* 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.
With citric acid In water at 22 - 25℃; for 7 - 23 h; Industry scale
3. 75 L of water was added to (S)-epichlorohydrin (99. 3percent ee), and while stirring 4. 76 kg of 25percent aqueous sodium cyanide solution and 3. 30 kg of 50percent aqueous citric acid solution were dropped for 1 h 50 min to the solution under maintaining the reaction condition to pH 7. 9~8. 2 and 22~25C. After additional 10h stirring, 0. 7 kg of sodium chloride was added and dissolved. The resulting solution was extracted with 20 L of ethyl acetate. 0. 2 Kg of anhydrous sodium sulphate was added to the ethyl acetate layer, and then the solution was stirred for 30 min and filtered. The ethyl acetate was evaporated under reduced pressure, and the residue was distilled with thin film distillator (110 C/1 mbar) to give 1. 77 kg of the targeted compound (yield 91. 3percent, chemical purity 99. 1percent). Optical purity (GC) = 99. 3percent ee In the same manner as described in the Experimental Example l, the reaction was performed under various conditions summarized in Table 1
82%
With sulfuric acid In water at 22 - 25℃; for 9 h; Industry scale
3. 75 L of water was added to (S)-epichlorohydrin (99. 3percent ee), and while stirring 4. 76 kg of 25percent aqueous sodium cyanide solution and 3. 30 kg of 50percent aqueous citric acid solution were dropped for 1 h 50 min to the solution under maintaining the reaction condition to pH 7. 9~8. 2 and 22~25C. After additional 10h stirring, 0. 7 kg of sodium chloride was added and dissolved. The resulting solution was extracted with 20 L of ethyl acetate. 0. 2 Kg of anhydrous sodium sulphate was added to the ethyl acetate layer, and then the solution was stirred for 30 min and filtered. The ethyl acetate was evaporated under reduced pressure, and the residue was distilled with thin film distillator (110 C/1 mbar) to give 1. 77 kg of the targeted compound (yield 91. 3percent, chemical purity 99. 1percent). Optical purity (GC) = 99. 3percent ee In the same manner as described in the Experimental Example l, the reaction was performed under various conditions summarized in Table 1
75.8%
With acetic acid In water at 22 - 25℃; for 19 h; Industry scale
3. 75 L of water was added to (S)-epichlorohydrin (99. 3percent ee), and while stirring 4. 76 kg of 25percent aqueous sodium cyanide solution and 3. 30 kg of 50percent aqueous citric acid solution were dropped for 1 h 50 min to the solution under maintaining the reaction condition to pH 7. 9~8. 2 and 22~25C. After additional 10h stirring, 0. 7 kg of sodium chloride was added and dissolved. The resulting solution was extracted with 20 L of ethyl acetate. 0. 2 Kg of anhydrous sodium sulphate was added to the ethyl acetate layer, and then the solution was stirred for 30 min and filtered. The ethyl acetate was evaporated under reduced pressure, and the residue was distilled with thin film distillator (110 C/1 mbar) to give 1. 77 kg of the targeted compound (yield 91. 3percent, chemical purity 99. 1percent). Optical purity (GC) = 99. 3percent ee In the same manner as described in the Experimental Example l, the reaction was performed under various conditions summarized in Table 1
To a solution of <strong>[127913-44-4](S)-4-chloro-3-hydroxy butanenitrile</strong> (52.5 g) in THF (150 mL) was added trimethyl silyl chloride (57.2 g) under inert atmosphere at 25 C. The resulting reaction mixture was stirred for 10 min at 20C. A solution of triethyl amine (53.4 g) in THF (100 mL) was added to above reaction mixture by maintaining reaction temperature below 40 C. To the resulting reaction mixture catalytic amount of sodium iodide was added and stirred further for 5 h at 40C. Reaction was monitored on GC as well TLC for complete conversion of starting material. After cooling to 0 C, a 21% aqueous solution of sodium chloride (500 mL) was added and extracted with ethyl