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CAS No. : | 50533-97-6 | MDL No. : | MFCD00023144 |
Formula : | C7H16N2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | YFJAIURZMRJPDB-UHFFFAOYSA-N |
M.W : | 128.22 | Pubchem ID : | 417391 |
Synonyms : |
|
Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P264-P271-P280-P301+P330+P331-P304+P340-P303+P361+P353-P305+P351+P338-P310-P363-P403+P233-P501 | UN#: | 2735 |
Hazard Statements: | H314 | Packing Group: | Ⅲ |
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 |
---|---|---|
88% | Stage #1: With 1,1'-carbonyldiimidazole In tetrahydrofuran at 50℃; for 2 h; Stage #2: at 53℃; for 16 h; |
To a slurry of 4-(3-(4-(4,6-dimorpholin-4-yl-1,3,5-triazine-2-yl)phenyl)ureido)benzoic acid (7, 45.5 g, 0.09 mol) in dry THF (1.6 L) heated to 50 0C was added N,N'-carbonyl diimidazole (28 g, 0.17 mol). The reaction mixture was heated for 2 hours and followed by dimethylaminopiperidine (8, 23.5 g, 0.18 mol) and stirred at 53 0C for 16 hours. The reaction mixture was cooled to the room temperature and filtered. The cake was washed with 2-propanol and air-dried to give 97 percent pure white powder in 88percent yield (49.2 g, 0.08 mol). To the solids stirred in dimethyl acetamide (DMAC, 165 ml) at 70° C for 1 hour was added 2-propanol (640 ml) and the mixture was stirred at 65 0C for additional 1 hour. The solids were filtered, washed with 2-propanol and dried in a vacuum oven at 700C for 16 hour to give crystalline white powder (45 g) with >;99percent purity. The above-mentioned work up process and crystallization procedure gave a Pd residue of 20 ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; for 24h;Heating / reflux; | Preparation XXII; Synthesis of [l-(4-amino-phenylVpiperidin-4-yl]-dimethyl-amine; Step 1; . Synthesis of dimethyl- Fl -C4-nitro-phenylVpiperidin-4-y 11 -amine; <n="118"/>l-Fluoro-4-nitrobenzene (2.6Og, 18.40 mmol) was dissolved in acetonitrile (50ml), 4-dimethylamino piperidine (2.5g, 19.5 mmol) and Hunig's base (3.4 ml, 19.5 mmol) were added and the mixture heated to reflux over 24 h. The reaction mixture was allowed to cool to room temperature and evaporated in vacuo. The solid residue was triturated with diethyl ether and filtered to afford the title compound as a bright yellow solid (4.33g, 94%) (LCMS: Rt 2.71, [M+H]+250]. |
85% | With triethylamine; In dimethyl sulfoxide; at 100℃; for 22h;Inert atmosphere; | EXAMPLE 36AA 100 niL flask charged with l-fluoro-4-nitrobenzene (2.122 rnL, 20 mmol), DMSO (30 ml), N,N-dimethylpiperidin-4-amine (2.82 g, 22.00 mmol) and triethylamine (5.58 mL, 40.0 mmol). The mixture was heated at 100 0C under nitrogen for 22 hours. Upon cooling, the mixture was poured into stirring cold water (1000 mL) and the resulting solid was collected by filtration, washed with water, and dried to give the title compound (4.24 g, 85%). MS (ESI(+)) m/e 250 (M+H)+, (ESI(-)) m/e 248 (M-H)". |
85% | With potassium carbonate; In dimethyl sulfoxide; at 20℃;Inert atmosphere; Schlenk technique; | General procedure: A solution of 4-fluoronitrobenzene 6 (2 g, 14.2 mmol) and anhydrous K2CO3 (2.2 g, 15.6 mmol) in DMSO (5 mL) was stirred at room temperature for 10 min. The appropriate secondary amine (14.2 mmol) was added dropwise, and the resulting reaction mixture was stirred at room temperature for 10 h. The mixture was then poured into ice-water to form a precipitate collected by filtration then dried to give the nitrophenyl derivative 7a-7e. |
With triethylamine; In dimethyl sulfoxide; at 100℃; for 14h; | A 100 ml flask charged with l-fluoro-4-nitrobenzene (2.122 ml, 20 mmol), dimethylsulfoxide (30 ml), N,N-dimethylpiperidin-4-amine (2.82 g, 22.00 mmol) and triethylamine (5.58 ml, 40.0 mmol). The resulting solution was heated at 100C for 24 hours. After cooling to ca. 40 C the reaction mixture was poured in stirring cold water (1000 ml) and the resulting solid was collected by filtration, washed well with water and dried. MS (ESI(+)) m/e 250 (M+H)+, (ESI(-)) m/e 248 (M-H)-. | |
With potassium carbonate; In dimethyl sulfoxide; | General procedure: The reaction of 2,4-dichloro-5-nitropyrimidine withisopropylamine produced intermediate 2-chloro-N-isopropyl-5-nitropyrimidin-4-amine. 4-Fluoronitrobenzene reacted with1-methylpiperazine in DMSO yielded the intermediate 1-methyl-4-(4-nitrophenyl)piperazine in the presence of K2CO3. The catalytichydrogenation of 1-methyl-4-(4-nitrophenyl)piperazine with palladiumon carbon (Pd/C, 5%) quantificationally provided thedesired 4-(4-methylpiperazin-1-yl) aniline. Refluxing of the 2-chloro-N-isopropyl-5-nitropyrimidin-4-amine with 4-(4-methylpiperazin-1-yl)aniline in n-butanol yielded N4-isopropyl-N2-(4-(4-methylpiperazin-1-yl)phenyl)-5-nitropyrimidine-2,4-diamine,which was reduced to intermediate A1 with a good yield by catalytichydrogenation using Pd/C as a catalyst. Intermediates A wereprepared as these steps and used for the next step without furtherpurification. These processes were carried out as reported | |
With triethylamine; In dimethyl sulfoxide; at 100℃; for 24h;Inert atmosphere of nitrogen; | A 100 ml flask was charged with l-fluoro-4-nitrobenzene (2.122 ml, 20 mmol), dimethylsulfoxide (30 ml), N,N-dimethylpiperidin-4-amine (2.82 g, 22.00 mmol) and triethylamine (5.58 ml, 40.0 mmol). The resulting solution was stirred at 100 0C under nitrogen for 24 hours. The reaction mixture was allowed to cool, and was poured in stirring cold water (1000 ml) and the solid collected by filtration and washed with water. The precipitate was vacuum dried to provide the title compound. MS (ESI(+)) m/e 249.9 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.6% | With potassium carbonate; L-proline;copper(l) iodide; In N,N-dimethyl-formamide; at 100℃; | Step A: Preparation of 1-(4-(4-amino-2-fluorophenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-N,N-dimethylpiperidin-4-amine: A 100 mL round-bottomed flask was charged with 4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (50.0 mg, 0.102 mmol, prepared in Example 7, step B), N,N-dimethylpiperidin-4-amine (39.2 mg, 0.306 mmol), copper(I)iodide (3.88 mg, 0.0204 mmol), (S)-pyrrolidine-2-carboxylic acid (4.70 mg, 0.0408 mmol), K2CO3 (70.5 mg, 0.510 mmol) and DMF (10 mL). The reaction mixture was stirred at 100 C. overnight. Then the reaction was cooled to room temperature and partitioned between EtOAc and H2O. The phases were separated and the aqueous phase was re-extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to afford product (35.8 mg, 71.6%). LRMS (APCI pos): >98% purity, 254 nm, m/e 491 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64.03% | With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 90℃; for 16h;Inert atmosphere; | Step 1 N,N-dimethyl-1-(6-nitropyridin-3-yl)piperidine-4-amine In a nitrogen atmosphere, to a solution of N,N-dimethylpiperidine-4-amine (100.00 mg, 779.97 mumol, 1.00 equivalent) and 5-bromo-2-nitropyridine (158.33 mg, 779.97 mumol, 1.00 equivalent) in dioxane (5 mL) were added B1NAP (48.57 mg, 78.00 mumol. 0.10 equivalent), cesium carbonate (508.26 mg, 1.56 mmol, 2.00 equivalents) and Pd(OAc)2 (17.51 mg , 78.00 mumol, 0.10 equivalent). The reaction mixture was then heated to 90C and stirred for 16 hours. TLC showed completion of the reaction of the starting material. The reaction mixture was filtered and concentrated to give a crude product. The crude product was purified by preparative TLC (dichloromethane: methanol = 10: 1) to give the title compound (125.00 mg, 499.40 mumol, 64.03% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) delta 8.20-8.14 (m, 2H), 7.21 (dd, J = 9.2, 3.2 Hz, 1H), 3.99 (d, J = 13.2 Hz, 2H), 3.12-3.02 (m, 2H), 2.47-2.39 (m, 1H). 2.33 (s, 6H), 2.01 (d, J = 12.4 Hz, 2H), 1.70-1.64 (m, 2H). LC/MS (ESI) m/z: 251.1 (M+1). |
38% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; for 60h;Heating / reflux; | Preparation XXI; Synthesis of 4N.4N-dimethyl-3.4,5.6 tetrahvdro-2H-? ,3'lbvpyridmylV4.6'-diamine; <n="117"/>Step 1. Synthesis of dimethyl-r6'-nitro-3.4.5.6-tetrahvdro-2H-ri,3'1bvpyridinyl-4- ylVamine5-Bromo-2-nitropyridine; (3.7Og, 18.40 mmol) was dissolved in acetonitrile (40ml), 4-dimethylamino piperidine (2.5g, 19.5 mmol) and Hunig's base (3.4 ml, 19.5 mmol) were added and the mixture heated at reflux for 60 h. The reaction mixture was allowed to cool to room temperature and the desired product was collected by filtration as a yellow solid (1.73 g, 38 %) (LCMS: R12.29, [M+H]+251). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 12h; | Methyl 2-bromo-3-cyclohexyl-lH-indole-5-carboxylate (from Step 2) was alkylated and deprotected as described in Example 1, Steps 4 and 5 to afford [2-bromo-3- CYCLOHEXYL-5- (METHOXYCARBONYL)-LH-INDOL-1-YL] acetic acid. A solution (0. 3 M) of this material in CH2C12 was treated with N,N-dimethylpiperidin-4-amine (1.5 eq. ), DIPEA (4 eq. ) and HATU (1.5 eq. ). The solution was stirred at 20 C for 12 h. The mixture WAS DILUTED WITH CH2C12 then washed with aqueous NaOH (2 N) and brine. The organic layer was dried and concentrated to give A residue that was purified by flash chromatography on silica gel (5: 95 ETOAC/PETROLEUM ETHER) to afford the title compound (70 %) as a solid. 1H NMR (300 MHz, DMSO-D6, 300 K) 81. 31-1.56 (m, 5H), 1.67-1. 96 (M, 9H), 2.21 (s, 6H), 2.30-2. 44 (m, 1H), 2. 60-2. 74 (m, 1H), 2. 80-2. 97 (M, 1H), 3.07-3. 24 (m, 1H), 3. 88 (s, 3H), 3.99-4. 13 (m, 1H), 4.17-4. 32 (m, 1H), 5.13-5. 34 (M, 2H), 7.54 (D, J 8. 6 Hz, 1H), 7.75 (d, J 8. 6 Hz, 1H), 8. 34 (s, 1H); MS (ES+) m/z 504,506 (M+H) +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With potassium carbonate; In dimethyl sulfoxide; at 100℃; for 16h; | Example 1a; 3-Phenylsulfonyl-8-[(4-dimethylamino)-piperidin-1-yl]-quinoline (E1a); A solution of 8-fluoro-3-(phenylsulfonyl)quinoline (D2) (287 mg, 1.0 mmol) and 4- dimethylamino-piperidine (770 mg, 5.0 mmol) in DMSO was stirred with potassium carbonate (276 mg, 2.0 mmol) in DMSO (2 ml) at 100C for 16 h under an argon atmosphere. The mixture was cooled to RT, poured into water (50 ml) and extracted with ethyl acetate (50 ml). The organic phase was then washed a further three times with water, dried, (anhydrous sodium sulfate) and concentrated in vacuo to afford the 3- phenylsulfonyl-8- [(4-dimethylamino)-piperidin-1-yl]-quinoline (E1a) (413 mg, 0.95 mmol, 95%) as a yellow solid. ¹H NMR (CDCI3) 8 1.85-2.01 (4H, m), 2.35 (6H, s), 2.38 (1H, m), 2.73-2.86 (2H, m), 3.90-4.02 (2H, m), 7.29 (1 H, d, J = 2.6 Hz), 7.45-7.62 (5H, m), 7.98-8.06 (2H, m), 8.76 (1 H, d, J = 2.6 Hz), 9.22 (1 H, d, J = 2.6 Hz). MS: m/z (M+H)+ 396; C22H25N302S requires 395. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); DavePhos; In 1,4-dioxane; at 80℃; for 7h; | Example 12; 1-{3-((4-Fluorophenyl)sulfonyl]-8-quinolinyl}-N,N-dimethyl-4-piperidinamine hydrochloride (E12); A suspension of 8-chloro-3- [(4-fluorophenyl)sulfonyl]quinoline (232 mg, 1 equivalent), N, N-dimethyl-4-piperidinamine (139 mg, 1.5 equivalents), tris(dibenzylideneacetone)dipalladium(0) (20.1 mg, 0.03 equivalents), 2- dicyclohexylphosphino-2'- (N,N-dimethylamino)-biphenyl (25.6 mg, 0.09 equivalents) and sodium t-butoxide (104 mg, 1.5 equivalents) was stirred in dioxan (2.5 ml) at 80C for 7 hours. The solvent was then evaporated and the reaction mixture dissolved in ethyl acetate and filtered. The mixture was washed with water then brine, dried with magnesium sulphate, filtered and evaporated to dryness, producing a yellow oil. This was then purified on silica eluting with dichloromethane and dichloromethane/methanol/ammonia (79/20/1, 0-50%). 1-{3-[(4-Fluorophenyl)sulfonyl]-8- quinolinyl}-N,N-dimethyl-4-piperidinamine was obtained as a yellow oil (165 mg, 55%). This was then converted to the hydrochloride salt using hydrogen chloride (1 M in diethyl ether), and crystallised from ethanol and diethyl ether to afford 1-{3-[(4- fluorophenyl)sulfonyl]-8-quinolinyl}-N,N-dimethyl-4-piperidinamine hydrochloride (E12) as a yellow solid (110 mg). ¹ H NMR (CDCI3) No. 2.18 (2H, m), 2.39 (2H, d, J=12 Hz), 2.82 (6H, s), 2.86 (2H, m), 3.32 (1 H, m), 4.08 (2H, d, J=12 Hz), 7.24 (2H, t), 2.29 (1 H, m), 7.60 (2H, m), 8.04 (2H, m), 8.76 (1 H, d, J=2.5 Hz), 9.20 (1 H, d, J=2.0 Hz), 12.8 (1 H, broad s). MS: m/z (M+H)+ 414; C22H24FN302S requires 413. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen;palladium; In methanol; | A solution of the <strong>[64168-08-7]1-benzyl-4-dimethylaminopiperidine</strong> in 125 ml. of methanol was shaken with 1.0 gm. of 10 percent palladium on carbon under 50 psi of hydrogen at 50C. until one equivalent of hydrogen was consumed. The suspension was filtered and the filtrate concentrated at atmospheric pressure. The residue was distilled at 20 mm. Hg. to give 4-dimethylaminopiperidine, b.p. 90-92C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium hydroxide; triethylamine; In N-methyl-acetamide; methanol; chloroform; water; | 5.3. (S)-5-(8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-3-[1-[5-[4-(dimethyl_amino)piperidin-1-yl]-5-oxopentyl]pyrrolidin-3-yl]-1,3,4-oxadiazol-2-(3H)-one 0.24 g (0.51 mmol) of (S)-3-[5-[7-chloro-8-amino-2,3-dihydro-1,4-benzodioxin-5-yl]2-oxo-2,3-dihydro-1,3,4-oxadiazol-3-yl]pyrrolidine-1-pentanoic acid dissolved in 2.5 ml of dimethylformamide, and 0.14 ml (1.01 mmol) of triethylamine are introduced into a 25 ml three-necked round-bottomed flask. A solution of 0.16 g (1.01 mmol) of 1,1'-carbonylbis-1H-imidazole in 1.1 ml of dimethylformamide is added dropwise and the mixture is stirred at room temperature for 2 h 30 min. A solution of 0.76 mmol of 4-(dimethylamino)piperidine in 1.8 ml of dimethylformamide (prepared beforehand by heating a suspension of 0.16 g (0.76 mmol) of <strong>[4876-59-9]4-(dimethylamino)piperidine dihydrochloride</strong> in 1.8 ml of dimethylformamide and 0.28 ml (2.02 mmol) of triethylamine at 60 C. for 2 h) is added and the mixture is stirred at room temperature for 18 h. The reaction medium is poured into 30 ml of water and extracted with chloroform. The product is purified by chromatography on silica gel, eluding with a 95/5/0.5 and then 80/20/2 mixture of chloroform, methanol and aqueous ammonia. 0.08 g of product is thus obtained in the form of a sticky paste. [alpha]20D =+26 (c=0.4, CHCl3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | In N,N-dimethyl-formamide; at 80℃; for 1h; | Example 204; Preparation of N-(2,4-difluorophenyl)-5-{3-[4-(dimethylamino)-1-piperidinyl]-6-quinoxalinyl}-3-pyridinesulfonamide; a) 1-(7-bromo-2-quinoxalinyl)-N,N-dimethyl-4-piperidinamine; A solution of <strong>[89891-65-6]7-bromo-2-chloroquinoxaline</strong> (1.20 mmol) in N,N-dimethylformamide (5 ml) was treated with an amine (or an alcohol) such as 1,1-dimethylethyl [2-(1-piperazinyl)ethyl]carbamate (3.60 mmol) then heated at 80 C. for 1 hour. The reaction was cooled to ambient temperature then poured into water (25 ml). Product precipitated out of solution, which was filtered and dried. Alternatively, after the reaction is cooled to ambient temperature and poured into water (25 ml), it was extracted into ethyl acetate (3×25 ml). The extracts were washed with brine then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (400 mg, 99%) as a yellow solid. MS (ES)+ m/e 336.2 [M+]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With N-ethyl-N,N-diisopropylamine; In ISOPROPYLAMIDE; at 100℃; for 4h; | 4-(Dimethylamino)piperidine (2.89 g) was added to a stirred solution of 2-ethoxy-4-fluoro- 1 -nitrobenzene (3.79 g) and DIPEA (7.1 mL) in DMA (17.5 mL). The mixture was then heated to 1000C for 4h. The mixture was then concentrated in vacuo and purified by SCX, eluting with 7M NH3/ MeOH to afford the title compound (6.10 g, 102 %) as a yellow solid; 1H NMR: 1.39 (5H, m), 1.82 (2H, d), 2.19 (6H, s), 2.36 (IH, m), 2.96 (2H, t), 4.00 (2H, d), 4.19 (2H, q), 6.50 (IH, dd), 6.58 (IH, d), 7.86 (IH, d); m/z: MH+ 294. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | Reference Example 9[l-(2-ChIoro-9-ethyl-6-morpholin-4-yl-9/-r-purin-8-ylmethyl)-piperidiii-4-yI]-dimethyl- amine To a stirred solution of 2-chloro-9-ethyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde(250 mg; 0.85 mmol), 4-dimethylaminopiperidine (0.16 g; 1.25 mmol) and AcOH (0.05 ml) in 1,2-dichloroethane (4 mL) was added NaB(OAc)3H (0.27 g; 1.27 mmol) and the resulting mixture was stirred at RT overnight (16 h). The reaction was quenched with 2 M HCl (10 ml) <n="60"/>and stirred vigorously for 30 min. The layers were separated and the aqueous layer was basified to pH 11 with saturated Na2CO3 solution. This aqueous mixture was extracted with CH2Cl2 (20 mL), the organic layer was separated, dried (Na2SO4) and the solvent evaporated to give the title compound as an off-white solid (300 mg; 87 %). deltaH (400 MHz, CDCl3) 1.44 (t, J = 7.2, 3H), 1.47-1.54 (m, 2H), 1.83-1.86 (m, 2H), 2.10-2.16 (m, 3H), 2.29 (s, 6H), 2.88-2.91 (m, 2H), 3.69 (s, 2H), 3.82-3.85 (m ,4H), 4.30 (br s, 4H) 4.32 (q, J = 7.2, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 100℃; for 0.666667h; | To a 100 mL single-necked round- bottom flask were placed 2,5-dibromopyridine (2 g, 8 mmol), 4-(dimethylamino)piperidine (1 ml, 8 mmol), tris(dibenzylideneacetone)dipalladium (o) (0.07 g, 0.08 mmol), 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (0.1 g, 0.2 mmol), and sodium /-butoxide (1 g, 12 mmol). The flask was subjected to 3 cycles of evacuation and back-filling with N2 before toluene (40 mL) was introduced under N2. The resulting mixture was stirred at a preheated oil bath at 1000C for 40 min. The crude mixture was poured into ice and 4 N NaOH aqueous solution and extracted with ethyl acetate (2 X). The combine organics were dried over sodium sulfate and concentrated in vacuo to give 2.7 g crude product. Trituration with ethyl acetate/hexanes gave highly pure l-(5-bromopyridin-2-yl)-N,N- dimethylpiperidin-4-arnine (91) (1.9 g, 95%) 1H NMR (400 MHz, CDCl3) delta 8.18 (1 H, d, J = 2.3 Hz), 7.52 (1 H, dd, J = 9.0, 2.7 Hz), 6.58 (1 H, d, J = 9.0 Hz), 4.30 (2 H, d, J = 12.9 Hz), 2.79 - 2.91 (2 H, m), 2.49 (1 H, br. s.), 2.37 (6 H, s), 1.97 (2 H, d, J = 12.5 Hz), 1.45 - 1.60 (2 H, m) ppm. |
With potassium carbonate; In dimethyl sulfoxide; at 100℃;Inert atmosphere; | The compound 2,5-dibromopyridine (200 mg, 1.0 eq),N,N-Dimethylpiperidin-4-amine (160 mg, 1.1 eq) and potassium carbonate (470 mg, 3.0 eq) were mixed and added to DMSO (10 ml), and stirred at 100 C overnight under nitrogen atmosphere, diluted with water.Extract with ethyl acetate, wash the organic phase three times with water, and wash with saturated brine.Dry over anhydrous sodium sulfate to give a solid i (300 mg). No further purification is required. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.8% | With triethylamine; In tetrahydrofuran; at 70℃; for 17h; | N,N-dimethylpiperidin- 4-amine (0.505 g, 3.94 mmol), <strong>[17973-86-3]3,6-dibromopyridazine</strong> (0.511 g, 2.15 mmol), and triethylamine (0.599 mL, 4.30 mmol) were combined in 5 mL of THF. The solution was heated at 700C for 17 hours. The solution was cooled to room temperature and then purified on CombiFlash column (dry loaded), eluting with 10% methanol/0.5%NH4OH(~28% in water)/DCM isocratic. The fractions containing the product were combined and concentrated under vacuum to give compound 201 (0.550 g, 89.8% yield) as an off white solid. 1H NMR (500 MHz, MeOD-d3) 6 7.51 (1 H, d, J= 9.8 Hz), 7.24 (1 H, d, J= 9.8 Hz), 4.45 (2 H, d, J= 13.7 Hz), 2.98 (2 H, td, J= 13.0, 2.2 Hz), 2.61 (1 H, tt, J= 11.5, 3.8 Hz), 2.38 (6 H, s), 1.99 - 2.07 (2 H, m), 1.45 - 1.58 (2 H, m, J= 12.5, 12.2, 12.2, 4.2 Hz) ppm; LCMS-ESI (POS), M/Z, M+l : Found 285.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Ethyl 3-[4'-formyl-2-(3-methoxypropoxy)biphenyl-4-yl]propanoate (1 g, 2.7 mmol) was dissolved in dichloroethane (20 mL). At 0 C., acetic acid (0.02 mL, 0.4 mmol) was added, followed by N,N-dimethylpiperidine (0.4 g, 3 mmol) and sodium triacetoxyborohydride-(0.86 g, 4 mmol) portionwise. The mixture was stirred at room temperature overnight. At 0 C., saturated aqueous sodium bicarbonate was added. The aqueous layer was extracted three times with dichloromethane. The combined organic layers were washed with brine and water, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to yield 1.18 g (90%) of the desired product as a brown oil used in the following step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With triethylamine; In tetrahydrofuran; at 20℃; for 96h; | 4-Bromobenzyl bromide (0.5 g, 2.0 mmol) was stirred with 4- dimethylaminopiperidine (0.51 g, 4.0 mmol) and triethylamine (0.42 mL, 3.0 mmol) in THF (20 mL) at ambient temperature for 96 h. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL). The organic phase was separtated, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford the title compound (0.51 g, 86%). 