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CAS No. : | 109-78-4 | MDL No. : | MFCD00002826 |
Formula : | C3H5NO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | WSGYTJNNHPZFKR-UHFFFAOYSA-N |
M.W : | 71.08 | Pubchem ID : | 8011 |
Synonyms : |
|
Num. heavy atoms : | 5 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.67 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 17.45 |
TPSA : | 44.02 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.4 cm/s |
Log Po/w (iLOGP) : | 0.8 |
Log Po/w (XLOGP3) : | -0.94 |
Log Po/w (WLOGP) : | -0.11 |
Log Po/w (MLOGP) : | -0.78 |
Log Po/w (SILICOS-IT) : | -0.25 |
Consensus Log Po/w : | -0.25 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | 0.38 |
Solubility : | 170.0 mg/ml ; 2.39 mol/l |
Class : | Highly soluble |
Log S (Ali) : | 0.5 |
Solubility : | 225.0 mg/ml ; 3.16 mol/l |
Class : | Highly soluble |
Log S (SILICOS-IT) : | -0.06 |
Solubility : | 62.0 mg/ml ; 0.873 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.08 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P501-P260-P264-P280-P302+P352-P312-P337+P313-P305+P351+P338-P362+P364-P332+P313 | UN#: | N/A |
Hazard Statements: | H302+H312-H315-H319-H373 | 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 |
---|---|---|
50% | With hydrogenchloride; thionyl chloride In water at 0 - 20℃; for 6 h; Reflux | Ethanol (1L) was placed in a three-necked flask, stirred and cooled to 0 ° C.Concentrated hydrochloric acid (80 mL) was added dropwise slowly.Then slowly add thionyl chloride (132 mL).The system slowly rise to room temperature.3-Hydroxypropionitrile (250 g) was slowly added dropwise, and the system was refluxed for 6 hours.A large amount of white powder appeared.The system was cooled to 0 ° C and the pH was adjusted to about 7 with solid sodium carbonate.Filtration, concentration of the filtrate, distillation to obtain 208 g of ethyl 3-hydroxypropionate, yield 50percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97.3% | With aluminum oxide; boron trifluoride diethyl etherate In propylene glycol at -10 - 10℃; for 28h; | 7 Example 7 2.70 g of hydrogen cyanide and 4.40 g of ethylene oxide were charged into a closed reactor equipped with a cooling device,Stir; then add 1.0g white solid in Example 5, the reaction was stirred at -10 4h,The reaction was stirred at 10 ° C for another 24h. After the reaction is completed, a small amount of sodium hypochlorite is not involved in the reaction of cyanideHydrogen after the detection of 3-hydroxy-propionitrile content. The results show that under this condition,The yield of 3-hydroxypropionitrile was as high as 97.3%. |
With water at 50℃; in Gegenwart eines Kationenaustauschers (Salzform); | ||
at 50 - 60℃; |
With sodium hydroxide In water at 107℃; | It was an object of the invention to develop a process which enables virtually complete conversion of the reactants used in a continuous process, with simultaneously high space-time yield.It was a further object of the invention to provide a suitable apparatus for performing the process.The object is achieved by a process for continuously preparing ethylene cyanohydrin from ethylene oxide and hydrocyanic acid, characterized in that the reactants are fed in aqueous solution continuously to a reactor, the reaction is effected by means of a tube coil at a pressure of 11-25 bar and a temperature of 101-110° C., and the pH is controlled by means of the addition of sodium hydroxide solution.It has been found that the process according to the invention can achieve conversions of 90-98%.It has likewise been found that simple process control can be effected via the addition of sodium hydroxide solution. The unconverted reactants are stripped out. The resulting distillate is neutralized and then fed back to the reactor without further workup steps. The pH required for the reaction is established by the metering of sodium hydroxide solution into the reactor.The reaction is effected under basic conditions. Preference is given to a pH between 8 and 13. This pH is established with bases, preferably with dilute sodium hydroxide solution. 1-50% sodium hydroxide solution, preferably 5-8% NaOH, is used.The process is performed under elevated pressure, preferably at a pressure of 11 to 25 bar, more preferably at 12-14 bar. The temperature is controlled according to the prevailing pressure. The temperature range is between 100 and 110° C. Preference is given to working at a pressure of 12-14 bar and a temperature around 107° C. (107° C.+/-1° C.).The distillate removed from the reaction mixture comprises hydrocyanic acid (0.1-30%), ethylene oxide (0.1-60%) and water (90-30%). The distillate is first neutralized. This is done with conventional acids. Preference is given to using formic acid. The pH of the distillate is adjusted to 3-4 with the acid and fed back to the reactor via the reactant stream.The invention additionally relates to an apparatus for continuously preparing ethylene cyanohydrin, characterized in that, in a closed reactor system, the reactants are fed to a reactor whose working temperature is between 101 and 110° C., unconverted reactants are drawn off via a downstreams column, collected in a distillate vessel and then metered back into the reactor, and the crude product is drawn off at the column bottom. The product thus obtained is fed to further distillation stages for purification.The unconverted reactants, for example hydrocyanic acid, ethylene oxide and water, are removed from the system via the top of the column. The top of the column has a temperature between 85-95° C. and a pressure of 900 to 1000 mbar.At the bottom of the column, the crude product is removed at a temperature of 105-120° C. The crude product is purified in downstream distillation stages which free the crude product of low and high boilers.As a result, the ethylene cyanohydrin is present in a very high purity. There are thus various possible uses. The ethylene cyanohydrin is preferably used as a precursor in the pharmaceuticals and cosmetics industry. | |
With triethylamine at 15 - 20℃; for 2h; | 1 Add 275 g (2.04 mol) of 20% aqueous hydrocyanic acid solution and 0.5 g (catalyst) of triethylamine to a closed and pressure-resistant cyanide reaction kettle.Keep temperature at 15-20 , add 88.9g (2.0mol) of ethylene oxide (99%), and react for 2h;Sampling GC analysis showed that the content of ethylene oxide was less than 1%. The reaction was stopped. 268.0 g (2.2 mol) of 30% hydrochloric acid was added to the reaction solution. After the addition, the temperature was raised to a boiling reaction for 4 hours. Sampling HPLC was used to analyze the content of 3-hydroxypropionitrile ( Calculated by area normalization method) less than 1%, cooled, neutralized with ammonia to pH = 4.0-4.5, and separated by continuous chromatography (stationary phase: ammonium ion exchange resin; mobile phase: 0.008mol / L HCl solution; flow rate: 16mL / min; column temperature: 25 ° C) to obtain an ammonium chloride solution and a 3-hydroxypropionic acid solution. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With toluene-4-sulfonic acid; hydroquinone unter Entfernen des entstehenden Methanols; | ||
With sulfuric acid | ||
With toluene-4-sulfonic acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: 3-Hydroxypropionitrile With acetyl chloride In methanol; toluene at 0 - 20℃; for 18h; Stage #2: With ammonia In methanol at 0 - 20℃; for 18h; | Intermediate I-54A: 3-hydroxypropanimidamide, HCl To a mixture of MeOH (5 mL, 124 mmol)/toluene (30.1 mL) at 0 °C was added acetyl chloride (3.00 mL, 42.2 mmol) slowly over 10 minutes. The reaction mixture was allowed to stir at 0 °C for 10 minutes then at room temperature for 10 minutes. Thereaction mixture was cooled to 0 °C and 3-hydroxypropanenitrile (1.5 g, 21.10 mmol) dissolved in 5 mL of toluene added and the reaction mixture was allowed to stir at room temperature for 18 h. The reaction mixture was cooled to 0 °C and 7N ammonia in MeOH (15.07 mL, 106 mmol) was added carefully over 5 minutes. The reaction mixture was then allowed to warm to room temperature and stirred for 18 h at room temperature.The mixture was then filtered through celite and the filter cake washed with 2:1 toluene/MeOH. The filtrate was concentrated to yield Intermediate I-54A in quantitative yield. The product was brought forward without further purification. ‘H NMR (400MHz, DMSO-d6) ö 3.70 (t, J=5.9 Hz, 2H), 2.77 (t, J5.9 Hz, 2H). |
With hydrogenchloride; methanol; diethyl ether Umsetzen des Reaktionsprodukts mit NH3 in Metahnol bei 0grad; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With ammonium hydroxide; hydrogen; silver nitrate In methanol at 45 - 75℃; High pressure; Inert atmosphere; Autoclave; | 1-10 A method for preparing 3-aminopropanol comprises the following steps: The nickel catalyst and silver nitrate are sucked into the high pressure reduction kettle through a vacuum pump, and then methanol and 3-hydroxypropionitrile are inhaled.Close the vacuum valve, open the vent valve, and replace the air in the kettle with nitrogen, at least three times.0.2MPa each time and slowly exhausted to vent, after the replacement is completed, close the vent valve and the vent valve, open the ammonia valve,Start stirring, open the jacket cooling water, and pass liquid ammonia;After the ammonia is completed, the stirring is stopped and the ammonia valve is closed, the hydrogen valve is opened, and the hydrogen gas is replaced three times to remove the residual nitrogen gas.Each time 0.2MPa and slowly exhaust venting, after the end of the replacement, close the valve and then start stirring and open the steam valve to raise the temperature to 45 °C to start the hydrogen.Keep the pressure inside the kettle 3MPa, the reduction kettle jacket and the inner coil pass the cooling water,The reaction temperature in the autoclave was controlled at 75 °C. When the hydrogen pressure no longer drops, it indicates that the reaction has reached the end point, stop stirring, and let stand for half an hour.Cool with jacket water to a temperature of 40 ° C in the kettle, relieve pressure, and then replace it three times with nitrogen.After that, it was pressed into the high-level settling tank with nitrogen gas to stand still for 6 hours.A small amount of catalyst and impurities are collected in the lower layer, and the upper layer is distilled. The nickel catalyst at the bottom of the reduction vessel still settles to the bottom, and the methanol is replenished for use.Put the upper layer of the settling tank into the distillation pot, open the vent valve, and heat up.When the liquid temperature starts at 95 ° C, the liquid is collected to collect methanol;After the methanol is collected, the temperature of the cooling kettle is 60 ° C for vacuum distillation, and the vacuum is kept below -0.09 MPa.When the top temperature reaches 90 ° C, the former fraction (very small amount of methanol) is collected, and when the top temperature reaches 95 ° C, the main fraction is collected.When the main fraction is collected, the temperature of the liquid is controlled to 110 ° C until the end of the collection, and the chromatographic test is performed.The content is more than 99% as a qualified product, and the yield is 98%. The molar ratio of 3-hydroxypropionitrile to aqueous ammonia was 1:1.15; the Raney nickel catalyst was used in an amount of 0.006% by mass of 3-hydroxypropionitrile. |
