted with methylene chloride. The organic phase was washed with water and saturated brine. The organic phase was then dried over sodium sulfate and evaporated in vacuo to afford a yellow oil. The oil was chromatographed on silica gel (elution with 5% methanol in methylene chloride with 1. ml/100ml of cone ammonium hydroxide) to afford 890 mg (58 %) of an oil. Mass spectrum APCI m/z = 416 (p+1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | Step 2 Preparation of N-Acetyl-4-Aminopiperidine A solution of N-acetyl-1-benzyl-4-aminopiperidine (17.4 g, 75 mmol) and palladium catalyst in ethanol was treated with hydrogen gas. The ethanol was evaporated under reduced pressure to give a solid which was recrystallized from about 120 mL of ethyl acetate to give 6.32 g of product. Yield: 59%. MS(FD) M+142. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65%. | Step 3 Preparation of N-Acetyl-1-(3-(4-Fluorophenoxy)propyl)-4-Aminopiperidine N-Acetyl-4-aminopiperidine (5.80 g, 41 mmol) and O-(p-toluenesulfonyl)-3-(4-fluorophenoxy)propanol (13.24 g, 41 mmol) were converted to the title compound by the procedure of Preparation 2, Step 3 to give a crude product which was recrystallized from ethyl acetate to give 7.82 g of the title compound. Yield: 65%. m.p. 134 C.-136 C. EA calculated for C16 H23 N2 O2 F: C, 65.28; H, 7.88; N, 9.52. Found: C, 65.49; H, 7.91; N, 9.54. MS(FD) M+1 295. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium cyanoborohydride; In toluene; | EXAMPLE 14 By the procedure of Example 13, 1-acetyl-3-piperidone is converted, using sodium cyanoborohydride, to 1-acetyl-4-aminopiperidine. Refluxing 1-acetyl-3-aminopiperidine with 9-acetoxyxanthene in dry toluene by the procedure of Example 1 gives N-(N-acetyl-3-piperidinyl)-9-xanthenylamine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 12h; | To a solution of compound 10 (2 g, 13.9 mmol) in DCM (100 mL), DIEA (2.39 mL, 13.9 mmol) was added 4-nitrophenyl chloroformate (2.81 g, 13.9 mmol) and the resulting mixture was stirred at room temperature for 12 h. The reaction mixture was then extracted with DCM, and washed with 10% aq. hydrochloric acid. The residue obtained on removal of solvent was purified by column chromatography using 5% methanol in DCM to obtain the carbamate 11 (2.72 g, 64%) as a yellow crystalline solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With triethylamine; In dichloromethane; at 0 - 20℃; for 18h; | To a solution of 4-amino-1-acetylpiperidine 2 (852 mg, 6.0 mmol) in CH2Cl2 (18 mL) was added Et3N (2.5 mL, 18.0 mmol) followed by 2,2,2-trichloroethyl chloroformate (0.96 mL, 7.2 mmol, 1.2 eq.) at 0-5 C. The reaction mixture was allowed to warn to rt and was stirred for 18 h before being diluted with CH2Cl2 (60 mL). The resulting mixture was washed with water (30 mL), sat. NaHCO3 (30 mL), water (30 mL), brine (30 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The resulting crude carbamate was triturated with hexanes (30 mL) to afford 2,2,2-trichloroethyl carbamate of 4-amino-1-acetylpiperidine 3 (1.7 g, 88%) as a off-white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 4-Boc-aminopiperidine 1 (12.0 g, 12.0 mmol) in CH2Cl2 (48 mL) was added Et3N (5.0 mL, 36.0 mmol) followed by acetic anhydride (1.4 mL, 14.4 mmol, 1.2 eq.) at 0-5 C. The reaction mixture was allowed to warm to rt and was stirred for 18 h before being diluted with CH2Cl2 (120 mL). The resulting mixture was washed with water (50 mL), sat. NaHCO3 (50 mL), water (50 mL), brine (50 mL), dried over Na2SO4, filtered, and concentrated under vacuum to afford crude 4-BOC-amino-1-acetylpiperidine. This crude product was dissolved in MeOH (36 mL) and was added to 4.0 M HCl solution in dioxane (15.0 mL, 60.0 mmol) at rt. The resulting clear solution was stirred for 18 h at rt and then the solvent was evaporated under vacuum. The residue was dissolved in water (50 mL) and washed with EtOAc (2×50 mL). The water layer was basified (pH<10) with 10% aqueous NaOH solution and water was evaporated under vacuum. The residue (salt and compound) was triturated with CHCl3/IPA (3:1) and decanted. The CHCl3/IPA supernatant, after drying over Na2SO4, was filtered and concentrated under vacuum. The residue was dried at high vacuum for 18 h to give 4-amino-1-acetylpiperidine 2 (937 mg, 55%) as a light yellow oil. | ||
2.2 g | With hydrogenchloride; In 1,4-dioxane; at 20℃; for 5h; | To a stirred suspension of ie f-butyl (1 -acetylpiperidin-4-yl) carbamate (6.61 g, 27.310 mmol) in dioxane (10 ml) was added 2.5 N HCI in dioxane (20 ml) at room temperature and the resulting reaction mixture was stirred at room temperature for 5 h. The resulting reaction mixture was concentrated under reduced pressure yielding 1 -(4-aminopiperidin-1 -yl) ethanone (2.20 g, 15.490 mmol) which was used in the next step without further purification. LCMS: Method B, 0.624 min, MS: ES+ 143.4 (M+1 ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 102 N-(1-acetyl-piperidin-4-y)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzamide (I-102) A mixture of 0.045 g (0.1 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid (I-22), 0.042 g (0.110 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.052 ml (0.300 mmole) of ethyldiisopropyl amine and 1.0 mL of dimethylformamide was stirred for 5 minutes and then 0.017 g (0.12 mmole) of 1-(4-Amino-piperidin-1-yl)-ethanone was added. The mixture was stirred for 3 hours, then diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography, eluding with water-acetonitrile (gradient, 0:100-80:20) to give 0.05 g of N-(1-acetyl-piperidin-4-yl)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzamide (I-102) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5 - Bromo-2- [N-(3 -chloro-4-fluorophenyl)] -4-(methy 1 sulfonyl)pyrimidin-2 -amine (Intermediate 69, Ig, 2.63 mmol) was suspended in NMP (5 mL), treated with N5N- diisopropylethylamine (0.5 mL, 3.02 mmol), and l-(4-amino-piperidin-l-yl)-ethanone (1 eq 2.63 mmol) in a sealed tube. The reaction was heated in the microwave reactor at 100 0C for 30 min. The reaction mixture was added to water and stirred for 15 min. The precipitated solid was filtered and dried to provide the l-{4-[5-bromo-2-(3-chloro-4-fluoro-phenylamino)-pyrimidin- 4-ylamino]-piperidin- 1 -yl} -ethanone (800 mg). MS(ES): 442.7 (M) and 444 (M+2) for Ci7Hi8BrClFN5O.400 MHz, DMSO-de : delta 1.4-1.75 (m, 2H), 1.83-1.88 (m, 2H), 2.02 (s, 3H), 2.6-2.63 (m, IH), 3.11 (t, J = 12.00 Hz, IH), 3.87-3.9 (m, IH), 4.15-4.19 (m, IH), 4.42-4.45 (m, IH), 6.71 (d, J = 8.00 Hz, IH), 7.32 (t, J = 9.04 Hz, IH), 7.49-7.53 (m, IH), 8.06 (s, IH), 8.11 (dd, J = 6.86, 2.60 Hz, IH), 9.50 (s, IH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 140℃; | Intermediate 37 (150 mg, 0.47 mmol), l-(4-aminopiperidin-l-yl)ethanone (332 mg, 2.34 mmol), DIPEA (0.42 mL, 2.34 mmol) and NMP (3 mL) were combined in a sealed tube and heated to 1400C overnight. After cooling, the mixture was dissolved in a 1 :1 mixture OfEt2O and EtOAc (100 mL) and washed with saturated brine (3 x 25 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. Purification by chromatography (SiO2, 0-5% MeOH in DCM) gave a yellow gum (94 mg, 47%). LCMS (ES+) 427 (M+Eta)+. The yellow gum (75 mg, 0.176 mmol) was dissolved in DCM (3 mL) and TFA (2 mL) and the solution obtained was stirred at r.t. for 2 h. The excess solvent was removed in vacuo and the residue azeotroped with toluene (3 x 10 mL). To the residue obtained were added 6-chloropurine (65 mg, 0.26 mmol), DIPEA (0.16 mL, 0.88 mmol) and n-butanol (2.5 mL) and the reaction mixture was heated under microwave irradiation at 12O0C for 1 h. After cooling, the mixture was dissolved in a 1:1 mixture of Et2O and EtOAc (100 mL) and washed with saturated brine (3 x 25 mL). The organic layer was dried (MgSO4), filtered and evaporated to dryness. Purification by preparative HPLC gave the title compound (29.6 mg, 38%) as a brown gum. deltaH (CDCl3) 8.35 (IH, s), 8.06 (IH, s), 7.95 (IH, s), 7.51 (IH, d, J8.18 Hz), 7.44 (IH, d, J7.05 Hz), 6.47 (IH, br s), 5.85 (IH, br s), 5.46 (IH, d, J 8.00 Hz), 4.05 (IH, br s), 3.90 (IH, d, J 12.75 Hz), 3.65- 3.43 (IH, m), 3.41-3.34 (IH, m), 2.97 (IH, d, J 8.22 Hz), 2.71 (3H, s), 2.13 (IH, d, J 11.43 Hz), 2.06 (IH, d, J 9.91 Hz), 2.01 (3H, s), 1.87-1.70 (2H, m), 1.66 (3H, d, J6.72 Hz), IH under CHCl3. LCMS (ES+) 445 (M+H)+, RT 2.33 minutes {Method 2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 140℃; | Intermediate 23 (200 mg, 0.58 mmol), l-(4-aminopiperidin-l-yl)ethanone (416 mg, 2.93 mmol), DIPEA (0.52 mL, 2.93 mmol) and NMP (2 mL) were combined in a sealed tube and heated to 14O0C overnight. After cooling, the mixture was dissolved in a 1.1 mixture OfEt2O and EtOAc (100 mL) and washed with saturated brine (3 x 25 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 50% EtOAc in isohexane) gave a yellow gum (140 mg, 54%). LCMS (ES+) 447, 449 (M+Eta)+. The yellow gum (140 mg, 0.31 mmol) was dissolved in DCM (6 mL) and TFA (4 mL) and the solution was left to stand at r.t. for 2 h. The excess solvent was removed in vacuo and the residue azeotroped with toluene. Purification by ion exchange chromatography (SCX cartridge eluting with NH3 in MeOH) gave a yellow gum (100 mg, 90%). LCMS (ES+) 347, 349 (M+H)+. The yellow gum (55 mg, 0.16 mmol), 6-chloropurine (47 mg, 0.19 mmol), DIPEA (0.086 mL, 0.48 mmol) and NMP (1.5 mL) were combined and heated under microwave irradiation to 15O0C for 1 h. After cooling, the mixture was dissolved in a 1:1 mixture OfEt2O and EtOAc (100 mL) and washed with saturated brine (3 x 25 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. Purification by preparative HPLC gave the title compound (15.8 mg, 21%) as a light brown solid. deltaH (CDCl3) 8.37 (IH, s), 8.08 (IH, s), 7.97 (IH, s), 7.68 (IH, dd, J7.52, 1.33 Hz), 7.55 (IH, dd, J 8.09, 1.35 Hz), 7.26-7.22 (IH, m), 6.34 (IH, br s), 5.83 (IH, br s), 5.48 (IH, d, J7.91 Hz), 4.11-4.00 (2H, m), 3.76- 3.67 (IH, m), 3.51-3.41 (IH, m), 3.05 (IH, t, J 11.81 Hz), 2.19-2.05 (2H, m), 2.01 (3H, s), 1.93-1.78 (2H, m), 1.73-1.61 (4H, m). LCMS (ES+) 465 (M+H)+, RT 2.47 minutes (Method 2). |
22% | With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 140℃; for 18h; | A mixture of Intermediate 23 (0.34 g, 1 mmol), l-(4-aminopiperidin-l-yl)- ethanone (0.25 g, 1.76 mmol) and DIPEA (0.84 mL, 5 mmol) in NMP (10 mL) was heated at 14O0C for 18 h. After cooling, the reaction mixture was partitioned between Et2O (200 mL) and water (100 mL). The organic layer was washed with water (3 x 100 mL), brine (100 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 0-100% EtOAc in isohexane) to give the title compound (0.1 g, 22%) as a pale orange gum. deltaH (CDCl3) 7.70 (IH, s), 7.62 (IH, dd, J 7.56, 1.40 Hz), 7.47 (IH, dd, J7.93, 1.39 Hz), 7.08 (IH, t, J 7.74 Hz), 6.39 (IH, br s), 4.97-4.87 (IH, m), 4.59 (IH, br d, J9.95 Hz), 4.50-4.42 (2H, m), 3.85-3.78 (IH, m), 3.37-3.27 (IH, m), 3.08-2.96 (IH, m), 2.40-2.25 (IH, m), 2.23-2.13 (IH, m), 2.12 (3H, d, J 3.80 Hz), 1.67-1.62 (3H, m), 1.60-1.47 (2H, m), 1.44 (9H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | In methanol; for 18h;Reflux; | 14. 1 -{4-6-(3-Fluoro-4-methoxybenzyl)-2-hydroxy-1,2,3,7-tetrahydro-4H-indolo[2,3- c][1,8]naphthyridin-4-yl]piperidin-1-yl}ethanone; Step 1 : tert-Butyl 4-{3-[(1-acetylpiperidin-4-yl)amino]-2-hydroxypropyl}-1-(3-fluoro-4-methoxybenzyl)-3- [(trifluoromethyl)sulfonyl]oxy}-9H-beta-carboline-9-carboxylate.; tert-Butyl 1-(3-fluoro^4- methoxybenzylH-Ioxiran^-ylmethyll-S-II^rifluoromethyOsulfonylloxyJ-ThetaH-beta-carboline-g-carboxylate (example A20) (500 mg) and 1-acetylpiperidin^4-amine (580 mg) are dissolved in methanol (10 ml) and the solution is refluxed for 18 h. The solution is concentrated in vacuo and the crude product is purified by flash chromatography (silica gel, eluting with ethyl acetate / triethylamine / methanol 9:1 :1 (v/v/v)) to yield 394 mg (74%) of tert-butyl 4-{3-[(1-acetylpiperidin^4-yl)amino]-2-hydroxypropyl}-1-(3- fluoro^-methoxybenzy^-S-^trifluoromethy^sulfonylJoxyJ-ThetaH-beta-carboline-theta-carboxylate as a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | In propyl cyanide; at 150℃; for 0.75h;Sealed microwave tube; | 1-Acetylpiperidin-4-amine (339 mg, 2.38 mmol) was added to 4-cyclopentyl-N-(5-hydroxy-2-adamantyl)-2-methylsulfonylpyrimidine-5-carboxamide (400 mg, 0.95 mmol) in butyronitrile (3 mL). The reaction mixture was sealed into a microwave tube. The reaction was heated to 150 C. for 45 minutes in the microwave reactor and cooled to RT. The reaction mixture was evaporated to dryness, redissolved in DCM and washed with water. The organic layer was dried by passing