* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With sodium tetrahydroborate; iodine In tetrahydrofuran at 0℃; for 5 h; Reflux
A mixture of (11?, 21?) - 1,2-cyclohexanedicarboxylic acid (248, 1.41101),Sodium borohydride (159.8, 4.2 mol) and iodine (156 g, 0.7 mol) were added to THF (1000 mL)Stir, reflux 5 h. Cool to 0 ° C,Methanol (500 mL) was added dropwise,The organic layer was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and dried to give white solid II (178 g, 17.09 mmol), which was dried over magnesium sulfate and concentrated to dryness. , 88.4percent), mp 57- 59 ° C.
85.2%
With Red-Al In tetrahydrofuran; toluene for 5 h; Inert atmosphere; Reflux
Red-Al (70percent solution in toluene) (134 g, 460 mmol) was added to solution of 10 (16 g, 93 mmol) in THF (160 mL) at 0–5 °C under a nitrogen atmosphere. The reaction mixture was refluxed for 5h, the mixture was cooled to 0–5 °C, and then 20percent aqueous NaOH solution (320 mL) was added. The reaction temperature was allowed to warm to room temperature and the reaction was stirred for 1h. It was extracted with toluene, and the organic layer was concentrated to dryness under reduced pressure. The residue was cooled to 0–5 °C. DCM (2.4 mL) and n-hexane (40 mL) were added to the residue and stirred at 0–5 °C for 30 min and filtered to obtain an off-white color solid. Yield: 85.2percent. 1H NMR (DMSO-d6, 400 MHz): d 4.37 (t, J4.8 Hz, 1H), 3.49–3.33 (m,1H), 3.31–3.26 (m,1H), 1.71–1.63 (m,2H), 1.21–1.11 (m,2H), 1.04 (t, J11.2 Hz,1H). 13C NMR (DMSO-d6, 400 MHz): 64.5, 42.1, 29.6, 26.0. HRMS (ESI TOFMS): calcd. forC8H16O2Na, 145.1229; found,145.1226. HPLC conditions: column: Zorbax XDB-C8 (250×4) mm, 3.5 μm; column temp:40 °C; RID sensitivity: 65; RID temp.:35 °C; run time: 40 min; flow :0.8ml/min. Purity by HPLC(AUC): 99.28percent, retention time 5.182.
15.5 g
Stage #1: With 1,1'-carbonyldiimidazole In tetrahydrofuran at 25 - 30℃; for 1 h; Stage #2: With sodium tetrahydroborate; water In tetrahydrofuran for 1 h;
To a solution of iran5(R,R)-l,2-cyclohexane dicarboxylic acid (25.0 g) in THF (250 mL), carbonyl diimidazole (60 g) was added and stirred for one hour at 25-30 °C. To the intermediate obtained sodium borohydride (22.0 g) and water (44.0 mL) were added and stirred for one hour. To this reaction mass, 10percent solution of acetic acid (500 mL) and dichloromethane (500 mL) were added, stirred and layers separated. The aqueous layer was washed with dichloromethane (250 mL). The organic layer was washed with 10percent sodium bicarbonate solution followed by water. The dichloromethane is distilled off from organic layer under vacuum to give an oily mass. To the oily mass dichloromethane (100 mL), water (100 mL) and 12.5mL cone, hydrochloric acid (35percent) were added, stirred and layers obtained were separated. The dichloromethane was distilled off completely at 40 °C to obtain oily mass (15.5 g).
