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Multistep Mechanochemical Synthesis of PZ-1190, a Multitarget Antipsychotic Agent
Canale, Vittorio ; Kaminski, Michal ; Trybala, Wojciech ; Abram, Michal ; Marciniec, Krzysztof ; Bantreil, Xavier , et al.
Abstract: A solid-state approach was used to synthesize compound PZ-1190, a multitarget ligand for serotonin and dopamine receptors with potential antipsychotic activity in rodents. Compared to the classical batch synthesis approach, the developed multistep mechanochem. protocol improved the overall yield (from 32% to 56%), reduced the reaction time (from 42 to 4 h), and decreased the use of toxic reagents and organic solvents. All synthesized intermediates and PZ-1190 were isolated in high purity by extraction without the requirement of chromatog. purification PZ-1190 was obtained in high enantiomeric purity (≥99% ee) with no impact of grinding processes on the integrity of stereocenter. The described procedures represent rare examples of mechanochem. reduction of a carboxylic function, which might open up the possibility to obtain crucial β- and γ-amino alcs. in a sustainable manner. The oxidation of an aliphatic alc. into an aldehyde using mechanochem. has also been reported for the first time. The obtained results confirmed the suitability of mechanochem. as a sustainable and efficient method of synthesizing candidates for preclin. development.
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Keywords: Azinesulfonamide derivatives ; Multistep mechanochemicalsynthesis ; Medicinal mechanochemistry ; Green chemistry ; Antipsychotic agents
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Purchased from AmBeed: 134441-93-3 ; 13139-15-6 ; 69610-40-8 ; 87691-87-0 ; 56502-01-3 ; 15761-39-4 ; 26250-84-0 ; 82010-31-9 ; 530-62-1 ; 846038-18-4 ; 198493-30-0 ; 88790-38-9 ; 13139-15-6 ; 347146-79-6
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CAS No. : | 87691-87-0 |
Formula : | C11H13N3S |
M.W : | 219.31 |
SMILES Code : | C1(N2CCNCC2)=NSC3=C1C=CC=C3 |
MDL No. : | MFCD04117970 |
InChI Key : | KRDOFMHJLWKXIU-UHFFFAOYSA-N |
Pubchem ID : | 2772144 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H317-H319 |
Precautionary Statements: | P280-P305+P351+P338 |
* 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 |
---|---|---|
97.3% | With calcium hydroxide; In isopropyl alcohol; for 20h;Reflux; Industrial scale; | A solution of 3 (14.9 kg, 68.1 mol) in isopropyl alcohol (235 1) and calcium hydroxide (15.1 kg, 204.3 mol) is added to this solution. The reaction is then heated at reflux temperature for 20 hours, and monitored by UPLC. When the reaction is complete, the mixture is left to cool at room temperature, and the salts are centrifuged and washed with isopropyl alcohol (43 1). The organic solution isthen concentrated, and toluene (65 1) is added to the suspension. The solid is then centrifuged and washed with toluene (32 1) to obtain 4 as a white solid, 28.8 kg, yield 97.3%, purity [HPLC] 99.87%). |
91% | With potassium carbonate; In water; acetonitrile; at 82℃; for 3h; | In the reaction flask into 6g (20mmol)(1R, 2R) -1,2-bis(Methanesulfonate oxymethyl)Cyclohexanewith4.9 g (22.3 mmol) of 3- (1-piperazinyl) -1,2-benzisothiazole and 3.5 g (25.3 mmol) of potassium carbonate were added 50 ml of acetonitrile and1.5g (83mmol) of water, heated to reflux (82 ) for 3h,After the reaction was cooled to room temperature, filtered to remove inorganic salts,The solution was concentrated under reduced pressure to the solvent, 25ml of ethyl acetate was added and stirred for crystallization.5 filter, dried in vacuo to give white crystals (Condensate 1) 7.7g(91% yield, HPLC> 98.0%). |
