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CAS No. : | 1197-18-8 | MDL No. : | MFCD00001466 |
Formula : | C8H15NO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | GYDJEQRTZSCIOI-UHFFFAOYSA-N |
M.W : | 157.21 | Pubchem ID : | 5526 |
Synonyms : |
cyclocapron;AMCA;Tranexamic Acid, TXA, Trans AMCHA, Cyklokapron;TXA
|
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.11% | With barium hydroxide octahydrate; hydrogen In ethanol; water at 250℃; for 7.5 h; | To a 1 L hydrogenation kettle, methyl 4-acetamidomethylcyclohexylcarboxylate (28. 00 g, 0.13 mol), 100 mL of ethanol, 200 mL of water,Barium hydroxide octahydrate (95. 82g, 0.30mol), shut down the reaction dad, pass the IMPa hydrogen to replace the air 3 times (or replace with nitrogen)And then pass 1MPa of hydrogen leak detection, if not leak, the pressure transferred to 4MPa, stir to raise the temperature to 250 ° C reaction 7. 5 hours,Stop the reaction, open the kettle, the reaction solution poured out, placed in a reaction flask, add water 200mL, heated to 70 ° C,Neutralized with carbon dioxide to pH 3. 3, barium carbonate was removed by filtration, the filtrate was adjusted to pH 3 with sulfuric acid, allowed to stand for 3 hours, filtered, washed with water,Add 5 g of activated charcoal decolorization, filtration, the filtrate sprinkled to 50mL, then add ethanol 50mL crystallization, cooling to 10 ° C, filtration, crystallization with ethanol washing, drying, white solid trans-4-aminomethylcyclohexylformic acid, Mass of 17.37g, mp: 384-388 ° (decomposition), molar yield of 85.11percent By liquid phase detection, trans-body content of 99.6910percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | at 0 - 70℃; for 1.16667 h; | First, trans-4-(aminomethyl)cyclohexaneethylcarboxylate hydrochloride was synthesized using trans-4-(aminomethyl)cyclohexanecarboxylic acid purchased form TCI (Japan). Trans-4-(aminomethyl)cyclohexanecarboxylic acid (1.57 g, 10 mmol) was added to 40 mL of ethanol at 02C and stirred. After slowly adding thionyl chloride (0.9 mL, 12 mmol), the mixture was stirred for 10 min while keeping cold. Then, after refluxing at 702C for 1 h, the reaction mixture was cooled to room temperature. After completely removing the solvent under reduced pressure, the residue was washed twice with hexane (25 mL) to remove the remaining solvent. The mixture with the solvent completely removed was dried in dried under vacuum for 6 h to obtain trans-4-(aminomethyl)cyclohexaneethylcarboxylate hydrochloride. Yield was 2.13 g (96percent). 1H NMR (d6-DMSO): δ=4.03 (q, J=7.08, 2H, OCH2CH3), 2.61 (m, 1H, H13), 2.21 (m, 1H, H10), 1.85 (m, 2H, H9), 1.27 (m, 4H, H12H11), 1.16 (t, J=7.06, 3H, OCH2CH3), 0.96 (m, 4H, H12H11). Anal. Calc. for C10H20ClNO2: C, 54.17; H, 9.09; N, 6.32. Found: C, 53.78; H, 8.91; N, 6.34. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With sodium hydrogencarbonate In water at 20℃; for 18h; Industrial scale; | 1 Preparation of Compound 1 Example 1 Preparation of Compound 1 Water (10.0 L) and (Boc)2O (3.33 kg, 15.3 mol) were added to a solution of trans-4-aminomethyl-cyclohexanecarboxylic acid (compound 1-I, 2.0 kg, 12.7 mol) and sodium bicarbonate (2.67 kg, 31.8 mol). The reaction mixture was stirred at ambient temperature for 18 hours. The aqueous layer was acidified with concentrated hydrochloric acid (2.95 L, pH=2) and then filtered. The resultant solid was collected, washed three times with water (15 L), and dried in a hot box (60° C.) to give trans-4-(tert-butoxycarbonylamino-methyl)-cyclohexanecarboxylic acid (compound 1-II, 3.17 kg, 97%) as a white solid. Rf=0.58 (EtOAc). LC-MS m/e 280 (M+Na+). 1H NMR (300 MHz, CDCl3) δ 4.58 (brs, 1H), 2.98 (t, J=6.3 Hz, 2H), 2.25 (td, J=12, 3.3 Hz, 1H), 2.04 (d, J=11.1 Hz, 2H), 1.83 (d, J=11.1 Hz, 2H), 1.44 (s, 9H), 1.35˜1.50 (m, 3H), 0.89˜1.03 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 181.31, 156.08, 79.12, 46.41, 42.99, 37.57, 29.47, 28.29, 27.96. M.p. 134.8˜135.0° C. |
95% | With sodium hydrogencarbonate In 1,4-dioxane | |
94% | With sodium hydroxide In water; <i>tert</i>-butyl alcohol for 18h; Ambient temperature; |
90% | With triethylamine In 1,4-dioxane; water Cooling with ice; | 131 131: 2-Chloro-4-((5-(3,5-dimethylisoxazol-4-yl)-2-methylphenyl)(((1r,4r)-4-(((2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)amino)methyl)cyclohexyl)methyl)a mino)benzonitrile (131) [0405] Compound (1r,4r)-4-(aminomethyl)cyclohexane-1-carboxylic acid (549 mg, 3.50 mmol) was added to 10 mL mixed solution of dioxane and water (v/v, 1:1), to which was added Et3N (531 mg, 5.20 mmol) in an ice bath, and finally (Boc)2O (840 mg, 3.80 mmol) was slowly added. After addition, the ice bath was removed, and the reaction solution was stirred overnight at room temperature. The reaction solution was diluted with EA. The organic phase was washed twice with 2 N HCl solution, washed with saturated NaCl solution, dried over anhydrous sodium sulfate, and rotatory evaporated to dry, to provide (1r,4r)-4-(((t-butoxycarbonyl)amino)methyl)cyclohexane-1-carboxylic acid (810 mg, 3.15 mmol), with a yield of 90%. LC/MS (ESI+) calcd for: C13H23NO4 (M + H+) m/z, 258.3; found, 258.3. |
90% | With triethylamine In 1,4-dioxane; water Cooling with ice; | 131 131: 2-Chloro-4-((5-(3,5-dimethylisoxazol-4-yl)-2-methylphenyl)(((1r,4r)-4-(((2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)amino)methyl)cyclohexyl)methyl)a mino)benzonitrile (131) [0405] Compound (1r,4r)-4-(aminomethyl)cyclohexane-1-carboxylic acid (549 mg, 3.50 mmol) was added to 10 mL mixed solution of dioxane and water (v/v, 1:1), to which was added Et3N (531 mg, 5.20 mmol) in an ice bath, and finally (Boc)2O (840 mg, 3.80 mmol) was slowly added. After addition, the ice bath was removed, and the reaction solution was stirred overnight at room temperature. The reaction solution was diluted with EA. The organic phase was washed twice with 2 N HCl solution, washed with saturated NaCl solution, dried over anhydrous sodium sulfate, and rotatory evaporated to dry, to provide (1r,4r)-4-(((t-butoxycarbonyl)amino)methyl)cyclohexane-1-carboxylic acid (810 mg, 3.15 mmol), with a yield of 90%. LC/MS (ESI+) calcd for: C13H23NO4 (M + H+) m/z, 258.3; found, 258.3. |
90% | With triethylamine In 1,4-dioxane; water Cooling with ice; | 131 131: 2-Chloro-4-((5-(3,5-dimethylisoxazol-4-yl)-2-methylphenyl)(((1r,4r)-4-(((2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)amino)methyl)cyclohexyl)methyl)a mino)benzonitrile (131) [0405] Compound (1r,4r)-4-(aminomethyl)cyclohexane-1-carboxylic acid (549 mg, 3.50 mmol) was added to 10 mL mixed solution of dioxane and water (v/v, 1:1), to which was added Et3N (531 mg, 5.20 mmol) in an ice bath, and finally (Boc)2O (840 mg, 3.80 mmol) was slowly added. After addition, the ice bath was removed, and the reaction solution was stirred overnight at room temperature. The reaction solution was diluted with EA. The organic phase was washed twice with 2 N HCl solution, washed with saturated NaCl solution, dried over anhydrous sodium sulfate, and rotatory evaporated to dry, to provide (1r,4r)-4-(((t-butoxycarbonyl)amino)methyl)cyclohexane-1-carboxylic acid (810 mg, 3.15 mmol), with a yield of 90%. LC/MS (ESI+) calcd for: C13H23NO4 (M + H+) m/z, 258.3; found, 258.3. |
82% | With hydrogenchloride; sodium hydroxide In 1,4-dioxane; water | 16.1 (16-1) (16-1) Synthesis of trans-4-(N-t-Butyloxycarbonylaminomethyl)cyclohexanecarboxylic Acid: In 300 ml of a mixture of dioxane and water (2:1 by volume) was dissolved 15.7 g of tranexamic acid and 100 ml of an aqueous solution of 1 mol of sodium hydroxide and 50 ml of a dioxane solution of 24.0 g of di-t-butyl dicarbonate were added dropwise to the solution under ice-cooling over a period of 10 minutes. After stirring the mixture for 2.5 hours at room temperature, the reaction mixture was concentrated under reduced pressure to about 1/3 of the original volume on a water bath at an external temperature of from 50° to 60° C. and then about 85 ml of 1N hydrochloric acid was added dropwise to the mixture under ice-cooling to adjust the pH thereof to from 3 to 4. The product was extracted three times, each time with 80 ml of ethyl acetate, the organic layer obtained was washed with 30 ml of purified water and then 30 ml of a saturated aqueous sodium chloride solution, and after drying with magnesium sulfate, the solvent was distilled off under reduced pressure. The crude crystals thus formed were washed with isopropyl ether and recrystallized from ethyl acetate to provide 21.2 g (yield 82%) of colorless powdery trans-4-(N-t-butyloxycarbonylaminomethyl)cyclohexanecarboxylic acid. |
80% | With sodium hydroxide; potassium hydrogensulfate In 1,4-dioxane; water | 6.a a) a) N-t-butyloxy carbonyl-trans-4-aminomethyl cyclohexyl carboxylic acid Aqueous sodium hydroxide (1N, 100 ml, 100 mmol) was added to a solution of 4-trans-aminomethyl-cyclohexyl-carboxylic acid (9.0g, 60 mmol), in dioxane (100 ml), water (100 ml) at 0 degrees C. Boc anhydride (15.9 g, 66 mmol) was added and the reaction was warmed to rt and stirred overnight. The solution was concentrated to 50 ml, then was diluted with EtOAc (100 ml) and acidified to pH 2 with adqueous KHSO4(1N). The organic layer was then extracted with water (100 ml) two times, and the organics were concentrated in vacuo. The solid was recrystallized from EtOAc/ hexanes to yield 9.2g + 3.4g (second crop) of a white solid. (80% yield). MS (ES) m/e 242 [M+H]+. |
75% | With sodium hydroxide In water; acetonitrile at 0 - 20℃; for 16h; | |
67% | With sodium hydroxide In <i>tert</i>-butyl alcohol at 20℃; for 18h; | |
57% | With sodium hydrogencarbonate In diethyl ether; water at 20℃; | Boc2O (41.7 g, 190 mmol) was added to a stirred biphasic solution containing trans-4-(aminomethyl)cyclohexanecarboxylic acid (25.0 g, 159 mmol), NaHCO3 (20.0 g, 238 mmol), water (300 mL) and Et2O (200 mL) at rt. The pH of the solution was adjusted to pH~9.0 by adding additional quantities of saturated aqueous NaHCO3. After stirring for 24 h at rt, the layers were separated and the aqueous layer was acidified to pH 4.0 with 1M aqueous HCl. The aqueous layer was extracted with EtOAc. The organic layer was isolated and washed successively with water and brine. The organic layer was concentrated in vacuo and dried under high vacuum to yield the desired product as a colorless solid (23.3 g, 57%). 1H NMR (CDCl3) δ 4.60 (br s, 1H), 2.99 (t, 2H, J=6.4 Hz), 2.29-2.23 (m, 3H), 2.05 (dd, 2H, J=13.6 and 3.2 Hz), 1.84 (dd, 2H, J=13.2 and 2.8 Hz), 1.44 (s, 9H), 1.42 (br m, 1H), 0.97 (dq, 2H, J=25.6, 12.4 and 3.2 Hz). |
44.6% | With triethylamine In dichloromethane at 0℃; | |
With sodium hydroxide In 1,4-dioxane at 20℃; | ||
48 g (59%) | In tetrahydrofuran; sodium hydroxide; <i>tert</i>-butyl alcohol | EXAMPLE 12 STR47 A) Preparation of N-Boc-trans-4-(aminomethyl)cyclohexanecarboxylic acid EXAMPLE 12 STR47 A) Preparation of N-Boc-trans-4-(aminomethyl)cyclohexanecarboxylic acid To a solution of trans-4-(aminomethyl)cyclohexanecarboxylic acid (50 g, 318 mmol) in 1 N sodium hydroxide (334 mL, 334 mmol) and t-butanol (400 mL) was added a solution of di-t-butyl dicarbonate (73 g, 334 mmol) in tetrahydrofuran (50 mL). After stirring for 20 hours, the solvents were removed in vacuo and the residue was partitioned between water (500 mL) and diethyl ether (250 mL). The aqueous phase was washed again with diethyl ether (250 mL) and then acidified with solid citric acid, which resulted in the formation of a white precipitate. The solid was filtered, washed twice with water (100 mL) and dried in vacuo to yield 48 g (59%) of white powder. |
48 g (59%) | In tetrahydrofuran; sodium hydroxide; <i>tert</i>-butyl alcohol | EXAMPLE 12 STR53 A) Preparation of N-Boc-trans-4-(aminomethyl)cyclohexanecarboxylic acid. EXAMPLE 12 STR53 A) Preparation of N-Boc-trans-4-(aminomethyl)cyclohexanecarboxylic acid. To a solution of trans-4-(aminomethyl)cyclohexanecarboxylic acid (50 g, 318 mmol) in 1N sodium hydroxide (334 mL, 334 mmol) and t-butanol (400 mL) was added a solution of di-t-butyl dicarbonate (73 g, 334 mmol) in tetrahydrofuran (50 mL). After stirring for 20 hours, the solvents were removed in vacuo and the residue was partitioned between water (500 mL) and diethyl ether (250 mL). The aqueous phase was washed again with diethyl ether (250 mL) and then acidified with solid citric acid, which resulted in the formation of a white precipitate. The solid was filtered, washed twice with water (100 mL) and dried in vacuo to yield 48 g (59%) of white powder. |
48 g (59%) | In tetrahydrofuran; sodium hydroxide; <i>tert</i>-butyl alcohol | 12.A A) A) Preparation of N-Boc-trans-4-(aminomethyl)cyclohexanecarboxylic acid To a solution of trans-4-(aminomethyl)cyclohexanecarboxylic acid (50 g, 318 mmol) in 1N sodium hydroxide (334 mL, 334 mmol) and t-butanol (400 mL) was added a solution of di-t-butyl dicarbonate (73 g, 334 mmol) in tetrahydrofuran (50 mL). After stirring for 20 hours, the solvents were removed in vacuo and the residue was partitioned between water (500 mL) and diethyl ether (250 mL). The aqueous phase was washed again with diethyl ether (250 mL) and then acidified with solid citric acid, which resulted in the formation of a white precipitate. The solid was filtered, washed twice with water (100 mL) and dried in vacuo to yield 48 g (59%) of white powder. |
