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CAS No. : | 5331-43-1 | MDL No. : | MFCD00041890 |
Formula : | C8H10N2O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | RXUBZLMIGSAPEJ-UHFFFAOYSA-N |
M.W : | 166.18 | Pubchem ID : | 79242 |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.12 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 43.4 |
TPSA : | 64.35 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.65 cm/s |
Log Po/w (iLOGP) : | 1.54 |
Log Po/w (XLOGP3) : | 0.93 |
Log Po/w (WLOGP) : | 0.63 |
Log Po/w (MLOGP) : | 1.15 |
Log Po/w (SILICOS-IT) : | 0.06 |
Consensus Log Po/w : | 0.86 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.56 |
Solubility : | 4.55 mg/ml ; 0.0274 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.87 |
Solubility : | 2.25 mg/ml ; 0.0136 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.18 |
Solubility : | 1.11 mg/ml ; 0.00667 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.83 |
Signal Word: | Danger | Class: | N/A |
Precautionary Statements: | P264-P280-P302+P352-P362+P364-P332+P313-P305+P351+P338+P310 | UN#: | N/A |
Hazard Statements: | H315-H318 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium carbonate; hydrazine hydrate In tetrahydrofuran at -20℃; for 2 h; | In the three-port the reaction bottle, by adding hydrazine hydrate (2.0 mol) and potassium carbonate (2.0 mol) and 50 ml tetrahydrofuran, the reaction system to lower the temperature to -20 degrees, instillment chlorine formic acid benzyl ester (2.0 mol). Dropwise after the completion of the reaction to 2 hours, after filtering to remove the potassium carbonate, water washing. The concentrated organic phase to obtain the product (yield 95.0percent, purity of 96.0percent, high-efficient gas chromatographic (GC) method in). hydrazine benzyl formate salt crude product purification: In the three-port the reaction bottle, by adding hydrazine carboxylic acid animal pen ester thick (96.0percent purity, high-efficient gas chromatographic (GC) method in) 40.0g and 400 ml dichloromethane, adding dropwisely the reaction system 80mL30percent hydrochloric acid. Solids are separated in the reaction system. In the reaction system by adding 150 ml of water to the solid part dissolved. Separating the organic layer, retaining layer. Adding dropwisely to the water 80 ml ammonia, to the solution to get alkaline. With 250 ml methylene chloride extraction layer three times. The concentrated organic phase get the pure product hydrazine carboxylic acid benzyl ester 36.0g (99.5percent purity, high-efficient gas chromatographic (GC) method in the, yield 90.0percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5.78 g | With hydrazine hydrate In dichloromethane at 0 - 20℃; for 1.5 h; | General procedure: Alcohol 1 (40 mmol) was added in portions to the solid-liquidmixture of CH2Cl2 (40 mL) and N,N'-carbonyldiimidazole (6.95 g, 42 mmol) at room temperature. The solid-liquid mixture turned into a yellowish solution, and was stirred at room temperature for 30 min after feeding. Then the solution was washed with water (2 x 40 mL). The organic phase was transferred to a three-necked flask, and cooled to 0-5 °C. Hydrazine hydrate (2.27 g, 44 mmol) was added dropwise and amorphous white solid produced after a while. The mixture was stirred at room temperature for 30 min, and then filtered. The white solid was washed with water. The filtrate was concentrated in vacuo leading to a white solid and filtered. The white solid was also washed with water. Both of the white solid was collected and dried in vacuo to get the product 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.8% | With triethylamine In tetrahydrofuran at 25℃; for 5 h; | General procedure: Di-tert-butyl dicarbonate (8.02 g, 36 mmol) dissolved in THF (10 mL) was added dropwise to the solid-liquid mixture of 3 (30 mmol), TEA (3.64 g, 36 mmol) and THF (15 mL) at 25 °C. The mixture was stirred for 5 h. The resulting clear colorless solution was concentrated in vacuo, recrystallizing with CH2Cl2 and then filtered. The white solid was washed with petroleum ether and water. The filtrate was washed with 1 M HCl (20 mL). Then the organic phase was concentrated and white solid precipitated. The mixture was filtered and the solid was washed with petroleum ether and water. Both of the white solid was collected and dried in vacuo to afford the desired product 4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With lithium carbonate; hydrazine hydrate; In ethyl acetate; at 30 - 120℃; for 2.75h;Inert atmosphere; | Dissolve the hydrazine hydrate in ethyl acetate, add the catalyst, stir and stir for at least 5 minutes, then pass through the lithium carbonate to discharge the air, and then carry out the reaction under the protection of nitrogen, wherein the hydrazine hydrate and the solvent are in accordance with The weight ratio is 1:8 in order; Step 2, the benzyl chloroformate is added dropwise to the reaction vessel in the first step, the dropping temperature is 30 C, the dropping time is 15 min, and after the completion of the dropwise addition, the temperature is heated at 30 C for at least 2 h, and then the temperature is raised to The reaction is carried out at 120 C for at least 30 min, and after cooling to below 80 C, it is allowed to stand for at least 30 min, and the filtrate is obtained by atmospheric filtration. The filter residue was washed three times with ethyl acetate, and the filtrate and the washing liquid were combined, and the solvent was distilled off under reduced pressure. The distillation temperature under reduced pressure was 50 C, and the pressure under reduced pressure was 0.05 MPa, wherein hydrazine hydrate, a catalyst, and benzyl chloroformate. According to the molar ratio, the order is 4.0:0.25:1.0; Step 3: The residue after vacuum distillation is added to the purified water for at least 5 min, the ultrasonic temperature is 45 C, the ultrasonic frequency is 35 kHz, and the temperature is -15 after the ice salt bath is allowed to stand for at least 30 min. At 0 C, the supernatant was separated and removed, and after methanol was dissolved, the methanol was evaporated to the end, and the methanol was allowed to react at a temperature of 65 to 67 C to obtain a pure benzyl carbazate. |
90% | With potassium carbonate; hydrazine hydrate; In tetrahydrofuran; at -20℃; for 2h; | In the three-port the reaction bottle, by adding hydrazine hydrate (2.0 mol) and potassium carbonate (2.0 mol) and 50 ml tetrahydrofuran, the reaction system to lower the temperature to -20 degrees, instillment chlorine formic acid benzyl ester (2.0 mol). Dropwise after the completion of the reaction to 2 hours, after filtering to remove the potassium carbonate, water washing. The concentrated organic phase to obtain the product (yield 95.0%, purity of 96.0%, high-efficient gas chromatographic (GC) method in). hydrazine benzyl formate salt crude product purification: In the three-port the reaction bottle, by adding hydrazine carboxylic acid animal pen ester thick (96.0% purity, high-efficient gas chromatographic (GC) method in) 40.0g and 400 ml dichloromethane, adding dropwisely the reaction system 80mL30% hydrochloric acid. Solids are separated in the reaction system. In the reaction system by adding 150 ml of water to the solid part dissolved. Separating the organic layer, retaining layer. Adding dropwisely to the water 80 ml ammonia, to the solution to get alkaline. With 250 ml methylene chloride extraction layer three times. The concentrated organic phase get the pure product hydrazine carboxylic acid benzyl ester 36.0g (99.5% purity, high-efficient gas chromatographic (GC) method in the, yield 90.0%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.8% | With triethylamine; In tetrahydrofuran; at 25℃; for 5h; | General procedure: Di-tert-butyl dicarbonate (8.02 g, 36 mmol) dissolved in THF (10 mL) was added dropwise to the solid-liquid mixture of 3 (30 mmol), TEA (3.64 g, 36 mmol) and THF (15 mL) at 25 °C. The mixture was stirred for 5 h. The resulting clear colorless solution was concentrated in vacuo, recrystallizing with CH2Cl2 and then filtered. The white solid was washed with petroleum ether and water. The filtrate was washed with 1 M HCl (20 mL). Then the organic phase was concentrated and white solid precipitated. The mixture was filtered and the solid was washed with petroleum ether and water. Both of the white solid was collected and dried in vacuo to afford the desired product 4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With pyridine; In diethyl ether; dichloromethane; at 0 - 20℃; | a) methyl 3-[N'-benzyloxycarbonyl-hydrazinocarbonyl)-benzoate; 10.80 g (54.4 mmol) methyl 3-chlorocarbonyl-benzoate in 100 mL diethyl ether are added dropwise to a solution of 9.04 g (54.4 mmol) benzyl hydrazine carboxylate in 100 mL diethyl ether, 100 mL dichloromethane and 4.83 mL pyridine while cooling with an ice bath. The reaction mixture is stirred overnight at ambient temperature and then combined with water. The precipitated solid is filtered off and washed with diethyl ether. White solid. Yield: 14.1 g (79%); mass spectroscopy [M-H]+=327. |
79% | With pyridine; In diethyl ether; dichloromethane; at 0 - 20℃;Cooling with ice; | 10.80 g (54.4 mmol) methyl 3-chlorocarbonyl-benzoate in 100 mL diethyl ether are added dropwise to a solution of 9.04 g (54.4 mmol) benzyl hydrazinecarboxylate in 100 mL diethyl ether, 100 mL dichloromethane and 4.83 mL pyridine while being cooled with an ice bath. The reaction mixture is stirred overnight at ambient temperature and then combined with water. The precipitated solid is filtered off and washed with diethyl ether. White solid. Yield: 14.1 g (79%); mass spectroscopy [M-H]+=327. |
