| 73% |
With pyridine; at 0 - 20℃; for 12h;Inert atmosphere; |
To a stirred solution of <strong>[2568-33-4]3-methyl-1,3-butanediol</strong> (4.19g, 40.2mmol) in pyridine (100mL) was added tosyl chloride (9.15g, 48.0mmol) at 0C. After being stirred for 12h at room temperature, the reaction mixture was quenched with water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, concentrated in vacuo, and azeotroped with toluene. The resulting pale yellow oil was purified by column chromatography (hexane/EtOAc 3:2 to 1:1) to afford 14 (7.62g, 73%) as a colorless oil; numax (neat) 3518 (br), 2970, 1597, 1465, 1354, 1172cm-1; deltaH (500MHz, CDCl3) 7.80 (d, J=8.3Hz, 2H), 7.35 (d, J=8.1Hz, 2H), 4.21 (t, J=6.9Hz, 2H), 2.45 (s, 3H), 1.86 (t, J=6.9Hz, 2H), 1.22 (s, 6H); deltaC (125MHz, CDCl3) 144.7, 132.7, 129.7, 127.7, 69.3, 67.5, 41.5, 29.4, 21.4; m/z (FAB) 259 (M+H), 241 (M-OH); HRMS (FAB): [M+H]+, found 259.0975. C12H19O4S requires 259.0999. |
| 73% |
With pyridine; at 0℃; for 2h; |
A mixture of 3-methylbutane-1 ,3-diol (6.6 g, 63.4 mmol), 4-methylbenzenesulfonyl chloride (18 g, 94 mmol), in dry pyridine (60 mL) was stirred at 0 C for 2 hours, then poured into cold HCI (2M, 150 mL) and extracted with ethyl acetate (3 x 180mL). Combined organic phase was washed with HCI (2M, 4 x 180mL), brine (90 mL), dried over magnesium sulfate and evaporated to dryness. Purified by flash column chromatography (divided material into two halves, purified each using 100g silica, 0-50% ethyl acetate in cyclohexane), recombined pure fractions from each column to give the title compound (12 g, 73%, 46.5 mmol) as a clear oil. 1 H NMR (500MHz, chloroform-d) delta 7.81 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 7.6 Hz, 2H), 4.22 (t, J = 6.9 Hz, 2H), 2.46 (s, 3H), 1.87 (t, J = 6.9 Hz, 2H), 1.23 (s, 6H). |
| 72.7% |
With dmap; triethylamine; In dichloromethane; for 17h; |
3-Methylbutane-1,3-diol 3a (1.0 mL, 9.60 mmol)Dissolved in 40 mL of dichloromethane, and added with triethylamine(2 · 7 mL, 19 · 20 mmol),4-dimethylaminopyridine (117 mg, 0.96 mmol)And p-toluenesulfonyl chloride (1.83 g,9.60mmo 1), the reaction 17 hours. The reaction was washed sequentially with water (50 mL X 3), saturated sodium bicarbonate solution (50 mL X3) and saturated sodium chloride solution (50 mL X 3). The combined organic phases were dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the title product 3-hydroxy-3-methyl-4-methylbenzenesulfonamide Butyl 3b (1.80 g, yellow oil), yield: 72.7% |
| 66% |
With pyridine; at 0℃; for 4h; |
To a solution of 3-methylbutane-l,3-diol (213 mul, 2 mmol) in pyridine (2 ml) at 0 0C was added /?alphara-toluenesulfonyl chloride (836 mg, 4.4 mmol). After 4 hours, the reaction was quenched with water (4 ml) and raised to room temperature. EtOAc (30 ml) was added and the organic layer was washed with IM aq. HCl (20 ml), saturated aq. NaHCO3 (20 ml) and brine (20 ml), dried (MgSO4), filtered and concentrated at reduced pressure to give the title compound (340 mg, 66%) as colourless oil.NMR data: 1H NMR (400 MHz, CDCl3) delta 7.33 - 7.47 (4 H, m), 4.37 (3 H, s), 4.24 (2 H, t, J=6.9 Hz), 1.84 (2 H, t, J=6.9 Hz), 1.21 (6 H, s). |
| 42% |
With dmap; triethylamine; In dichloromethane; at 20℃; for 3h; |
