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Structure of 1068-57-1 * Storage: {[proInfo.prStorage]}
* 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.
Reference：
[1] Journal of Organic Chemistry, 1966, vol. 31, p. 3442 - 3444
6
[ 506-68-3 ]
[ 1068-57-1 ]
[ 52838-39-8 ]
Reference：
[1] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1975, vol. 11, p. 1272 - 1277[2] Khimiya Geterotsiklicheskikh Soedinenii, 1975, vol. 11, # 11, p. 1493 - 1498
(2) Preparation of oxadiazolone:Methyl acetate 2000ml into 5000ml three bottles,Under stirring, 740 g of acetylhydrazine was added,Frozen down to 0 below, put 1680g sodium bicarbonate,Seal the reaction bottle.To the reaction bottle in the continuous access to phosgene, phosgene flow rate of 15m3 / h.After the end of the reaction, the solvent was distilled off, crystallized at 0 ° C and filtered to give a white solid 988.2 g, yield: 99percent.
Reference：
[1] Russian Journal of Organic Chemistry, 1994, vol. 30, # 10, p. 1630 - 1636[2] Zhurnal Organicheskoi Khimii, 1994, vol. 30, # 10, p. 1548 - 1553
[3] Russian Journal of Organic Chemistry, 1994, vol. 30, # 10, p. 1630 - 1636[4] Zhurnal Organicheskoi Khimii, 1994, vol. 30, # 10, p. 1548 - 1553
[5] Russian Journal of Organic Chemistry, 1994, vol. 30, # 10, p. 1630 - 1636[6] Zhurnal Organicheskoi Khimii, 1994, vol. 30, # 10, p. 1548 - 1553
15
[ 1068-57-1 ]
[ 556-61-6 ]
[ 38942-50-6 ]
Yield
Reaction Conditions
Operation in experiment
38.9%
Stage #1: for 6 h; Heating / reflux Stage #2: With sodium hydroxide In ethanol; water for 1 h; Heating / reflux
Acetic hydrazide (7.4 g, 100 mmol) in ethanol (75 mL) was placed in a 200 mL 3-necked round bottomed flask outfitted with a magnetic stir bar and a reflux condenser. Methyl isothiocyanate (7.3 g, 100 mmol) in ethanol (75 mL) was added to the pot. The mixture was refluxed, under N2, for 6 h. The reaction was cooled to room temperature and the solvent removed on the rotovap. The resulting wet solid was triturated with ether and filtered to give a sticky, yellow solid. This solid was triturated with hot CH2Cl2/ethyl acetate (1:1), which afforded a white solid of the uncyclized intermediate. The solid and all liquids associated with the reaction were combined, dissolved in ethanol. Aqueous NaOH (1 M, 50 mL) was added and the mixture refluxed under N2 for 1 h. Acetic acid was used to acidify to a pH of 4-5. The mixture was then cooled on an ice bath to facilitate precipitation. White solid formed, was filtered and washed with ether. (repeated the crystallization process three times with mother liquors). Combined all solids collected and chromatographed through silica gel, eluting with 14percent MeOH/ethyl acetate. The collected fractions were concentrated, washed with ether and filtered to yield 5.02 g (38.9percent) of the desired product. 1H NMR (DMSO-d6): d 2.27 (s, 3H) 3.37 (s, 3H) 13.36 (broad s, 1H). MS (APCI) calcd for C4H7N3S: 129.18; found (M+H+) 130.0.
Stage #1: With sodium methylate In methanol at 20℃; for 1 h; Stage #2: for 10 h; Reflux
General procedure: 5 ml of sodium methoxide methanolic solution (35 wtpercent) was added to a solution of 2-cyanopyridine (0.05 mol) in20 ml of methanol and stirred at room temperature for 1 h. Then the respective hydrazide was added to the generate dimino ester solution and refluxed for 10 h. The obtained mixture was cooled to room temperature and the solvent removed in vacuo. The resulting residue was diluted with water and acidified with 2 ml of acetic acid to produce a white solid. The crystals were separated via filtration, dried and recrystallized from toluene (HL1–3). The physical properties and analytical data of compounds HL1-3 are listed in Table 1, and the spectral data of compounds HL1-3are listed in Table 2.
Reference：
[1] Chemical Papers, 2017, vol. 71, # 10, p. 2003 - 2009
In a 500mL two neck round-bottomed flask equipped with a magnetic stir bar was dissolved amide 5 (3.40g, 8.13mmol) in THF (60mL) and cooled to −78°C. While stirring at −78°C, potassium tert-butoxide (1.0M solution in THF, 8.95mL, 8.94mmol, 1.10equiv) was added. The reaction mixture was warmed to −10°C and stirred for 30min. The reaction mixture was cooled to −78°C and diphenyl chlorophosphate (2.02mL, 9.76mmol) was added to the reaction mixture. The resulting mixture was warmed to −10°C and stirred at this temperature for 45min. Acetylhydrazide (0.90, 12.20mmol, 1.50equiv) was added to the reaction mixture. The reaction mixture was stirred at room temperature. After 1h, 1-butanol (70mL) was added to the reaction mixture, which was heated to 90°C. After 1h, all solvents were removed under reduce pressure. The residue was dissolved in CH2Cl2 and washed with saturated aq. NaHCO3, brine, dried over anhydrous Na2SO4 and concentrated in vacuo to obtain crude (+)-JQ1, which was purified by flash column chromatography on silica gel (0–100percent ethyl acetate in hexanes) to afford (+)-JQ1 (3.04g, 82percent) as a white solid and with a 91:9 er (determined with Supercritical Fluid Chromatography (SFC) using the CHIRALPAK AS-H column, CO2–EtOH (3:1), 210nm, tR (R-enantiomer) 1.62min, tR (S-enantiomer) 3.51min). This product was further purified by preparative SFC using a CHIRALPAK AS-H column to obtain (+)-JQ1 (S-enantiomer) with >99percent ee. The spectral data of (+)-JQ1 matched with those described in the literature6 with the exception of the optical rotation. [α]D22 +41 (c 0.50, CHCl3), (Lit. [α]D22 +55 (c 0.50, CHCl3);12 (−)-JQ1: >99percent ee, [α]D22 −39 (c 0.55, CHCl3), (Lit. [α]D22 −55 (c 0.50, CHCl3).6