acetate (2 X 300 mL). Combined organic layer was dried with anhydrous sodium sulphate, filtered and concentrated under reduced pressure to obtain (S)-4-chloro-3-((trimethylsilyl) oxy)butanenitrile as light brown liquid (84.0 g, 99%). GC analysis conditions: Gas Chromatographic system: Instrument : Gas Chromatograph. Column : DB-5, length: 30 metre. , Dia.: 0.53mm, 5.0muiotaeta Capillary Column. Detector : Flame Ionization Detector. Carrier gas : Nitrogen. Gas Chromatograph parameters: Carrier gas pressure : 5.0 psi Detector Temperature : 260C Injector Temperature : 220C Split Ratio : 1: 10 Injection volume : 0.2 mu. Approximate retention time for (5)-4-chloro-3-((trimethylsilyl)oxy)butanenitrile is about 8.3 min. Approximate retention time for f5)-4-chloro-3-hydroxy butyronitrile is about 7.0 min. NMR for (S)-4-chloro-3-((trimethylsilyl)oxy)butanenitrile: -NMR (CDC13) delta 0.19 (S, 9H), 2.58-2.75 (m, 2H), 3.44-3.55 (m, 2H), 4.08-4.12 (1H, m), 13C- delta 0.01, 24.2, 46.6, 68.5, 116.9. IR: 691, 844, 1110, 1253, 1361, 1445, 2254, 2960 cm"1
99%
With triethylamine; sodium iodide; In tetrahydrofuran; at 40℃; for 5h;Inert atmosphere;
Step1: To a stirred solution of <strong>[127913-44-4](S)-4-chloro-3-hydroxybutanenitrile</strong> (52.5 g, 0.44 mol) in THF (150 mL), trimethylsilylchloride (57.2 g, 0.5 mol) was added under inert atmosphere at 25C. A solution of triethyl amine(53.4 g, 0.52 mol) in THF (100 mL) was slowly added while maintaining the reaction temperature below 40C. Catalytic amount of sodium iodide was added and reaction mixture was stirred for 5 h at 40C. After cooling to 0C, a 21% aqueous solution of sodium chloride(500 mL) was added and extracted with ethyl acetate(2 × 300 mL). Combined organic layer was dried with anhydrous sodium sulphate, filtered and concentrated under reduced pressure to obtain (S)-4-chloro-3-((trimethylsilyl)oxy)butanenitrile 2 as a light brown liquid(84.0 g, 99% yield). Step2: To a stirred suspension of zinc dust (32.0 g,0.5 mol) in THF (400 mL) was slowly added solutionof trimethylsilyl chloride (1.8 mL) in THF (10 mL) in an inert atmosphere and stirred for 10-15 min at 25C.A solution of methane sulfonic acid (1.8 mL) in THF(10 mL) was added at 25C and further stirred for 15 min.Reaction mixture was slowly heated to reflux temperature (63-65C) and at this temperature, a solution of (S)-4-chloro-3-((trimethylsilyl)oxy)butanenitrile(43.8 g, 0.23 mol) in THF (200 mL) was slowly added and stirred for 30 min, after which, solution of tert-butyl bromoacetate (66.5 g, 0.34 mol) in THF(100 mL) was added slowly such that a gentle reflux was maintained and stirred further for 2 h at 65C. After cooling to 0C, 2N aqueous solution of hydrochloric cid (100 mL) was slowly added and stirred for 1 h at 0C, after which, organic volatile material was removed under reduced pressure and residue was extracted with ethyl acetate (3 × 200 mL). Combined organic layer was washed with 10% aqueous solution of sodium bicarbonate (210 mL) and dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to obtain (S)-tert-butyl 6-chloro-5-hydroxy-3-oxohexanoate as a light brown oil (53.0 g, 98%).1H NMR (400MHz, CDC13): delta 1.47 (9H), 2.86 (t, 2H),3.20 (t, 2H), 3.40 (s, 2H), 3.54-3.6 (m, 2H), 4.29-4.32(t, 1H); 13C NMR (100MHz, CDC13): delta 3 27.9, 46.4,48.3, 51.1, 67.3, 82.5, 166.0, 202.7; IR: 747, 1045, 1582,1712, 1731, 3444 cm-1; (ESI): m/z calculated 236.08 and 238.08 observed 237.08 and 239.08
With citric acid; In water; at 22 - 25℃; for 7 - 23h;pH 7.5 - 8.7;Industry scale;Product distribution / selectivity;