88% | With hydrogen; nickel In isopropyl alcohol at 60℃; 20-24 h; | |
80% | With ammonium hydroxide; hydrogen at 80℃; for 6h; Sealed tube; | 1.2 (2) Add the pure 3-hydroxypropionitrile to the high-pressure reaction kettle,Add wet Raney nickel catalyst (addition amount is 6wt% of 3-hydroxypropionitrile mass),Close the kettle lid, replace the air in the kettle with nitrogen three times, and then replace it with hydrogen once.Then press in 80g of liquid ammonia as a solvent and pressurize it with hydrogen to 8MPa,After holding the reaction at 80 for 6h, it was cooled to room temperature and ammonia gas was absorbed by the tail gas absorption device.The kettle liquid was filtered with suction, and the filter cake was washed with dichloromethane,The filtrate was concentrated under reduced pressure and prepared by rectification to obtain pure 3-aminopropanol with a yield of 80%. |
With nickel; formamide at 130℃; Hydrogenation.unter Druck, anschliessendes Erhitzen mit wss.Natronlauge; | ||
With ammonia; nickel at 75 - 90℃; Hydrogenation.unter Druck; | ||
With ammonia; nickel at 75 - 90℃; Hydrogenation.unter Druck; | ||
With nickel; formic acid ethyl ester at 130℃; Hydrogenation.unter Druck, anschliessendes Erhitzen mit wss.Natronlauge; | ||
95 g (86.5%, corr.) | With ammonia In methanol | 4.a (a) (a) Methanol/Ammonia, 75 bar (7.5 MPa) Hydrogen 100 g (1.39 mol, 99% according to GC) of 3-hydroxypropionitrile in 100 ml of methanol were placed in a 500 ml steel stirring autoclave equipped with a gasification stirrer. The solution was saturated with 60 g of gaseous ammonia. Subsequently, 10 g of Raney nickel were added and, after flushing with nitrogen, the autoclave was closed. The autoclave was pressurized to 22 bar (2.2 MPa) with hydrogen and the mixture was heated to 100° C. within one hour. The mixture was hydrogenated further at 100° C. while increasing the hydrogen pressure to 75 bar (7.5 MPa). After cooling the contents of the autoclave were filtered over 25 g of Speedex-Dicalite and rinsed with methanol. The major part of the methanol was removed by distillation at about 25 mbar (2.5 kPa)/40° C. This gave 108 g of a blue colored residue, which still contained some methanol. Distillation over a 10 cm packed column at 2-3 mbar (0.2-0.3 kPa) gave 95 g (86.5%, corr.) of 3-aminopropanol as a colorless distillate, b.pt. 59-63° C./2-3 mbar (0.2-0.3 kPa); content according to GC: 95.3%; 1H-NMR (CDCl3, 400 MHz): 1.68 (quint., J=6 Hz, 2H), 2.97, 2.3 (b, 3H), 2.97 (t, J=7 Hz, 2H), 3.81 (t, J=6 Hz, 2H); IR (film, cm1): 3350 (b, OH, NH2), 1050 (J). The residue weighed 6.5 g. |
With hydrogen In isopropyl alcohol | 4.d (d) (d) Isopropanol, 50 Bar (5.0 MPa) Hydrogen 100 g (1.39 mol, 99% according to GC) of 3-hydroxypropionitrile were placed in 100 g of isopropanol in a 500 ml steel stirring autoclave equipped with a gasification stirrer. 10 g of Raney nickel were added thereto while gassing with nitrogen and the autoclave was closed. The mixture was hydrogenated for 7 hours at 100° C. and 50 bar/5.0 MPa hydrogen pressure. Working up of the reaction, as in the foregoing variants (a)-(c), gave 112 g of a green-blue, oily residue, which was distilled, as usual, at 2-3 mbar/0.2-0.3 kPa. In this manner there were obtained 71.7 g (57.6%, corr.) of 3-aminopropanol as a colorless oil, b.pt. 61.3-64.7° C./2-3 mbar (0.2-0.3 kPa). Content according to GC: 84.1%. 1H-NMR (CDCl3, 400 MHz): identical with the spectrum given previously under (b). The invention being thus described, it will be obvious that the same may be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the invention and all such modifications are intended to be included within the scope of the following claims. | |
With ammonia; hydrogen | 4.c (c) (c) Ammonia, 50 bar (5.0 MPa) Hydrogen 200 g (2.78 mol, 99% according to GC) of 3-hydroxypropionitrile were placed in a 500 ml steel stirring autoclave equipped with a gasification stirrer, 20 g of Raney nickel were added and, after closing the autoclave, 60 g of ammonia were compressed in from a steel cylinder. After the additional compression of 22 bar (2.2 mbar) of hydrogen, the mixture was heated to 100° C., the hydrogen pressure was increased to 50 bar (5.0 MPa) and the mixture was hydrogenated at this temperature for 4 hours. After cooling the ammonia was evaporated off and the residue was filtered with methanol over 25 g of Speedex-Dicalite, rinsed with methanol and the major part of the methanol was removed under reduced pressure. This gave 211 g of a green-blue, oily residue, which was distilled over a 10 cm packed column at 2-3 mbar/0.2-0.3 kPa. In this manner there were obtained 182.2 g (83%, corr.) of 3-aminopropanol as a colorless oil, b.pt. 60-62.3° C./2-3 mbar (0.2-0.3 kPa). The oil crystallized at about 0° C. Content according to GC: 95.1%. 1H-NMR (CDCl3, 400 MHz): identical with the spectrum given previously under (b). | |
89.7 g (81%, corr.) | With ammonia In methanol | 4.b (b) (b) Methanol/Ammonia, 50 bar (50 MPa) Hydrogen 100 g (1.39 mol; 99% according to GC) of 3-hydroxypropionitrile were placed in 100 ml of methanol. The solution was saturated at 15-20° C. with 25 g of gaseous ammonia and thereafter transferred into a 500 ml steel stirring autoclave equipped with a gasification stirrer. Then 10 g of Raney nickel were added and, after flushing with nitrogen, the autoclave was closed. The autoclave was pressurized to 22 bar (2.2 MPa) with hydrogen and the mixture was heated to 100° C. within one hour. The hydrogen pressure was increased to 50 bar (5.0 MPa) and the 3-hydroxypropionitrile was hydrogenated for a further 5 hours at 100° C. After cooling the mixture was filtered over 25 g of Speedex-Dicalite, rinsed with methanol and the major part of the methanol was removed under reduced pressure. This gave 104 g of a blue-green residue. Distillation over a 10 cm packed column at 2-3 mbar/0.2-0.3 kPa gave 89.7 g (81%, corr.) of 3-aminopropanol as a colorless oil, b.pt. 60.2-64° C./2-3 mbar (0.2-0.3 kPa). The oil crystallized at about 0° C. Content according to GC: 93.6%; 1H-NMR (CDCl3, 400 MHz): 1.68 (quint., J=6 Hz, 2H), 2.27 (b, OH, NH2, 3H), 2.97 (t, J=7 Hz, 2H), 3.81 (t, J=6 Hz, 2H). |
With ammonia; hydrogen at 100℃; | 1 Ethylene cyanohydrin (450 kg/h) was converted together with ammonia (850 kg/h) in the presence of hydrogen at a pressure of 180 bar and a temperature of 100° C. in a tubular reactor. The catalyst used was a catalyst according to Example A of EP-A-0742045. The catalyst hourly space velocity was 0.3 kg of ECHD/kg of catalyst/hour.The reaction output was introduced into a distillation column which was operated at column top pressure of 17 bar (ammonia removal). The distillation column had 12 theoretical plates. The feed point was in the region of the 10th plate. The bottom temperature was 185° C.The output from the ammonia removal was analyzed by gas chromatography and comprised: 93 area % of 3-aminopropanol;2.5 area % of ammonia;3.0 area % of dihydroxypropylamine0.3 area % of diaminopropyl ether0.2 area % of ethanediol | |
With ammonia; nickel at 75 - 90℃; Hydrogenation.unter Druck; | ||
With ammonia; nickel at 75 - 90℃; Hydrogenation.unter Druck; | ||
With ammonia; hydrogen at 100℃; | 10 The catalyst prepared by the above method was evaluated in a fixed bed reactor. Before the reaction, it was activated in a hydrogen atmosphere, the temperature was 500°C, the pressure was normal pressure, the volumetric space velocity of hydrogen gas was 1500h-1, and the activation time was 5h. After the activation treatment, the temperature was lowered to the reaction temperature. The reaction temperature is 100, the reaction pressure is 8.0MPa, the liquid volumetric space velocity of 3-hydroxypropionitrile is 0.5h-1, the volumetric space velocity of hydrogen gas is 1000h-1, and the molar ratio of ammonia to 3-hydroxypropionitrile is 5.0:1.0 . For sampling and analysis, Agilent 7890 gas chromatograph was used for analysis. The chromatographic column was a DB-35 capillary column and the detector was a hydrogen flame detector. N,N-dimethylformamide (DMFA) was used as an internal standard for quantitative analysis. The results of the reaction are summarized in Table 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.1% | 3-hydroxypropionitrile 8 (10 mmol) was added to saturated aqueous sodium hydroxide (20 ml), and the mixture was stirred under reflux for 8 h. After acidized by concentrated hydrochloric acid, the resulting mixture was extracted with ethyl acetate (50 ml × 3). The combined organic extracts were dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under vacuum to afford 3-hydroxypropionic acid 9. Yield 92.1%, colourless oil. To a solution of 9 (5 mmol) and DIPEA (7.5 mmol) in CH2Cl2 (5 ml) was dropwise added a solution of TMSCl (6 mmol) in CH2Cl2 (5 ml) at 0 C. Then the mixture was stirred at rt for 1 h. After diluted in ethyl acetate (50 ml), the organic phase was washed with saturated brine (50 ml × 3), dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under vacuum to afford crude product 3-trimehylsilylpropionic acid 10. Yield 95.0%, light yellow oil. To a solution of 10 (4 mmol) and shikonin (2 mmol) in CH2Cl2 (10 ml) were added DCC (5 mmol) and DMAP (0.3 mmol). The mixture was stirred at rt for 1 h. After filtration, the solvent of the filtrate was removed to give the residue which was purified by flash column chromatography to give 11. Yield 87.5%, red oil. To a solution of 11 (2 mmol) in EtOH (5 ml) was added acetic acid (0.5 ml). The mixture was stirred for 15 min at rt. After dissolved in ethyl acetate (50 ml), the resulting mixture was washed with saturated NaHCO3 (50 ml) and brine (50 ml). The organic phase was dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under vacuum to afford the crude material which was purified by flash column chromatography to give 7a. Yield 74.5%. | |
