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CAS No. : | 160969-03-9 | MDL No. : | MFCD16038209 |
Formula : | C11H13F3O5S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | HOJMCBMXHWZNKX-UHFFFAOYSA-N |
M.W : | 314.28 | Pubchem ID : | 10519307 |
Synonyms : |
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Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280-P305+P351+P338-P310 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H332-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.5% | With triethylamine; In dichloromethane; at 0 - 20℃; for 4h;Reflux; | In a 5000 mL four-necked flask equipped with mechanical stirring, 200 g (0.85 mol, 1.0 eq) of 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl alcohol which was involved in the reaction was sequentially added. ,The temperature of the reaction system was lowered to about 0 C under 155 g (1.53 mol, 1.8 eq) of triethylamine and 2400 ml of ice cream in dichloromethane.388 g (3.4 mol, 4.0 eq) of methanesulfonyl chloride dissolved in 1000 ml of dichloromethane was slowly added dropwise.The temperature of the reaction system was controlled to be not higher than 20 C. After the addition is completed, remove the ice salt bath.The temperature was raised to reflux for 4 hours, cooled to room temperature, and triethylamine hydrochloride was removed by filtration.The filtrate was washed with 1000 ml of *3 saturated sodium carbonate.Dry over anhydrous sodium sulfate, filter, dry EtOAc m.400 g of isopropanol was added and stirred at 0 C for 6 hours, and filtered.Vacuum drying to 247 g of a white solid.Melting point 39-42 C,The yield is 92.5%.The purity is 98.3%. |
With triethylamine; In dichloromethane; water; | NMR (CDCl3) delta: 2.24(1H, br s), 3.90-4.00(2H, m), 4.10-4.15(2H, m), 4.39(2H, q, J=8.3Hz), 6.90-7.10(4H, m) To a solution of 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethanol (210 mg) in methylene chloride (1 ml) were added triethylamine (186 mul) and methanesulfonyl chloride (83 mul) with stirring under ice cooling, and the mixture was reacted at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. To the concentrate was added water, and the mixture was extracted with diethyl ether. The extract was washed with water, dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on silica gel using a mixture of hexane and ethyl acetate (2/1) as eluent to give 273 mg of 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methansulfonate melting at 40.5-42.0 C. IR (KBr): upsilonSO2 1350, 1120 cm-1 | |
With triethylamine; In dichloromethane; at 20℃; for 1h;Cooling with ice; | Example 5: Preparation of 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methane sulfonate (IX): To a solution of 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethanol (287 g, 1216 mmol) in methylene chloride (1435 ml) were added triethyl amine (307 g, 3040 mmol) and methane sulfonyl chloride (145.5 g, 1276 mmol) under ice cooling. The mixture was stirred at room temperature for 1 hrs and water (700 ml) was added to it. The organic layer was separated and washed with water (700 ml). The solvent was evaporated under reduced pressure and the obtained thick gel was crystallized from Hexane (860 ml) at low temperature to give 193 g of 2-[2- (2,2,2-trifluoroethoxy)phenoxy] ethyl methane sulfonate (IX) as a white solid (HPLC purity is 97-98%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Proceeding as in Example 1, Step (a), but replacing cyclopropylmethylbromide with 2-iodo-1,1,1-trifluoroethane, and then correspondingly as in Example 1, Step (b), gave 2-[2-(2,2,2-trifluoroethyloxy)phenoxy]ethyl methanesulfonate, m.p. 36-38 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In ethyl acetate; N,N-dimethyl-formamide; | Reference Example 6 2-[2-(2,2,2-Trifluoroethoxy)phenoxy]ethyl methanesulfonate To a solution of <strong>[160968-99-0]2-(2,2,2-trifluoroethoxy)phenol</strong> (200 mg) in dry N,N-dimethylformamide (2 ml) were added ethyl bromoacetate (138 mul) and potassium carbonate (216 mg), and the mixture was reacted with stirring at room temperature for 1 hour, and then for 1 hour at 60 C. To the reaction mixture was added ethyl acetate, and ethyl acetate solution was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 270 mg of ethyl 2-(2,2,2-trifluoroethoxy)phenoxyacetate as an oil. IR (neat): upsilonC=O 1760 cm-1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Proceeding as in Example 3, but replacing 2-[2-(cyclopropylmethyloxy)phenoxy]ethyl methanesulfonate with 2-[2-(2,2,2-trifluoroethyloxy)phenoxy]ethyl methanesulfonate, gave [2-(5-chloro-1H-indol-3-yl)-1,1-dimethylethyl]-{2-[2-(2,2,2-trifluoroethyloxy)phenoxy]ethyl}amine hydrochloride, m.p. 152-154 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With potassium carbonate; potassium iodide; In acetonitrile; for 16h;Inert atmosphere; Reflux; | To a mixture of amine A (20 g, 82.7 mmol) and mesylate C (20 g, 63.63 mmol) in dry acetonitrile (300 mL) were added K2CO3 (26.3 g, 190.9 mmol) and KI (3.16 g, 19.09 mmol), and the reaction mixture was refluxed for 16 h. The solvent was evaporated in vacuo. The residue was diluted with water (500 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash chromatography (10-15% methanol in dichloromethane) to afford racemic compound 1 (24 g, 93%), which was further subjected for the chiral resolution. |