3. 75 L of water was added to (S)-epichlorohydrin (99. 3% ee), and while stirring 4. 76 kg of 25% aqueous sodium cyanide solution and 3. 30 kg of 50% aqueous citric acid solution were dropped for 1 h 50 min to the solution under maintaining the reaction condition to pH 7. 9~8. 2 and 22~25C. After additional 10h stirring, 0. 7 kg of sodium chloride was added and dissolved. The resulting solution was extracted with 20 L of ethyl acetate. 0. 2 Kg of anhydrous sodium sulphate was added to the ethyl acetate layer, and then the solution was stirred for 30 min and filtered. The ethyl acetate was evaporated under reduced pressure, and the residue was distilled with thin film distillator (110 C/1 mbar) to give 1. 77 kg of the targeted compound (yield 91. 3%, chemical purity 99. 1%). Optical purity (GC) = 99. 3% ee In the same manner as described in the Experimental Example l, the reaction was performed under various conditions summarized in Table 1
82.0%
With sulfuric acid; In water; at 22 - 25℃; for 9h;pH 7.9 - 8.2;Industry scale;Product distribution / selectivity;
3. 75 L of water was added to (S)-epichlorohydrin (99. 3% ee), and while stirring 4. 76 kg of 25% aqueous sodium cyanide solution and 3. 30 kg of 50% aqueous citric acid solution were dropped for 1 h 50 min to the solution under maintaining the reaction condition to pH 7. 9~8. 2 and 22~25C. After additional 10h stirring, 0. 7 kg of sodium chloride was added and dissolved. The resulting solution was extracted with 20 L of ethyl acetate. 0. 2 Kg of anhydrous sodium sulphate was added to the ethyl acetate layer, and then the solution was stirred for 30 min and filtered. The ethyl acetate was evaporated under reduced pressure, and the residue was distilled with thin film distillator (110 C/1 mbar) to give 1. 77 kg of the targeted compound (yield 91. 3%, chemical purity 99. 1%). Optical purity (GC) = 99. 3% ee In the same manner as described in the Experimental Example l, the reaction was performed under various conditions summarized in Table 1
75.8%
With acetic acid; In water; at 22 - 25℃; for 19h;pH 7.9 - 8.2;Industry scale;Product distribution / selectivity;
3. 75 L of water was added to (S)-epichlorohydrin (99. 3% ee), and while stirring 4. 76 kg of 25% aqueous sodium cyanide solution and 3. 30 kg of 50% aqueous citric acid solution were dropped for 1 h 50 min to the solution under maintaining the reaction condition to pH 7. 9~8. 2 and 22~25C. After additional 10h stirring, 0. 7 kg of sodium chloride was added and dissolved. The resulting solution was extracted with 20 L of ethyl acetate. 0. 2 Kg of anhydrous sodium sulphate was added to the ethyl acetate layer, and then the solution was stirred for 30 min and filtered. The ethyl acetate was evaporated under reduced pressure, and the residue was distilled with thin film distillator (110 C/1 mbar) to give 1. 77 kg of the targeted compound (yield 91. 3%, chemical purity 99. 1%). Optical purity (GC) = 99. 3% ee In the same manner as described in the Experimental Example l, the reaction was performed under various conditions summarized in Table 1
To a flame dried flask equipped with stir bar was added tert-butyl (2S, [4S)-4- {] [tert-butyl (dimethyl) silyl] [OXY}-2-PHENYLPYRROLIDINE-1-CARBOXYLATE] (2-1, prepared from (S)- (-)-4-chloro-3-hydroxybutyronotrile by the method of Maeda, et al Synlett 2001,1808-1810, 7.8 g, 20.7 mmol) and anhydrous acetonitrile (20.0 mL). The resulting solution was treated with triethylamine trihydrofluoride (10.1 mL, 62.0 mmol) while stirring under N2. The reaction stirred 12 hours at [40C.] The reaction was then diluted with EtOAc (100 mL) and poured into 5% aq. [NAHC03.] Following cessation of gas evolution, the organic layer was washed three addition times with 5% aq. [NAHC03.] The organic layer was dried over magnesium sulfate, filtered and concentrated to provide crude product. Recrystallization was effected from EtOAc/hexanes to provide tert-butyl (2S, [4S)-4-HYDROXY-2-PHENYLPYRROLIDINE-1-] carboxylate (2-2) as a white crystalline solid NMR (300 MHz, [CDCL3)] rotamers 8 7.38-7. 18 (m, [5H),] 4.90 (m, 1H), 4.42 (m, 1H), 3.88 (m, 1H), 3.56 (dd, [J=] 11.5, 4.0 Hz, 1H), 2.60 (m, 1H), 2.03 (m, 1H), 1.50 and 1.20 (br s, 9H); MS 208.0 found, 208.1 (M-C (CH3) 3) required.