89% | With hydrogenchloride; water; for 4h; | Add 275 g (2.04 mol) of 20% aqueous hydrocyanic acid solution and 0.5 g (catalyst) of triethylamine to a closed and pressure-resistant cyanide reaction kettle.Keep temperature at 15-20 , add 88.9g (2.0mol) of ethylene oxide (99%), and react for 2h;Sampling GC analysis showed that the ethylene oxide content was less than 1%. The reaction was stopped. 268.0 g (2.2 mol) of 30% hydrochloric acid was added to the reaction solution. After the addition, the temperature was raised to a boiling reaction for 4 hours.Sampling HPLC analysis of 3-hydroxypropionitrile content (calculated by area normalization method) less than 1%, cooling, neutralization with ammonia to pH = 4.0-4.5, and continuous chromatography separation (stationary phase: ammonium ion exchange resin; mobile phase : 0.008 mol / L HCl solution; flow rate: 16 mL / min; column temperature: 25 C.) to obtain an ammonium chloride solution and a 3-hydroxypropionic acid solution.The 3-hydroxypropionic acid solution was concentrated by distillation under reduced pressure and crystallized to obtain 163.4 g of a solid product with a content of 98.1% (determined by HPLC external standard method).The yield was calculated using the calculation method listed below and was 89.0% (calculated as ethylene oxide). After the ammonium chloride solution is concentrated, cooled and crystallized, and separated by a solid-liquid separator, ammonium chloride solids and mother liquor are obtained. The mother liquor contains a small amount of product, which can be recycled to the continuous chromatography process to recover some products and improve product yield. |
68% | With water; calcium chloride; In aq. buffer; at 30℃; for 5h;pH 8.0;Catalytic behavior; | To evaluate the reusability of the immobilized cells, two kinds of reaction media, Tris-HCl buffer and distilled water, were used for batch reaction. The reaction was performed with free or immobilized cells (containing 20 g/L of wet cells) suspending in 10 mL of reaction medium contained 3.0 mol/L of substrate and 20 mmol/L of CaCl2 at 30C for 5 h. After each reaction, the beads were washed by distilled water and transferred to fresh reaction mixture. Repeated batch reaction was carried out under the same conditions as the first cycle. |
With water; In aq. phosphate buffer; at 37℃;pH 7.0;Green chemistry; Enzymatic reaction; | General procedure: A typical reaction mixture (5 mL in 25 mL shake flask) contained thenitrile substrate and appropriate amount of E. coli cell mass expressingthe selected nitrilase suspended in 100mM phosphate buffer pH 7. Inthe case of mandelonitrile, conversion experiments were performed inaqueous buffer containing 10 % methanol to aid substrate solubility.The catalytic reaction was performed at 37 C with agitation at 150 rpmin an incubator shaker. Aliquots (100 mul) were withdrawn at regularpredetermined time intervals and quenched with 10 mul of 1M HCl. Thereaction mixture was centrifuged and filtered using a 0.45 mum syringefilter, and the product formed was monitored through HPLC analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With triethylamine In ethyl acetate at 20 - 60℃; | Synthesis of 2-cyano-ethylacetoacetate (Intermediate I) In the reactor were successively added 720g of ethyl acetate, 370g 3-hydroxy propionitrile, 10g triethylamine, stirring slowly dropped 400g diketene, in the process of dropping the temperature gradually increased to reflux and in reflux state of completion of the addition. After the completion of dropwise addition, the reaction was heated to 60°C was cooled to room temperature and stirred for 2 to 3 hours, thereto was added a saturated aqueous 800ml sodium bicarbonate , stirring and liquid separation. The organic phase was washed successively with 800ml water and 800ml saturated sodium chloride aqueous solution, anhydrous sodium sulfate, and concentrated under reduced pressure to give 640g yellow liquid intermediate I, after testing HPLC purity 99.84% (see Figure 1), yield 86%. |
85.8% | With triethylamine In ethyl acetate at 80℃; Large scale; | 1.1; 2.1 Example 1 Preparation of Barnidipine Hydrochloride (1) 600 g of 3-hydroxypropionitrile, 400 g of ethyl acetate, and 15 g of triethylamine were added to the reaction flask.The temperature was raised to 80 ° C, while diketene (645 g) / ethyl acetate solution (1100 g) was slowly added dropwise.After about 1~2h, the addition is completed; then the reaction is kept for 1~2h, and the TLV detection reaction is completed.After cooling to room temperature, a saturated sodium hydrogencarbonate solution was added dropwise to the reaction solution, and the mixture was stirred.The organic phase is taken, washed with purified water, dried over organic phase, filtered and concentrated.1021 g of Intermediate 1 was obtained in a yield of 85.8%. |
With sodium acetate for 16h; Ambient temperature; |
at 70 - 80℃; for 2.5h; | ||
With triethylamine In toluene | ||
at 10 - 90℃; | 1.1 This embodiment of the process for synthesizing hydrochloric acid ramiah of lercanidipine, comprising the following steps: (1) 3-hydroxy-propionitrile (I) and (II) organic ketene dimer in the presence of catalyst the reaction, the reaction temperature is 10 °C, preferably 90 °C, the reaction time is 72h, is preferably 3, compound (VI) can be obtained; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | MeOH(50mL) was placedinathreeneckroundedflaskattachedacondenserandanadditionfunnelandwascooledat0C.ConcentratedHCl12M(4mL,38.8mmol,0.26eq,222mmolH2O,1.2eq)wasadded.Thionylchloride(6.6mL,91.5mmol,0.5eq)wasaddeddropwiseover10min,andthereactionmixturewaswarmeduptoroomtemperature.3-Hydroxypropionitrile(12.5mL,183mmol,1.0equiv)wasaddeddropwiseover20min,thenthemixturewasreluxedin 5h producing white precipitate. Then the reaction mixture was cooled in an ice bath,neutralized with Na2CO3. Solids were removed by filtration, the biphasic filtrate wasconcentratedunderreducedpressure,andthecrudematerialwaspurifiedbydistillation(0.25mmHg,41-44C,collectingfractionsinanicebath)toyieldmethyl-3-hydroxy-propionoate(8.9g,86mmol,47%).1HNMR(300MHz,CDCl3)delta3.84(t,J=6.1Hz,2H);3.63(s,3H);2.76(brs,1H,OH);2.55(td,J=5.8,1.6Hz,2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With triethylamine In diethyl ether at 0 - 23℃; for 16.3333h; | |
98.5% | Stage #1: 3-Hydroxypropionitrile With triethylamine at 0℃; Stage #2: chloro-trimethyl-silane In diethyl ether at 0℃; for 0.583333h; | 4 Example 4 A, 1 mol of 3-hydroxypropionitrile and 1.07 mol of triethylamine were mixed and stirred and cooled to 0 ° C to obtain a mixed solution; B, control temperature 0 ° C,0.87 mol of trimethylchlorosilane was added to the ether.Magnetic stirring for 11min,The mixture obtained in the step A is added dropwise three times in a ratio of 2:3:4 by volume.The dropping time of three times of control was 12 min, 10 min, and 8 min, respectively.Stir until no trimethylchlorosilane is detected.The reaction is completed (timed, the reaction time is 35 min),Filtration, distillation under reduced pressure, drying,122.6 g of 3-[(trimethylsilyl)oxy]propanenitrile were obtained. |
98% | With triethylamine In diethyl ether at 0 - 23℃; for 16h; Inert atmosphere; Schlenk technique; |
92% | With triethylamine In diethyl ether at 0℃; for 16h; Inert atmosphere; | |
71.4% | With urea at 20℃; for 4h; | |
80.92 g | With triethylamine In diethyl ether at 0℃; for 2h; | |
With triethylamine In diethyl ether |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With dmap; dicyclohexyl-carbodiimide In dichloromethane for 5h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 15% 2: 78% | With amino(methyl)aluminum chloride In toluene at 80℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With pyridine In acetonitrile at 20℃; for 8.5h; Cooling with ice; | 11 (Synthesis of Compound Ce-1) N,N′-Disuccinimidyl carbonate (8.0 g, 31.2 mmol) and pyridine (2.7 mL, 33.5 mmol) were added to a solution of 2-cyanoethanol (1.85 ml, 27.3 mmol) in acetonitrile (160 mL) under ice cooling, and the resultant solution was stirred at room temperature for 8 hours and 30 minutes. The reaction solution was subjected to distillation under reduced pressure, then dichloromethane and an aqueous sodium bicarbonate solution were added to a residue, and the resultant solution was extracted with dichloromethane. An organic layer thus obtained was washed with saturated saline, and was then dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was removed by filtration, and then a filtrate was subjected to distillation under reduced pressure to produce a crude product, and the crude product was purified by silica gel column chromatography (dichloromethane:acetonitrile=1:0 to 4:1) to produce compound Ce-1 (5.58 g, 96%) as a white solid substance.1H NMR (CDCl3) δ 2.86 (2H, t, J=6 Hz), 2.87 (4H, s), 4.53 (2H, t, J=7 Hz). |
87% | In pyridine; acetonitrile for 6h; | |
87% | With pyridine In acetonitrile for 7h; Inert atmosphere; | 1 Preparation of N-(2-cyanoethoxycarbonyloxy)succinimide (CEOC-O-Succinimide) To a stirred solution of 2-cyanoethanol (7.23 grams, 102 mmol) in anhydrous CH3CN (300 ml), under argon atmosphere, N,N′-disuccinimidyl carbonate (34.0 grams, 133 mmol) was added, followed by the addition of pyridine (11.3 ml, 140 mmol). The resulting suspension was stirred and became a clear solution after about 1 hour. The solution was stirred for additional 6 hours and was then concentrated under reduced pressure. The residue was re-dissolved in dichloromethane (200 ml), and was washed with a saturated NaHCO3 solution (3×50 ml) and a saturated NaCl solution (3×50 ml). The organic layer was then dried over anhydrous Na2SO4 and concentrated to afford the crude product as a white solid. Traces of pyridine were removed from the crude product by co-evaporation with dry acetonitrile. The obtained white solid was dried overnight under reduced pressure and was then triturated with ether (150 ml) to yield 20.23 grams (94% yield) of partially purified Compound 1 as a colorless amorphous powder. The partially purified product was stable at room temperature, when stored in desiccators for an extended period (1-2 years). Proton and carbon NMR spectra showed that the partially purified compound is homogeneous. Further purification of the product was performed by chromatography on silica gel using a 50:50 CH2Cl2:EtOAc mixture as eluent, to give pure Compound 1 a white crystalline compound (18.72 grams, 87% yield). TLC: (50:50 CH2Cl2:EtOAc) Rf=0.21; m.p.=105.5° C.; 1H-NMR (CDCl3): δ=2.85 (t, J=6.62 Hz, 2H), 2.86 (s, 4H), 4.45 (t, J=5.96 Hz). |
84% | With pyridine In acetonitrile at 20℃; for 7h; Inert atmosphere; | |