1H NMR (CDCl3, 400MHz): 7.44-7.40 (m, 2H), 7.21-7.16 (m, 2H), 3.43 (s, 2H), 2.91-2.85 (m, 2H), 2.27 (s, 6H), 2.17-2.07 (m, 1H), 2.00-1.91 (m, 2H), 1.80-1.72 (m, 2H), 1.58-1.45 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With N-ethyl-N,N-diisopropylamine; 1,1'-carbonyldiimidazole;dmap; In dimethyl sulfoxide; at 38℃; for 6h; | N,N-dimethylpiperidin-4-amine (57.54mg, 0.449 mmol) was weighed into a greenhouse tube and treated with a solution of 4-(5-amino-6-(phenylcarbamoyl)pyrazin-2- yl)benzoic acid (50mg, 0.150 mmol), CDI (48.5 lmg, 0.299 mmol) and DMAP (1.82mg, 0.015 mmol) in DMSO (ImL of a stock solution). DIPEA (78.2uL, 0.449 mmol) was then added and the mixture stirred at 38C for 6 hours. The reaction mixture was filtered and the resultant residue was purified by reverse phase preparative HPLC [Waters Sunfire C 18, lOuM, IOOA column, gradient 10% - 95%B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25mL/min]. The fractions were freeze-dried to give the title compound as a solid (54.65, 80% Yield). (ES+) 445 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With lithium hexamethyldisilazane; DavePhos;tris-(dibenzylideneacetone)dipalladium(0); In tetrahydrofuran; for 1h;Inert atmosphere; Reflux; | Tris(dibenzilideneacetone)dipalladium (2.6 mg, 0.003 mmol), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)- biphenyl (2.4 mg, 0.006 mmol), 5-[2-(4-Bromo-2-methoxy-phenylamino)-pyrimidin-4-yl]-1 -methyl-1 H-pyrrole-3- carboxylic acid (2,6-diethyl-phenyl)-amide (150 mg, 0.281 mmol) in THF (5 mL) were charged in a round-bottom flask flushed with argon. The flask was evacuated and backfilled with argon. LiN(TMS)2 solution (1M in THF, 1.7 mL) and <strong>[50533-97-6]dimethyl-piperidin-4-yl-amine</strong> (108 mg, 0.842 mmol) were added and the reaction mixture refluxed for 1 h.The reaction mixture was then allowed to cool to room temperature and concentrated. The crude solid was purified by flash chromatography on silica gel (eluant: dichloromethane/methanol 96/4) to afford 124 mg (76 % yield) of the title compound.MS calc: 582.3551; MS found: 582.3552 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With triethylamine; In dichloromethane; at 20℃; for 0.5h; | [00203] 4-(2,5-Difluorophenoxy)-3-(4-(dimethylamino)piperidin-l- ylsulfonyl)benzonitrile 59. To a solution of compound 23 (0.080 g, 0.24 mmol) in DCM (10.00 niL) was added 4-dimethylaminopiperidine (0.040 g, 0.31 mmol) and TEA (0.043 g, 0.31 mmol). The reaction was monitored with TLC (25% EtOAc in hexanes, Rf = 0.0). The reaction was complete after stirring at room temperature for 30 min, as indicated by the absence of the starting material (TLC). Water was then added and extracted twice with DCM. Combined organic extracts were washed sequentially with water and brine, dried over MgSO4, filtered, and evaporated in vacuo to form a yellow oil. The oil was triturated with DCM and hexanes, and filtered to yield compound 59 as a white powder (0.85 g, 97.4% HPLC purity, 84% yield). 1H NMR (500 MHz, DMSO-4): delta 8.27 (d, / = 2 Hz, IH), 8.08 (dd, J1 = 2 Hz, J2 = S Hz, IH), 7.56 (m, IH), 7.40 (m, IH), 7.26 (m, IH), 7.19 (d, / = 9 Hz, IH), 3.71 (d, / = 13 Hz, 2H), 2.77 (t, / = 13 Hz, 2H), 2.18 (m, IH), 2.12 (s, 3H), 1.76 (d, / = 11 Hz, 2H), 1.35 (m, 2H); MS (ESI, EI+): m/z = 422 (MH+); melting point: 154 - 157 0C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 102 (method 2) (Synthetic Intermediate)(2-Bromo-pyridin-4-yl)-[5-(4-dimethylamino-piperidin-1-yl)-1-(2-trimethylsilanyl- ethoxymethyl)-1 H-benzoimidazol-2-yl]-methanone (as a mixture with the 6- regioisomer). Starting with Example 25, Step 1 was performed by following procedures describe for Example 42. Step 2 and Step 3 were performed by following procedures describe for Example 48. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 102 (method 2) (Synthetic Intermediate)(2-Bromo-pyridin-4-yl)-[5-(4-dimethylamino-piperidin-1-yl)-1-(2-trimethylsilanyl- ethoxymethyl)-1 H-benzoimidazol-2-yl]-methanone (as a mixture with the 6- regioisomer). Starting with Example 25, Step 1 was performed by following procedures describe for Example 42. Step 2 and Step 3 were performed by following procedures describe for Example 48. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With potassium carbonate; In water; N,N-dimethyl-formamide; at 100℃; for 0.166667h;Irradiation; | Example 135[5-(4-Dimethylamino-piperidin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl]-(2-isoquinolin-4- yl-pyridin-4-yl)-methanone Step i Step 2toluene, Step 1 : A solution of theta-chloro-S-nitro-pyridine^-yl-amine (7 g, 40.6 mmol), dimethylpiperidine-4-yl-amine (5.7 g, 44.5 mmol), K2CO3 (6.39 g, 60.9 mmol) and DMF/water (4:1 , 100 ml_) was heated at 100 0C for 10 minutes in microwave reactor. After cooling, water was added and the resulting precipitate was collected by filtration and dried to give 6-(4-dimethylamino-piperidin-1-yl)-3-nitro-pyridin-2-yl- amine (9.48 g, 88%) as a yellow solid. 1H NMR (400MHz, CD2CI2)delta: 1.48 (m, 2H), 1.72 (m, 2H), 2.28 (s, 6H), 2.42 (m, 1 H), 3.01 (m, 2H), 4.50 (m, 2H), 6.16 (d, J=9.54 Hz, 1 H), 8.14 (d, J=9.54 Hz,1 H). HRMS: m/z 266.1628 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 2h;Sealed tube; | Step 1: Preparation of 1-(3-methoxy-4-nitrophenyl)-N,N-dimethylpiperidin-4-amine The reaction tube containing DMF (30 mL) of a mixture of 4-fluoro-2-methoxy-1-nitrobenzene (5.00 g, 29.22 mmol), N,N-dimethylpiperidin-4-amine (6.53 g, 35.06 mmol), and K2CO3 (6.06 g, 43.83 mmol) was sealed with a Teflon-lined cap, and the above reaction mixture was stirred for 2 hours at 90 C. The above mixture was concentrated under reduced pressure. The above reaction mixture was diluted in ethyl acetate (300 mL), washed with water (100 mL), and then, washed with brine (100 mL). The residue was purified by silica gel flash column chromatography (CH2Cl2/meOH, 9:1) to obtain 1-(3-methoxy-4-nitrophenyl)-N,N-dimethylpiperidin-4-amine (9.73 g, pale yellow solid) in a yield of 99%. 1H NMR (300 MHz, CDCl3) delta 7.99 (d, J = 9.4 Hz, 1 H), 6.42 (dd, J = 9.4, 2.6 Hz, 1 H), 6.31 (sd, J = 2.5 Hz, 1 H), 3.94 (s, 3 H), 3.92 (d, J = 13.0 Hz, 2 H), 2.97 (td, J = 12.3, 2.8 Hz, 2 H), 2.43-2.33 9 (m, 1 H), 2.30 (s, 6 H), 1.95 (d, J = 13.0 Hz, 2 H), 1.58 (qd, J = 11.9, 4.0 Hz, 2 H); LC-MS calcd for C14H21N3O3 279.2, found 280.0 (M + H+) |
88% | With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 18h; | 1) . N,N- dimethyl piperidine -4- amines (374 mg, 2.92 mM) and K2CO3s (0.808 g, 5.84 mM) were added in the solution of 5- fluoro -2- nitroanilines (500 mg, 2.92 mM) among DMF of 3 ml. In 120 the reaction mixture, it was stirred for 18 hours. The NaHCO3saturated solution was added in the reaction mixture and the obtained mixture was extracted in the ethyl acetate. The organic phase was refined with chromatography. It is manufactured: 11a of 88% (0.712 g). |
A solution of 4-fluoro-2-methoxy-l -nitrobenzene (1.711 g, 10 mmol), N,N- dimethylpiperidin-4-amine (1.410 g, 11.00 mmol) and N-ethyl-N-isopropylpropan-2- amine (3.48 mL, 20.00 mmol) in anhydrous N,N-dimethylformamide (25 mL) was stirred at 70 0C overnight. The mixture was concentrated and the residue was mixed with water (60 mL), adjusted to pH 12, then extracted with CH^C^- The crude product was purified on a silica el column eluting with 7.5 % methanol in CH2CI2 saturated with NH3 to provide the title compound. (ESI+) m/e 280.1 (M+H)+. |
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 70℃; | EXAMPLE 12AA solution of 4-fluoro-2-methoxy-l -nitrobenzene (1.711 g, 10 mmol), N,N- dimethylpiperidin-4- amine (1.410 g, 11.00 mmol) and N-ethyl-N-isopropylpropan-2- amine (3.48 ml, 20.00 mmol) in anhydrous N,N-dimethylformamide (25 mL) was stirred at 70 0C overnight. The mixture was cooled, concentrated and the residue was mixed with water (60 mL), adjusted to pH 12, then extracted with CIH^C^. The crude product was purified on a silica gel column eluting with 7.5 % methanol in CH2CI2 saturated with NH3 to give 2.76 g of a yellow oil which turned into a solid upon standing.(ESI(+)) m/e 280.1 (M+H)+. | |
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 5h; | To an anhydrous DMF solution (10 mL) was added compound 1A-1 (0.5 g, 2.92 mmol), compound 2A-5 (0.375, 2.92 mmol) and potassium carbonate (1.21 g, 8.77 mmol), and then the mixture was heated to 80C and stirred for 5 hours. After TLC indicated the reaction was completed, the reaction mixture wad extracted with ethyl acetate (100 mL), and washed with saturated aqueous sodium chloride three times, followed by phase separation. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product 3A-5 (0.684 g, yield 83.8%), which was directly used for the next step without purification. | |
A 100 ml flask was charged with 4-fluoro-2-methoxy- 1 -nitrobenzene (5.13 g, 30 mmol), N,N-dimethylpiperidin-4-amine (4.23 g, 33.0 mmol) and N,N- dimethylformamide (60 ml). To the mixture was added N-ethyl-N-isopropylpropan-2- amine (10.45 ml, 60.0 mmol) and the mixture was heated at 70 0C overnight under nitrogen. The reaction mixture was concentrated under high vacuum and the residue was partitioned between brine (100 ml) and methylene chloride (100 ml) and the pH adjusted to ca. 12-14 with sodium hydroxide. The layers were separated and the aqueous layer was extracted with methylene chloride (3 x 100 ml). The combined organics were dried over sodium sulfate, filtered and adsorbed directly on to silica gel (ca. 25 g). This was split in two portions each of which was purified on a silica gel cartridge (150 g) eluted with a 2.5, 4.5, 6 % 7N methanolic ammonia in methylene chloride step gradient. The combined product fractions were concentrated to provide the title compound. MS (DCI(+)) m/e 280.2 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | 200 mg (0.7 mmol) of the compound from Example 23 and 187 mg (1.5 mmol) of 4-(N-(dimethyl-amino)piperidine are initially charged in 3 ml of THF. The reaction mixture is reacted in a single-mode microwave oven (Emrys Optimizer) at 180 C. for 5 min. The cooled reaction solution is then concentrated on a rotary evaporator, and the residue is chromatographed by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid). 1 ml of a 4 N solution of hydrogen chloride in dioxane is added to the resulting formate salt of the target compound, and the mixture is stirred at RT for 30 min. The suspension is then concentrated under reduced pressure, and the residue is dried.Yield: 257 mg (80% of theory)LC-MS (Method 9): Rt=0.76 min; MS (ESIpos): m/z=366 [M+H]+;1H-NMR (400 MHz, DMSO-d6): delta=11.32-11.05 (m, 1H), 9.34 (s, 1H), 9.03 (br. s, 1H), 8.87 (d, 1H), 8.58 (s, 2H), 8.49 (d, 1H), 7.95 (dd, 1H), 7.51 (s, 1H), 4.62-4.58 (m, 1H), 3.59-3.33 (m, 2H), 3.13-3.09 (m, 1H), 2.90-2.88 (m, 1H), 2.71 (s, 6H), 2.14-2.10 (m, 2H), 1.95-1.91 (m, 1H), 1.69-1.67 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With lithium hexamethyldisilazane; DavePhos;tris-(dibenzylideneacetone)dipalladium(0); In tetrahydrofuran; for 0.25h;Inert atmosphere; Reflux; | Example 3 N-[6-(2-Benzyloxy-ethoxy)-1H-indazol-3-yl] -(4-dimethylamino^iperidin-1-yl)-benzam (Cpd. 15)Scheme 2, Step N)A solution of N-[6-(2-benzyloxy-ethoxy)-1 H-indazol-3-yl]-4-bromo-benzamide (1.3 g, 2.79 mmol) and 4- dimethylamino-piperidine (1.18 ml, 8.37 mmol) in dry THF (20 ml) was degassed by three vacuum-argon atmosphere cycles and treated at r.t., under argon atmosphere, with Pd2(dba)3 (50 mg), 2-dicyclohexylphosphino-2'-(N,N- dimethylamino)biphenyl (50 mg) and 1 M LiHMDS in THF (22.3 ml, 22.3 mmol). The reaction mixture was heated to reflux and stirred for 15 min then cooled to r.t., poured into 200 ml of water and extracted with 200 ml of EtOAc. The organic layer was separated, dried over sodium sulfate and evaporated to dryness. The crude residue was purified by chromatography (Biotage SP1 Flash Purification system) on a silica gel cartridge (Varian SF40-120g) using DCM as eluant A and DCM / 7N NH3 in MeOH 10:1 as eluant B. Elution with a gradient from A / B 100:0 to 0:100 over 