With sodium hydrogencarbonate; In ethanol; water; | Reference Example 10 1-Acetyl-5-[2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethylamino]propyl]indoline-7-carbonitrile To a solution of 1-acetyl-5-(2-aminopropyl)indoline-7-carbonitrile (18.85 g) and 2-[2-(2,2,2-trifluoroethoxy)phenoxy] ethyl methanesulfonate (24.34 g) in ethanol (155 ml) was added sodium bicarbonate (7.81 g), and the mixture was refluxed for 24 hours. To the reaction mixture was added water (1 l), and the mixture was extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by flash column chromatography on silica gel using a mixture of chloroform and methanol (10/1) as eluent to give 23.48 g of 1-acetyl-5-[2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethylamino]propyl]indoline-7-carbonitrile. The physical properties of this compound were completely identical to those of the compound prepared in Reference Example 8. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.0% | With tetrabutylammomium bromide; potassium carbonate; potassium iodide; In water; at 80℃; for 6h; | the reaction vessel , adding compound (V) 144.1gPotassium carbonate 66g Tetrabutylammonium bromide , potassium iodide , 3.1g, water 1000ml, heated to 80 degrees C, drop adding compound, VI149.5g , Drop80 degrees Celsius and then react 6 hours , use Ethyl acetate extraction, Organic layer, respectively , Sodium bicarbonate wash , Saturatedsalt water washing , Collection of organic layersuse of anhydrous sodium sulfate , drying, Filtration, filtrate decompression concentration , Oil like thing , compound(VII) 203.0g, yield: 88%. |
54% | With sodium carbonate; In ethanol; tert-butyl alcohol; at 50 - 90℃; for 42h; | Example 6Sodium carbonate (0.541 g, 5.106 mmol, 1.16 eq) was added to a solution of compound B (1 .6 g, 4.402 mmol, 1 .0 eq) obtained in example 5 above and compound (F) (1.6 g, 5.150 mmol, 1.17 eq) in tert-butanol (14 ml) + ethanol (2 ml). The reaction mixture was stirred at 85-90C for 10 h and 32 h at 50C. The reaction was monitored by TLC (4% MeOH in DCM on Silica plates). TLC showed the product and a minor amount of the dialkylated product.The reaction mixture was cooled to ambient temperature and was concentrated to half of its volume and 50 ml water was added. This was extracted with ethyl acetate (3 x 20 ml), dried over sodium sulphate and evaporated in vacuo to give 2.9 g of a viscous brown oil.The above was repeated to give a second amount of 1.5 g crude reaction product as a viscous brown oil. The reaction product from the two reaction runs were mixed and purified by using combiflash companion on a 40 g column using 2% MeOH-DCM as eluent to give 2.1 g (54%, 3.610mmol) end product. LCMS showed 89.4% peak area with M+ 1 = 582.3. HNMR is OK. |
4.6 kg | (R)-3-(5-(2-aminopropyl)-7-cyanoindolin- 1 -yl)propyl benzoate (II) (3.5kg) was dissolved in t-BuOH (50L), added Na2CO3 (1.l2eq.,) to the mass, stirred for 10mm, added 2-(2-(2, 2, 2-trifluoroethoxy) phenoxy) ethyl methane sulfonate (III) (1. Seq.,) to the reaction mass, stirred the reaction mass for reaction completion at 81C around 45 to S0hrs. Water (25L) and Toluene (25L) was added to the reaction mass and stirred it for 10 mm, layers were separated and organic layer was washed with bicarbonate solution, followed by brine solution. Organic layer was concentrated completely to thick syrup, (R)-3-(7-cyano-5-(2-(2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethylamino)propyl)indolin- 1-yl)propyl benzoate (IV) (4.6kg syrup). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate; triethylamine; In tert-butyl alcohol; for 30h;Reflux; | A mixture of methyl 3-{5-[(2i?)-2-aminopropyl]-7-carbamoyl-2,3-dihydro-lH- indol-l-yl} propanoate hydrochloride salt (1.2 g), 2-[2-(2,2,2- trifiuoroethoxy)phenoxy] ethyl methanesulfonate (0.6 g) and sodium carbonate (lg) was refluxed for 4 hours in t-Butanol. Triethyl amine was added (0.7ml) to the reaction mixture and was refluxed for 5 hours further followed by addition of 2-[2-(2,2,2- trifluoroethoxy)phenoxy] ethyl methanesulfonate in lots (0.3 g). After 16 hours of overnight refluxing, <strong>[160969-03-9]2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate</strong> (0.25 g) was added and further refluxed for 5 hours. t-Butanol was distilled off on rotavapour and ethyl acetate (20 ml) and water (20 ml) were added to the residue. The reaction mixture was acidified to pH 3 with concentrated hydrochloric acid. The aqueous layer was washed twice with ethyl acetate (20 ml x 2). The aqueous layer was basified with ammonium hydroxide and the free base was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over sodium sulfate and distilled off under vacuum at 55C to obtain the titled compound.Yield: 450 mgThis was purified by column chromatography on silica gel column for analysis. H'NMR (400MHZ,CDC13): 1.059-1.07(d,3H), 2.49-2.55(dd, 1H), 2.57-2.6 l(t,2H), 2.71(dd,lH), 3.37-3.47(m,4H), 3.66(s,3H), 4.1(m,2H), 4.11-4.33(q, 2H), 5.6-5.7(brs,lH), 6.89-7.05(m, 7H) 7.34(s, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | in a container having an inner volume of 5 E and equipped with a reflux condenser, a thermometer, and a stirrer, 317 g (0.62 moles) of 3-{5-[(2R)-2-aminopropyl]-7- cyano-2,3-dihydro-1H-indol-l-yl}propio benzoate.mono(2R,3R)-tartrate, 1.8 E of ethyl acetate, and 1280 g (1.83moles) of a 20% aqueous potassium carbonate solution were mixed and stirred at room temperature for 1 hout10108] After completion of the stirring, an organic phase was separated from the reaction liquid, and the obtained organic phase was concentrated under reduced pressure. The concentrate, 1.8 E of acetonitrile, 69 g (0.65 moles) of sodium carbonate, 10 g (0.03 moles) of tetrabutylammonium bromide, and 233 g (0.74 moles) of 2-[2-(2,2,2-trifluoroeth- oxy)phenoxy]ethyl methanesulfonate were mixed and subjected to reaction under stirring at 75 to 85 C. for 30 hours. 10109] After completion of the reaction, the reaction liquid was cooled to room temperature and then filtered, with the result that 2.2 kg of an acetonitrile solution of 3-(7-cyano- 5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl] -2,3-dihydro-l H-indol-l -yl}propylbenzoate (content: 14.2 mass %, 0.53 moles) was obtained (yield: 85%). | |