With pyridine In acetonitrile |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With 1H-imidazole In N,N-dimethyl-formamide at 0 - 30℃; | 32.1 Step 1; Synthesis of 3-(tert-butyl-dimethyl-silanyloxy)-propionitrile To a solution of 3- hydroxy-propionitrile (50g, 704.2 mmol) in dimethylformamide (250 ml) was added imidazole (72 g, 1056 mmol) under stirring at 25-30°C and allowed to cool to 0°C. To the resulted reaction mass was added solid tert-butyl dimethylsilyl chloride (106 g, 704 mmol) under stirring. The progress of reaction was monitored by TLC (hexane: ethyl acetate, 1: 1). After complete consumption of starting material the reaction was quenched by adding it to water (2.5 L) and extracted with diethyl ether (3x500 ml). The combined organic extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 130 g of 3-(tert-butyl-dimethyl-silanyloxy)- propionitrile as colourless oil in 100% yield |
98% | With 1H-imidazole In tetrahydrofuran at 40℃; for 15h; | |
94% | With 1H-imidazole In dichloromethane at 20℃; |
86% | With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 0.5h; | |
77% | With 1H-imidazole In tetrahydrofuran at 0 - 20℃; for 16h; | |
75% | With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 17h; | 16.1 Example 16 Example 16: Synthesis of (2S,5R)-2-( 5-( ( 1 -guanidinocyclopropyl)methyl)isoxaz.ol-3-yl)-7- Synthetic scheme: TBSCI, imidazole DMF, rt, 17 h 75% 30% 90% Characterization: (2S,5R)-2-(5-((l-guanidinocyclopropyl)methyl)isoxazol-3-yl)-7-oxo-l,6- diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate (613, 28 mg) was obtained as a white solid after prep-HPLC purification using ammonium formate buffer. ESI-MS (ΕΓ, m/z) 401.3. 1H NMR (300 MHz, D20) δ 6.35 (s, 1H), 4.61 (d, / = 6.6 Hz, 1H), 4.12 (br s, 1H), 3.11 - 3.09 (m, 1H), 3.08 - 2.98 (m, 2H), 2.89 (d, / = 12.0 Hz, 1H), 2.20 - 2.00 (m, 3H), 1.89 - 1.78 (m, 1H), 0.97 - 0.95 (m, 4H). |
75% | With 1H-imidazole In N,N-dimethyl-formamide at 0 - 20℃; for 12h; | 23.1 Example 23: Synthesis of (2S,5R)-2-( 5-( ( 1 -aminocyclopropyl)methyl)-l ,3 ,4-oxadiazol-2-yl)- -oxo-l,6-diazabicyclo[3.2.11octan-6-yl hydrogen sulfate ( Compound 724): Step 1 Example 23: Synthesis of (2S,5R)-2-( 5-( ( 1 -aminocyclopropyl)methyl)-l ,3 ,4-oxadiazol-2-yl)- -oxo-l,6-diazabicyclo[3.2.11octan-6-yl hydrogen sulfate ( Compound 724): Step 1: Synthesis of 3-(tert-butyldimethylsilyloxy)propanenitrile: Imidazole (33.6 g, 495 mmol) and ieri-butyldimethylsilyl chloride (27.2 g, 180 mmol) were added to a 0 °C solution of 3-hydroxypropanenitrile (10.6 g, 150 mmol) in DMF 50 mL). The mixture was allowed to warm to rt, then was stirred at rt for 12 hrs. The mixture was quenched with water (500 mL), and then extracted with EtOAc (3x). The combined organic layer was dried over Na2S04 and concentrated. The residue was purified by silica gel column chromatography (gradient elution 0-5% EtO Ac/petroleum ether) to give 3-(tert- butyldimethylsilyloxy) propanenitrile (18 g, 75%) as a colorless oil. 1H NMR (400 MHz, CDCI3): δ 3.74 (t, / = 6.0 Hz, 2H), 2.43 (t, / = 6.0 Hz, 2H), 0.81 (s, 9H), 0.00 (s, 6H). Step 2: Synthesis of 1 -(2-(tert-butyldimethylsilyloxy)ethyl)cyclopropanamine: To a solution of 3-(ieri-butyldimethylsilyloxy)propanenitrile (11.1 g, 60 mmol) in Et20 (400 mL) was added titanium tetraisopropanolate (28.9 g, 102 mmol) under N2 atmosphere. Ethylmagnesium bromide (3M in Et20, 50 mL) was slowly added drop-wise at 0 °C. The mixture was stirred at rt for 1 hr. Boron trifluoride etherate (17.0 g, 120 mmol) was slowly added at 0 °C. The mixture was stirred at rt for 1 hr. The mixture was quenched with 10% aq. NaOH (300 mL) and then extracted with DCM (3x). The combined organic layer was dried over Na2S04 and concentrated. The residue was purified by silica gel column chromatography (gradient elution 5-50% EtOAc/petroleum ether) to afford -{2-{tert- butyldim ethylsilyloxy )ethyl)cyclopropanamine (3.9 g, 30%) as a colorless oil. ESI-MS (EI+, m/z): 216.2 [M+H]+. Step 3: Synthesis of tert-butyl 1 -(2-(tert-butyldimethylsilyloxy)ethyl)cyclopropyl-carbamate: A solution of l-(2-(ieri-butyldimethylsilyloxy)ethyl)cyclopropanamine (1.9 g, 8.8 mmol), (Boc)20 (2.9 g, 13.2 mmol), NaHC03 (1.5 g, 17.6 mmol) in THF/H20 (20 mL/20 mL) was stirred at rt for 17 hrs. The mixture was extracted with EtOAc (3x). The combined organic layer was dried over Na2S04 and concentrated. The residue was purified by silica gel column chromatography (0-15% gradient elution EtO Ac/petroleum ether) to afford ieri-butyl l-(2- (ieri-butyldimethylsilyloxy)ethyl)cyclopropylcarbamate (2.5 g, 90%) as a colorless oil. ESI- MS (EI+, m/z): 316 [M+H]+. Step 4: Synthesis of tert-butyl l-(2-hydroxyethyl)cyclopropylcarbamate: A solution of ieri-butyl l-(2-(ieri-butyldimethylsilyloxy)ethyl)cyclopropylcarbamate (11.9 g, 37.8 mmol) and 3HF TEA (22.0 g) in DCM (50 mL) was stirred at rt for 17 hrs. The mixture was concentrated and the residue was purified by silica gel column chromatography (0-20% gradient elution EtO Ac/petroleum ether) to afford ieri-butyl l-(2- hydroxyethyl)cyclopropylcarbamate (4.6 g, 60%) as a white solid. Step 5: Synthesis of2-(l-(tert-butoxycarbonylamino)cyclopropyl)acetic acid: RuCi3.H20 (124 mg, 0.6 mmol) was added to a solution of ieri-butyl l-(2- hydroxyethyl)cyclopropylcarbamate (6.1 g, 30 mmol), and NaI04 (19.0 g, 90 mmol) in DCM/H20/CH3CN (20 mL/40 mL/20 mL). The mixture was stirred at rt for 3 hrs. The mixture was then diluted with H20 (100 mL), and extracted with DCM (3x). The combined organic layer was dried over Na2S04 and concentrated. The residue was purified by silica gel column chromatography (0-30% gradient elution EtO Ac/petroleum ether) to afford 2-(l- (ieri-butoxycarbonylamino)cyclopropyl)acetic acid (6.0 g, 90%) as a white solid. ESI-MS (EI+, m/z): 238 [M+Na]+. Step 6: Synthesis of tert-butyl l-(2-(2-((2S, 5R)-6-(benzyloxy)-7-oxo-l, 6-diaza- bicyclo[3.2.1]octane-2-carbonyl)hydrazinyl)-2-oxoethyl)cyclopropylcarbamate: A solution of 2-(l-(ieri-butoxycarbonylamino)cyclopropyl)acetic acid (1.5 g, 6.9 mmol), (25',5 ?)-6-(benzyloxy)-7-oxo-l,6-diaza-bicyclo[3.2.1]octane-2-carbohydrazide (3.1 g, 7.6 mmol), DIPEA (2.7 g, 21.0 mmol), and HATU (3.9 g, 10.45 mmol) in DMF (20 mL) was stirred at 0 °C for 1 hr. The mixture was quenched with saturated sodium chloride (150 mL) and EtOAc (150 mL). The organic layer was separated and washed with saturated sodium chloride (2x), dried over Na2S04, and concentrated. The residue was purified by silica gel column chromatography (0-80% gradient elution EtO Ac/petroleum ether) to afford ieri-butyl l-(2-(2-((25,5/?)-6-(benzyloxy)-7-oxo-l,6-diaza-bicyclo[3.2.1]octane-2- carbonyl)hydrazinyl)-2-oxoethyl)cyclopropylcarbamate (2.4 g, 70%) as a white solid. ESI- MS (EI+, m/z): 488 [M+H]+. Step 7: Synthesis of 'tert-butyl l-((5-((2S,5R)-6-(benzyloxy)-7-oxo-l,6-diaza- bicyclo[ 3.2.1 ]octan-2-yl)-l,3,4-oxadiazol-2-yl)methyl)cyclopropylcarbamate: Method A: Pyridine (5.2 g, 65.6 mmol) was added to a O °C solution of ieri-butyl l-(2-(2-((25,5/?)-6- (benzyloxy)-7-oxo-l,6-diaza-bicyclo [3.2.1 ]octane-2-carbonyl)hydrazinyl)-2- oxoethyl)cyclopropylcarbamate (4.0 g, 8.2 mmol) in DCM (40 mL). Tf20 (5.7 g, 20.5 mmol) was added slowly at 0 °C. The reaction mixture was stirred at 0 °C for 3.5 hrs. Sat. NaHCC>3 was added very slowly at 0 °C. The organic layer was separated and washed with saturated sodium chloride (2x), dried over Na2S04, and concentrated. The residue was purified by silica gel column chromatography (0-70% gradient elution EtOAc/petroleum ether) to afford ieri-butyl l-((5-((25,5/?)-6-(benzyloxy)-7-oxo-l,6-diaza-bicyclo[3.2.1]octan-2-yl)-l,3,4- oxadiazol-2-yl)methyl)cyclopropylcarbamate (2.6 g, 65%) as a yellow solid. ESI-MS (EI+, m/z): 470 [M+H]+. Method B: To s solution of PPh3 (5.2 g, 20.0 mmol) in dry DCM (60 mL) was added I2 (5.1 g, 20.0 mmol). After I2 was dissolved completely, TEA (7.0 mL, 50.0 mmol) was added quickly at rt. The mixture was stirred for 15 mins. 7ri-butyl l-(2-(2-((25',5 ?)-6-(benzyloxy)-7-oxo-l,6- diaza-bicyclo[3.2.1]octane-2-carbonyl)hydrazinyl)-2-oxoethyl)cyclopropyl-carbamate (4.9 g, 10.0 mmol) was added and the mixture was stirred at rt for 1 hr. The solvent was concentrated. EtO Ac (250 mL) was added, and the solution was filtered to remove ΡΡ10. The filtrate was concentrated and the residue was purified by silica gel column chromatography (0-60% gradient elution EtOAc/petroleum ether) to afford ieri-butyl l-((5- ((25',5 ?)-6-(benzyloxy)-7-oxo-l,6-diaza-bicyclo[3.2.1]octan-2-yl)-l,3,4-oxadiazol-2- yl)methyl)cyclopropyl-carbamate (4.1 g, 87%) as a white solid. ESI-MS (EI+, m/z): 470 [M+H]+. Step 8-10: Following Steps 3-5 in Example 4, replacing ieri-butyl (2-(5-((2S,5R)-6- (benzyloxy)-7-oxo-l,6-diazabicyclo[3.2.1]octan-2-yl)-l ,3,4-oxadiazol-2-yl)ethyl)carbamate in Step 3 with ieri-butyl (l-((5-((2S,5R)-6-(benzyloxy)-7-oxo-l,6-diazabicyclo[3.2.1]octan- 2-yl)-l,3,4-oxadiazol-2-yl)methyl)cyclopropyl)carbamate; (2S,5R)-2-(5-((l- aminocyclopropyl)methyl)-l,3,4-oxadiazol-2-yl)-7-oxo-l ,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate (0.78 g) was obtained as a white solid after prep-HPLC purification using ammonium formate buffer. ESI-MS (EI+, m/z): 360.1. *H NMR (300 MHz, D20) δ 4.75 (d, J = 6.4 Hz, 1H), 4.16 (br s, 1H), 3.25 (s, 2H), 3.17 (br d, / = 12.7 Hz, 1H), 2.95 (d, / = 12.4 Hz, 1H), 2.34 - 2.03 (m, 3H), 2.00 - 1.82 (m, 1H), 1.08 - 0.86 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With dmap; triethylamine In tetrahydrofuran at 20℃; for 3.5h; | |
48.23% | With 1H-imidazole In dichloromethane at 20℃; for 1h; Inert atmosphere; | 28.1 Step 1: Synthesis of 3-((tert-butyldiphenylsilyl)oxy)propanenitrile To a stirred solution of ethylene cyanohydrin (1.00 g, 14.07 mmol, 1.00 equiv) and imidazole (1.92 g, 28.14 mmol, 2.00 equiv) in DCM (30.00 mL) was added tert-butyl(chloro)diphenylsilane (4.64 g, 16.88 mmol, 1.20 equiv). The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. The resulting mixture was washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 3-[(tert-butyldiphenylsilyl)oxy]propanenitrile (2.1 g, 48.23%) as a colorless oil. |
5.0 g | With 1H-imidazole In dichloromethane for 14h; |
With dmap; triethylamine In dichloromethane at 20℃; | 20.A A)_ Preparation of 3-(tert-butyldiphenyl-silyloxy)propanenitrile._ ;To a solution of 3-hydroxypropanenitrile (7.1 g, 0.1 mol) and DMAP (1.22 g, 0.01 mmol) in 30 mL of dry DCM at room temperature was added NEt3 (30.3 g, 0.3 mol), followed by tert-butyldiphenyl-silylchloride (27.5 g, 0.1 mol). A lot of white solid appeared. After stirring at room temperature overnight, the reaction mixture was quenched with Sat. NH4Cl solution, extracted with DCM, dried over Na2SO4, and evaporated in vaco. Flash chromatography (SiO2, hexane/EtOAc=100:2 to 100:5 to 100:10) gave the title compound as a white solid. | |
With dmap; triethylamine In dichloromethane at 20℃; | 8.i 3-(tert-butyldiphenylsilyloxy)-propanenitrile.To a solution of 3-hydroxypropanenitrile (7.1 g, 0.1 mol) and DMAP (1.22 g, 0.01 mmol) in dry DCM (30 mL) at room temperature was added NEt3 (30.3 g, 0.3 mol), followed by TBDPSCl (27.5 g, 0.1 mol). A lot of white solid appeared. After stirring at room temperature overnight, the reaction mixture was quenched with sat. NH4Cl solution, extracted with DCM, dried over Na2SO4, and evaporated in vacuo. Flash chomatography (SiO2, hexane/EtOAc = 100:2 to 100:5 to 100:10) of the crude material gave the title compound as a white solid. | |