10 CV, followed by an isocratic elution with eluant B (5 CV), gave a yellow solid that was triturated with EtOAc (15 ml), filtered, washed with EtOAc and dried affording 1.04 g (yield: 73%) of the title compound as a white solid.1H-NMR (400 MHz), delta (ppm, DMSO-cie): 12.44 (s, 1 H) 10.35 (s, 1 H) 7.85 - 8.01 (m, 2 H) 7.59 (d, J=8.91 Hz, 1 H) 7.33 - 7.40 (m, 4 H) 7.25 - 7.32 (m, 1 H) 6.93 - 7.06 (m, 2 H) 6.85 (d, J=2.07 Hz, 1 H) 6.71 (dd, J=8.91 , 2.08 Hz, 1 H) 4.58 (s, 2 H) 4.14 - 4.26 (m, 2 H) 3.86 - 3.98 (m, 2 H) 3.73 - 3.85 (m, 2 H) 2.74 - 2.90 (m, 2 H) 2.23 - 2.35 (m, 1 H) 2.19 (s, 6 H) 1.77 - 1.87 (m, 2 H) 1.35 - 1.50 (m, 2 H)ESI (+) MS m/z 514 (MH+)ESI (+) HRMS calcd for C3oN503H35 + H+: 514.2813; found 514.2817 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59.7% | With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 2h; | In a dried reaction flask,2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-pyrazolo[3,4-f]quinoline-7-carboxyli c acid (0.421g, 1.0mmol), 4-dimethylaminopiperidine (0.167g, 1.3mmol), DIEA (0.2mL, 1.15mmol), and HATU (0.418g, 1.1mmol) were added to a mixed solvent of DMF (4mL) and dichloromethane (8mL). The mixture was stirred at room temperature for 2hr and concentrated under reduced pressure. Water was added to the residue. The mixture was filtered and the resulting solid was washed with water and methanol to obtain a yellow solid (0.317g) in 59.7% yield.Molecular formula: C30H35ClN6O; mass spectrum (M+H): 531.3 1H-NMR(DMSO-d6, 400 MHz): delta 8.43 (1H, d), 7.71 (1H, d), 7.49 (1H, d), 7.43 (1H, s), 7.21 (1H, d), 5.14-4.85 (1H, m), 4.67-4.40 (1H, m), 3.90-3.78 (1H, m), 3.75-3.60 (1H, m), 3.15-2.97 (4H, m), 2.87-2.76 (1H, m), 2.58 (6H, s), 2.35-2.21 (1H, m), 2.19-1.65 (6H, m), 1.61-1.15 (8H, m). |
0.317 g | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 2h; | In a dried reaction flask, 2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-pyrazolo[3,4-f]quinoline-7-carboxylic acid (0.421 g, 1.0 mmol), 4-dimethylaminopiperidine (0.167 g, 1.3 mmol), DIEA (0.2 mL, 1.15 mmol), and HATU (0.418 g, 1.1 mmol) were added to a mixed solvent of DMF (4 mL) and dichloromethane (8 mL).The mixture was stirred at room temperature for 2 hr and concentrated under reduced pressure.Water was added to the residue.The mixture was filtered and the resulting solid was washed with water and methanol to obtain a yellow solid (0.317 g) in 59.7% yield.Molecular formula: C30H35ClN6O; mass spectrum (M+H): 531.3 1H-NMR (DMSO-d6, 400 MHz): delta 8.43 (1H, d), 7.71 (1H, d), 7.49 (1H, d), 7.43 (1H, s), 7.21 (1H, d), 5.14-4.85 (1H, m), 4.67-4.40 (1H, m), 3.90-3.78 (1H, m), 3.75-3.60 (1H, m), 3.15-2.97 (4H, m), 2.87-2.76 (1H, m), 2.58 (6H, s), 2.35-2.21 (1H, m), 2.19-1.65 (6H, m), 1.61-1.15 (8H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | Step 1 : To a solution of 4-(3-bromoimidazo[l,2-b]pyridazin-6-yl)benzoic acid (500 mg, 1.57 mmol) in DMF (5 mL) was added NMM (317 mg, 3.14 mmol) followed by HATU (754.7 mg, 2.35 mmol) and the solution was stirred for 30 min at rt. NN-dimethylpiperidin-4-amine (221 mg, 1.72 mmol) was added to the reaction mixture and stirred for an additional 16 h. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over anhydrous Na S04 and concentrated under reduced pressure to obtain crude product. The crude residue was purified by column chromatography (silica gel, eluent CH2Cl2/MeOH 95:5) to afford (4-(3-bromoimidazo[l,2-b]pyridazin-6-yl)phenyl)(4- (dimethylamino)piperidin-l-yl)methanone (350 mg, 52%) as an off-white solid. 1H NMR (400 MHz, DMSO- 6) delta 13.01 (bs, 1H), 8.3-8.01 (m, 5H), 7.85 (d, J= 7.2 Hz, 2H); MS (ESI) m/z 317 [M]+. | |
52% | To a solution of 4-(3-bromoimidazo[1,2-b]pyridazin-6-yl)benzoic acid (500 mg, 1.57 mmol) in DMF (5 mL) was added NMM (317 mg, 3.14 mmol) followed by HATU (754.7 mg, 2.35 mmol) and the solution was stirred for 30 min at rt. N,N-dimethylpiperidin-4-amine (221 mg, 1.72 mmol) was added to the reaction mixture and stirred for an additional 16 h. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain crude product. The crude residue was purified by column chromatography (silica gel, eluent CH2Cl2/MeOH 95:5) to afford (4-(3-bromoimidazo[1,2-b]pyridazin-6-yl)phenyl)(4-(dimethylamino)piperidin-1-yl)methanone (350 mg, 52%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) delta 13.01 (bs, 1H), 8.3-8.01 (m, 5H), 7.85 (d, J=7.2 Hz, 2H); MS (ESI) m/z 317 [M]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72.4% | With dmap; In N,N-dimethyl-formamide; at 20℃; for 16h; | Step 2: To a solution of 7-bromo-lH-benzo[d][l,3]oxazine-2,4-dione (1 g, 4.13 mmol), N,N- dimethylpiperidin-4-amine (0.58 g, 4.54 mmol) in dry DMF (10 mL) was added DMAP (50.4 mg, 0.41 mmol) at rt. The reaction mixture was stirred for 16 h, then was diluted with H20 (30 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layer was dried over Na2S04 and concentrated under reduced pressure to afford (2-amino-4-bromophenyl)(4- (dimethylamino)piperidin-l-yl)methanone (0.97 g, 72.4%, LC-MS 99.5%). 1HNMR (400 MHz, CDC13) delta (ppm) 6.92 (d, J= 8.0 Hz, 1H), 6.88 (s, lH), 6.83 (d, J= 6.8 Hz, 1H), 4.4 (s, 2H), 2.96 (bs, 2H), 2.39-2.37 (m, 1H), 2.36 (s, 6H), 1.89 (d, J= 1 1.6 Hz, 2H), 1.49-1.41 (m, 2H); MS (ESI) m/z 327 [C14H20BrN3O+ H]+. |
72.4% | With dmap; In N,N-dimethyl-formamide; at 20℃; for 16h; | To a solution of <strong>[76561-16-5]7-bromo-1H-benzo[d][1,3]oxazine-2,4-dione</strong> (1 g, 4.13 mmol), N,N-dimethylpiperidin-4-amine (0.58 g, 4.54 mmol) in dry DMF (10 mL) was added DMAP (50.4 mg, 0.41 mmol) at rt. The reaction mixture was stirred for 16 h, then was diluted with H2O (30 mL) and extracted with EtOAc (3*100 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford (2-amino-4-bromophenyl)(4-(dimethylamino)piperidin-1-yl)methanone (0.97 g, 72.4%, LC-MS 99.5%). 1H NMR (400 MHz, CDCl3) delta (ppm) 6.92 (d, J=8.0 Hz, 1H), 6.88 (s, 1H), 6.83 (d, J=6.8 Hz, 1H), 4.4 (s, 2H), 2.96 (bs, 2H), 2.39-2.37 (m, 1H), 2.36 (s, 6H), 1.89 (d, J=11.6 Hz, 2H), 1.49-1.41 (m, 2H); MS (ESI) m/z 327 [C14H20BrN3O+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With 4-methyl-morpholine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃; for 16h;Inert atmosphere; | To a solution of 4-(3-(4-cyanophenyl)imidazo[l,2-a]pyridin-6-yl)benzoic acid (0.2 g, 0.58 mmol) in DMF (5 mL) were added HATU (0.33 g, 0.88 mmol), N-methyl morpholine (0.18 g, 1.76 mmol) and N,N-dimethylpiperidin-4-amine (81 mg, 0.70 mmol). The reaction mixture was stirred at 0 C to room temperature under inert atmosphere for 16 h, then it was diluted with water (15 mL) and extracted with EtOAc (3x25 mL). The combined organic layer was dried over Na2S04 and was concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, eluent CH2Cl2/MeOH 95:5) to afford 4-(6-(4- (4-(dimethylamino)piperidine-l -carbonyl)phenyl)imidazo[ 1 ,2-a]pyridin-3-yl)benzonitrile (140 mg, 57%, AUC HPLC >99%) as an off-white solid; m.p. 128-132 C. 1H NMR (400 MHz, CDC13) delta (ppm): 8.49 (s, 1H), 7.84-7.71 (m, 5H), 7.60-7.50 (m, 5H), 7.80 (m, 3H), 7.71 (m, 1H), 7.45 (q, 2H), 4.45 (bs, 1H), 3.65 (bs, 1H), 3.15-2.8 (m, 2H), 2.39 (m, 1H), 2.22 (bs, 6H), 1.9-1.6 (m, 2H),1.35 (m, 2H); MS (ESI) m/z 450.3 [C28H27N50+ H]+. |
57% | With 4-methyl-morpholine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 16h;Inert atmosphere; | To a solution of 4-(3-(4-cyanophenyl)imidazo[1,2-a]pyridin-6-yl)benzoic acid (0.2 g, 0.58 mmol) in DMF (5 mL) were added HATU (0.33 g, 0.88 mmol), N-methyl morpholine (0.18 g, 1.76 mmol) and N,N-dimethylpiperidin-4-amine (81 mg, 0.70 mmol). The reaction mixture was stirred at 0 C. to room temperature under inert atmosphere for 16 h, then it was diluted with water (15 mL) and extracted with EtOAc (3*25 mL). The combined organic layer was dried over Na2SO4 and was concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, eluent CH2Cl2/MeOH 95:5) to afford 4-(6-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)imidazo[1,2-a]pyridin-3-yl)benzonitrile (140 mg, 57%, AUC HPLC >99%) as an off-white solid; m.p. 128-132 C. 1H NMR (400 MHz, CDCl3) delta (ppm): 8.49 (s, 1H), 7.84-7.71 (m, 5H), 7.60-7.50 (m, 5H), 7.80 (m, 3H), 7.71 (m, 1H), 7.45 (q, 2H), 4.45 (bs, 1H), 3.65 (bs, 1H), 3.15-2.8 (m, 2H), 2.39 (m, 1H), 2.22 (bs, 6H), 1.9-1.6 (m, 2H), 1.35 (m, 2H); MS (ESI) m/z 450.3 [C28H27N5O+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With formaldehyd; In ethanol; at 75℃; for 18h; | Example 18(2S ,3R)-N-((4-(Dimethylamino)- 1 -piperidinyl)methyl)-N?-((3 S)- 1 -methyl-2-oxo-5 -phenyl-2,3 -dihydro- 1 H-i ,4-benzodiazepin-3 -yl)-2,3 -bis(3 ,3 ,3 -trifluoropropyl)succinamide [00211j To a solution of Compound A (0.020 g, 0.036 mmol) in ethanol (1.2 mL), was added N,N-dimethylpiperidin-4-amine (0.922 g, 7.19 mmol) followed by the addition of formaldehyde (0.535 mL, 7.19 mmol) and the mixture was heated at 75 C for 18 h. The mixture was concentrated under reduced pressure, diluted with water (7 mL) andextracted with EtOAc (2x5 mL). The combined organic layers were dried with Na2SO4, filtered and concentrated to dryness. The crude material was purified by preparative reversed-phase HPLC (Column: Symmetry C 18 (300x1 9)mm 7ji, Mobile Phase A: 0.1% TFA in water: Acetonitrile (90:10), Mobile Phase B: Acetonitrile, Flow rate: 15 ml/min) to afford Example 18 (0.0 195 g, 78%): ?H NMR (400 MHz, DMSO-d6) oe ppm 9.75 (br s,1H), 9.59 (d, J=7.28 Hz, 1H), 7.67-7.79 (m, 1H), 7.53-7.59 (m, 3H), 7.43-7.50 (m, 2H),7.32-7.38 (m, 2H), 5.32 (d, J7.53 Hz, 1H), 4.33 (br s, 2H), 3.40 (s, 3H), 2.90 (t, J=i0.54 Hz, 2H), 2.60-2.77 (m, 9H), 2.07-2.31 (m, 6H), 1.50-1.84 (m, 8H). HPLC: RT 7.854 mill (Column: XBridge Phenyl (4.6x150)mm, 3.5 micron, Buffer:0.05% TFA in water pH2.5 adjusted with dilute NH3, Mobile Phase A: Buffer: Acetonitrile (95:5), Mobile PhaseB: Acetonitrile: Buffer (95:5), Flow rate: imlmin, monitored at 220 nm); MS(ES): m/z =697 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With sodium cyanoborohydride; acetic acid; In methanol; at 20℃; for 5h; | NaBH3CN (13mg, 0.2mmol) was added to an anhydrous MeOH (2.5mL) solution of aldehyde S-14 (described in supporting information) (37mg, 0.1mmol), AcOH (cat., 1 drop) and N,N-dimethylpiperidin-4-amine (14mg, 0.1mmol). The mixture was stirred at room temperature (5h) then evaporated under vacuum. The crude residue was purified by flash column chromatography on silica gel with acetone/MeOH (10/0 to 8/2) as the eluant to obtain a colorless oil of 30b (43mg, 91%): 1H NMR (400MHz, CDCl3) delta 1.37-1.42 (m, 2H), 1.61-1.64 (br d, J=11.9Hz, 2H), 1.84-1.91 (m, 2H), 2.26 (s, 2NCH3), 2.30-2.40 (m, 1H), 2.71-2.77 (br d, J=11.9Hz, 2H), 3.61 (s, 2H), 3.75 (s, 3H), 5.12 (s, 2H), 6.78 (d, J=8.9Hz, 1H), 6.98-7.03 (br m, 2H), 7.18-7.27 (m, 2H), 7.33-7.39 (m, 3H), 7.44-7.49 (br d, J=7.2Hz, 2H), 7.98 (d, J=7.8Hz, 1H); 13C NMR (100MHz, CDCl3) delta 26.8, 39.9, 52.2, 53.1, 57.3, 61.9, 70.8, 106.4, 109.5, 110.1, 112.3, 117.3, 119.8, 121.2, 127.2, 128.3, 128.6, 128.9, 129.4, 132.0, 