48 g (59%) | In tetrahydrofuran; sodium hydroxide; <i>tert</i>-butyl alcohol | EXAMPLE 12 STR42 A) Preparation of N-Boc-trans-4-(aminomethyl)cyclohexanecarboxylic acid EXAMPLE 12 STR42 A) Preparation of N-Boc-trans-4-(aminomethyl)cyclohexanecarboxylic acid To a solution of trans-4-(aminomethyl)cyclohexanecarboxylic acid (50 g, 318 mmol) in 1N sodium hydroxide (334 mL, 334 mmol) and t-butanol (400 mL) was added a solution of di-t-butyl dicarbonate (73 g, 334 mmol) in tetrahydrofuran (50 mL). After stirring for 20 hours, the solvents were removed in vacuo and the residue was partitioned between water (500 mL) and diethyl ether (250 mL). The aqueous phase was washed again with diethyl ether (250 mL) and then acidified with solid citric acid, which resulted in the formation of a white precipitate. The solid was filtered, washed twice with water (100 mL) and dried in vacuo to yield 48 g (59%) of white powder. |
48 g (59%) | In tetrahydrofuran; sodium hydroxide; <i>tert</i>-butyl alcohol | EXAMPLE 12 STR53 A) Preparation of N-Boc-trans-4-(aminomethyl)cyclohexanecarboxylic acid EXAMPLE 12 STR53 A) Preparation of N-Boc-trans-4-(aminomethyl)cyclohexanecarboxylic acid To a solution of trans-4-(aminomethyl)cyclohexanecarboxylic acid (50 g, 318 mmol) in 1N sodium hydroxide (334 mL, 334 mmol) and t-butanol (400 mL) was added a solution of di-t-butyl dicarbonate (73 g, 334 mmol) in tetrahydrofuran (50 mL). After stirring for 20 hours, the solvents were removed in vacuo and the residue was partitioned between water (500 mL) and diethyl ether (250 mL). The aqueous phase was washed again with diethyl ether (250 mL) and then acidified with solid citric acid, which resulted in the formation of a white precipitate. The solid was filtered, washed twice with water (100 mL) and dried in vacuo to yield 48 g (59%) of white powder. |
With potassium hydroxide In 1,4-dioxane at 0 - 25℃; | 257 KOH (14 g) and Boc2O (33.3 g) were added to a solution of trans-4-(Aminomethyl)cyclohexane-carboxylic acid (20 g) in dioxane (112 mL) at 0° C. The reaction was stirred at 25° C. overnight. The solution was concentrated to half of the original volume under vacuum, acidified with 2.5 N HCl (PH=3), and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated to give a white solid Intermediate 257-I (31.9 g). To a suspension of the above solid in toluene (150 mL) were added phosphorazidic acid diphenyl ester (32.4 g) and Et3N (11.9 g) at 25° C. for 1.0 hour. The reaction mixture was warmed to 80° C. for 3.0 hours and then cooled to 25° C. After benzyl alcohol (20 g) was added, the reaction mixture was stirred at 80° C. for another 3.0 hours and then warmed to 120° C. overnight. It was then concentrated and dissolved again in EtOAc and H2O. The organic layer was then collected. The aqueous layer was extracted with EtOAc. The combined organic layer was washed with 2.5 N HCl, saturated aqueous NaHCO3 and brine, dried over anhydrous MgSO4, filtered, and concentrated. The residue thus obtained was purified by column chromatography on silica gel (EtOAc/Hexane=1/2) to give Intermediate 257-II (35 g) in a 79% yield. To a suspension of Intermediate 257-II (1.9 g) in MeOH (10 mL) was added 10% Pd/C (190 mg). The mixture was stirred at ambient temperature under hydrogen atmosphere for 4.0 hours, filtered, and concentrated. The residue thus obtained was purified by column chromatography on silica gel (using EtOAc and MeOH as an eluant) to give Intermediate 257-III (750 mg) in a 60% yield. 222-III (1,198 mg) prepared from Example 222 was added to a solution of Intermediate 257-III (750 mg) in CH2Cl2 (30 mL). The mixture was stirred at 25° C. for 2 hours. NaBH(OAc)3 (1,046 mg) was then added at 25° C. for 12 hours. After the solution was concentrated, a saturated aqueous NaHCO3 solution was added to the resultant residue. The mixture was extracted with CH2Cl2. The organic layer was collected and concentrated. The residue thus obtained was purified by column chromatography on silica gel (using EtOAc and MeOH as an eluant) to afford Intermediate 257-IV (1,200 mg) in a 78% yield. A solution of Intermediate 257-IV (5.2 g) treated with 4 N HCl/dioxane (39 mL) in MeOH (52 mL) was stirred at room temperature for 8 hours. After ether (104 mL) was added, the solution was filtered. The solid thus obtained was dried under vacuum. K2CO3 (21 g) was added to a suspension of this solid in CH3CN (230 mL) at room temperature for 10 minutes. After water (9 mL) was added, the reaction mixture was stirred at room temperature for 2 hours. The mixture was then filtered, dried over anhydrous MgSO4, and concentrated to afford crude Intermediate 257-V (2.8 g). Crude Intermediate 257-V (2.8 g) and Et3N (1.3 mL) in 1-pentanol (11.3 mL) was allowed to react with 2,4-dichloro-6-aminopyrimidine (1,633 mg) at 100° C. for 12 hours. The solvent was then removed and the residue was purified by column chromatography on silica gel (21% NH3 (aq)/MeOH=1/19) to afford Intermediate 257-VI (3.3 g) in a 75% yield. A solution of Intermediate 252-VI (3.3 g) and Boc2O (4.189 g) in CH2Cl2 (60 mL) was added to Et3N (1.0 mL) at 25° C. overnight. The solution was then concentrated and the resultant residue was purified by column chromatography on silica gel (using EtOAc and Hexane as an eluant) to give Intermediate 257-VII (3.2 g) in a 64% yield. Intermediate 257-VII (2.6 g) and piperazine (1.127 g) in 1-pentanol (5.2 mL) was added to Et3N (0.5 mL) at 120° C. for 18 hours. After the solution was concentrated, the residue was treated with water and extracted with CH2Cl2. The organic layer was collected and concentrated. The residue thus obtained was purified by column chromatography on silica gel (using EtOAc/MeOH to 21% NH3 (aq)/MeOH as an eluant) to afford Intermediate 257-VIII (1.8 g) in a 64% yield. To a solution of Intermediate 257-VIII (200 mg) in CH3CN (20 mL) were added ethyl bromoacetate (52 mg) and K2CO3 (128 mg). The mixture was stirred at 60° C. for 2 hours. The solution was filtered and concentrated. The residue was purified by column chromatography on silica gel (using EtOAc and MeOH as an eluant) to afford Intermediate 257-IX (140 mg) in a 62% yield. 0.5 M of a LiOH aqueous solution (10 mL) was added to Intermediate 257-IX (500 mg) dissolved in THF (10 mL). The mixture was stirred at room temperature for 15 hours. It was then acidified with 2.5 M HCl (pH=9) and filtered to obtain a yellow solid. The yellow solid was purified by column chromatography on silica gel (using EtOAc/MeOH to 21% NH3 (aq)/MeOH as an eluant) to afford Intermediate 257-X (337 mg) in a 70% yield. 20% TFA/CH2Cl2 (10 mL) was added to a solution of Intermediate 257-X (400 mg) in CH2Cl2 (8 mL). The solution was stirred at room temperature for 2 hours and then concentrated. To the residue in acetone (7 mL) was added HCl (4 M in dioxane, 1.3 mL) at room temperature for 30 minutes. After the solvents were removed, the residue was treated with ether and filtered to give hydrochloride salt of Compound 257 (257 mg).CI-MS (M++1): 503.4. | |
In 1,4-dioxane; water at 0 - 20℃; for 4h; | ||
With hydrogenchloride; sodium hydroxide In 1,4-dioxane; chloroform; water | 24.1 Example 24-1 Example 24-1 Synthesis of N-Boc-tranexamic acid (Compound XVII-2) Tranexamic acid (3.14 g) was dissolved in dioxane(63 ml). After the addition of di-t-butyl-di-carbonate (4.59 ml) and 1 mol/l aqueous solution of sodium hydroxide (20 ml), the mixture was stirred for 3.5 hours at room temperature. After the reaction, the solvent was removed by distillation. The residue was dissolved in 1 mol/l aqueous solution of sodium hydroxide (20 ml) and distilled water (10 ml). 1 mol/l aqueous solution of hydrochloric acid was added to produce crystals. The crystals were collected by filtration, dissolved in chloroform, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed by distillation to obtain the target compound (4.88 g) as a white solid. MS(FAB,Pos.):m/z=258[M+1]+ 1H-NMR(500MHz,DMSO-d6):δ=0.95(2H,qd,J=12 8,3.0Hz),1.20-1.58 (12H,m),1.83(2H,d,J=11.5Hz),2.04(2H,dd,J=13.9,3.0Hz),2.25(1 H,tt,J=12.2,3.0Hz),2.99(2H,t,J=6.3Hz),4.66(1H,brs). | |
With sodium hydroxide In 1,4-dioxane; water at 0 - 20℃; for 16h; | 2.1 (1) Preparation of 4-[(tert-butoxycarbonyl)methyl]cyclohexanecarboxylic acid Under ice-water bath at 0°C, tranexamic acid (8.35 g, 53.1 mmol) was dissolved in 100 mL of 1,4-dioxane and 60 mL of water, and sodium hydroxide (4.25 g, 106.2 mmol) was added. Then, di-tert-butyl dicarbonate (13.9 g, 63.7 mmol) was added dropwise to the bottle, and the reaction was carried out at room temperature for 16 h. After the reaction, it was concentrated, diluted with ethyl acetate, and adjusted to pH ≈ 3 by adding an aqueous solution of citric acid. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to give a white solid. To the white solid, n-hexane was added and vigorously stirred, and the white filter cake obtained by filtration was the target product 4-[(tert-butoxycarbonyl)methyl]cyclohexanecarboxylic acid, which was directly used in the next step. | |
97.9 % | With sodium hydroxide In 1,4-dioxane at 0 - 20℃; | 1.1 Step 1: Synthesis of trans-4-(((tert-butoxycarbonyl)amino)methyl)cyclohexane-1-carboxylic acid [0335] To a stirred solution of trans-4-(aminomethyl)cyclohexane-1-carboxylic acid (500 mg, 3.18 mmol, 1.0 eq.), in dioxane (3 mL) was added NaOH (254 mg, 4.8 mmol, 1.5 eq.) and followed by addition of di-tert-butyl dicarbonate (1040 mg, 6.36 mmol, 2.0 eq.) at 0 °C. The resulting reaction mixture was allowed to stir at RT overnight. Product formation was confirmed by 1H NMR. Upon completion, the reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in water (10 mL), and acidified with 6 M HCl (pH ~ 3). The resulting solid was filtered off and dried under vacuum to obtain trans-4-(((tert-butoxycarbonyl)amino)methyl)cyclohexane-1-carboxylic acid (800 mg, 97.9 % yield) as a white solid. LCMS 258.0 [M+H]+; 1H NMR (400 MHz, DMSO-d6) G 11.97 (br. s., 1H), 6.79 (br. s., 1H), 2.75 (t, J = 6.1Hz, 2 H), 2.09 (t, J = 12.3 Hz, 1H), 1.87 (d, J = 11.8 Hz, 2 H), 1.69 (d, J = 10.5 Hz, 3 H), 1.37 (s, 9 H), 1.28 - 1.13 (m, 2 H), 0.91 - 0.68 (m, 2 H). |
97.9 % | With sodium hydroxide In 1,4-dioxane at 0 - 20℃; | 1.1 Step 1: Synthesis of trans-4-(((tert-butoxycarbonyl)amino)methyl)cyclohexane-1-carboxylic acid [0335] To a stirred solution of trans-4-(aminomethyl)cyclohexane-1-carboxylic acid (500 mg, 3.18 mmol, 1.0 eq.), in dioxane (3 mL) was added NaOH (254 mg, 4.8 mmol, 1.5 eq.) and followed by addition of di-tert-butyl dicarbonate (1040 mg, 6.36 mmol, 2.0 eq.) at 0 °C. The resulting reaction mixture was allowed to stir at RT overnight. Product formation was confirmed by 1H NMR. Upon completion, the reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in water (10 mL), and acidified with 6 M HCl (pH ~ 3). The resulting solid was filtered off and dried under vacuum to obtain trans-4-(((tert-butoxycarbonyl)amino)methyl)cyclohexane-1-carboxylic acid (800 mg, 97.9 % yield) as a white solid. LCMS 258.0 [M+H]+; 1H NMR (400 MHz, DMSO-d6) G 11.97 (br. s., 1H), 6.79 (br. s., 1H), 2.75 (t, J = 6.1Hz, 2 H), 2.09 (t, J = 12.3 Hz, 1H), 1.87 (d, J = 11.8 Hz, 2 H), 1.69 (d, J = 10.5 Hz, 3 H), 1.37 (s, 9 H), 1.28 - 1.13 (m, 2 H), 0.91 - 0.68 (m, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride | ||
With hydrogenchloride In 1,4-dioxane for 18h; | ||
With thionyl chloride |
With thionyl chloride | General procedure for methyl ester protection of amino acids The amino acid (22.45 mmol, 1.0 eq) was suspended in MeOH (20 mL per 10 mmol of amino acid) and reaction mixture was cooled to 0 °C. Thionyl chloride (4 eq) was carefully added dropwise and the reaction mixture was left to stir for 12h at room temperature. The mixture was concentrated under reduced pressure and diethylether was added (10 mL per 10 mmol of amino acid). Precipitate was collected and washed with cooled diethyether (10 mL per 10 mmol of amino acid). | |
With thionyl chloride In methanol at 0 - 25℃; for 12h; | 1.2.3 General procedure for the preparation of intermediates 5a-5e. General procedure: To a solution of 4a-4e (1.0 equiv) in MeOH was added SOCl2 (1.5 equiv) dropwise at 0 °C. The mixture was stirred for 12 h at 25 °C. The solvent was evaporated under vacuum. The crude product was recrystallized to give 5a-5e (yield 85%-90%) as white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With sodium hydroxide In tetrahydrofuran; water at 20℃; for 2h; | |
With sodium hydroxide | ||
With sodium hydroxide for 1h; |
With hydrogenchloride In sodium hydroxide | 1.1 Step 1: Step 1: trans-4-(N-carbobenzyloxy)aminomethyl-1-cyclohexane carboxylic acid To a 0° C. solution of trans-4-aminomethyl-1-cyclohexane carboxylic acid (6.28 g, 0.04 mol) in 10% aqueous NaOH (16 mL) was added dropwise benzyl chloroformate (8.29 g, 0.049 mol) and 10% aqueous NaOH (20 mL). The cold bath was removed and the reaction mixture was stirred vigorously for one hour. The thick white paste was shaken with aqueous 1M HCl (100 mL) and the white solid was isolated by filtration, washed with H2 O, and dried overnight in vacuo to give trans-4-(N-carbobenzyloxy)aminomethyl-1-cyclohexane carboxylic acid. | |
With hydrogenchloride In sodium hydroxide | 30.1 Preparation of 3-[trans-4-[(1H-2-methylimidazo[4.5-c]pyrid-1-yl)methylcyclohex-1-yl]carbonyl}indole-1,4-dicarboxylic acid 1-dimethyl amide 4-methyl ester hydrochloride. Step 1: trans-4-(N-carbobenzyloxy)aminomethyl-1-cyclohexane carboxylic acid. To a 0° C. solution of trans-4-aminomethyl-1-cyclohexane carboxylic acid (6.28 g, 0.04 mol) in 10% aqueous NaOH (16 mL) was added dropwise benzyl chloroformate (8.29 g, 0.049 mol) and 10% aqueous NaOH (20 mL). The cold bath was removed and the reaction mixture was stirred vigorously for one hour. The thick white paste was shaken with aqueous 1M HCl (100 mL) and the white solid was isolated by filtration, washed with H2 O, and dried overnight in vacuo to give trans-4-(N-carbobenzyloxy)aminomethyl-1-cyclohexane carboxylic acid. | |