down a isolute phase separator and evaporated to afford a pale yellow solid (459 mg). The crude product was purified by preparative HPLC using decreasingly polar mixtures of water (containing 0.5% NH3) and MeCN as eluents to afford the title compound (105 mg, 23%) as a cream solid; 1H NMR (400 MHz) 1.36 (5H, m), 1.58 (6H, m), 1.80 (12H, m), 2.00 (5H, m), 2.71 (1H, m), 3.12 (1H, t), 3.42 (1H, m), 3.79 (1H, d), 3.91 (2H, m), 4.25 (1H, d), 4.39 (1H, s), 7.25 (1H, s), 8.02 (1H, d), 8.13 (1H, s); m/z MH+=482; HPLC tR=1.52 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 60℃; for 15h; | Example 43(rac)-2-((1 -Acetyl piperidin-4-yl)amino)-7-methyl-7,8-dihydroquinazolin-5(6H)-one[00188]A mixture of 1 -(4-aminopiperidin-1 -yl)ethanone (1 .42 g, 10.00 mmol), 1 H- pyrazole-1 -carboximidamide hydrochloride (1 .48 g, 10.00 mmol), and DIPEA (1 .65 mL, 10 mmol) in DMF (5.5 mL) is stirred at 60 C for 15 h, cooled down to roomtemperature, diluted with DEE and stirred at room temperature for 10 min. Then the ether solution is decanted and discarded. The obtained slurry is triturated withDEE/acetonitrile mixture (3:2). The formed solid is collected by filtration, washed with DEE (3x20 mL) and air-dried to give 1 -(1 -acetylpiperidin-4-yl)guanidine hydrochloride (1 .71 g, 77%) as light beige solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With triethylamine; In ethanol; water; at 20℃; for 16h;Reflux; | General procedure: To a solution of 10 (100 mg, 0.4 mmol, 1.0 equiv) in ethanol (10 mL) was added a solution of 70% ethylamine (70% in water) (48 lL, 0.6 mmol, 1.5 equiv), followed by triethylamine (83 lL, 0.6 mmol, 1.5 equiv) at room temperature. The reaction mixture was refluxed for 16 h and after completion of the reaction (TLC), the reaction mixture was allowed to cool to room temperature. Dichloromethane was added and the organic phase was then washed two times with a saturated solution of NaHCO3, and one time with brine. It was then dried over Na2SO4, and concentrated in vacuo. Flash column chromatography on silica gel (ethyl acetate/hexane 75:25) afforded the desired product |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: To a stirred solution of 47 (107 mg, 0.3 mmol) in dimethylacetamide(3 mL) was added N,N,N0 ,N0-tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate (TBTU) (115 mg, 0.36 mmol) Afterstirring for 15 min at room temperature, N,N-diisopropylethylamine(0.104 mL, 0.6 mmol) and 2-fluoroethylamine hydrochloride(45 mg, 0.45 mmol) were added. After stirring overnight, thereaction mixture was poured into a saturated solution of sodiumhydrogen carbonate and thoroughly extracted with EtOAc, washedwith brine, dried over Na2SO4 and evaporated to dryness. The residuewas purified by Biotage SP1 flash chromatography (gradientelution from 2% to 10% of MeOH in DCM) to afford 8 (86 mg,71%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 90℃; | Example 73a 1-(4-((2-(7-methoxy-1-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-4-nitrophenyl)amino)piperidin-1-yl)ethanone Example 23a (0.1 g, 0.332 mmol) and <strong>[160357-94-8]1-(4-aminopiperidin-1-yl)ethanone</strong> (0.052 g, 0.365 mmol) were dissolved in dimethyl sulfoxide (0.6 mL), treated with N-ethyl-N-isopropylpropan-2-amine (0.29 mL, 1.66 mmol) and stirred at 90 C. overnight. Additional <strong>[160357-94-8]1-(4-aminopiperidin-1-yl)ethanone</strong> (0.052 g, 0.365 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.29 mL, 1.66 mmol) were added and heating was continued at 90 C. for another 24 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, treated with mercapto-functionalized silica gel for 20 minutes, dried over anhydrous magnesium sulfate, filtered through a plug of Celite and concentrated. The residue was purified by flash chromatography (silica gel, 0-7% methanol in dichloromethane) to provide 0.156 g (>100%) of the title compound with ethyl acetate as an excipient. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In tetrahydrofuran; at 90℃; for 1h;Microwave irradiation; | General procedure: Intermediate IV.1A mixture of 2-fluoro-4-methoxy-1-nitro-benzene (17.3 g; 0.10 mol) and ethylamine (2M in THF; 180 ml; 360 mmol) is stirred for 1 h at 90C (microwave heating). The mixture is diluted with water and extracted with ethyl acetate. The organic layer is separated, dried and evaporated. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
325 g | With triethylamine; In isopropyl alcohol; at 60℃; for 16h; | (h) (^-6-((l-acetylpiperidin-4-yl)amino)-N-(3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)pyrimidine-4-carboxamide _:A solution of (,S)-6-chloro-N-(3-(3,4-dihydroisoquinolin-2(lH)-yl)-2- hydroxypropyl)pyrimidine-4-carboxamide (190 g, 0.55 mmol), l-(4-aminopiperidin-l- yl)ethanone (78 g), and triethylamine (100 g, 1 mol) in isopropanol (2000 mL) was stirred at 60 C for 16 hours. The mixture was concentrated and the residue was purified by flash chromatography to give the desired product. Four batches were run in parallel and produced a combined crude product weight of 482 g. This material was further purified by preparative HPLC to give the title compound (325 g, >98% purity, free base form). 1H NMR (400 MHz, MeOD-d4) delta 8.26 (s, 1H), 7.15-7.02 (m, 5H), 4.46 (m, 1H), 4.15-4.07 (m, 2H), 3.88 (m, 1H), 3.74 (s, 2H), 3.53 (m, 2H), 3.33 (m, 1H), 2.95-2.86 (m, 5H), 2.68 (m, 2H), 2.14-2.01 (m, 5H), 1.48-1.42 (m, 2H); LCMS (m/z): 453.3 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 100℃; for 3h; | [00519] To a solution of (S)-6-chloro-N-(3- (3 ,4-dihydro-2,6-naphthyridin-2( 1 H)-yl) -2- hydroxypropyl)pyrimidine-4-carboxamide (150 mg, 0.43 mmol) in 2-propanol (15 mL) was added N,N-diisopropylethylamine (166 mg, 1.29 mmol) and 1-(4-aminopiperidin-1- yl)ethanone (92 mg, 0.65 mmol). The reaction was stirred at 100 C for 3 h, following which the solvent was removed in vacuo. The resulting residue was purified by preparative HPLC to give the TFA salt of the title compound (30 mg, 15.4%). ?H NMR (400 MHz, CD3OD, oe):8.84- 8.72 (m, 1 H), 8.71 - 8.48 (m, 2 H), 7.86-7.66 (m, 1 H), 7.32-7.07 (m, 1 H), 4.81 -4.71 (m, 2 H), 4.55 - 4.24 (m, 3 H), 4.01 - 3.91 (m, 1 H), 3.84- 3.68 (m, 2 H), 3.65 - 3.32(m, 7 H), 2.94- 2.79 (m, 1 H), 2.13 (s, 5 H), 1.66 - 1.39 (m, 2 H). LCMS (nilz): 454.2 (M+ 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 