Reference：
[1] Patent: CN105732644, 2016, A, . Location in patent: Paragraph 0006; 0007
[2] Synthetic Communications, 2015, vol. 45, # 23, p. 2676 - 2682
[3] Tetrahedron, 1965, vol. 21, p. 1701 - 1709
[4] Patent: WO2013/121440, 2013, A1, . Location in patent: Page/Page column 27
[5] Patent: WO2016/59649, 2016, A1, . Location in patent: Paragraph 20
[6] Patent: WO2016/59649, 2016, A1,
[7] Patent: CN106916151, 2017, A,
2
[ 140459-96-7 ]
[ 65376-05-8 ]
Yield
Reaction Conditions
Operation in experiment
74%
Stage #1: With diisobutylaluminium hydride In toluene at -5 - 20℃; for 6 h; Inert atmosphere Stage #2: With hydrogenchloride; water In toluene at -5 - 40℃; for 13 h;
trans (R,R)-l,2-dimethyl cyclohexane dicarboxylate (20 g) was dissolved in toluene (200 mL) at about 0°C to about -5°C in an inert atmosphere. Diisobutyl aluminum hydride (248.5 ml, 20percent solution in toluene) was added drop-wise into the above solution. The reaction mixture was warmed to an ambient temperature and stirred for about 6 hours. The reaction was quenched by drop-wise addition of about IN HC1 (125 mL) at about -5°C to about 40°C. The reaction mixture was further stirred for about 13 hours to get freely filterable inorganic solids. The solids were filtered out and the filtrate was concentrated under reduced pressure to obtain trans (R,R)-1,2- bis(hydroxymethyl)cyclohexane as an oil Yield: 74percent
Reference：
[1] Patent: WO2012/131606, 2012, A1, . Location in patent: Page/Page column 13
[2] Tetrahedron, 1965, vol. 21, p. 1701 - 1709
[3] Patent: WO2014/37886, 2014, A1, . Location in patent: Page/Page column 20; 21
[4] Patent: CN106916151, 2017, A, . Location in patent: Paragraph 0017; 0024; 0031
3
[ 65376-04-7 ]
[ 65376-05-8 ]
Reference：
[1] Journal of the American Chemical Society, 1982, vol. 104, # 17, p. 4659 - 4665
[2] Organic Syntheses, 1985, vol. 63, p. 10 - 10
4
[ 65376-03-6 ]
[ 65376-05-8 ]
Reference：
[1] Journal of the American Chemical Society, 1982, vol. 104, # 17, p. 4659 - 4665
5
[ 439919-46-7 ]
[ 65376-05-8 ]
Reference：
[1] Journal of the American Chemical Society, 1982, vol. 104, # 17, p. 4659 - 4665
6
[ 15753-50-1 ]
[ 65376-05-8 ]
Reference：
[1] Journal of the American Chemical Society, 1982, vol. 104, # 17, p. 4659 - 4665
7
[ 89395-29-9 ]
[ 65376-05-8 ]
Reference：
[1] Journal of the American Chemical Society, 1982, vol. 104, # 17, p. 4659 - 4665
8
[ 13149-00-3 ]
[ 65376-05-8 ]
Reference：
[1] Journal of the American Chemical Society, 1982, vol. 104, # 17, p. 4659 - 4665
Intermediate 1 (10.6 kg, 73.5 mol) is dissolved in a mixture of methylisobutyl ketone (315 1) and triethylamine (35 1). The solution is then cooled tobetween 0C and 5C, and mesyl chloride (11.7 1, 151 mol) is added in 60 minutes. After the addition, the mass is stirred until the reaction is complete, and water (315 1) is added. The two phases are then separated, and the organic phase is concentrated to obtain a solution containing 20.44 kg of 2, yield 92.6%.
92%
With triethylamine; In dichloromethane; at 0 - 20℃;Inert atmosphere;
Methanesulfonyl chloride (12 mL,150 mmol) was added to a mixture of 2 (10 g, 69 mmol) in DCM (100mL) and TEA (25.0 mL, 170mmol) at 0-5 C. It was then allowed to room temperature. The reaction mixture was stirred for 2 h and diluted with DCM (50 mL). The compound was extracted into DCM, washed with water, and dried over anhydrous Na2SO4. The DCM layer was distilled under reduced pressure and the obtained crude compound was further purified using n-hexane (100 mL).Yield: 92%, [alpha]D20 = -27.5 (C 4%, benzene at 20 C); lit. [alpha]D24:5 = -29.2 (C 4%, benzene).[16] 1H NMR (CDCl3, 400 MHz): d 4.35 (d, J10 Hz,1H), 4.18 (d, J10 Hz,1H), 3.03 (s,3H), 1.82-1.78 (m,2H), 1.71 (m,1H), 1.29-1.27 (m,2H). 13C NMR (DMSO-d6, 400 MHz): 72.1, 37.0, 36.3, 28.3, 24.7. HRMS (ESI TOFMS): calcd. for C10H21O6S2 301.0780; found: 301.0778. HPLC conditions: chemical column: Zorbax XDB-C8 (250×4) mm, 3.5 mum; column temp: 40 C; RID sensitivity: 65; RID temp.: 35 C; run time: 40 min; flow: 0.8 ml/min. HPLC(AUC): 99.10% retention time 18.041. Chiral column: Chiral PAK IC(250×4.6 mm) 5.0 mum; mobile phase: n-hexane/IPA/EtOH/DEA (650:200:150:5); column temp.: 27 C; flow: 1.0 ml/min; inj.10 mul. Purity by HPLC :99.71 (R,R-isomer) retention time 24.566;and 0.28% (S,S isomer) retention time 23.005; enantiomeric excess (ee): 99.43%.