Stage #1: trans-4-aminomethyl-cyclohexyl-carboxylic acid; benzyl chloroformate With sodium hydroxide In water at 0℃; for 1.25h; Stage #2: With hydrogenchloride In water | trans-4-(Aminomethyl)cyclohexanecarboxylic acid (10.00 g, 0.06361 mol), in a 10% aq solution of NaOH (5.60 g in 55 mL) was cooled to 0° C. and treated over 15 min with vigorous stirring, with benzyl chloroformate (11 mL, 0.076 mol). After one hour the solution was acidified (1M HCl(aq)) and the resulting the white precipitate collected by filtration, washed with water and hexane then dried in vacuo oven overnight to afford 17.23 g of the title compound. 1H NMR (400 MHz, CDCl3): δ 0.93-0.99 (m, 2H), 1.38-1.46 (m, 2H), 1.82-1.85 (m, 2H), 2.03-2.06 (m, 2H), 2.25 (m, 1H), 3.06 (t, J=5.6 Hz, 2H), 4.83 (m, 1H), 5.09 (s, 2H), 7.31-7.36 (m, 5H). MS (ES+): m/z 292 [MH+]. | |
With sodium hydrogencarbonate In 1,4-dioxane; water | 60 To (trans)-4-(aminomethyl)cyclohexanecarboxylic acid (10 g, 44.5 mmol) in 1 ,4-dioxane (75 ml) and water (75 ml) was added dropwise benzyl chloroformate (6.99 ml, 49.0 mmol). The pH was kept between 7 and 8 by adding saturated aqueous sodium carbonate.After stirring for two hours the reaction mixture was concentrated in vacuo till half volume, 1 M sodium hydroxide (aq) was added till pH=9 and the mixture was extracted with diethylether. 2M Hydrochloric acid was added till pH=1 was the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried (Na2SC>4) and concentrated to yield (trans)-4-((benzyloxycarbonylamino)methyl)cyclohexanecarboxylic acid (12.03 g) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With sodium carbonate In water at 20℃; | Synthesis of 4-[(toluene-4-sulfonylamino)-methyl]-cyclohexanecarboxylic acid (VI) Tranxemic acid (4 g, 25.4 mmol) was dissolved inwater (50 mL).p-Toluenesulfonyl chloride (4.85 g, 25.4 mmol) was added to itunder stirring at room temperature keeping the pH of a mixtureabout 8e9 using 1 M sodium carbonate solution until thecompletion of reaction. The dissolution of suspended sulfonylchloride to clear solution indicates the progress of reaction. Oncompletion the pH of solutionwas decreased to 2e3 by adding 1 MHCl. The precipitates produced were filtered, washed by distilledwater and recrystallized from methanol [20] (Yield: 84%) mp192-194 C. |
With sodium hydroxide at 20℃; for 48h; | ||
With sodium hydroxide In chloroform; water at 20℃; for 48h; |
With sodium hydroxide In chloroform; water at 20℃; for 72h; | ||
With sodium hydrogencarbonate In water at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With sodium carbonate In water at 20℃; | Synthesis of 4-[(4-bromo-benzenesulfonylamino)-methyl]-cyclohexanecarboxylic acid (VIII) Tranxemic acid (2 g, 12.7 mmol) was dissolved inwater (50 mL).4-Bromobenzenesulfonyl chloride (3.24 g,12.7 mmol)was added toit under stirring at room temperature keeping the pH of a mixtureabout 8e9 using 1 M sodium carbonate solution until thecompletion of reaction. The dissolution of suspended sulfonylchloride to clear solution indicates the progress of reaction. Oncompletion the pH of solutionwas decreased to 2e3 by adding 1 MHCl. The precipitates produced were filtered, washed by distilledwater and recrystallized from methanol (Yield: 91%) mp 199 C. |
21% | With sodium hydroxide In water at 20℃; for 24h; | |
With sodium hydroxide at 20℃; for 48h; |
With sodium hydroxide In chloroform at 20℃; for 48h; | ||
With sodium hydroxide In chloroform; water at 20℃; for 48h; | ||
With sodium hydroxide In chloroform; water at 20℃; for 72h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With sodium hydroxide In dichloromethane at 0 - 20℃; for 24h; | Step 1. 4-Fluorobenzenesulfonyl chloride (1.95 g, 10 mmol) in CH2Cl2 (20 mL) was added dropwise to a mixture of 4-(aminomethyl)cyclohexane-1-carboxylic acid (1.57 g, 10 mmol) in 2N NaOH (30 mL) at 0 °C. The resulting mixture was stirred at rt for 24h. The CH2Cl2 was removed in vacuo and the residue was acidified with 1N HCl. The precipitate was filtered, washed with cold water and dried in vacuo at 40 °C to afford 4-(((4-fluorophenyl)sulfonamido)methyl)cyclohexane-1-carboxylic acid (30)3 (2.1 g, 67%) as a white solid. |
With sodium hydroxide In chloroform; water at 20℃; for 72h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | In acetonitrile at 20℃; for 6h; Inert atmosphere; | |
56% | With acetic acid at 20℃; for 11h; | 3.1 1) Preparation of Maa-CR-OH 4-(Aminomethyl)cyclohexane-1-carboxylic acid (2.0 g, 20.4 mM) was dissolved in acetic acid (100 mL), stirred to dissolve, maleic anhydride (3.2 g, 20.4 mM) was added, and stirred at room temperature, and the resulting reaction solution was clear and transparent, and stirred continuously to react for 1 hour at room temperature, white insoluble substance was precipitated out, and the reaction was continued for 10 hours. The reaction solution was filtered, the filter cake was washed with acetonitrile to obtain a white powdery solid, the white powdery solid was weighed as 2.91 g, and the yield was 56%. 1H-NMR(400M, DMSO-d6): δ 14.92(br, 1H), 12.13(br, 1H), 9.08(t, 1H), 6.42(d, J=12.6 Hz, 1H), 6.23(d, J=12.6 Hz, 1H), 3.03(t, 2H), 2.13(tt, 1H), 1.90(dd, 2H), 1.74(dd, 2H), 1.43(m, 1H), 1.26(qd, 2H), 0.94(qd, 2H). MS m/z 254.3([M-H]-). |
56% | With acetic acid at 20℃; for 11h; | 3.1 1) Preparation of Maa-CR-OH 4-(Aminomethyl)cyclohexane-1-carboxylic acid (2.0 g, 20.4 mM) was dissolved in acetic acid (100 mL), stirred to dissolve, maleic anhydride (3.2 g, 20.4 mM) was added, and stirred at room temperature, and the resulting reaction solution was clear and transparent, and stirred continuously to react for 1 hour at room temperature, white insoluble substance was precipitated out, and the reaction was continued for 10 hours. The reaction solution was filtered, the filter cake was washed with acetonitrile to obtain a white powdery solid, the white powdery solid was weighed as 2.91 g, and the yield was 56%. 1H-NMR(400M, DMSO-d6): δ 14.92(br, 1H), 12.13(br, 1H), 9.08(t, 1H), 6.42(d, J=12.6 Hz, 1H), 6.23(d, J=12.6 Hz, 1H), 3.03(t, 2H), 2.13(tt, 1H), 1.90(dd, 2H), 1.74(dd, 2H), 1.43(m, 1H), 1.26(qd, 2H), 0.94(qd, 2H). MS m/z 254.3([M-H]-). |
With acetic acid at 20℃; | ||
With acetic acid at 20℃; | 3.1 Trans-4-(aminomethyl)-cyclohexanecarboxylic acid (500 mg, 3.18 mmol) was dissolved in 3 ml of glacial acetic acid, maleic anhydride (31 1 mg, 3.18 mmol) was added and the mixture stirred at room temperature until a white precipitate of trans-4-([(2Z)-3-carboxyprop-2-enoyl]amino}methyl)cyclohexanecarboxylic acid was formed. The mixture was then heated under reflux to complete the cyclization of the trans-4-(N-maleimidemethyl)cyclohexane-1 -carboxylic acid, and the mixture is concentrated under reduced pressure to remove acetic acid. The crude product was purified by flash column chromatography (S1O2- CHCU/MeOH, eluting with gradient 99: 1 -> 90: 10. The product was obtained as a cream solid, yield 435 mg (58%), ESI-ITMS: m/z (%): 236 (M - H)-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 67 percent / aq. NaOH / 2-methyl-propan-2-ol / 18 h / 20 °C 2: Et3N / CH2Cl2 / 0.83 h / 0 °C 3: NaBH4 / tetrahydrofuran; methanol / 3 h / 4 °C | ||
Multi-step reaction with 2 steps 1: aq. NaOH / dioxane / 20 °C 2: 52 percent / LiAlH4 / dioxane; tetrahydrofuran | ||
Multi-step reaction with 2 steps 1: triethylamine / lithium hydroxide monohydrate; 1,4-dioxane / Cooling with ice 2: borane-THF / tetrahydrofuran / 2 h / 20 °C |
Multi-step reaction with 2 steps 1: borane-THF / tetrahydrofuran / 20 °C / Inert atmosphere 2: triethylamine / 1,4-dioxane / 6 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: triethylamine / H2O / 6 h / 40 - 60 °C 2: 8 h / Heating | ||
Multi-step reaction with 2 steps 1: triethylamine / H2O / 6 h / 40 - 60 °C 2: 12 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With sulfuric acid In ethanol for 17h; Heating / reflux; | 10 0.4 ml of sulphuric acid is added to a solution of 0.2 g of trans-4-(aminomethyl)cyclohexanecarboxylic acid in 5 ml of ethanol. The reaction medium is brought to reflux for 17 hours and then concentrated under reduced pressure. The residue is taken up in ethyl acetate. The solution is basified to pH=9 by addition of a 1.0M aqueous sodium hydroxide solution, washed with water, dried over sodium sulphate then concentrated under reduced pressure, making it possible to obtain 0.129 g of a yellow oil, corresponding to the expected product. Yield: 55% MS: MH+ 186 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With 4-methyl-morpholine; thionyl chloride In methanol; dichloromethane | R.44 Methyl N-tert-butoxycarbonyltranexamate Referential Example 44 Methyl N-tert-butoxycarbonyltranexamate To methanol (20 ml), thionyl chloride (1 ml) was added dropwise under ice cooling, followed by the addition of tranexamic acid (2.04 g). The resulting mixture was heated under reflux for 3 hours. The residue obtained by distilling off the reaction mixture under reduced pressure was pulverized in ether and then collected by filtration, whereby colorless crystals (2.31 g) were obtained. The resulting crystals (2.10 g) were dissolved in dichloromethane (40 ml), followed by the addition of N-methylmorpholine (1.2 ml). To the resulting mixture, a solution of di-tert-butyl dicarbonate (2.51 g) in dichloromethane (dichloromethane: 3 ml) was added under ice cooling. The resulting mixture was stirred at room temperature for 18 hours. After diluted with dichloromethane, the reaction mixture was washed with water and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (hexane:ethyl acetate=10:1~3:1), followed by recrystallization from a mixed solvent of hexane and ethyl acetate, whereby colorless crystals (2.09 g, 65%) was obtained. 1H-NMR (CDCl3) δ: 0.90-1.10(2H,m), 1.40-1.60(12H,m), 1.80-1.90(2H,m), 2.00-2.10(2H,m), 2.24(1H,m), 2.98(2H,m), 3.66(3H,s), 4.58(1H,br). |
65% | With 4-methyl-morpholine; thionyl chloride In methanol; dichloromethane | [Referential Example 44] Methyl N-tert-butoxycarbonyltranexamate [Referential Example 44] Methyl N-tert-butoxycarbonyltranexamate To methanol (20 ml), thionyl chloride (1 ml) was added dropwise under ice cooling, followed by the addition of tranexamic acid (2.04 g). The resulting mixture was heatedunder reflux for 3 hours. The residue obtained by distilling the reaction mixture under reduced pressure was pulverized in ether and then collected by filtration, whereby colorless crystals (2.31 g) were obtained. The resulting crystals (2.10 g) were dissolved in dichloromethane (40 ml), followed by the addition of N-methylmorpholine (1.2 ml). To the resulting mixture, a solution of di-tert-butyl dicarbonate (2.51 g) in dichloromethane (dichloromethane: 3 ml) was added under ice cooling. The resulting mixture was stirred at room temperature for 18 hours. After diluted with dichloromethane, the reaction mixture was washed with water and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (hexane: ethyl acetate = 10:1 ~ 3:1), followed by recrystallization from a mixed solvent of hexane and ethyl acetate, whereby colorless crystals (2.09 g, 65%) was obtained. 1H-NMR (CDCl3) δ: 0.90-1.10(2H,m), 1.40-1.60(12H,m), 1.80-1.90(2H,m), 2.00-2.10(2H,m), 2.24(1H,m), 2.98(2H,m), 3.66(3H,s), 4.58(1H,br). Elementary analysis for C14H25NO4 Calculated: C, 61.97; H, 9.29; N, 5.16. Found: C, 62.15; H, 9.42; N, 5.12. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With hydrogenchloride In 1,4-dioxane; sodium hydroxide | A trans-4- (tert-Butoxycarbonylamino-methyl)-cyclohexanecarboxylic acid: (a) Step A, Scheme 2 trans-4- (tert-Butoxycarbonylamino-methyl)-cyclohexanecarboxylic acid: To a solution of trans-4-(aminomethyl)cyclohexanecarboxylic acid (10 g, 57 mmol) in 1 N NaOH (110 mL) cooled to 0° C. was added a solution of di-tert-butyl dicarbonate (15 g, 69 mmol) in dioxane (50 mL). The reaction mixture was stirred at 0° C. for 12 h. The reaction mixture was neutralized by 1 N HCl solution to pH 3, extracted with ethyl ether (2*300 mL), washed with brine (2*300 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford the titled compound (16 g, 100%); white solid, mp 128-9° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With borane In tetrahydrofuran; methanol | 4 trans-4-(Aminomethyl)cyclohexanemethanol hydrochloride trans-4-(Aminomethyl)cyclohexanemethanol hydrochloride A 1.0 M solution of borane in tetrahydrofuran (250 mL, 260 mmol.) was added slowly dropwise to a suspension of trans-4-(aminomethyl)cyclohexanecarboxylic acid (10.0 g, 64.0 mmol.) in tetrahydrofuran (250 mL). Gas evolution was observed. The reaction mixture was heated at reflux for 14 hours. The resulting solution was cooled to 0° C. and carefully treated dropwise with 1 N methanolic hydrochloric acid (250 mL). Gas evolution was observed. The white suspension obtained was stirred for 1 hour at 23° C. and subsequently concentrated. Methanol was added to the residue and the suspension was concentrated. This procedure was repeated twice to give trans-4-(Aminomethyl)cyclohexanemethanol hydrochloride (10.6 g, 93% yield) as a white solid. 