Example 9: Preparation of SilodosinProcedure 1: To a solution of Tartrate salt of 3-(5-((R)-2-aminopropyl)-7- cyanoindolin-l-yl) propyl benzoate (I) (50, 0.097 mol) in ethyl acetate (500 ml) was added water (500 ml) followed by addition of aqueous solution of Potassium carbonate (Potassium carbonate (130 g) dissolved in water (200 ml)). The mixture was stirred for lh at room temperature and the layers were separated. The organic layer was washed with water (500 ml) and concentrated under reduced pressure. The obtained crude was dissolved in Isopropyl alcohol (750 ml), Sodium carbonate (11.3 g, 0.107 mol) and 2- [2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methane sulfonate of Formula XIII (36.7 g, 1.16 mol) were added. The mixture was stirred at 80C for 40-50 h. After completion of the reaction, the mixture was cooled and water (500 ml) was added. The organic layer was extracted with ethyl acetate twice (2 x 500 ml). The combined organic layers were evaporated to obtain the product and the product obtained was purified by column chromatography using dichloromethane and methanol in different ratios as a mobile phase. The appropriate fractions were combined together and distilled under reduced pressure to give 38 gm of 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)- phenoxy]ethyl}amino)propyl)-2,3-dihy dro-lH-indol-l-yl) -propyl benzoate of Formula XIV (HPLC purity: 99.5%).The conversion of Formula XIV to Silodisn was followed by procedures disclosed in any of the prior art including United States patent application 20070197627 and United States patent 5,387,603. | ||
3-{5-(2R)-2-aminopropyl}-7-cyano-{2,3-dihydro-1H-indol-1-yl}propylbenzoate(2R,3R)tartarate(Mono-tartaric acid salt of the compound of formula (II)),A mixture of potassium carbonate (80 g) and a mixed solvent of acetonitrile and dimethylacetamide (ACN / DMAC = 500 mL / 500 mL) was heated to 80 DEG C and stirred for 30 minutes. To the reaction mixture70 g of 2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethyl methanesulfonate (compound of formula 3) and 9.70 g of KI were added,The reaction was carried out at the same temperature for 10 hours.The reaction mixture was cooled to room temperature, 1 L of ethyl acetate and 1.5 L of water were extracted.The organic layer obtained by layer separation was washed with 1 L of brine,After drying over 40 g of anhydrous MgSO4 for 30 minutes,After washing again with 200 mL of ethyl acetate, the solvent was removed by distillation. |
Preparation of 3- {7-cyano-5 - [(2R) -2 - ({2- [2- (2,2,2- trifluoroethoxy) phenoxy] ethyl} Propyl benzoate fumaric acid salt A mixture of 3- {5- (2R) -2-aminopropyl} -7-cyano-2,3-dihydro-1H- (2R, 3R) -monotartaric acid salt (monotartaric acid salt of the compound of formula (2)), potassium carbonate (80 g), and a mixed solvent of acetonitrile and dimethylacetamide ACN / DMAC = 500 mL / 500 mL) was warmed to 80 & lt; 0 & gt; C and stirred for 30 min. To the reaction mixture, 70 g of 2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethyl methanesulfonate (compound of formula (III)) and 9.70 g of KI were added, Lt; / RTI & gt; The reaction mixture was cooled to room temperature and extracted with 1 L of ethyl acetate and 1.5 L of water. The organic layer obtained by layer separation was washed with 1 L of brine, dried over 40 g of anhydrous MgSO4 for 30 minutes, and then washed again with 200 mL of ethyl acetate. 23 g of fumaric acid was added to the obtained organic layer, and the mixture was heated to 50 DEG C, cooled to room temperature, and stirred for 2 hours. reaction The mixture was filtered, and the resulting solid was washed with 200 mL of ethyl acetate and dried in vacuo to yield 113 g of the title compound | ||
In a 500 ml reaction vessel150 g of purified water and 135 g of ethyl acetate were added and 40.4 g of potassium carbonate was dissolved.To this was added 15 g of 5-[(2R)-2-aminopropyl]-1-[3-(benzyloxy)propyl]2,3-dihydro-1H-indole-7-carbonitrile was added,And stirred for 2 hours.The ethyl acetate layer was separated, dehydrated with anhydrous sodium sulfate and concentrated, and then 50 g of toluene,12 g of 2-[2-(2,2,2-trifluoroethoxy)phenoxy] ethanol-1-methanesulfonate,3.3 g of sodium carbonate was added, and the mixture was stirred under reflux.After completion of the reaction, an aqueous solution of sodium hydrogencarbonate and ethyl acetate were added, layered and then dehydrated with anhydrous sodium sulfateAnd concentrated under reduced pressure to give 2,3-dihydro-1-[3-(benzoyloxy)propyl]-5-[(2R)-2-[(2,2,2-trifluoroethoxy)phenoxy]ethyl]amino]propyl]-1H-indole-7-carbonitrile (Purity: 79.9%, dialkyl content: 12.0%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 1: Preparation of tartrate salt of 3-[7-cyano-5[(2R)-2-({2-[2-(2,2,2- trifluoroethoxy) phenoxy] ethyl}amino)propyl]-2,3-dihydro-lH-indol-l- yl}propyl benzoate (IV) Method A: To the solution of 3-{7-cyano-5-[(2R)-2-aminopropyl]-2,3-dihydro-lH- indol-l-yl} propyl benzoate (II) (1 mole) in acetonitrile were added sodium carbonate (41.3 grams) and 2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl methane sulfonate of formula (III) (79.6 grams) and heated to reflux temperature till reaction completion. After completion, reaction mass cooled to room temperature, water and ethylacetate added over it, stirred and layer separated. The obtained organic layer was washed with brine solution. To the organic layer, L (+) tartaric acid (29.2 grams) was added at room temperature and stirred. The solid obtained was filtered the solid and dried under vacuum at 50 - 55 C; Yield: 110 grams. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With potassium carbonate; In acetonitrile; for 16h;Inert atmosphere; Reflux; | To a mixture of amine A (0.46 g, 1.9 mmol) and mesylate C (0.5 g, 1.59 mmol) in acetonitrile (50 mL) was added K2CO3 (0.65 g, 4.77 mmol) and the reaction mixture was refluxed for 16 h. The solvent was evaporated in vacuo. The residue was diluted with water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash chromatography (10-15% methanol in dichloromethane) to afford compound 9 (0.201 g, 52%). 