Stage #1: With potassium <i>tert</i>-butylate In tetrahydrofuran at -78 - 23℃; for 0.5 h; Stage #2: With diethyl chlorophosphate In tetrahydrofuran at -10℃; for 0.75 h; Stage #3: at 23 - 90℃; for 2 h;
Potassium tert-butoxide (1.0 M solution in THF, 0.3 ml, 0.30 mmol, 1.10 equiv) was added to a solution of S5 (114 mg, 0.27 mmol, 1 equiv) in THF (1.8 ml, 0.15 M) at -78 °C. The reaction mixture was warmed to -10 °C, and stirred at 23 °C for 30 min. The reaction mixture was cooled to -78 °C. Diethyl chlorophosphate (0.047 ml, 0.32 mmol, 1.20 equiv) was added to reaction mixture 22. The resulting mixture was warmed to -10 °C over 45 min. Acetic hydrazide (30 mg, 0.40 mmol, 1.50 equiv) was added to reaction mixture. The reaction mixture was stirred at 23 °C. After 1 h, 1-butanol (2.25 ml) was added to reaction mixture, which was heated to 90 °C. After 1 h, all solvents were removed under reduce pressure. The residue was purified with flash column chromatography (Combiflash system, 4 g silica gel, gradient 0 to 100 percent ethyl acetate-hexanes) to afford (+)-JQl (114 mg, 92 percent) as white solid with 90 percent enantiomeric purity (determined with Berger Supercritical Fluid Chromatography (SFC) using AS-H column, 85 percent hexanes- methanol, 210 nm, tR (R- enantiomer) = 1.59 min, tR (S-enantiomer) = 3.67 min). The product was further purified by chiral preparative HPLC (Agilent High Pressure Liquid Chromatography using an OD-H column) to provide the S-enantiomer in greater than 99 percent ee.1H NMR (600 MHz, CDC13, 25 °C) δ 7.39 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H),4.54 (t, J = 6.6 MHz, 1H), 3.54-3.52 (m, 2H), 2.66 (s, 3H), 2.39 (s, 3H), 1.67 (s, 3H), 1.48 (s, 9H).13C NMR (150 MHz, CDC13, 25 °C) δ 171.0, 163.8, 155.7, 150.0, 136.9, 131.1, 130.9, 130.6, 130.3, 128.9, 81.2, 54.1, 38.1, 28.4, 14.6, 13.5, 12.1.HRMS(ESI) calc'd for C2iH24ClN203S [M+H]+: 457.1460, found 457.1451 m/z.TLC (EtOAc), Rf: 0.32 (UV)[a]22D = + 75 (c 0.5, CHCl3)
In a 500mL two neck round-bottomed flask equipped with a magnetic stir bar was dissolved amide 5 (3.40g, 8.13mmol) in THF (60mL) and cooled to −78°C. While stirring at −78°C, potassium tert-butoxide (1.0M solution in THF, 8.95mL, 8.94mmol, 1.10equiv) was added. The reaction mixture was warmed to −10°C and stirred for 30min. The reaction mixture was cooled to −78°C and diphenyl chlorophosphate (2.02mL, 9.76mmol) was added to the reaction mixture. The resulting mixture was warmed to −10°C and stirred at this temperature for 45min. Acetylhydrazide (0.90, 12.20mmol, 1.50equiv) was added to the reaction mixture. The reaction mixture was stirred at room temperature. After 1h, 1-butanol (70mL) was added to the reaction mixture, which was heated to 90°C. After 1h, all solvents were removed under reduce pressure. The residue was dissolved in CH2Cl2 and washed with saturated aq. NaHCO3, brine, dried over anhydrous Na2SO4 and concentrated in vacuo to obtain crude (+)-JQ1, which was purified by flash column chromatography on silica gel (0–100percent ethyl acetate in hexanes) to afford (+)-JQ1 (3.04g, 82percent) as a white solid and with a 91:9 er (determined with Supercritical Fluid Chromatography (SFC) using the CHIRALPAK AS-H column, CO2–EtOH (3:1), 210nm, tR (R-enantiomer) 1.62min, tR (S-enantiomer) 3.51min). This product was further purified by preparative SFC using a CHIRALPAK AS-H column to obtain (+)-JQ1 (S-enantiomer) with >99percent ee. The spectral data of (+)-JQ1 matched with those described in the literature6 with the exception of the optical rotation. [α]D22 +41 (c 0.50, CHCl3), (Lit. [α]D22 +55 (c 0.50, CHCl3);12 (−)-JQ1: >99percent ee, [α]D22 −39 (c 0.55, CHCl3), (Lit. [α]D22 −55 (c 0.50, CHCl3).6
A solution with a temperature of 50 to 60 C. of 222 g (3.0 moles) of anhydrous acethydrazide in 600 ml of anhydrous 1,2-dichloroethane is added dropwise to 450 g (4.5 moles) of phosgene in 3000 ml of anhydrous 1,2-dichloroethane at 10 C. with cooling and stirring over a period of 45 to 60 minutes. The reaction temperature of the mixture should not rise above 25 C. during this addition. When the addition has ended the mixture is heated to 40 C. to 50 C. until the evolution of gas subsides after about 60 minutes. While continuing to introduce phosgene (about 50 g per hour) the mixture is heated further to the refluxing temperature and phosgenated for 1 hour under reflux. For the working-up 1500 ml of solvent and excess phosgene are distilled off and the mixture is filtered while hot, the filtrate is concentrated and the residue is distilled in vacuo. 277 g (92% of theory) of 2-methyl-1,3,4-oxadiazol-5(4H)-one are obtained with a boiling point of 140 to 143 C. at 16 mbar and with a melting point of 110 to 111 C.