1 H NMR (CD3 OD): 3.38 (d, 2H), 2.71 (d, 2H), 1.88 (d, 4H), 1.48 (m, 2H), 1.01 (m, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.1% | With thionyl chloride | 3.a Preparation of methyl 4-[N-(3',4'-methylenedioxybenzylidene)aminomethyl]cyclohexane-1-carboxylate: (a) After dropping 12.5 g of thionyl chloride into 82 ml of icewater-cooled methanol while stirring well, the cooling bath for methanol was removed, and then after adding 11.0 g of trans-4-aminomethylcyclohexane-1-carboxylic acid to the mixture, the thus formed mixture was heated for 5 hours at 50° to 60° C. Then, the reaction mixture was filtered while warm and the filtrate was concentrated to about 25 ml under a reduced pressure. The crystals educing on adding 140 ml of ether to the concentrated solution were collected by filtration after icewater-cooling and recrystallized from a mixture of methanol and ether to obtain 13.4 g of colourless plate-like crystals of methyl trans-4-aminomethylcyclohexane-1-carboxylate hydrochloride in a yield of 92.1% giving the following elementary analytical data: Elementary analytical data: Found(%) C: 51.70, H: 9.00, N: 6.80. Calcd.(%) as C9 H18 NO2 Cl C: 52.04, H: 8.74, N: 6.74. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | In methanol; water; acetone | 1 Example 1. Example 1. In 75 ml of methanol was dissolved 5 g. of trans-4-cyanocyclohexane-1-carboxylic acid. To this solution were added 5 ml of concentrated ammonia water (about 28 %) and 1 g. of Raney nickel developed by a known method. The mixture was placed in an autoclave and shaken at a room temperature for 4 hours in an atmosphere of hydrogen, the initial pressure of which being 20 kg/cm2. After the completion of the reaction, the catalyst was removed by filtration and the filtrate was concentrated under a reduced pressure. The residue was dissolved in water and the solution was passed through a column of a strongly acidic ion-exchange resin (NH4 type), and concentrated under a reduced pressure. The final residue, upon recrystallization from a mixed solution of water and acetone, gave 4.72 g. (yield, 92 %) of trans-4-aminomethylcyclohexane-1-carboxylic acid in the form of five needles, mp. 380° - 390°C (decomp. uncorrect in air bath) Analysis for C8 H15 O2 N. Calculated (%) C 61.12, H 9.62, N 8.91. Found (%) C 61.20, H 9.65, N 8.63. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | In tert-butyl methyl ether; water; acetone at 20℃; for 12h; | 3 A screw-capped 40 mL glass vial equipped with a magnetic stir bar was charged with trαrø-4-(aminomethyl)cyclohexanecarboxylic (tranexamic) acid (472 mg, 3.0 mmol). The appropriate acyloxyalkyl N-hydroxysuccinimide carbonic acid ester (2.0 mmol) was added either as a solid or was dissolved in a small volume of solvent (for oily materials). A mixture of methyl tert-butyl ether (MTBE), acetone, and water (v/v/v = 4:3:1) (15-20 mL) was added, and the reaction mixture stirred for ca. 12 hours at room temperature. Upon completion of the reaction, the mixture was diluted with ethyl acetate and 1 N aqueous hydrochloric acid {ca. 10 mL) was added. After vigorous mixing followed by phase separation, the aqueous layer was extracted once more with EtOAc, and the combined organic extracts were washed with brine. The solvents were evaporated under reduced pressure, the dry residue was dissolved in a mixture of 60% (v/v) acetonitrile/water, and the solution filtered through a 0.2 μm nylon syringe filter. Final purification was achieved by mass-guided preparative EPO HPLC. After lyophilization of the solvents, the pure compounds were obtained as white powders.; Following the general nucleophilic carbamoylation procedure, tranexamic acid (472 mg, 3.0 mmol) and l-[(2,5- dioxopyrrolidinyl)oxycarbonyloxy]methyl 2-methylpropanoate (518 mg, 2.0 mmol) were reacted in the MTBE/acetone/water mixture (16 niL) to yield the title compound4 (397 mg, 66% yield) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ = 0.82-0.95 (br. m, 2H), 1.08 (d, J= 7.2 Hz, 6H), 1.17-1.39 (br. m, 3H), 1.64-1.73 (br. m, 2H), 1.82-1.91 (br. m, 2H)5 2.10 (tt, J= 11.8, 3.8 Hz, IH), 2.55 (hept, J= 7.2 Hz, IH), 2.78-2.88 (br. m, 2H), 5.61 (s, 2H), 7.55 (t, J= 5.6 Hz, IH), 11.98 (br. s, IH). MS (ESI) m/z 302.09 (M+H)+; 299.99 (M-H)". |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With thionyl chloride at 75℃; for 1h; | |
82% | With thionyl chloride at 0 - 75℃; for 1.16667h; | 1-2.1 1-2. Synthesis of DO3A-tranexamic Acid Ester Derivative 2 (1) Synthesis of allyl-trans-4-(aminomethyl)cyclohexaneethylcarboxylate hydrochloride (1c) First, allyl-trans-4-(aminomethyl)cyclohexaneethylcarboxylate hydrochloride was synthesized using trans-4-(aminomethyl)cyclohexanecarboxylic acid purchased form TCI (Japan). Trans-4-(aminomethyl)cyclohexanecarboxylic acid (3.93 g, 25 mmol) was added to 50 mL of allyl alcohol at 0° C. and stirred. After slowly adding thionyl chloride (3.57 g, 30 mmol), the mixture was stirred for 10 min while keeping cold. Then, after refluxing at 75° C. for 1 h, the reaction mixture was cooled to room temperature. After completely removing the solvent under reduced pressure, the residue was washed three times with hexane (30 mL) to remove the remaining solvent. The mixture with the solvent completely removed was dried in dried under vacuum for 6 h to obtain allyl-trans-4-(aminomethyl)cyclohexaneethylcarboxylate hydrochloride. Yield was 4.79 g (82%). 1H NMR (d6-DMSO, 400 MHz): δ=7.81 (br s, 3H, NH2HCl), 5.71 (m, 1H), 5.16 (m, 2H, OCH2CH═CH2), 4.32 (m, 2H, OCH2CH═CH2), 2.40 (d, J=7.00, 2H, H9), 2.07 (m, 1H, H13), 1.66 (m, 4H, H11/H12), 1.33 (m, 1H, H10), 0.92 (m, 4H, H11/H12). 13C NMR (d6-DMSO, 100 MHz): δ=174.77 (C1), 133.12 (OCH2CH═CH2), 117.78 (OCH2CH═CH2), 64.46 (OCH2CH═CH2), 44.01 (CH2NH2), 42.32 (C2), 35.12 (C4), 29.02 (C3, C5), 28.20 (C2, C6). Anal. Calc. for C11H19NO2.HCl: C, 56.52; H, 8.62; N, 5.99. Found: C, 56.37; H, 8.54; N, 5.76%. FABMS (m/z): Calc. for C11H20NO2, 198.28 ([MH]+). Found: 198.10. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With lithium aluminium hydride In tetrahydrofuran at 0℃; for 3h; Reflux; | |
With lithium aluminium hydride In tetrahydrofuran at 0℃; for 4h; Inert atmosphere; Reflux; | 2.2.2 [Trans-4-(N-benzyloxycarbonylaminomethyl)cyclohexyl]methanol (7) To an ice-bath cooled suspension of lithium aluminum hydride (302 mg, 7.9 mmol) in anhydrous THF (20 mL) was added dropwise a suspension of trans-4-(aminomethyl)cyclohexylcarboxylic acid 5 (500 mg, 3.18 mmol) in anhydrous THF (20 mL). The reaction mixture was stirred at 0 °C for 1 h then it was heated under reflux for 3 h. The mixture was cooled to room temperature and quenched with water. The aqueous phase was extracted by dichloromethane. Addition of a few drops of aqueous solution of Rochelle salt avoids emulsion formation. Combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo to give [trans-4-(aminomethyl)cyclohexyl]methanol 6 as a yellow oil (320 mg, 70% yield) which should be used without delay. To an ice-bath cooled suspension of compound 6 (320 mg, 2.23 mmol) and sodium carbonate (475 mg, 4.48 mmol) in water (20 mL) was added dropwise benzyl chloroformate (540 μL, 3.79 mmol). The reaction mixture was stirred at room temperature overnight then filtered. The precipitate was washed with water then recristallised from cyclohexane to give compound 7 as a white solid (432 mg, 70% yield). Mp = 95-96 °C; 1H NMR (CDCl3) δ: 7.40-7.30 (m, 5H, 5 * H-phenyl), 5.09 (s, 2H, CH2Ph), 4.80 (bs, 1H, NH), 3.45 (d, 2H, J = 6.2 Hz, CH2O), 3.05 (t, 2H, J = 6.3 Hz, CH2N), 1.9-0.9 (m, 11H, 10 * H-cyclohexyl, OH) ppm; 13C NMR (CDCl3) δ: 156.7 (COO), 136.8 (C-phenyl ipso), 128.7 (2 * C-phenyl meta), 128.29 (2 * C-phenyl ortho), 128.26 (C-phenyl para), 68.6 (OCH2), 66.8 (OCH2), 47.4 (NCH2), 40.6 (CH), 38.5 (CH), 30.1 (2 * CH2 cyclohexyl), 29.0 (2 * CH2 cyclohexyl) ppm; MS(ESI): m/z (%) 577 (100) [2M+Na]+, 300 (65) [M+Na]+; HRMS(ESI): m/z calcd for C16H23NO3 + Na: 300.1570; found: 300.1577. | |
With borane-THF In tetrahydrofuran at 20℃; Inert atmosphere; | 149 149: 1-(4-((5-(Dimethylisoxazol-4-yl)-2-methylphenyl)(((1r,4r)-4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dicarbonylisoindolin-5-yl)amino)methyl)cyclohexyl)methyl)amino)phenylcyclopropanecarbonitrile (149) [0456] Tranexamic acid was dissolved in tetrahydrofuran, and the system was purged with nitrogen, to which was added the tetrahydrofuran complex of borane. The mixture was stirred overnight at room temperature. After the reaction was completed, water was carefully and slowly added to quench the reaction. The resultant solution was extracted with ethyl acetate, dried, concentrated, and directly used in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | In tert-butyl methyl ether; water; acetone at 20℃; for 12h; | 3 General Nucleophilic Carbamoylation Procedure for Synthesis of Acyloxyalkyl Carbamates of Tranexamic Acid A screw-capped 40 mL glass vial equipped with a magnetic stir bar was charged with trans-4-(aminomethyl)cyclohexanecarboxylic (tranexamic) acid (about 472 mg, about 3.0 mmol). The appropriate acyloxyalkyl N-hydroxysuccinimide carbonic acid ester (about 2.0 mmol) was added either as a solid or was dissolved in a small volume of solvent (for oily materials). A mixture of methyl tert-butyl ether (MTBE), acetone, and water (v/v/v=4:3:1) (about 15-20 mL) was added, and the reaction mixture stirred for about 12 hours at room temperature. Upon completion of the reaction, the mixture was diluted with ethyl acetate and 1 N aqueous hydrochloric acid (about 10 mL) was added. After vigorous mixing followed by phase separation, the aqueous layer was extracted once more with EtOAc, and the combined organic extracts were washed with brine. The solvents were evaporated under reduced pressure, the dry residue was dissolved in a mixture of 60% (v/v) acetonitrile /water, and the solution filtered through a 0.2 μm nylon syringe filter. Final purification was achieved by mass-guided preparative HPLC. After lyophilization of the solvents, the pure compounds were obtained as white powders.Example 3 trans-4-[1-(2-Methylpropanoyloxy)ethoxycarbonyl]-aminomethyl}-Cyclohexanecarboxylic Acid (3) Following the general nucleophilic carbamoylation procedure, tranexamic acid and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]ethyl 2-methylpropanoate 2 were reacted to provide the title compound 3 (333 mg, 53% yield) as a colorless powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.82-0.94 (br. m, 2H), 1.058 (d, J=6.4 Hz, 3H), 1.062 (d, J=6.8 Hz, 3H), 1.17-1.36 (br. m, 3H), 1.38 (d, J=5.6 Hz, 3H), 1.65-1.73 (br. m, 2H), 1.83-1.91 (br. m, 2H), 2.10 (tt, J=12.0, 3.6 Hz, 1H), 2.49 (hept., J=6.8 Hz, 1H), 2.77-2.85 (br. m, 2H), 6.62 (q, J=5.2 Hz, 1H), 7.45 (t, J=6.0 Hz, 1H), 11.97 (br. s, 1H). MS (ESI) m/z 338.08 (M+Na)+; 314.01 (M-H)-. |
Yield | Reaction Conditions | Operation in experiment |
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96% | With thionyl chloride; at 0 - 70℃; for 1.16667h; | First, trans-4-(aminomethyl)cyclohexaneethylcarboxylate hydrochloride was synthesized using trans-4-(aminomethyl)cyclohexanecarboxylic acid purchased form TCI (Japan). Trans-4-(aminomethyl)cyclohexanecarboxylic acid (1.57 g, 10 mmol) was added to 40 mL of ethanol at 02C and stirred. After slowly adding thionyl chloride (0.9 mL, 12 mmol), the mixture was stirred for 10 min while keeping cold. Then, after refluxing at 702C for 1 h, the reaction mixture was cooled to room temperature. After completely removing the solvent under reduced pressure, the residue was washed twice with hexane (25 mL) to remove the remaining solvent. The mixture with the solvent completely removed was dried in dried under vacuum for 6 h to obtain trans-4-(aminomethyl)cyclohexaneethylcarboxylate hydrochloride. Yield was 2.13 g (96%). 1H NMR (d6-DMSO): delta=4.03 (q, J=7.08, 2H, OCH2CH3), 2.61 (m, 1H, H13), 2.21 (m, 1H, H10), 1.85 (m, 2H, H9), 1.27 (m, 4H, H12H11), 1.16 (t, J=7.06, 3H, OCH2CH3), 0.96 (m, 4H, H12H11). Anal. Calc. for C10H20ClNO2: C, 54.17; H, 9.09; N, 6.32. Found: C, 53.78; H, 8.91; N, 6.34. |
Yield | Reaction Conditions | Operation in experiment |
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87% | Stage #1: trans-4-aminomethyl-cyclohexyl-carboxylic acid With sodium hydroxide In tetrahydrofuran for 0.5h; Inert atmosphere; Stage #2: maleic anhydride In tetrahydrofuran for 12h; Inert atmosphere; Reflux; | |
In 1,4-dioxane at 20℃; for 48h; | 1.A A solution of trans-4-aminomethylcyclohexane carboxylic acid (7.00 g, 44.5 mmol) in 1,4-dioxane (70 mL) was treated with maleic anhydride (4.89 g, 49.9 mmol) and stirred at ambient temperature for 48 h. The reaction was evaporated in vacuo to a white solid that can be stored or caffied on to the next step without further purification. 1H NMR (300 MHz, DMSO-d6) 5 9.11 (m, 1H), 6.44 (d, 1H, J= 13Hz), 6.24 (d, 1H, J= 13Hz), 3.05 (t, 2H, J= 6Hz), 2.13 (tt, 1H, J= 12Hz, 4Hz), 1.90 (m, 2H), 1.75 (m, 2H), 1.44 (m, 1H), 1.28 (m, 2H), 0.96 (m, 2H). | |
Stage #1: maleic anhydride; trans-4-aminomethyl-cyclohexyl-carboxylic acid In N,N-dimethyl-formamide at 15 - 25℃; Stage #2: With 2,4,6-trimethyl-pyridine In N,N-dimethyl-formamide at -5 - 5℃; for 0.333333h; | 1.1 This example is intended to illustrate the preparation of a crude SMCC. Step 1: 31.44 g (200 mmol) of trans-tranexamic acid, 19.60 g (200 mmol) of maleic anhydride and 1 L of DMF were placed in a three-necked flask equipped with a thermometer, and the reaction was stirred at 15 ° C to 25 ° C for 6-8 h. Cooling to -5 to 0 ° C, dropwise addition of 2,4,6-trimethylpyridine 50.09 g (420 mmol);During the dropwise addition process, the temperature is maintained between -5 ° C and 5 ° C, the addition is completed, and the mixture is stirred at this temperature for 20 min, and is ready for use; |
Yield | Reaction Conditions | Operation in experiment |