136.7, 148.9, 153.0, 154.3, 155.8; LRMS (M+H+)(ESI+) 471.2 [M+H+] (calcd for C30H34N2O3H+ 471.2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With potassium carbonate; In water; isopropyl alcohol; at 160℃; for 5h;Microwave irradiation; | General procedure: To a mixture of 2-[3-(3-chloro-pyrazin-2-yloxy)-azetidin-1-yl]-quinoline (312 mg, 1.0 mmol) and piperidin-4-ol (0.101 g,1.0 mmol) and potassium carbonate (0.276 g, 2.0 mmol) was added iPrOH (3 mL) and water (1.0 ml). The solution was heated to 160 Cin the microwave for 5 h. The mixture was concentrated andextracted with EtOAc (2 30 mL). The combined organic extractswere washed with water (10 mL) and brine (10 mL), dried overNa2SO4, and filtered. The filtrate was evaporated in vacuo andthe residue was purified by flash co lumn chromatography elutingwith 20-60% EtOAc/petroleum ether to give 67 mg (18%) ofthe title product as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With potassium carbonate; In N,N-dimethyl-formamide; at 40℃; for 18h; | 4-Bromomethyl benzonitrile (2 g, 10.2 mmol), 4-dimethylamino piperidine (1.56 g, 12.2 mmol) and K2003 (1.7 g, 12.2 mmol) in DMF (30 mL) were heated at 4000 for 18 h. Thereaction was diluted with H20 (50 mL) and extracted with EtOAc (3 x 60 mL). The combined organic extracts were washed with H20 (2 x 50 mL), brine (3 x 50 mL) and dried over Mg504. The reaction mixture was concentrated in vacuo and the crude material was purified by silica gel column chromatography, eluting with CH2CI2 and increasing the polarity to 30% MeOH/CH2CI2 to obtain 4-(4-dimethylamino-piperidin-1-ylmethyl)-benzonitrile as a white solid (1.4g, 56%).AnalpH2_MeOH_4min(1): Rt 2.40 mm; mlz 244 [M+1]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With sodium tris(acetoxy)borohydride; In 1,2-dichloro-ethane; at 20℃; | 4-Bromopicolinaldehyde (300 mg, 1 .61 mmol) was dissolved in dichloroethane (30 mL). N,N-Dimethylpiperidin-4-amine (227 mg, 1.77 mmol) and sodium triacetoxyborohydride (1.025 g, 4.84 mmol) were added and the mixture was stirred at room temperature overnight. The mixture was partitioned between water and ethylacetate. The aqueous phase was basified to pH=10 with a diluted sodium hydroxide solution. The aqueous phase was then extracted with dichloromethane. The combined organics were dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to give 390 mg (81percent yield) of the title compound as an orange oil.LRMS (M+1): 298, 3001H NMR (400 MHz, Chloroform-d)oe ppm 1.59 (qd, J = 12.2, 3.8 Hz, 3H), 1.73?1.86(m, 2H), 2.02 ? 2.23 (m, 3H), 2.29 (s, 7H), 2.92 (d, J = 11.9 Hz, 2H), 3.61 (s, 2H), 7.33(dd, J = 5.3, 1.9 Hz, 1 H), 7.63 (d, J = 1.5 Hz, 1 H), 8.35 (d, J = 5.3 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With potassium carbonate; In acetone; at 20℃; for 18h; | i-Bromo-2-chloroethane (1.95 mL, 23.43 mmol) was added to a solution of N,Ndimethylpiperidine-4-amine (2.0 g, 15.60 mmol) and potassium carbonate (4.31 g, 31.20 mmol) in acetone (10 mL) and the reaction mixture was stirred at room temperature for 18 hours. The solid was filtered and the filtrate was evaporated to yield the title compound (2.65 g, 89%) which was used in the next synthetic step without any further purification.LRMS (mlz): 191 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With tris-(dibenzylideneacetone)dipalladium(0); tris-(o-tolyl)phosphine; sodium t-butanolate; In 1,4-dioxane; at 110℃; for 4h;Inert atmosphere; | [00371] N,N-dimethylpiperidin-4-ainine (30 mg, 0.15 mmol), NaOi-Bu (70 mg, 0.73 mmol) and 37 (40 mg, 0.09 mmol) were dissolved in 1 ,4-Dioxane (3 mL), and the mixture thoroughly degassed. Pd2(dba)3 (5 mg, 0.05 mmol) and tri(o-tolyl) (3 mg, 0.09 mmol) were added. The mixture was heated to 110 C for 4 hours. LC-MS analysis showed conversion to the desired product. The mixture was filtered and purified by reversed-phase HPLC using a gradient of 10-60% CH3CN/H20 with 0.035 % TFA to give the desired compound as a brown solid (18 mg, 45 % yield). lH NMR (DMSO-tVtf, 400 MHz) delta 12.76 (s, IH), 8.31 (d, J = 8 Hz, 2H), 8.04 (s, I H) 7.98 (s, IH), 7.58 (d, 7 = 8 Hz, I H), 7.34 (s, IH), 6.51 (s, I H), 4.07 (m, 4H), 2.80 (s, 6H), 3.14 (m, 4H), 2.71 (q, J = 7.2 Hz, 2H) 1.74 (s, 6H), 1.23 (t, J = 8 1 1 ). MS m/z 382.43 [M+ l ]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | In N,N-dimethyl-formamide; at 20℃; for 2h; | General procedure: A mixture ofdifferent fluoro substituted 2-nitrobenzoate (1.5 mmol) and various amines (7.5 mmol) in DMF (3 mL) was stirred atroom temperature for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and brine. After dried by sodium sulfate and concentration, the residue was purified by chromatography on silica gel to give as yellowish solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.8% | With potassium carbonate; In N,N-dimethyl-formamide; at 40℃; | General procedure: Compound 3a (3b) (0.5mmol, 96mg) was mixed with corresponding amines (mmol) and K2CO3 in 2mL of DMF and stirred at 40C for 2-3h. The mixture was poured into 10mL cold water and the solid was filtered, dried and recrystallized from methanol to give the title compounds 4-15a (4-15b). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.8% | With potassium carbonate; In N,N-dimethyl-formamide; at 40℃; | General procedure: Compound 3a (3b) (0.5mmol, 96mg) was mixed with corresponding amines (mmol) and K2CO3 in 2mL of DMF and stirred at 40C for 2-3h. The mixture was poured into 10mL cold water and the solid was filtered, dried and recrystallized from methanol to give the title compounds 4-15a (4-15b). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | To 3-methyl-2-propionyl-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one (280 mg, 1.254 mmol) and N,N-dimethylpiperidin-4-amine (325 mg, 2.53 mmol) was added Ti(OiPr)4 (0.80 mL, 2.73 mmol) and benzene (3 mL). The reaction was stirred at 80 C for 18 h. The reaction was diluted with MeOH (3 mL), then NaBH3CN (315 mg, 5.02 mmol) was added in two portions over 2 h. The reaction was heated at 60 C and stirred for an additional 2 h. The reaction was evaporated to dryness under vacuum, taken up in (9: 1) DCM/MeOH (15 mL) and treated with IN Na2C03 (10 mL). The resulting suspension was stirred for 30 min. The suspension was filtered through a pad of Celite (slow) and rinsed with (9: 1) DCM/MeOH (5 mL). The clear filtrate was transfered to a separatory funnel. The lower organic phase was removed, dried (Na2SO4), filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (Isco RediSep Rf Gold 40 g, 5 to 20% (5% NH4OH/MeOH) in DCM). The pure fractions were combined and evaporated to dryness to give 2-(1-(4-(dimethylamino)piperidin-1-yl)propyl)-3-methyl-6,7- dihydrothieno[3,2-c]pyridin-4(5H)-one (360 mg, 1.019 mmol, 81 % yield) as a colorless oil. (Solidified to a white solid foam under vacuum.). 1H NMR (400 MHz, CDCl3) delta 5.59 (br. s., 1H), 3.69 (dd, J=4.7, 9.5 Hz, 1H), 3.59 (dt, J=2.8, 6.8 Hz, 2H), 3.18 - 3.07 (m, 1H), 3.01 (t, J=6.8 Hz, 2H), 2.97 - 2.93 (m, 1H), 2.44 (s, 3H), 2.29 (s, 6H), 2.17 - 1.88 (m, 4H), 1.88 - 1.72 (m, 2H), 1.70 - 1.39 (m, 3H), 0.81 (t, J=7.3 Hz, 3H). MS(ES) [M+H]+ 336.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; for 5h; | DIPEA (4.82 mmol) and (3-isocyanatopropyl) benzene (2.41 mmol) were added to a solution of N, N-dimethylpiperidin-4-amine (2.53 mmol) in THF (10 ml)The mixture was stirred at the same temperature for 5 hours.After removing the solvent with an evaporator, diethylEther (15 ml) was added and stirred for 10 minutes.The resulting solid was filtered through a sintered funnel, washed with diethyl ether (2 x 5 ml) and dried in vacuo to give 4- (dimethylamino) -N- (3-phenylpropyl) piperidine- 1-carboxyRespectively. |
75% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 5h; | DIPEA (4.82 mmol) and (3-isocyanatopropyl) benzene (2.41 mmol) were added to a solution of N,N-dimethylpiperidin-4-amine (2.53 mmol) in THF (10 ml) for 5 h. The solvent was removed using an evaporator, diethyl ether (15 ml) was added, and the mixture was stirred for 10 minutes. The resulting solid compound was filtered through a sintered funnel, washed with diethyl ether (2 x 5 ml) and dried in vacuo to give 4-(dimethylamino)-N-(3-phenylpropyl)piperidine-1-carboxamide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | In isopropyl alcohol; at 20℃; for 4h; | <strong>[40851-91-0]2-methoxy-3-nitro-6-chloropyridine</strong> (376mg, 2mmol) was dissolved in 4mL of isopropanol, was added 4-dimethylamino-piperidine (0.56mL, 4mmol), reacted at room temperature for 4 hours, the reaction solution the precipitated solid was filtered, the filter cake was rinsed with isopropyl alcohol and drying, the product yield obtained 300mg 54% . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In chloroform; at 20℃; for 12h; | Diisopropylethylamine (0.392 mL, 2.24 mmol), HBTU (0.680 g, 1.79 mmol), and 4-(dimethylamino)piperidine (0.167 mL, 1.42 mmol) were added to a solution of a crude product of 3-(1-(2-(tert-butoxy)-2-oxoethyl)-1H-imidazol-2-yl)propanoic acid (0.380 g) in chloroform (15.0 mL) at room temperature, and the reaction liquid was stirred at the same temperature for 12 hours. A saturated aqueous solution of potassium carbonate and a 10% aqueous solution of sodium chloride were added to the reaction liquid, and the resulting mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, chloroform/ethyl acetate) to obtain tert-butyl 2-(2-(3-(4-(dimethylamino)piperidin-1-yl)-3-oxopropyl)-1H-imidazol-1-yl)acetate (0.349 g, 0.957 mmol, 62%) as a colorless oil. |
0.349 g | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In chloroform; at 20℃; for 12h; | Reference Example 14 Synthesis of tert-butyl 2-(2-(3-(4-(dimethylamino)piperidin-1-yl)-3-oxopropyl)-1H-imidazol-1-yl)acetate (0376) (0377) Diisopropylethylamine (0.392 mL, 2.24 mmol), HBTU (0.680 g, 1.79 mmol), and 4-(dimethylamino)piperidine (0.167 mL, 1.42 mmol) were added to a solution of a crude product of 3-(1-(2-(tert-butoxy)-2-oxoethyl)-1H-imidazol-2-yl)propanoic acid (0.380 g) in chloroform (15.0 mL) at room temperature, and the reaction liquid was stirred at the same temperature for 12 hours. A saturated aqueous solution of potassium carbonate and a 10% aqueous solution of sodium chloride were added to the reaction liquid, and the resulting mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, chloroform/ethyl acetate) to obtain tert-butyl 2-(2-(3-(4-(dimethylamino)piperidin-1-yl)-3-oxopropyl)-1H-imidazol-1-yl)acetate (0.349 g, 0.957 mmol, 62%) as a colorless oil. (0378) 1H-NMR (400 MHz, CDCl3) delta: 1.29-1.42 (2H, m), 1.47 (9H, s), 1.81-1.83 (2H, m), 2.27-2.36 (7H, m), 2.55-2.62 (1H, m), 2.91 (4H, s), 2.96-3.03 (1H, m), 3.98-4.01 (1H, m), 4.57-4.60 (1H, m), 4.63 (2H, s), 6.81 (1H, d, J=1.2 Hz), 6.96 (1H, d, J=1.2 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In chloroform; at 20℃; for 60h; | Diisopropylethylamine (2.76 mL, 15.81 mmol), HBTU (4.80 g, 12.65 mmol), and 4-(dimethylamino)piperidine (1.12 mL, 10.01 mmol) were added to a solution of a crude product of 3-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-imidazol-2-yl)propanoic acid (3.15 g) in chloroform (56.5 mL) at room temperature, and the reaction liquid was stirred at the same temperature for 12 hours. A saturated aqueous solution of potassium carbonate and a 10% aqueous solution of sodium chloride were added to the reaction liquid, and the resulting mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, chloroform/methanol) to obtain 3-(1-(2-((tertbutyldimethyl silyl)oxy)ethyl)-1H-imidazol-2-yl)-1-(4-(dimethylamino)piperidin-1-yl)propan-1-one (2.88 g, 7.05 mmol, 70%) as a white solid. |