89.5% | With sodium carbonate; In acetonitrile; at 80 - 85℃; for 24h; | To a solution of methane sulfonic acid 2-methanesulfonyloxymethyl-cyclohexylmethylester, 38g in 380ml of acetonitrile added 3-(1-piperazinyl)-1 ,2-benzisothiazole, 27.7g and sodium carbonate, 13.45g and heated to reflux (80-85C) for about 24 h. After the completion of the reaction (followed by TLC), filtered the solid under hot condition and washed with 40ml of pre heated acetonitrile. The filtrate concentrated completely under vacuum at 40-45C. To the obtained residue, added 190ml of ethyl acetate and stirred for about 1 h at 30-35C. The solid formed filtered and washed with 80 ml of ethyl acetate. The solid dried under vacuum at 60-65C for 10-12 h to get trans -3a,7aoctahydroisoindolium-2-spiro-1'-[ 4-(1 ,2-benzisothiazol-3-yl)]piperazine methane sulfonate as a yellow solid (48g, 1.26 w/w; 89.5%) |
88% | With sodium carbonate; In acetonitrile; for 30h;Reflux; | 3-(l-Piperazinyl-l,2-benzisothiazole) (13.2 g) and sodium carbonate (6.5 g) were added to a solution of trans (R,R)-l,2-bis(methanesulfonylmethyl)cyclohexane (18 g) in acetonitrile (180 mL) at ambient temperature. The reaction mixture was refluxed for about 30 hours, filtered and washed with acetonitrile (2x25 mL). The combined filtrate was concentrated at about 60C under reduced pressure. Acetone (40 mL) was added to the residue and the reaction mixture was stirred at about 40C until the product precipitated out. Hexane (50 mL) was added. The reaction mixture was stirred for about 30 minutes at ambient temperature, filtered and dried under reduced pressure at about 45C for about 8 hours to obtain trans (R,R)-3a,7a-octahydroisoindolium-2-spiro-l '-[4'- (l,2-benzoisothiazole-3-yl)]piperazine methane sulfonate.Yield: 88% |
80% | With potassium carbonate; In acetonitrile; for 20h;Reflux; | A mixture of (1R,2R)-cyclohexane-1,2-diyldimethanediyl dimethanesulfonate (1) (11.7 g, 38.9 mmol), 3-(piperazin-1-yl)-1,2-benzisothiazole (2) (7.76 g, 35.4 mmol), potassium carbonate (4.9 g, 35.4 mmol) and acetonitrile (200 ml) was refluxed for 20 hours. The mixture was filtrated at the hot state thereof, and the filtrate was concentrated to give Compound (3) (12 g, 28.3 mmol, yield: 80%). |
With dipotassium hydrogenphosphate; tetra(n-butyl)ammonium hydrogensulfate; In water; toluene; for 15h;Reflux;Product distribution / selectivity; | Example 1To a mixed solution of 4-(1,2-benzisothiazol-3-yl)piperazine [Compound (A)] (20.0 g, 91.2 mmol), <strong>[186204-35-3](1R,2R)-1,2-bis(methanesulfonyloxymethyl)cyclohexane</strong> [Compound (B)] (32.9 g, 109.5 mmol), and toluene (280 g) were added dibasic potassium phosphate (47.7 g, 273.9 mmol), water (1.4 g, 77.8 mmol) and tetra-n-butyl ammonium hydrogen sulfate (1.2 g, 3.5 mmol). The mixture was stirred under reflux for 15 hours (water (0.5 g) was added in mid-course) to give a reaction mixture containing 4'-(1,2-benzisothiazol-3-yl)-(3aR,7aR)-octahydro-spiro[2H-isoindole-2,1'-piperazinium]methanesulfonate [Compound (C)]. | |