With dmap; triethylamine In dichloromethane at 20℃; | 21.1 Step 1: Preparation of 3-(tert-butyldiphenylsilyloxy)-propanenitrile:; To a solution of 3-hydroxypropanenitrile (7.1 g, 0.1 mol) and DMAP (1.22 g, 0.01 mmol) in 30 mL of dry DCM at room temperature was added NEt3 (30.3 g, 0.3 mol), followed by TBDPSCl (27.5 g, 0.1 mol). A lot of white solid appeared. After stirring at room temperature overnight, the reaction mixture was quenched with sat. NH4Cl solution, extracted with DCM, dried over Na2SO4, and evaporated in vaco. Flash chomatography (SiO2, hexane/EtOAc=100:2 to 100:5 to 100:10) gave of 3-(tert-butyldiphenylsilyloxy)propanenitrile as a white solid. | |
With triethylamine at 20℃; | 7.A To a solution of 3-hydroxypropanenitrile (7.1 g, 0.1 mol) and DMAP (1.22 g, 0.01 mmol) in dry DCM (30 mL) at room temperature was added Et3N (30.3 g, 0.3 mol), followed by TBDPSCl (27.5 g, 0.1 mol). A lot of white solid were formed. After stirring at room temperature overnight, the reaction mixture was quenched with sat. NH4Cl solution, extracted with DCM, dried over Na2SO4, and evaporated in vaco. Flash chromatography (SiO2, hexane/EtOAc = 100:2 to 100:5 to 100: 10) of the crude gave of 3-(tert-butyldiphenyl- silyloxy)propanenitrile as a white solid. | |
With dmap; triethylamine In dichloromethane at 20℃; | 7.A Reference 7; Synthesis of 2-(5(Λ/5)-amino-5,6,7,8-tetrahydroquinazolin-2-yl)ethanol; Step A: Synthesis of 3-(tert-butyldiphenylsilyloxy)-propanenitrile; To a solution of 3-hydroxypropanenitrile (7.1 g, 0.1 mol) and DMAP (1.22 g, 0.01 mmol) in dry DCM (30 mL) at room temperature was added Et3N (30.3 g, 0.3 mol), followed by TBDPSCl (27.5 g, 0.1 mol). A lot of white solid were formed. After stirring at room temperature overnight, the reaction mixture was quenched with sat. NH4Cl solution, extracted with DCM, dried over Na2SO4, and evaporated in vaco. Flash chromatography (SiO2, hexane/EtOAc = 100:2 to 100:5 to 100:10) of the crude gave of 3-(tert- butyldiphenylsilyloxy)propanenitrile as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzene at 40 - 50℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With dicyclohexyl-carbodiimide In pyridine at 0 - 20℃; for 24.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With hydrogen In methanol at 20℃; for 53h; | |
81% | With palladium 10% on activated carbon; hydrogen In methanol at 20℃; for 53h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With acetic anhydride; acetic acid at 20℃; for 48h; | |
70% | Stage #1: dimethyl sulfoxide; 3-Hydroxypropionitrile With acetic anhydride; acetic acid at 20℃; for 24h; Stage #2: With water; sodium hydrogencarbonate for 1h; | 1.1 Step 1 Production of methylthiomethyl 2-cyanoethyl ether 3-Hydroxypropionitrile (32 g, 450 mmol) was dissolved in 450 mL of dimethylsulfoxide, and 324 mL of acetic anhydride and 231 mL of acetic acid were added thereto, and the reaction solution was stirred at room temperature for 24 hours. Sodium bicarbonate (990 g) was dissolved in 4.5 L of water, and the reaction solution was added to the aqueous sodium bicarbonate solution dropwise over 1 hour, and was subjected to extraction with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained oily product was purified by silica gel column chromatography to obtain 41 g of methylthiomethyl 2-cyanoethyl ether as a colorless oily product (yield 70 %). 1H-NMR (CDCl3): 2.18 (s, 3H), 2.66 (t, 2H, J = 6.3 Hz), 3.77 (t, 2H, J = 6.3 Hz), 4.69 (s, 2H) |
70% | Stage #1: dimethyl sulfoxide; 3-Hydroxypropionitrile With acetic anhydride; acetic acid at 20℃; for 24h; Stage #2: With sodium hydrogencarbonate In water at 20℃; for 1h; | 1 3-Hydroxypropionitrile (32 g, 450 mmol) was dissolved in 450 mL of dimethylsulfoxide, and 324 mL of acetic anhydride and 231 mL of acetic acid were added thereto, and the reaction solution was stirred at room temperature for 24 h. Sodium bicarbonate (990 g) was dissolved in 4.5 L of water, and the reaction solution was added dropwise to the aqueous sodium bicarbonate solution over 1 h, and was subjected to extraction with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The oily product obtained was purified by silica gel column chromatography to give 41 g of methylthiomethyl 2-cyanoethyl ether as a colorless oily product (yield 70%). 1H-NMR (CDCl3) : 2.18 (s, 3H), 2.66 (t, 2H, J = 6.3 Hz), 3.77 (t, 2H, J = 6.3 Hz), 4.69 (s, 2H). |
70% | With acetic anhydride; acetic acid at 20℃; for 24h; | 1.1 Production of methylthiomethyl 2-cyanoethyl ether Step 1 Production of methylthiomethyl 2-cyanoethyl ether 3-Hydroxypropionitrile (32 g, 450 mmol) was dissolved in 450 mL of dimethylsulfoxide, and 324 mL of acetic anhydride and 231 mL of acetic acid were added thereto, and the reaction solution was stirred at room temperature for 24 hours. Sodium bicarbonate (990 g) was dissolved in 4.5 L of water, and the reaction solution was added to the aqueous sodium bicarbonate solution dropwise over 1 hour, and was subjected to extraction with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained oily product was purified by silica gel column chromatography to obtain 41 g of methylthiomethyl 2-cyanoethyl ether as a colorless oily product (yield 70%). 1H-NMR (CDCl3): 2.18 (s, 3H), 2.66 (t, 2H, J=6.3 Hz), 3.77 (t, 2H, J=6.3 Hz), 4.69 (s, 2H) |
70% | Stage #1: dimethyl sulfoxide; 3-Hydroxypropionitrile With acetic anhydride; acetic acid at 20℃; for 24h; Stage #2: With sodium hydrogencarbonate In water for 2h; | 1.1 3-Hydroxypropionitril (32 g, 450 mmol) was dissolved in 450 mL of dimethylsulfoxide, and 324 mL of acetic anhydride and 231 mL of acetic acid were added thereto, and the reaction solution was stirred at room temperature for 24 hours. Sodium bicarbonate (990 g) was dissolved in 4.5 L of water, and the reaction solution was added to the aqueous sodium bicarbonate solution dropwise over 1 hour. The reaction solution was stirred for 1 hour, and was subjected to extraction with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained oily product was purified by silica gel column chromatography to obtain 41 g of methylthiomethyl 2-cyanoethylether as a colorless oily product (yield 70 %). 1H-NMR (CDCl3) : 2.18 (s, 3H); 2.66 (t, 2H, J =6.3 Hz); 3.77 (t, 2H, J =6.3 Hz); 4.69 (s, 2H). |
44% | With acetic anhydride; acetic acid at 20℃; for 48h; | 1; 43 3-(methylthio)methoxy)propanenitrile (2). 3-(methylthio)methoxy)propanenitrile (2). To a stirred solution of 3-hydroxypropanenitrile (1, 3g, 42.3mmol) in dry DMSO (78ml), acetic acid (36ml) and acetic anhydride (120ml) were added. The mixture was stirred at room temperature for 2 days, and then quenched by adding to a saturated NaHCCb solution (150ml). The aqueous solution was extracted with ethyl acetate (150 mL x 3) and the combined organic phase was dried over anhydrous NaaSO/t. The crude product 2 was concentrated and purified by flash column chromatography (ethyl acetate :hexane 8:2). Light yellow oil (2.41 g, 44%) was afforded. NMR (400 MHz, Chloroform-d) δ 4.69 (s, 2H), 3.77 (t, J = 6.2 Hz, 2H), 2.65 (t, J = 6.3 Hz, 2H), 2.19 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.2% | With N-Bromosuccinimide In toluene at 90℃; for 3h; | 1-3 Example 1, Synthesis of acetoacetic acid nitrile ethyl ester: 28.4 g of 3-hydroxypropionitrile, 46.4 g of methyl acetoacetate, 14.2 g of N-bromosuccinimide (NBS) were added to a 250 ml reaction flask, 150 ml of toluene was added, and the temperature was raised to 90 ° C. After reacting for 3 h, it was cooled to room temperature, filtered, and the filtrate was washed three times with water and then dried to give a yellow liquid, 59 g, yield 95.2%, and HPLC purity of 92%. |
88% | With Candida antarctica lipase B at 40℃; | |
37.4% | With N-Bromosuccinimide In toluene at 120℃; Inert atmosphere; | 1 Preparation of Intermediate 1-3: To a toluene (100 mL) solution of methyl 3-oxobutyrate (10.0 g) was added 3-hydroxypropionitrile (16.4 g), NBS (5.0 g). The resulting suspension was stirred overnight under the protection of nitrogen at 120°C. TLC (petroleum ether: ethyl acetate = 3:1) indicated that the reaction was complete. Then water was added to quench the reaction, extracted with ethyl acetate, the organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. Purification by silica gel chromatography (petroleum ether: ethyl acetate=3:1 elution) gave Intermediate 1-3 (5.0 g, 37.4% yield) as a yellow oily liquid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With 1,2-bis-(diphenylphosphino)ethane; cobalt(II) chloride; zinc In 1-methyl-pyrrolidin-2-one at 25℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 75% 2: 7% | In chlorobenzene at 20℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1,4-dioxane; ethanol; chloroform; | Synthesis of 5,5'-dithiobis(2-nitrobenzoate)propionitrile <strong>[69-78-3]5,5'-dithiobis(2-nitrobenzoic acid)</strong> [Ellman's reagent] (500 mg,1.26 mmol) was dissolved in 4.0 ml dioxane. Dicylohexylcarbodiimide (540 mg, 2.6 mmol) and 3-hydroxypropionitrile (240 muL, 188 mg, 2.60 mmol) were added. The reaction mixture was stirred overnight at room temperature. The urea precipitate was removed by centrifugation. The dioxane was removed on rotary evaporator. The residue was washed with saturated bicarbonate, water, and brine; and dried over magnesium sulfate. Solvent removal yielded 696 mg yellow/orange foam. The residue was purified using normal phase HPLC (Alltech econosil, 250*22 nm), flow rate=9.0 ml/min, mobile phase=1% ethanol in chloroform, retention time=13 min. Removal of solvent afforded 233 mg (36.8%) product as a yellow oil. TLC (silica: 5% methanol in chloroform; rf=0.51). H1 NMR ? 8.05 (d, 4H), 7.75 (m, 4H), 4.55 (t, 4H), 2.85 (t, 4H). | |
233 mg (36.8%) | In 1,4-dioxane; ethanol; chloroform; | Example 1 Synthesis of 5,5'-Dithiobis(2-nitrobenzoate)propionitrile <strong>[69-78-3]5,5'-dithiobis(2-nitrobenzoic acid)</strong> (500 mg, 1.26 mmol, Aldrich Chemical Company) was taken up in 4.0 mL dioxane. Dicylohexylcarbodiimide (540 mg, 2.6 mmol, Aldrich Chemical Company) and 3-hydroxypropionitrile (240 muL, 188 mg, 2.60 mmol, Aldrich Chemical Company) were added. The reaction mixture was stirred overnight at room temperature. The precipitate was removed by centrifugation, and the solvent concentrated under reduced pressure. The residue was washed with saturated sodium bicarbonate, water, and brine; and dried over magnesium sulfate. Solvent removal (aspirator) yielded 696 mg yellow/orange foam. The residue was purified using normal phase HPLC (Alltech econosil, 250*22 nm), flow rate=9.0 mL/min, mobile phase=1% ethanol in chloroform, retention time=13 min. Removal of solvent (aspirator) afforded 233 mg (36.8%) of 5,5'-dithiobis(2-nitrobenzoate)propionitrile as a yellow oil. TLC (silica: 5% methanol in chloroform; Rf=0.51). H1 NMR 8.05 (d, 4 H), 7.75 (m, 4H), 4.55 (t, 4H), 2.85 (t, 4H). |