1H NMR (300 MHz, CDCl3) delta 6.94 (m, 6H), 4.36 (q, J=8.4 Hz, 2H), 4.20-3.98 (m, 2H), 3.64 (t, J=8.5 Hz, 2H), 3.16-2.92 (m, 4H), 2.64 (dd, J=13.6, 6.3 Hz, 1H), 2.57-2.32 (m, 2H), 1.06 (d, J=6.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) delta 154.14, 149.99, 147.74, 131.23, 130.36, 129.66, 129.24, 124.59, 122.11, 118.57-117.87 (m), 115.37, 114.93, 90.12, 71.34, 69.04, 68.58, 68.11, 67.66, 61.35, 54.73, 47.43, 46.55, 42.87, 29.46, 22.37, 20.19; MS (EI+) m/z: 420.2 (M+H+); IR (cm-1, neat): 3420-3210, 3037, 2958, 2935, 2875, 2211, 1500, 750. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33 g | With potassium carbonate; potassium iodide; In acetonitrile; for 14h;Inert atmosphere; Reflux; | In a 500 mL round bottom flask equipped mechanical stirrer, refrigerator, and thermometer, pure crystalline compound (VIII), obtained in Example 7 (22.0g; 0.072 mol), acetonitrile (220 mL) and 2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl) methanesulfonate (IX) (20.5g; 0.065 mol) ) K2CO3 (26.9g; 0.195 mol) and KI (3.2g; 0.019 mol )are introduced under a nitrogen. The reaction mixture is stirred at reflux temperature for 14 hours, then, cooled to 20 degrees C and treated with H2O. The mixture thus obtained is concentrated under reduced pressure to remove acetonitrile and the aqueous phase is extracted several times with AcOEt. The combined organic phasesare washed with aqueous 1M HCl, aqueous NaOH 10%, and brine. The organic phase is dried over Na2SO4, filtered and concentrated under reduced pressure to give (R)-1-benzoyl-5-(2-((2-(2-(2,2,2-trifluoroethoxy)phenoxy) ethyl) (amino) propyl) indoline-7-carbonitrile (X) (33.0g) as a oil which is used in the next step of a synthesis, without any further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21.0 g | Example 1Preparation of Crude Silodosin:Method D:To the solution of 20g (0.055 mol) of (3-(5-((R)-2-aminopropyl)-7-cyanoindolin-1-yl)propyl benzoate) in 200ml of toluene was added 28.6g (0.165 mol) of dipotassium hydrogen phosphate and 16.4g (0.0522 mol) of <strong>[160969-03-9]2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methane sulfonate</strong> followed by addition of 4.0g (0.11 mol) of tetrabutyl ammonium iodide and stirred the reaction mass at 85-90C for 10-12h. Added de-mineralized water and stirred at room temperature for half an hour. Separated the toluene layer to which was added a solution of 8.8g of sodium hydroxide dissolved in 20ml of water and stirred the reaction at ambient temperature till completion. Quenched the reaction mass with water and separated the layers. Washed the toluene layer with brine and concentrated under reduced pressure to get crude mass. Dissolved the crude mass so obtained in 200ml of dimethyl sulfoxide and added a solution of 3.9g (0.0976 mol) of sodium hydroxide dissolved in 16ml of water followed by addition of 15g (0.132 mol) of 30% w/w of hydrogen peroxide. Stirred the reaction mass at room temperature followed by addition of 400ml of aqueous solution of sodium sulfite and extracted the compound in ethyl acetate. Washed the organic layer with brine and concentrated under reduced pressure to get 21.0g of crude Silodosin.Nu,Nu-dialkyl impurity is 2.8% as per HPLC |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a 100mL three-necked flask fitted with a stirring blade, a thermometer, acondenser, indoline derivative tartrate salt (purity99.9%) 5.0 g, butyl acetate 15 mL and separately adjusted 20% aqueous potassiumcarbonate solution 14mL were added & stirred, and warmed in the vicinity of45 & stirred, and it was made sure that the solid was dissolved, to obtain aprimary reaction solution.To the primary reaction liquid obtained in theneutralization step, 1- (2-methanesulfonyloxy-ethoxy) -2-(2,2,2-trifluoroethoxy) benzene 3.67g was added as N- alkylating agent and stirred,after stirring for 18 hours under heating to reflux, then cooled to about 30 C, to obtain a secondary reaction solution (reaction conversion rate 95.4%).The aqueous layer was removed from the secondary reaction mixture, the resulting organic layer was washed successively with saturated aqueous sodiumbicarbonate solution 10 mL and 10% aqueous sodium chloride 10 mL, to obtain butylacetate solution (purity 81.0 %, dialkyl body content 9.4%) of N-alkylated indoline derivative. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.3% | 40 g of 3-5-[(2R) -2-aminopropyl] -7-cyano-2,3-dihydro-1H-indol-1-yl propylbenzoate (2R, 3R) -tartrate,Acetonitrile 320 ml,20.6 g of anhydrous sodium carbonate, 26.9 g of 2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethyl methanesulfonate was added and stirred under reflux for 24 hours.The reaction solution was cooled, filtered, concentrated under reduced pressure, and 400 ml of ethyl acetate and 320 ml of purified water were added to the concentrate, followed by stirring, separating the layers, and concentrating the organic layer under reduced pressure.To the concentrate, 240 ml of ethanol and 10.5 g of L-(+)-tartaric acid were added, stirred at room temperature for 5 hours, filtered and dried under reduced pressure to make 3-7-cyano-5-[(2R) -2- (2- [ 2- (2,2,2-trifluoroethoxy) phenoxy] ethyl amino) propyl] -2,3-dihydro-1H-indol-1-yl propylbenzoate (2R, 3R) -tartrate Obtained 45.1 g. (Yield 79.3%, ee value = 99.97% or more). | |