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General procedure: Method: SPPS_P; SPPS_P was performed on a Prelude Solid Phase Peptide Synthesizer from Protein Technologies (Tucson, Ariz. 85714 U.S.A.) at 250-mumol scale using six fold excess of Fmoc-amino acids (300 mM in NMP with 300 mM HOAt or Oxyma Pure) relative to resin loading, e.g. low load Fmoc-Gly-Wang (0.35 mmol/g). Fmoc-deprotection was performed using 20% piperidine in NMP. Coupling was performed using 3:3:3:4 amino acid/(HOAt or Oxyma Pure)/DIC/collidine in NMP. NMP and DCM top washes (7 ml, 0.5 min, 2×2 each) were performed between deprotection and coupling steps. Coupling times were generally 60 minutes. Some amino acids including, but not limited to Fmoc-Arg(Pbf)-OH, Fmoc-Aib-OH or Boc-His(Trt)-OH were ?double coupled?, meaning that after the first coupling (e.g. 60 min), the resin is drained and more reagents are added (amino acid, (HOAt or Oxyma Pure), DIC, and collidine), and the mixture allowed to react again (e.g. 60 min).; Method: SC_P; The N-epsilon-lysine protection group was removed as described above and the chemical modification of the lysine was performed by one or more automated steps on the Prelude peptide synthesiser using suitably protected building blocks as described above. Double couplings were performed as described in SPPS_P with 3 hours per coupling.; Method: CP_M1; After synthesis the resin was washed with DCM, and the peptide was cleaved from the resin by a 2-3 hour treatment with TFA/TIS/water (95/2.5/2.5 or 92.5/5/2.5) followed by precipitation with diethylether. The peptide was dissolved in a suitable solvent (such as, e.g., 30% acetic acid) and purified by standard RP-HPLC on a C18, 5 mum column, using acetonitrile/water/TFA. The fractions were analysed by a combination of UPLC, MALDI and LCMS methods, and the appropriate fractions were pooled and lyophilised.; If desired the peptide counter ion can be exchanged to sodium using methods known in the art. As an example approx. 2 g peptide was dissolved in 250 ml acetonitrile/water (50/50) and loaded onto a Waters X-Bridge C8, 5 muM, 50×250 mm column on a preparative RP-HPLC system. Following loading, the column was washed with water for 8 min at a flow rate of 60 ml/min and 0.01 N NaOH pH 11 at a flow rate of 60 ml/min for 2×8 min. The sodium salt of the peptide was eluted using an isocratic flow of water at 60 ml/min for 10 min followed by a linear gradient of 5% to 85% acetonitrile over 30 min. |
Yield | Reaction Conditions | Operation in experiment |
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General procedure: Method: SPPS_P; SPPS_P was performed on a Prelude Solid Phase Peptide Synthesizer from Protein Technologies (Tucson, Ariz. 85714 U.S.A.) at 250-mumol scale using six fold excess of Fmoc-amino acids (300 mM in NMP with 300 mM HOAt or Oxyma Pure) relative to resin loading, e.g. low load Fmoc-Gly-Wang (0.35 mmol/g). Fmoc-deprotection was performed using 20% piperidine in NMP. Coupling was performed using 3:3:3:4 amino acid/(HOAt or Oxyma Pure)/DIC/collidine in NMP. NMP and DCM top washes (7 ml, 0.5 min, 2×2 each) were performed between deprotection and coupling steps. Coupling times were generally 60 minutes. Some amino acids including, but not limited to Fmoc-Arg(Pbf)-OH, Fmoc-Aib-OH or Boc-His(Trt)-OH were ?double coupled?, meaning that after the first coupling (e.g. 60 min), the resin is drained and more reagents are added (amino acid, (HOAt or Oxyma Pure), DIC, and collidine), and the mixture allowed to react again (e.g. 60 min).; Method: SC_P; The N-epsilon-lysine protection group was removed as described above and the chemical modification of the lysine was performed by one or more automated steps on the Prelude peptide synthesiser using suitably protected building blocks as described above. Double couplings were performed as described in SPPS_P with 3 hours per coupling.; Method: CP_M2; After synthesis the resin was washed with DCM, and the peptide was cleaved from the resin by a 2-3 hour treatment with TFA/TIS/water (95/2.5/2.5 or 92.5/5/2.5) followed by precipitation with diethylether. The peptide was dissolved in a suitable solvent (such as, e.g., 30% acetic acid) and purified by standard RP-HPLC on a Kinetex C18, 5 mum column, eluting with a binary mixture of 0.09M diammoniumhydrogenphosphate in water/acetonitrile (90:10, pH 3.0) and acetonitrile/2-propanol/water (60:20:20). The peptide was then further purified by standard RP-HPLC on a C18, 5 mum column, using acetonitrile/water/TFA. The fractions were analysed by a combination of UPLC, MALDI and LCMS methods, and the appropriate fractions were pooled and lyophilised.; If desired the peptide counter ion can be exchanged to sodium using the methods known in the art. As an example approx. 2 g peptide was dissolved in 250 ml acetonitrile/water (50/50) and loaded onto a Waters X-Bridge C8, 5 muM, 50×250 mm column on a preparative RP-HPLC system. Following loading, the column was washed with water for 8 min at a flow rate of 60 ml/min and 0.01 N NaOH pH 11 at a flow rate of 60 ml/min for 2×8 min. The sodium salt of the peptide was eluted using an isocratic flow of water at 60 ml/min for 10 min followed by a linear gradient of 5% to 85% acetonitrile over 30 min. |
Yield | Reaction Conditions | Operation in experiment |
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94% | With sodium carbonate In water at 20℃; | Synthesis of 4-([(2,5-dichlorophenyl)sulfonyl]amino}methyl)cyclohexanecarboxylic acid (VII) Tranxemic acid (2 g, 12.7 mmol) was dissolved inwater (50 mL).2,5-Dichlorobenzenesulfonyl chloride (3.11 g, 12.7 mmol) wasadded to it under stirring at room temperature keeping the pH of amixture about 8e9 using 1 M sodium carbonate solution until thecompletion of reaction. The dissolution of suspended sulfonylchloride to clear solution indicates the progress of reaction. On completion the pH of solutionwas decreased to 2e3 by adding 1 MHCl. The precipitates produced were filtered, washed by distilledwater and recrystallized from methanol (Yield: 94%) mp 180 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With sodium carbonate In water at 20℃; | Synthesis of 4-[(4-acetylamino-benzenesulfonylamino)-methyl]-cyclohexane carboxylic acid (XI) Tranxemic acid (2 g, 12.7 mmol) was dissolved inwater (50 mL).4-Acetylamino benzenesulfonyl chloride (2.96 g, 12.7 mmol) wasadded to it under stirring at room temperature keeping the pH ofmixture about 8e9 using 1 M sodium carbonate solution until thecompletion of reaction. The dissolution of suspended sulfonylchloride to clear solution indicates the progress of reaction. Oncompletion the pH of solutionwas decreased to 2e3 by adding 1 MHCl. The precipitates produced were filtered, washed by distilledwater and recrystallized from methanol (Yield: 87%) mp208e210 C. |
Yield | Reaction Conditions | Operation in experiment |
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Multi-step reaction with 2 steps 1.1: sodium hydrogencarbonate / water / 18 h / 20 °C / Industrial scale 2.1: chloroformic acid ethyl ester; triethylamine / tetrahydrofuran / 3 h / -10 - 20 °C 2.2: 18 h / -10 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: sodium hydrogencarbonate / water / 18 h / 20 °C / Industrial scale 2.1: chloroformic acid ethyl ester; triethylamine / tetrahydrofuran / 3 h / -10 - 20 °C 2.2: 18 h / -10 - 20 °C 3.1: trifluoroacetic anhydride; triethylamine / dichloromethane; water / 3 h / -10 °C |
Yield | Reaction Conditions | Operation in experiment |
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85.11% | With barium hydroxide octahydrate; hydrogen In ethanol; water at 250℃; for 7.5h; | 5 Preparation of trans-4-aminomethylcyclohexylformic acid To a 1 L hydrogenation kettle, methyl 4-acetamidomethylcyclohexylcarboxylate (28. 00 g, 0.13 mol), 100 mL of ethanol, 200 mL of water,Barium hydroxide octahydrate (95. 82g, 0.30mol), shut down the reaction dad, pass the IMPa hydrogen to replace the air 3 times (or replace with nitrogen)And then pass 1MPa of hydrogen leak detection, if not leak, the pressure transferred to 4MPa, stir to raise the temperature to 250 ° C reaction 7. 5 hours,Stop the reaction, open the kettle, the reaction solution poured out, placed in a reaction flask, add water 200mL, heated to 70 ° C,Neutralized with carbon dioxide to pH 3. 3, barium carbonate was removed by filtration, the filtrate was adjusted to pH 3 with sulfuric acid, allowed to stand for 3 hours, filtered, washed with water,Add 5 g of activated charcoal decolorization, filtration, the filtrate sprinkled to 50mL, then add ethanol 50mL crystallization, cooling to 10 ° C, filtration, crystallization with ethanol washing, drying, white solid trans-4-aminomethylcyclohexylformic acid, Mass of 17.37g, mp: 384-388 ° (decomposition), molar yield of 85.11% By liquid phase detection, trans-body content of 99.6910% |
Yield | Reaction Conditions | Operation in experiment |
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With sodium hydroxide In tetrahydrofuran at 10 - 15℃; for 2.5h; | Preparation of Cds 1-7 General procedure: Diacetyl caffeic acid (20 mmol) and 15 mL SOCl2 were added into a 50 mL round-bottom flask and reacted in a 60 °C oil bath for 5 h with stirring. Subsequently, the solvents were removed by a rotary evaporator, and diacetyl caffeic acyl chloride was obtained. Glycine, β-alanine, γ-propalanine, 6-amidocaproic acid, taurine, tranexamic acid, or p-aminomethylbenzoic acid (40 mmol)was dissolved in 20 mL of a 2 M NaOH solution in a 50 mL round-bottom flask. At 10-15 °C in awater bath with stirring, diacetyl caffeic acyl chloride THF solution (adding 5 mL THF to dissolve obtained diacetyl caffeic acyl chloride) was slowly added to the flask. After a 2.5 h reaction, the pH of the mixture was adjusted to 4-5 by adding diluted HCl. The mixture was left standing at room temperature for 24 h, followed by vacuum filtration, washing, and 60 °C oven drying to obtain Cds.1-7 (The Synthetic route of Cds. 1-7 was shown in Scheme 1). |
Yield | Reaction Conditions | Operation in experiment |
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With sodium hydroxide In tetrahydrofuran at 10 - 15℃; for 2.5h; | Preparation of Cds 1-7 General procedure: Diacetyl caffeic acid (20 mmol) and 15 mL SOCl2 were added into a 50 mL round-bottom flask and reacted in a 60 °C oil bath for 5 h with stirring. Subsequently, the solvents were removed by a rotary evaporator, and diacetyl caffeic acyl chloride was obtained. Glycine, β-alanine, γ-propalanine, 6-amidocaproic acid, taurine, tranexamic acid, or p-aminomethylbenzoic acid (40 mmol)was dissolved in 20 mL of a 2 M NaOH solution in a 50 mL round-bottom flask. At 10-15 °C in awater bath with stirring, diacetyl caffeic acyl chloride THF solution (adding 5 mL THF to dissolve obtained diacetyl caffeic acyl chloride) was slowly added to the flask. After a 2.5 h reaction, the pH of the mixture was adjusted to 4-5 by adding diluted HCl. The mixture was left standing at room temperature for 24 h, followed by vacuum filtration, washing, and 60 °C oven drying to obtain Cds.1-7 (The Synthetic route of Cds. 1-7 was shown in Scheme 1). |
Yield | Reaction Conditions | Operation in experiment |
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68% | With N-ethyl-N,N-diisopropylamine; In water; acetonitrile; at 22℃; for 14h;Inert atmosphere; | Purge a 100-mL, three-neck cylindrical flask, equipped with a mechanical stirrer, a J-Kem temperature controller, and a nitrogen inlet, with nitrogen Charge the flask with <strong>[71875-81-5]SMCC</strong> and AMCA, followed by acetonitrile and water with stirring Add DIPEA slowly and allow the mixture stir at ambient temperature (22 ± 2 C) overnight (14 h) Analyze the mixture by HPLC for disappearance of <strong>[71875-81-5]SMCC</strong> and formation of BCH Dilute the reaction mixture with MTBE (61 mL) and stir for 5 minutes Filter the solid and wash with MTBE (2 chi 20 mL) Dissolve the resulting white solid in 20% MeOH/DCM (407 mL) Wash the organic solution with 15% brine solution (2 x 40.7 mL) Separate the organic solution and extract the combined aqueous solution with DCM (40.7 mL) Dry the combined organic solution over Na2S04 (270 g) for 10 min Filter the solution and wash the filter with DCM (122 mL) Concentrate the solution to a white solid at 20-25 C Slurry the solid in acetone (61 mL) at ambient temperature for 30 min Filter the solid and wash with acetone (20 mL) and 1 : 1 MTBE/acetone (2 chi 20 mL) Dry the solid under high vacuum at 20-30 C for a minimum of 24 h This process gave BCH as a white solid (3.106 g, 68% yield) with a purity of > 99.9% by HPLC and NMR. Analytical data including, 1H- MR & 13C- MR, and Mass spec were consistent with the structure of the molecule. |
Yield | Reaction Conditions | Operation in experiment |
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61% | With ammonium hydroxide; tetrachlorosilane In methanol for 2h; Reflux; | [Si(TXA)2(Cl)4] complex, (4) mixture of 10mmol of SiCl4 and 20mmol of tranexamic acid were mixed in methanol (50mL), neutralized the mixture at pH=7-8 using NH4OH, then refluxed for 2h, giving a clear solution which was concentrated and left four days yielding a white precipitate, yield 61%. Dec. temp., >300°C. Anal. (Calc.) Found, %: C, (39.68) 39.45; H; (6.24) 6.18; N, (5.78) 5.61; Cl, (29.28) 29.05. ΛM 28Ω-1cm2.mol-1. |
Yield | Reaction Conditions | Operation in experiment |
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65% | With ammonium hydroxide In methanol for 2h; Reflux; | [W(TXA)2(Cl)2]Cl2 complex, (2) mixture of 10mmol of WCl6 and 20mmol of tranexamic acid were mixed in methanol (50mL), neutralized the mixture at pH=7-8 using NH4OH, then refluxed for 2h, giving a blue clear solution which was concentrated and left four days yielding a blue precipitate, yield 65%. Dec. temp., >300°C. Anal. (Calc.) Found, %: C, (30.12) 30.06; H; (4.42) 4.31; N, (4.39) 4.27; Cl, (22.23) 22.05. ΛM 86Ω-1cm2.mol-1. |