233 mg (36.8%) | In 1,4-dioxane; ethanol; chloroform; | Example 11 Synthesis of 5,5'-Dithiobis(2-nitrobenzoate)propionitrile <strong>[69-78-3]5,5'-dithiobis(2-nitrobenzoic acid)</strong> (500 mg, 1.26 mmol, Aldrich Chemical Company) was taken up in 4.0 mL dioxane. Dicylohexylcarbodiimide (540 mg, 2.6 mmol, Aldrich Chemical Company) and 3-hydroxypropionitrile (240 muL, 188 mg, 2.60 mmol, Aldrich Chemical Company) were added. The reaction mixture was stirred overnight at room temperature. The precipitate was removed by centrifugation, and the solvent concentrated under reduced pressure. The residue was washed with saturated sodium bicarbonate, water, and brine; and dried over magnesium sulfate. Solvent removal (aspirator) yielded 696 mg yellow/orange foam. The residue was purified using normal phase HPLC (Alltech econosil, 250*22 nm), flow rate=9.0 mL/min, mobile phase=1% ethanol in chloroform, retention time=13 min. Removal of solvent (aspirator) afforded 233 mg (36.8%) of 5,5'-dithiobis(2-nitrobenzoate)propionitrile as a yellow oil. TLC (silica: 5% methanol in chloroform; Rf=0.51). H1NMR ? 8.05 (d, 4 H), 7.75 (m, 4H), 4.55 (t, 4H), 2.85 (t, 4H). |
In 1,4-dioxane; methanol; ethanol; chloroform; | Synthesis of Activated Disulfide Containing Co-monomers Synthesis of 5,5'-dithiobis(2-nitrobenzoate)propionitrile: <strong>[69-78-3]5,5'-dithiobis(2-nitrobenzoic acid)</strong> [Ellman's reagent] (500 mg, 1.26 mmol) was dissolved in 4.0 ml dioxane. Dicylohexylcarbodiimide (540 mg, 2.6 mmol) and 3-hydroxypropionitrile (240 muL, 188 mg, 2.60 mmol) were added. The reaction mixture was stirred overnight at room temperature. The urea precipitate was removed by centrifugation. The dioxane was removed on rotary evaporator. The residue was washed with saturated bicarbonate, water, and brine; and dried over magnesium sulfate. Solvent removal yielded 696 mg yellow/orange foam. The residue was purified using normal phase HPLC (Alltech econosil, 250*22 nm), flow rate=9.0 ml/min, mobile phase=1% ethanol in chloroform, retention time=13 min. Removal of solvent afforded 233 mg (36.8%) product as a yellow oil. TLC (silica: 5% methanol in chloroform; rf=0.51). H1 NMR delta8.05 (d, 4 H), 7.75 (m, 4H), 4.55 (t, 4H), 2.85 (t, 4H). | |
In 1,4-dioxane; methanol; ethanol; chloroform; | Synthesis of Activated Disulfide Containing Co-monomers Synthesis of 5,5'-dithiobis(2-nitrobenzoate)propionitrile: <strong>[69-78-3]5,5'-dithiobis(2-nitrobenzoic acid)</strong> [Ellman's reagent] (500 mg, 1.26 mmol) was dissolved in 4.0 ml dioxane. Dicylohexylcarbodiimide (540 mg, 2.6 mmol) and 3-hydroxypropionitrile (240 muL, 188 mg, 2.60 mmol) were added. The reaction mixture was stirred overnight at room temperature. The urea precipitate was removed by centrifugation. The dioxane was removed on rotary evaporator. The residue was washed with saturated bicarbonate, water, and brine; and dried over magnesium sulfate. Solvent removal yielded 696 mg yellow/orange foam. The residue was purified using normal phase HPLC (Alltech econosil, 250*22 mn), flow rate=9.0 ml/min, mobile phase=1% ethanol in chloroform, retention time=13 min. Removal of solvent afforded 233 mg (36.8%) product as a yellow oil. TLC (silica: 5% methanol in chloroform; rf=0.51). H1 NMR delta8.05 (d, 4 H), 7.75 (m, 4H), 4.55 (t, 4H), 2.85 (t, 4H). | |
In 1,4-dioxane; methanol; ethanol; chloroform; | Synthesis of Activated Disulfide Containing Co-monomers Synthesis of 5,5'-dithiobis(2-nitrobenzoate)propionitrile: <strong>[69-78-3]5,5'-dithiobis(2-nitrobenzoic acid)</strong> [Ellman's reagent] (500 mg,1.26 mmol) was dissolved in 4.0 ml dioxane. Dicylohexylcarbodiimide (540 mg, 2.6 mmol) and 3-hydroxypropionitrile (240 muL, 188 mg, 2.60 mmol) were added. The reaction mixture was stirred overnight at room temperature. The urea precipitate was removed by centrifugation. The dioxane was removed on rotary evaporator. The residue was washed with saturated bicarbonate, water, and brine; and dried over magnesium sulfate. Solvent removal yielded 696 mg yellow/orange foam. The residue was purified using normal phase HPLC (Alltech econosil, 250*22 nm), flow rate=9.0 ml/min, mobile phase=1% ethanol in chloroform, retention time=13 min. Removal of solvent afforded 233 mg (36.8%) product as a yellow oil. TLC (silica: 5% methanol in chloroform; rf=0.51). H1NMR ? 8.05 (d, 4H), 7.75 (m, 4H), 4.55 (t, 4H), 2.85 (t, 4H). | |
In 1,4-dioxane; ethanol; chloroform; | Synthesis of 5,5'-dithiobis(2-nitrobenzoate)propionitrile <strong>[69-78-3]5,5'-dithiobis(2-nitrobenzoic acid)</strong> [Ellman's reagent] (500 mg,1.26 mmol) was dissolved in 4.0 ml dioxane. Dicylohexylcarbodiimide (540 mg, 2.6 mmol) and 3-hydroxypropionitrile (240 muL, 188 mg, 2.60 mmol) were added. The reaction mixture was stirred overnight at RT. The urea precipitate was removed by centrifugation. The dioxane was removed on rotary evaporator. The residue was washed with saturated bicarbonate, water, and brine; and dried over magnesium sulfate. Solvent removal yielded 696 mg yellow/orange foam. The residue was purified using normal phase HPLC (Alltech econosil, 250*22 nm), flow rate=9.0 ml/min, mobile phase=1% ethanol in chloroform, retention time=13 min. Removal of solvent afforded 233 mg (36.8%) product as a yellow oil. TLC (silica: 5% methanol in chloroform; rf=0.51). H1 NMR ?8.05 (d, 4 H), 7.75 (m, 4H), 4.55 (t, 4H), 2.85 (t, 4H). | |
233 mg (36.8%) | In 1,4-dioxane; ethanol; chloroform; | Example 11 Synthesis of 5,5'-Dithiobis(2-nitrobenzoate)propionitrile <strong>[69-78-3]5,5'-dithiobis(2-nitrobenzoic acid)</strong> (500 mg, 1.26 mmol, Aldrich Chemical Company) was taken up in 4.0 mL dioxane. Dicylohexylcarbodiimide (540 mg, 2.6 mmol, Aldrich Chemical Company) and 3-hydroxypropionitrile (240 muL, 188 mg, 2.60 mmol, Aldrich Chemical Company) were added. The reaction mixture was stirred overnight at room temperature. The precipitate was removed by centrifugation, and the solvent concentrated under reduced pressure. The residue was washed with saturated sodium bicarbonate, water, and brine; and dried over magnesium sulfate. Solvent removal (aspirator) yielded 696 mg yellow/orange foam. The residue was purified using normal phase HPLC (Alltech econosil, 250*22 nm), flow rate=9.0 mL/min, mobile phase=1% ethanol in chloroform, retention time=13 min. Removal of solvent (aspirator) afforded 233 mg (36.8%) of 5,5'-dithiobis(2-nitrobenzoate)propionitrile as a yellow oil. TLC (silica: 5% methanol in chloroform; Rf=0.51). H1NMR ? 8.05 (d, 4 H), 7.75 (m, 4H), 4.55 (t, 4H), 2.85 (t, 4H). |
In 1,4-dioxane; ethanol; chloroform; | Synthesis of 5,5'-dithiobis(2-nitrobenzoate)propionitrile: <strong>[69-78-3]5,5'-dithiobis(2-nitrobenzoic acid)</strong> [Ellman's reagent] (500 mg,1.26 mmol) was dissolved in 4.0 ml dioxane. Dicylohexylcarbodiimide (540 mg, 2.6 mmol) and 3-hydroxypropionitrile (240 muL, 188 mg, 2.60 mmol) were added. The reaction mixture was stirred overnight at room temperature. The urea precipitate was removed by centrifugation. The dioxane was removed on rotary evaporator. The residue was washed with saturated bicarbonate, water, and brine; and dried over magnesium sulfate. Solvent removal yielded 696 mg yellow/orange foam. The residue was purified using normal phase HPLC (Alltech econosil, 250*22 nm), flow rate=9.0 mlmin, mobile phase=1% ethanol in chloroform, retention time=13 min. Removal of solvent afforded 233 mg (36.8%) product as a yellow oil. TLC (silica: 5% methanol in chloroform; rf=0.51). H1NMR ?8.05 (d, 4 H), 7.75 (m, 4H), 4.55 (t, 4H), 2.85 (t, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In 1,4-dioxane; water; isopropyl alcohol; | Method B: A mixture of 894 mg of ethyl 3-(furan-3-yl)-3-oxopropionate (4.90 mmol) and 347 mg of 3-hydroxypropionitrile (4.88 mmol) was heated in an oil bath to 180-205 C. for 0.5 hrs. The reaction mixture was cooled and distilled under reduced pressure. Three fractions were obtained. 1 H NMR indicated that the third fraction (bp 100-140 C. (0.5 mm Hg)) was a 1:1 mixture of ethyl 3-(furan-3-yl)-3-oxopropionate and 2-cyanoethyl 3-(furan-3-yl)-3-oxopropionate. This mixture was used in the condensation step after spectral characterization. A solution of the 3-oxoesters (approximately 1.67 mmol), 192 mg of methyl 3-aminocrotonate (1.67 mmol), and 252 mg of 4-nitrobenzaldehyde (1.67 mmol) in 5 mL of isopropanol was heated at reflux temperature for 30 hrs, cooled, and the solvent was removed in vacuo. The residue was dissolved in 15 mL of dioxane and 15 mL of water (containing 35 mg of NaOH), stirred for 0.5 hr, and concentrated in vacuo. The residue was partitioned between ethyl acetate and water (20 mL each), separated, and the aqueous extract was washed with ethyl acetate (2*20 mL). The organic solutions were discarded. The aqueous extract was acidified with concentrated HCl (pH=3), and the resulting cloudy mixture was extracted with ethyl acetate (2*30 mL). The combined organic extracts were dried (Na2 SO4), and the solvent was removed in vacuo to give 2-(furan-3-yl)-1,4-dihydro-5-methoxycarbonyl-6-methyl-4-(4-nitro)phenylpyridine-3-carboxylic acid as a yellow oil that partially solidified under reduced pressure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