Example 1: Preparation of (S)-3-hydroxy-y-butyrolactone [52] [53] (S)-4-chloro-3-hydroxy BUTYRONITRILE (10 g, 83.6 MMD) was mixed with 16.7 mL of concentrated hydrochloric acid, and the resulting reaction solution was heated to 60 C. Upon completing the hydrolysis reaction, the reaction solution was coded in iced bath, and 50% of sodium hydroxide was added dropwise to the reaction solution to adjust pH 7.5. The reaction mixture was extracted with 25mL of ACETONITRILE 5 times, and the organic layer was concentrated under reduced pressure to obtain 6.4 g of (S)-3-hydroxy-y-butyrolactone. [54] Yield : 88.8% [55] Optical purity (GC): 100% ee; Example 2: Preparation of (S)-3-hydroxy-y-butyrolactone [58] [59] (S)-4-chbro-3-hydroxy BUTYRONITRILE (800 g, 6. 69mol) was mixed with 0.9 kg of concentrated hydrochloric acid, and the reaction solution was heated to 70 C. Upon completing the hydrolysis reaction, the reaction solution was cooled to 10 C, and 50% of sodum hydroxide was added dropwise to the reaction solution to adjust the pH to 7.7. The reaction mixture was extracted with 2.5 L of n-butanol twice. The organic layer was concentrated under reduced pressure, diluted with 0.5 L of ethyl acetate, and the formed solid was filtered. The filtrate was concentrated to provide 545 g of (S)-3-HYDROXY-Y-BUTYROLACTONE. [60] Yield : 80.0% [61] Optical purity (GC): 100% ee
200 kg
With dipotassium hydrogenphosphate; potassium dihydrogenphosphate; In water; at 36 - 38℃;pH 7;Large scale;
(1) Configure the buffer,Add 50 kg of dipotassium hydrogen phosphate to the reaction kettle.50kg potassium dihydrogen phosphate,600kg deionized water,Stir and dissolve,Add 200kg of A1 to the buffer,Adjust the pH to 6-8, preferably PH value 7.The temperature is adjusted to 36-38 C,Add 20kg of cyanohydrolase,20-40 C insulation reaction,Preferably it is 28-32 C,Adjust the pH between pH 6.8-7.0 with lye during the heat preservation process.The reaction is complete,Adjust the pH to 3-4 with dilute sulfuric acid,Stir for 20min,Extracted with ethyl acetate,Organic phase combinationThe mixture was concentrated to dryness to obtain 200 kg of A2.