90.8%
With triethylamine; In chloroform; at 0 - 20℃; for 5h;
Methane sulfonyl chloride (23.85 g) was added to a solution of (R,R) trans 1,2- £/s(hydroxymethyl)cyclohexane (10.0 g) and triethylamine (15.45 g) in chloroform (100 mL) at about 0C to about 5C. The reaction mixture was stirred at an ambient temperature for about 5 hours. De-ionized water (120 mL) was added. The organic layer was separated and concentrated under reduced pressure at about 45C. Diisopropyl ether (120 mL) was added. The reaction mixture was stirred at ambient temperature for about 60 minutes, filtered and dried under reduced pressure at about 40C to obtain trans (R,R)- l,2-bis(methanesulfonylmethyl)cyclohexane.Yield: 90.8%
85.8%
With triethylamine; In dichloromethane; at 0 - 5℃; for 2h;
To a solution of 1 ,2-bis(hydroxymethyl)cyclohexane, 70g (0.4854 moles) in 700 ml of dichloromethane and triethylamine, 223ml (1.602 moles, 3.3 mol eq) added methanesulfonyl chloride, 97.7ml (1.262 moles,2.6 mol eq) drop wise at 0-5C. Thereaction mass stirred for about 2 h. After the completion of the reaction (followed by GC), the reaction mass washed twice with 280ml of process water. The dichloromethane layer collected and concentrated under vacuum at 40C. Purification using Isopropyl alcohol The residue obtained by the above method was dissolved in 350 ml of isopropyl alcohol at 70-75C, cooled to 30-35C and further chilled down to 5-10C. The solid formed filtered and washed with 70ml of chilled isopropyl alcohol. The solid dried under vacuum at 40C to get methane sulfonic acid 2-methanesulfonyloxymethyl-cyclohexylmethylester (bis-mesylate) as off-white to pale brown solid (125g, 1.78 w/w; 85.8%; GC purity:99.86%).
80%
With triethylamine; In toluene; at 0℃; for 5h;
1,2-cyclohexanedimethanol (132 g, 0.9 mol) and triethylamine (266 g, 2.6 mol) were added at 0 C to a solution ofTo toluene (3000mL), stirring, dropping methanesulfonyl chloride (286g, 2.5mol), drops finished, stirring 5h. The reaction solution was successively washed with water(1000 mL X2) and 15% aqueous sodium chloride (800 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure.The residue was recrystallized from ethyl acetate to give a white solid III (220 g, 80.0%), which was recrystallized from ethyl acetate (200 mL)Mp87~89.
100 g (lR,2- )-(-)-trans-cyclohexane-l,2-diyldimethanol of Formula (A) and 1400 mL of methylene dichloride were added to RBF at 25 to 35C under nitrogen atmosphere and stirred for 15 minutes followed by addition of 210 g of triethylamine at 0C. The reaction mixture was stirred for 10 minutes and cooled to -5C followed by addition of 200 g of methanesulfonyl chloride. The temperature was raised to 25 to 30C. The reaction mixture was stirred for 3 hours and settled to separate the organic layer. The separated organic layer was washed with 1000 mL water and distilled under vacuum to obtain residue. The residue was treated with 800 mL diethyl ether and filtered to obtain the title compound as (lR,2R)-(-)-trans-cyclohexane-l,2- diylbis(methylene)dimethanesulfonate of Formula (B
15.8 g
With triethylamine; In dichloromethane;
To a suspension of irafts(R,R)-l,2-bis(hydroxymethyl)cyclohexane (15.0g) in dichloro methane (300 mL), triethyl amine (43.7 mL) followed by methane sulphonyl chloride (17.8 mL) were added over a period of 30-45 minutes. Reaction mass was stirred for 2-3 hrs. Reaction was monitored by HPLC (RI detector). After the completion of reaction, water was added, stirred and layers separated. The organic layer was washed with 10% sodium bicarbonate solution (150 mL) followed by water (150 mL). The dichloromethane was distilled off from organic layer under vacuum at 40-55 C to give an oily mass. Methanol (30 mL) was added to the oily mass and strip off under vacuum at 40C, added methanol (150 mL) and stirred for 1 h at 10-15C and the solid obtained was filtered, washed with methanol (15 mL) and dried under vacuum to get the product (15.8g).