to the 5000L into link cauldron bromide of the dichloroethane solution added in, close the manhole cover, stirring cooling to 10 C; (2) check and open tail gas absorption system, 10 - 20 C dropping previously pumped into the elevated tank liquid phosgene; (3) after the completion of the dropping, into the temperature in link cauldron 45 C following reaction 24 h, after the reaction is finished by adding a small amount of NaHCO3 In the and in the solution containing a small amount of hydrogen chloride; (4) after the reaction is finished, nitrogen is introduced 1 h; The generated HCl gas (containing trace did not participate in the reaction of phosgene) collection wrinkles to two-stage water falling-film absorption and level liquid caustic soda drum bubble absorption by the 25 m high exhaust emissions (1 of the exhaust). The exhaust gas is not collected by the acetamide base three qinqin alkone workshop set cover to collect for spraying absorption of water after the 15 m high exhaust emissions (5 of the exhaust). (5) are added in the kettle of water metered, standing 2 hours to be layered; (6) the lower organic layer is dichloroethane solution, pumping to desolution cauldron, the upper layer is the waste water; (7) desolution cauldron (temperature 79 C) boil off of the dichloroethane after condensation and mechanically, and the rest is the 2 - methyl - 1, 3, 4 - oxadiazole -5 (4H) - one and a small amount of dichloroethane, by centrifugal after drying in hot air circulating drying box get intermediate product 2 - methyl - 1, 3, 4 - oxadiazole -5 (4H) - ketone, centrifugal mother liquor is recycled
Acetic hydrazide (7.4 g, 100 mmol) in ethanol (75 mL) was placed in a 200 mL 3-necked round bottomed flask outfitted with a magnetic stir bar and a reflux condenser. Methyl isothiocyanate (7.3 g, 100 mmol) in ethanol (75 mL) was added to the pot. The mixture was refluxed, under N2, for 6 h. The reaction was cooled to room temperature and the solvent removed on the rotovap. The resulting wet solid was triturated with ether and filtered to give a sticky, yellow solid. This solid was triturated with hot CH2Cl2/ethyl acetate (1:1), which afforded a white solid of the uncyclized intermediate. The solid and all liquids associated with the reaction were combined, dissolved in ethanol. Aqueous NaOH (1 M, 50 mL) was added and the mixture refluxed under N2 for 1 h. Acetic acid was used to acidify to a pH of 4-5. The mixture was then cooled on an ice bath to facilitate precipitation. White solid formed, was filtered and washed with ether. (repeated the crystallization process three times with mother liquors). Combined all solids collected and chromatographed through silica gel, eluting with 14% MeOH/ethyl acetate. The collected fractions were concentrated, washed with ether and filtered to yield 5.02 g (38.9%) of the desired product. 1H NMR (DMSO-d6): d 2.27 (s, 3H) 3.37 (s, 3H) 13.36 (broad s, 1H). MS (APCI) calcd for C4H7N3S: 129.18; found (M+H+) 130.0.
A vigorous stream of phosgene is passed into a solution of 74.0 g (1.0 mole) of acethydrazide and 53 g (0.5 mole) of anhydrous sodium carbonate in 300 ml of water, with stirring and cooling at -5 C. to +5 C., until the solution is weakly acid (methyl orange as indicator). A further 53 g (0.5 mole) of sodium carbonate are then added and phosgene is passed in a second time until the indicator changes. For working up, excess phosgene is removed by flushing with nitrogen, the mixture is then extracted with ethyl acetate for 24 hours, the ethyl acetate phase is concentrated to incipient crystallization, cooled and filtered, the mother liquor is concentrated to one quarter of the volume and cooled, and a second fraction is obtained by filtration. After drying, 80 g (80% of theory) of 2-methyl-1,3,4-oxadiazol-5(4H)-one of melting point 112 C. are obtained. STR10
1-trichloroacetimidoyl-2-acetylhydrazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 2 Preparation of 1-Trichloroacetimidoyl-2-Acetylhydrazine A mixture of 5.0 g (0.07 mole) acetylhydrazine and 20 ml (28.5 g, 0.16 mole) <strong>[2533-69-9]methyl 2,2,2-trichloroacetimidate</strong> was stirred 16 hours at room temperature. The resulting solid was recrystallized from toluene to yield 7.3 g. Addition of petroleum ether to the filtrate gave another 1.5 g. The total yield was 8.8 g (59%; mp 130-132 C.). An analytical sample (mp 131-132 C.) was prepared by recrystallization from toluene. The structure was confirmed via infrared and elemental analysis.
Production Example 12-1: Ethyl 5-methyl-[1,3,4]thiadiazole-2-carboxylate: Triethylamine (7.5 mL) and ethyl chloroglyoxalate (3.6 mL) were added to a chloroform suspension (35 mL) of acetohydrazide (2.0 g), and the resulting suspension was stirred overnight at room temperature. After the reaction, the reaction liquid was entirely concentrated, the resulting residue was suspended in toluene (135 mL), and a Lawesson's reagent (7.6 g) was added thereto. After heated under reflux for 3 hours, the reaction liquid was entirely concentrated, and the resulting residue was purified through silica gel column chromatography (hexane/ethyl acetate = 3/1) to obtain the entitled compound (110 mg).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In water; dimethyl sulfoxide; for 24h;
Step 1: To <strong>[1007-16-5]3-bromo-4-fluorobenzoic acid</strong> (2.50 g, 110 mmol) in DMSO (35 ml) add acetic hydrazide (1.029, 13.7 mmol). Add EDCl (2.63 g, 13.7 mmol), then HOBt-H2O (1.85 g, 13.7 mmol). Stir 24 h. Partition with EtOAc and water. Dry (MgSO4) and concentrate to obtain the hydrazide as a yellow oil.
N'-Acetyl-4-bromo-2-methoxybenzohydrazide. A solution of 4-bromo-2-methoxybenzoc acid (950.7 mg, 4.11 mmol) in 8 ml of DMF was treated sequentially with EDC (1 183 mg, 6.17 mmol) and HOBT (945 mg, 6.17 mmol) and stirred at room temperature for 10 minutes. The reaction was then treated with acetic hydrazide (366 mg, 4.94 mmol) and stirred at room temperature overnight. The reaction was dissolved in EtOAc and washed sequentially with saturated bicarbonate solution and brine. The aqueous washes were extracted once with EtOAc. Organics were combined, dried over sodium sulfate, and concentrated under reduced pressure to a white solid (1.37 g crude),1H NMR (500 MHz, CDCl3) delta 10.53 (s, 1 H), 9.18 (s, 1 H), 8.04 (d, J= 8.4 Hz, 1H), 7.25 (dd, J = 8.3, 1.7 Hz, 1 H), 7.16 (d, J= 1.7 Hz, 1H), 4.04 (s, 3H), 2.13 (s, 3H); MS (EI) [M+1]+ calc'd 287.0, 289.0, found 287.0, 289.0.