To a solution of 3-methylbutane-1 ,3-diol (1.36 g, 13 mmol) in DCM(20 ml) was added N,N-dimethylpyridin-4-amine (122 mg, 1 mmol), TEA (2.6 g, 26 mmol),and 4-methylbenzenesulfonyl chloride (2.5 g, 13 mmol). The reaction mixture was stirred atrt for 3 h, concentrated, and the residue was purified by column chromatography using ethyl acetate in petroleum ether (1/4) to afford 3-hydroxy-3-methylbutyl 4-methylbenzenesulfonate (1.4 g, 42% yield). LCMS (ESI) m/z: 259.5 (M + 1f. |
| 35% |
With pyridine; at 0 - 20℃; for 27h; |
Example 123(3R*,4R*)-N-[3,5-bis(trifluoromethyl)benzyl]-3-(4-fluoro-2-methylphenyl)-1-(3-hydroxy-3-methylbutyl)-N-methylpiperidine-4-carboxamide monohydrochloride(step 1)To a solution of <strong>[2568-33-4]3-methyl-1,3-butanediol</strong> (1.0 g) in pyridine (10 mL) was added p-toluenesulfonyl chloride (2.26 g) at 0 C., and the mixture was stirred at room temperature for 27 hr. The reaction mixture was poured into ethyl acetate, organic layer was washed with 1N hydrochloric acid and water and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 0?100% ethyl acetate/hexane) to give 3-hydroxy-3-methylbutyl 4-methylbenzenesulfonate (878 mg, 35%) as a colorless oil.1H-NMR (300 MHz, CDCl3):delta 1.22 (6H, s), 1.34 (1H, s), 1.86 (2H, t, J=6.8 Hz), 2.45 (3H, s), 4.21 (2H, t, J=6.8 Hz), 7.35 (2H, d, J=8.0 Hz), 7.80 (2H, d, J=8.3 Hz) |
|
With triethylamine; In dichloromethane; at 0℃; for 0.5h; |
EXAMPLE 9 4-[(4-Fluorobenzyl)oxy]-l-[4-(3-hydroxy-3-methylbutoxy)phenyl]pyridin-2(lH)-oneStep A: 3-Hydroxy-3-methylbutyl 4-methylbenzenesulfonateTo a solution of 3-methylbutane-l,3-diol (1.0 g, 9.6 mmol) and triethylamine (1.6 mL, 11 mmol) in 10 mL of methylene chloride at 0C, 4-methylbenzenesulfonyl chloride (2.0 g, 4.4 mmol) in 5 mL of methylene chloride was added slowly. After stirring at 0C for 30 min, the reaction was quenched with the addition of water (10 mL), and the pH of the aq layer was adjusted to 10 with 1M NaOH. The organic layer was separated, washed with water (2x), dried over magnesium sulfate, filtered and concentrated to give title compound, which was used without further purification. 1HNMR (400MHz, DMSO_ 6, delta ppm): 7.54 (2H, d, J= 8.4Hz ), 7.52 (2H, d, J= 8.0Hz), 4.36 (IH, s), 4.07 (2H, t, J= 7.2Hz), 2.39 (3H, s), 1.66 (2H, s), 1.0 (6H, s). |
| 3.2 g |
With pyridine; In dichloromethane; at 0 - 20℃; for 12h; |
Step 1: 3-Hydroxy-3-methylbutyl 4-methylbenzenesulfonate To a solution of 3-methylbutane-1,3-diol (2.5 mL) in dichloromethane (30 mL) and pyridine (2.1 mL) is added at 0 C. p-toluene-sulfonylchloride (4.6 g) in portions. The mixture is stirred for 12 hours at room temperature, diluted with dichloromethane and washed with 1 M aqueous HCl solution and brine. After drying (MgSO4) the solvent is evaporated and the product is purified by chromatography on silica gel (cyclohexane/ethyl acetate 90:10?70:30) to give the title compound. Yield: 3.2 g; Mass spectrum (ESI+): m/z=276 [M+NH4]+. |
| 3.2 g |
With pyridine; In dichloromethane; at 0 - 20℃; for 12h; |
To a solution of 3-methylbutane-1 ,3-diol (2.5 ml_) in dichloromethane (30 ml_) and pyridine (2.1 ml_) is added at 0C p-toluene-sulfonylchloride (4.6 g) in portions. The mixture is stirred for 12 hours at room temperature, diluted with dichloromethane and washed with 1 M aqueous HCI solution and brine. After drying (MgSO4) the solvent is evaporated and the product is pu rified by ch romatog raphy on s il ica gel (cyclohexane/ethyl acetate 90:10?70:30) to give the title compound. Yield : 3.2 g; Mass spectrum (ESI+): m/z = 276 [M+NH4]+. |