With triethylamine; In dichloromethane; at 20℃; for 1.5h;
(4) methanesulfonate esterification reaction to obtain 1R, 2R-cyclohexanedimethyldimethanesulfonate;1R, 2R-cyclohexanedimethanol,Adding methylene chloride and triethylamine,Methylsulfonyl chloride was added dropwise. The temperature was raised to 20 C and the reaction was carried out for 1.5 hours. The residue was washed with ethyl acetate and n-hexane to give 1R, 2R-cyclohexanedimethanesulfonate.
trans (R,R)-l,2-dimethyl cyclohexane dicarboxylate (20 g) was dissolved in toluene (200 mL) at about 0C to about -5C in an inert atmosphere. Diisobutyl aluminum hydride (248.5 ml, 20% solution in toluene) was added drop-wise into the above solution. The reaction mixture was warmed to an ambient temperature and stirred for about 6 hours. The reaction was quenched by drop-wise addition of about IN HC1 (125 mL) at about -5C to about 40C. The reaction mixture was further stirred for about 13 hours to get freely filterable inorganic solids. The solids were filtered out and the filtrate was concentrated under reduced pressure to obtain trans (R,R)-1,2- bis(hydroxymethyl)cyclohexane as an oil Yield: 74%
The trans (R,R)-l,2-dimethyl cyclohexane dicarboxylate (Formula X; 810 mL) obtained above as the organic layer was added slowly to diisobutyl aluminum hydride (1200 g, 25% solution in toluene) at 0C to 20C in an inert atmosphere. The reaction mixture was warmed to ambient temperature, stirred for 4 hours, and then quenched by drop-wise addition of about 2N HC1 (420 mL) at 0C to 40C. The reaction mixture was further stirred for 18 hours and filtered. The filtrate was concentrated under reduced pressure to obtain the trans (R,R)- 1 ,2-bis(hydroxymethyl) cyclohexane (Formula XI; 915 mL) as the organic layer.
With methanol; sodium tetrahydroborate; In tetrahydrofuran; at 40℃; for 3h;Reflux;
1R, 2R-cyclohexanedicarboxylate, THF, NaBH4 was added to the reaction flask, heated to 40 C, and methanol was slowly added dropwise, and the mixture was refluxed 3h, after treatment to get 1R, 2R-cyclohexanedimethanol.
With sodium tetrahydroborate; iodine; In tetrahydrofuran; at 0℃; for 5h;Reflux;
A mixture of (11?, 21?) - 1,2-cyclohexanedicarboxylic acid (248, 1.41101),Sodium borohydride (159.8, 4.2 mol) and iodine (156 g, 0.7 mol) were added to THF (1000 mL)Stir, reflux 5 h. Cool to 0 ° C,Methanol (500 mL) was added dropwise,The organic layer was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and dried to give white solid II (178 g, 17.09 mmol), which was dried over magnesium sulfate and concentrated to dryness. , 88.4percent), mp 57- 59 ° C.