Example 1: Production of (S)-1-(tert-butoxycarbonyl)-3-pyrrolidinol (S)-4-Chloro-3-hydroxybutyronitrile (2.41g) was dissolved in methanol (12.4 ml), and concentrated hydrochloric acid (2.51 g) and 10% palladium carbon containing 50wt% of water (0.48 g) were added thereto. Under pressured hydrogen at 4 atm, the mixture was stirred at 25C for 23 hours and at 50C for 6 hours. Then, 5% palladium carbon containing 50wt% of water (0.48 g) was added thereto, and the mixture was stirred at 50C for 11 hours. The catalyst was removed with filtration under reduced pressure, and the obtained filtrate was concentrated under reduced pressure. To the concentrate, methanol (6.4 ml) and distilled water (1.6 ml) and triethylamine (2.29 g) were added, and the mixture was stirred at 25C for 20 hours and at 40C for 8 hours. To the reaction mixture, di-tert-butyldicarbonate (4.82 g) and triethylamine (2.10 g) were added, and the mixture was stirred at 25C for 2 hours. The reaction mixture was concentrated to 9.92 g under reduced pressure. To the concentrate, toluene (20 ml) and distilled water (3.5 ml) were added in order to extract the target compound into the organic layer. The obtained organic layer was washed with distilled water 1 ml) and concentrated under reduced pressure to obtain 3.94 g of the target compound as a brown oil (content amount: 67.5.wt%, yield: 71%). 1H-NMR (CDCl3): delta (ppm) 1.48(s, 9H), 1.86-2.04(m, 3H), 3.26-3.56(m, 4H), 4.45(m, 1H)
With di-(p-nitrobenzyl) azodicarboxylate; triphenylphosphine; In dichloromethane; at 0 - 20℃; for 1.8h;Inert atmosphere;
General procedure: An alcohol (1.0 equiv) was added to a solution of acidic pronucleophile (1.1 equiv) and phosphine reagent (1.1 equiv) in anhydrous CH2Cl2 or THF under a N2 atmosphere at 0 C. The resulting suspension/solution was treated with azo-reagent (1.1 equiv) and the reaction mixture was continued stirring at room temperature up to completion of the reaction, indicated by TLC monitoring (The reaction mixture was filtered to recover the reduced azodicarboxylate 2 if DNAD was used as the azo-reagent.). The solvent was evaporated and the residue dissolved in cyclohexane. The triphenylphosphane oxide precipitated and was filtered off and then the filtrate evaporated under reduced pressure. The product was purified by column chromatography on silica gel to afford the pure products.
Add 200 kg of A1 to the reaction kettle.Pump 1000kg of 36percent hydrochloric acid in ethanol solution,The temperature was raised to 50 ° C and the reaction was stirred for 8 h.Concentrated and concentrated to recover hydrochloric acid ethanol under reduced pressure.The hydrogen chloride gas is absorbed by a tertiary water absorption tower.Add 400 kg of water to the kettle.500kg of dichloroethane, stirred for 20min,Let stand layering,The aqueous phase was extracted with 200 kg of dichloroethane.Combine the organic phase,Concentrated under reduced pressure to give 215 kg of A4.The GC purity is 90percent.
Example 3Preparation of (S)-3-hydroxy-4-(l-phenyltetrazole-5-sulfanyl)butyronitrile To 200 g of Nu,Nu-dimethylformamide was added triethylamine(42.5 g) and sodium iodide (2.4 g). After the mixture was stirred to dissolve the reactants, a solution of l-phenyl-5-mercaptotetrazole (69.0 g) in DMF was added. After stirred for about 30 minutes at room temperature, <strong>[127913-44-4](S)-4-chloro-3-hydroxybutyronitrile</strong> (38.6 g) was added dropwise into the mixture, and the reaction mixture was heated to about 90 C and stirred for 15 hours to 16 hours. After the reaction mixture was cooled to room temperature, 800 g water was added and then it was stirred for about 1 hour. The reaction mixture was filtered and the filter cake was washed with water, and then dried to give the product as a white solid (73.1 g).
73.1 g
To 200 g of N,N-dimethylformamide was added triethylamine (42.5 g) and sodium iodide (2.4 g). After the mixture was stirred to dissolve the reactants, a solution of 1-phenyl-5-mercaptotetrazole (69.0 g) in DMF was added. After stirred for about 30 minutes at room temperature, <strong>[127913-44-4](S)-4-chloro-3-hydroxybutyronitrile</strong> (38.6 g) was added dropwise into the mixture, and the reaction mixture was heated to about 90 C. and stirred for 15 hours to 16 hours. After the reaction mixture was cooled to room temperature, 800 g water was added and then it was stirred for about 1 hour. The reaction mixture was filtered and the filter cake was washed with water, and then dried to give the product as a white solid (73.1 g).