79% | With pyridine; In diethyl ether; dichloromethane; at 20℃;Cooling with ice; | Intermediate product 5: methyl 3-[1-(3-amino-3-methyl-butyl)-5-methyl-1H-[1,2,4]triazol-3-yl]-benzoate a) methyl 3-[N'-benzyloxycarbonyl-hydrazinocarbonyl)-benzoate: 10.80 g (54 4 mmol) methyl 3-chlorocarbonyl-benzoate in 100 mL diethyl ether are added dropwise to a solution of 9.04 g (54 4 mmol) benzyl hydrazinecarboxylate in 100 mL diethyl ether, 100 mL dichloromethane and 4.83 mL pyridine while cooling with an ice bath. The reaction mixture is stirred overnight at ambient temperature and then mixed with water. The solid precipitated is filtered off and washed with diethyl ether.Yield: 14.1 g (79%); mass spectroscopy [M-H]+=327. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In methanol; at 20℃; for 24h; | General procedure: To a methanolic solution (20 mL) of <strong>[5331-43-1]benzyl carbazate</strong> (0.166 g, 0.001 mol), 0.001 mol of a suitable ketone such as the simple ketones (dmk, 0.07 mL and dpk, 0.14 mL) and the cyclic ketones (cb, 0.07 mL; cp, 0.09 mL; ch,0.1 mL and chp, 0.12 mL) was added drop wise. The resulting solution was covered with filter paper and kept at room temperature for crystallization. The compounds formed after a day were filtered off, washed with water and air-dried. The same procedure was adopted with the heteroaromatic ketones (2, 3 and 4 ap, 0.11 mL) using 1:1 methanol-H2O as the solvent. Details of the preparations of the Schiff bases are shown in Scheme 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With triethylamine; In dichloromethane; at 0 - 20℃; for 2h; | General procedure: A solution of BocNHNH2 (3a) (3.0 mmol, 498 mg) or CbzNHNH2 (3b)(3.0 mmol, 396 mg) in anhydrous CH2Cl2 (~30 ml) was placed in an ice bath (~0C). Next, triethylamine (4.5 mmol, 455 mg) was added, and after ca. 20 min, the appropriate fluorinated anhydride (3.2 mmol) was added dropwise while cooling the reaction flask in an ice bath.The reaction mixture was stirred at room temperature for 2 h. Then the solvent was evaporated, and the crude products were purified by column chromatography (SiO2,hexane-AcOEt, 1:1). Analytically pure samples were obtained after crystallization from an appropriate solvent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In isopropyl alcohol; at 80℃; for 16h; | Compound 8; <strong>[5331-43-1]Benzyl carbazate</strong> (17.3195 g, 104.2 mmol) and 4-(2-pyridyl)benzaldehyde (20.047 g, 109.4 mmol) were dissolved in isopropanol (315 mL) and stirred at 8O0C for 16 h. The product, i.e., Compound 8, was precipitated out of solution by addition of ice, filtered and dried under vacuum at 40C to give a solid (34.529 g, 104.2 mmol, 100%). Mass spectrum: (M+H)+ = 332.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | In isopropyl alcohol; at 80℃; for 18h; | Compound 22; <strong>[5331-43-1]Benzyl carbazate</strong> (1.475 g, 8.88 mmol) and 4-[4-(tert-butyl)-l,3-thiazol-2- yl]benzaldehyde (2.175 g, 8.88 mmol) were suspended in isopropanol (27.0 mL) and heated to 800C for 18h. The reaction was cooled to r.t. and the precipitate that formed was filtered off and dried under vacuum at 400C to give Compound 22 as a white solid (3.467g, 8.81 mmol, 99%). Mass spectrum: (M+H)* = 394.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.6% | Reference Example 5 (S)-tert-Butyl 2-(2-((benzyloxy)carbonyl)hydrazinecarbonyl)pyrrolidine-1-carboxylate [0247] (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (1.076 g, 5.00 mmol) was stirred under an argon atmosphere at room temperature with dehydrated methylene chloride (16 mL). Then, N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC, 1.15 g), 1-hydroxybenzotriazole-monohydrate (HOBt·H2O, 0.918 g), and triethylamine (1.01 g) were added, followed by stirring for 10 minutes. Benzyl hydrazinecarboxylate (1.66 g) was added, followed by stirring for 18 hours. After completion of the reaction, the reaction solution was washed with 0.5M hydrochloric acid and saturated brine, then the organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, after that, the resulting residue was subjected to silica gel column chromatography (hexane/ethyl acetate = 4/1 ? 0/1 ? ethyl acetate/methanol = 30/1) to afford 1.48 g of the title compound (yield 81.6%). 1H NMR (400 MHz, CDCl3) delta 1.45 (s, 9H), 1.64 (m, 1H), 1.87-2.16 (m, 2H), 2.38 (m, 1H), 3.31-3.45 (m, 2H), 4.32 (m, 1H), 5.14-5.19 (m, 2H), 6.68 (br s, 1H), 7.34-7.40 (m, 5H), 8.76 (br s, 1H); MS m/z 364 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | In dichloromethane; at 20℃; | To the solution of Boc-L-Proline succinamide ester (1.0 g, 3.2 mmol) in DCM (15 mL) Fmoc- hydrazine (0.56 g, 3.2 mmol) was added and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with 1N HCl (15 mL),10 % NaHCO3 (15 mL), brine (15 mL), dried (Na2SO4) and concentrated to give 1.1 g (94%) of product as a sticky mass. Rf = 0.28 (1:1 EtOAc/Pentane) [alpha]D -82.0 (c 0.5, MeOH) 1H NMR (200 MHz, CDCl3) delta (ppm) 8.76 (br s, 1H), 7.25 (s, 5H), 6.94 (br s, 1H), 5.07 (s, 2H), 4.22 (br s, 1H), 3.32 (br s, 2H), 1.68-2.21 (m, 4H), 1.37 (s, 9H). 13C NMR (200 MHz, CDCl3) delta (ppm) 171.99, 156.02, 135.66, 128.48, 128.25, 128.1, 80.79, 67.64, 58.24, 47.03, 28.32, 24.41, 14.15. IR (KBr) nu 4000 - 3280 (br), 2979, 1699 (br), 1456, 1404, 1367, 1219, 1164, 742, 697 cm-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | To the solution of Boc-L-phenylalanine (3.0 g, 11.31 mmol) in DCM (50 mL) was added HOBt (1.6 g, 11.87 mmol) followed by DCC (2.45 g, 11.87 mmol) and stirred for 30 min at room temperature. To this Z- hydrazine (1.88 g, 11.31 mmol) was added and the mixture was stirred overnight at room temperature. The precipitated DCHU was removed by filtration and the filtrate was evaporated. The additional DCHU was removed by subsequent trituration with cold ethyl acetate and filtration. The ethyl acetate solution was washed with 1N HCl (30 mL),10 % NaHCO3 (30 mL), brine (30 mL), dried (Na2SO4) and concentrated to give 6.4 g of crude compound which was purified by column chromatography to give 4.2 g (89%) of product as a off - white solid; mp. 112 - 113C. Rf = 0.23 (1.5: 3.5 EtOAc/petrol ether) [alpha]D -10.2 (c 0.5, MeOH) 1H NMR (200 MHz, CDCl3) delta (ppm) 8.65 (br s, 1H, d2o exch.), 7.12-7.22 (m, 11H), 5.27 (br s, 1H, d2o exchangeable), 5.03 (s, 2H), 4.45 (m,1H), 2.78-3.21 (m, 2H), 1.24 (s, 9H). 13C NMR (200 MHz, CDCl3) delta (ppm) 171.65, 156.14, 155.79, 136.42, 135.64, 129.39, 128.50, 128.27, 128.14, 126.81, 80.42, 67.71, 53.99, 38.27, 28.2. IR (KBr) nu 4000 - 3372, 3313, 3002, 2971, 2929, 1762, 1688, 1672, 1628, 1526 cm-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | To the solution of Boc-L-tryptophan (1.5 g, 4.93 mmol) in DCM (30 mL) was added HOBt (0.7 g, 5.18 mmol) followed by DCC (1.07 g, 5.18 mmol) and stirred for 30 min at room temperature. To this Z- hydrazine (0.86 g, 5.18 mmol) was added and the mixture was stirred overnight at room temperature. The precipitated DCHU was removed by filtration and the filtrate was evaporated. The additional DCHU was removed by subsequent trituration with cold ethyl acetate and filtration. The ethyl acetate solution was washed with 1N HCl (30 mL), 10 % NaHCO3 (30 mL), brine (30 mL), dried (Na2SO4) and concentrated to give 2.16 g (96%) of product as a viscous oil which after triturating with pentane gives off-white powder; mp. 88-89C. Rf = 0.42 (1:1 petrol ether/EtOAc) [alpha]D -18.2 (c 0.5, MeOH) 1H NMR (200 MHz, CDCl3) delta (ppm) 8.35 (br s, 2H), 7.49 (d, J = 7.44 Hz, 1H), 6.91-7.18 (m, 10H), 5.25 (br d, 1H), 4.94 (s, 2H), 4.45 (m, 1H), 3.1 (m, 2H), 1.26 (s, 9H). 13C NMR (200 MHz, CDCl3) delta (ppm) 171.94, 156.21, 155.71, 135.97, 135.56, 128.52, 128.31, 128.1, 127.54, 123.67, 121.96, 119.47, 118.51, 111.29, 109.53, 80.51, 67.72. 53.79, 34.11, 28.2. IR (KBr) nu 4000 - 3303 (br.), 3036, 2977, 1687 (br.), 1499, 1457, 1393, 1367, 1226, 1165, 1049, 741, 697, cm-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | To the solution of Boc-L-Leucine (1.5 g, 6.02 mmol) in DCM (30 mL) was added HOBt (0.85 g, 6.32 mmol) followed by DCC (1.3 g, 6.32 mmol) and stirred for 30 min at room temperature. To this Z- hydrazine (1.05 g, 6.32 mmol) was added and the mixture was stirred overnight at room temperature. The precipitated DCHU was removed by filtration and the filtrate was evaporated. The additional DCHU was removed by subsequent trituration with cold ethyl acetate and filtration. The ethyl acetate solution was washed with 1N HCl (30 mL),10 % NaHCO3 (30 mL), brine (30 mL), dried (Na2SO4) and concentrated to give 2.16 g (94%) of product as a viscous oil which after triturating with pentane gives off-white powder; mp. 57-59C. Rf = 0.76 (1:1 petrol ether/EtOAc) [alpha]D -42.6 (c 0.5, MeOH) 1H NMR (200 MHz, CDCl3) delta (ppm) 8.96 (br s, 1H), 7.31 (s, 6H), 5.21 (br s, 1H), 5.12 (s, 2H), 4.3 (m, 1H), 1.51-1.71 (m, 3H), 1.4 (s, 9H), 0.88-0.93 (m, 6H). 13C NMR (200 MHz, CDCl3) delta (ppm) 172.85, 156.23, 156.04, 135.63, 128.46, 128.24, 128.12, 80.49, 67.64, 51.21, 41.16, 28.24, 24.5, 22.85, 21.82. IR (KBr) nu 4000 - 3296 (br.), 2959, 1683 (br.), 1521, 1393, 1368, 1221, 1166, 1047, 741, 696, cm-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | To the solution of Boc-L-alanine (4.0 g, 21.14 mmol) in DCM (50 mL) was added HOBt (3.0 g, 22.2 mmol) followed by DCC (4.58 g, 22.2 mmol) and stirred for 30 min at room temperature. To this Z- hydrazine (3.69 g, 22.2 mmol) was added and the mixture was stirred overnight at room temperature. The precipitated DCHU was removed by filtration and the filtrate was evaporated. The additional DCHU was removed by subsequent trituration with cold ethyl acetate and filtration. The ethyl acetate solution was washed with 1N HCl (30 mL),10 % NaHCO3 (30 mL), brine (30 mL), dried (Na2SO4) and concentrated to give 6.9 g (96 %) of product as a white solid; mp. 130-131C. Rf = (petrol ether/EtOAc) [alpha]D -43.6 (c 0.5, MeOH) 1H NMR (200 MHz, CDCl3 -2 drops DMSO-d6) delta (ppm) 9.37 (bs, 1H), 8.29 (bs, 1H), 7.3 (s, 5H), 5.72 (bs, 1H), 5.1 (s, 2H), 4.23 (bs, 1H), 1.4 (s, 9H), 1.31 (d, J = 6.64 Hz, 3H). 13C NMR (200 MHz, CDCl3 -2 drops DMSO-d6) delta (ppm) 177.7, 161.11, 160.02, 140.87, 133.15, 132.84, 132.75, 84.19, 71.77, 53.33, 33.08, 23.55. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | To the solution of Boc-L-Tyr(2-Br-Z)-OH (1.0 g, 2.02 mmol) in DCM (15 mL) was added HOBt (0.29 g, 2.12 mmol) followed by DCC (0.44 g, 2.12 mmol) and stirred for 30 min at room temperature. To this Z- hydrazine (0.35 g, 2.12 mmol) was added and the mixture was stirred overnight at room temperature. The precipitated DCHU was removed by filtration and the filtrate was evaporated. The additional DCHU was removed by subsequent trituration with cold ethyl acetate and filtration. The ethyl acetate solution was washed with 1N HCl (15 mL), 10 % NaHCO3 (15 mL), brine (15 mL), dried (Na2SO4) and concentrated to give 1.26 g (96%) of product as a viscous oil which after triturating with pentane gives off-white powder; mp. 64-66C. Rf = 0.78 (1:1 petrol ether / EtOAc) [alpha]D -15.6 (c 0.5, MeOH) 1H NMR (200 MHz, CDCl3) delta (ppm) 8.61 (br s, 1H), 7.61 (d, J = 7.82 Hz, 1H), 7.5 (dd, J = 1.36, 1.18 Hz,1H), 7.07-7.38 (m, 12H), 5.36 (br s, 3H), 5.13 (s, 2H), 4.51 (m, 1H), 2.89-3.19 (m, 2H), 1.36 (s, 9H). 