85.2%
With Red-Al; In tetrahydrofuran; toluene; for 5h;Inert atmosphere; Reflux;
Red-Al (70percent solution in toluene) (134 g, 460 mmol) was added to solution of 10 (16 g, 93 mmol) in THF (160 mL) at 0?5 °C under a nitrogen atmosphere. The reaction mixture was refluxed for 5h, the mixture was cooled to 0?5 °C, and then 20percent aqueous NaOH solution (320 mL) was added. The reaction temperature was allowed to warm to room temperature and the reaction was stirred for 1h. It was extracted with toluene, and the organic layer was concentrated to dryness under reduced pressure. The residue was cooled to 0?5 °C. DCM (2.4 mL) and n-hexane (40 mL) were added to the residue and stirred at 0?5 °C for 30 min and filtered to obtain an off-white color solid. Yield: 85.2percent. 1H NMR (DMSO-d6, 400 MHz): d 4.37 (t, J4.8 Hz, 1H), 3.49?3.33 (m,1H), 3.31?3.26 (m,1H), 1.71?1.63 (m,2H), 1.21?1.11 (m,2H), 1.04 (t, J11.2 Hz,1H). 13C NMR (DMSO-d6, 400 MHz): 64.5, 42.1, 29.6, 26.0. HRMS (ESI TOFMS): calcd. forC8H16O2Na, 145.1229; found,145.1226. HPLC conditions: column: Zorbax XDB-C8 (250×4) mm, 3.5 mum; column temp:40 °C; RID sensitivity: 65; RID temp.:35 °C; run time: 40 min; flow :0.8ml/min. Purity by HPLC(AUC): 99.28percent, retention time 5.182.
With lithium aluminium tetrahydride; In tetrahydrofuran; at 65℃; for 3h;
60 g Lithium aluminum hydride and 470 mL tetrahydrofuran were added to a round bottom flask at 25°C and stirred for 10 min to obtain reaction mixture. The reaction mixture was heated to 65°C and 100 g (li?,2i?)-cyclohexane-l,2-dicarboxylic acid solution in 1200 mL THF was added. The reaction mixture was stirred for 3 hours and cooled to 5°C. 500 mL aqueous tetrahydrofuran solution was added and stirred for 30 min. The reaction mixture was filtered and washed with 200 mL tetrahydrofuran. The salt was treated with 670 mL tetrahydrofuran at 65°C and cooled. The reaction mixture was filtered. The filtrate was distilled to remove tetrahydrofuran to obtain thick oily residue. The residue was treated with cyclohexane (600 mL) and stirred for 1 hour at 15°C. The product obtained was filtered and washed with cyclohexane to obtain (l/?,2./?)-(-)-trans-cyclohexane-l,2-diyldimethanol of Formula (A).
15.5 g
To a solution of iran5(R,R)-l,2-cyclohexane dicarboxylic acid (25.0 g) in THF (250 mL), carbonyl diimidazole (60 g) was added and stirred for one hour at 25-30 °C. To the intermediate obtained sodium borohydride (22.0 g) and water (44.0 mL) were added and stirred for one hour. To this reaction mass, 10percent solution of acetic acid (500 mL) and dichloromethane (500 mL) were added, stirred and layers separated. The aqueous layer was washed with dichloromethane (250 mL). The organic layer was washed with 10percent sodium bicarbonate solution followed by water. The dichloromethane is distilled off from organic layer under vacuum to give an oily mass. To the oily mass dichloromethane (100 mL), water (100 mL) and 12.5mL cone, hydrochloric acid (35percent) were added, stirred and layers obtained were separated. The dichloromethane was distilled off completely at 40 °C to obtain oily mass (15.5 g).
(5aR,9aR)-octahydrobenzo[e][1,3,2]dioxathiepine 3-oxide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With thionyl chloride; In acetonitrile; at 0 - 10℃;
<strong>[65376-05-8][(1R,2R)-cyclohexane-1,2-diyl]dimethanol</strong> (mol. wt. 144.21) is added to acetonitrile providing a reaction mixture in the form of a suspension. The mixture is stirred and cooled to 0-5 C. Thionyl chloride is added to the mixture at a temperature of 0-10 C. which results in a clear solution. The solution is stirred at 0-5 C. and assayed periodically to confirm completion of the reaction. (0064) In a separate vessel, an aqueous solution of potassium bicarbonate (2.5 eq) is added prepared and then cooled to 0-5 C. The completed reaction solution above is then quenched into the aqueous potassium bicarbonate solution. The batch is then warmed to 20-25 C. and the upper acetonitrile layer is separated and collected. The aqueous layer is extracted with acetonitrile and the organic layers are combined resulting in a solution of (5aR,9aR)-octahydrobenzo[e][1,3,2]dioxathiepine 3-oxide (mol. wt. 190.26). (0065) In a separate vessel, 50% ruthenium oxide hydrate (0.1 wt. %) and sodium periodate (1.1 eq.) are slurried in water (and EtOAc at 20-25 C. The (5aR,9aR)-octahydrobenzo[e][1,3,2]dioxathiepine 3-oxide solution above is then added to the sodium periodate/ruthenium oxide slurry while maintaining the temperature at ?30 C. After the reaction is complete, the batch is then filtered, after which the filter cake is washed with EtOAc. The upper organic layer is collected and washed with 20% aqueous sodium chloride. The organic layer is distilled to a minimum volume after which isopropanol is added to the distillate. The resulting slurry is heated to 40-45 C. after which it is cooled to 0-5 C., and then filtered. The solids are washed with isopropanol and dried in a vacuum oven resulting in (5aR,9aR)-octahydrobenzo[e][1,3,2]dioxathiepine 3,3-dioxide (mol. wt. 206.26).