4.6 g | To the Butyl acetate solution of N- alkylated indoline derivative obtained in the reaction step, 35mL of butyl acetate and tartaric acid 1.3 g were added and stirred, and then heated to around 80 C andstirred. After confirming that the tartaric acid was dissolved, then cooled toabout 20 C and stirred for 2 hours. The precipitated solid was collected by filtration, and the resulting wet material was dried under reduced pressure in the vicinity of 40 , to obtain N- alkylated indoline derivative tartrate salt4.6g (purity 96.1%, dialkyl body content 0. 38%) (64.7% yield from the indoline derivative tartrate salt) as a white crystalline. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With potassium carbonate; In tert-butyl alcohol; | The Exampleobtained by the 2 (R) -5- (2- aminopropyl) -1- (3-hydroxypropyl) indoline-7-carboxamide 26 g,was charged to tert- butanol 260ml, K 2 CO 3 64.76 g (468mmol, 5eq) were charged, andcharged separately 2- (2- (2,2,2-trifluoroethoxy) phenoxy) ethyl methanesulfonate 88.41g(282mmol, 3eq) and 3-4 times, reaction after completion, it was injected purified water962.96Ml, washed with ethyl acetic acid 481.48Ml, and the organic layer was washed with 20%aqueous hydrochloric acid 481.48ml. By injecting sodium hydroxide 48g in aqueous layer wasadjusted to pH 8 or higher, followed by stirring separated by injecting an ethyl acetic acid481.48ml. The organic layer was washed with a 20% sodium chloride aqueous solution481.48ml, and dried with magnesium sulfate. After concentrating the filtrate, it was dissolved byheating to 5060 C by injecting toluene 481.48ml to the concentrated residue. This graduallycooled to deposit crystals at room temperature and, after cooling to 0 to 5 C, filtered andstirred for 2 hours and dried to 1- (3-hydroxypropyl) -5 - [(2R) -2 - ({2- [2- (2,2,2-trifluoroethoxy)phenoxy] ethyl} amino) propyl] -2,3-dihydro -1H- indole-7-carboxamide (also known as silodosin)27.93G ( It was obtained 60%). (Purity 99.1%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | After adding ethyl acetate (100ml), in 3- {7-cyano -5 -[(2R) -2- aminopropyl] -2,3-dihydro -1H- indol-1-yl} propyl benzoate monotartrate (10.0g; formula 2),Here it was added to an aqueous solution obtainedby dissolving potassium carbonate (27g) in water (100ml) to dissolve thecompound of formula 2. and The ethyl acetate layer was separated,and Theaqueous layer was further extracted with ethyl acetate (100 ml).After washingthe combined ethyl acetate layer was dissolved in an aqueous solution ofpotassium carbonate (2.7g) in water (100ml),And dried over anhydrous sodiumsulfate (20 g).After removing anhydrous sodium sulfate by filtration ,Thefiltrate was distilled under reduced pressure to remove the solvent.The resulting concentrate was dissolved in isopropyl alcohol(50 ml) and After addition of 1-ethyl-3-methylimidazolium bromide (10.0 g;Formula 4),Sodium carbonate (2.3 g) was added and the temperature was raised tothe reflux temperature. Then, 2- {2- (2,2,2-trifluoroethoxy) phenoxy} ethylmethanesulfonate (7.0 g;formula-3), was added,and It was refluxed for 22 hours. The reaction mixture was distilled under reduced pressure atroom temperature to remove the solvent,and Here it was added an aqueoussolution (50ml) dissolved in sodium hydrogen carbonate (3.5g) in water(70ml),And extracted with ethyl acetate (140 ml).The aqueous layer was furtherextracted with ethyl acetate (70 ml) and The collected mixture was washedsuccessively with an aqueous solution of sodium hydrogencarbonate (3.5 g)dissolved in water (70 ml) and saturated brine (70 ml),The residue wassubjected to vacuum distillation to obtain 3- {7-cyano-5 - [(2R) -2 - ({2- [2-(2,2,2- trifluoroethoxy) phenoxy] ethyl} amino,)propyl]-2,3-dihydro-1H-indol-1-yl}propyl benzoate (Formula 5). The compound thus obtained was dissolved in acetone (100 ml)2-oxoglutaric acid (2.84 g; Formula 7)Was dissolved in acetone (30 ml)[0099]The dissolved solution was slowly added to precipitate crystals. After stirring at room temperature for about 2 hours, the mixture was filtered,(10.7 g, 75%; formula 5b). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.2% | 20.0 g (0.031 mol) white solid obtained in Example3 was dissolved in 100 mE methanol. A saturated sodium carbonate solution was added to adjust the pH value to 910. 100 mE ethyl acetate was then used to extract for three times. The organic phase was washed with 100 mE water and 100 mE saturated brine. The combined organic phase was dried on magnesium sulfate and then concentrated to obtain an oily substance. The oily substance was added to the reactor, and then 18.5 g (0.062 mol) compound IV, 10.0 g (0.031 mol) tetrabutylammonium bromide, 12.0 g (0.093 mol) diisopropylethylamine and 20 mE N-methylpyrrolidone were added under stirring, the reaction mixture was heated to 120 C. and reacted for 30 h. After cooling to 100 C., 40 mE toluene and 100 mE water were added and stirred for 10 mm. Separated, the aqueous phase was extracted with 40 mE toluene for two times. The organic phase was combined and was sequentially washed with 40 mE 1 N hydrochloric acid, 40 mE saturated sodium bicarbonate and 40 mE saturated brine and then was dried on magnesium sulfate. Afier concentration, the concentrate passed through colunm chromatography (ethyl acetate: petroleum ether=1:10) to obtain 18.1 g. The mass spectrum showed a molecular ion peak wherein [M+1] is 704, and the yield is 83.2%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75.2% | With tetrabutylammomium bromide; N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 120℃; for 40h; | 20.0 g (0.028 mol) white solid obtained in Example4 was dissolved in 100 mE methanol, and NaOH solution was added to adjust the pH value to 13. The reaction was conducted for a half hour. Subsequently, 100 mE ethyl acetate was used to extract for 3 times. The organic phase was washed with 100 mE water and 100 mE saturated brine. After drying on magnesium sulfate and concentration, an oily substance (9.8 g) was obtained as 3-(7-cyano-5-((R)-2- ((R)- 1 -phenylethylamino)propyl) 1 -H-indolyl)propyl alcohol (compound II, wherein R is H). The oily substance was added to the reactor, and then 16.7 g (0.056 mol) compound IV, 9.0 g (0.028 mol) tetrabutylammonium bromide, 10.8 g (0.084 mol) diisopropylethylamine and 15 mE