13C NMR (200 MHz, CDCl3) delta (ppm) 171.39, 156.1, 155.74, 153.41, 150.02, 135.57, 134.29, 134.23, 132.93, 130.5, 130.16, 130.08, 128.52, 128.32, 128.15, 127.63, 123.46, 121, 80.62, 69.59, 67.78, 53.9, 37.48, 28.20. IR (KBr) nu 4000 - 3287 (br), 3034, 2978, 2932, 1764, 1683 (br), 1509, 1379, 1368, 1219, 1163, 1028, 1018, 751 cm-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | To the solution of Boc-L-phenylalanine (0.4 g, 1.51 mmol) in DCM (30 mL) was added HOBt (0.21 g, 1.58 mmol) followed by DCC (0.33 g, 1.58 mmol) and stirred for 30 min at room temperature. To this Z- hydrazine (0.26 g, 1.58 mmol) was added and the mixture was stirred overnight at room temperature. The precipitated DCHU was removed by filtration and the filtrate was evaporated. The additional DCHU was removed by subsequent trituration with cold ethyl acetate and filtration. The ethyl acetate solution was washed with 1N HCl (15 mL), 10 % NaHCO3 (15 mL), brine (15 mL), dried (Na2SO4) and concentrated to give 650 mg of crude compound which was purified by column chromatography to give 617 mg (98%) of product as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With acetic acid; In ethanol; at 80℃; for 1h; | 1.50 g (9.60 mmol) of 4-oxononanal obtained in (6b) was dissolved in 45 ml of ethanol-acetic acid (2:1) solution mixture, and 1.60 g (9.60 mmol) of benzyl hydrazinecarboxylate was added thereto, followed by stirring for 1 hour at 80C. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent; hexane : ethyl acetate = 2:1) to give 2.12 g of the title compound as a yellow oil (77% yield). 1H-NMR spectrum (400MHz, CDCl3) delta ppm: 7.36 (5H, bs), 7.21 (1H, ds), 6.63-6.59 (1H, m), 6.07 (1H, t, J=4Hz), 5.89-5.84 (1H, m), 5.22 (2H, ds), 2.46-2.36 (2H, m), 1.63-1.49 (2H, m), 1.37-1.22 (4H, m), 0.88 (3H, t, J=7Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.1% | With acetic acid; In methanol; tert-butyl alcohol; at 45℃; for 1h;Heating / reflux; | Compound 2: <strong>[5331-43-1]Benzyl carbazate</strong> (300 g, 1.81 moles) was dissolved in 1.2 L of methyl alcohol in a 3 L 4-neck flask equipped with reflux condenser, thermometer, magnetic stirring, and a 500 mL addition funnel. Glacial acetic acid (5 mL) was added to the mixture that was then brought to 45 0C. Pivaldehyde (248.8 g of solution, 2.17 moles, ca. 75% in t-butanol) was added portionwise over 30 minutes. The reaction was heated at reflux for 30 minutes, while monitoring by TLC. The mixture was allowed to cool to nearly room temperature and was concentrated on a rotary evaporator to a total volume of ca. 700 mL. Ca. 7 g activated charcoal was added at ca. 30 0C. The mixture was stirred overnight and filtered through a pad of Celite in a pore size "C" glass fritted Bchner funnel. The solvent was removed in vacuo to leave a light yellow oil that was poured into a crystallizing dish and induced to crystallize by manipulation with a spatula. The material was granulated and residual solvent was allowed to evaporate in air at room temperature for several days, leaving 420.4 g crude product. Recrystallization at room temperature from an initially boiling mixture of 300 mL ethyl acetate and 1 L hexanes produced 363.2 g of (E)-N'-(2,2-dimethyl-propylidene)-hydrazinecarboxylic acid benzyl ester as an off-white solid. A second crop of 43.1 g and identical melting point was obtained from a mixture of ca. 150 mL hexanes and 45 mL ethyl acetate. Total yield: 96.1%. Rf = 0.32 (2:1 hexanes:ethyl acetate); mp = 74-74.5 C; 1H NMR (400 MHz, CDCl3)S 8.0 (IH, br s), 7.4-7.3 (5H, m), 7.1 (IH, s), 5.20 (2H, s), 1.1 (9H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73.7% | With acetic acid; In ethanol; at 20℃; for 8h; | Compound 2: <strong>[5331-43-1]Benzyl carbazate</strong> (25 g, 150.44 mmoles) was dissolved in 200 mL ethanol under a nitrogen atmosphere in a round bottom flask equipped with magnetic stirring. Cyclohexanecarbaldehyde (17.7 g, 158 mmoles) and acetic acid (1 mL) were added to the solution and the mixture was stirred at room temperature for 8 h. The resultant solid precipitate was filtered, washed with hexanes, crystallized from ethyl acetate, and dried overnight on the open bench to provide 28.87 g (73.7% yield) white crystalline N'-cyclohexylmethylene-hydrazinecarboxylic acid benzyl ester. Rf = 0.67 (1:3 hexanes:ethyl acetate), 1H NMR (400 MHz, CDCl3) delta 7.8 (IH, br s), 7.4 (5H, m), 7.1 (IH, br s), 5.3 (2H, s), 2.4 (IH, m), 1.7-1.9 (4H, m), 1.3 (6H, m); HRMS (ESI) m/z calcd for C15H21N2O2 [M+H]+ 261.1603, found 261.1592, calcd for C15H20NaN2O2 [M+Na]+ 283.1426, found 283.1417. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 2h; | 2-Cyclopentyl-6-methoxy-isonicotinic acid hydrazide; a) To a solution of 2-cyclopentyl-6-methoxy-isonicotinic acid (2.00 g, 9.04 mmol), hydrazinecarboxylic acid benzyl ester (1.50 g, 9.04 mmol) and DIPEA (2.34 g, 18.1 mmol) in DCM (40 mL), TBTU (3.19 g, 9.94 mmol) is added. The mixture is stirred at rt for 2 h before it is diluted with EA (250 mL), washed twice with sat. aq. NaHCO3 solution (150 mL) followed by brine (100 mL), dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give N'-(2-cyclopentyl- 6-methoxy-pyridine-4-carbonyl)-hydrazinecarboxylic acid benzyl ester (2.74 g) as pale yellow oil; LC-MS**: tR = 0.74 min, [M+1]+ = 369.69; 1H NMR (D6-DMSO): £ 1.62-1.83 (m, 6 H), 1.95-2.05 (m, 2 H), 3.10-3.21 (m, 1 H), 3.88 (s, 3 H), 5.13 (s, 2 H), 6.97 (s, 1 H), 7.23 (s, 1 H), 7.28-7.40 (m, 5 H), 9.45 (s, 1 H), 10.52 (s, 1 H). | |
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 2h; | a) To a solution of 2-cyclopentyl-6-methoxy-isonicotinic acid (2.00 g, 9.04 mmol), hydrazinecarboxylic acid benzyl ester (1.50 g, 9.04 mmol) and DIPEA (2.34 g, 18.1 mmol) in DCM (40 mL), TBTU (3.19 g, 9.94 mmol) is added. The mixture is stirred at rt for 2 h before it is diluted with EA (250 mL), washed twice with sat. aq. NaHCO3 solution (150 mL) followed by brine (100 mL), dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give N'-(2-cyclopentyl-6-methoxy-pyridine-4-carbonyl)-hydrazinecarboxylic acid benzyl ester (2.74 g) as pale yellow oil; LC-MS**: tR=0.74 min, [M+1]+=369.69; 1H NMR (D6-DMSO): delta 1.62-1.83 (m, 6 H), 1.95-2.05 (m, 2H), 3.10-3.21 (m, 1H), 3.88 (s, 3H), 5.13 (s, 2H), 6.97 (s, 1H), 7.23 (s, 1H), 7.28-7.40 (m, 5H), 9.45 (s, 1H), 10.52 (s, 1H). | |
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 2h; | a) To a solution of 2-cyclopentyl-6-methoxy-isonicotinic acid (2.00 g, 9.04 mmol), hydrazinecarboxylic acid benzyl ester (1.50 g, 9.04 mmol) and DIPEA (2.34 g, 18.1 mmol) in DCM (40 mL), TBTU (3.19 g, 9.94 mmol) is added. The mixture is stirred at rt for 2 h before it is diluted with EA (250 mL), washed twice with sat. aq. NaHC03 solution (150 mL) followed by brine (100 mL), dried over MgS04, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give N'-(2-cyclopentyl- 6-methoxy-pyridine-4-carbonyl)-hydrazinecarboxylic acid benzyl ester (2.74 g) as a pale yellow oil; LC-MS**: tR = 0.74 min, [M+1 ]+ = 369.69; 1H NMR (D6-DMSO): £ 1.62-1 .83 (m, 6 H), 1 .95-2.05 (m, 2 H), 3.10-3.21 (m, 1 H), 3.88 (s, 3 H), 5.13 (s, 2 H), 6.97 (s, 1 H), 7.23 (s, 1 H), 7.28-7.40 (m, 5 H), 9.45 (s, 1 H), 10.52 (s, 1 H). |
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 2h; | a) To a solution of 2-cyclopentyl-6-methoxy-isonicotinic acid (2.00 g, 9.04 mmol), hydrazinecarboxylic acid benzyl ester (1.50 g, 9.04 mmol) and DIPEA (2.34 g, 18.1 mmol) in DCM (40 mL), TBTU (3.19 g, 9.94 mmol) is added. The mixture is stirred at rt for 2 h before it is diluted with EA (250 mL), washed twice with sat. aq. NaHCO3 solution (150 mL) followed by brine (100 mL), dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give N'-(2-cyclopentyl-6-methoxy-pyridine-4-carbonyl)-hydrazinecarboxylic acid benzyl ester (2.74 g) as a pale yellow oil; LC-MS**: tR=0.74 min, [M+1]+=369.69; 1H NMR (D6-DMSO): delta 1.62-1.83 (m, 6H), 1.95-2.05 (m, 2H), 3.10-3.21 (m, 1H), 3.88 (s, 3H), 5.13 (s, 2H), 6.97 (s, 1H), 7.23 (s, 1H), 7.28-7.40 (m, 5H), 9.45 (s, 1H), 10.52 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | Undecanal (5 mL, 24.37 mmol) and <strong>[5331-43-1]benzyl carbazate</strong> (4.45 g, 26.8 mmol) were stirred in MeOH (120 mL) at room temperature. After 1 hour, formic acid (0.5 mL) and NaBH3CN (7.66 g, 121.85 mmol) were added and the reaction mixture was stirred for 5 hours at room temperature. The MeOH was then removed by evaporation under reduced pressure, and the resulting mixture was diluted with EtOAc and washed with saturated NaHCO3 (aq) and brine. The combined organic layers were then dried over anhydrous Na2SO4 (s). The filtrate was concentrated under reduced pressure and purified by silica gel flash column chromatography (EtOAc: Hex = 1: 4, v / v) to give the title compound S12-1 as an amorphous white solid (5.94 g, 76%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 16h; | To a mixture of 7 (17.7 g, 58.7 mmol), benzyl hydrazinecarboxylate (10.7 g, 64.6 mmol) and HOBt (8.73 g, 64.6 mmol) in DMF (70 mL) was added WSC (12.4 g, 64.6 mmol) and the mixture was stirred for 16 h at room temperature. The mixture was diluted with EtOAc and the solution was washed with 0.5M HCl, aqueous 10% K2CO3, brine, dried over Na2SO4. The solution was passed through NH silica gel column chromatography to provide 8 (26.4 g, quant.) as an oil. MS m/z 450 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With N-ethyl-N,N-diisopropylamine; In toluene; at 75℃; | Benzyloxycarbonylhydrazine (3.0 g, 18 mmol), bromoacetic acid tert-butyl ester (7.9 mL, 54 mmol) and diisopropylethylamine (6.3 mL, 36 mmol) were dissolved in toluene (30 mL), and the mixture was stirred at 75C overnight. After allowing to cool to room temperature, saturated brine was added, and the mixture was extracted three times with dichloromethane. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to give the title compound (5.8 g, 15 mmol, 81%). 1H-NMR(400Mz, CDCl3) delta 7.40-7.20(5H, m), 7.00(1H, br s), 5.20(2H, s), 3.60(4H, s), 1.45(18H, s). MS(ESI) m/z 397(M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 80℃; for 20h;Inert atmosphere; | [0210] To a mixture of benzyl hydrazinecarboxylate (5.0 g, 30.3 mmol, 1 eq.) and DIEA (15.0 mL, 90.9 mmol, 3 eq.) in DMF (20 mL) was added 3,3,3-trifluoropropyl bromide (10.7 g 60.6 mmol, 2 eq.) at rt. The mixture was heated at 80 C for 20 h, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to benzyl 2-(3,3,3- trifluoropropyl)hydrazinecarboxylate (4.2 g; 53%) as a white solid. NMR (400 MHz, CDC13) delta 7.33 - 7.17 (m, 5H), 6.1 1 (s, 1H), 5.01 (s, 2H), 4.00 (s, 1H), 3.00 (dd, J= 12.2, 7.1 Hz, 2H), 2.17 (qt, J= 10.8, 7.3 Hz, 2H). LRMS (M+H*) m/z 263.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; at 10 - 35℃; for 12h; | (1) Synthesis of benzyl 2-[dihydrofuran-3(2H)-ylidene]hydrazinecarboxylate 3-oxotetrahydrofuran (5.70 g) was dissolved in methanol (150 mL), and benzyl carbazate (10 g) was added to the solution. The mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated. 14.8 g of a residue was obtained as a crude purified product. This was used for the next reaction without further purification. | |