100℃; for 3h; | To a solution of (S)-6-chloro-N- (3- (7 ,8-dihydro- 1 ,6-naphthyridin-6(5H)-yl)-2- hydroxypropyl)pyrimidine-4-carboxamide (150 mg, 0.43 mmol) in 2-propanol (15 mL) was added N,N-diisopropylethylamine (166 mg, 1.29 mmol) and 1-(4-aminopiperidin-1- yl)ethanone (122 mg, 0.86 mmol). The mixture was stuffed at 100 C for 3 h, whereupon the solvent was removed in vacuo. The resulting residue was purified by preparative HPLC to give the title compound as the TFA salt (83 mg, 41.0%). ?H-NMR (400 MHz, CD3OD, oe):8.70 - 8.53 (m, 2 H), 8.11 -7.95 (m, 1 H), 7.72-7.56 (m, 1 H), 7.34-7.14 (m, 1 H), 4.78 -4.62 (m, 2 H), 4.59 - 4.24 (m, 3 H), 4.05 - 3.92 (m, 1 H), 3.90 - 3.76 (m, 2 H), 3.62- 3.31 (m, 7 H), 2.96 - 2.80 (m, 1 H), 2.21 - 1.98 (m, 5 H), 1.68 - 1.42 (m, 2 H). LCMS (mlz):454.2 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In isopropyl alcohol; at 80℃; for 12h; | A mixture of (S)-6-chloro-N-(2-hydroxy-3-(3-phenyl-6,7-dihydro- 1 Hpyrazolo [4,3-c]pyridin-5 (4H)-yl)propyl)pyrimidine-4-carboxamide (100 mg, 0.24 mmol), 1-(4-aminopiperidin-1-yl) ethanone (45 mg, 0.32 mmol), and triethylamine (0.1 mL) in 2-propanol (10 mL) was stirred at 80 C for 12 h. The solvent was evaporated and the resultingresidue was purified by preparative HPLC to give the TFA salt of the title compound (91 mg,73%) as white solid. ?H-NMR (400 MHz, CD3OD, ): 8.65 - 8.54 (m, 1 H), 7.59 - 7.54 (m,2 H), 7.53 -7.48 (m, 2 H), 7.46 - 7.40 (m, 1 H), 7.33 -7.09 (m, 1 H), 4.78 - 4.57 (m, 2 H),4.55 -4.46 (m, 1 H), 4.44- 4.24 (m, 2 H), 4.20 - 3.88 (m, 2 H), 3.86 - 3.46 (m, 5 H), 3.43 -3.35 (m, 1 H), 3.25 - 3.14 (m, 2 H), 2.96 -2.81 (m, 1 H), 2.18 -2.14 (m, 3 H), 2.05 (s, 2 H),1.63 - 1.44 (m, 2 H). LCMS (mlz): 519.2 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17.8% | With triethylamine; In isopropyl alcohol; at 30 - 100℃; for 3h; | To a solution of (S)-6-chloro-N-(3- (6,7-dihydrothieno [3 ,2-c]pyridin-5 (4H)-yl)-2- hydroxypropyl) pyrimidine-4-carboxamide (150 mg, 0.28 mmol) in 2-propanol (10 mL) was added triethylamine (200 mg, 1.98 mmol) and <strong>[160357-94-8]1-(4-aminopiperidin-1-yl)ethanone</strong> (100 mg, 0.88 mmol) at 30 C. The mixture was stuffed at 100 C for 3 h, cooled to ambient temperature, and concentrated in vacuo. The resulting residue was purified by preparative HPLC to give the title compound (33 mg, 17.8%) as a white solid. ?H-NMR (400 MHz, CD3OD, ): 8.38-8.30 (m, 1 H), 7.14 (d, J= 5.14 Hz, 1 H), 7.08 (s, 1 H), 6.73 (d, J= 5.15 Hz, 1 H), 4.43 (d, J= 12.42 Hz, 1 H), 4.14 (br. s, 1 H), 4.05 (quin, J= 5.96 Hz, 1 H), 3.93 (d, J = 14.05 Hz, 1 H), 3.65 (s, 2 H), 3.58 - 3.43 (m, 2 H), 3.30 - 3.24 (m, 1 H), 2.95 -2.87 (m, 5 H), 2.68 (d, J= 6.15 Hz, 2 H), 2.12 (s, 3 H), 2.10- 1.97 (m, 2 H), 1.55- 1.36 (m, 2 H). LCMS (mlz): 459.2 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | To a solution of (S)-6-chloro-N-(2-hydroxy-3- (3- ((2- (trimethylsilyl)ethoxy)methyl)-6,7-dihydro-3H-imidazo [4,5-c]pyridin-5 (4H)-yl)propyl)pyrimidine-4-carboxamide (250 mg, 0.54 mmol) in i-PrOH (5 mL) was added <strong>[160357-94-8]1-(4-aminopiperidin-1-yl)ethanone</strong> (76.9 mg, 0.54 mmol) and TEA (109.1 mg, 1.08 mmol). The mixture was stirred at 80 C for 16 hours. The reaction mixture was evaporated and the residue was dissolved in DCM (10 mL), TFA (2 mL) was then added. The mixture was stuffed at 25C for 16 h. The mixture was then evaporated to dryness and the residue was purified by prep-HPLC to give the desired product (23.7 mg, yield: 10 %). ?H NMR (400MHz, CD3OD-d4): (ppm): = 8.72 (s, 1H), 8.51 (s, 1H), 7.15 (br. s., 1H), 4.55 (s, 2H), 4.45 (d, J=13.1 Hz, 1H), 4.36 - 4.15 (m, 2H), 3.95 (d, J=13.6 Hz, 1H), 3.74 (br. s., 2H), 3.62- 3.34 (m, 4H), 3.27 - 3.02 (m, 3H), 2.89 (t, J=11.5 Hz, 1H), 2.18 - 1.98 (m, 5H), 1.60 - 1.39 (m, 2H). LCMS (mlz): 443.3 [M+H] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In isopropyl alcohol; at 19 - 90℃; for 12h; | To a mixture of (S)-6-chloro-N- (2-hydroxy-3 -(1 -methyl-6,7-dihydro- 1 Hpyrazolo [4,3-c]pyridine -5 (4H)-yl)propyl)pyrimidine-4-carboxamidel (80 mg, 0 .22mmol) and 1-(4-aminopiperidin-1-yl) ethanone (62 mg, 0.44mmol) in i-PrOH (10 mL) was added Et3N (0.1 mL) at 19 C. The mixture was stirred at 90 C for 12 h or until the reaction was shown to be complete by LCMS analysis. The reaction mixture was then concentrated to give the crude product which was purified by prep-HPLC to give the target compound (S)-6-((1-acetylpiperidin-4-yl)amino)-N- (2-hydroxy-3 -(3-methyl-4,5-dihydrothieno [2,3-c]pyridin-6(7H)-yl)propyl)pyrimidine-4-carboxamide as yellow oil (15.5 mg, 14.9%). ?H NMR (MeOD,400 MHz) (ppm): 8.37 (s, 1 H) 7.11 (s, 1 H) 6.83 (s, 1 H) 4.46 (d, J=13.55 Hz, 1 H) 4.19(br. s., 1 H) 4.09 (dt, J=11.98, 5.93 Hz, 1 H) 3.95 (d, J=12.80 Hz, 1 H) 3.86 (s, 2 H) 3.53-3.58 (m, 1 H) 3.45 - 3.51 (m, 1 H) 3.28 (br. s., 1 H) 2.96- 3.06 (m, 2 H) 2.91 (t, J=11.29 Hz,1 H) 2.73 - 2.82 (m, 2 H) 2.64 - 2.72 (m, 2 H) 2.13 (d, J=6.78 Hz, 6 H) 1.94 - 2.10 (m, 1 H)1.40 - 1.54 (m, 2 H). LCMS (mlz): 473.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With triethylamine; In isopropyl alcohol; at 80℃; for 12h; | A mixture of (S)-6-chloro-N- (2-hydroxy-3- (3-methyl-6,7-dihydrothieno [3,2- c]pyridin-5 (4H)-yl)propyl)pyrimidine-4-carboxamide (150 mg, 0.4 mmol), 1-(4-aminopiperidin- 1-yl)ethanone (113 mg, 0.8 mmol) and TEA (0.1 mL) in i-PrOH (10 mL) was stirred at 80C for 1 2h. Then the solvent was removed to give the crude product and purified by Pre-HPLC separation to give the desired product (54.1mg, 28% yield). ?H NMR (400MHz, METHANOL-d4) (ppm): 8.34 (s, 1H), 7.10 (s, 1H), 6.76 (s, 1H), 4.45 (d, J=13.6 Hz, 1H), 4.18 (br. s., 1H), 4.11 -4.04 (m, 1H), 3.95 (d, J=13.8 Hz, 1H), 3.62- 3.52 (m, 3H), 3.52 - 3.37 (m, 1H), 3.32 - 3.23 (m, 1H), 2.94 (d, J=3.8 Hz, 1H), 2.91 - 2.78 (m, 4H), 2.72 (d, J=6.0 Hz, 2H), 2.19 - 2.12 (m, 3H), 2.12 - 1.89 (m, 5H), 1.60 - 1.38 (m, 2H); LCMS (mlz):459.1 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7.5%; 4.1% | To a solution of (S)-6-chloro-N-(2-hydroxy-3- (1 -methyl-6,7-dihydro- 1 Himidazo [4,5-c]pyridin-5 (4H)-yl)propyl)pyrimidine-4-carboxamide and (S)-6-chloro -N-(2- hydroxy-3-(3-methyl-6,7-dihydro-3H-imidazo [4,5-c] pyridin-5 (4H)-yl)propyl) pyrimidine-4- carboxamide (500 mg, 1.43 mmol) in i-PrOH (20 mL) was added DIPEA (369 mg, 2.86 mmol) and <strong>[160357-94-8]1-(4-aminopiperidin-1-yl)ethanone</strong> (305 mg, 2.15 mmol). The solution was stuffed at 100 C for 16h. Once complete by TLC analysis the reaction solution was concentrated and the residue purified by HPLC to give (S)-6-((1-acetylpiperidin-4-yl)amino)-N-(2-hydroxy-3- (1 -methyl-6,7-dihydro- 1 H-imidazo [4,5-c]pyridin-5 (4H)-yl)propyl)pyrimidine-4-carboxamide (49 mg, 7.5%). ?HNMR (CD3OD, 400MHz) (ppm): 8.37 (s, 1H), 7.45 (s, 1H), 7.08 (s, 1H), 4.43 (d, 1=13.3 Hz, 1H), 4.17 (br. s., 1H), 4.03 (quin, 1=5.9 Hz, 1H), 3.93 (d, 1=13.8 Hz, 1H),3.62 - 3.50 (m, 6H), 3.48 - 3.39 (m, 1H), 3.30 - 3.21 (m, 1H), 2.97 - 2.84 (m, 3H), 2.75 - 2.58 (m, 4H), 2.12 (s, 3H), 2.09 - 1.97 (m, 2H), 1.56 - 1.35 (m, 2H). LCMS (mlz): 457.3 [M+H]+ Also from the separation, (S)-6-(( 1 -acetylpiperidin-4-yl)amino)-N-(2-hydroxy-3- (3-methyl-6,7-dihydro-3H-imidazo [4,5-c]pyridin-5 (4H)-yl)propyl)pyrimidine-4-carboxamide (27 mg, 4.1%). ?HNMR (CH3OD, 400MHz) (ppm): 8.92 (s, 1H), 8.59 (s, 1H), 7.20 (br. s., 1H), 4.65 (s, 2H), 4.48 (d, 1=12.5 Hz, 1H), 4.37 (br. s., 2H), 3.97 (d, 1=13.8 Hz, 1H), 3.88 -3.83 (m, 3H), 3.82 - 3.68 (m, 2H), 3.62 - 3.46 (m, 3H), 3.43 - 3.34 (m, 1H), 3.30 - 3.24 (m, 1H), 3.15 (d, 1=5.3 Hz, 2H), 2.87 (t, 1=11.5 Hz, 1H), 2.16 - 1.99 (m, 5H), 1.68 - 1.38 (m, 2H). LCMS (mlz): 457.3 [M+H] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With triethylamine; In isopropyl alcohol; at 80℃; for 12h; | A mixture of (S)-6-chloro-N- (3- (6,7-dihydrothiazolo [5 ,4-c]pyridin-5 (4H)-yl)-2- hydroxypropyl) pyrimidine-4-carboxamide (80 mg, 0.23 mmol), 1 -(4-aminopiperidin- 1- yl)ethanone (65 mg, 0.46 mmol) and TEA (0.1 mL) in i-PrOH (10 mL) was stirred at 80C for 12h. TLC showed the reaction completed and solvent was evaporated to dryness, residue was then purified by Pre-HPLC separation to afford the desired product (29 mg, 27% yield). ?H NMR (400MHz, METHANOL-d4) (ppm): 8.86 (s, 1H), 8.34 (s, 1H), 7.10 (s, 1H), 4.45 (d, J=13.6 Hz, 1H), 4.18 (br. s., 1H), 4.05 (quin, J=6.0 Hz, 1H), 3.95 (d, J=13.8 Hz, 1H), 3.88 (s, 2H), 3.60 - 3.54 (m, 1H), 3.53 - 3.45 (m, 1H), 3.32 - 3.22 (m, 1H), 3.06 - 2.98 (m, 2H), 2.96 (d, J=5.8 Hz, 2H), 2.93 - 2.86 (m, 1H), 2.74 (d, J=6.0 Hz, 2H), 2.14 (s, 3H), 2.10 (d, J=13.8 Hz, 1H), 2.02 (d, J=11.0 Hz, 1H), 1.56 - 1.48 (m, 1H), 1.47 - 1.38 (m, 1H), 1.10-1.13 (m, 1H); LCMS (mlz): 460.2 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16% | With triethylamine; In isopropyl alcohol; at 80℃; for 12h; | A mixture of (S)-6-chloro-N- (2-hydroxy-3- (2-methyl-6,7-dihydrothiazolo [5,4- c]pyridin-5 (4H)-yl)propyl)pyrimidine-4-carboxamide (100 mg, 0.27 mmol), 1- (4- aminopiperidin- 1-yl)ethanone (76 mg, 0.54 mmol) and TEA (0.1 mL) in i-PrOH (10 mL) was stirred at 80C for 12h. TLC showed the reaction completed and solvent was removed and residue was then purified by Pre-HPLC separation to give the desired product (21 mg, 16% yield). ?H NMR (400MHz, METHANOL-d4) (ppm): 8.35 (s, 1H), 7.10 (s, 1H), 4.45 (d, J=13.3 Hz, 1H), 4.18 (br. s., 1H), 4.04 (quin, J=5.9 Hz, 1H), 3.95 (d, J=13.6 Hz, 1H), 3.78 (s, 2H), 3.58 - 3.47 (m, 2H), 3.03 - 2.83 (m, 6H), 2.71 (d, J=6.0 Hz, 2H), 2.66 (s, 3H), 2.14 (s, 3H), 2.10 (d, J=13.6 Hz, 1H), 2.03 (d, J=11.0 Hz, 1H), 1.56 - 1.48 (m, 1H), 1.47 - 1.38 (m, 1H); LCMS (mlz): 474.3 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With triethylamine; In isopropyl alcohol; at 80℃; for 12h; | A mixture of (S)-6-chloro-N-(2-hydroxy-3- (2-methyl-6,7-dihydrooxazolo [4,5- c]pyridin-5 (4H)-yl)propyl)pyrimidine-4-carboxamide (90 mg, 0.25 mmol), 1- (4- aminopiperidin- 1-yl)ethanone (64 mg, 0.5 mmol) and TEA (0.1 mL) in i-PrOH (10 mL) was stirred at 80C for 12h. TLC showed the reaction completed and solvent was removed under vacuum, residue was then purified by Pre-HPLC separation to give the desired product (43.4 mg, 36% yield). ?H NMR (400MHz, MeOD) (ppm): 8.40 (s, 1H), 7.11 (s, 1H), 4.45 (d,J=13.3 Hz, 1H), 4.19 (br. s., 1H), 4.07 - 4.00 (m, 1H), 3.95 (d, J=14.1 Hz, 1H), 3.59 - 3.51 (m,3H), 3.50 - 3.43 (m, 1H), 3.32 - 3.26 (m, 1H), 2.99 - 2.93 (m, 2H), 2.93 - 2.86 (m, 1H), 2.75(br. s., 2H), 2.71 (d, J=6.0 Hz, 2H), 2.43 (s, 3H), 2.14 (s, 3H), 2.12 - 1.98 (m, 2H), 1.57 - 1.48(m, 1H), 1.48 - 1.38 (m, 1H); LCMS (mlz): 458.3 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 100℃; for 3h; | To a solution of (S)-6-chloro-N-(3- (5 ,6-dihydro- 1 ,7-naphthyridin-7 (8H)-yl)-2- hydro xylpropyl)pyrimidine-4-carboxamide (150 mg, 0.43 mmol) in 2-propanol (15 mL) were added N,N-diisopropylethylamine (166 mg, 1.29 mmol) and 1-(4-aminopiperidin-1- yl)ethanone (122 mg, 0.86 mmol). Following the addition, the mixture was stirred at 100 C for 3 h, at which time LCMS analysis indicated completion of the reaction. The solvent was evaporated and the residue purified by preparative HPLC to give the TFA salt of the desired compound (62 mg, 32 %) as a white solid. ?H NMR (400 MHz, CD3OD, ): 8.58 (s, 1 H), 8.53-8.44 (m, 1 H), 7.79 (d, J= 7.8 Hz, 1 H), 7.42 (dd, J= 4.8, 7.8 Hz, 1 H), 7.20 (br. s., 1 H), 4.59 (s, 2 H), 4.49 (d, J= 12.4 Hz, 1 H), 4.44-4.25 (m, 2 H), 3.98 (d, J= 14.1 Hz, 1 H), 3.73 (br. s, 2 H), 3.60 - 3.40 (m, 4 H), 3.29 - 3.22 (m, 2 H), 2.94- 2.86 (m, 1 H), 2.20 - 1.97 (m, 6 H), 1.60 - 1.43 (m, 2 H). LCMS (mlz): 454.1 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 100℃; for 3h; | To a solution of (S)-6-chloro-N-(3- (3 ,4-dihydro-2,7-naphthyridin-2( 1 H)-yl-2- hydroxy propyl)pyrimidine-4-carboxamide (120 mg, 0.345 mmol) in 2-propanol (15 mL) was added N,N-diisopropylethylamine (145 mg, 1.04 mmol) and 1-(4-aminopiperidin-1- yl)ethanone (123 mg, 0.69 mmol). The resulting mixture was stirred at 100 C for 3 h, following which time the solvent was removed in vacuo. The residue was purified by preparative HPLC to give the title compound (50 mg, 32 %). 