toluene-4-sulfonic acid; In water; ethyl acetate; toluene; | 2-Cyanoethyl 4-(2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethoxy)-3-oxobutanoate Ethyl 4-(2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) ethoxy)-3-oxobutanoate (8g, 25mmoles) and 3-hydroxypropionitrile (12g, 170mmoles) were heated at 100 under N2 for 10 hours in toluene (100ml) containing a catalytic amount of 4-methylphenylsulphonic acid. Ethyl acetate and water were added; the organic layer was separated, washed with water, dried (MgSO4) and the solvent evaporated. Chromatography on silica eluding with ethyl acetate/petroleum ether (60-80) mixtures gave the title ester (8.9g). M/e 345 M+1+; NMR delta (CDCl3) 4.14 (s,2H), 3.53 (s,2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With boron trifluoride diethyl etherate In dimethyl amine at 120℃; for 15h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1H-tetrazole; In acetonitrile; at 20℃; for 0.333333h; | Example 12'-deoxythymidine monocyaniminomonophosphate370 mg (0.5 mmol) 3'-dimethoxytriyl-2'-deoxythymidine, 5'-[(2-cyanoethyl)- (N,N-diisopropyl)]-phosphoramidite (GlenResearch) is dissolved under argon in 2.5 ml anhydrous acetonitrile and firstly 2.2 ml of a 0.45 M solution of tetrazole in acetonitrile (Fluka) and then 150 mul (1.5 mmol) 3-hydroxypropionitrile are successively added. The reaction mixture is stirred for 20 minutes at room temperature and subsequently 1.56 ml of a 0.32 M solution of cyanogen azide in acetonitrile is added (cyanogen azide prepared according to: McMurry, J.E., et al., J. Organic Chemistry 38(16) (1973) 2821-7). After 30 minutes the solution is diluted <n="16"/>with ethyl acetate and shaken out with water. The organic phase is dried with sodium sulphate and the solvent is evaporated on a rotary evaporator. 8 ml 7 N methanolic ammonia solution is added to the residue and allowed to stand for 5 hours at room temperature in a sealed vessel. The solvent is removed, water is added to the residue and the water is also removed. The oily residue is dissolved in 40 ml of an 80 % acetic acid solution and stirred for 15 min at room temperature. The acetic acid is removed on a rotary evaporator. The residue is dissolved in 10 ml 37 % aqueous ammonia, afterwards the ammonia is removed and the product is purified over a DEAE Sephadex A25 anion exchanger (eluant gradient: from 0.1 M ammonium acetate solution pH = 7 in 120 minutes to 1 M ammonium acetate solution pH = 7). Mass (ESI) M/e 347.1 (calculated C11H15N4O7P 345.2), IH NMR (D2O, ppm) 7.76 (s, IH), 6.34 (t, IH), 4.42 (m, IH), 4.16 (m, IH), 4.04 (m, 2H), 2.36 (m, 2H), 1.94 (s, 3H), 31P NMR (D2O, ppm) 1.5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 75% 2: 7% | With (triphenylphosphine)gold(I) chloride; silver trifluoromethanesulfonate In chlorobenzene at 20℃; for 16h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In N,N-dimethyl-formamide at 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 69% 2: 8.5% | Stage #1: 3-Hydroxypropionitrile With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1h; Stage #2: benzyl bromide In tetrahydrofuran at -78 - 0℃; | 1 Preparation of 3-amino-2-benzyl-1-propanesulfonic acid (Compound N4); To a cold (-78° C.) solution of 3-hydroxypropionitrile (1 g, 14.06 mmol) in THF (30 mL), was added a solution of lithium bis(trimethylsilyl)amide (1 M in THF, 28 mL). After the reaction mixture was stirred for 1 h at -78° C., benzyl bromide (1.67 mL, 14.06 mmol) was added dropwise and the reaction mixture was warmed to reach 0° C. at which temperature the mixture was stirred overnight. The reaction was quenched with 1N HCl and extracted with EtOAc. The organic layer was washed with 1N HCl, dried over Na2SO4 and concentrated. The residue was applied on silica gel column (eluant:Hexanes:EtOAc 70:30 to 50:50) to afford 1.3 g (69%) of the 2-benzyl-3-hydroxypropionitrile. 1H NMR (300 MHz, CDCl3) δ 2.80 (bs, 1H), 2.95 (m, 3H), 3.77 (m, 2H), 7.20-7.35 (m, 5H); 13C NMR (125 MHz, CDCl3) δ 34.71, 37.03, 61.98, 120.78, 127.58, 129.06, 129.25, 136.71. The dialkylated product was isolated in 8.5% yield. To a solution of 2-benzyl-3-hydroxypropionitrile (obtained in step 1, 3 g, 24.75 mmol) in EtOH (60 mL) was added an aqueous solution of NH4OH (30%, 20 mL), followed by Ra-Ni (3 g). The suspension was stirred under atmosphere H2 pressure for 15 hours and then filtered. The filtrate was concentrated under high vacuum; and the residual product (3-1mino-2-benzyl-1-propanol) was used in the next step without purification. A solution of the crude 3-amino-2-benzyl-1-propanol (4.5 g, 27.23 mmol) in anhydrous CHCl3 (24 mL) was saturated with HCl (g), and then SOCl2 (5.2 mL, 71.0 mmol) was added dropwise at reflux. The reaction was maintained under reflux for an additional 2 hours. The reaction was then concentrated to yield a syrupy product. The crude 3-chloro-2-benzyl-1-propylamine thus obtained was used in the next step without further purification. A solution of the crude 3-chloro-2-benzyl-1-propylamine (obtained in step 3) in water (10 mL) was added dropwise to a solution of Na2SO3 (6.8 g, 54.46 mmol) in water (25 mL) under reflux. After the end of the addition, the reaction was stirred at reflux for 1 hour, then cooled down and concentrated under reduced pressure. HCl (conc. 16 mL) were added to dissolve the aminosulfonic acid and precipitate the inorganic salts which were removed by filtration. The filtrate was concentrated; and ethanol was added. The title amino sulfonic acid was precipitated as white solid which was collected by filtration, washed with EtOH and Et2O, then dried under high vacuum to give a white solid (1.87 g, 30% yield over three steps). 1H NMR (500 MHz, D2O) δ 2.52 (m, 1H), 2.8 (m, 2H), 2.94 (m, 2H), 3.08 & 3.18 (ABX, J=13.0 & 7.0 Hz, 2H), 7.25-7.37 (m, 5H). 13C NMR (125 MHz, D2O) δ 35.47, 37.78, 42.67, 52.55, 127.15, 129.09, 129.54, 138.32. ES-MS 228 (M-1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With N-ethyl-N,N-diisopropylamine at 150℃; for 1h; Inert atmosphere; Neat (no solvent); | General procedure: Alcohol (1 mmol), p-methoxybenzyl chloride (1.1 mmol) and diisopropylethylamine (2 mmol) were charged in reaction vessel equipped with magnetic stirring bar under nitrogen atmosphere. The mixture was refluxed in 150 °C bath for 2 h. The resulting mixture typically showed two phases. Ethyl acetate (5 mL) and 10% aqueous sodium bisulphate (5 mL) were added to the mixture and the organic phase extracted by three potions of EtOAc. Combined organic layer was dried over magnesium sulfate and the solvent evaporated in vacuo. Further purification was carried out by silica gel column chromatography. |
70% | Stage #1: 3-Hydroxypropionitrile With sodium hydride In tetrahydrofuran at 0℃; for 0.166667h; Stage #2: benzyl bromide In tetrahydrofuran; N,N-dimethyl-formamide at 0℃; for 2h; | 67 3-Benzyloxypropionitrile (I-67) A 12.3 g (0.308 mol) portion of sodium hydride was suspended in tetrahydrofuran (200 ml), 20.0 ml (0.293 mol) of 3-hydronypropionitrile was added dropwise thereto while keeping the internal temperature below 0°C, and the mixture was stirred at the same temperature for 10 minutes. Subsequently, 36.6 ml (0.308 mol) of benzyl bromide was added thereto, and then N,N-dimethylformamide (40 ml) was added thereto by taking care of exothermic reaction. After 2 hours of stirring at 0°C, the reaction solution was concentrated, and the resulting residue was poured into saturated ammonium chloride aqueous solution. This was extracted with chloroform, and the organic layer was washed with brine and then dried over magnesium sulfate. The solvent was evaporated, and the thus obtained residue was applied to a silica gel column chromatography, and 33.0 g (70%) of the title compound was obtained as a pale yellow oily substance from a n-hexane-ethyl acetate (5:1 v/v) eluate. 1H-NMR (CDCl3)δ: 2.62 (2H, t, J= 6.4 Hz), 3.68 (2H, t, J= 6.4 Hz), 4.58 (2H, s), 7.25-7.37 (5H, m). |
44% | With N-ethyl-N,N-diisopropylamine at 150℃; for 2h; | 1 A mixture of 3-hydroxypropanenitrile (10.0 g, 141 mmol, 9.52 mL, 1.00 eq), (bromomethyl)benzene (24.1 g, 141 mmol, 16.7 mL, 1.00 eq) and N,N-diisopropylethylamine (21.8 g, 169 mmol, 29.4 mL, 1.20 eq) was heated to 150 °C and stirred at 150 °C for 2 h. The mixture was cooled to room temperature and diluted with sulfuric acid (1 M, 100 mL) and ethyl acetate (100 mL). The organic layer was washed with water (100 mL), dried over sodium sulfate, filtered and the filtrate was concentrated to afford a brown oil. The brown oil was distilled under vacuum (~5 torr) and collected the distillate between 140 to 150 °C to give 3- (benzyloxy)propanenitrile (10 0 g, 62.0 mmol, 44% yield) as colorless oil 1H NMR (400 MHz, CDC13) d = 7.43 - 7.28 (m, 5H), 4.58 (s, 2H), 3.68 (t, J = 6.4 Hz, 2H), 2.62 (t, J = 6.4 Hz, 2H). |
24.7 g | Stage #1: 3-Hydroxypropionitrile With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.666667h; Stage #2: benzyl bromide In tetrahydrofuran; mineral oil at 0 - 20℃; | 4-1.1 Synthesis of 3-(benzyloxy)propanenitrile (1) Synthesis of 3-(benzyloxy)propanenitrile To a suspension of sodium hydride (60% dispersion in mineral oil; 14.6 g) in tetrahydrofuran (281 mL), ethylene cyanohydrin (21.0 mL) was added dropwise at 0°C and the mixture was stirred at that temperature for 40 minutes. After adding benzyl bromide (44.4 mL) to the reaction mixture, the resulting mixture was stirred overnight as it was brought to room temperature. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, which was then extracted with ethyl acetate three times. The combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (n-hexane:ethyl acetate = 100:0-70:30) to give 3-(benzyloxy)propanenitrile as a colorless oil (24.7 g). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.63 (t, J=6.4 Hz, 2 H) 3.69 (t, J=6.4 Hz, 2 H) 4.59 (s, 2 H) 7.27 - 7.41 (m, 5 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Example 27; A 3.0 g quantity (6.7 iranol) of <strong>[150683-30-0]tolvaptan</strong> (compound (2)) were added in small portions to a pyridine solution (15 ml) of 3.8 ml (20 mmol) of diphenyl phosphite, and the obtained mixture was stirred at room temperature for 0.5 hours. To this mixture was added 2.8 ml (40 mmol) of 3-hydroxypropionitrile, and stirring was performed at room temperature for 0.5 hours. To the obtained reaction mixture was added 1 N hydrochloric acid, and extraction was performed with ethyl acetate. The ethyl acetate layer was washed with water, dried over sodium sulfate, and then filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate : methanol = 100 : 0 ? 10 : 1) . The purified product was concentrated under reduced pressure to give 2.8 g of white amorphous solid target compound. Yield: 75%1H-NMR (Toluene-d8, 100 0C) delta ppm : 1.4-2.0 (6H, m) , 2.33 (3H, s), 2.40 (3H, s), 3.1-3.8 (4H, m) , 5.40 (0.5H, d, J = 3.1Hz), 5.3-5.4 (IH, m), 6.5-6.7 (IH, m) , 6.7-6.9 (IH, m) , 6.9-7.2 (6H, m) , 7.2- 7.5 (2H, m), 7.76 (0.5H, d, J = 8.5 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 5'-O-dimethoxytrityl-N-isobutyryldeoxyguanosine With pyridine; diphenyl hydrogen phosphite for 2h; Inert atmosphere; Stage #2: 3-Hydroxypropionitrile for 2h; | A.1.1 Step 1-2N-Isobutyryl-3'-O-(2-Cyanoethyl)H-Phosphonate-5'O-Dimetoxytrityl deoxyguanosine (A4-I)2N-Isobutyryl-50-Dimetoxytrityl deoxyguanosine (0.5 g, 0.78 mmol) was dried by co-evaporation with dry toluene and suspended in dry pyridine (10 mL) under inert atmosphere. Diphenyl phosphite (250 μL, 1.3 mmol) was added and stirred for 2 h. 3-hydroxypropionitrile (150 μL, 2.16 mmol) was added. After stirring for 2 hr, the solvent was evaporated. The oily crude was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 4-2N-Isobutyryl-5'O-Dimetoxytrityl-3'O-tertbutyldimethylsilyl-2'-O-(2-cyanoethyl)H-Phosphonate Guanosine (A9-V)Compound (A9-IV) (0.78 mmol) was dried by co-evaporation with dry toluene and suspended in dry pyridine (10 mL) under inert atmosphere. Diphenyl phosphite (250 muL, 1.3 mmol) was added and stirred for 2 h. 3-hydroxypropionitrile (150 muL, 2.16 mmol) was added. After stirring for 2 hr, the solvent was evaporated. The oily crude was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With palladium 10% on activated carbon; hydrogen In methanol at 20℃; for 48h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.2% | With dihydrogen peroxide In water monomer; acetonitrile at 20℃; for 0.25h; | 3 Example 3 Add 5ml of acetonitrile and 3a (0.97mmol, 0.15g) into a 25ml round-bottomed flask in turn, stir evenly,Then add FeBr2 (0.10mmol, 0.021g) or FeBr3 (0.10mmol, 0.029g) to the mixture in turn,Aqueous H2O2 (30 wt%, 0.97 mmol, 98 ul), and the reaction was stirred at room temperature for 15 min. After completion of the reaction, the reaction was quenched with Na2S2O3 solution (0.1M) and extracted with ethyl acetate. The organic phases were combined, washed with water in sequence, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target product 2b (yield: 94.2%). |