(3aR,4S,7R,7aS)-2-(((1R,2R)-2-((4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)methyl)cyclohexyl)methyl)hexahydro-1H-4,7-methanoisoindole-1,3(2H)-dione hydrochloride[ No CAS ]
((R,R)-cyclohexane-1,2-diyl)bis((1H-imidazol-1-yl)methanone)[ No CAS ]
[ 65376-05-8 ]
Yield
Reaction Conditions
Operation in experiment
15.5 g
With sodium tetrahydroborate; water; In tetrahydrofuran; for 1h;
To a solution of ((R,R)-cyclohexane-l,2-diyl)bis((lH-imidazol-l-yl)methanone) (25 g) in THF (250 mL), sodium borohydride (22.0 g) followed by water (44.0 mL) are added and stirred for one hour. To this reaction mass, 10% solution of acetic acid (500 mL) and dichloromethane (500 mL) are added, stirred and layers separated. The organic layer is washed with 10% sodium bicarbonate solution followed by water. The dichloromethane is distilled off from organic layer under vacuum to give an oily mass. To the oily mass dichloromethane (100 mL), water (100 mL) and 12.5mL cone, hydrochloric acid (35%) are added, stirred and layers obtained are separated. The dichloromethane is distilled off completely from organic layer at 40 C to obtain oily mass (15.5 g).
With triethylamine; In dichloromethane; at -10 - 0℃; for 3h;
Open the cryogenic cooling circulation pump, set the temperature -10 , add 400mL methylene chloride to the reaction flask, turn on the stirring, points Do not call it(1R, 2R) -1,2-cyclohexane-1,2-diylEthanol(50.0 g, 346.7 mmol), triethylamine (87.7 g, 866.8 mmol)Was added to the reaction system, the temperature was controlled at -10-0 C, and p-toluenesulfonyl chloride (165.3 g, 866.8 mmol) was added to the reaction system in portions. With the addition of p-toluenesulfonyl chloride, the system changed from colorless and clear to a yellow suspension Liquid, p-toluenesulfonyl chloride feed is completed, continue to control temperature -10-0 reaction 3h, TLC monitoring reaction was complete. The filtrate was collected by suction filtration, the filtrate was collected, and an equal volume of saturated sodium chloride solution was added to wash the filtrate once. The organic phase was collected and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 162.3 g of crude intermediate I. The resulting crude product was recrystallized from 1600 mL of 50% aqueous acetone to give Intermediate I, 145.2 g, yield 92.5%.