Yield | Reaction Conditions | Operation in experiment |
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79% | Stage #1: [2-methyl-4-oxo-3-(4-chlorophenyl)-4H-chromen-7-yl]oxy}acetic acid With 1-hydroxy-pyrrolidine-2,5-dione; diisopropyl-carbodiimide In 1,4-dioxane at 20℃; for 2h; Stage #2: trans-4-aminomethyl-cyclohexyl-carboxylic acid With sodium hydrogencarbonate In 1,4-dioxane; water | General Method for Synthesizing N-([2-Methyl-4-oxo-3-(4-chlorophenyl)-4H-chromen-7-yl]oxy}acetyl)aminoAcids 6-19. General procedure: A solution of 5 (1.03 g, 3 mmol) and SuOH (0.38 g, 3.3 mmol) in anhydrous dioxane (20 mL) was stirredvigorously, treated with DIC (0.52 mL, 3.3 mol), and stirred for 2 h (course of reaction monitored by TLC). The resultingactivated ester was treated with a solution of the appropriate amino acid (3.3 mmol) and NaHCO3 (0.28 g, 3.3 mmol) in H2O(20 mL), and stirred vigorously for 2-4 h (course of reaction monitored by TLC). When the reaction was finished,the precipitate of diisopropylurea was filtered off. The filtrate was treated with H2O (200 mL) and acidified to pH 5-6.The resulting precipitate was filtered off and crystallized from aqueous i-PrOH. |
Yield | Reaction Conditions | Operation in experiment |
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93% | With N-ethyl-N,N-diisopropylamine In methanol at 25℃; for 5h; | General procedure a for the synthesis of hydrazones and 1-substituted 1,2,3-triazoles General procedure: To a dried Schlenk flask, amines (0.4 mmol, 2.0 eq), difluoroacetaldehyde N-tosylhydrazone (0.2 mmol, 49.6 mg, 1.0 eq), base (3 eq or 6.0 eq), and MeOH (4 mL) were added. Then the resultant solution was stirred at room temperature for 5 h, then diluted with 5 mL of CH2Cl2 and filtered through a plug of celite, followed by washing with 20 mL of CH2Cl2. The combined residue was concentrated under reduced pressure, and then the resulting crude product was purified by silica gel column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
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79% | Stage #1: trans-4-aminomethyl-cyclohexyl-carboxylic acid With potassium hydroxide In ethanol at 20℃; for 0.166667h; Inert atmosphere; Stage #2: 3,4-dibromo-5-methoxy-2(5H)-furanone In ethanol; dichloromethane at 20℃; for 24h; Inert atmosphere; | Synthesis offuranonyl amino acid derivatives 5a-7k General procedure: Referring to the reported method (Luo etal. 2019), the mixtureof 0.600mmol amino acid (4), 0.672mmol potassiumhydroxide and 5mL ethanol in a two-neck flask was stirredat room temperature for 10min. Then, under the atmosphereof nitrogen, the mixture of 0.300mmol furanone (3) and5mL dichloromethane (DCM) in a constant pressure funnel was slowly dripped into the two-neck flask for about 30min.The reaction was carried out at room temperature for 24h.After the completion of reaction, the solvent in the mixturewas evaporated. The residue was dissolved in distilled water,and the 15% hydrochloric acid was added to adjust the pH to3-4, a large amount of product was precipitated out. Onceextracted with ethyl acetate (3 × 15mL), the organic layerwas dried over anhydrous sodium sulfate. After filtration andevaporation of the solvent under reduced pressure, the crudeproduct was purified by column chromatography on silicagel to afford desired compound. |
79% | Stage #1: trans-4-aminomethyl-cyclohexyl-carboxylic acid With potassium hydroxide In ethanol at 20℃; for 0.166667h; Inert atmosphere; Stage #2: 3,4-dibromo-5-methoxy-2(5H)-furanone In ethanol; dichloromethane at 20℃; for 24h; Inert atmosphere; | Synthesis offuranonyl amino acid derivatives 5a-7k General procedure: Referring to the reported method (Luo etal. 2019), the mixtureof 0.600mmol amino acid (4), 0.672mmol potassiumhydroxide and 5mL ethanol in a two-neck flask was stirredat room temperature for 10min. Then, under the atmosphereof nitrogen, the mixture of 0.300mmol furanone (3) and5mL dichloromethane (DCM) in a constant pressure funnel was slowly dripped into the two-neck flask for about 30min.The reaction was carried out at room temperature for 24h.After the completion of reaction, the solvent in the mixturewas evaporated. The residue was dissolved in distilled water,and the 15% hydrochloric acid was added to adjust the pH to3-4, a large amount of product was precipitated out. Onceextracted with ethyl acetate (3 × 15mL), the organic layerwas dried over anhydrous sodium sulfate. After filtration andevaporation of the solvent under reduced pressure, the crudeproduct was purified by column chromatography on silicagel to afford desired compound. |
Yield | Reaction Conditions | Operation in experiment |
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52% | Stage #1: trans-4-aminomethyl-cyclohexyl-carboxylic acid With potassium hydroxide In ethanol at 20℃; for 0.166667h; Inert atmosphere; Stage #2: C6H5Br3O3 In ethanol; dichloromethane at 20℃; for 24h; Inert atmosphere; | Synthesis offuranonyl amino acid derivatives 5a-7k General procedure: Referring to the reported method (Luo etal. 2019), the mixtureof 0.600mmol amino acid (4), 0.672mmol potassiumhydroxide and 5mL ethanol in a two-neck flask was stirredat room temperature for 10min. Then, under the atmosphereof nitrogen, the mixture of 0.300mmol furanone (3) and5mL dichloromethane (DCM) in a constant pressure funnel was slowly dripped into the two-neck flask for about 30min.The reaction was carried out at room temperature for 24h.After the completion of reaction, the solvent in the mixturewas evaporated. The residue was dissolved in distilled water,and the 15% hydrochloric acid was added to adjust the pH to3-4, a large amount of product was precipitated out. Onceextracted with ethyl acetate (3 × 15mL), the organic layerwas dried over anhydrous sodium sulfate. After filtration andevaporation of the solvent under reduced pressure, the crudeproduct was purified by column chromatography on silicagel to afford desired compound. |
52% | Stage #1: trans-4-aminomethyl-cyclohexyl-carboxylic acid With potassium hydroxide In ethanol at 20℃; for 0.166667h; Inert atmosphere; Stage #2: C6H5Br3O3 In ethanol; dichloromethane at 20℃; for 24h; Inert atmosphere; | Synthesis offuranonyl amino acid derivatives 5a-7k General procedure: Referring to the reported method (Luo etal. 2019), the mixtureof 0.600mmol amino acid (4), 0.672mmol potassiumhydroxide and 5mL ethanol in a two-neck flask was stirredat room temperature for 10min. Then, under the atmosphereof nitrogen, the mixture of 0.300mmol furanone (3) and5mL dichloromethane (DCM) in a constant pressure funnel was slowly dripped into the two-neck flask for about 30min.The reaction was carried out at room temperature for 24h.After the completion of reaction, the solvent in the mixturewas evaporated. The residue was dissolved in distilled water,and the 15% hydrochloric acid was added to adjust the pH to3-4, a large amount of product was precipitated out. Onceextracted with ethyl acetate (3 × 15mL), the organic layerwas dried over anhydrous sodium sulfate. After filtration andevaporation of the solvent under reduced pressure, the crudeproduct was purified by column chromatography on silicagel to afford desired compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | Stage #1: trans-4-aminomethyl-cyclohexyl-carboxylic acid With potassium hydroxide In ethanol at 20℃; for 0.166667h; Inert atmosphere; Stage #2: (S)-3,4-dibromo-5-(((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl)oxy)furan-2(5H)-one In ethanol; dichloromethane at 20℃; for 24h; Inert atmosphere; | Synthesis offuranonyl amino acid derivatives 5a-7k General procedure: Referring to the reported method (Luo etal. 2019), the mixtureof 0.600mmol amino acid (4), 0.672mmol potassiumhydroxide and 5mL ethanol in a two-neck flask was stirredat room temperature for 10min. Then, under the atmosphereof nitrogen, the mixture of 0.300mmol furanone (3) and5mL dichloromethane (DCM) in a constant pressure funnel was slowly dripped into the two-neck flask for about 30min.The reaction was carried out at room temperature for 24h.After the completion of reaction, the solvent in the mixturewas evaporated. The residue was dissolved in distilled water,and the 15% hydrochloric acid was added to adjust the pH to3-4, a large amount of product was precipitated out. Onceextracted with ethyl acetate (3 × 15mL), the organic layerwas dried over anhydrous sodium sulfate. After filtration andevaporation of the solvent under reduced pressure, the crudeproduct was purified by column chromatography on silicagel to afford desired compound. |
83% | Stage #1: trans-4-aminomethyl-cyclohexyl-carboxylic acid With potassium hydroxide In ethanol at 20℃; for 0.166667h; Inert atmosphere; Stage #2: (S)-3,4-dibromo-5-(((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl)oxy)furan-2(5H)-one In ethanol; dichloromethane at 20℃; for 24h; Inert atmosphere; | Synthesis offuranonyl amino acid derivatives 5a-7k General procedure: Referring to the reported method (Luo etal. 2019), the mixtureof 0.600mmol amino acid (4), 0.672mmol potassiumhydroxide and 5mL ethanol in a two-neck flask was stirredat room temperature for 10min. Then, under the atmosphereof nitrogen, the mixture of 0.300mmol furanone (3) and5mL dichloromethane (DCM) in a constant pressure funnel was slowly dripped into the two-neck flask for about 30min.The reaction was carried out at room temperature for 24h.After the completion of reaction, the solvent in the mixturewas evaporated. The residue was dissolved in distilled water,and the 15% hydrochloric acid was added to adjust the pH to3-4, a large amount of product was precipitated out. Onceextracted with ethyl acetate (3 × 15mL), the organic layerwas dried over anhydrous sodium sulfate. After filtration andevaporation of the solvent under reduced pressure, the crudeproduct was purified by column chromatography on silicagel to afford desired compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | Stage #1: trans-4-aminomethyl-cyclohexyl-carboxylic acid With potassium hydroxide In ethanol at 20℃; for 0.166667h; Inert atmosphere; Stage #2: 5-bornyloxy-3,4-dibromo-2(5H)furanone In ethanol; dichloromethane at 20℃; for 24h; Inert atmosphere; | Synthesis offuranonyl amino acid derivatives 5a-7k General procedure: Referring to the reported method (Luo etal. 2019), the mixtureof 0.600mmol amino acid (4), 0.672mmol potassiumhydroxide and 5mL ethanol in a two-neck flask was stirredat room temperature for 10min. Then, under the atmosphereof nitrogen, the mixture of 0.300mmol furanone (3) and5mL dichloromethane (DCM) in a constant pressure funnel was slowly dripped into the two-neck flask for about 30min.The reaction was carried out at room temperature for 24h.After the completion of reaction, the solvent in the mixturewas evaporated. The residue was dissolved in distilled water,and the 15% hydrochloric acid was added to adjust the pH to3-4, a large amount of product was precipitated out. Onceextracted with ethyl acetate (3 × 15mL), the organic layerwas dried over anhydrous sodium sulfate. After filtration andevaporation of the solvent under reduced pressure, the crudeproduct was purified by column chromatography on silicagel to afford desired compound. |
89% | Stage #1: trans-4-aminomethyl-cyclohexyl-carboxylic acid With potassium hydroxide In ethanol at 20℃; for 0.166667h; Inert atmosphere; Stage #2: 5-bornyloxy-3,4-dibromo-2(5H)furanone In ethanol; dichloromethane at 20℃; for 24h; Inert atmosphere; | Synthesis offuranonyl amino acid derivatives 5a-7k General procedure: Referring to the reported method (Luo etal. 2019), the mixtureof 0.600mmol amino acid (4), 0.672mmol potassiumhydroxide and 5mL ethanol in a two-neck flask was stirredat room temperature for 10min. Then, under the atmosphereof nitrogen, the mixture of 0.300mmol furanone (3) and5mL dichloromethane (DCM) in a constant pressure funnel was slowly dripped into the two-neck flask for about 30min.The reaction was carried out at room temperature for 24h.After the completion of reaction, the solvent in the mixturewas evaporated. The residue was dissolved in distilled water,and the 15% hydrochloric acid was added to adjust the pH to3-4, a large amount of product was precipitated out. Onceextracted with ethyl acetate (3 × 15mL), the organic layerwas dried over anhydrous sodium sulfate. After filtration andevaporation of the solvent under reduced pressure, the crudeproduct was purified by column chromatography on silicagel to afford desired compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Stage #1: trans-4-aminomethyl-cyclohexyl-carboxylic acid With potassium hydroxide In ethanol at 20℃; for 0.166667h; Inert atmosphere; Stage #2: C14H20Cl2O3 In ethanol; dichloromethane at 20℃; for 24h; Inert atmosphere; | Synthesis offuranonyl amino acid derivatives 5a-7k General procedure: Referring to the reported method (Luo etal. 2019), the mixtureof 0.600mmol amino acid (4), 0.672mmol potassiumhydroxide and 5mL ethanol in a two-neck flask was stirredat room temperature for 10min. Then, under the atmosphereof nitrogen, the mixture of 0.300mmol furanone (3) and5mL dichloromethane (DCM) in a constant pressure funnel was slowly dripped into the two-neck flask for about 30min.The reaction was carried out at room temperature for 24h.After the completion of reaction, the solvent in the mixturewas evaporated. The residue was dissolved in distilled water,and the 15% hydrochloric acid was added to adjust the pH to3-4, a large amount of product was precipitated out. Onceextracted with ethyl acetate (3 × 15mL), the organic layerwas dried over anhydrous sodium sulfate. After filtration andevaporation of the solvent under reduced pressure, the crudeproduct was purified by column chromatography on silicagel to afford desired compound. |