In methanol; at 20℃; for 12h; | 3-oxotetrahydrofuran (5.70 g) was dissolved in methanol (150 mL), and benzyl carbazate (10 g) was added to the solution. The mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated. 14.8 g of a residue was obtained as a crude product. This was used for the next reaction without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | Step 3: preparation of tert-butyl 6-{2-[(benzyloxy)carbonyl]hyd razi no}-1 ,4- oxazepane-4-carboxylate. To a solution of tert-butyl 6-oxo-1 ,4-oxazepane-4- carboxylate (2.0 g, 9.29 mmol) in tetrahydrofuran (30 mL) was added benzylhydrazinecarboxylate (1.54 g, 9.29 mmol). The reaction was allowed to stir at ambient temperature over 24h, then cooled to 0C, after which sodium cyanoborohydride (584 mg, 9.29 mmol) was added, followed by drop wise addition of a solution of para-toluene sulfonic acid (1 .77 g, 9.29 mmol) in tetrahydrofuran (30 mL). The reaction was then allowed to warm to ambient temperature for an additional 24 h, then concentrated invacuo. The resulting residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate. To the organic layer was then added 1 N sodium hydroxide (15 mL), and the mixture was allowed to stir for 3h, after which the organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was dissolved in diethyl ether and passed through a silica gel plug to afford the title compound as an oil (2.9 g, 89%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With copper(l) iodide; 1,10-Phenanthroline; caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 1.66667h;Inert atmosphere; | 00284] 28E. benzyl l-(4-((2'-fluoro-5'-methoxy-3-methylbiphenyl-4- yl)methyl)phenyl)hydrazinecarboxylate: A flask containing 28D (8.50 g, 19.7 mmol), benzyl hydrazinecarboxylate (3.92 g, 23.6 mmol), CS2CO3 (9.30 g, 28.5 mmol), anhydrous 1,10-phenanthroline (0.748 g, 4.15 mmol) and copper(I) iodide (0.386 g, 2.03 mmol) was evacuated and backfilled with argon. DMF (17 mL) was added under argon and the mixture was degassed with argon for 5 min. The mixture was stirred and heated at 80 C. After 1 h 40 min, the reaction mixture was cooled to rt, diluted with EtOAc (200 mL) and filtered through a pad of silica gel. The filter cake was rinsed with EtOAc and the combined filtrate and rinse were concentrated. The residue was co-evaporated with toluene. The crude product was purified by flash chromatography to give 28E as a yellow oil, (8.15 g, 17.0 mmol, 86% yield). LC-MS Anal.Calc'd for C29H27FN203 470.54, found [M+H] 471.2. H NMR (400 MHz, CDC13) delta 7.41-7.29 (m, 9H), 7.18-7.10 (m, 3H), 7.05 (t, J= 9.3 Hz, 1H), 6.93 (dd, J= 6.1, 3.3 Hz, 1H), 6.80 (dt, J= 8.8, 3.3 Hz, 1H), 5.22 (2, 2H), 4.52 (s, 2H), 4.00 (s, 2H), 3.82 (s, 3H), 2.30 (s, 3H). 13C NMR (101 MHz, CDC13) 6 156.1, 155.7, 154.2 (d, JC.F = 239.1 Hz), 140.6, 138.5, 137.3, 136.7, 136.0, 134.0, 130.7 (d, JC.F = 2.5 Hz), 129.9, 129.4 (d, JC.F = 15.3 Hz), 128.8 (2C), 128.5 (2C), 128.2, 128.0 (2C), 126.5 (d, JC_F = 3.8 Hz), 128.4 (2C), 1 16.5 (d, JC_F= 25.4 Hz), 115.3 (d, JC_F = 3.8 Hz), 113.6 (d, JC_F = 7.6 Hz), 68.0, 55.8, 38.6, 19.8. 19F NMR (376 MHz, CDCI3) delta -128.6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97.8% | In ethanol; at 20℃; for 0.666667h; | Salicylaldehyde (0.17 g, 1 × 10-3 mol) was added to benzylcarbazate (0.16 g, 1.3 × 10-3 mol) in ethanol (1mL)with constant stirringfor 40min at 20 C. Awhite precipitate formedwas filtered, rinsed afew times with distilled water and chilly ether, and dried in vacuum togive the clean white solid (0.26 g; 97.8%); 1HNMR inDMSO-d6: delta 11.48(s, 1H), 10.81 (s, 1H), 8.24 (s, 1H), 7.47 (d, J=8.1 Hz, 1H), 7.38 (m, 5H),7.25 (t, J=8.2 Hz, 1H), 6.89 (d, J=8.2 Hz, 1H), 6.87 (d, J=12 Hz, 1H),5.19 (s, 2H); 13C NMR in DMSO-d6: delta = 156.81, 153.17, 144.63, 136.39,130.88, 128.64, 128.46(2C), 128.11(3C), 119.30, 118.91, 116.22, 66.16.ESI-MS (m/z): [BCS+H+]+ calcd 271.11, found, 271.00. |
91.5% | In ethanol;Reflux; | General procedure: A solution in absolute ethanol (30 mL/mmol) of the adequate aldehyde (1 equiv) and hydrazine (1 equiv) was heated under reflux for 5-18 h depending on the reactants. After cooling to room temperature, the precipitated solid was collected by filtration and dried under vacuum to afford the corresponding hydrazone. If no precipitate was observed, the reaction mixture was concentrated under reduced pressure. 4.2.12 (E)-Benzyl 2-(2-hydroxybenzylidene)hydrazinecarboxylate (6c) Colorless solid, yield: 91.5%, mp: 162-163 C. IR (neat) numax: 3236, 1735, 1724 cm-1. 1H NMR (300 MHz, DMSO-d6) delta: 5.19 (s, 2H); 6.87 (m, 2H); 7.24 (m, 1H); 7.34-7.42 (m, 5H); 4.16 (m, 1H); 8.24 (s, 1H); 10.81 (s, 1H); 11.45 (br s, 1H). 13C NMR (75 MHz, DMSO-d6) delta: 66.1; 116.1; 118.8; 119.2; 128.0; 128.4 (2C); 128.7; 130.8; 136.3; 144.7; 153.1; 156.8. HRMS (DCI, CH4) m/z calcd for C15H15N2O3 [M+H]+: 271.1083, found: 271.1075. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.4% | With sodium hydrogencarbonate; In tetrahydrofuran; water; for 1h;Cooling with ice; | Reference Example 3 Benzyl 2-(furan-2-carbonyl)hydrazinecarboxylate [0245] Benzyl hydrazinecarboxylate (1.66 g, 10.0 mmol) was dissolved in tetrahydrofuran (20 mL) and water (20 mL) and added sodium hydrogen carbonate (1.68 g) thereto. Under ice cooling, furan-2-carbonyl chloride (1.30 g, 10 mmol) was gradually added, followed by stirring for 1 hour. After completion of the reaction, to the reaction solution was added 300 ml of ethyl acetate, followed by washing with saturated ammonium chloride solution and saturated brine. The organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and 5ml of ethyl acetate was dissolved in the resulting residue, followed by gradually adding hexane (100 ml) to afford 2.30 g of the title compound as a solid (yield 88.4%). 1 H NMR (400 MHz, CDCl3) delta 5.18 (s, 2H), 6.51 (m, 1H), 6.91(br s, 1H), 7.17 (m, 1H), 7.33 (m, 5H), 7.47 (m, 1H), 8.17 (br s,1H); MS m/z 261 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.1% | Reference Example 4 (R)-tert-Butyl 2-(2-((benzyloxy)carbonyl) hydrazinecarbonyl)-5-oxopyrrolidine-1-carboxylate [0246] A solution of (R)-1-(tert-butoxycarbonyl)-5-oxopyrrolidine-2-carboxylic acid (1.146 g, 5.00 mmol) in dehydrated methylene chloride (25 mL) was cooled to 0 C under an argon atmosphere and gradually added dropwise isobutyl chloroformate (0.682 g) so that the temperature does not exceed 0 C. Then, triethylamine (0.505 g) was gradually added so that the temperature does not exceed 0 C, followed by stirring 30 minumtes, thereby a mixed acid anhydride was prepared in the reaction system. To this reaction mixture was gradually added benzyl hydrazinecarboxylate (0.830 g), after the addition, followed by raising the temperature to room temperature and stirring for 1 hour. This reaction mixture was washed with 0.5M hydrochloric acid and saturated brine, the organic layer was dried over magnesium sulfate and then distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane/ethyl acetate = 4/1 ? 0/1 ? ethyl acetate/methanol = 30/1) to afford 1.53 g of the title compound (yield 80.1%). 1H NMR (400 MHz, CDCl3) delta 1.45 (s, 9H), 2.20 (m, 2H), 2.45 (m, 1H), 2.63 (m, 1H), 4.59 (br s, 1H), 5.16 (m, 2H), 6.84 (br s, 1H), 7.33 (m, 5H), 8.17 (br s, 1H); MS m/z 378 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 80℃; for 24h; | Step 1: Synthesis of benzyl 2-(3 ,3 ,4,4,4-pentafluorobutyl)hydrazinecarboxylate. A mixture containing Hunig?s base (3 equiv.), 3,3,4,4,4-pentafluoro-1 -iodobutane (1.7 equiv.) and carbobenzoxyhydrazide (1 equiv.) in DMF was heated to 80 C for 24 h. The mixture was diluted in ethyl acetate and washed with water. The organic layer was dried, filtered, and evaporated to give a crude oil which was purified via silica gel chromatography (0 to 100% ethyl acetate in hexanes) to deliver the desired intermediate, benzyl 2-(3 ,3 ,4,4,4-pentafluorobutyl)hydrazinecarboxylate (10.8 g, 58% yield) as a white solid.?H NMR (500 MHz, CD3OD) ppm 7.28 -7.41 (m, 5 H), 5.12 (s, 2 H), 2.98-3.17 (m, 2 H), 2.19-2.39 (m, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | Fmoc-Asp-OtBu (1, 206 mg, 0.5 mmol) was pre-activated with HATU(190 mg, 0.5 mmol) and DIPEA (166 mL, 1 mmol) in DMF (3 mL) for30 min, then was added into a solution of benzyl hydrazinecarbox-ylate (2, 83 mg, 0.5 mmol) in DMF (2 mL). The mixture was stirred atroom temperature for 3 h, and water (5 mL) was added. The residuewas extracted with EtOAc (3 5 mL) and the organic layers werecombined and washed with water (5 mL) and brine (5 mL), driedover anhydrous sodium sulfate. After filtration, the liquid wasconcentrated and subject to silica gel chromatograph. The columnwas eluted with DCM:MeOH = 30:1 to give Fmoc-Asn(NHNHCbz)-OtBu (3) as a white solid (250 mg, yield 89%). 1H NMR (400 MHz,DMSO-d6): d 9.76 (s, 1H), 9.25 (s, 1H), 7.90 (d, 2H, J = 7.5 Hz), 7.72 (d,2H, J = 7.5 Hz), 7.60 (d, 1H, J = 8.4 Hz), 7.48-7.27 (m, 9H), 5.09 (s,2H), 4.39-4.16 (m, 4H), 2.61 (m, 2H), 1.38 (s, 9H); HRMS (ESI-MS)calcd. for C31H33N3O7Na [M+Na]+ 582.2216, found 582.2218. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trifluoroacetic acid; In ethanol; water;Reflux; | General procedure: One equiv. of carbazate was suspended in EtOH containing 10% (by vol.) of water(approx. 5 ml per mmol of the carbazate) and 1.05 equiv. of the acetal or ketal wasadded, followed by the addition of 0.05 equiv. of TFA. The reaction mixture was heatedto reflux and the progress of the reaction was monitored by TLC (thin layer chromatographyon silica gel) using ethyl acetate or a mixture of ethyl acetate-light petroleummixture (for the correct eluent, see characterization data of the compounds). After thereaction was complete, the reaction mixture was cooled to about 45C and three (3)equiv. of acetic acid was added, followed by the dropwise addition of a THF solutionof three (3) equiv. of NaBH3CN (approx. 1 ml of THF per 1.5 mmol of NaBH3CN).The reaction mixture was stirred at approx. 45C for 80 min. Subsequently, the reactionmixture was cooled to room temperature, acidified using 0.5 M HCl aqueous solution(6 ml of 0.5 M HCl per 1 mmol of starting carbazate) and stirred until the liberation ofhydrogen ceased. The reaction mixture was neutralized (to pH 8) by the dropwise additionof a saturated NaHCO3 solution (4 ml per 1 mmol of carbazate). The volatileswere removed under reduced pressure at approx. 