1H NMR (400 MHz, CD3OD, ):8.34-8.15 (m, 3 H), 7.22 (d, J= 5.1 Hz, 1 H), 7.10 (s, 1 H), 4.45 (d, J= 13.4 Hz, 1 H), 4.27-4.02 (m, 2 H), 3.95 (d, J= 15.3 Hz, 1 H), 3.78 (s, 2 H), 3.60 - 3.50 (m, 2 H), 3.32- 3.25 (m, 1 H), 3.05-2.96 (m, 2 H), 2.93-2.85 (m, 3 H), 2.71 (d, J= 6.3 Hz, 2 H), 2.18-2.00 (m, 5 H), 1.53 - 1.38 (m, 2 H). LCMS (mlz): 454.3 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 48h; | A mixture of 2-(3-fluoropyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.150 g, 0.5 mmol), <strong>[160357-94-8]1-(4-aminopiperidin-1-yl)ethanone</strong> (0.142 g, 1.0 mmol) and K2CO3 (0.207 g, 1.5 mmol)in DMF (5.0 mL) was heated to 110 C with stirring for 48 h. After that time the reaction mixture was cooled to rt and concentrated under reduced pressure. The residue was dissolved in CH2CI2 (20 mL), washed with water (10 mL) then brine (10 mL), dried ( gS0 ) and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 90:10 ethyl acetate methanol) to give 2-(3-((1-acetylpiperidin-4-yl)amino)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.020 g, 10%) as a yellow solid: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In 1,4-dioxane; at 20℃; for 24h; | The title compound is prepared according to General Procedure 13 described in Example 52, using 3-[8-(1-methyl-1 - -indol-6-yl)quinoxalin-6- yl]amino}pyridine-4-carboxylic acid (Intermediate 42, 50 mg; 0.13 mmol; 1 eq.), <strong>[160357-94-8]1-(4-aminopiperidin-1-yl)-ethanone</strong> (22 muIota; 0.16 mmol; 1.25 eq.), EDC'HCI (65 mg; 0.34 mmol; 2.70 eq.), HOBt hydrate (52 mg; 0.34 mmol; 2.70 eq.), triethylamine (0.08 ml0.63 mmol; 5 eq.) and dioxane (7 ml_). Conditions: room temperature for 24 h. Purification by reversed-phase preparative HPLC (column: Gemini NX C18 5u 11 OA (100x30 mm), ACN gradient in water) affords A/-(1-acetylpiperidin-4-yl)-3-[8-(1-methyl-1 - -indol- 6-yl)quinoxalin-6-yl]amino}pyridine-4-carboxamide (20 mg; 0.04 mmol; 30%; yellow powder; HPLC purity: 100%). |
30% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In 1,4-dioxane; at 20℃; for 24h;Inert atmosphere; | General procedure: 3-[8-(1-Methyl-1H-indol-6-yl)quinoxalin-6-yl]amino}pyridine-4-carboxylic acid6[11](70 mg; 0.18 mmol; 1 eq.),EDC?HCl(62 mg; 0.32 mmol; 1.8 eq.) andHOBt hydrate(50 mg; 0.32 mmol; 1.8 eq.) were dissolved in dioxane (7 mL) at room temperature. Triethylamine (0.11 mL; 0.88 mmol; 5 eq.) was added followed by methylamine hydrochloride (18 mg; 0.26 mmol; 1.5 eq.), after 30 minutes. After 48 hours of stirring at room temperature under argon, dioxane was evaporatedin vacuoand the residue was vigorously stirred in a 1:1 (v/v, 50 mL) mixture of water and EtOAc. The medium was neutralized with 1M HCl and the phases were separated. The aqueous phase was extracted twice with EtOAc, and the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentratedin vacuo. The resulting residue waspurified by automated flash chromatography (0-100% EtOAc gradient in hexane and continued with 0-10% MeOH gradient in EtOAc)to affordN-methyl-3-[8-(1-methyl-1H-indol-6-yl)quinoxalin-6-yl]amino}pyridine-4-carboxamide11as a yellow powder (62 mg; 0.15 mmol; yield: 83%; LCMS purity: 97%, method B). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With triethylamine; In dichloromethane; at 20℃; | Under anhydrous conditions, a solution of (2-oxaadamantan-1 -yl)isocyanate (323 mg, 1.80 mmol) in anh. DCM (20 mL) was added to a solution of 1 -acetyl-4- aminopiperidine (308 mg, 2.16 mmol) in anh. DCM (10 mL), followed by TEA (0.50 mL, 3.61 mmol). The reaction mixture was stirred at room temperature overnight. The solution was then concentrated under vacuo to give an orange gum (720 mg). Purification by column chromatography (Si02, DCM/methanol mixture) gave the title compound lf (300 mg, 52% yield) as a white solid. The analytical sample was obtained by washing with pentane, mp 172-173 C. IR (ATR): 3322, 2920, 2850, 2153, 2000, 1637, 1549, 1428, 1369, 1313, 1264, 1234, 1 192, 1 139, 1090, 1046, 995, 959, 879, 816, 773, 731 cm"1. MS (DIP), m/e (%): 321 (M +, 34), 197 (32), 179 (34), 169 (14), 155 (1 1 ), 154 (100), 153 (18), 143 (12), 138 (13), 137 (33), 136 (32), 127 (10), 126 (15), 125 (51 ), 124 (14), 122 (21 ), 1 1 1 (17), 1 10 (13), 99 (12), 96 (41 ), 95 (18), 94 (45), 93 (1 1 ), 85 (10), 84 (19), 83 (37), 82 (54), 81 (10), 79 (22), 70 (12), 69 (10), 68 (13), 67 (20), 57 (23), 56 (32), 55 (15). Anal. Calcd for Ci7H27N3O3-0.2H2O: C 62.82, H 8.50, N 12.93. Found: C 62.70, H 8.59, N 12.74. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30 mg | Under argon atmosphere, to a solution of N-(1-[6-chloro-2-(pyrazolo[5,1-b][1,3]thiazol-7-yl)pyrimidin-4-yl]carbonyl}piperidin-4-yl)cyclopropanecarboxamide (30 mg) obtained in Reference Example 15 in 2-propanol (2 mL) were added DIPEA (48 muL) and <strong>[160357-94-8]1-(4-amino-1-piperidyl)ethanone</strong> (15 mg), and the mixture was stirred at 90 C for 1 h. NMP (0.5 mL) was further added, and the mixture was stirred at 120 C for 2 h. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (30 mg). MS (m/z): 537 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; for 3h;Heating; | General procedure: A mixture of 5 (1 eq.) and amine (2 eq.) in ethanol was stirred at 85 C for 3 h. The mixture was concentrated and purified by flash column chromatography to give compound 6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 100℃; for 7h;Inert atmosphere; | A solution of Pd(OAc)2 (55 mg, 0.24 mmol) and BINAP (299 mg, 0.48 mmol) in 1,4-dioxane (5 ml.) under N2 (g) was heated at 40 C for 1 h. A solution of benzyl 2,3- dichloroisonicotinate (227 mg, 0.81 mmol) and 1-(4-aminopiperidin-1 -yl)ethanone (230 mg, 1 .6 mmol) in degassed 1,4-dioxane (2 mL) was added followed by CS2CO3 (369 mg, 1 .1 mmol) and the resulting mixture heated at 100 C for 6 hours. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic fractions were washed with water, brine, dried (Na2S04), filtered and concentrated. The residue was purified by column chromatography (EtOAc/petroleum ether=1/5) to give the crude title product (200 mg, 64%) as yellow solid which was used without further purification. LCMS: RT 2.78 min; m/z 388.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 40 - 100℃;Inert atmosphere; | To a suspension of Pd(OAc)2 (45 mg, 0.20 mmol) in 1,4-dioxane (12 mL)was added BINAP(250 mg, 0.40 mmol) under nitrogen. The mixture was stirred for 1 hour at 40 00. A solutionof benzyl 2-chloro-3-ethoxyisonicotinate A5 (200 mg, 0.68 mmol) and <strong>[160357-94-8]1-(4-aminopiperidin-1-yl)ethanone</strong> A2 (195 mg, 1 .36 mmol, free base) in degassed 1 ,4-dioxane (4 mL) and 0S2003(313 mg, 0.96 mmol) were then added and the reaction stirred at 100 00 overnight. Thesolvent was removed under reduced pressure and the residue obtained dissolved in EtOAc(50 mL) and washed with water (50 mL). The aqueous layer was extracted with EtOAc (50 mL) and the combined organic fractions washed with brine (50 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography (3% v/v methanol in DCM) then further purified by preparative TLC (3% v/v methanol in DCM) to give the titlecompound as yellow oil (90 mg, 22%). LOMS: RT 2.64 mm; m/z 398.2 [M+H] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With sodium hydroxide; In water; for 2h;pH 11; | To a solution of tert-butyl (1-acetylpiperidin-4-yl)carbamate Al (4.8 g, 19.8 mmol) in amixture of DOM (20 mL) and MeOH (20 mL) was added a solution of HCI in Et20 (1 .8 M, 20mL). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue washed with EtOAc (20 mL) to give l-(4- aminopiperidin-l-yl)ethanone hydrochloride as a white solid (3.2 g, 91%). 1H NMR (400 MHz, Methanol-d4) 64.60-4.57 (m, 1H), 4.05-4.01 (m, 1H), 3.43-3.37 (m,1H), 3.26-3.19 (m,1H), 2.77-2.70(m, 1H), 2.14 (s, 3H), 2.10-2.04 (m, 2H), 1.65-1.43(m, 2H); LCMS: RT 0.25 mm; m/z 143.1 [M+H]. The free base was prepared as follows: to a solution of 1-(4- aminopiperidin-1-yl)ethanone hydrochloride (3.0 g, 16.8 mmol) in water (20 mL) was added a 4 M aqueous Na0H solution and adjusted to pH 11. The mixture was lyophilized. The solidwas extracted with DCM (6x40 mL) and concentrated to give the title compound (0.8 g, 35%) as a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 20℃; | General procedure: A solution of 4-chloro-6-[1-(4-methylbenzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]quinoline (Intermediate 4) (0.15 g, 0.35 mmol, 1.0 eq.), (S)-3-(Boc-amino)piperidine (0.14 g, 0.7 mmol, 2.0 eq.), DIPEA (0.09 g, 0.7 mmol, 2.0 eq.) in i-PrOH (3 mL) was heated at 140 C. under microwave irradiation for 1.5 h. After cooling to rt, solvent was evaporated and the crude reaction mixture was used in consecutive step without further purification (UPLC purity: 71%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14% | A mixture of (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-S -(4-(4-fluorophenethoxy)phenyl)-2-methyl-6-(((trifluoromethyl)sulfonyl)oxy)pyridin-3 -yl)acetate (0.02 g, 0.027 mmol), <strong>[160357-94-8]1-(4-aminopiperidin-1-yl)ethanone</strong> (0.015 g, 0.108mmoland sodium tert-butoxide (5.20 mg, 0.054 mmol) in NMP (1 mL) was heated at 180C for 5 h. The reaction was then cooled to ambient temperature. Ethanol (0.5 mL) and 5M NaOH (0.054 mL, 0.27 1 mmol) were added to the reaction mixture and heated at 80for 2 h, cooled to ambient temperature, and filtered. The crude mixture was purified via preparative HPLC to afford the desired product (2.7 mg, 14%). LCMS (M+1) = 689.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.49 g | With triethylamine; In dichloromethane; at 0℃; for 1h; | To a stirred solution of methyl 2,6-dichloropyrimidine-4-carboxylate (CAS Number 6299-85-0; available from Ark Pharma) (2.32 g, 1 1.200 mmol) in dichloromethane (50 ml) were added triethylamine (3.12 ml, 22.400 mmol) and 1 -(4-aminopiperidin-1 -yl) ethanone (2.20 g, 15.490 mmol) at 0C and the reaction mixture was stirred for 1 h. The resulting reaction mixture was poured into water (100 ml) and extracted with dichloromethane (3 x 25 ml). The combined organic phase was dried over Na2SC>4, filtered and concentrated under reduced pressure. The resulting crude material was purified by flash chromatography (2% methanol in dichloromethane) yielding methyl 6-[(1 -acetylpiperidin-4-yl) amino]-2-chloropyrimidine-4- carboxylate (3.49 g, 1 1 .180 mmol). LCMS: Method A, 1 .548 min, MS: ES+ 312.9 (M+1 ).Step d |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In 1,4-dioxane; at 90℃; for 24h; | (0218) A 5 ml round-bottomed flask was charged with Compound 53A (120 mg), 1-acetylpiperidin-4-amine (28 mg), and triethylamine (0.064 ml) in dioxane (2 ml). The reaction mixture was heated to 90 C. for 24 hours. The reaction mixture was cooled to room temperature, and added to a silica gel column and purified by eluting with 0-5% methanol in dichloromethane. 1H NMR (300 MHz, dimethylsulfoxide-d6) delta 11.66 (br s, 1H), 8.65 (d, 1H), 8.24 (d, 1H), 8.03 (d, 1H), 7.83 (dd, 1H), 7.54-7.46 (m, 3H), 7.35 (d, 2H), 7.19 (d, 1H), 7.04 (d, 2H), 6.68 (dd, 1H), 6.39 (m, 1H), 6.20 (d, 1H), 4.28 (d, 1H), 3.97-3.75 (m, 2H), 3.07 (br s, 4H), 2.87-2.70 (m, 4H), 2.29-2.10 (m, 6H), 2.02 (s, 3H), 2.00-1.89 (m, 4H), 1.66-1.54 (m, 2H), 1.39 (t, 2H), 0.92 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | General procedure: N,N-Diisopropylethylamine (3.0-4.0 eq) was added to 8-methoxyquinoline-3-carboxylic acid (1.0 eq) in solvent (dichloromethane, tetrahydrofuran,or N,N-dimethylformamide, 0.05 to 0.2 M) at room temperature. Then, 1-((dimethylamino)(dimethyliminio)methyl)-1H-[1,2,3]triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate(V)(1.0-1.5 eq) was added and the reaction mixture was stirred for five minutes. Then, amine (1.0 - 2.0 eq) was added and the reaction mixture was stirred for one to sixteen hours. 10% Aqueous citric acid was added and the reaction mixture was extracted with dichloromethane, washed with saturated sodium bicarbonate, dried over magnesium sulfate, filtered,and concentrated. The resulting residue was purified by RP HPLC or silica gel chromatography to give the quinoline-3-carboxamide (1%-95% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12% | In tetrahydrofuran; at 120℃; for 48h;Sealed tube; | A solution of Example 30 (110 mg, 0.37 mmol, 1.0 eq) and <strong>[160357-94-8]1-(4-aminopiperidin-1-yl)ethanone</strong> (53 mg, 0.37 mmol, 1.0 eq) in THF (10 mL) was heated at 120 C. in a sealed tube for 2 days. The mixture was allowed to cool to RT, diluted with water (20 mL) and extracted with EtOAc (30 mL*3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by prep-TLC (DCM:MeOH, 10/1, v/v) to afford the title compound (20 mg, 12%) as a white solid. LCMS: [M+H]+ 417.2. 