| 970 mg |
With pyridine; In dichloromethane; |
Step 1. Toluene-4-sulfonic acid 3-hydroxy-3-methyl-butyl ester 3-Methyl-1,3-butanediol (1.5 mL, 14.06 mmol) is suspended in dry dichloromethane (5 mL) and pyridine (1.24 mL, 15.46 mmol) is added followed by 4-toluenesulfonyl chloride (2.68 g, 14.06 mmol). The mixture is stirred overnight then washed with 1M aqueous hydrochloric acid, dried and the solvent removed under vacuum. The residue is purified by flash chromatography (0-30% ethyl acetate in cyclohexane) to give the title compound. (Yield 970 mg). LC (LC METHOD 4): tR=5.67 min; Mass spectrum (ES+): m/z=258 [M+H]+. |
| 970 mg |
With pyridine; In dichloromethane; |
Step 1. Toluene-4-sulfonic acid 3-hydroxy-3-methyl-butyl ester3-Methyl-1 ,3-butanediol (1.5 ml, 14.06 mmol) is suspended in dry dichloromethane (5 ml)and pyridine (1.24 ml, 15.46 mmol) is added followed by 4-toluenesulfonyl chloride (2.68g, 14.06 mmol). The mixture is stirred overnight then washed with 1M aqueoushydrochloric acid, dried and the solvent removed under vacuum. The residue is purified byflash chromatography (0-30% ethyl acetate in cyclohexane) to give the titlecompound.(Yield 970 mg).LC (LC METHOD 4): tR = 5.67 min; Mass spectrum (ES+): m/z = 258 [M+Hr |
| 535 g |
With pyridine; In toluene; acetonitrile; at 20℃; for 6h;Inert atmosphere; |
Under a nitrogen atmosphere, 3-methylbutane-1,3-diol (300 g) was dissolved in pyridine (900 ml), and a solution of 4-methylbenzenesulfonyl chloride (500 g) in toluene (900 ml) and acetonitrile (125 ml) was added dropwise over 2 hr. The reaction mixture was stirred at room temperature for 4 hr, and toluene (500 ml) and water (1800 ml) were added to allow for layer separation. The obtained organic layer was washed successively with aqueous sulfuric acid and water (twice). The solvent in the obtained organic layer was evaporated, and the residue was azeotropically evaporated with toluene (500 ml) to give the title compound (535 g). [0191] 1H-NMR (CDCl3) delta: 7.81-7.76 (2H, m), 7.36-7.31 (2H, m), 4.20 (2H, td, J=6.8, 1.6 Hz), 2.44 (3H, s), 1.85 (2H, td, J=6.8, 1.6 Hz), 1.33 (1H, s), 1.21 (6H, s) |
| 15.3 g |
With pyridine; In dichloromethane; at 20℃; for 16h;Cooling with ice; |
Step 1: Toluene-4-sulfonic acid 3-hydroxy-3-methylbutyl ester [0229] 10.0 ml (93.7 mmol) of 3-methylbutane-1,3-diol and 7.60 ml (94.9 mmol) pyridine are dissolved in 100 ml DCM. The mixture is cooled in an ice bath. 15.0 g (78.7 mmol) of 4-methylbenzenesulfonyl chloride are added portionwise. The reaction mixture is stirred at r.t. for 16 h. The reaction mixture is poured into 100 ml of 1N aq. HCl and stirred for 10 min. Then the layers are separated. The aq. layer is extracted with DCM. The combined organic layers are washed with brine and dried. The solvent is evaporated and the residue is chromatographed on silica gel (PE/EtOAc) to give the title compound. Yield: 15.3 g; Mass spectrum (ESI+): m/z=276 [M+NH4]+. |
| 15.3 g |
With pyridine; In dichloromethane; at 20℃; for 16h;Cooling with ice; |