Potassium tert-butoxide (1.0 M solution in THF, 0.3 ml, 0.30 mmol, 1.10 equiv) was added to a solution of S5 (114 mg, 0.27 mmol, 1 equiv) in THF (1.8 ml, 0.15 M) at -78 C. The reaction mixture was warmed to -10 C, and stirred at 23 C for 30 min. The reaction mixture was cooled to -78 C. Diethyl chlorophosphate (0.047 ml, 0.32 mmol, 1.20 equiv) was added to reaction mixture 22. The resulting mixture was warmed to -10 C over 45 min. Acetic hydrazide (30 mg, 0.40 mmol, 1.50 equiv) was added to reaction mixture. The reaction mixture was stirred at 23 C. After 1 h, 1-butanol (2.25 ml) was added to reaction mixture, which was heated to 90 C. After 1 h, all solvents were removed under reduce pressure. The residue was purified with flash column chromatography (Combiflash system, 4 g silica gel, gradient 0 to 100 % ethyl acetate-hexanes) to afford (+)-JQl (114 mg, 92 %) as white solid with 90 % enantiomeric purity (determined with Berger Supercritical Fluid Chromatography (SFC) using AS-H column, 85 % hexanes- methanol, 210 nm, tR (R- enantiomer) = 1.59 min, tR (S-enantiomer) = 3.67 min). The product was further purified by chiral preparative HPLC (Agilent High Pressure Liquid Chromatography using an OD-H column) to provide the S-enantiomer in greater than 99 % ee.1H NMR (600 MHz, CDC13, 25 C) delta 7.39 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H),4.54 (t, J = 6.6 MHz, 1H), 3.54-3.52 (m, 2H), 2.66 (s, 3H), 2.39 (s, 3H), 1.67 (s, 3H), 1.48 (s, 9H).13C NMR (150 MHz, CDC13, 25 C) delta 171.0, 163.8, 155.7, 150.0, 136.9, 131.1, 130.9, 130.6, 130.3, 128.9, 81.2, 54.1, 38.1, 28.4, 14.6, 13.5, 12.1.HRMS(ESI) calc'd for C2iH24ClN203S [M+H]+: 457.1460, found 457.1451 m/z.TLC (EtOAc), Rf: 0.32 (UV)[a]22D = + 75 (c 0.5, CHCl3)
With potassium tert-butylate; diethyl chlorophosphate; In tetrahydrofuran;
This chiral triazole-fused thiphenodiazepine acetic acid was prepared according to the literature using the synthetic scheme above (Nature 468, 1067-1073, 2010; FN AS 113, 7124- 7129, 2016), NMR (400 MHz, DMSO_d6): delta 1.63 (s, 3H), 2.42 (s, 3H), 2.60 (s, 3H), 3.31-3.41 (m, 2H), 4.45 (t, J = 7.2 Hz, 1H), 7.45-7.49 (m, 4H); LC/MS 401.1 [M+l]+
A solution of the product from stage 4 (20.0 g) in tetrahydrofuran (320 ml) was cooled to - 40 C and treated dropwise over 1 h with a 25% toluene solution of potassium amylate (27.3 g). After stirring at -40 C for 1 h, a solution of diphenyl chlorophosphate (16.8 g) in tetrahydrofuran was added over 0.3 h. The reaction mixture was warmed to -10 C over 1.5 h and stirred at this temperature for 0.5 h.A suspension of acetyl hydrazide (5.1 g) in toluene (30 ml) was added with the aid of additional toluene (30 ml) and the mixture was allowed to warm over 0.5 h to 20 C. Stirring was continued for 1 h, more toluene (200 ml) added and the reaction mixture was heated at 80 C for 1 h. Solvent was removed under reduced pressure to a residual volume of ca. 400 ml, water (80 ml) was added and the two phase mixture was stirred at 20 C for 0.3h. The organic layer was separated and washed with 0.1N aqueous sulphuric acid (80 ml), 5% aqueous sodium carbonate (80 ml) and water (80 ml) then evaporated under reduced pressure, yielding crude stage 5 product (-25 g) which was used directly in the subsequent step. The deprotection can also be conducted with potassium tert.-butoxide and/or at temperatures of up to 20C with essentially no depreciation on yield or enantiomeric purity.
General procedure: A mixture of acid hydrazide (1 mmol) and trimethylsilyl isothiocyanate (1 mmol) and ethanol (10 ml) was refluxed for 3-5h and then 2ml of 4N NaOH was added, resulting in the formation of clear solution, the solution was refluxed for an additional 4-6 h, cooled and poured into ice-cold water and adjusted the pH (5-6) with acetic acid resultant solid was filtered on a Buchner funnel and dried. This on recrystallization from ethanol afforded pure product 3a-l.
trans-2-(N"-acetylhydrazinocarbonyl)-5-benzyloxyamino-piperidine-1-carboxylic acid-tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With benzotriazol-1-ol; In N,N-dimethyl-formamide;
Step-1: Preparation of trans-2-(N"-acetylhydrazinocarbonyl)-5-benzyloxyamino-piperidine-1-carboxylic acid-tert-butyl ester To a solution of trans-5-benzyloxyamino-piperidine-1,2-dicarboxylic acid-1-tert-butyl ester (12 gm, 0.034 mol) in N,N-dimethyl formamide (60 ml), EDC-HCl (9.82 gm, 0.051 mol) and N-methyl morpholine (11.4 ml) were added successively at 10 C. to 15 C. under stirring. To the reaction mixture, were added acetyl hydrazide (2.79 gm, 0.0377 mol) and HOBt (4.62 gm, 0.034 mol). The resulting mixture was allowed to warm at 25 C. to 35 C. and stirred for 16 hours. The reaction mixture was poured into water (600 ml) and stirred for 30 min. The separated solid was filtered and the filtrate was extracted with ethyl acetate (3*400 ml). The combined organic extract was dried over sodium sulphate and the solvent was evaporated under vacuum to provide a residue. The residue was purified by column chromatography to obtain the Step-1 product, as a pale yellow thick oil in 9.8 gm quantity (yield 70%). Analysis: MS: 407 (M+H); MF: C20H30N4O5; MW: 406.49.
N'-acetyl-4-cyano-3-methylbenzohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
Step i:To a stirred solution of <strong>[73831-13-7]4-cyano-3-methylbenzoic acid</strong> (1 mmol) in 4 ml of dry CH2C12 was added HATU (1 mmol), followed by the addition of DIEA (2 mmol) and the mixture was stirred for 5 mm. Then, acetic hydrazide (1.2 mmol)was added and the mixture was stirred under N2, at r.t., overnight. The solvents were concentrated in vacuo and the residue was purified by column chromatography to obtain the desired product in 76% yield.
tert-butyl 4-(4-(2-acetylhydrazinyl)-4-oxobutyl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In ethyl acetate; at 20℃; for 2h;
4-(1 -(tert- Butoxycarbonyl)piperidin-4-yl)butanoic acid (commercially available) (2.00 g, 6.50 mmol) and acetohydrazide (0.588 g, 7.15 mmol) were placed in a flask with EtOAc (10 mL). DIPEA (3.40 mL, 19.49 mmol) was added followed by the slow addition of T3P (50% in EtOAc) (5.69 mL, 9.75 mmol). The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo and the crude product was purified by chromatography on silica eluting with iso-hexane/( EtOAc:MeOH - 10:1) to afford the title compound.