In toluene; for 3h;Reflux;Product distribution / selectivity; | Example 1A mixed solution of 4-(1,2-benzisothiazol-3-yl)piperazine [Compound (A)] (20.0 g, 91.2 mmol), <strong>[186204-35-3](1R,2R)-1,2-bis(methanesulfonyloxymethyl)cyclohexane</strong> [Compound (B)] (13.7 g, 45.6 mmol), and toluene (140 g) was stirred under reflux for 3 hours to give a reaction mixture containing 4'-(1,2-benzisothiazol-3-yl)-(3aR,7aR)-octahydro-spiro[2H-isoindole-2,1'-piperazinium]methanesulfonate [Compound (C)]. And, the production rate of by-product (R) was 0.025% (which was calculated with the following formula (a)). | |
With tetra(n-butyl)ammonium hydrogensulfate; sodium carbonate; In acetonitrile; at 80 - 85℃; for 24h; | 100 g ( lR,2/?)-(-)-trans-cyclohexane- 1 ,2-diylbis(methylene)dimethanesulfonate of Formula (B) and 70 g 3-(piperazin-l-yl)benzo[d]isothiazole of Formula (F), 1500 mL acetonitrile and 35 g sodium carbonate and 0.975..g tetrabutyl ammonium hydrogen sulfate were added to round bottom flask at 25C to 35C and stirred for 10 min. The reaction mixture was heated to 80 to 85C for 24 hours. 35 g sodium carbonate and 0.975 g tetrabutyl ammonium hydrogen sulfate and stirred for 21 hours at 80 to 85C. After completion of the reaction, the reaction mixture was filtered and washed with acetonitrile. The wet-cake was heated with 300 mL acetonitrile at 80 to 85C and charcoalized. The reaction mixture was filtered and washed with acetonitrile. The filtrate was distilled under vacuum to remove acetonitrile. The residue was treated with 800 mL acetone and heated to 60C for 1 hour followed by cooling. The precipitated product was stirred for 2 hours at 25C and filtered. The wet-cake was recrystallized in 50 mL acetone at 60C to obtain titled compound (3aR,7aR)-4'-(benzo[d]isothiazol-3- yl)octahydrospiro[isoindole-2,l'-piperazin]-r-ium mesylate of Formula (G). X-ray powder diffraction pattern (FIG.5), DSC (FIG.6). | |
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In 1,4-dioxane; dimethyl sulfoxide; at 106℃; for 11h; | Example 2 Synthesis of Lurasidone Base 480 g of compound 4 and 400 g of compound 5 are added to a mixture consisting of dioxane (960 mL) and dimethyl sulphoxide (48 mL). The mixture is heated to the reflux temperature of 106 C., and 560 g of DBU is dripped into it in 60 minutes. After ten hours' heating, 280 g of compound 2 and 560 g of DBU are added to the solution of compound 3 thus obtained and heated to 125-130 C., distilling about 300 mL of solvent. After ten hours' heating at said temperature 40 mg of DBU is added, and heating continues for a further 12 h. The mixture is then cooled to ambient temperature, diluted with 14 L of an acetone/water 1:2 mixture, and the lurasidone base (450 g) is filtered and dried. | |
12.5 g | With sodium carbonate; In acetonitrile; for 20h;Reflux; | To a suspension of iran5(R,R)-l,2-bis(methanesulfonylmethyl)cyclohexane (15 g) in acetonitrile (150 mL) l-(l,2-benzisothiazol-3-yl)piperazine (10.95g) and sodium carbonate (7.8 g) were added, heated and stirred for 20 hrs at reflux temperature. Reaction was monitored by HPLC. After the completion of reaction, mass was cooled to 40-45 C, filtered and washed with acetonitrile (20 mL). The acetonitrile was distilled off under vacuum at 45-50 C. To the residue acetone (100 mL) was added, stirred for 1 hour, filtered, washed with acetone (10 mL), dried at 50-55C for 6-8 hours to get the product (12.5 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44.1% | Methylsulfonyl chloride (4.2g, 36.6mmol) in ethyl acetate (10mL) was added dropwise with stirring to a solution of 42 (2.4g, 