| 99% |
With pyridine In dichloromethane at 0 - 20℃; for 15h; |
8.8-3 4-Methylbenzenesulfonic acid [(3S)-oxolan-3-yl] (Compound 8e)
To a dichloromethane solution (3.78 mL) of (3S)-oxolan-3-ol (Compound 8d, 500 mg, 5.68 mmol) was added pyridine (1.28 mL, 15.9 mmol) and 4-methylbenzenesulfonyl chloride (1.51 g, 7.95 mmol) at 0° C. The solution was stirred at room temperature, then 15 h. later, water and 1N hydrochloric acid were added to separate out the organic layer. The organic layer was washed sequentially with saturated sodium hydrogen carbonate solution, and brine. The solvent was removed by evaporation under reduced pressure to obtain the titled Compound 8e (1.36 g, yield 99%).LC/MS retention time: 0.96 min. (Analysis Condition: SMD-FA05-1). 1H-NMR (400 MHz, CDCl3) δ: 7.79 (2H, d, J=8 Hz), 7.35 (2H, d, J=8 Hz), 5.12 (1H, m), 3.93-3.76 (4H, m), 2.46 (3H, s), 2.13-2.05 (2H, m). |
| 95% |
With trimethylamine hydrochloride; triethylamine In acetonitrile at 0 - 20℃; for 16h; |
|
| 89.1% |
With dmap; triethylamine In dichloromethane at 20℃; for 3h; Inert atmosphere; |
31 Compound 31A
(S)-3-hydroxytetrahydrofuran (2.00 g, 22.7 mmol) was dissolved in dichloromethane (20.0 mL) at room temperature and under nitrogen protection.Then, p-toluenesulfonyl chloride (5.19 g, 27.2 mmol), triethylamine (4.59 g, 45.4 mmol) and 4-dimethylaminopyridine (catalytic amount) were sequentially added to the above reaction solution.The reaction system was stirred at room temperature for 3 hours.After LCMS monitoring showed that the raw materials disappeared, water (50 mL) was added to the reaction system to quench.The mixture was extracted with dichloromethane (50 ml×3 times), the organic phases were combined, then dried over anhydrous sodium sulfate, filtered, and finally the filtrate was concentrated under reduced pressure.The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 1/3) to obtain 4.90 g of compound 31A as a colorless oil (yield: 89.1%). |
| 85% |
With citric acid In pyridine |
197 4-{(S)-tetrahydrofuran-3-yl}toluenesulphonate
Example 197 4-{(S)-tetrahydrofuran-3-yl}toluenesulphonate To a solution of (S)-3-hydroxytetrahydrofuran (2.0 g, 23 mmol) in pyridine (40 ml) at 0° C. was added tosylchloride portionwise (4.8 g, 25 mmol). The solution was stirred at 0° C. for 1 hr and then at room temperature overnight. The pyridine was evaporated in vacuo and the residue was partioned between EtOAc and saturated aquoeus citric acid (200 ml each). The aqueous layer was extracted with EtOAc (2*200 ml) and the combined organics were dried (sodium sulphate), filtered and evaporated to leave an oil (4.5 g, 85%). 1H NMR (CDCl3, 250 MHz): 7.78 (2H, d), 7.35 (2H, d), 5.12 (1H, m), 3.76-3.93 (4H, m), 2.45 (3H, s), 2.01-2.20 (2H, m). |
| 80% |
Stage #1: (S)-3-hydroxytetyrahydrofurane With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h;
Stage #2: p-toluenesulfonyl chloride In tetrahydrofuran; mineral oil at 25℃; for 15h; |
1 Step 1:
To a suspension of NaH (673 mg, 28.0 mmol) in THF (20 mL) was added a solution of (S)- tetrahydro-furan-3-ol (2.06 g, 23.4 mmol) in THF (40 mL) drop wise over 30 min with stirring at 0°C. Then a solution of 4-methyl-benzenesulfonyl chloride (5.33 g, 28.1 mmol) in THF (30 mL) was added drop wise. The resulting mixture was kept at 25°C for 15 h. The mixture was quenched with water and extracted with EtOAc (100 mL). The combined organic layers were dried over Na2S04 and evaporated to dryness. Flash chromatography (silica, petroleum ether: EtOAc 10:1 ) gave reagent 2 as a colorless solid (4.50 g, 80%). 1H NMR (CDCI3) 5 7.79 (d, J = 8.0 Hz, 2 H), 7.35 (d, J = 8.0 Hz, 2 H), 5.10-5.13 (m, 1 H), 3.78-3.84 (m, 4 H), 2.45 (s, 3 H), 2.08-2.12 (m, 2 H). |
| 70% |
With 1,4-diaza-bicyclo[2.2.2]octane In dichloromethane at 20 - 28℃; for 17h; Cooling with ice; |
12 Synthesis of Compound 12-c
