Structure of 186204-37-5
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CAS No. : | 186204-37-5 |
Formula : | C20H29N3O3S2 |
M.W : | 423.59 |
SMILES Code : | CS(=O)([O-])=O.[H][C@@]1(CCCC2)[C@]2([H])C[N+]3(CCN(C4=NSC5=CC=CC=C45)CC3)C1 |
MDL No. : | MFCD28125607 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-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 |
---|---|---|
88% | With potassium carbonate; In acetonitrile;Reflux; | A 2 L reaction flask was charged with 88.5 g (lR, 2R) -1,2-cyclohexanedimethanol dimethanesulfonate, 71.8 g3- (1-piperazinyl) -1,2-benzisothiazole hydrochloride, 77.5 g of potassium carbonate and 1 L of acetonitrile were added and the mixture was heated under reflux with stirring. After the reaction is complete, hotFiltration, filter cake rinse with acetonitrile, the filtrate concentrated to dry under vacuum, in an off-white solid 104. 6g, 88% yield, HPLC purity is greater than99%, m.p. 228-230 C. |
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%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.4% | With potassium carbonate; In acetonitrile; at 80℃; | 300.4 g (1 mol) of (R, R) -1,2-bis (methanesulfonyloxymethyl) cyclohexane,Add 1.1 mol of 3- (1-piperazinyl) -1,2-benzoisothiazole hydrochloride, 1.8 mol of anhydrous potassium carbonate, and acetonitrile (the amount is 12 times the weight of the raw material 1) to the reaction kettle,The reaction was stirred at 80 C until TLC detection (acetone / ethyl acetate = 1: 9) until the spots of the starting material (raw material 1) disappeared; cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to 1/3 volume.Then add ethanol (the amount is 4 times the weight of the raw material 1), stir for 2 hours, evaporate the solvent; add toluene (the amount is 5 times the weight of the raw material 1),After stirring at 80 C for 1 hour, the solvent was evaporated to concentrate the material to 2/3 volume, cooled to 2-8 C, and filtered.The filter cake was dried under vacuum at 60 C for 5 h to obtain an off-white solid intermediate I with a yield of 92.4% and a HPLC purity of 98.1%; |
Tags: 186204-37-5 synthesis path| 186204-37-5 SDS| 186204-37-5 COA| 186204-37-5 purity| 186204-37-5 application| 186204-37-5 NMR| 186204-37-5 COA| 186204-37-5 structure
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