82% | Stage #1: trans-4-aminomethyl-cyclohexyl-carboxylic acid With potassium hydroxide In ethanol at 20℃; for 0.166667h; Inert atmosphere; Stage #2: C14H20Cl2O3 In ethanol; dichloromethane at 20℃; for 24h; Inert atmosphere; | Synthesis offuranonyl amino acid derivatives 5a-7k General procedure: Referring to the reported method (Luo etal. 2019), the mixtureof 0.600mmol amino acid (4), 0.672mmol potassiumhydroxide and 5mL ethanol in a two-neck flask was stirredat room temperature for 10min. Then, under the atmosphereof nitrogen, the mixture of 0.300mmol furanone (3) and5mL dichloromethane (DCM) in a constant pressure funnel was slowly dripped into the two-neck flask for about 30min.The reaction was carried out at room temperature for 24h.After the completion of reaction, the solvent in the mixturewas evaporated. The residue was dissolved in distilled water,and the 15% hydrochloric acid was added to adjust the pH to3-4, a large amount of product was precipitated out. Onceextracted with ethyl acetate (3 × 15mL), the organic layerwas dried over anhydrous sodium sulfate. After filtration andevaporation of the solvent under reduced pressure, the crudeproduct was purified by column chromatography on silicagel to afford desired compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | Stage #1: trans-4-aminomethyl-cyclohexyl-carboxylic acid With potassium hydroxide In ethanol at 20℃; for 0.166667h; Inert atmosphere; Stage #2: C14H18Cl2O3 In ethanol; dichloromethane at 20℃; for 24h; Inert atmosphere; | Synthesis offuranonyl amino acid derivatives 5a-7k General procedure: Referring to the reported method (Luo etal. 2019), the mixtureof 0.600mmol amino acid (4), 0.672mmol potassiumhydroxide and 5mL ethanol in a two-neck flask was stirredat room temperature for 10min. Then, under the atmosphereof nitrogen, the mixture of 0.300mmol furanone (3) and5mL dichloromethane (DCM) in a constant pressure funnel was slowly dripped into the two-neck flask for about 30min.The reaction was carried out at room temperature for 24h.After the completion of reaction, the solvent in the mixturewas evaporated. The residue was dissolved in distilled water,and the 15% hydrochloric acid was added to adjust the pH to3-4, a large amount of product was precipitated out. Onceextracted with ethyl acetate (3 × 15mL), the organic layerwas dried over anhydrous sodium sulfate. After filtration andevaporation of the solvent under reduced pressure, the crudeproduct was purified by column chromatography on silicagel to afford desired compound. |
46% | Stage #1: trans-4-aminomethyl-cyclohexyl-carboxylic acid With potassium hydroxide In ethanol at 20℃; for 0.166667h; Inert atmosphere; Stage #2: C14H18Cl2O3 In ethanol; dichloromethane at 20℃; for 24h; Inert atmosphere; | Synthesis offuranonyl amino acid derivatives 5a-7k General procedure: Referring to the reported method (Luo etal. 2019), the mixtureof 0.600mmol amino acid (4), 0.672mmol potassiumhydroxide and 5mL ethanol in a two-neck flask was stirredat room temperature for 10min. Then, under the atmosphereof nitrogen, the mixture of 0.300mmol furanone (3) and5mL dichloromethane (DCM) in a constant pressure funnel was slowly dripped into the two-neck flask for about 30min.The reaction was carried out at room temperature for 24h.After the completion of reaction, the solvent in the mixturewas evaporated. The residue was dissolved in distilled water,and the 15% hydrochloric acid was added to adjust the pH to3-4, a large amount of product was precipitated out. Onceextracted with ethyl acetate (3 × 15mL), the organic layerwas dried over anhydrous sodium sulfate. After filtration andevaporation of the solvent under reduced pressure, the crudeproduct was purified by column chromatography on silicagel to afford desired compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | Stage #1: trans-4-aminomethyl-cyclohexyl-carboxylic acid With potassium hydroxide In ethanol at 20℃; for 0.166667h; Inert atmosphere; Stage #2: 5-phenoxy-3,4-dibromo-2(5H)-furanone In ethanol; dichloromethane at 20℃; for 24h; Inert atmosphere; | Synthesis offuranonyl amino acid derivatives 5a-7k General procedure: Referring to the reported method (Luo etal. 2019), the mixtureof 0.600mmol amino acid (4), 0.672mmol potassiumhydroxide and 5mL ethanol in a two-neck flask was stirredat room temperature for 10min. Then, under the atmosphereof nitrogen, the mixture of 0.300mmol furanone (3) and5mL dichloromethane (DCM) in a constant pressure funnel was slowly dripped into the two-neck flask for about 30min.The reaction was carried out at room temperature for 24h.After the completion of reaction, the solvent in the mixturewas evaporated. The residue was dissolved in distilled water,and the 15% hydrochloric acid was added to adjust the pH to3-4, a large amount of product was precipitated out. Onceextracted with ethyl acetate (3 × 15mL), the organic layerwas dried over anhydrous sodium sulfate. After filtration andevaporation of the solvent under reduced pressure, the crudeproduct was purified by column chromatography on silicagel to afford desired compound. |
37% | Stage #1: trans-4-aminomethyl-cyclohexyl-carboxylic acid With potassium hydroxide In ethanol at 20℃; for 0.166667h; Inert atmosphere; Stage #2: 5-phenoxy-3,4-dibromo-2(5H)-furanone In ethanol; dichloromethane at 20℃; for 24h; Inert atmosphere; | Synthesis offuranonyl amino acid derivatives 5a-7k General procedure: Referring to the reported method (Luo etal. 2019), the mixtureof 0.600mmol amino acid (4), 0.672mmol potassiumhydroxide and 5mL ethanol in a two-neck flask was stirredat room temperature for 10min. Then, under the atmosphereof nitrogen, the mixture of 0.300mmol furanone (3) and5mL dichloromethane (DCM) in a constant pressure funnel was slowly dripped into the two-neck flask for about 30min.The reaction was carried out at room temperature for 24h.After the completion of reaction, the solvent in the mixturewas evaporated. The residue was dissolved in distilled water,and the 15% hydrochloric acid was added to adjust the pH to3-4, a large amount of product was precipitated out. Onceextracted with ethyl acetate (3 × 15mL), the organic layerwas dried over anhydrous sodium sulfate. After filtration andevaporation of the solvent under reduced pressure, the crudeproduct was purified by column chromatography on silicagel to afford desired compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | Stage #1: trans-4-aminomethyl-cyclohexyl-carboxylic acid With potassium hydroxide In ethanol at 20℃; for 0.166667h; Inert atmosphere; Stage #2: 3,4-dibromo-5-butoxy-5<i>H</i>-furan-2-one In ethanol; dichloromethane at 20℃; for 24h; Inert atmosphere; | Synthesis offuranonyl amino acid derivatives 5a-7k General procedure: Referring to the reported method (Luo etal. 2019), the mixtureof 0.600mmol amino acid (4), 0.672mmol potassiumhydroxide and 5mL ethanol in a two-neck flask was stirredat room temperature for 10min. Then, under the atmosphereof nitrogen, the mixture of 0.300mmol furanone (3) and5mL dichloromethane (DCM) in a constant pressure funnel was slowly dripped into the two-neck flask for about 30min.The reaction was carried out at room temperature for 24h.After the completion of reaction, the solvent in the mixturewas evaporated. The residue was dissolved in distilled water,and the 15% hydrochloric acid was added to adjust the pH to3-4, a large amount of product was precipitated out. Onceextracted with ethyl acetate (3 × 15mL), the organic layerwas dried over anhydrous sodium sulfate. After filtration andevaporation of the solvent under reduced pressure, the crudeproduct was purified by column chromatography on silicagel to afford desired compound. |
60% | Stage #1: trans-4-aminomethyl-cyclohexyl-carboxylic acid With potassium hydroxide In ethanol at 20℃; for 0.166667h; Inert atmosphere; Stage #2: 3,4-dibromo-5-butoxy-5<i>H</i>-furan-2-one In ethanol; dichloromethane at 20℃; for 24h; Inert atmosphere; | Synthesis offuranonyl amino acid derivatives 5a-7k General procedure: Referring to the reported method (Luo etal. 2019), the mixtureof 0.600mmol amino acid (4), 0.672mmol potassiumhydroxide and 5mL ethanol in a two-neck flask was stirredat room temperature for 10min. Then, under the atmosphereof nitrogen, the mixture of 0.300mmol furanone (3) and5mL dichloromethane (DCM) in a constant pressure funnel was slowly dripped into the two-neck flask for about 30min.The reaction was carried out at room temperature for 24h.After the completion of reaction, the solvent in the mixturewas evaporated. The residue was dissolved in distilled water,and the 15% hydrochloric acid was added to adjust the pH to3-4, a large amount of product was precipitated out. Onceextracted with ethyl acetate (3 × 15mL), the organic layerwas dried over anhydrous sodium sulfate. After filtration andevaporation of the solvent under reduced pressure, the crudeproduct was purified by column chromatography on silicagel to afford desired compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: trans-4-aminomethyl-cyclohexyl-carboxylic acid With potassium hydroxide In ethanol at 20℃; for 0.166667h; Inert atmosphere; Stage #2: 5-isopropoxy-3,4-dibromo-2(5H)-furanone In ethanol; dichloromethane at 20℃; for 24h; Inert atmosphere; | Synthesis offuranonyl amino acid derivatives 5a-7k General procedure: Referring to the reported method (Luo etal. 2019), the mixtureof 0.600mmol amino acid (4), 0.672mmol potassiumhydroxide and 5mL ethanol in a two-neck flask was stirredat room temperature for 10min. Then, under the atmosphereof nitrogen, the mixture of 0.300mmol furanone (3) and5mL dichloromethane (DCM) in a constant pressure funnel was slowly dripped into the two-neck flask for about 30min.The reaction was carried out at room temperature for 24h.After the completion of reaction, the solvent in the mixturewas evaporated. The residue was dissolved in distilled water,and the 15% hydrochloric acid was added to adjust the pH to3-4, a large amount of product was precipitated out. Onceextracted with ethyl acetate (3 × 15mL), the organic layerwas dried over anhydrous sodium sulfate. After filtration andevaporation of the solvent under reduced pressure, the crudeproduct was purified by column chromatography on silicagel to afford desired compound. |
91% | Stage #1: trans-4-aminomethyl-cyclohexyl-carboxylic acid With potassium hydroxide In ethanol at 20℃; for 0.166667h; Inert atmosphere; Stage #2: 5-isopropoxy-3,4-dibromo-2(5H)-furanone In ethanol; dichloromethane at 20℃; for 24h; Inert atmosphere; | Synthesis offuranonyl amino acid derivatives 5a-7k General procedure: Referring to the reported method (Luo etal. 2019), the mixtureof 0.600mmol amino acid (4), 0.672mmol potassiumhydroxide and 5mL ethanol in a two-neck flask was stirredat room temperature for 10min. Then, under the atmosphereof nitrogen, the mixture of 0.300mmol furanone (3) and5mL dichloromethane (DCM) in a constant pressure funnel was slowly dripped into the two-neck flask for about 30min.The reaction was carried out at room temperature for 24h.After the completion of reaction, the solvent in the mixturewas evaporated. The residue was dissolved in distilled water,and the 15% hydrochloric acid was added to adjust the pH to3-4, a large amount of product was precipitated out. Onceextracted with ethyl acetate (3 × 15mL), the organic layerwas dried over anhydrous sodium sulfate. After filtration andevaporation of the solvent under reduced pressure, the crudeproduct was purified by column chromatography on silicagel to afford desired compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | Stage #1: trans-4-aminomethyl-cyclohexyl-carboxylic acid With potassium hydroxide In ethanol at 20℃; for 0.166667h; Inert atmosphere; Stage #2: 5-ethoxy-3,4-dibromo-2(5H)-furanone In ethanol; dichloromethane at 20℃; for 24h; Inert atmosphere; | Synthesis offuranonyl amino acid derivatives 5a-7k General procedure: Referring to the reported method (Luo etal. 2019), the mixtureof 0.600mmol amino acid (4), 0.672mmol potassiumhydroxide and 5mL ethanol in a two-neck flask was stirredat room temperature for 10min. Then, under the atmosphereof nitrogen, the mixture of 0.300mmol furanone (3) and5mL dichloromethane (DCM) in a constant pressure funnel was slowly dripped into the two-neck flask for about 30min.The reaction was carried out at room temperature for 24h.After the completion of reaction, the solvent in the mixturewas evaporated. The residue was dissolved in distilled water,and the 15% hydrochloric acid was added to adjust the pH to3-4, a large amount of product was precipitated out. Onceextracted with ethyl acetate (3 × 15mL), the organic layerwas dried over anhydrous sodium sulfate. After filtration andevaporation of the solvent under reduced pressure, the crudeproduct was purified by column chromatography on silicagel to afford desired compound. |