In tetrahydrofuran; butan-1-ol; at 20 - 90℃; for 2h;
In a 500mL two neck round-bottomed flask equipped with a magnetic stir bar was dissolved amide 5 (3.40g, 8.13mmol) in THF (60mL) and cooled to -78C. While stirring at -78C, potassium tert-butoxide (1.0M solution in THF, 8.95mL, 8.94mmol, 1.10equiv) was added. The reaction mixture was warmed to -10C and stirred for 30min. The reaction mixture was cooled to -78C and diphenyl chlorophosphate (2.02mL, 9.76mmol) was added to the reaction mixture. The resulting mixture was warmed to -10C and stirred at this temperature for 45min. Acetylhydrazide (0.90, 12.20mmol, 1.50equiv) was added to the reaction mixture. The reaction mixture was stirred at room temperature. After 1h, 1-butanol (70mL) was added to the reaction mixture, which was heated to 90C. After 1h, all solvents were removed under reduce pressure. The residue was dissolved in CH2Cl2 and washed with saturated aq. NaHCO3, brine, dried over anhydrous Na2SO4 and concentrated in vacuo to obtain crude (+)-JQ1, which was purified by flash column chromatography on silica gel (0-100% ethyl acetate in hexanes) to afford (+)-JQ1 (3.04g, 82%) as a white solid and with a 91:9 er (determined with Supercritical Fluid Chromatography (SFC) using the CHIRALPAK AS-H column, CO2-EtOH (3:1), 210nm, tR (R-enantiomer) 1.62min, tR (S-enantiomer) 3.51min). This product was further purified by preparative SFC using a CHIRALPAK AS-H column to obtain (+)-JQ1 (S-enantiomer) with >99% ee. The spectral data of (+)-JQ1 matched with those described in the literature6 with the exception of the optical rotation. [alpha]D22 +41 (c 0.50, CHCl3), (Lit. [alpha]D22 +55 (c 0.50, CHCl3);12 (-)-JQ1: >99% ee, [alpha]D22 -39 (c 0.55, CHCl3), (Lit. [alpha]D22 -55 (c 0.50, CHCl3).6
2-chloro-4-(5-methyl-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
27%
With trichlorophosphate; at 70℃; for 2h;
2-Ch[oro-5-(trif[uoromethy[)isonicotinic acid [CAS RN: 505084-58-2] (400 mg,1 .77 mmo[, 1 .0 eq) in 5.6 mL phosphoryl. chloride was treated with acetohydrazide [CAS-RN: 1068-57-1] (394 mg, 5.32 mmol, 3.0 eq). The resulting reaction mixture was stirred at 70 °C for 2 h. On cooling, the reaction mixture was concentrated in vacuo. The crude material was diluted with toluene and concentrated at the rotary evaporator. This process was repeated two times.The crude material was hydrolysed, treated with 2M sodium carbonate solution and extracted with ethyl acetate (2x). The combined organic phases were washed with brine. The phases were separated by the use of a Whatman filter. The volatile components were removed in vacuo and the crude material was purified via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane ->hexane/ethyl acetate 4/1 -> ethyl acetate ) to give 150 mg (27percent yield of theory) of the title compound.1H-NMR (400 MHz, DMSO-d6): oe [ppm] = 2.64 (5, 3H), 8.21 (5, 1H), 9.09 (5, 1H).
N’-acetyl-2,5-dichloroisonicotinohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59%
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; In ethyl acetate; at 80℃; for 6.5h;
2,5-Dichloroisonicotinic acid [CAS RN: 88912-26-9] (500 mg, 2.60 mmo[, 1.0 eq) in 17.6 mL ethyl. acetate was treated with T3P solution [50 percent in ethyl acetate] (3.88 mL, 6.51 mmol, 2.5 eq) and with acetohydrazide [CAS-RN: 1068-57-1] (193 mg, 2.60 mmol, 1.0 eq). The resulting solution was stirred at 80 °C for 6.5 h. The reaction mixture was hydrolysed with ice-water and extracted with ethylacetate (3x). The combined organic phases were washed with brine. The phases were separated by the use of a Whatman filter. The volatile components of the resulting organic phase were removed in vacuo and the crude material was stirred with dichlorormethane/methanol. The precipitate formed was isolated by filtration and dried to give 353 mg (59percent yield of theory) of the titlecompound.UPLC-MS (Method 1): R = 0.58 mm; MS (EI0): m/z = 248 [M].1H-NMR (400 MHz, DMSO-d6): oe [ppm] = 1.91 (5, 3H), 7.61 (5, 1H), 8.63 (5, 1H),10.21 (5, 1H), 10.64 (5 br, 1H).
2-(2-chloro-1,3-thiazol-5-yl)-5-methyl-1,3,4-oxadiazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; In ethyl acetate; at 80℃; for 6.5h;
2-Chloro-1,3-thiazole-5-carboxylic acid [CAS RN: 101012-12-8] (500 mg, 2.96mmol, 1.0 eq) in 20 mL ethyl acetate was treated with T3P solution [50 % in ethyl acetate] (4.41 mL, 7.41 mmol, 2.5 eq) and with acetohydrazide [CAS-RN:1068-57-1] (219 mg, 2.96 mmol, 1.0 eq). The resulting solution was stirred for6.5 h at 80 C. The reaction mixture was hydrolysed and extracted with ethyl acetate (3x). The combined organic phases were washed with brine. After phase separation via a Whatman-filter the volatile components were removed. The material observed this way (230 mg, 26% yield of theory, -70 % purity based on UPLC area-%) was used in the following step without further purification.UPLC-MS (Method 1): R = 0.80 mm; MS (EI0): m/z = 202 [M+H].