92% | With silica-supported NaHSO4 In methanol at 20℃; for 0.25h; | |
81% | With zinc(II) trifluoromethanesulfonate In methanol at 20℃; for 0.666667h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.3% | Stage #1: benzonitrile; 3-Hydroxypropionitrile With hydrazine hydrate; 3-mercaptopropionic acid In ethanol at 0 - 40℃; for 13h; Inert atmosphere; Stage #2: With hydrogenchloride; sodium nitrite In ethanol; water | |
66.3% | Stage #1: benzonitrile; 3-Hydroxypropionitrile With hydrazine hydrate; 3-mercaptopropionic acid at 40℃; for 13h; Stage #2: With hydrogenchloride; sodium nitrite In water at 0℃; | 3 Preparation of tetrazine compounds of the present invention Benzonitrile (102μL, 1mmol), 3-hydroxypropionitrile (272μL, 4mmol), 3-mercaptopropionic acid (87μL, 1mmol) was added to the 10mL reaction tube, the reaction tube was placed in an ice bath, hydrazine hydrate (777μL, 16mmol) was added, and then stirred at 40 °C for 13h, the reaction is complete; pour the reaction solution into an ice water solution of sodium nitrite (1.03g, 15mmol), and slowly add hydrochloric acid (1M) at 0°C to the solution pH=4, the reaction was carried out. After the completion of the reaction was detected by TLC, the resulting solution was extracted 3 times with ethyl acetate, 20 ml each time separate the liquids in a separatory funnel, combine the organic phases extracted three times, wash once with saturated brine (20ml), and separate the liquids in a separatory funnel to obtain the organic phase. The organic phase was dried with anhydrous sodium sulfate and filtered with a glass sand funnel to obtain the filtrate. The filtrate was transferred to a round bottom flask, and concentrated under reduced pressure to obtain a crude red solid. After purification by silica gel chromatography, a pink solid compound (134 mg) was obtained with a yield of 66.3%. |
36% | Stage #1: benzonitrile; 3-Hydroxypropionitrile With zinc trifluoromethanesulfonate; hydrazine In 1,4-dioxane at 70℃; for 40h; Inert atmosphere; Stage #2: With hydrogenchloride; sodium nitrite In 1,4-dioxane; water Inert atmosphere; Cooling with ice; |
36% | Stage #1: benzonitrile; 3-Hydroxypropionitrile With zinc trifluoromethanesulfonate; hydrazine In 1,4-dioxane at 70℃; for 40h; Inert atmosphere; Stage #2: With hydrogenchloride; sodium nitrite In 1,4-dioxane Inert atmosphere; | 6 Example 6 Synthesis of 3-phenyl-6-hydroxyethyl-s-tetrazine Tze Example 6 Synthesis of 3-phenyl-6-hydroxyethyl-s-tetrazine Tze To a 50 mL flask equipped with a stir bar, Zn(OTf)2 (363 mg, 1.0 mmol), 3-hydroxy-propionitrile (430 mg, 6 mmol), benzonitrile (206 mg, 2 mmol), and anhydrous hydrazine (1.5 mL, 50 mmol), dioxane (1 mL) were added. The reaction was protected with a shield. Under N2 gas, the mixture was stirred in an oil bath at 70° C. for 40 hours. Sodium nitrite (20 mmol, 1.4 g) in 20 mL of ice water was slowly added to the solution, followed by slow addition of 1M HCl during which the solution turned bright red in color and gas evolved. Addition of 1M HCl continued until gas evolution ceased and the pH value was 3. The solution was extracted with EtOAc (50 mL*3), the combined organic layer was dried over Na2SO4 and evaporated. The residue was purified by silica column (Hexanes:EtOAc=1.5:1) to afford 143 mg Tze product as pink solid, with a yield of 36%. 1H NMR (500 MHz, CDCl3) δ 8.65-8.50 (m, 2H), 7.70-7.53 (m, 3H), 4.30 (t, J=5.8 Hz, 2H), 3.62 (t, J=5.8 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 168.66, 164.93, 133.17, 131.92, 129.69, 129.69, 128.37, 128.37, 60.44, 37.85. HRMS [M+H]+ m/z calcd. for C10H11N4O]+ 203.0927, found 203.0925. |
With zinc trifluoromethanesulfonate; hydrazine hydrate at 70℃; Schlenk technique; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With aluminum dihydrogen phosphate | Scheme 16 depicts a synthesis scheme for 1ND1N. 1ND1N cannot be chemically dried with sodium (Na), calcium oxide (CaO), or calcium hydride (CaH2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With formic acid; 5%-palladium/activated carbon; In water; at 20℃; | Example 9 3-Diethylaminopropanol Using Water Diethylamine (3.78 mL; 36.6 mmol; 2.5 equiv) and water (2.47 mL) were added to a 100-mL flask. Formic acid (96%; 1.21 mL; 30.7 mmol; 2.1 equiv) was added dropwise with a small exotherm. The cooling bath was removed and the mixture was allowed to warm to ambient temperature. 3-Hydroxypropionitrile (1.0 mL; 14.6 mmol) was added followed by 5% palladium on carbon (42.3% in water; 180 mg; 7.5 wt % based on hydroxypropionitrile). The mixture was stirred at RT and samples were removed and analyzed for conversion of 3-hydroxypropionitrile to 3-diethylaminopropanol by 1H NMR: 1 h, 39% conversion; 2 h, 52% conversion; 3 h, 60% conversion. 1H NMR (DMSO-d6): delta 3.42 (t, 2H, J=6.30 Hz); 2.46 (q, 4H, J=7.00 Hz); 2.45 (t, 2 h, J=6.80 Hz); 1.53 (m, 2H); 0.94 (t, 6H, J=7.10 Hz). | |
With 5%-palladium/activated carbon; hydrogen; In water; at 20℃; under 3087.28 Torr; for 4h; | 5% Palladium on carbon (49.5% in water; 218 mg; 5 wt% based on 3-hydroxypropionitrile) was added to a Parr pressure bottle. Water (3.21g) was added followed by diethylamine (2.68 g; 36.6 mmol; 1 .25 equiv) and 3- hydroxypropionitrile (2.08 g; 29.3 mmol). The mixture was placed under 45 psig hydrogen and shaken at ambient temperature. The reaction was stopped after 4h and sampled and analyzed by 1H NMR to indicate 72% conversion. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 5%-palladium/activated carbon; hydrogen; In water; at 20℃; under 3087.28 Torr; for 4h; | 5% Palladium on carbon (49.5% in water; 218 mg; 5 wt% basedon 3-hydroxypropionitrile) was added to a Parr pressure bottle. Water (3.21g) was added followed by diethylamine (2.14 g; 29.3 mmol; 1.0 equiv). Diethylamine hydrochloride (0.802g; 7.32 mmol; 0.25 equiv) was added followed by 3-hydroxypropionitrile (2.08 g; 29.3 mmol). The mixture was placed under 45 psig hydrogen and shaken at ambient temperature. Thereaction was stopped after 4h and sampled and analyzed by 1H NMR to indicate 69% conversion. 1H NMR (DMSO-d6) O (ppm): 3.45 (t, 2H, J = 6.3 Hz); 2.50 (t, 2H, J= 7.4 Hz); 2.44 (q, 4H, J= 7.2 Hz); 1.54 (m(5), 2H, J= 6.3 Hz); 0.95 (t, 6H, J= 7.1 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With hydrogenchloride; thionyl chloride; In water; at 0 - 20℃; for 6h;Reflux; | Ethanol (1L) was placed in a three-necked flask, stirred and cooled to 0 C.Concentrated hydrochloric acid (80 mL) was added dropwise slowly.Then slowly add thionyl chloride (132 mL).The system slowly rise to room temperature.3-Hydroxypropionitrile (250 g) was slowly added dropwise, and the system was refluxed for 6 hours.A large amount of white powder appeared.The system was cooled to 0 C and the pH was adjusted to about 7 with solid sodium carbonate.Filtration, concentration of the filtrate, distillation to obtain 208 g of ethyl 3-hydroxypropionate, yield 50% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With bismuth(III) chloride In acetonitrile at 80℃; for 24h; | General procedure for the hydroalkoxylation of α,β-unsaturated ketone General procedure: 1-(4-Methoxyphenyl)prop-2-en-1-one (1h, 0.1622 g, 1.0 mmol, 1.0 equiv.), alcohol 3 (6.0mmol, 6 equiv.) and BiCl3 (0.0631 g, 0.20 mmol, 20 mol%) were stirred in CH3CN (1 mL) at 80 °C for 24 h. Upon completion of the reaction (as indicated by TLC), the reaction mixture was directly concentrated in vacuo. The obtained crude residue was purified by silica gel column chromatography using ethyl acetate and petroleum ether as eluant to afford the pure β-alkoxylketone 4. |
88% | With chromium(III) chloride hexahydrate In acetonitrile at 80℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1H-tetrazole In acetonitrile at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With 1H-tetrazole; diisopropylamine In acetonitrile at 20℃; for 2h; | 4.1.4. O-(2-Cyanoethyl)-O'-(S-pivaloyl-2-thioethyl)-N,N-diisopropylaminophosphoramidite (7) To a solution of 2-hydroxypropionitrile (0.38 mL, 5.61 mmol) inacetonitrile (55 mL) were added S-pivaloyl-2-thioethyl N,N-bis(-diisopropylamino)phosphine (3.30 g, 8.41 mmol), N,N-diisopropylamine(1.57 mL, 11.22 mmol) and 1H-tetrazole (0.714 g,11.22 mmol). The mixture was stirred at room temperature for 2 hand then diluted in ethyl acetate (200 mL). This solution waswashed with satured aq. NaHCO3. The resulting organic layer wasdried over Na2SO4, filtered and concentrated under reduced pressure.After co-evaporation with cyclohexane/1% NEt3, silica gelcolumn flash-chromatography (gradient ethyl acetate 0-10% incyclohexane/1% NEt3) gave the desired phosphoramidite 7 ascolorless oil (1.85 g, 84%). Rf (cyclohexane/AcOEt/NEt3, 80/19/1, v/v/v): 0.58; NMR 1H (DMSO-d6, 400 MHz) δ 3.66 (m, 6H, OCH2CH2S,OCH2CH2CN, CH(CH3)2), 3.04 (t, 2H, J = 6.3 Hz, OCH2CH2S), 1.17 (1s,9H, C(CH3)3), 1.13-1.11 (2d, 12H, J = 6.8 Hz, CH(CH3)2); NMR 13C(DMSO-d6, 100 MHz) δ 205.4 (1s, CO), 118.9 (1s, CN), 61.6 (1d, JPC 17.4 Hz, OCH2CH2S), 58.3 (1d, JP-C 18.2 Hz, OCH2CH2CN), 45.9(1s, C(CH3)3), 42.5 (1d, JP-C 12.3 Hz, CH(CH3)2), 30.3 (1d, JPC 7.1 Hz, OCH2CH2S), 26.9 (1s, C(CH3)3), 24.3 (1d, JP-C 7.3 Hz,CH(CH3)2), 19.8 (1d, JP-C 6.8 Hz, OCH2CH2CN); NMR 31P (DMSO-d6,81 MHz) δ 148.53; MS FAB>0 (GT) m/z 379 (M + O + H)+, 363(M + H)+; Anal. Calculated for C16H31N2O3PS (MW: 362.47): C,53.02; H, 8.62; N, 7.73; S: 8.85. Found: C, 52.77; H, 8.52; N, 7.61; S:8.85. |
Tags: 109-78-4 synthesis path| 109-78-4 SDS| 109-78-4 COA| 109-78-4 purity| 109-78-4 application| 109-78-4 NMR| 109-78-4 COA| 109-78-4 structure
[ 19295-57-9 ]
3-Hydroxy-2,2-dimethylpropanenitrile
Similarity: 0.73
[ 19295-57-9 ]
3-Hydroxy-2,2-dimethylpropanenitrile
Similarity: 0.73
[ 19295-57-9 ]
3-Hydroxy-2,2-dimethylpropanenitrile
Similarity: 0.73
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