2.88 g | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In chloroform; at 20℃; for 12h; | Reference Example 13 Synthesis of 3-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-imidazol-2-yl)-1-(4-(dimethylamino)piperidin-1-yl)propan-1-one (0372) (0373) Diisopropylethylamine (2.76 mL, 15.81 mmol), HBTU (4.80 g, 12.65 mmol), and 4-(dimethylamino)piperidine (1.12 mL, 10.01 mmol) were added to a solution of a crude product of 3-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-imidazol-2-yl)propanoic acid (3.15 g) in chloroform (56.5 mL) at room temperature, and the reaction liquid was stirred at the same temperature for 12 hours. A saturated aqueous solution of potassium carbonate and a 10% aqueous solution of sodium chloride were added to the reaction liquid, and the resulting mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, chloroform/methanol) to obtain 3-(1-(2-((tertbutyldimethyl silyl)oxy)ethyl)-1H-imidazol-2-yl)-1-(4-(dimethylamino)piperidin-1-yl)propan-1-one (2.88 g, 7.05 mmol, 70%) as a white solid. (0374) 1H-NMR (400 MHz, CDCl3) delta: -0.05 (6H, s), 0.84 (9H, s), 1.30-1.42 (2H, m), 1.82-1.85 (2H, m), 2.27-2.36 (7H, m), 2.55-2.63 (1H, m), 2.90-3.03 (5H, m), 3.82 (2H, t, J=5.4 Hz), 4.01-4.05 (3H, m), 4.60-4.63 (1H, m), 6.88 (1H, d, J=1.2 Hz), 6.92 (1H, d, J=1.2 Hz). (0375) ESI-MS: m/z=409 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With piperidine; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 90℃; for 6h;Inert atmosphere; | The compound 2-a-4 (14.0g, 50mmol) was dissolved DMA (70mL), 4-dimethylaminopiperidine was added, piperidine (7.56g, 60mmol), N, N- diisopropylethylamine ( 12.9g, 100mmol). The mixture under nitrogen, and heated to 90 deg. C for 6 hours. After cooling to room temperature, poured into ice water, and extracted with ethyl acetate (400mL). The organic phase was separated, washed with brine (300mL). Dried over anhydrous sodium sulfate, and filtered. The filtrate was spin-dried to give an orange solid 3-a-2 (19.1g, yield: 81%). MS m/z (ESI): 395 [M+H] +, purity = 99% (UV214). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With potassium carbonate; In dichloromethane; acetonitrile; at 20℃; | S0 (16.7mg, 0.05mmol), 4-dimethylaminopiperidine (22.0mg, 0.17mmol) and potassium carbonate (28.0mg, 0.20mmol) was added to 0.4mL of dichloromethane /1.2mL acetonitrile, stirred at room temperature. After completion of the reaction by TLC was extracted with water, the organic layer was washed successively with water, saturated brine, dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated under reduced pressure, the crude product by column chromatography to give a red-brown solid 12.0mg, 64% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.5% | In tetrahydrofuran; at 0 - 25℃; for 2.5h;Inert atmosphere; | Dry THF (135 g) and F-rifa I (10.0 g, 12.2 mmol) were charged to the reactor under N2. The reactor contents were cooled to 0-5 C before N,N-dimethylpiperidin-4-amine (2.3g, 17.9 mmol) was charged over 0.5 h while maintaining an internal temperature of <5 C. After the addition, the reactor contents were warmed to 20-25 C and held for 2 h. EtOAc (135 g) was charged and the mixture agitated for 0.5 h. The contents were filtered and washed with EtOAc (25 g). The combined filtrates were distilled under vacuum to 25 mL volume. After cooling to 20-25 C, EtOAc (185 g) was charged, followed by 7% aq. (0140) NaHC03 solution (45 g), 25% aq. NaCl solution (45 g), and purified water (45 g). After phase separation, the aqueous layer was removed and 25% aq. NaCl solution (45 g) and purified water (45 g) were added to the organic phase. The aq. layer was removed and the organic layer subjected to treatment with 7% aq. NaHC03 solution (45 g), 25% aq. NaCl solution (45 g), and purified water (45 g). After phase separation, the aqueous layer was removed and 25% aq. NaCl solution (45 g) and purified water (45 g) were added to the organic phase. The organic phase was filtered and the filtrate concentrated to 25 mL volume prior to dilution with heptane (90 g). Further concentration to 25 mL volume was followed by dilution with heptane (90 g) and a final concentration to 25 mL volume. Filtration of the suspension and washing of the cake with heptane (2 x 20 g) gave a solid, which once dried under vacuum to give dimethylaminopiperidyl rifa IVa (10.6 g, 93.5% yield). XH NMR (600 MHz, Toluene-c g) delta 16.53 (s, 1H), 11.59 (s, 1H), 9.86 (s, 1H), 7.35 (s, 1H), 6.47 - 6.32 (m, 1H), 6.21 (d, J= 11.9 Hz, 1H), 5.87 (s, 1H), 5.62 (s, 1H), 5.44 (d, J = 11.4 Hz, 1H), 5.30 - 5.18 (m, 1H), 4.87 (dd, J= 14.6, 10.0 Hz, 1H), 3.58 (d, J = 7.7 Hz, 1H), 3.26 - 3.11 (m, 2H), 3.03 (d, J = 10.9 Hz, 1H), 2.91 (d, J= 12.1 Hz, 1H), 2.73 (s, 3H), 2.64 (s, 3H), 2.28 (s, 2H), 2.24 (s, 3H), 2.15 (s, 3H), 2.04 (s, 6H), 2.00 (s, 1H), 1.97 - 1.89 (m, 1H), 1.79 (d, J = 28.4 Hz, 2H), 1.66 (s, 3H), 1.64 (s, 5H), 1.17 (d, J = 6.9 Hz, 6H), 0.78 (d, J = 6.3 Hz, 3H), 0.49 (d, J = 6.5 Hz, 5H). 13C NMR (151 MHz, Tol) delta 193.0, 182.6, 175.7, 175.1, 171.5, 171.2, 158.0, 157.2, 146.4, 145.2, 144.5, 142.2, 131.5, 131.0, 130.9, 128.9, 128.0, 119.6, 114.0, 112.6, 111.5, 109.4, 107.7, 106.3, 95.0, 92.9, 79.9, 79.0, 74.8, 73.8, 61.5, 55.2, 47.0, 46.4, 44.1, 42.4, 42.3, 37.3, 33.1, 29.2, 29.0, 23.6, 23.1, 21.4, 16.4, 13.2, 13.0, 11.7, 8.5. |
at 60℃; | Alternatively, (5 -fluoro-2-nitro- 1,3 -phenylene)bis(oxy)bis(methylene)dibenzene 7 was hydrogenated under hydrogen gas with palladiumlcarbon catalyst in tetrahydrofuranlmethanol solvent to remove the benzyl groups to give 2-amino-5-fluorobenzene-1,3-diol 8. LCMS (ESI):M+H = 144.04. Commercially available Rifamycin S or Rifamycin SV sodium salt (ChemShuttle Inc., Fremont, CA) was reacted with 2-amino-5-fluorobenzene-1,3-diol 8 by oxidative condensation in air or potassium ferric cyanide in ethyl acetate at 60 C to give fluorobenzoxazino rifamycin 9. Displacement of fluoride with N,N-dimethylpiperidin-4-amine gave dimethylpipBOR 6. LCMS (ESI): M+H = 927.43 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With sodium tris(acetoxy)borohydride; In 1,2-dichloro-ethane; at 20℃; for 4h; | (S)-3-Fluoro-5-(4-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydrop yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-a]pynm yl)benzaldehyde (40 mg, 0.06 mmol) was dissolved in 5 mL dichloroethane. N,N- Dimethylpiperidin-4-amine (25 mg, 0.19 mmol) and sodium triacetoxyborohydride (45 mg, 0.21 mmol) were added and stirred at room temperature for 4 h. The reaction mixture was diluted with dichloromethane and washed twice with water and brine. The organics were washed with brine, dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue was purified using SP1 Purification System (dichloromethane- dichloromethane/methanol/NI-UOH) to give 34 mg (75% yield) of the title compound. LRMS (m/z): 750 (M+1 )+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 2h;Inert atmosphere; | Step 5 N-(4-(4-(dimethylamino)piperidin-1-yl)-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidin-2-amine (compound 4-6) The reaction substrate 4-5 (146 mg, 0.25 mmol) and potassium carbonate (104 mg, 0.75 mmol) were added into a 25 ml reaction flask, DMF (10 mL) was added to completely dissolve the substrate. Afterwards, 4-dimethylamino piperidine (42 mg, 0.325 mmol) was added, and the reaction system was heated at 100 C. for 2 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction solution was extracted with EA/water system for three times, the organic layer was separated, washed with water, saturated brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the title compound 4-6 (120 mg, 98%). MS m/z (ESI): 504.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With acetic acid; In water; at 0 - 20℃; for 12h;Inert atmosphere; | General procedure: In an oven-dried RB flask, 4-chloro-2-phenyl-1H-pyrrolo[3,2-c]pyridine 6b (250 mg, 1.09 mmol) and formaldehyde solution, 37 wt.% in H2O (0.2 mL, 2.73 mmol) were mixed in glacial acetic acid(5 mL). N-methyl piperazine (273.8 mg, 2.73 mmol, CAS 109-01-3)was added drop wise at 0C. The resulting mixture was stirred atroom temperature for 12 h. After completion of the reaction, the excess solvent was evaporated to dryness under reduced pressure.The residue was neutralized with 10% NaHCO3 solution, the solidf ormed was collected by filtration, washed with water and dried.The crude product was purified by silica gel column chromatographyto provide title compound as an off-white solid (326.3 mg,88%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 4h; | 4-dimethylaminopiperidine (106 mg, 0.83 mmol) and potassium carbonate (286 mg, 2.07 mmol) were added into a solution of compound 4-a (300 mg, 0.69 mmol) in 20 ml of DMF. The mixture was vigorously stirred at 100 C. for 4 h. The reaction progress was monitored by TLC. After the substrate was completely consumed, the reaction mixture was extracted with ethyl acetate/water system for three times, the organic phase was separated, and concentrated under reduced pressure to obtain compound 5a-1 (400 mg, 95%), MS m/z(ESI): 544.2[M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 1h; | 4-dimethylaminopiperidine (106 mg, 0.83 mmol) and potassium carbonate (152 mg, 1.10 mmol) were added to compound 22a-1 (371 mg, 0.55 mmol) in 6 ml of DMF. The reaction was vigorously stirred at 100 C. for 1 h. The reaction progress was monitored by TLC. After the substrate was completely consumed, the reaction mixture was extracted with ethyl acetate/water system for three times, and the organic phase was separated, concentrated under reduced pressure to obtain a crude product which was purified by Combi-flash column chromatography [PE: EA=100:085:15] to obtain compound 22a-2 (323 mg, yield 100%). MS m/z(ESI): 578.3 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 60 - 80℃; | General procedure: To a stirred solution of compounds 7a-c (0.25g, 0.68mmol) in DMF (5mL) was added K2CO3 (1.5:1), KI (0.01:1) and various substituted aniline (1.5:1). The solution was heated at 80C for 6-10h. Then the reaction mixture was cooled to room temperature, diluted with water (200mL) and extracted with ethyl acetate (3×20mL), combined organic layer, washed with brine, dried with anhydrous Na2SO4 and concentrated under vacuum to afford the target products as a solid. Compounds 8-41 were characterized as follows. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | Pd-Catalyzed amination make use of KOtBu (1.5 mmol,169 mg) and Pd-PEPPSI-Mes (12, 2 mol%, 13.6 mg) wereweighed into a 3 ml screw-cap threaded vial that was sealedwith a septum. The amines (1.2 mmol) was added via syringe,and the reaction was allowed to stir for 2-3 min DME(1 ml) was then injected via syringe followed by the compound(2) (1.0 mmol) it was introduced into the vial prior topurging with argon. At this time, the reaction stirred for 24 hat the indicated temperature, unless specified otherwise. Thereaction mixture was filtered through a bed of Celite andwashed with Et2O. The filtrate was concentrated in vacuoand purified via silica gel flash chromatography. 1-(6-(1H-benzo[d]imidazol-2-yl)pyrazin-2-yl)-N,Ndimethylpiperidin-4-amine (3a) Yield: 93%; pale yellowsolid; M.P.: 245-247 C; Rf: 0.72 (ethyl acetate and petether; 4:1); IR (KBr): 3461 (NH), 3157 (C=C), 2970(C=N), 2683, 1740, 1466, 1382, 1216, 992, 756 cm-1;1HNMR (400 MHz, DMSO-d6, ppm): delta 12.95 (s, 1H, NH),8.69 (s, 1H, pyrazine), 8.46 (s, 1H, pyrazine), 7.72 (d, J =7.78 Hz, 1H, benzimidazole), 7.61 (d, J = 6.01 1H, benzimidazole),7.32 (m, 2H, benzimidazole), 4.83 (d, J = 13.30Hz, 2H, piperidine), 2.97 (t, J = 12.6 Hz, 2H, piperidine),2.68 (m, 1H, piperidine), 2.66 (s, 6H, -N(CH3)2), 2.13 (d, J= 11.04 Hz, 2H, piperidine), 1.66 (q, J = 12.04 Hz, 2H,piperidine); 13CNMR (100MHz, DMSO-d6, ppm): delta 154.4(1C, C14-pyrazine), 149.3 (1C, pyrazine), 141.3 (3C, C4,C5-benzimidazole, C10-pyrazine), 134.3 (1C, C11-pyrazine),133.6 (1C, C13-pyrazine), 125.4 (2C, C1,C2-benzimidazole),118.8 (2C, C3,C6-benzimidazole), 72.4 (1C,C19-piperidine), 55.6 (2C, C17,C21-piperidine), 45.8 (2C,-N(CH3)2), 26.2 (2C, C18,C20-piperidine); MS m/z 323.2(M + H)+; HRMS m/z calcd. for C18H23N6 ([M + H]+):323.19787 Found: 323.19730. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With triethylamine; In dichloromethane; at 20℃; for 3h; | To a solution of 4-iodobenzene-1-sulfonyl chloride (2 g, 6.61 mol) and N, N-dimethylpiperidin-4-amine (0.848 g, 6.61 mmol) in DCM (20 ml) was added TEA (1.115 ml, 7.93 mmol) . The mixture was stirred at rt for 3 h. LC-MS indicated the reaction was complete. The mixture was concentrated. The residue was purified by flash chromatography (MeOH: DCM0: 100 to 10: 100) to give the title compound (2.85 g , 98) as a white solid. 1H-NMR (400 MHz, MeOD-d4) delta ppm 1.38 -1.61 (m, 2H) , 1.86 (br d, J11.80 Hz, 2H) , 2.19 -2.56 (m, 6H) , 3.01 (br d, J6.53 Hz, 3H) , 3.61 (br d, J11.80 Hz, 2H) , 7.49 (d, J8.53 Hz, 2H) , 8.02 (s, 2H) . LC-MS: [M+H] + 394.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | In tetrahydrofuran; at 20℃; | 12. Synthesis of intermediate 5c (0389) Exact Mass: 363.22 (0390) (0391) 4 5c (0392) [00135] To the solution of intermediate 4 (6.5 g, 27.7 mmol) in THF (100 mL) was added intermediate c (3.6 g, 27.7 mmol), and the solution was stirred at room temperature overnight. After completion of the reaction, the solvent was removed in vacuo, the residue was purified by chromatography column (PE EA = 3/1) to afford intermediate 5c (7.2 g, 72%) as yellow oil. 3 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate; In toluene; at 110℃; for 18h;Inert atmosphere; | A mixture of tert-butyl (5-bromopyrimidin-2-yl) carbamate (17a) (360 mg, 0.96 mmol) , N, N-dimethylpiperidin-4-amine (246 mg, 1.92 mmol) , Pd2 (dba) 3 (44 mg, 0.048 mmol) , Xantphos (56 mg, 0.096 mmol) , t-BuONa (184 mg, 1.92 mmol) in toluene (11 mL) was heated at 110 for 18 h under N2. The mixture was cooled to room temperature and concentrated in vacco. The residue was purified by chromatography on silica gel eluting with DCM /MeOH (10: 1) to give tert-butyl (5- (4- (dimethylamino) piperidin-1-yl) pyrimidin-2-yl) carbamate (17b) . MS-ESI (m/z) : 322 [M + 1] +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 0.25h; | A suspension of intermediate 86 (0.35 g, 1.70 mmol), 4-(dimethylamino)piperidine(0.41 g, 1.87 mmol) and CsCO3 (1.10 g, 3.41 mmol) in DMF (4 mL) was heated to 80C for 15 mm. The reaction mixture was partitioned between EtOAc and a saturatedsolution of NaHCO3. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo to give the 553 mg of intermediate 87 (quant. yield, yellow oil). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53.4% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; for 4h;Inert atmosphere; Reflux; | N- (4-bromo-2-nitrophenyl) acetamide 8a (3.00 g, 11.58 mmol),N, N-dimethylpyridin-4-amine 9a (1.63 g, 12.74 mmol),4,5-bisdiphenylphosphine-9,9-dimethylxanthene (670 mg, 1.16 mmol),Tris (dibenzylideneacetone) dipalladium (530 mg, 0.579 mmol)And cesium carbonate (5.66 g, 17.37 mmol) were dissolved in 80 mL of toluene,Argon gas was refluxed for 4 hours.The reaction solution was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluent: System A)getN- (4- (4- (dimethylamino) piperidin- 1 -yl) -2- nitrophenyl) acetamide 9b (1.90 g, brown black solid)Yield: 53.4percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With pyridine; In dichloromethane; at 0 - 20℃; for 16h; | (Reference Example 5) Synthesis of 1-(4-(dimethylamino)piperidin-1-yl)ethanone: Pyridine (0.922 mL, 9.75 mmol) and acetic anhydride (0.946 mL, 11.7 mmol) were added to a solution of 4-dimethylaminopiperidine (1.00 g, 7.79 mmol) in dichloromethane (7.8 mL) at 0C and the reaction liquid was stirred at room temperature for 16 hours. A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction liquid, and the reaction liquid was extracted with chloroform. The organic layer was washed with a 10% aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (NH silica gel, chloroform/methanol) to obtain 1-(4-(dimethylamino)piperidin-1-yl)ethanone (0.869 g, 6.78 mmol, 87%) as a colorless oil. 1H-NMR (400 MHz, CDCl3) delta: 1.30-1.47 (2H, m), 1.79-1.92 (2H, m), 2.10 (3H, s), 2.25-2.40 (7H, m), 2.53-2.63 (1H, m), 3.01-3.11 (1H, m), 3.81-3.90 (1H, m), 4.58-4.66 (1H, m). ESI-MS: m/z= 171 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 0.0833333h; | To a solution of 2,6-dichloro-4-cyclopropylpyridine-3,5-dicarbonitrile (synthesis described in example 4 step 2, 200 mg, 0.85 mmol) in N,N-dimethylformamide (9 mL) was added N,N- dimethylpiperidin-4-amine (108 mg, 0.85 mmol) and triethylamine (0.12 mL, 0.85 mmol). The mixture was stirred at room temperature for 5 minutes. Water was added to the reaction. The solid was filtered and dried to give 2-chloro-4-cyclopropyl-6-(4- (dimethylamino)piperidin-1-yl)pyridine-3,5-dicarbonitrile (210 mg, 75% yield). LCMS m/z = 330.3 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With N-ethyl-N,N-diisopropylamine; In methanol; at 70℃; for 24h;Inert atmosphere; | A mixture of N,N-dimethylpiperidin-4-amine (42 mg, 0.328 mmol) and (R)-1-(3-((3'-(3-bromopropoxy)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) in methanol (1 mL) and N,N-diisopropylethylamine (30 muL, 0.172 mmol) was heated at 70 C for 24 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5-mum particles;Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 5- 45% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to give the pure title compound: (20.1 mg, 89%). LC/MS Condition E: ret time 1.22 min; m/e = 510 (M+H)+.LC/MS Condition F: ret time 1.05 min; m/e = 510 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | A solution of compound 9 (160 mg, 0.67 mmol), HOBT (136.7 mg, 1.01 mmol), EDCI (193.6 mg, 1.01 mmol) and Et3N (0.3 mL,2.01 mmol) in DMF(5 mL) was stirred for 3 h at ambient temperature. Then N,N-dimethylpiperidin-4-amine (113 tL, 0.80 mmol) was added. After stirred for overnight at ambient temperature, the mixture was dissolved in DCM and H20. The organic phase was washed with brine, dried over Na2SO4 and concentrated . The crude product was purified by column chromatography (PE / EA = 5 : 1 to EA) to give compound 10 (200 mg, yield: 85%). ?H NMR (CDC13, 400MHz):7.40-7.34 (m, 4H), 6.59 (s, 1H), 2.80-2.77 (m, 3H), 2.48-2.45 (m, 2H), 2.33 (s, 6H), 1.88-1.84 (m, 2H), 1.52 (s, 9H), 1.48-1.45 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 110℃; for 2h; | General procedure: differentamines (0.1 mmol) was added to a solution of 16a-d (0.9 mmol) andDIPEA (0.1 mmol) in DMF. The mixture was heated at 110C for 2 h.The solvent was removed in vacuo, and the crude product waspuried by ash silica gel chromatography (4% 7 N NH3/MeOH inCH2Cl2) to obtain the title product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.8 g | With caesium carbonate; In N,N-dimethyl-formamide; at 60.0℃; | <strong>[66684-60-4]1,2-difluoro-3-methoxy-4-nitrobenzene</strong> (2.5 g),N,N-Dimethylpiperidin-4-amine (2.0 g) and cesium carbonate (8.5 g) were added in sequenceHeated in 50 ml of DMF at 60 C overnight, concentrated under reduced pressure to remove solvent.The resulting residue was dissolved in a small amount of ethyl acetate and water.Extracted with ethyl acetate, and the extract was washed with brine.After drying and concentration with anhydrous sodium sulfate, the obtained residue was subjected to flash chromatography on silica gel.(dichloromethane:methanol, 15:1, v/v) isolated and purified to give the desired product(Brown oily liquid, 1.8 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 20℃; | A mixture of 50mg (108 pmol) 4-[(4,4-difluoro-8-methyl-1,5-dioxo-1,5-dihydro-2H- spiro[cyclohexane- 1 ,3-imidazo[1 ,5-a]pyridin]-6-yl)am ino]thieno[2,3-d]pyrim idine-6-carboxylic acid (prepared according to example 80), 1 .7 mL N,N-dimethylacetamide, 151 pL N-ethyl-Nisopropylpropan-2-amine, 56 mg N,N-dimethylpiperidin-4-amine and 194 pL 2,4,6-tripropyl- 1 ,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide solution (50% in N,N-dimethylformamide) wasstirred at RT overnight. The mixture was concentrated and purified by flash chromatography (Biotage SNAP cartridge silica 10 g + NH 11 g, methanol: dichloromethane) to give 52 mg (80%) of the title compound.LC-MS: m/z = 572.4 [M+H].1HNMR (400 MHz, DMSO-d6), 6[ppm]= 1.46 (2H), 1.69 (2H), 1.87 (2H), 2.10-2.37 (9H),2.41 -2.61 (5H*), 2.77-3.27 (2H), 3.27-3.39 (2H*), 4.33 (2H), 8.20 (1H), 8.61 (1H), 8.71 (1H),9.34 (1H), 10.42 (1H);*: at least partially hidden by solvent or water signal |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.73 g | With potassium carbonate; In acetonitrile; | Add N,N-dimethylacridin-4-amine (0.586g) with K2CO3 (1.160 g) to a solution of <strong>[168173-56-6]2-bromo-5-(chloromethyl)pyridine</strong> (0.853 g) in acetonitrile (10 mL). Add water (30mL), extracted with EA (50 mL×3), the combined organic layers were dried with EtOAc, 730 g of 1-((6-bromopyridin-3-yl)methyl)-N,N-dimethylpiperidin-4-amine were obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.37 g | With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 50℃; for 1h; | K2CO3 (0.578g), KI (0.070 g) and N,N-dimethyl acridine-4-amine (0.322 g) were sequentially added to a solution of <strong>[120276-59-7]3-chloro-6-(chloromethyl)pyridazine</strong> (0.340 g) in DMF (15 mL) in, The oil bath was heated to 50 C for 1 hour. Cool to room temperature, Add DCM (50 mL), the combined organic layers were washed with a saturated NaCl solution. Dry with anhydrous Na2SO4, oncentrate, purified by column chromatography (DCM / MeOH = 10/1) 0.370 g of 1-((6-chloropyridazin-3-yl)methyl)-N,N-dimethylpiperidin-4-amine was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | tert-butyl (4-formyl-1 ,3-thiazol-2-yl)carbamate (200 mg, 0.88 mmol) in DMA (3 mL) was treated with N,N- dimethylpiperidin-4-amine (0.155 mL, 1.3 mmol) and stirred at rt over 1 h. AcOH (0.025 mL, 0.43 mmol) and sodium triacetoxyborohydride (465 mg, 2.19 mmol) were added to the reaction and stirred at rt for 20 h. The residue was partitioned between EtOAc and saturated aqueous NaHC03. The organic layer was dried over Na2S04 and evaporated to dryness. The crude was purified by column chromatography over silica gel (DCM:7N NH3 in MeOH = 9:1) to give the title compound as colourless oil (225 mg, 75%).1H NMR (500 MHz, DMSO-de) delta ppm 1.27 - 1.38 (m, 2 H) 1.47 (s, 9 H) 1.61 - 1.75 (m, 2 H) 1.87 - 2.03 (m, 3 H) 2.13 (s, 6 H) 2.78 - 2.89 (m, 2 H) 3.37 (s, 2 H) 6.85 (s, 1 H).HRMS (ESI+): calcd. for C16H29N4O2S [M + H]+341.2006; found 341.2008. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | General procedure: 3-Formyl-rifamycin SV (RAL)was purchased from LKT Laboratories Inc. (>98%). RAL (250.0mg, 0.34 mmol) was dissolved in 50 ml CH2Cl2 and afterthe addition of catalyst (0.025 mmol HCl/EtOH) respective mixtures wereprepared with each of the following compounds taken separately: 1-adamantylamine,1-methylpiperazine,1-(2-pyridyl)piperazine,1-(4-fluorobenzyl)piperazine,1-(2,4,6-trimethylbenzyl)piperazine, 1-bis(4-fluorophenyl)methylpiperazine, 1-(ethanesulfonyl)piperazine, 1-(methylsulfonyl)piperidin-4-amine, 4-(dimethylamino)-piperidine,1-(4-pyridyl)piperazine, 1-(2-pyrimidyl)piperazinedihydrochloride, 1,9-dimethyl-1,4,9-triazaspiro[5.5]undecanetrihydrochloride, 3,4-dihydro-2H-spiro[isoquinoline-1,4?-piperidine],n-piperidin-4-yl-methanesulfonamide,1-[3-(trifluoromethyl)pyrid-2-yl]piperazine,1-(cyclohexylmethyl)-4-piperidinamine,1,4?-bipiperidine-4-carboxylic acid dihydrochloride, (4-amino-1-piperidinyl)acetic acid dihydrochloride, 2-oxo-2-(1-piperidinyl)ethanamine,1-(2-amino-ethyl)-pyrrolidin-2-one,4-amino-1-Boc-piperidine, 3-amino-2-piperidinonehydrochloride, 1-acetyl-4-aminopiperidine hydrochloride in1 ml of CH3OH. Amines containinghydrochloride were neutralized with an equivalent amount of KOH/EtOH (0.06 mmolor 0.12 mmol or 0.18 mmol) solution. The mixtures were stirred at 40C for halfan hour and after that 3/4 of the solvent volume was distilled off. To thecooled reaction mixture (room temperature) the reductant NaBH3CN (13mg, 0.15 mmol) was added portionwise over 1 min. The reaction mixture wasstirred for one hour. Next the reaction mixture was evaporated to dryness,dissolved in 50 ml of CH2Cl2 and extracted twice with 50ml of water and brine (theses stages were omitted for reactions with1,4?-bipiperidine-4-carboxylic acid dihydrochloride,(4-amino-1-piperidinyl)acetic acid dihydrochloride). The separated organiclayer was evaporated and the synthesized derivatives of <strong>[13292-22-3]<strong>[13292-22-3]3-formylrifamycin</strong> SV</strong>(compounds 1-23) were next purified by column chromatography with silicagel (25 cm × 1 cm, silica gel 60, 0.040-0.063 mm/230-400 mesh ASTM, Fluka) withdichloromethane/methanol (from 200:1 to 3:1) as an eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 20℃; for 2h; | 32 mg of powdered ferric acid and 5 mL of dichloromethane were dissolved, 19 mL of diisopropylethylamine, 47 mg of condensing agent HATU, and finally 19.3 mg of 4-dimethylaminopiperidine, and uniformly stirred at room temperature for 2 h, to be reacted The reaction was quenched by the addition of water and then extracted with dichloromethane, and the dichloromethane phase was evaporated to dryness.The target compound is isolated and purified. |
63% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 20℃; | General procedure: To the solution of the alepterolic acid (32 mg, 0.1 mmol) in dichloromethane(5 mL) was added N,N-diisopropylethylamine (19 mg,0.15 mmol), HATU (47 mg, 0.123 mmol), and respectful amine(0.15 mmol). In the cases of compound 1 and 2, the HCl salts of methylamineand ethylamine were used, and additional 0.15 mmol of N,Ndiisopropylethylaminewas added to the reaction. The mixture wasstirred at r.t for 2-20 hr. When TLC indicated complete conversion(dichloromethane/ MeOH, 20/1), the reaction was quenched withwater, extracted with dichloromethane, purified by semi-preparativeHPLC. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.5% | With potassium carbonate; In acetonitrile; at 85℃; for 12h; | 4-Fluoro-2-methoxy-5-nitroaniline (1 g, 7.25 mmol) was dissolved in acetonitrile (30 mL), and N, N-dimethylpiperidine-4-amine (1.1 g, 8.7 mmol) was added. Potassium carbonate (1.5 g, 10.75 mmol) was reacted at 85 C under reflux for 12 hours. The reaction was monitored by TLC to complete the reaction. The temperature was lowered to room temperature, and the reaction solution was poured into 200 mL of water. It was extracted with dichloromethane (100 mL3), and the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by evaporation under reduced pressure to dryness. Purified by silica gel column chromatography, eluting with 2-6% 7N methanol-ammonia in dichloromethane to obtain a brown solid (1.4 g, 87.5%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With triethylamine; In dichloromethane; at 0℃; for 0.666667h; | TEA (0.37 mL, 2.63 mmol) and a solution of N,N-dimethylpiperidine-4-amine (247 mg, 1.93 mmol) in DCM (1 mL) were added to a solution of 5-bromo-2-methoxybenzenesulfonyl chloride (500 mg, 1.75 mmol) in DCM (15 mL) at 0C. The reaction mixture was stirred at 0C for 40 min, washed with diluted NaHCO3 (5 mL) and water (5 mL), dried and evaporated. The crude product was purified by chromatography on silica eluting with 2-12% (2M NH3 in MeOH) in DCM affording a white solid (627 mg, 95%). M/z 377/379 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 16h; | To a stirred solution of 5-bromo-2-methoxybenzoic acid (3 g, 12.9 mmol) in DMF (30 mL) was added Et3N (5.5 mL, 38.9 mmol), N,N-dimethylpiperidin-4-amine (1.82 g, 14.2 mmol) and T3P (12 mL, 19.2 mmol) at room temperature and stirred for 16 h. The reaction mixture was diluted with water (60 mL), extracted with EtOAc (2 x 100 mL) and combined organic layer was dried, filtered and evaporated. The crude was purified by chromatography on neutral alumina eluting with 10% MeOH in DCM affording a pale brown solid (3.1 g, 75%). M/z 341.1 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | General procedure: Compounds 13 (1 equiv.), amines (1.5 equiv.), EDCI (1.5 equiv.), HOBT (1.5 equiv.), DIPEA (1.5 equiv.) weresuspended in DMF and the mixture was stirred at room temperature for several hours, monitoring by TLC. Afterthe reaction was completed, the mixture diluted by water, extracted with EtOAc thrice, washed with water and brine,dried over anhydrous Na2SO4 and filtered. The solvent was removed under vacuum. The residue was applied on asilica-gel column (using CH2Cl2/MeOH=80/1) to afford the corresponding products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With potassium iodide; In N,N-dimethyl-formamide; at 20℃; for 4h; | General procedure: Compound 6 (1.0 equiv) with catalytic equivalent KI was dissolved in freshly distilled DMF in an oven-dried round bottom flask. Different aliphatic amines (3.0 equiv) was added dropwise. The reaction mixture was stirred at room temperature for about 4h. After the reaction monitored by TLC was over, water was added to the reaction mixture under stirring, and the suspended mixture was filtered. The crude residue was purified by column chromatography on silica gel to obtain the final products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With potassium iodide; In N,N-dimethyl-formamide; at 20℃; for 4h; | General procedure: Compound 6 (1.0 equiv) with catalytic equivalent KI was dissolved in freshly distilled DMF in an oven-dried round bottom flask. Different aliphatic amines (3.0 equiv) was added dropwise. The reaction mixture was stirred at room temperature for about 4h. After the reaction monitored by TLC was over, water was added to the reaction mixture under stirring, and the suspended mixture was filtered. The crude residue was purified by column chromatography on silica gel to obtain the final products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With potassium iodide; In N,N-dimethyl-formamide; at 20℃; for 4h; | General procedure: Compound 6 (1.0 equiv) with catalytic equivalent KI was dissolved in freshly distilled DMF in an oven-dried round bottom flask. Different aliphatic amines (3.0 equiv) was added dropwise. The reaction mixture was stirred at room temperature for about 4h. After the reaction monitored by TLC was over, water was added to the reaction mixture under stirring, and the suspended mixture was filtered. The crude residue was purified by column chromatography on silica gel to obtain the final products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With potassium iodide; In N,N-dimethyl-formamide; at 20℃; for 4h; | General procedure: Compound 6 (1.0 equiv) with catalytic equivalent KI was dissolved in freshly distilled DMF in an oven-dried round bottom flask. Different aliphatic amines (3.0 equiv) was added dropwise. The reaction mixture was stirred at room temperature for about 4h. After the reaction monitored by TLC was over, water was added to the reaction mixture under stirring, and the suspended mixture was filtered. The crude residue was purified by column chromatography on silica gel to obtain the final products. |
Tags: 50533-97-6 synthesis path| 50533-97-6 SDS| 50533-97-6 COA| 50533-97-6 purity| 50533-97-6 application| 50533-97-6 NMR| 50533-97-6 COA| 50533-97-6 structure
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Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
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P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
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P240 | Ground/bond container and receiving equipment. |
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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: |
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P311 | Call a POISON CENTER or doctor/physician. |
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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. |
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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. |
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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 |
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