1H NMR (400 MHz, DMSO-d6) delta 11.9 (s, 1H), 7.93-7.72 (m, 2H), 7.13 (dd, J=9.2, 2.4 Hz, 1H), 6.90-6.85 (m, 1H), 3.95-3.85 (m, 2H), 3.85-3.75 (m, 3H), 3.61 (s, 2H), 3.36-3.34 (m, 1H), 3.31-3.27 (m, 1H), 3.10-2.95 (m, 3H), 1.94-1.84 (m, 2H), 1.84-1.81 (m, 2H), 1.79 (s, 3H), 1.35-1.51 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; for 3h;Reflux; Inert atmosphere; | To a stirred solution of 7-bromo-2-(2-((tert-butyldimethylsilyl)oxy)-3-(3, 4-dihydro isoquinolin-2(lH)-yl)propyl)-3,4-dihydroisoquinolin-l(2H)-one (1.00 g, 1.89 mmol, 1.0 eq) in 1,4-dioxane (20 ml) was added l-(4-aminopiperidin-l-yl)ethan-l-one (1.10 g, 7.74 mmol, 4.1 eq), solid Cs2C03 (1.83 g, 5.67 mmol, 3.0 eq), catalytic Pd2(dba)3 and XantPhos, and the resultant mixture was heated to reflux under nitrogen gas atmosphere for 3 hours. The reaction mixture was concentrated to dryness, and the residue was treated with water/EA. Organic phase was dried over MgS04, and was concentrated to dryness. The residue was purified by column chromatography (DCM/MeOH=20/ 1-10/1) to afford 7-((l-acetylpiperidin-4-yl)amino)- 2-(2-((tert-butyldimethylsilyl)oxy)-3-(3,4-dihydroisoquinolin-2(lH)-yl)propyl)-3,4-dihydroisoqu inolin-l (2H)-one (0.51 g, 46% yield) as a yellow solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With triethylamine; In dichloromethane; at 20℃;Inert atmosphere; | Under argon atmosphere, tricyclo[3.3.1.03,7]nonane-3-isocyanate (18) (360 mg, 2.20 mmol) was dissolved in anh. DCM (10 mL). 1-acetyl-4-aminopiperidine (375 mg, 2.64 mmol) and Et3N (445 mg, 4.40 mmol) were added. The reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was dissolved in EtOAc and washed with 2 N HCl. The organics were dried over anh. Na2SO4, filtered and evaporated in vacuo affording a white yellowish solid which was washed with acetone and EtOAc affording the urea 25 as a yellowish solid (240 mg, 36% yield), mp 164-165 C. IR(ATR) nu: 638, 705, 783, 860, 904, 974, 992, 1059, 1139, 1230, 1269,1318, 1361, 1429, 1555, 1620, 1659, 2351, 2919, 3328 cm-1. 1H NMR(400 MHz, CDCl3) delta: 1.16-1.29 (complex signal, 2H, 4-Hax and 5-Hax),1.47-1.61 [complex signal, 4H, 9?-H2 and 6?(8?)-Hax], 1.80 [dd,J=10.0 Hz, J?=2.8 Hz, 2H, 2?(4?)-Hax], 1.84-2.01 [complex signal,6H, 6?(8?)-Heq, 2?(4?)-Heq, 4-Heq and 5-Heq], 2.07 (s, 3H, 8-H), 2.23 [broad singlet, 2H, 1?(5?)-H], 2.34 (t, J=6.8 Hz, 1H, 7?-H), 2.74 (dt,J=11.2 Hz , J?=2.4 Hz, 1H, 2-Hax or 6-Hax), 3.13 (dt, J=12 Hz,J?=2.4 Hz, 1H, 6-Hax or 2-Hax), 3.71-3.85 (complex signal, 2H, 2-Heqor 6-Heq and 4-H), 4.43 (d, J=13.6 Hz, 1H, 6-Heq or 2-Heq), 4.89 (d,J=8.0 Hz, 1H, NH), 5.11 (s, 1H, NH). 13C NMR (100.6 MHz, CDCl3) delta:21.4 (CH3, COCH3), 32.5 (CH2, C4 or C5), 33.7 (CH2, C5 or C4), 34.8(CH2, C9?), 37.3 [CH, C1?(5?)], 40.7 (CH2, C2 or C6), 43.4 [CH2,C6?(8?)], 43.7 (CH, C7?), 45.4 (CH2, C6 or C2), 46.7 (CH, C4), 49.30 and49.32 (CH2, C2? and C4?), 64.1 (C, C3?), 157.1 (CO, urea), 169.0 (CO,COCH3). Elemental analysis: Calcd for C17H27N3O2·0.15C5H12: C 67.42,H 9.18, N 13.29. Found: C 66.38, H 9.00, N 13.05. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | In dichloromethane; at 20℃;Inert atmosphere; | Diamantane-3-isocyanate (20) (155 mg, 0.67 mmol) was dissolved in DCM (3 mL) and 1-acetyl-4-aminopiperidine (115 mg, 0.811 mmol) dissolved in DCM (2 mL) was added. The mixture was stirred at room temperature overnight. Evaporation of the solvent gave a white solid (272 mg). Column chromatography (Dichloromethane/Methanol mixtures) gave the urea 26 (160 mg, 65% yield) as a white solid, mp 230-231 C. IR (ATR) nu: 669, 727, 770, 808, 862, 917, 989, 1047, 1136,1240, 1319, 1364, 1453, 1560, 1629, 1794, 1855, 1893, 1944, 1977,2051, 2102, 2153, 2209, 2270, 2352, 2418, 2545, 2596, 2734, 2877,3020, 3071, 3275, 3316, 3494, 3566, 3688 cm-1. 1H NMR (400 MHz,CD3OD) delta: 1.32 [complex signal, 2H, 3(5)-Hax], 1.66-1.82 (complexsignal, 16H, diamantane-H), 1.85-1.98 (complex signal, 4H, 3-Heq, 5-Heq, 2 diamantane-H), 2.10 (s, 3H, COCH3), 2.91 (dt, J=11.2 Hz,J?=2.8 Hz, 1H, 2-Hax or 6-Hax), 3.25 (dt, J=11.2 Hz, J?=3.2 Hz, 2H,6-Hax or 2-Hax), 3.71-3.78 (complex signal, 2H, 4-H and 1?-H), 3.85 (dt,J=14 Hz, J?=2.4 Hz, 2H, 6-Heq or 2-Heq), 4.29 (dt, J=13 Hz,J?=2.8 Hz, 2H, 2-Heq or 6-Heq). 13C NMR (100.6 MHz, CD3OD) delta: 21.2(CH3, COCH3), 27.7 (CH), 31.8 (CH), 33.3 (CH2, C3 or C5), 33.4 (CH2),33.6 (CH2), 34.1 (CH2, C5 or C3), 38.0, 38.1, 38.6, 38.7 (2 carbon),38.91, 38.94 and 39.0 (3 CH2 and 5 CH, diamantane signals), 41.6(CH2, C2 or C6), 43.3 (CH, C4?), 46.3 (CH2, C6 or C2), 47.7 (CH, C4),55.9 (CH, C3?), 159.7 (C, CO urea), 171.5 (C, COCH3). HRMS-ESI+ m/z[M+H]+ calcd for [C22H33N3O2+H]+: 372.2646, found: 372.2644. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | In 1,2-dichloro-ethane; at 50℃; for 21h;Inert atmosphere; | N,N?-carbonyldiimidazole (400 mg, 2.46 mmol) was suspended in anh. 1,2-dichloroethane (15 mL) under nitrogen. Then 1-acetyl-4-aminopiperidine (22) (250 mg, 1.76 mmol) was added and the reaction mixture was heated to 50 C for 21 h. With an external ice bath, the mixture was cooled down for 30 min. The resulting solid was collected by filtration in vacuo and washed with 1,2-DCE (20 mL) affording 23(312 mg, 75% yield) as a white solid, mp 191-193 C. IR (ATR) nu: 3216,3118, 3038, 2918, 2342, 2074, 1709, 1613, 1542, 1479, 1463, 1441,1369, 1358, 1320, 1281, 1272, 1233, 1195, 1137, 1111, 1090, 1068,1053, 1001, 984, 974, 916, 902, 859, 799, 748, 652 cm-1. 1H NMR(400 MHz, CDCl3) delta: 1.37 (complex signal, 2H, 3-Hax, 5-Hax), 1.99 (dm,J=12.8 Hz, J?=4 Hz, 1H) and 2.21 (dm, J=12.8 Hz, J?=4 Hz, 1H)(3?-Heq and 5?-Heq), 2.09 (s, 3H, COCH3), 2.69 (ddd, J=13 Hz,J?=2.6 Hz, 1H) and 3.21 (ddd, J=13 Hz, J?=2.6 Hz, 1H) (2?-Hax and 6?-Hax), 3.86 (dm, J=13.6 Hz, 1H) and 4.67 (dm, J=13.6 Hz, 1H) (2?-Heq and 6?-Heq), 4.10 (m, 1H, 4?-H), 7.06 (dd, J=1.6 Hz, J?=0.8 Hz,1H, 4-H), 7.29 (broad d, J=7.6 Hz, 1H, NH), 7.60 (dd, J=1.6 Hz,J?=1.2 Hz, 1H, 5-H), 8.29 (dd, J=1.2 Hz, J?=0.8 Hz, 1H, 2-H). 13CNMR (100.6 MHz, CDCl3) delta: 21.5 (CH3, COCH3), 31.4 and 33.1 (CH2,C3? and C5?), 40.9 and 45.6 (CH2, C2? and C6?), 48.2 (CH, C4?), 116.2(CH, C5), 130.3 (CH, C4), 136.2 (CH, C2), 148.5 (C, NHCNH), 169.2 (C,COCH3). MS (DIP), m/z (%); significant ions: 169 (10), 168 (100), 153(19), 126 (53), 125 (31), 85 (19), 84 (42), 83 (20), 82 (23), 81 (21), 68(98), 57 (40), 56 (56), 55 (16). HRMS-ESI+ m/z [M+H]+ calcd for[C11H16N4O2+H]+: 237.1346, found: 237.1345. |
Tags: 160357-94-8 synthesis path| 160357-94-8 SDS| 160357-94-8 COA| 160357-94-8 purity| 160357-94-8 application| 160357-94-8 NMR| 160357-94-8 COA| 160357-94-8 structure
[ 214147-48-5 ]
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P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
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 |
Sorry,this product has been discontinued.
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