2-(2-chloro-1,3-thiazol-4-yl)-5-methyl-1,3,4-oxadiazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; In ethyl acetate; at 80℃;
2-Ch[oro-1,3-thiazo[e-4-carboxy[ic acid [CAS RN: 5198-87-8] (430 mg,2.55 mmo[, 1.0 eq) in 17 mL ethyl. acetate was treated with T3P solution [50 % in ethyl acetate] (3.80 mL, 6.37 mmol, 2.5 eq) and with acetohydrazide [CASRN: 1068-57-1] (189 mg, 2.55 mmol, 1.0 eq). The resulting solution was stirred at 80 C overnight. The reaction mixture was hydrolysed with ice-water and extracted with ethyl acetate (3x). The combined organic phases were washedwith brine. The phases were separated by the use of a Whatman filter. The volatile components of the resulting organic phase were removed in vacuo and the crude material contained 350 mg (50% yield of theory) of the title compound in 80% purity (UPLC area-%), which were used without further purification.UPLC-MS (Method 2): R = 0.90 mm; MS (EI0): m/z = 202 [M+H].1H-NMR (400 MHz, DMSO-d6): oe [ppm] = 2.41 (5, 3H), 8.71 (5, 1H).
3-amino-6-bromo-pyrazine-2-carboxylic acid N’-acetyl-hydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; HATU; In dichloromethane; at 20℃; for 24h;
Step 1: 3-Amino-6-bromo-pyrazine-2-carboxylic acid N?-acetyl-hydrazideHATU (3.4 g, 9.05 mmol) and triethylamine (1.2 g, 12.06 mmol) were added to a suspension of 2-Amino-S-bromopyrazine-3-carboxylic acid (1 .40g, 6.03 mmol) and acetohydrazide (0.44 g, 6.03 mmol) in DCM (100 ml) and the resultant solution was stirred at ambient temperature for 24 hr. The reaction was monitored by TLC. The reaction mixture was poured into water(200 ml) and the solid collected by filtration and dried under vacuum to afford 3-amino-6- bromo-pyrazine-2-carboxylic acid N?-acetyl-hydrazide;LCMS: Rt 0.57mins MS mlz 274.0 [M+H}+; Method 2minLowpHvol
N'-acetyl-2-amino-5-bromonicotinohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In d7-N,N-dimethylformamide; at 20℃; for 72h;Inert atmosphere;
Step 1 : N'-acetyl-2-amino-5-bromonicotinohydrazide To a mixture of <strong>[52833-94-0]2-amino-5-bromonicotinic acid</strong> (2 g, 9.22 mmol), acetohydrazide (0.819 g, 11.06 mmol) and TEA (5.14 ml, 36.9 mmol) in DMF (60 ml) under N2 was added T3P (50percent in DMF) (8.23 ml, 27.6 mmol) over 5 mins and the reaction left stirring at room temperature for 3 days. The resulting mixture was added to 1 M HCI (10ml) and extracted into EtOAc, washed with 1M NaOH (10ml), brine and dried over magnesium sulfate before being concentrated under reduced pressure. The acidic washings were neutralised by addition of NaOH and extracted again into EtOAc, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. Used without further purification. LCMS: Rt = 0.38mins MS m/z [M+H]+ = 273.3 (smaller Br isotope reported) Method: 2minl_owpHv01
5-bromo-3-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With trichlorophosphate; at 100℃; for 1h;Inert atmosphere;
Intermediate C14 5-Bromo-3-(5-methyl-1 ,3,4-oxadiazol-2-yl)pyridin-2-amineA stirred mixture of <strong>[52833-94-0]2-amino-5-bromonicotinic acid</strong> (200 mg, 0.922 mmol) in POCI3 (2 ml) was treated with acetohydrazide (68.3 mg, 0.922 mmol) and stirred under N2 at 100°C for 1 hour. The resulting mixture was added dropwise to crushed ice over 10 minutes and left for 5 minutes. The mixture was neutralized by addition of 2M NaOH and extracted with DCM (3x30 ml). The combined organic extracts were dried over MgS04, filtered and concentrated under reduced pressure. Purification of the crude residue by chromatography on silica eluting with 0-100percent EtOAc in iso-hexane afforded the title compound as a white solid;LCMS: Rt = 0.88 mins MS m/z 255.3 [M+H]+; Method 2minLowpHv01.
N'-(di(pyridin-3-yl)methylene)acetohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90.5%
With toluene-4-sulfonic acid; In ethanol; for 2.5h;Reflux;
General procedure: Method D A suspension of ketone(2 mmol, 1.0 equiv), acethydrazide (2.2 mmol, 1.1 equiv), and p-TsOH·H2O (38 mg, 0.2 mmol,0.1 equiv) in ethanol (5 mL) was heated at reflux for 2.5 hours. After coolingto room temperature, the reaction mixture was concentrated to dryness in vacuum.Brine was added to the residue. The resulting slurry was extracted with CH2Cl2for three times. The organic layer was collected and dried over anhydrous Na2SO4.The drying agent was removed by filtration and the solvent was removed invacuum. After purification by medium-pressure column chromatography, the productwas obtained.
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 N,N-dimethyl-formamide; at 20℃; for 3h;
Compound BB-13-3 (1.65g, 6.13mmol) was dissolved in N, N - dimethylformamide (20 mL), followed by addition ofacetyl hydrazide (0.499g, 6.74mmol), N, N - diisopropylethylamine amine (2.37g, 18.38mmol), 2- ( 7-benzotriazole azo-yl) - N, N, N ', N' - tetramethyluronium hexafluorophosphate (3.03g, 7.96mmol), the reaction It was stirred at room temperature for 3 hours.After completion of the reaction was added water, extracted with ethyl acetate (50 ml x), the organic phase was washed with brine (20 mL), dried over anhydrous sodiumsulfate, filtered, and concentrated to give the crude product.Fast by column (eluent, ethyl acetate / petroleum ether = 4/1) to give the title compound bb-14-1 (white solid, 1.6 g of, yield: 80%).
N'-acetyl-1H-pyrrolo[2,3-b]pyridine-5-carbohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
56%
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 20℃; for 12h;Inert atmosphere;
Step 2: Preparation of N?-acetyl-1H-pyrrolo[2,3-b]pyridine-5-carbohydrazide (0750) (0751) A mixture of <strong>[754214-42-1]1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid</strong> (100 mg, 0.62 mmol), acethydrazide (69 mg, 0.93 mmol), EDCI (236 mg, 1.23 mmol) and HOBt (125 mg, 0.93 mmol) in DME (6.2 mL) was added with NMM (200 muL, 1.85 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 12 hours. The resulting mixture was purified with prep. HPLC system (water, ACN/H2O) to give the title compound (76 mg, 56%) as a white solid.
General procedure: 5 ml of sodium methoxide methanolic solution (35 wt%) was added to a solution of 2-cyanopyridine (0.05 mol) in20 ml of methanol and stirred at room temperature for 1 h. Then the respective hydrazide was added to the generate dimino ester solution and refluxed for 10 h. The obtained mixture was cooled to room temperature and the solvent removed in vacuo. The resulting residue was diluted with water and acidified with 2 ml of acetic acid to produce a white solid. The crystals were separated via filtration, dried and recrystallized from toluene (HL1-3). The physical properties and analytical data of compounds HL1-3 are listed in Table 1, and the spectral data of compounds HL1-3are listed in Table 2.