40C. The residue was dissolved inethyl acetate, washed with saturated NaHCO3, twice with water and finally with saturatedaqueous sodium chloride. The combined aqueous washes were extracted twicewith ethyl acetate (25 ml per 1 mmol of expected product) and the extracts werewashed with saturated aqueous sodium chloride and combined with the organic phase. After drying over anhydrous Na2SO4 and evaporation of the solvent under reduced pressure,the residue was purified by column chromatography on silica gel using ethyl acetate-light petroleum (1:1 or 1:2) or ethyl acetate as eluent. For specific informationabout the eluent used to monitor the progress of the reaction and for purification, seethe Rf data for each compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trifluoroacetic acid; In ethanol; water;Reflux; | General procedure: One equiv. of carbazate was suspended in EtOH containing 10% (by vol.) of water(approx. 5 ml per mmol of the carbazate) and 1.05 equiv. of the acetal or ketal wasadded, followed by the addition of 0.05 equiv. of TFA. The reaction mixture was heatedto reflux and the progress of the reaction was monitored by TLC (thin layer chromatographyon silica gel) using ethyl acetate or a mixture of ethyl acetate-light petroleummixture (for the correct eluent, see characterization data of the compounds). After thereaction was complete, the reaction mixture was cooled to about 45C and three (3)equiv. of acetic acid was added, followed by the dropwise addition of a THF solutionof three (3) equiv. of NaBH3CN (approx. 1 ml of THF per 1.5 mmol of NaBH3CN).The reaction mixture was stirred at approx. 45C for 80 min. Subsequently, the reactionmixture was cooled to room temperature, acidified using 0.5 M HCl aqueous solution(6 ml of 0.5 M HCl per 1 mmol of starting carbazate) and stirred until the liberation ofhydrogen ceased. The reaction mixture was neutralized (to pH 8) by the dropwise additionof a saturated NaHCO3 solution (4 ml per 1 mmol of carbazate). The volatileswere removed under reduced pressure at approx. 40C. The residue was dissolved inethyl acetate, washed with saturated NaHCO3, twice with water and finally with saturatedaqueous sodium chloride. The combined aqueous washes were extracted twicewith ethyl acetate (25 ml per 1 mmol of expected product) and the extracts werewashed with saturated aqueous sodium chloride and combined with the organic phase. After drying over anhydrous Na2SO4 and evaporation of the solvent under reduced pressure,the residue was purified by column chromatography on silica gel using ethyl acetate-light petroleum (1:1 or 1:2) or ethyl acetate as eluent. For specific informationabout the eluent used to monitor the progress of the reaction and for purification, seethe Rf data for each compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With triethylamine; In dichloromethane; at 0 - 20℃; for 2h; | General procedure: A solution of BocNHNH2 (3a) (3.0 mmol, 498 mg) or CbzNHNH2 (3b)(3.0 mmol, 396 mg) in anhydrous CH2Cl2 (~30 ml) was placed in an ice bath (~0C). Next, triethylamine (4.5 mmol, 455 mg) was added, and after ca. 20 min, the appropriate fluorinated anhydride (3.2 mmol) was added dropwise while cooling the reaction flask in an ice bath.The reaction mixture was stirred at room temperature for 2 h. Then the solvent was evaporated, and the crude products were purified by column chromatography (SiO2,hexane-AcOEt, 1:1). Analytically pure samples were obtained after crystallization from an appropriate solvent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | In ethanol; for 18h;Reflux; | General procedure: A mixture of the appropriate hydrazine or hydrazide (2 equiv)and dialdehyde (1 equiv) was dissolved in absolute EtOH (30 mL/mmol) and heated under reflux for 18 h. After cooling to room temperature,the precipitated solid was collected by filtration anddried under vacuum to afford the corresponding bis-hydrazone. Ifno precipitate was observed, the reaction mixture was concentratedunder reduced pressure. 4.2.2. (2E,2'E)-Benzyl 2,2'-(6,6'-dihydroxy-5,5'-dimethoxybiphenyl-3,3'-diyl)bis(methan-1-yl-1-ylidene)bis(hydrazinecarboxylate)(1e)Following the general procedure, starting with 1 (50 mg,0.165 mmol) and benzyl hydrazinecarboxylate (55 mg, 0.33 mmol)in ethanol, compound 1e was obtained as a yellow solid (94 mg,95% yield). Mp: 135-137 C; IR (neat): mmax = 3440, 1718,1622 cm1; 1H NMR (300 MHz, (CD3)2SO): d = 3.88 (s, 6H), 5.16 (s,4H), 6.97 (d, J = 1.8 Hz, 2H), 7.21 (d, J = 1.8 Hz, 2H), 7.37-7.41 (m,10H), 7.95 (s, 2H), 8.92 (br s, 2H), 11.11 (br s, 2H); 13C NMR(75 MHz, (CD3)2SO): d = 55.9, 65.7, 107.4, 123.4, 124.8, 125.1,127.9, 128.0, 128.4, 136.7, 144.9, 145.8, 148.0, 153.4; HRMS (ESI+)m/z [M+Na]+ calcd for C32H30N4O8Na: 621.1961, found: 621.1960. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75.9% | <strong>[2476-35-9]5-bromo-2-methoxybenzoic acid</strong> (841 mg, 3.64 mmol) was dissolved in dichloromethane (17 ml). There oxalyl chloride (0.328 ml, 3.82 mmol),Was stirred at room temperature for 1.5 hours added the DMF (1 drop).There to benzyl hydrazine carboxylate (665 mg, 4 mmol)Was stirred overnight at room temperature was added. After the reaction, it was washed with a saturated saline solution by the addition of chloroform / methanol solution. Dried with magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (SNAP 25 g, chloroform / methanol) to give the title compound (1.048 g, 75.9%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | 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 26℃; for 16h; | The reaction was BB-13-3 (2.00g, 7.43mmol) was dissolved in N, N - dimethylformamide (20 mL), followed by additioncarbazate benzyl ester (1.23g, 7.43mmol), N, N - bis diisopropylethylamine (2.88g, 22.3mmol), 2- ( 7-azo-benzotriazole) - N, N, N ', N' - tetramethyluronium hexafluorophosphate (4.24g, 11.1 mmol).The reaction was stirred at 26 16hours.Was added water (40 mL), filtered, and the filter cake was dissolved in dichloromethane (50 mL), dried, filtered, and concentrated to give the title compound bb-13-4 (white solid, 2.5 g of, yield: 81%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium sulfate; In methanol; at 20℃; for 2h; | Compound BB-10-3 (0.450g, 1.95mmol) was dissolved in methanol (5mL), followed by addition of <strong>[5331-43-1]benzyl carbazate</strong>(0.356g, 2.14mmol), sodium sulphate (0.50g), the reaction was stirred at room temperature for 2 hour.The reaction mixture was filtered, the filtrate was concentrated to givethe title compound BB-11-1 (gray solid, 0.740 g, yield: 100%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With dipotassium peroxodisulfate; copper phthalocyanine; In 2-methyl-propan-1-ol; at 100℃; | Reaction flask was added N- phenyl-benzamide (0.5mmol), formic hydrazide group Bian (0.5mmol), copper phthalocyanine (0.075 mmol), potassium persulfate (4.5mmol) and 12 ml of isobutanol, 100 reaction; TLC until complete reaction was followed over; after the reaction, the crude product obtained was purified by column chromatography (petroleum ether: ethyl acetate = 15: 1) to give the desired product (yield 78%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With dipotassium peroxodisulfate; copper phthalocyanine; In acetic acid butyl ester; at 100℃; | Reaction flask was added N- acetyl-p-aminophenol (0.5mmol), formic hydrazide group Bian (0.5mmol), copper phthalocyanine (0.06 mmol), potassium persulfate (4.5mmol) and 8 ml of butyl acetate, 100 the reaction ; TLC until complete reaction was followed over; after the reaction, the crude product obtained was purified by column chromatography (petroleum ether: ethyl acetate = 12: 1) to give the desired product (yield 72%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Step 1: The mixture of 38_1 (1.20 g, 11.99 mmol, 1.40 eq) and benzyl N- aminocarbamate (1.42 g, 8.56 mmol, 1.00 eq) in MeOH (15 mL) was stirred at 30C for 2 h. NaBCN (2.69 g, 42.82 mmol, 5.00 eq) was added. The resulting mixture was stirred at 30 C for 16 h. The mixture was concentrated and diluted with water (50 mL) and EA (50 mL). The organic layer was concentrated and purified by column chromatography (PE:EA=10:1~2:1) to give 38_2 (1.50 g, 5.99 mmol, 70% yield) as a colorless oil. LCMS: RT = 0.568 min, m/z 273.2 [M+H]+ NMR (CDCb, 400 MHz) S 7.40-7.35 (m, 5H), 6.25 (s, 1H), 5.26-5.14 (m, 2H), 3.86-3.73 (m, 3H), 3.48-3.30 (m, 2H), 1.91-1.85 (m, 2H), 1.59-1.46(m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.5% | 1) 500 ml of a clean anhydrous reaction flask was charged with 20 g (0.083 mol) of 5-chloro-2-methoxycarbonyl-2-hydroxy-1-indanoneWas dissolved in xylene and then 13.8 g (0.083 mol) of <strong>[5331-43-1]benzyl carbazate</strong> and 4.0 g (0.028 mol) of phosphorus pentoxide were added and controlledThe temperature is 50 .(2) After 3 h reaction, the intermediate 5-chloro-2-methoxycarbonyl-2-hydroxy-1-indanone was homogenized by ? 0.5%, 41.6 g (0.4 mol) of diethoxymethane was added to the reaction solution.(3) A reflux of 200 g of xylene was carried out at a reaction temperature of 140 C, and the reaction solution of step (1)Benzene, the reaction solution 6-7h within the uniform drip, the top of the temperature at 78 began to collect by-product ethanol.