N-methylpyrrolidone were added under stirring, the reaction mixture was heated to 120 C. and reacted for 40 h. After cooling to 100 C., 40 mE toluene and 100 mE water were added and stirred for 10 mm. Separated, the aqueous phase was extracted with 40 toluene for two times. The organic phase was combined and was sequentially washed with 40 mE 1 N is hydrochloric acid, 40 mE saturated sodium bicarbonate and 40 mE saturated brine and then was dried on magnesium sulfate. Afier concentration, the concentrate passed through colunm chromatography (ethyl acetate: petroleum ether=1:10) to obtain 12.2 g. The mass spectrum showed a molecular ion peak wherein [M+1] is 582, and the yield is 75.2%. ?H NMR spectrum (DMSO-d6): oeppm 0.8 (3H, s), 1.2-1.3 (3H, m), 2.0-2.1 (2H, m), 2.2-2.3 (2H, m), 2.8-3.0 (4H, m), 3.3 (2H, s), 3.4-3.6 (2H, m), 3.6-3.7 (2H, s), 3.9-4.1 (3H, m), 4.3 (2H, s), 4.5-4.6 (2H, m), 6.7 (2H, s), 6.9-7.1 (1H, m), 7.1-7.2 (1H, m), 7.2-7.4 (7H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | 3- {5- (2R) -2-aminopropyl} -7-cyano-2,3-dihydro-1H-indol-1-yl}Propyl benzoate(2R, 3R) -mono-tartaric acid salt(Mono-tartaric acid salt of the compound of formula (II)),Potassium carbonate (80 g),And a mixed solvent of acetonitrile and dimethylacetamide (ACN / DMAC = 500 mL / 500 mL) was heated to 80 DEG C,Stir for 30 min. To the reaction mixture were added 70 g of 2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethyl methanesulfonate (compound of formula 3) and 9.70 g of KI,The reaction was carried out at the same temperature for 10 hours.The reaction mixture was cooled to room temperature,And extracted with 1 L of ethyl acetate and 1.5 L of water.The organic layer obtained by layer separation was washed with 1 L of brine,After drying over 40 g of anhydrous MgSO4 for 30 minutes,After washing again with 200 mL of ethyl acetate, the solvent was removed by distillation. 400 mL of methanol, 100 mL of water and 20 g of KOH were added to the obtained residue. After the mixture was stirred at room temperature for 10 hours,1 L of ethyl acetate and 1 L of water were added and extracted for 10 minutes.The organic layer obtained by layer separation was washed sequentially with 1 L of saturated aqueous solution and 1 L of saturated brine,After drying over 40 g of anhydrous MgSO4 for 30 minutes,After washing with 200 mL of ethyl acetate,18 g of oxalic acid was added.The reaction mixture was stirred at 50 for 30 minutes, It cooled to room temperature.600 mL of isopropyl ether was added to the reaction mixture,Stirred for 2 hours, and then filtered.The obtained crystals were washed with 200 mL of isopropyl ether,At 40 for 10 hours to give the titled compound as a dried in vacuo to 88 g. Yield: 82%Purity: 99.5%Impurities (dimer): Not more than 0.1% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | General procedure: 3- {5- (2R) -2-aminopropyl} -7-cyano-2,3-dihydro-1H-indol-1-yl}Propyl benzoate(2R, 3R) -mono-tartaric acid salt(Mono-tartaric acid salt of the compound of formula (II)),Potassium carbonate (80 g),And a mixed solvent of acetonitrile and dimethylacetamide (ACN / DMAC = 500 mL / 500 mL) was heated to 80 DEG C,Stir for 30 min. To the reaction mixture were added 70 g of 2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethyl methanesulfonate (compound of formula 3) and 9.70 g of KI,The reaction was carried out at the same temperature for 10 hours.The reaction mixture was cooled to room temperature,And extracted with 1 L of ethyl acetate and 1.5 L of water.The organic layer obtained by layer separation was washed with 1 L of brine,After drying over 40 g of anhydrous MgSO4 for 30 minutes,After washing again with 200 mL of ethyl acetate, the solvent was removed by distillation. 400 mL of methanol, 100 mL of water and 20 g of KOH were added to the obtained residue. After the mixture was stirred at room temperature for 10 hours,1 L of ethyl acetate and 1 L of water were added and extracted for 10 minutes.The organic layer obtained by layer separation was washed sequentially with 1 L of saturated aqueous solution and 1 L of saturated brine,After drying over 40 g of anhydrous MgSO4 for 30 minutes,After washing with 200 mL of ethyl acetate,18 g of oxalic acid was added.The reaction mixture was stirred at 50 for 30 minutes, It cooled to room temperature.600 mL of isopropyl ether was added to the reaction mixture,Stirred for 2 hours, and then filtered.The obtained crystals were washed with 200 mL of isopropyl ether,At 40 for 10 hours to give the titled compound as a dried in vacuo to 88 g.The reaction was carried out in the same manner as in Example 1, except that 23 g of succinic acid was used instead of oxalic acid to obtain 92 g of tabular compound.Yield: 82%Purity: 99.5%Impurities (dimer): Not more than 0.1% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | General procedure: 3- {5- (2R) -2-aminopropyl} -7-cyano-2,3-dihydro-1H-indol-1-yl}Propyl benzoate(2R, 3R) -mono-tartaric acid salt(Mono-tartaric acid salt of the compound of formula (II)),Potassium carbonate (80 g),And a mixed solvent of acetonitrile and dimethylacetamide (ACN / DMAC = 500 mL / 500 mL) was heated to 80 DEG C,Stir for 30 min. To the reaction mixture were added 70 g of 2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethyl methanesulfonate (compound of formula 3) and 9.70 g of KI,The reaction was carried out at the same temperature for 10 hours.The reaction mixture was cooled to room temperature,And extracted with 1 L of ethyl acetate and 1.5 L of water.The organic layer obtained by layer separation was washed with 1 L of brine,After drying over 40 g of anhydrous MgSO4 for 30 minutes,After washing again with 200 mL of ethyl acetate, the solvent was removed by distillation. 