With phosgene; sodium hydrogencarbonate; at 0℃;Sealed tube; Green chemistry; Large scale;
(2) Preparation of oxadiazolone:Methyl acetate 2000ml into 5000ml three bottles,Under stirring, 740 g of acetylhydrazine was added,Frozen down to 0 below, put 1680g sodium bicarbonate,Seal the reaction bottle.To the reaction bottle in the continuous access to phosgene, phosgene flow rate of 15m3 / h.After the end of the reaction, the solvent was distilled off, crystallized at 0 C and filtered to give a white solid 988.2 g, yield: 99%.
To a mixture of A-30.1 (2.00 g, 8.42 mmol) in dry DCM (50 mL) is added A-30.2 (0.83 g, 10.1 mmol) and the reaction is stirred at RT for lh. Additional A-30.2 (0.83 g, 10.1 mmol) is added and the reaction is stirred overnight. MeOH (5 mL) is added and the solvent is reduced tohalf the volume, the precipitate is filtered off to provide 1 .50 g of A-30.3. ESI-MS: 275/ 277 [M+H] HPLC (Rt): 0.09 mm (method D)
N-((quinolin-8-yl)methylene)acetohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90.6%
In ethanol; at 20℃; under 760.051 Torr; for 5h;
1.57 g of <strong>[38707-70-9]quinoline-8-carbaldehyde</strong> was dissolved in 50 mL of absolute ethanol,An additional 0.94 g of acetohydrazide,The reaction was stirred at room temperature and pressure 5h,Precipitation of a large number of solids,Vacuum filtration,The residue was washed with anhydrous ethanol to give a white solid as the target product,The yield of the target product was 90.6%.
62%
In ethanol; at 20℃; for 0.5h;
As shown in Scheme 1, a mixture of <strong>[38707-70-9]8-formylquinoline</strong> (1.57g, 10mmol) and acethydrazide (0.74g, 10mmol) in ethanol (30ml) were stirred at room temperature for 0.5h, clear brown solution was formed. The pale-yellow solid was precipitated after stirring for another 4h, then filtered and washed three times with ethanol. Yield: 1.32g (62%). M.p.: 168-170C. Elemental analysis for HL (C12H11N3O) (%): Calc.: C: 67.59; H: 5.20; N: 19.71; Found: C: 67.48; H: 5.27; N: 19.64. FT-IR (cm-1): v(C=O) 1673, v(C=N, imine) 1615, v(C=N, quinoline) 1584. 1H NMR (400MHz, d6-DMSO) delta:11.69/11.45 (1H, s, 1:2, OH/NH), 9.45/9.28 (1H, s, 1:2, H10), 8.97-8.99 (1H, m, H1)/8.42-8.46 (1H, m, H7)/8.30-8.33 (1H, m, H3)/8.05-8.08 (1H, m, H5)/7.67-7.72 (1H, m, H6)/7.60-7.64 (1H, m, H2) for Ar-H, 2.28/1.99 (3H, s, 2:1, H12). 13C NMR (400MHz, d6-DMSO) delta: 172.58/166.01 (C11), 150.83/150.80 (C1), 145.74/145.65 (C9), 143.00/140.11 (C10), 137.15/137.10 (C3), 131.71/131.59 (C8), 130.31/130.08 (C5), 128.49 (C7), 127.01/126.98 (C4), 125.93/125.55 (C6), 122.35 (C2), 22.13/20.87 (C12). ESI-MS: m/z=214.0990 for [M+H]+.
N’-acetyl-6-chloropyrimindine-4-carbohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a solution of <strong>[37131-91-2]6-chloropyrimindine-4-carboxylic acid</strong> (1 g, 6.31 mmol) and DMF (9.8 jiL,0.126 mmol) in THF (60 mL) stirred under nitrogen at 0C was added oxalyl chloride 2 M solution in DCM (4.73 mL, 9.46 mmol) dropwise. The reaction minxture was allowed to warm to rt and stirred for further 1 h. The reaction minxture was evaporated in vacuo to give a brown oil. This residue was dissolved in 1,4-dioxane (60 mL) and acetohydrazide (0.935 g, 12.6mmol) added in one charge. The reaction minxture was allowed to warm to rt and stirred for further 1 h. The reaction minxture was evaporated in vacuo to afford N?-acetyl-6- chloropyrimindine-4-carbohydrazide (1.94 g, 9 mmol, purity: 37 %, recovery: 143 %) as an off-white solid, which was taken on to the next step without further purification. LCMS (mlz) 215 and 217 (M+H), retention time: 1.38 min LC/MS Method 2.
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-hydroxysulfosuccinimide sodium salt; In water; at 20℃; for 12.5h;
Accurately weigh 1.97g (5mmol) of <strong>[3543-75-7]<strong>[3543-75-7]bendamustine</strong> hydrochloride</strong> dissolved in 5mL of deionized water.95.8 mg of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.5 mmol) was addedAnd 65.1 mg of N-hydroxysulfosuccinimide sodium salt (0.3 mmol) were stirred for 30 min in order to activate the carboxyl group.0.60 mg (8 mmol) of acetohydrazine was accurately weighed and slowly added to the above solution under stirring, and reacted at room temperature for 12 hours.The solvent was removed by rotary evaporation and the product was purified by chromatography.Drying in vacuo gave 1.37 g of a white solid, yield 66.1%.
ethyl 1-(2-acetylhydrazine-1-carbonyl)cyclopropane-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
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℃;
A flask was charged with l-(ethoxycarbonyl)cyclopropane-l-carboxylic acid (6.60 g, 40.0 mmol, 1.00 equiv), HATU (22.8 g, 60.0 mmol, 1.50 equiv), DIPEA (15.5 g, 120 mmol, 3.00 equiv), acetohydrazide (2.96 g, 40.0 mmol, 1.00 equiv) and DCM (100 mL). The resulting mixture was stirred overnight at room temperature and quenched with water (60 mL). The mixture was extracted with DCM (2 x 50mL) and the organic layers were combined, washed with brine (2 x 30 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by recrystallization to provide 4.77 g (crude) of ethyl l -(2- acetylhydrazine-l-carbonyl)cyclopropane-l-carboxylate. LCMS (ESI, m/z): 215 [M+H]+
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 17h;Inert atmosphere;
Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed <strong>[10385-30-5]4-(benzyloxy)butanoic acid</strong> (1.0 g, 5.15 mmol) in dichloromethane (10 mL). Acetohydrazide (724 mg, 9.77 mmol) was added followed by triethylamine (1.249 g, 12.34 mmol), 4-dimethylaminopyridine (1.25 g, 10.23 mmol) and EDC (1.98 g, 10.31 mmol). The resulting solution was stirred for 17 h at room temperature. The pH value of the solution was adjusted to 2 with hydrochloric acid (1N). The resulting solution was extracted with 2x20 mL of ethyl acetate and the organic layers combined. The resulting mixture was concentrated under vacuum affording the title compound (1 g, 78%) as a white solid. MS: (ES, m/z): 251 [M+H]+.