(4) After the ethanol was collected, the reaction solution was subjected to negative pressure depressurization, the reaction solvent was removed, the desolvation temperature was controlled to 80 C,Then, 130 g of petroleum ether was added to the remaining liquid, and the mixture was crystallized at 0 C, filtered and dried to give 7-chloroindene [1,2-e]4] oxadiazine-2,4a (3H, 5H) -dicarboxylic acid-4a-methyl ester-2-benzyl ester The dry weight of the product is 31.6g, the content is 97.5% and the yield is 92.5%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20 - 30℃; | To a clean flask containing a solution of [5-(ethoxycarbonyl)-lH-tetrazol-l- yl] acetic acid (6 g, 30 mmol, product obtained in step 2) in dimethylformamide (60 ml) was added benzyl hydrazinecarboxylate (5g, 30 mmol) at 25-30C under stirring. To this stirred solution EDC.HC1 (8.59 g, 45 mmol) and hydroxy benzotriazole (4g, 30 mmol) was added. Finally N- methyl morpholine (10 ml, 90 mmol) was added and the reaction mixture was stirred at ambient temperature. The progress of reaction was monitored by thin layer chromatography using mixture of chloroform and methanol (9: 1) as solvent system. After complete consumption of starting material the reaction was quenched by adding it to water (600 ml) and then extracted with ethyl acetate (3x200 ml). The organic extracts were combined and washed with potassium hydrogen sulfate solution (1x250 ml), saturated sodium hydrogen carbonate solution (1x250 ml), brine (1x250 ml). The volatiles were removed under reduced pressure to provide 7.2 g of ethyl l-(2-{2- [(benzyloxy)carbonyl]hydrazinyl}-2-oxoethyl)-lH-tetrazole-5-carboxylate in 68% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 25 - 30℃; for 16h; | To a solution of [5-(2-ethoxy-2-oxoethyl)- lH-tetrazol- l-yl] acetic acid (6g, 28 mmol, obtained from step 2) in dimethylformamide (60 ml) was added benzyl hydrazinecarboxylate (4.65g, 28 mmol) at 25-30C followed by EDC.HC1 (8g, 42 mmol) and hydroxy benzotriazole monohydrate (4.28g, 195.3 mmol) under stirring. Further, N-methyl morpholine (9.3 ml, 84 mmol) was added. After 16 hours, the thin layer chromatography (chloroform: methanol 9: 1) confirmed completion of reaction. Then the reaction was quenched by adding water (600 ml) and extracted with ethyl acetate (3x150 ml). The organic extracts were combined and washed with KHSO4 solution (100 ml), saturated NaHC03 solution (100 ml), brine (100 ml) and dried over anhydrous sodium sulfate. The volatiles were removed under reduced pressure to provide 10 g of benzyl 2- { [5-(2-ethoxy-2-oxoethyl)- lH-tetrazol- l-yl] acetyl jhydrazine carboxylate in 98% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 25 - 30℃; | To a solution of [2-(ethoxycarbonyl)- lH-imidazol- l-yl] acetic acid (7 g, 35.3 mmol) in dimethylformamide (70 ml) was charged benzyl hydrazinecarboxylate (5.86 g, 35.3 mmol) at 25-30C followed by EDC.HC1 ( 10.11 g, 52.9 mmol), hydroxy benzotriazole monohydrate (5.94 g, 38.8 mmol) and finally N-methyl morpholine (11.64 ml, 105.9 mmol) was added under continuous stirring. The progress of reaction was monitored by TLC (chloroform: methanol, 9: 1). After complete consumption of starting material the reaction mixture was distilled out on rotavapour till dryness. The reaction mass was partitioned in dichloromethane (70 ml) and water (70 ml). Aqueous layer was re-extracted with dichloromethane (2x70 ml). The organic extracts were combined and washed with brine (70 ml) and dried over anhydrous sodium sulfate. The volatiles were removed under reduced pressure to yield 8 g of ethyl l-(2-{2- [(benzyloxy)carbonyl]hydrazinyl}-2-oxoethyl)- lH-imidazole-2-carboxylate in 65% yield |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In methanol; water; at 20℃; for 72h; | To a methanolic solution (10 mL) of <strong>[5331-43-1]benzyl carbazate</strong> (166 mg, 1 mmol) and ammonium thiocyanate (76 mg, 1 mmol), an aqueous solution of one of the metal nitrates [Co(NO3)2·6H2O (146 mg) or Ni(NO3)2·6H2O (146 mg); 0.5 mmol] was added. The resulting solution was layered with 3-acetylpyridine (0.1 mL, 1 mmol) and kept at room temperature for evaporation. Well-shaped crystals of the cobalt(II) and nickel(II) compounds formed over three days and were separated as before. Compound 2: Dark pink, 85% yield. Anal. Calcd for C40H42N10O7S2Co: N2H4, 10.70; Co, 6.57; C, 53.52; H, 4.68; N, 15.61; S, 7.14%. Found: N2H4, 10.10; Co, 6.10; C, 53.10; H, 4.20; N, 15.30; S, 6.95%. IR (cm-1): 3446, 3239, 2085, 1735, 1677, 1519, 1032. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | In methanol; water; at 20℃; for 48h; | General procedure: To a methanolic solution (10 mL) of <strong>[5331-43-1]benzyl carbazate</strong> (166 mg, 1 mmol) and ammonium thiocyanate (76 mg, 1 mmol), an aqueous solution of one of the metal nitrates [Co(NO3)2·6H2O (146 mg) or Ni(NO3)2·6H2O (146 mg); 0.5 mmol] was added. The resulting solution was layered with 3-acetylpyridine (0.1 mL, 1 mmol) and kept at room temperature for evaporation. Well-shaped crystals of the cobalt(II) and nickel(II) compounds formed over three days and were separated as before. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | In methanol; water; at 20℃; for 72h; | General procedure: To a methanolic solution (10 mL) of <strong>[5331-43-1]benzyl carbazate</strong> (166 mg, 1 mmol) and ammonium thiocyanate (76 mg, 1 mmol), an aqueous solution of one of the metal nitrates [Co(NO3)2·6H2O (146 mg) or Ni(NO3)2·6H2O (146 mg); 0.5 mmol] was added. The resulting solution was layered with 3-acetylpyridine (0.1 mL, 1 mmol) and kept at room temperature for evaporation. Well-shaped crystals of the cobalt(II) and nickel(II) compounds formed over three days and were separated as before. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | In methanol; at 20℃; for 24h; | A methanolic solution (10 mL) of Ni(CH3COO)2·4H2O [124 mg; 0.5 mmol) was mixed with a suspension of <strong>[5331-43-1]benzyl carbazate</strong> (166 mg, 1 mmol) and 2-acetylpyridine (0.1 mL, 1 mmol) in 10 mL of methanol. The resulting green solution was kept aside at room temperature and the color of the solution changed from green to reddish brown over 30 min. By slow evaporation, reddish-brown single crystals of compound 1 were obtained after two days. These were filtered off, washed with water and air dried. (0006) Compound 1: Reddish brown, 80% yield. Anal. Calcd for C30H28N6O4Ni: N2H4, 10.76; Ni, 9.87; C, 60.54; H, 4.71; N, 14.13%. Found: N2H4, 9.90; Ni, 9.70; C, 60.10; H, 4.20; N, 14.00%. IR (cm-1): 1530, 1031. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | Step 1-2: (0238) (0239) To a solution of carboxylic acid compound (1) (536.1 mg, 1.0 mmol) in CH2Cl2 (20 mL) was added HOBT (142.2 mg, 1.05 mmol) and DCC (217.1 mg, 1.05 mmol). The reaction mixture was allowed to stir at room temperature for 30 min before addition of <strong>[5331-43-1]benzyl carbazate</strong> (174.9 mg, 1.05 mmol). Then the reaction was allowed to stir for overnight. The crude was filtered and further washed with EtOAc. The filtrate was then concentrated. The resulting crude was purified by CombiFlash (20 g SiO2, EtOAc/hexanes=0->50%) to give the compound (2) as a white solid, 602.6 mg, 88% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | In methanol; at 20℃; for 24h; | General procedure: To a methanolic solution (20 mL) of <strong>[5331-43-1]benzyl carbazate</strong> (0.166 g, 0.001 mol), 0.001 mol of a suitable ketone such as the simple ketones (dmk, 0.07 mL and dpk, 0.14 mL) and the cyclic ketones (cb, 0.07 mL; cp, 0.09 mL; ch,0.1 mL and chp, 0.12 mL) was added drop wise. The resulting solution was covered with filter paper and kept at room temperature for crystallization. The compounds formed after a day were filtered off, washed with water and air-dried. The same procedure was adopted with the heteroaromatic ketones (2, 3 and 4 ap, 0.11 mL) using 1:1 methanol-H2O as the solvent. Details of the preparations of the Schiff bases are shown in Scheme 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | In methanol; at 20℃; for 24h; | General procedure: To a methanolic solution (20 mL) of <strong>[5331-43-1]benzyl carbazate</strong> (0.166 g, 0.001 mol), 0.001 mol of a suitable ketone such as the simple ketones (dmk, 0.07 mL and dpk, 0.14 mL) and the cyclic ketones (cb, 0.07 mL; cp, 0.09 mL; ch,0.1 mL and chp, 0.12 mL) was added drop wise. The resulting solution was covered with filter paper and kept at room temperature for crystallization. The compounds formed after a day were filtered off, washed with water and air-dried. The same procedure was adopted with the heteroaromatic ketones (2, 3 and 4 ap, 0.11 mL) using 1:1 methanol-H2O as the solvent. Details of the preparations of the Schiff bases are shown in Scheme 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | In methanol; at 20℃; for 24h; | General procedure: To a methanolic solution (20 mL) of <strong>[5331-43-1]benzyl carbazate</strong> (0.166 g, 0.001 mol), 0.001 mol of a suitable ketone such as the simple ketones (dmk, 0.07 mL and dpk, 0.14 mL) and the cyclic ketones (cb, 0.07 mL; cp, 0.09 mL; ch,0.1 mL and chp, 0.12 mL) was added drop wise. The resulting solution was covered with filter paper and kept at room temperature for crystallization. The compounds formed after a day were filtered off, washed with water and air-dried. The same procedure was adopted with the heteroaromatic ketones (2, 3 and 4 ap, 0.11 mL) using 1:1 methanol-H2O as the solvent. Details of the preparations of the Schiff bases are shown in Scheme 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | In methanol; at 20℃; for 24h; | General procedure: To a methanolic solution (20 mL) of <strong>[5331-43-1]benzyl carbazate</strong> (0.166 g, 0.001 mol), 0.001 mol of a suitable ketone such as the simple ketones (dmk, 0.07 mL and dpk, 0.14 mL) and the cyclic ketones (cb, 0.07 mL; cp, 0.09 mL; ch,0.1 mL and chp, 0.12 mL) was added drop wise. The resulting solution was covered with filter paper and kept at room temperature for crystallization. The compounds formed after a day were filtered off, washed with water and air-dried. The same procedure was adopted with the heteroaromatic ketones (2, 3 and 4 ap, 0.11 mL) using 1:1 methanol-H2O as the solvent. Details of the preparations of the Schiff bases are shown in Scheme 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | In methanol; at 20℃; for 24h; | General procedure: To a methanolic solution (20 mL) of <strong>[5331-43-1]benzyl carbazate</strong> (0.166 g, 0.001 mol), 0.001 mol of a suitable ketone such as the simple ketones (dmk, 0.07 mL and dpk, 0.14 mL) and the cyclic ketones (cb, 0.07 mL; cp, 0.09 mL; ch,0.1 mL and chp, 0.12 mL) was added drop wise. The resulting solution was covered with filter paper and kept at room temperature for crystallization. The compounds formed after a day were filtered off, washed with water and air-dried. The same procedure was adopted with the heteroaromatic ketones (2, 3 and 4 ap, 0.11 mL) using 1:1 methanol-H2O as the solvent. Details of the preparations of the Schiff bases are shown in Scheme 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | In methanol; water; at 20℃; for 24h; | General procedure: To a methanolic solution (20 mL) of <strong>[5331-43-1]benzyl carbazate</strong> (0.166 g, 0.001 mol), 0.001 mol of a suitable ketone such as the simple ketones (dmk, 0.07 mL and dpk, 0.14 mL) and the cyclic ketones (cb, 0.07 mL; cp, 0.09 mL; ch,0.1 mL and chp, 0.12 mL) was added drop wise. The resulting solution was covered with filter paper and kept at room temperature for crystallization. The compounds formed after a day were filtered off, washed with water and air-dried. The same procedure was adopted with the heteroaromatic ketones (2, 3 and 4 ap, 0.11 mL) using 1:1 methanol-H2O as the solvent. Details of the preparations of the Schiff bases are shown in Scheme 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | In methanol; water; at 20℃; for 24h; | General procedure: To a methanolic solution (20 mL) of <strong>[5331-43-1]benzyl carbazate</strong> (0.166 g, 0.001 mol), 0.001 mol of a suitable ketone such as the simple ketones (dmk, 0.07 mL and dpk, 0.14 mL) and the cyclic ketones (cb, 0.07 mL; cp, 0.09 mL; ch,0.1 mL and chp, 0.12 mL) was added drop wise. The resulting solution was covered with filter paper and kept at room temperature for crystallization. The compounds formed after a day were filtered off, washed with water and air-dried. The same procedure was adopted with the heteroaromatic ketones (2, 3 and 4 ap, 0.11 mL) using 1:1 methanol-H2O as the solvent. Details of the preparations of the Schiff bases are shown in Scheme 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | In methanol; water; at 20℃; for 24h; | General procedure: To a methanolic solution (20 mL) of <strong>[5331-43-1]benzyl carbazate</strong> (0.166 g, 0.001 mol), 0.001 mol of a suitable ketone such as the simple ketones (dmk, 0.07 mL and dpk, 0.14 mL) and the cyclic ketones (cb, 0.07 mL; cp, 0.09 mL; ch,0.1 mL and chp, 0.12 mL) was added drop wise. The resulting solution was covered with filter paper and kept at room temperature for crystallization. The compounds formed after a day were filtered off, washed with water and air-dried. The same procedure was adopted with the heteroaromatic ketones (2, 3 and 4 ap, 0.11 mL) using 1:1 methanol-H2O as the solvent. Details of the preparations of the Schiff bases are shown in Scheme 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | In methanol; at 20℃; | 0.166g (1mmol) of <strong>[5331-43-1]benzyl carbazate</strong> and 0.082g (0.5mmol) of 2,6-diacetylpyridine were combined in 20mL of methanol. Slow evaporation of the solvent from the mixture at room temperature resulted in a white crystalline precipitate which was isolated and washed with doubly- distilled water. Ligand bc2-dap: Colorless, 80% yield with respect to the amount of base (<strong>[5331-43-1]benzyl carbazate</strong>) taken. Anal. Calc. for C25H25N5O4: C, 65.36; H, 3.96; N, 15.25. Found: C, 65.15; H, 3.40; N, 14.95%. IR (cm-1): 3246, 1694, 1573, 1038. 1H NMR (400MHz, DMSO-d6): delta 10.55 (s, 1H), 10.44 (s, 1H), 7.82-8.22 (m, 3H), 7.33-7.46 (m, 10H), 5.24 (s, 2H), 5.23 (s, 2H), 2.39 (s, 3H), 2.35 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | In propan-1-ol; water; at 20℃; for 48h; | General procedure: <strong>[5331-43-1]Benzyl carbazate</strong> (0.166g, 1mmol) was dissolved in 10mL of a 16 propanol solution of 17 2,6-diacetylpyridine (0.082g, 0.5mmol). To this solution the various metal nitrates (M(NO3)2·6H2O, (Mn=0.144g, Co=0.146g, Zn=0.149g), 0.5mmol; Fe(NO3)3·9H2O, 0.202g, 0.5mmol) were added together with 18 ammonium thiocyanate (0.076g, 1mmol) dissolved in 10mL of doubly-distilled 19 water. The resulting mixture was kept at room temperature for crystallization. After two days, the manganese, 1, iron, 2, and zinc, 4, complexes were obtained as crystalline solids. In the case of 20 cobalt, both red, 3, and orange, 5, crystals were observed in the solution after two days and were isolated by filtration. These crystals were separated manually and used for further analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With zinc(II) nitrate hexahydrate; In propan-1-ol; water; at 20℃; | To a 10mL 16 propanol solution of <strong>[5331-43-1]benzyl carbazate</strong> (0.083g, 0.5mmol) and 17 2,6-diacetylpyridine (0.082g, 0.5mmol), a 10mL aqueous solution containing 35 cobalt(II) nitrate hexahydrate (0.146g, 0.5mmol), 36 zinc(II) nitrate hexahydrate (0.149g, 0.5mmol) and 18 ammonium thiocyanate (0.076g, 1mmol) was added slowly with constant stirring. The resulting orange solution was kept at room temperature for slow evaporation of the solvent. X-ray quality green crystals of 8 were obtained after two days and separated as before. Compound 8: Dark green, 72% yield with respect to the amount of metal salt taken. Anal. Calc. for C17H14N5O2S2Co: Co, 13.30; C, 46.06; H, 3.16; N, 15.80; S, 14.45. Found: Co, 13.10; C, 45.90; H, 3.05; N, 15.45; S, 14.10%. IR (cm-1): 3068, 2091, 1734, 1694, 1518, 1053. 1H NMR (400MHz, DMSO-d6): delta 10.57 (s, 1H), 7.91-8.22 (m, 3H), 7.33-7.46 (m, 5H), 5.23 (s, 2H), 2.50 (s, 3H), 2.38 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | In propan-1-ol; water; at 20℃; for 48h; | General procedure: <strong>[5331-43-1]Benzyl carbazate</strong> (0.166g, 1mmol) was dissolved in 10mL of a 16 propanol solution of 17 2,6-diacetylpyridine (0.082g, 0.5mmol). To this solution the various metal nitrates (M(NO3)2·6H2O, (Mn=0.144g, Co=0.146g, Zn=0.149g), 0.5mmol; Fe(NO3)3·9H2O, 0.202g, 0.5mmol) were added together with 18 ammonium thiocyanate (0.076g, 1mmol) dissolved in 10mL of doubly-distilled 19 water. The resulting mixture was kept at room temperature for crystallization. After two days, the manganese, 1, iron, 2, and zinc, 4, complexes were obtained as crystalline solids. In the case of 20 cobalt, both red, 3, and orange, 5, crystals were observed in the solution after two days and were isolated by filtration. These crystals were separated manually and used for further analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5% | With iron(II) phthalocyanine; In dichloromethane; at 0℃; for 0.5h;Inert atmosphere; | To a mixture of carbazate 1 (1.5 mmol), alkene 2 (0.5 mmol), and [Fe(Pc)] (5.0 mol%), freshly distilled CH2Cl2 (2 mL) were added under nitrogen at 0 oC. Then T-Hydro (4.0 mmol, 8 equiv) was dropped into the mixture under nitrogen at 0 oC. The mixture was stirred at 0 oC for 30 min. The resulting mixture was filtered through a pad of silica with ethyl acetate as eluent. The solvent was evaporated under vacuum to give the crude product 3. NMR yield was determined by 1 H NMR using dibromomethane as an internal standard. The residue was purified by flash column chromatography on silica gel (eluent: ethyl acetate/petroleum ether) to give the product 3 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | In methanol; at 20℃; for 48h; | The title compound (2) was synthesized starting from methyl a-D-glucopyranoside. Methyl a-D-glucopyranoside was converted tothe 2,3,4-Tri-O-benzyl-5,6-dideoxy-D-xylo-5-hexenose (1) after 5stepsaccording to the literature method [20e26]. 2,3,4-Tri-Obenzyl-5,6-dideoxy-D-xylo-5-hexenose (1) (200 mg, 0.48 mmol)was dissolved in MeOH (2 mL) and NH2NHCOOCH2Ph (<strong>[5331-43-1]benzyl carbazate</strong>)(96 mg, 0.58 mmol) was added. The resulting reactionmixture was stirred for 2 d at room temperature. The solventremoved in vacuo and purification by column chromatography(Petroleum ether/Ethyl acetate60:40) gave the title compoundas acolourless solid (67%) [Fig. 1]. Crystallization from petroleum ether/ethyl acetate gave colourless crystals (E:Z ratio>99:1) 376-377 K (mp103-105 C). The 32-Cycloaddition of the title compound (2)was reported by J?ager [15]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With copper(l) iodide; (1S,2S)-N,N'-dimethyl-1,2-diaminocyclohexane; caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 18h;Inert atmosphere; | 4-Iodo-2,3-dihydro- lH-inden-l-ol (586.1 mg, 2.254 mmol) was combined with benzyl hydrazinecarboxylate (899 mg, 5.41 mmol), cesium carbonate (2056 mg, 6.31 mmol), (l |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With toluene-4-sulfonic acid; In ethanol; water;Reflux; | General procedure: One equiv. of protected hydrazine was dissolved/suspended in EtOH containing 10% water (approx. 5 ml per 1 mmol of protected hydrazine), 1.05 eq of benzaldehyde acetal was added, followed by the addition of 0.05 equiv. of TsOH in an ethanolic solution (10 mg of TsOH per 0.5 ml of EtOH). The obtained reaction mixture was refluxed and monitored by TLC (silica gel) until full conversion of the starting material was observed. Ethyl acetate/light petroleum mixtures or pure ethyl acetate were used as TLC eluents. After completion of the reaction the solvent was removed under reduced pressure, approx. 15 ml of toluene was added to the residue and the solvent was again removed under reduced pressure. The obtained crude hydrazone was dissolved in commercial stabilized THF (approx. 4 ml per 1mmol of hydrazone), the flask was flushed with argon and 3 equiv. of 1M BH3-THF complex was added at room temperature, followed by 3 hours of stirring. The progress of the reaction was checked by TLC and if some unreacted hydrazone was left, stirring was continued for an additional 45 min. After thefull conversion of hydrazone EtOH (10 ml) was added to the reaction mixture (Caution: Liberation of hydrogen) and the obtained mixture was refluxed for 1 hour. After cooling to room temperature the solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate, washed with saturated NaHCO3 solution, water and saturated NaCl solution. The aqueous phase was extracted twice with ethyl acetate, the extracts were washed with saturated NaCl solution, combined with the organic phase, dried over anhydrous Na2SO4 and evaporated to dryness. The residue was purified by column chromatography on silica gel by using ethyl acetate/light petroleum 1:1 or 1:2 mixtures or pure ethyl acetate as eluent. For the exact information about the eluent used for monitoring reaction progress and chromatographic purifications, see the Rf value for each compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With methylbenzenesulfonic acid; In toluene; at 60℃; for 8h; | To a 500 mL four-necked flask equipped with a stirrer, a thermometer and a reflux trap, 50 g of methyl 5-chloro-2,3-dihydro-2-hydroxy-1-oxoindene-2-carboxylate 96%, 0.20 mol), <strong>[5331-43-1]benzyl carbazate</strong> 40 g (0.24 mol),250 g of toluene and 3.5 g (0.02 mol) of anhydrous methylbenzenesulfonic acid, The temperature was raised and then the vacuum was evacuated at 60 C, refluxing, The reaction was kept for 8 hours, The first reaction solution was obtained for use. To a 1000 mL four-necked flask equipped with a stirrer, a thermometer and a rectification column, 63 g (0.60 mol) of diethoxymethane and 150 g of toluene were added, and the first reaction solution was gradually added dropwise to the flask, and the reaction was simultaneously passed through distillation. The tower removed the ethanol produced by the reaction, the pot temperature was controlled at 120 C, and the top temperature of the rectification column was controlled at 70 C to obtain a second reaction liquid. After the second reaction liquid is passed through a filter to remove the methylbenzenesulfonic acid and a small amount of impurities, the toluene and the excess diethoxymethane are removed in vacuo; the methanol is added, the temperature is raised to 55 C, the solution is dissolved, frozen, crystallized, filtered, and dried to obtain product 77g. After testing to detected the product was methyl 7-chloro-2,3,4a,5-tetrahydro-2-(benzyloxy)carbonylindeno(1,3,4)oxadiazine-4a-carboxylate, the purity was 97 %, and the yield was 93.2 % | |