A round-bottom flask was charged with a solution of ((1R,2R)-cyclohexane-1,2-diyl)dimethanol 36(5.36 g, 37.17 mmol) in THF (150 mL). The flask was then capped with a rubber septum and Aratmosphere was established. Reaction mixture was cooled to 0 oC and the solution of nBuLi incyclohexane (3.64 mL, 2M) was added dropwise. The reaction was stirred at 0 oC for 15 min and atroom temperature for 3 h. Then, TBSCl (5.60 g, 37.17 mmol) was added and the reaction was stirredat room temperature for another 1 h. The reaction was quenched by addition of saturated watersolution of NaHCO3 (80 mL). Next, AcOEt (55 mL) was added, the phases were separated, and thewater phase was extracted with DCM (3x80 mL). Combined organic phases were dried overanhydrous MgSO4 and filtered. The solvents were removed in vacuo and the residue was thenpurified by flash column chromatography (hexane:AcOEt, 5:4) to yield SI-9 (9.47 g, 99%) as acolorless oil.1H NMR: (400 MHz, CDCl3) delta 3.61 (s, 1H), 3.57 (d, 2H), 3.52 - 3.45 (m, 1H), 1.79 - 1.69 (m, 2H),1.70 - 1.62 (m, 2H), 1.38 - 0.97 (m, 6H), 0.92 (s, 9H), 0.10 (t, 6H).13C NMR: (101 MHz, CDCl3) delta 68.59, 67.43, 45.52, 44.07, 30.07, 29.86, 26.16, 26.15, 25.81, 18.17, -5.45, -5.57.HRMS: (m/z): calcd for C14H30O2Si, [M+Na]+, 281.1913; found 281.1907
(3aR,4R,7S,7aS)-2-(((1R,2R)-2-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexyl)methyl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-dione[ No CAS ]
(3aR,4R,7S,7aS)-2-(((1R,2R)-2-((4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)methyl)cyclohexyl)methyl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-dione[ No CAS ]
The trans (R,R)-l,2-bis(hydroxymethyl)cyclohexane (Formula XI; 810 mL; obtained above as the organic layer) was taken, and methane sulfonyl chloride (154.2 g) and triethylamine (182 g) were added to it at 0C to 15C. The reaction mixture was stirred at ambient temperature for 2 hours. Deionized water (120 mL) was added, the reaction mixture was stirred at 40C to 45C for 30 minutes, and the layers were separated. The aqueous layer was further extracted with toluene (200 mL). The organic layers were combined, washed with about 5% brine solution (130 mL), and the trans (R,R)- 1 ,2-bis (methanesulfonylmethyl)cyclohexane was separated as the organic layer (Formula XII; l lOO mL).
Take 1R,2R-1,2-cyclohexanedimethanol (1.0 g, 7 mmol), 30 ml of tetrahydrofuran was added and stirred to dissolve. Sodium hydroxide (0.8g, 20mmol, 60% content) was added and a large amount of gray solids in reaction solution was produced and a large amount of bubbles were released. Intermediate A (5.2 g, 15.3 mmol) was added, and washed with 20 ml of tetrahydrofuran. The reaction solution was heated to 70 C and refluxed for 2 h. The completion of the reaction was monitored by TLC (developing agent ethyl acetate: n-hexane = 1:3, Rf related substance I-a = 0.40), 100 ml of water and 100 ml ethyl acetate were added, and stirred for 10 min. The reaction solution was allowed to stand for separation. The organic phase was washed once with 100 ml water, washed once with 100ml saturated saline solution, dried using anhydrous sodium sulfate 20g, filtered, the filtrate was concentrated to dryness to give 7 g of oil. The crude product was purified by column chromatography, components were collected, and concentrated to dryness under reduced pressure to obtain lurasidone-related substance I-a 3.3 g. The purity of the product was 99.52% by HPLC and the yield was 74%.
Take 1R,2R-1,2-cyclohexanedimethanol (14.5 g, 0.1 mol), 50 ml of tetrahydrofuran was added and stirred to dissolve. Sodium hydroxide (4.8g, 0.12mol, 60% content) was added, large amount of gray solids were produced in reaction solution and a large amount of air bubbles were released, and the mixture was further stirred and cooled to -10 C. Intermediate A (32.4 g, 0.095 mol) was dissolved in 200 mL of tetrahydrofuran, dropped into the reaction solution for 1h. The reaction was stirred at -10 C. The reaction was completed by TLC.(developing agent ethyl acetate: n-hexane = 1:3, Rf intermediate B = 0.25) 300 ml of water and methylene chloride (500 ml) were added and stirred for 10 min. The reaction solution was allowed to stand for separation, the organic phase was washed once with water 300ml, washed once with 300ml of saturated saline solution, dried using anhydrous sodium sulfate 50g, and filtered. The filtrate was concentrated to dryness to give 35 g of oil, purified by column chromatography, components were collected and concentrated under reduced pressure to obtain oil (12 g, Intermediate B).The yield was 32%.
Chemistry
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