benzyl N-[1-(N’-acetylhydrazinecarbonyl)cyclopropyl]carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87.5%
With 1,1'-carbonyldiimidazole; In dichloromethane;
To a solution of l-[(benzyloxy)carbonyl]aminocyclopropane-l-carboxylic acid (6.0 g, 25.5 mmol) in DCM (100 mL) at r.t. was added l-(lH-imidazole-l-carbonyl)-lH-imidazole (6.2 g, 38.3 mmol) in one portion. Upon completion of gas evolution (-20 min) acetohydrazide (3.78 g, 51.01 mmol) was added and the reaction mixture stirred overnight. The precipitate formed was collected by filtration, washed with DCM and dried to give benzyl N-[1-(N'- acetylhydrazinecarbonyl)cyclopropyl]carbamate (4.0 g). The filtrate was concentrated under reduced pressure. The residue was partitioned between EtOAc (100 mL) and aqueous sodium hydrogensulfate solution (lOOmL). The organic phase was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to afford second portion of product (2.5 g). Portions were combined to obtain benzyl N-[1-(N'- acetylhydrazinecarbonyl)cyclopropyl]carbamate (6.5 g, 22.31 mmol, 87.5% yield) as a white solid.
With sodium methylate; at -15℃;Reflux; Green chemistry;
In a 500 ml oxadiazolone reaction flask, a stirrer, a thermometer, a condenser and a rectification column were installed, and the instruments were all dry and anhydrous. At room temperature, add 200-250g of dimethyl carbonate, start stirring, cool down and cool, control the reaction temperature about 10 C, add 37.0g of acetylhydrazine, 10.0g of catalyst 30% sodium methoxide solution, after -15 C-30 C The reaction was kept for 2 hours, then slowly heated to reflux. During the reaction, the rectification is continuously carried out, and the azeotrope of by-product methanol-dimethyl carbonate is separated from the top of the rectification column, and the reaction is refluxed for 6-10 hours. Sampling analysis, when the acetylhydrazine residue is about 1.0%, the reaction is basically finished, the synthesis liquid is cooled to 20-30 C, and then the temperature is slowly lowered to -8 C and the crystal is kept for 1-2 hr.Vacuum filtration and filter cake were dried under vacuum at 70 C to obtain 44.8 g of oxadiazolone.The product yield is about 89.5%.The GC analysis content was ?99.0 %
With zinc diacetate; In 1,2-dichloro-ethane; at 20℃;Reflux; Green chemistry;
In a 1000 ml oxadiazolone reaction bottle, a stirrer, a thermometer, a constant pressure dropping funnel and a condenser were installed, and the instruments were all dry and anhydrous. At room temperature, 250 ml of solvent dichloroethane was added, stirring was started, 74.0 g of acetyl hydrazine and 9.2 g of zinc acetate catalyst were added, and then 214.3 g of diphenyl carbonate solution dissolved in 250 ml of dichloroethane was slowly added dropwise. The reaction was kept at room temperature for 1 hr, and the reaction was stabilized, and then slowly heated to reflux, and the reaction was kept for 5-7 hours. Sampling analysis, when the residual acetylhydrazine ? 1.0%, the reaction is finished, after a simple post-treatment, the filtrate is cooled down to -6 C for 1-2 hrs of incubation, vacuum filtration,The filter cake was vacuum dried at 65-70 C to obtain 93.6 g of the oxadiazolone product, the product yield was about 93.5%, and the GC analysis content was ?99.0%
6-(3,5-dimethyl-1,2,4-triazol-4-yl)-1H-pyrrolo[2,3-b]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
A mixture of lH-pyrrolo[2,3-b]pyridin-6-amine (2 g, 15.02 mmol, 1 eq), l, l-dimethoxy-N,N- dimethyl-ethanamine (18.22 g, 136.80 mmol, 20.00 mL, 9.11 eq) was stirred at 130 C for 1 h. The mixture was cooled to 0 C, cone. HC1 (4 mL) was added dropwise, followed by acetohydrazide (6.68 g, 90.12 mmol, 6 eq) and the resulting mixture was stirred at 0 C for 30 min. Then, the temperature was raised to 130 C and the solution was stirred for another 2 h. The resulting solution was concentrated. The residue was purified by column chromatography (SiCK DCM/MeOH = 70/1 to 7/1) to afford the title compound (10.5 g, crude, HC1) as a yellow oil. (Note: The reaction was combined with another reaction in 200 mg scale for work up)
With N-ethyl-N,N-diisopropylamine; In dichloromethane;
Acetohydrazide (0.37 g, 4.99 mmol) was stirred in DCM (10 mL) and DIPEA (0.87 mL, 4.99 mmol). 5- bromopyridine-2-carbonyl chloride (1 g, 4.54 mmol) was added in portions and the reaction was stirred for 15 minutes. The reaction was concentrated in vacuo to afford an oil. Water (10 mL) was added and the mixture sonicated which resulted in colloid formation, DCM (30 mL) was added and an emulsion formed, more water and DCM were added which resulted in flocculation. The mixture was filtered under vacuum to remove the brown solid. The filtrate was separated and the organic DCM layer was concentrated in vacuo to give a brown residue. The aqueous layer was added to this residue and the mixture sonicated, the resulting brown solid was collected by vacuum filtration and combined with the initial brown solid to afford the title compound (683 mg, 55% at 95% purity). dH (250 MHz, DMSO-d6) d 10.44 (s, 1H), 9.98 (s, 1H), 8.80 (d, J 1.8 Hz, 1H), 8.28 (dd, J 8.4, 2.3 Hz, 1H), 7.95 (dd, J 8.4, 0.5 Hz, 1H), 1.91 (s, 3H).
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