With toluene-4-sulfonic acid; In toluene; at 100 - 105℃; | (1) 60 g (0.25 mol) was added to a 1000 ml dry flask5-Chloro-2-methoxycarbonyl-2-hydroxy-1-indanone was dissolved in 350 g of toluene.Then add 3.53g (0.02mol) of p-toluenesulfonic acid and49.7 g (0.3 mol) of <strong>[5331-43-1]benzyl carbazate</strong>, controlled at a temperature of 100-105 C,After the reaction, the water is separated by a water separator;(2) sampling and testing after 4.5 hours,Liquid spectrum tracking when 5-chloro-2-methoxycarbonyl-2-hydroxy-1-indanone normalized content ?0.1% is the reaction is complete, and then cooled to 30 C,47.125 g (0.625 mol) of dimethoxymethane was added to the reaction mixture and stirred uniformly;(3) 150 g of toluene is rectified to a top temperature of 110 C, and the reflux condensation at the top of the column is stable.2.86 g (0.015 mol) of p-toluenesulfonyl chloride was added.The step (2) reaction is then dropped into toluene.Control the reaction solution to flow at a constant rate within 4 hours.The temperature at the bottom of the tower is at 100-115 C.When the temperature at the top of the tower drops to 50 C,Start collecting low boilers at a rate of 0.5 ml/s.When the top temperature of the top of the tower reaches 100 C, the collection speed is accelerated, and the collecting speed is 2 ml/s;(4) When the temperature at the top of the tower reaches 110 C, the collection is completed.Then, the reaction liquid of the step (3) is cooled to 30 C,Add 200g of water for water washing, and control the desolvation temperature to 60 C after washing.Carry out negative pressure desolvation,After removing the solvent, 180 g of petroleum ether was added to the remaining material.Cool down to 5 C crystallization,Filtration and drying to give 7-chloroindeno [1,2-e][1,3,4]oxadiazine-2,4a(3H,5H)-dicarboxylic acid-4a-methyl ester-2-benzyl ester dry weight 95.7 g, content 97.1%, yield 92.8%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With t-butyldimethylsiyl triflate; at 20℃; for 20h; | General procedure: To a solution of 1 (1.0 mmol) in DMF (1.0 mL), TBSOTf (1.0 mmol) was added at room temperature. After stirring for 20 h, the volatiles were evacuated, and the residue was directly chromatographed (eluent: dichloromethane:methanol, 20:1, v/v) to obtain 2 as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; In toluene; at 80℃; for 3.0h;Inert atmosphere; | tert-Butyl 6-{1-[(benzyloxy)carbonyl]hydrazino}pyridine-2-carboxylate tert-Butyl 6-chloropyridine-2-carboxylate (91.1 g, 0.43 mol), benzyl hydrazinecarboxylate (70.9 g, 0.43 mol), caesium carbonate (174 g, 0.53 mol) and 1,1'-bis(diphenylphosphino)ferrocene (17.1 g, 32.0 mmol) were suspended in toluene (1.00 l) under argon. Bis(dibenzylideneacetone)palladium(0) (9.76 g, 10.7 mmol) was added, and the reaction mixture was stirred at 80 C. for 3 h. The reaction mixture was admixed with water and ethyl acetate, filtered through kieselguhr and washed through with ethyl acetate. The organic phase was removed, washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulphate and filtered. The filtrate was admixed with silica gel, stirred for 10 min, then filtered and washed through with ethyl acetate. The filtrate was concentrated and the residue was purified via column chromatography (silica gel, eluent: heptane/ethyl acetate 4/1, 2/1, 1/1). The product-containing fractions were concentrated under reduced pressure, and 112 g (77% of theory) of the title compound were obtained. LC-MS (Method 7): Rt=0.81 min; MS (ESIpos): m/z=344 [M+H]+ 1H-NMR (400 MHz, CDCl3) delta [ppm]=1.59 (s, 9H), 5.30 (s, 2H), 7.31-7.39 (m, 3H), 7.42-7.45 (m, 2H), 7.76-7.78 (m, 2H), 7.98-8.12 (dd, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Ethyl 6-hydrazino-4-(trifluoromethyl)pyridine-2-carboxylate Under argon, ethyl 6-chloro-4-(trifluoromethyl)pyridine-2-carboxylate (1000 mg, 3.94 mmol) and benzyl hydrazinecarboxylate (721 mg, 4.34 mmol) were dissolved in toluene (10 ml), and tris(dibenzylideneacetone)dipalladium-chloroform complex (204 mg, 197 mumol), 1,1'-bis(diphenylphosphino)ferrocene (219 mg, 394 mumol) and caesium carbonate (1.54 g, 4.73 mmol) were added. The reaction mixture was stirred at 80 C. for 4 h and water and ethyl acetate were added. The organic phase was removed and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and filtered, and the filtrate was concentrated. The residue was purified via column chromatography (SiO2; eluent: isocratic, methanol/dichloromethane 8/92). The product-containing fractions were concentrated under reduced pressure and the residue obtained was converted further directly. The residue was dissolved in methanol (50 ml) under argon, and palladium on charcoal (223 mg, 10%) was added. The reaction mixture was stirred in a hydrogen atmosphere (1 bar) at room temperature overnight. Further palladium on charcoal (223 mg, 10%) was added, and the mixture was stirred in a hydrogen atmosphere (1 bar) at room temperature overnight. The suspension was diluted with methanol, filtered through kieselguhr and washed through with methanol. The solvent was removed under reduced pressure, and the residue was purified via preparative HPLC (Chromatorex C18, 10 mum, 125 mm*30 mm; eluent: acetonitrile/water gradient). The product-containing fractions were concentrated under reduced pressure, and 385 mg (93% purity, 38% of theory) of the title compound were obtained. LC-MS (Method 1): Rt=0.91 min; MS (ESIpos): m/z=250 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With tris(dibenzylideneacetone)dipalladium(0) chloroform complex; 1,1'-bis-(diphenylphosphino)ferrocene; caesium carbonate; In toluene; at 80℃; for 3h;Inert atmosphere; | Ethyl 6-{1-[(benzyloxy)carbonyl]hydrazino}-3-(trifluoromethyl)pyridine-2-carboxylate Under argon, ethyl 6-chloro-3-(trifluoromethyl)pyridine-2-carboxylate (2.24 g, 88% purity, 7.77 mmol) and benzyl hydrazinecarboxylate (1.42 g, 8.55 mmol) were dissolved in toluene (20 ml), and tris(dibenzylideneacetone)dipalladium-chloroform complex (402 mg, 389 mumol), 1,1'-bis(diphenylphosphino)ferrocene (441 mg, 777 mumol) and caesium carbonate (3.04 g, 9.33 mmol) were added. The reaction mixture was stirred at 80 C. for 3 h and then water and ethyl acetate were added. The organic phase was removed and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate and filtered, and the filtrate was concentrated. The residue was purified via column chromatography (silica gel; eluent: isocratic, ethyl acetate/dichloromethane). The product-containing fractions were concentrated under reduced pressure, and 1.80 g (60% of theory) of the title compound were obtained. LC-MS (Method 4): Rt=1.05 min; MS (ESIpos): m/z=384 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; In toluene; at 80℃; for 3h;Inert atmosphere; | Methyl 6-{1-[(benzyloxy)carbonyl]hydrazino}-5-(trifluoromethyl)pyridine-2-carboxylate Methyl 6-chloro-5-(trifluoromethyl)pyridine-2-carboxylate (3.00 g, 12.5 mmol), benzyl hydrazinecarboxylate (2.29 g, 13.8 mmol) and tris(dibenzylideneacetone)dipalladium (573 mg, 626 mumol) were suspended in toluene (60 ml) under argon. 1,1'-Bis(diphenylphosphino)ferrocene (694 mg, 1.25 mmol) and caesium carbonate (4.90 g, 15.0 mmol) were added and the reaction mixture was stirred at 80 C. for 3 h. The reaction mixture was admixed with water and ethyl acetate, and the organic phase was removed, washed with water and saturated aqueous sodium chloride solution, dried over sodium sulphate, filtered and concentrated. The residue was purified via column chromatography (silica gel; eluent: cyclohexane/ethyl acetate 9:1, 0:1). The product-containing fractions were concentrated under reduced pressure, and 1.87 g (86% purity, 35% of theory) of the title compound were obtained. LC-MS (Method 1): Rt=1.23 min; MS (ESIneg): m/z=368 [M-H]- 1H-NMR (500 MHz, DMSO-d6) delta[ppm]: -0.007 (1.19), 0.006 (0.87), 1.160 (2.79), 1.174 (5.66), 1.189 (2.80), 1.398 (1.98), 1.988 (10.25), 2.518 (0.42), 3.038 (0.55), 3.051 (0.56), 3.852 (16.00), 4.008 (0.77), 4.022 (2.29), 4.037 (2.24), 4.051 (0.73), 4.484 (1.47), 4.496 (1.51), 4.998 (0.87), 5.036 (1.06), 5.085 (0.93), 5.125 (7.85), 5.134 (1.18), 5.146 (1.34), 5.157 (0.63), 7.107 (0.52), 7.195 (0.84), 7.221 (0.64), 7.232 (0.48), 7.238 (0.48), 7.271 (0.56), 7.287 (0.79), 7.309 (5.08), 7.316 (2.18), 7.319 (2.37), 7.326 (1.95), 7.340 (1.80), 7.364 (2.08), 7.380 (3.95), 7.394 (6.93), 7.409 (1.97), 7.416 (1.42), 7.422 (1.02), 7.482 (1.90), 7.498 (2.13), 7.532 (0.42), 8.085 (2.06), 8.101 (1.89), 8.765 (2.66), 8.849 (0.45), 9.009 (0.47), 9.367 (2.77). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With tris(dibenzylideneacetone)dipalladium(0) chloroform complex; 1,1'-bis-(diphenylphosphino)ferrocene; caesium carbonate; In toluene; at 80℃; for 4h;Inert atmosphere; | tert-Butyl 6-{1-[(benzyloxy)carbonyl]hydrazino}-5-methylpyridine-2-carboxylate Under argon, tert-butyl 6-chloro-5-methylpyridine-2-carboxylate (2.50 g, 11.0 mmol) and benzyl hydrazinecarboxylate (3.28 g, 19.8 mmol) were dissolved in toluene (50 ml), and tris(dibenzylideneacetone)dipalladium-chloroform complex (568 mg, 549 mumol), caesium carbonate (4.29 g, 13.2 mmol) and 1,1'-bis(diphenylphosphino)ferrocene (609 mg, 1.10 mmol) were added. The reaction mixture was stirred at 80 C. for 4 h and water and ethyl acetate were added. The organic phase was removed and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and filtered, and the filtrate was concentrated. The residue was purified via column chromatography (SiO2; eluent: isocratic, ethyl acetate/cyclohexane 30/70). The product-containing fractions were concentrated under reduced pressure, and 1.81 g (46% of theory) of the title compound were obtained. LC-MS (Method 3): Rt=1.91 min; MS (ESIpos): m/z=358 [M+H]+ 1H-NMR (400 MHz, DMSO-d6) delta[ppm]: 1.514 (16.00), 2.157 (1.85), 5.112 (1.13), 7.292 (0.85), 7.310 (1.16), 7.377 (0.57), 7.396 (0.48), 7.408 (0.70), 7.446 (0.50), 8.196 (0.45), 9.097 (0.44). |
Tags: 5331-43-1 synthesis path| 5331-43-1 SDS| 5331-43-1 COA| 5331-43-1 purity| 5331-43-1 application| 5331-43-1 NMR| 5331-43-1 COA| 5331-43-1 structure
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P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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