With potassium carbonate; In water; at 20℃; for 0.25h;pH 8 - 10;
R-epichlorohydrin (9.25 g, 100 mmol), water (100 mL) were added to a three-necked flask, cooled to 0 C., 30% aqueous sodium cyanide solution (18 mL, 110 mmol) was added, and the pH was adjusted to 8.0 with a 50% aqueous sulfuric acid solution. Stir the reaction for 3 hours. The reaction mixture was extracted with dichloromethane (20 mL×3), and the organic layers were combined, washed with water (10 mL×3), dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to give a yellow solid. The above yellow solid was added to a three-necked bottle, 300 mL of water was further added, and a 1 mol/L potassium carbonate aqueous solution (95 mL, 95 mmol) was slowly added dropwise at room temperature to keep the pH of the reaction solution between 8.0-10.0. After stirring was completed, the mixture was stirred at room temperature for 15 minutes. . The reaction solution was adjusted to pH 7.5 with 10% aqueous sulfuric acid solution and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to give S-cyanopropylene oxide (5.6 g) represented by formula (II).67%.
With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃;
Into a 250 mL round-bottom flask was placed <strong>[127913-44-4](3S)-4-chloro-3-hydroxybutanenitrile</strong> (5.00 g, 41.8 mmol), /V,A/-dimethylformamide (80 mL), TBSCI (8.10 g, 53.74 mmol), imidazole (5.60 g, 82.3 mmol). The reaction mixture was stirred for 1 h overnight at RT. The solution was diluted with 200 mL of ethyl acetate. The mixture was concentrated under vacuum. The residue was purified over a silica gel column with ethyl acetate/petroleum ether (1 :10). This resulted in 7.80 g (80%) of (3S)-3-[(tert-butyldimethylsilyl)oxy]-4- chlorobutanenitrile as a colorless liquid.
A preparation process of rivaroxaban, comprising the following steps: S1, potassium phthalimide (73.4 g, 0.39 mol) was added to <strong>[127913-44-4](S)-4-chloro-3-hydroxybutyronitrile</strong> (39.5 g, 0.33 mol) in a solution of DMF (330 ml), the mixture was heated to 70 C for 4 h, and the reaction mixture was poured into water (440 ml), stirred for 10 min, and a white solid was precipitated, suction filtered, and the filter cake was dried under reduced pressure to give a white solid (73.6 g , 97.0%); mp 137 ~ 140 C, [alpha]D25-21.8(c1,CHCl3).
96.8%
In N,N-dimethyl-formamide; at 70℃; for 4h;
A potassium phthalimide salt (66.7 g, 0.36 mol) was added to the reaction flask, <strong>[127913-44-4](S)-4-chloro-3-hydroxybutyronitrile</strong> (compound 1, 35.9 g, 0.3 mol) and 300 mL of DMF were heated to 70 C for 4 h. The reaction solution was poured into 400 mL of water, stirred for 10 min, and dried under reduced pressure to obtain 66.9 g of a white solid (Compound 2) in a yield of 96.8%.
In a 1 L four-necked flask were successively added 150 g of toluene, 300 g of S-4-chloro-3-hydroxybutyronitrile,Stirred at room temperature for 15min until clear, the temperature of the control system is 10 ~ 35 , 306.25g hexamethyldisilazane is added dropwise,The system was heated to the end of the reaction under reflux conditions 4h,To be detected by HPLC S-4-chloro-3-hydroxybutyronitrile residue <0.5%, to stop the reaction;Drying under reduced pressure gave 445.34 g of an oily intermediate in a yield of 103.4% and was used in the next reaction without further purification.
R-epichlorohydrin (9.25 g, 100 mmol), water (100 mL) were added to a three-necked flask, cooled to 0 C., 30% aqueous sodium cyanide solution (18 mL, 110 mmol) was added, and the pH was adjusted to 8.0 with a 50% aqueous sulfuric acid solution. Stir the reaction for 3 hours. The reaction mixture was extracted with dichloromethane (20 mL×3), and the organic layers were combined, washed with water (10 mL×3), dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to give a yellow solid. The above yellow solid was added to a three-necked bottle, 300 mL of water was further added, and a 1 mol/L potassium carbonate aqueous solution (95 mL, 95 mmol) was slowly added dropwise at room temperature to keep the pH of the reaction solution between 8.0-10.0. After stirring was completed, the mixture was stirred at room temperature for 15 minutes. . The reaction solution was adjusted to pH 7.5 with 10% aqueous sulfuric acid solution and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to give S-cyanopropylene oxide (5.6 g) represented by formula (II).67%.