400 mL of methanol, 100 mL of water and 20 g of KOH were added to the obtained residue. After the mixture was stirred at room temperature for 10 hours,1 L of ethyl acetate and 1 L of water were added and extracted for 10 minutes.The organic layer obtained by layer separation was washed sequentially with 1 L of saturated aqueous solution and 1 L of saturated brine,After drying over 40 g of anhydrous MgSO4 for 30 minutes,After washing with 200 mL of ethyl acetate,18 g of oxalic acid was added.The reaction mixture was stirred at 50 for 30 minutes, It cooled to room temperature.600 mL of isopropyl ether was added to the reaction mixture,Stirred for 2 hours, and then filtered.The obtained crystals were washed with 200 mL of isopropyl ether,At 40 for 10 hours to give the titled compound as a dried in vacuo to 88 g.The reaction was carried out in the same manner as in Example 1, except that 23.5 g of fumaric acid was used instead of oxalic acid to obtain 92 g of the title compound.Yield: 81%Purity: 99.5%Impurities (dimer): Not more than 0.1% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With sodium carbonate; In acetonitrile;Reflux; | 259 g (1 mol) of the compound of formula XII was added,318 g (3 mol) of sodium carbonate and 79.6 g (0.254 mol) of the formula XIIIThe compound was reacted in acetonitrile (molar ratio of compound of formula XIII to acetonitrile: 1: 0.5)Heated to reflux temperature,To the end of the reaction.After the reaction,The reaction was cooled to room temperature,Add water and ethyl acetate,Stirring stratification,The organic phase was washed with brine,To obtain a compound of formula XIV,Dried under vacuum,The product was 110g, yield 91%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60.2% | In a 500 ml reaction vessel, 150 g of purified water and 135 g of ethyl acetate were added and 39 g of potassium carbonate was dissolved.15 g of 5 - [(2R) -2-aminopropyl] -1- [3- (benzyloxy) propyl] -2,3-dihydro-1H-indole-And stirred for 1 hour.The ethyl acetate layer was separated,Washed with 150 g of purified water, concentrated,To the concentrated residue were added 178 g of isopropyl alcohol,11 g of 2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethanol-1-methanesulfonate,3.4 g of sodium carbonate was added, and the mixture was stirred at 80C for 50 hours.After the reaction was completed, a 17.5% aqueous solution of potassium hydroxide(2.4 g of potassium hydroxide / 11.3 g of purified water)And the mixture was stirred for 12 hours. The mixture was concentrated under reduced pressure,The reaction solution was diluted with 75 ml of an aqueous sodium hydrogen carbonate solution (5%) and extracted twice with 135 g of ethyl acetate.The organic layer was washed with 75 g of purified water and concentrated under reduced pressure.The concentrated residue was diluted with 71 g of isopropyl alcohol,2.6 g of oxalic acid was added, and the mixture was stirred for 6 hours.The precipitated solid was filtered, washed with 12 g of isopropyl alcohol, and dried under reduced pressure at 50 C to obtain 2,3-dihydro-1-(3-hydroxypropyl)-5-[(2R)-2-[[2-[2-(2,2,2-Trifluoroethoxy)Phenoxy]ethyl] amino]propyl]-1H-indole-7-carbonitrile oxalate was obtained from(Yield: 60.2%, purity: 98.99%, dialkyl content: 0.33%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: Fifty grams of 5-[(2R)-2-aminopropyl]-1-[3-(bezoyloxy)propyl]-2,3-dihydro-1H-indol-7-carbonitrile (2R,3R)-2,3-dihydroxybutanedioate (tartrate salt of the compound of formula (III), 26.9 g of K2CO3, 39.8 g of 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanosulfonate and 250 mL of acetonitrile are introduced in a 500 mL reactor with mechanical stirring. It is heated to reflux for 24 h. After this time has elapsed, it is cooled at 20 C. and AcOEt (400 mL) and water (250 mL) are added. It is stirred for 30 min, and the phases are separated. The organic phase is dried with anhydrous sodium sulfate, filtered and concentrated to dryness, obtaining 70.9 g of 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propyl benzoate (free base). Eighteen grams of 3-{7-cyano-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indol-1-yl}propyl benzoate are weighed and dissolved in 90 mL of 96% EtOH. Fifteen milliliters are distributed in different balloons. A different acid (for example, 0.60 g of maleic acid) dissolved in 15 mL of 96% EtOH is added to each balloon. It is left under stirring at room temperature for two hours, and then cooled at 0-5 C., maintaining stirring. In the case of maleic acid, the maleate precipitates after 30 minutes. If a salt is formed, it is filtered, washed with 96 C. EtOH and vacuum dried. Table 2 shows the result obtained with different acids. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97.3% | With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 10h; | The foam form N-[(2R) -1- [1- (3-benzoyloxypropyl) -7-cyanoindoline-5-yl] propan-2-yl] -2-form prepared as in Example Nitrobenzene sulfonamide(Compound of formula 5)(32 g, 58.3 mmol)The dimethylformamide (150 mL)After dissolution in potassium carbonate (9.7 g, 1.2 equivalents) was added.To the reaction mixture was added 2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethyl methanesulfonate (22 g, 1.2 equivalents) and then warmed to about 110 C.,Stirred at the same temperature for 10 hours.After cooling to room temperature, add purified water (300 mL) to the reaction mixture,Extracted with dichloromethane (100 mL × 2).Combine the organic layers, wash with water and brine,After drying over anhydrous MgSO 4 for 30 minutes, it was filtered.The filtrate is concentrated under reduced pressure,Vacuum drying gave 43.53 g of the title compound in foam form.(Yield: 97.3%, HPLC purity: 96.71%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