16.6mmol) and triethylamine (9.0mL, 66.6mmol) in ethyl acetate (40mL) at 0°C. The resulting mixture was stirred for 3hat ambient temperature. The resulting mixture was filtered and washed with water (2×50mL) to give a colorless solid (3.93g, 78.7mmol). A mixture of this solid (2.6g, 11.9mmol), 3-(piperazin-1-yl)benzo[d]isothiazole (3.9g, 13.1mmol), sodium carbonate (2.5g, 23.8mmol), potassium iodide (0.01g, 0.05mmol), and acetonitrile (100mL) was stirred at reflux for 22h. The resulting solution was cooled to ambient temperature and filtered and washed with acetonitrile (30mL) to yield a colorless solid which was further purified using silica gel, eluting with 2.5percent methanol/dichloromethane to give 43 (2.2g, 44.1percent) as a white solid. Mp: 138?140°C. 1H NMR (CDCl3): delta 0.94?0.98 (m, 2H), 1.02?1.10 (m, 2H), 1.52?1.53 (m, 1H), 1.72?1.74 (m, 2H), 1.85?1.94 (m, 4H), 2.23 (d, 2H, J=4.0Hz), 2.61?2.63 (m, 4H), 3.00 (s, 3H), 3.54?3.55 (m, 4H), 4.04 (d, 2H, J=4.0Hz), 7.34?7.36 (m, 1H), 7.45?7.47 (m, 1H), 7.34?7.36 (m, 1H), 7.80?7.81 (m, 1H), 7.90?7.92 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In toluene; for 6h;Reflux; | 4 - (1,2-benzisothiazol-3-yl) - (3aR, 7aR) -cyclohexanone (2H-isoindole-2,1,Methanesulfonate synthesis: In the reaction flask, compound 4 (30.0 g) was added,Compound 3 (35 g),Anhydrous potassium carbonate (20 g), cyclodextrin (0.6 g), toluene (240 ml), reflux reaction for 6 h,HPLC homogenization method to detect the raw material compound 4 less than 0.5%, the end of the reaction,The reaction solution containing the product is used directly in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetra(n-butyl)ammonium hydrogensulfate; potassium carbonate; In water; N,N-dimethyl-formamide; for 5h;Reflux; | (5) condensation reaction to obtain crude lulaxine;Using 3-piperazinyl-1,2-benzisothiazole (SM-4)And 1R, 2R-cyclohexanedimethyldimethanesulfonate (SM-5)Stirred in DMF,While adding potassium carbonate,Tetra-n-butylammonium sulfate refluxing.The resulting quaternary ammonium salt was added to DMF, the appearance of norbornyl imide (SM-5), potassium carbonate and a small amount of water were refluxed for 5 hours, washed with water, extracted with DMF and concentrated to give luloxetone. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate; In acetonitrile; at 30℃; for 20h;Reflux; | The trans (R,R)-,2-bis (methanesulfonylmethyl)cyclohexane (Formula XII; 1 100 mL; obtained above as organic layer) was concentrated completely under reduced pressure at 60C. Acetonitrile (1300 mL), 3-(l-piperazinyl-l,2-benzisothiazole) (Formula VI; 94.5 g), and sodium carbonate (91.3 g) were added at 30C. The reaction mixture was refluxed for 20 hours, and then filtered at 70C. The inorganic salts were further stirred with acetonitrile (325 mL) at 70C, filtered, and washed with acetonitrile (65 mL). The combined filtrates and washings were concentrated at 60C under reduced pressure to obtain a residue. Acetone (325 mL) was added to the residue, and the reaction mixture was stirred at 40C till the product precipitated out. Hexane (325 mL) was added. The reaction mixture was stirred for 30 minutes at 30C, filtered, washed with a mixture of acetone and hexane (130 mL, 1 : 1 mixture), and dried under reduced pressure at 60C for 15 hours to obtain the trans (R,R)-3a,7a-octahydroisoindolium-2-spiro-l '-[4'-(l,2-benzoisothiazole-3- yl)]piperazine methane sulfonate (Formula Vila; HPLC purity: 99.35%). |