With tetrabutylammomium bromide; at 80 - 90℃; for 6h;
120 g of the compound of the formula 2, 120 g of sodium acetate and 10 g of tetrabutylammonium bromide were placed in a reaction flask, and the reaction was stirred at a temperature of 80 to 90 C for 6 hours.After the completion of the reaction, the mixture was filtered, and the filter cake was washed with 300 ml of ethyl acetate. The filtrate was combined and washed with water (200 ml).The organic layer was concentrated under reduced pressure at 60 to dryness to dryness to give an oily material, 138 g of compound of formula 3, yield 96%, GC purity 95.1%.
(3S,3'S)-4,4'-(butane-1,4-diylbis(benzylazanediyl))bis(3-hydroxybutanenitrile)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
44.6%
With sodium hydrogencarbonate; In ethanol; at 80 - 85℃;Inert atmosphere;
To a solution of N^^-dibenzylbutane-l, 4-diamine (90 g, 0.335 mol, 1 eq) in ethanol (900 ml) was added sodium bicarbonate (70.3 g, 0.836 mol, 2.5 eq) and (S)-4-chloro-3- hydroxybutanenitrile (88.2 g, 0.738 mol, 2.2 eq) at 25-30C under nitrogen atmosphere. The reaction mixture was heated to 80-85C for 24-28 h. The reaction was monitored by (0063) TLC/HPLC. As the starting material (N1, N4-dibenzylbutane-l, 4-diamine) was not consumed, a second lot of sodium bicarbonate (28. lg, 0.335 mol, 1.0 eq) and (S)-4-chloro-3- hydroxybutanenitrile (44.1 g, 0.034 mol, 1.1 eq) was added at 80-85C and maintained for 16-18 h. The reaction was monitored by TLC/HPLC. As the starting material (N1, N4- dibenzylbutane-l, 4-diamine) was not consumed, a third lot of sodium bicarbonate (28. lg, 0.335 mol, 1.0 eq) and <strong>[127913-44-4](S)-4-chloro-3-hydroxybutanenitrile</strong> (44.1 g, 0.034 mol, 1.1 eq) was added at 80-85C and maintained for 16-18 h. The reaction was monitored by TLC/HPLC, and when the reaction was deemed to be complete, the reaction mass was filtered through a celite bed. The filtrate was concentrated under reduced pressure at 45-50C followed by addition of the water (1800 ml) at 25-30C. The reaction mixture was extracted with dichloromethane (1800 ml*2). The organic layer was concentrated and purified with column chromatography using 60-120 silica gel eluting with 40-60% ethyl acetate in petroleum ether. The pure fraction was collected and concentrated under reduced pressure at 45-50C and product (65 g, 44.6% yield) was obtained as a viscous liquid. (0064) NMR (400 MHz, DMSO-de) d: l.35(s, 4H), 2.29-2.34(m, 4H), 2.36- 2.48(m, 6H), 2.64- 2.69(m, 4H), 3.53(dd, 4H), 3.82(bs, 2H), 5.23(s, 2H), 7.22-7.33(m, 10H); 13C NMR (75MHz, DMSO-de) d: 24.0, 24.7, 54.4, 59.3, 59.4, 65.3, 119.5, 127.3, 128.6, 129.1, 139.8; LCMS (El) m/e 435 (M+l).
With zinc In tetrahydrofuran for 3h; Inert atmosphere; Reflux;
1 Example 1: Synthesis of Intermediate 2
Under nitrogen protection, 92 g of zinc powder was added to 800 mL of tetrahydrofuran, stirred for 20 min, then 69 g of a was added, 112.4 g of b was slowly added at room temperature, and after heating to reflux for 3 h, 2 mol/L hydrochloric acid was slowly added dropwise, Adjust the pH to 5-6, add 400 mL of ethyl acetate and 400 mL of water, separate the organic phase, extract the aqueous layer with 200 mL of ethyl acetate three times, combine the organic phases, wash the organic phase with 200 mL of saturated brine, and dry It was dried with sodium sulfate, and then the solvent was removed by distillation under reduced pressure to obtain an oily substance c 101.2 g.
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