74% | Stage #1: trans-4-aminomethyl-cyclohexyl-carboxylic acid With potassium hydroxide In ethanol at 20℃; for 0.166667h; Inert atmosphere; Stage #2: 5-ethoxy-3,4-dibromo-2(5H)-furanone In ethanol; dichloromethane at 20℃; for 24h; Inert atmosphere; | Synthesis offuranonyl amino acid derivatives 5a-7k General procedure: Referring to the reported method (Luo etal. 2019), the mixtureof 0.600mmol amino acid (4), 0.672mmol potassiumhydroxide and 5mL ethanol in a two-neck flask was stirredat room temperature for 10min. Then, under the atmosphereof nitrogen, the mixture of 0.300mmol furanone (3) and5mL dichloromethane (DCM) in a constant pressure funnel was slowly dripped into the two-neck flask for about 30min.The reaction was carried out at room temperature for 24h.After the completion of reaction, the solvent in the mixturewas evaporated. The residue was dissolved in distilled water,and the 15% hydrochloric acid was added to adjust the pH to3-4, a large amount of product was precipitated out. Onceextracted with ethyl acetate (3 × 15mL), the organic layerwas dried over anhydrous sodium sulfate. After filtration andevaporation of the solvent under reduced pressure, the crudeproduct was purified by column chromatography on silicagel to afford desired compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Stage #1: trans-4-aminomethyl-cyclohexyl-carboxylic acid With potassium hydroxide In ethanol at 20℃; for 0.166667h; Inert atmosphere; Stage #2: 5-cyclohexyloxy-3,4-dibromo-2(5H)furanone In ethanol; dichloromethane at 20℃; for 24h; Inert atmosphere; | Synthesis offuranonyl amino acid derivatives 5a-7k General procedure: Referring to the reported method (Luo etal. 2019), the mixtureof 0.600mmol amino acid (4), 0.672mmol potassiumhydroxide and 5mL ethanol in a two-neck flask was stirredat room temperature for 10min. Then, under the atmosphereof nitrogen, the mixture of 0.300mmol furanone (3) and5mL dichloromethane (DCM) in a constant pressure funnel was slowly dripped into the two-neck flask for about 30min.The reaction was carried out at room temperature for 24h.After the completion of reaction, the solvent in the mixturewas evaporated. The residue was dissolved in distilled water,and the 15% hydrochloric acid was added to adjust the pH to3-4, a large amount of product was precipitated out. Onceextracted with ethyl acetate (3 × 15mL), the organic layerwas dried over anhydrous sodium sulfate. After filtration andevaporation of the solvent under reduced pressure, the crudeproduct was purified by column chromatography on silicagel to afford desired compound. |
84% | Stage #1: trans-4-aminomethyl-cyclohexyl-carboxylic acid With potassium hydroxide In ethanol at 20℃; for 0.166667h; Inert atmosphere; Stage #2: 5-cyclohexyloxy-3,4-dibromo-2(5H)furanone In ethanol; dichloromethane at 20℃; for 24h; Inert atmosphere; | Synthesis offuranonyl amino acid derivatives 5a-7k General procedure: Referring to the reported method (Luo etal. 2019), the mixtureof 0.600mmol amino acid (4), 0.672mmol potassiumhydroxide and 5mL ethanol in a two-neck flask was stirredat room temperature for 10min. Then, under the atmosphereof nitrogen, the mixture of 0.300mmol furanone (3) and5mL dichloromethane (DCM) in a constant pressure funnel was slowly dripped into the two-neck flask for about 30min.The reaction was carried out at room temperature for 24h.After the completion of reaction, the solvent in the mixturewas evaporated. The residue was dissolved in distilled water,and the 15% hydrochloric acid was added to adjust the pH to3-4, a large amount of product was precipitated out. Onceextracted with ethyl acetate (3 × 15mL), the organic layerwas dried over anhydrous sodium sulfate. After filtration andevaporation of the solvent under reduced pressure, the crudeproduct was purified by column chromatography on silicagel to afford desired compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With potassium hydroxide In water monomer at 200℃; for 6h; Sealed tube; | 8 Example 8: Preparation of Tranexamic Acid (8-1) In a pressure kettle,Add 15.4g of methyl 4-aminomethylcyclohexylcarboxylate (6-1)and 70mL of water,Then add potassium hydroxide 8.0g,The mixture was sealed and heated to 200°C, and the reaction was stirred for 6 hours.After the reaction, it was cooled, the system was adjusted to neutrality with acetic acid, activated carbon was added for decolorization, and the mother liquor was filtered to remove unnecessary ions with weakly acidic ion transfer resin.The effluent clear liquid was concentrated, then slowly cooled to 5°C, a large amount of solid was precipitated, filtered,Small amount of cold water wash, dry12.0 g of tranexamic acid (8-1) was obtained with a yield of 85%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With anhydrous sodium carbonate In water monomer at 200℃; for 6h; Sealed tube; | 9 Example 9: Preparation of Tranexamic Acid (8-1) In a pressure kettle,Add 22.1 g of ethyl 4-aminomethylcyclohexylcarboxylate hydrochloride (7-1) and 80 mL of water,Then add 15.0g of sodium carbonate,The mixture was sealed and heated to 200°C, and the reaction was stirred for 6 hours.After the reaction was completed, the system was cooled, and the system was adjusted to neutrality with acetic acid.Add activated carbon to decolorize,After filtration, the mother liquor was used to remove unnecessary ions with weakly acidic ion transfer resin.The effluent clear liquid was concentrated, then slowly cooled to 5°C, a large amount of solid was precipitated, filtered,A small amount of cold water washing, drying to obtain tranexamic acid (8-1) 14.0g,Yield 89%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 5% Ru/Al2O3; hydrogen; sodium hydroxide In lithium hydroxide monohydrate at 150℃; for 2h; Overall yield = 96 percent; | 5-8; 3 Example 5 General procedure: Add 160.0 g of aminotoluic acid (2) into 1 L of water, and add 63.5 g of sodium hydroxide to adjust the pH to 9.0-11.0 for later use. After the reactor B unit is replaced with nitrogen and hydrogen, the reaction temperature is controlled at 120 ° C, the hydrogen flow rate is controlled at 50 mL/min, the catalyst is 5% ruthenium-alumina, and the above-configured aminotoluic acid solution is flowed into the reactor, and the reaction pressure is controlled at 5.5 Mpa, the residence time of the reaction solution was 2 hours. After the reaction solution flows out of unit B of the reactor, the pH is adjusted to 6.0-7.0 with concentrated hydrochloric acid, concentrated to remove water, 1.6 L of ethanol is added to make pulp, filtered, and dried to obtain a tranexamic acid mixture (3) with a purity of 99.2% (cis 52% , trans 48%), yield 95%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.57% | In phenol at 160℃; for 6h; Inert atmosphere; | 1.F Step F: trans-4-[(7-(Trifluoromethylquinoline-4-yl)amino]methyl}cyclohexane-1-carboxylic acid Take 4-chloro-7-trifluoromethylquinoline 3.85g (0.017mol), tranexamic acid 3.46g (0.022mol), phenol 14.12g (0.150mol) in a 250ml solanum cellulite bottle, react at 160 °C under nitrogen protection for 6h, turn off heating, cool, add 100ml of ether and 100ml of 10% potassium iodide aqueous solution, stir, remove the ether layer, and then use ether (2×50ml) to extract 2 times, The combined ether layer is extracted once with 50 ml of 10% potassium iodide aqueous solution. Combine the aqueous phase and insoluble solids, add 10% sodium hydroxide aqueous solution to the solids to dissolve all, and extract impurities from the aqueous phase with ethyl acetate (3×50ml). Aqueous phase added 20ml of ethyl acetate, under vigorous stirring to adjust the pH to 6-7, precipitated a large number of white solids, the upper layer of ethyl acetate layer is golden yellow, filtered, to give trans-4- [(7-trifluoromethylquinoline-4-yl)amino]methyl} cyclohexane-1-carboxylic acid white solid 5.24g, yield 89.57%; M.p.: 260.3 ~ 261.4 °C; ESI-MS(m/z): 353.27 ([M+ H]+), 351.33([M-H]-) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.7% | In phenol at 160℃; for 6h; Inert atmosphere; | 14.F Step F: Preparation of 4-chloro-6-trifluoromethylquinoline Take 4-chloro-6-trifluoromethylquinoline 6.96 g (0.030 mol), tranexamic acid 6.16 g (0.039 mol), phenol 14.12 g (0.150 mol) in a 250 ml solanum bottle, react at 160 °C under nitrogen protection for 6h, turn off heating, cooling, add 100 ml of ether and 100 ml of 10% potassium iodide aqueous solution, stir, remove the ether layer, and then use ether (2×50 ml) to extract 2 times, The combined ether layer is extracted once with 50 ml of 10% potassium iodide aqueous solution. Combine the aqueous phase and insoluble solids, add 10% sodium hydroxide aqueous solution to the solids to dissolve all, and extract impurities from the aqueous phase with ethyl acetate (3×50ml). 20ml of ethyl acetate was added to the aqueous phase, the pH was adjusted to 6-7 under vigorous stirring, a large number of white solids were precipitated, and the upper layer of ethyl acetate was golden yellow, and it was filtered to give a 4-chloro-6-trifluoromethylquinoline white solid of 9.73g, with a yield of 91.70%; M.p.: 268.7 °C (decomposition); ESI-MS(m/z):353.1([M+H]+),350.9([M-H]-) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | In phenol at 160℃; for 6h; Inert atmosphere; | 21.F Step F: Preparation of trans-4-[(8-Methylquinoline-4-yl)amino]methyl}cyclohexane-1-carboxylic acid Take 4-chloro-8-methylquinoline 8.63g (0.0487mol), tranexamic acid 9.96g (0.0634mol), phenol 22.94g (0.244mol) in a 250ml solanum cellulite bottle, react at 160 °C under nitrogen protection for 6h, turn off heating, cooling, add 100ml of ether and 100ml of 8% potassium iodide aqueous solution, stir, remove the ether layer, and then extract 2 times with ether (2×50ml), The combined ether layer is extracted once with 8% potassium iodide aqueous solution 50 ml. Combine the aqueous phase and insoluble solids, add 10% sodium hydroxide aqueous solution to the solids to dissolve all, and extract impurities from the aqueous phase with ethyl acetate (3×50ml). Add 500ml of water in the aqueous phase, adjust the pH to about 7 with 6mol/L hydrochloric acid, precipitate a large number of black oily impurities, filtration, aqueous phase concentration, precipitate white solids, filtration, to give trans-4- {(8-methylquinoline-4-yl)amino] methyl} cyclohexane-1-carboxylic acid product 5.23g, yield 36.0%; M.p.: 241.8 °C (decomposition); ESI-MS(m/z):299.25([M+H]+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With barium(II) hydroxide In ethanol; lithium hydroxide monohydrate at 190℃; for 12h; | 13-14 Example 13: cis-trans isomer conversion step 200g of tranexamic acid cis-trans isomer mixture was added into the 3L reactor,Add barium hydroxide (3eq), pure water 1.2L, ethanol 400mL, heat to 190,The reaction was stopped for 12 hours, and when the temperature was lowered to room temperature, the pressure of the reactor was removed,The pH of the reaction solution was adjusted to 6.5-7.5 with sulfuric acid, and the barium sulfate solid was removed by suction filtration.The filtrate was concentrated to 1/3 of the original volume, cooled to 0 °C for crystallization, and dried by suction filtration.Trans-tranexamic acid was obtained with a purity of 99.1% (HPLC). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.9% | With bis(acetato){2,2'-bis(diphenylphosphino)-1,1'-binaphthyl}ruthenium(II); hydrogen In lithium hydroxide monohydrate at 30℃; for 1h; Autoclave; | 2-3; 5-6 Example 2 into a 2L autoclave,Add 138g (0.89mol) 4-(aminomethyl)-3-cyclohexene-1-carboxylic acid, 400g water, 1g Ru(OAc)2-BINAP, nitrogen replacement, hydrogen replacement,The reaction was carried out under the conditions of 30°C and 0.3MPa until there was no pressure drop, and the reaction was continued for 1 hour. After cooling to room temperature, the catalyst was recovered. The filtrate was transferred to a 2L bottle, 600 g of 0°C ethanol was added, and the temperature was controlled at 5 to 10°C for crystallization for 1 hour. , filtered, rinsed and dried to obtain 132 g of tranexamic acid crude product as a white crystalline solid with a yield of 95% and a purity of 99.8%. Example 3 In the 2L reaction flask, add 132g (0.84mol) crude tranexamic acid and 800g water, turn on stirring and heat up to 50-60°C to dissolve, add ethanol to the reaction flask until turbidity occurs, then heat up to reflux and dissolve clear. Then it was cooled to 60°C, 0.2g of seed crystals were added for 3 hours, and then the temperature was lowered to 20-30°C for 1 hour at a rate of 10°C/h, and 120g of tranexamic acid was obtained as an off-white solid with a yield of 90.9 %, the purity is 99.9%, and the particle size D90 is 220 μm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.7 % | Stage #1: 4-((2,5-dioxopyrrolidin-1-yl)methyl)cyclohexanecarboxylic acid With hydrogenchloride In water at 115℃; Stage #2: With barium(II) hydroxide In water at 220℃; | 1.5 (5) Hydrolysis and transformation Immerse 37.8g of compound E under 6N hydrochloric acid solution, heat in an oil bath at 115°C and reflux for 10h. After the reaction is complete, concentrate, wash the solid with acetone, and filter to obtain 26.0g of 4-aminomethylcyclohexanecarboxylate hydrochloride. Put 78.0g of barium hydroxide with a weight ratio of 1:3 in a high-pressure reactor, add an appropriate amount of water, raise the temperature to 220°C, react for 10 hours, dilute with water, adjust the pH value to 6.5-7.5 with dilute hydrochloric acid, and filter to obtain 20.0 g of trans-4-aminomethylcyclohexanecarboxylic acid (compound F), yield 80.7%. |
Tags: 1197-18-8 synthesis path| 1197-18-8 SDS| 1197-18-8 COA| 1197-18-8 purity| 1197-18-8 application| 1197-18-8 NMR| 1197-18-8 COA| 1197-18-8 structure
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Code | Phrase |
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H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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