717 g | General procedure: To a solution of SI-II (531 g, 1.46 mol) as the free base in tert-butanol (2.5 L) was added IM-A (528 g, 1.68 mol) and sodium carbonate (92.9 g, 0.876 mol), all in a round bottom flask (5 L). The reaction mixture was heated under reflux until TLC (dichloromethane/methanol, 20/1) showed the reaction to be complete. After cooling, the mixture was extracted with ethyl acetate twice (2 L 2). The combined organic layer was washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and iso-propanol (4 L) was added. To the solution was added an aqueous solution of L-tartaric acid (329 g, 2.19 mol) with stirring for 2 h at room temperature.The precipitate was collected and washed with iso-propanol/water (100 ml/100 ml) twice and recrystallized from iso-propanol/water (2.6 L/1.3 L) to give SI-IV tartrate(717 g, 67.2%, HPLC 98.5%) as a white solid. SI-III (free base): 1H NMR(400 MHz, CDCl3): d 1.01 (d, 3H), 2.07 (t, 2H), 2.40 (m, 1H), 2.56 (m, 2H), 2.63 (m,2H), 2.97 (m, 2H), 3.49 (t, 2H), 3.67 (t, 2H), 4.03 (m, 2H), 4.30 (m, 2H), 4.39 (t, 2H),6.81-6.96 (m, 6H), 7.36 (m, 2H), 7.47 (m, 1H), 7.91 (m, 2H), 8.01 (d, 2H). The motherliquor was purified by column chromatograph to give the IM-C as a yellow oil.15 IMC:1H NMR (400 MHz, CDCl3): d 1.03 (d, 3H), 2.13-2.38 (m, 5H), 2.82 (t, 2H), 3.03(m, 4H), 3.51 (t, 2H), 3.72 (t, 2H), 4.00 (m, 4H), 4.35 (q, 4H), 4.48 (t, 2H), 6.88-7.04(m, 12H), 7.45 (m, 2H), 7.55 (m, 1H), 8.08 (d, 2H). These NMR data agreed with theliterature values. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: To a solution of SI-II (531 g, 1.46 mol) as the free base in tert-butanol (2.5 L) was added IM-A (528 g, 1.68 mol) and sodium carbonate (92.9 g, 0.876 mol), all in a round bottom flask (5 L). The reaction mixture was heated under reflux until TLC (dichloromethane/methanol, 20/1) showed the reaction to be complete. After cooling, the mixture was extracted with ethyl acetate twice (2 L 2). The combined organic layer was washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and iso-propanol (4 L) was added. To the solution was added an aqueous solution of L-tartaric acid (329 g, 2.19 mol) with stirring for 2 h at room temperature.The precipitate was collected and washed with iso-propanol/water (100 ml/100 ml) twice and recrystallized from iso-propanol/water (2.6 L/1.3 L) to give SI-IV tartrate(717 g, 67.2%, HPLC 98.5%) as a white solid. SI-III (free base): 1H NMR(400 MHz, CDCl3): d 1.01 (d, 3H), 2.07 (t, 2H), 2.40 (m, 1H), 2.56 (m, 2H), 2.63 (m,2H), 2.97 (m, 2H), 3.49 (t, 2H), 3.67 (t, 2H), 4.03 (m, 2H), 4.30 (m, 2H), 4.39 (t, 2H),6.81-6.96 (m, 6H), 7.36 (m, 2H), 7.47 (m, 1H), 7.91 (m, 2H), 8.01 (d, 2H). The motherliquor was purified by column chromatograph to give the IM-C as a yellow oil.15 IMC:1H NMR (400 MHz, CDCl3): d 1.03 (d, 3H), 2.13-2.38 (m, 5H), 2.82 (t, 2H), 3.03(m, 4H), 3.51 (t, 2H), 3.72 (t, 2H), 4.00 (m, 4H), 4.35 (q, 4H), 4.48 (t, 2H), 6.88-7.04(m, 12H), 7.45 (m, 2H), 7.55 (m, 1H), 8.08 (d, 2H). These NMR data agreed with theliterature values. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate; In tert-butyl alcohol;Reflux; | General procedure: To a solution of SI-II (531 g, 1.46 mol) as the free base in tert-butanol (2.5 L) was added IM-A (528 g, 1.68 mol) and sodium carbonate (92.9 g, 0.876 mol), all in a round bottom flask (5 L). The reaction mixture was heated under reflux until TLC (dichloromethane/methanol, 20/1) showed the reaction to be complete. After cooling, the mixture was extracted with ethyl acetate twice (2 L 2). The combined organic layer was washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and iso-propanol (4 L) was added. To the solution was added an aqueous solution of L-tartaric acid (329 g, 2.19 mol) with stirring for 2 h at room temperature.The precipitate was collected and washed with iso-propanol/water (100 ml/100 ml) twice and recrystallized from iso-propanol/water (2.6 L/1.3 L) to give SI-IV tartrate(717 g, 67.2%, HPLC 98.5%) as a white solid. SI-III (free base): 1H NMR(400 MHz, CDCl3): d 1.01 (d, 3H), 2.07 (t, 2H), 2.40 (m, 1H), 2.56 (m, 2H), 2.63 (m,2H), 2.97 (m, 2H), 3.49 (t, 2H), 3.67 (t, 2H), 4.03 (m, 2H), 4.30 (m, 2H), 4.39 (t, 2H),6.81-6.96 (m, 6H), 7.36 (m, 2H), 7.47 (m, 1H), 7.91 (m, 2H), 8.01 (d, 2H). The motherliquor was purified by column chromatograph to give the IM-C as a yellow oil.15 IMC:1H NMR (400 MHz, CDCl3): d 1.03 (d, 3H), 2.13-2.38 (m, 5H), 2.82 (t, 2H), 3.03(m, 4H), 3.51 (t, 2H), 3.72 (t, 2H), 4.00 (m, 4H), 4.35 (q, 4H), 4.48 (t, 2H), 6.88-7.04(m, 12H), 7.45 (m, 2H), 7.55 (m, 1H), 8.08 (d, 2H). These NMR data agreed with theliterature values. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.44% | 20 mL of acetonitrile, 1.09 g of potassium carbonate (7.89 mmol) and 0.65 g of potassium iodide (3.92 mmol) were added to a 100 mL three-necked flask, and 2.02 g of 5-[(2S)-2-aminopropyl]-1-[3-(benzoyloxy)propyl]-2,3-dihydro-7-cyano-1H-indole tartrate (3.93 mmol) and 1.61g <strong>[160969-03-9]2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate</strong> (5.12 mmol), control the reaction temperature from 80 C to 85 C, and stir the reaction for 20h to 25h. Cool down to 20 C ~ 30 C, filter, and concentrate the filtrate under reduced pressure to dryness to obtain a residue. Add 50 mL of ethyl acetate to the residue, and wash with 20 mL of purified water and 20 mL of saturated brine. The organic phase is washed with anhydrous after washing. dry over sodium sulfate for 1-3 hours, filter, and concentrate the filtrate under reduced pressure to about 20 mL.Add 0.42 g of oxalic acid (4.67 mmol), heat and stir at reflux for 0.5 h, cool to 20 C. to 30 C., stir and crystallize for 1 h, and filter. The filter cake was dried under vacuum at 50 C. to 60 C. for 8 h to obtain 2.15 g of a white solid with a yield of 81.44 |
Tags: 160969-03-9 synthesis path| 160969-03-9 SDS| 160969-03-9 COA| 160969-03-9 purity| 160969-03-9 application| 160969-03-9 NMR| 160969-03-9 COA| 160969-03-9 structure
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P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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