In an ice bath, 1,4-diazabicyclo[2.2.2]octane (4.76 g, 42.43 mmol) and p-toluenesulfonyl chloride (3.09 g, 16.2 mmol) were added into a solution of (S)-tetrahydrofuran-3-methanol (1 mL, 12.48 mmol) in dichloromethane (10 mL) respectively. After the addition, the reaction solution was warmed to room temperature and stirred for 1 hour. Additional p-toluenesulfonyl chloride (1 g, 5.25 mmol) was added and the reaction solution was stirred at 28° C. for another 16 hours. The reaction solution was diluted with dichloromethane (30 mL) and washed with water (30 mL). The organic phase was dried over anhydrous sodium sulfate and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate=30:1) to give 12-c as an oil (2.1 g, yield 70%). |
| 69% |
With pyridine at 20℃; for 2h; |
1 Step 1. (S)-Tetrahydrofuran-3-yl 4-methylbenzenesulfonate
To a mixture of (5)-tetrahydrofuran-3-ol (1 g, 11.35 mmol) and pyridine (1.8 mL,22.7 mmol) in CH2C12 (20 mL) was addedp-toluenesulfonyl chloride (3.3 g, 17.3 mmol) at room temperature. The reaction mixture was stirred at this temperature for 2 h. After evaporation of the solvents, the crude product was diluted with EtOAc (50 mL), washed with water, then 1 N HC1. The organic layer was dried over Mg504, filtered andconcentrated in vacuo. The residue was purified by flash chromatography on 5i02 (0-50% EtOAc/hexanes) to afford (5)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (1.9 g, 69% yield) as a colorless oil. MS (ESI): m/z 243.1 [M+Hf ‘H NMR (400 MHz, CDC13) ö 7.81 (d,J= 8.1 Hz, 2H), 7.37 (d,J= 8.1 Hz, 2H), 5.14 (tt,J=4.8, 2.5 Hz, 1H), 3.99-3.75 (m, 4H), 2.48 (s, 3H), 2.17-2.05 (m, 2H). |
| 69% |
With pyridine In dichloromethane at 20℃; for 2h; |
1 Step 1. (S)-Tetrahydrofuran-3-yl 4-methylbenzenesulfonate
To a mixture of (-toluenesulfonyl chloride (3.3 g, 17.31 mmol). The reaction mixture was stirred at rt for 2 h. After evaporation of the solvent, the crude product was diluted with EtOAc (50 mL), washed with water, and then 1 N HCl. The organic layer was dried over anhydrous MgSCn, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (silica gel, hexanes: EtOAc, 100:0 to 50:50) to afford ( |
| 67.2% |
With triethylamine In dichloromethane at 25℃; for 16h; |
Step 1) Synthesis of (S) -tetrahydrofuran-3-yl 4-methylbenzenesulfonate
Add (S) -tetrahydrofuran-3-ol (2.0mL, 25mmol), p-toluenesulfonyl chloride (5.7g, 29.9mmol) and dichloromethane (30mL) to a 100mL single-necked round bottom flask at 25 ° C, then add Triethylamine (7.0 mL, 50.4 mmol), continue to stir the reaction for 16 hours; stop the reaction, add saturated sodium bicarbonate solution (30 mL), separate the liquid, collect the organic phase, spin dry under reduced pressure, and separate by column chromatography / Ethyl acetate (v / v) = 5/1) to give the title compound as a white solid (4.1 g, 67.2%). |
| 65% |
With trimethylamine hydrochloride; triethylamine In dichloromethane; water at 20℃; Inert atmosphere; Further stages; |
Intermediate 320: (3S)-oxolan-3-yl 4-methylbenzene-1 -sulfonate
A mixture of (3S)-oxolan-3-ol (910 mI, 1 1 mmol), triethylamine (2.4 ml, 17 mmol) and trimethylamine hydrochloride (108 mg, 1.13 mmol) in DCM (14 ml) was cooled to OTD and stirred for 10 minutes. Thereafter 4-methylbenzene-1 -sulfonyl chloride (2.38 g, 12.5 mmol) was added in 2 portions. The solution was stirred at rt overnight under nitrogen. The reaction mixture was treated with N,N-dimethylethylenediamine to consume the unreacted 4- methylbenzene-1 -sulfonyl chloride. Water was added to the mixture. Afterwards the aqueous phase was extracted with DCM (3 x) and concentrated to dryness. The titled compound (1.8 g, 65%) was obtained after silica chromatography purification. |
| 31.82% |
Stage #1: (S)-3-hydroxytetyrahydrofurane With dmap; triethylamine In dichloromethane at 0℃; for 0.166667h;
Stage #2: p-toluenesulfonyl chloride In dichloromethane at 0 - 55℃; for 1.5h; |
Step-1 synthesis of S)-THF-3-yl 4-methylbenzenesulfonate (Intermediate AA198-2)
To a solution of the Intermediate AA198-1 (4.0 g, 45.45 mmol, 1.0 eq) in DCM (40 mL) at 0° C. were added trimethylamine (6.3 mL, 45.45 mmol) and DMAP (1.6 g, 13.63 mmol, 0.3 eq). After stirring for 10 min at 0° C., 4-toluenesulfonyl chloride (6.4 mL, 45.45 mmol) was added dropwise. After stirring for 30 min at RT and at 55° C. for 1 h, the reaction was diluted with 1N HCl (80 mL) and extracted into DCM (3×40 mL). The combined organic layer was washed with brine, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 30% ethyl acetate in hexane to afford Intermediate AA198-2 (3.5 g, 31.82%) as a yellow oil. MS (ES): m/z 243.06 [M+H]+ |
|
|
1.4.2.1
To a solution of the compound (1-D) (68.1 g, 241 mmol) and potassium carbonate (66.5 g, 482 mmol) in DMF (1200 ml) was added (S)-3-tetrahydrofuranol p-toluenesulfonate (synthesized from (S)-3- hydroxytetrahydrofuran and p-toluenesulfonyl chloride) (69.9 g, 289 mmol) under ice-cooling, and the ice bath was removed. The mixture was stirred at room temperature overnight, and then diluted with ethyl acetate, washed sequentially with water and brine, dried over sodium sulfate and concentrated in vacuo to give the compound (1-D-l) (94.7 g, quantitatively) . |
|
With pyridine at 20℃; for 4h; |
188.a
To a stirred solution of (3S)-TETRAHYDROFURAN-3-OL (1.76g, 20mmol) dissolved in dry pyridine (20mL) was added 4-methylbenzenesulfonyl chloride (4.19g, 22mmol). The mixture was stirred at room temperature for 4 h, then was diluted with ethyl acetate and washed with aqueous citric acid. The organic extracts were washed with brine, dried (MgSO4), filtered and evaporated IN VACUO. The crude product was purified by flash chromatography on silica, eluting with ethyl ACETATE/CYCLOHEXANE (0: 100 to 30: 70), to yield the title compound as a white solid |
|
With triethylamine In dichloromethane at 0℃; |
5A.2
Step 2: Synthesis of (s)-tetrahy enzenesulfonate:To a stirred solution of (s)-tetrahydrofuran-3-ol (about 2.0 g, 22.7 mmol) in DCM (30 ml) triethylamine (about 9.5 ml, 68.1 mmol) was added at room temperature and cooled to about 0 °C, after ten minutes 4-methylbenzene-l- sulfinothioic chloride (step 1 , about 3.7 ml) was added and stirred for about 6 hours. Completion of the reaction was monitored by TLC, reaction mixture was neutralized with saturated NaHC03 and extracted with DCM, the organic layer was dried over Na2S04 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% ethyl acetate in hexane as eluent to furnish the title compound (3.5 g) as light yellow liquid. NMR (300 MHz, CDC13): 2.05-2.12 (m, 2H); 2.46 (s, 3H); 3.77-3.93 (m, 4H); 5.09-5.14 (m, 1H); 7.34-7.81 (m, 4H); ES Mass: (100%), [M+l] 243. |
|
With triethylamine In dichloromethane |
|
|
With triethylamine In dichloromethane at 20℃; for 8h; |
7.1
Step 1: Preparation of (S)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate To a mixture of (S)-tetrahydrofuran-3-ol (1 g, 11.4 mmol) and triethylamine (TEA) (2.3 g, 22.8 mmole) in dichloromethane (DCM) (20 mL) at 0° C. was added 4-methylbenzene-1-sulfonyl chloride (2.2 g, 11.4 mmole). The resulting mixture was stirred at room temperature for 8 h. The mixture was washed with water, dried over MgSO4, filtered, and concentrated. The crude product was purified by ISCO (silica gel, 15% ethyl acetate in hexane) to give the title compound (2.5 g). MS (ESI) m/z: Found: 243.3 (M++1). Calc. 242.3 (M+). |
| 3.7 g |
With pyridine; dmap In dichloromethane for 16h; |
39.1 Step 1
(S)-(+)-3-Hydroxytetrahydrofuran (5.0 g) in dichloromethane (50 mL) is allowed to react in the presence of pyridine (12 mL) and 4-dimethylaminopyridine (0.35 g) with 4-toluenesulfonyl chloride (14.5 g) for 16 h. The mixture is washed with water, dried and the solvent evaporated under vacuum. Purification of the residue by column chromatography (silica gel, dichloromethane:MeOH 100:0 to 90:10 gradient) gives the desired compound (3.7 g). LC (LC METHOD 2): tR=0.49 min; Mass spectrum (ES+): m/z=260 [M+NH4]+. |
| 3.7 g |
With pyridine; dmap In dichloromethane |
Step 1:0~~ Brwo 2013/178575 PCT/EP2013/06084483(S)-(+)-3-Hydroxytetrahydrofuran (5.0 g) in dichloromethane (50 ml) is allowed to react inthe presence of pyridine (12 ml) and 4-dimethylaminopyridine (0.35 g) with 4-toluenesulfonyl chloride (14.5 g) for 16 h. The mixture is washed with water, dried and thesolvent evaporated under vacuum. Purification of the residue by column chromatography(silica gel, dichloromethane: MeOH 100: 0 to 90: 10 gradient) gives the desiredcompound (3.7 g).LC (LC METHOD 2): tR = 0.49 min; Mass spectrum (ES+): m/z = 260 [M+NH4f. |
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