Step 1: Toluene-4-sulfonic acid 3-hydroxy-3-methyl-butyl ester 10.0 ml (93.7 mmol) of 3-methyl-butane-1 ,3-diol and 7.60 ml (94.9 mmol) pyridine are dissolved in 100 ml DCM. The mixture is cooled in an ice bath. 15.0 g (78.7 mmol) of 4-methyl-benzenesulfonyl chloride are added portionwise. The reaction mixture is stirred at r.t. for 16 h. The reaction mixture is poured into 100 ml of 1 N aq. HCI and stirred for 10 min. Then the layers are separated. The aq. layer is extracted with DCM. The combined organic layers are washed with brine and dried. The solvent is evaporated and the residue is chromatographed on silica gel (PE/EtOAc) to give the title compound.Yield: 15.3 g; Mass spectrum (ESI+): m/z = 276 [M+NH4]+. |
| 970 mg |
With pyridine; In dichloromethane; |
Toluene-4-sulfonic acid 3-hydroxy-3-methyl-butyl ester 3-Methyl-1,3-butanediol (1.5 mL, 14.1 mmol) is suspended in dry dichloromethane (5 mL) and pyridine (1.24 mL, 15.46 mmol) is added followed by 4-toluenesulfonyl chloride (2.68 g, 14.1 mmol). The mixture is stirred overnight then washed with 1 M aqueous hydrochloric acid, dried and the solvent removed under vacuum. The residue is purified by flash chromatography (0-30% ethyl acetate in cyclohexane) to give the title compound. (Yield 970 mg). LC (METHOD 2): tR=5.67 min; Mass spectrum (ES+): m/z=258 [M+H]+. |
| 970 mg |
With pyridine; In dichloromethane; |
Intermediate 10 Toluene-4-sulfonic acid 3-hydroxy-3-methyl-butyl ester 3-Methyl-1 ,3-butanediol (1 .5 mL, 14.1 mmol) is suspended in dry dichloromethane (5 mL) and pyridine (1 .24 mL, 15.46 mmol) is added followed by 4-toluenesulfonyl chloride (2.68 g, 14.1 mmol). The mixture is stirred overnight then washed with 1 M aqueous hydrochloric acid, dried and the solvent removed under vacuum. The residue is purified by flash chromatography (0-30 % ethyl acetate in cyclohexane) to give the title compound. (Yield 970 mg). LC (METHOD 2) : tR = 5.67 min ; Mass spectrum (ES+): m/z = 258 [M+H]+. |
|
With dmap; triethylamine; In dichloromethane; at 0 - 25℃; for 17.5h;Large scale; |
Variant 1 This variant was used for the production of technical batches at kg scale.To a solution of 100 g 3-methylbutane-1,3-diol (IX) in 200 ml (264 g) dichloromethane were added 147 ml (107 g) triethylamine along with 6.0 g 4-dimethylaminopyridine (DMAP). The reaction mixture was then cooled to 0 C (0±5 C).In parallel, 192 g of 4-toluenesulfonyl chloride (X) were dissolved in 400 ml (528 g)dichloromethane. The resulting slightly cloudy solution was then dropped over 1.5 h to thereaction mixture at 0 - 5 C. When the temperature of the reaction reached 5 C, the addition was paused and continued when the internal temperature had dropped to 0 C. After complete addition, the reaction mixture was warmed to ambient temperature (20- 25 C) over 1 h. The reaction mixture was then continuously stirred at ambient temperature for 12 - 18 h (preferably15 h).Subsequently, 500 ml of water were added to the reaction mixture. The mixture was stirred for additional 2 h at 20-25 C. The phases were separated. The mulm was collected in the aqueous phase. 500 ml of water were added to the organic phase and the pH was adjusted to 1.9 using 5 ml 2 N aq. HCI. After phases were separated, 500 ml Y2-saturated aq. NaCI-solution was addedto the organic phase. The pH was adjusted to 7 using sat. aq. NaHCO3-solution. The phases were separated and the organic phase was concentrated via rotary evaporation in vacuo (down to 14 mbar) at 40 C. The product was obtained as viscous yellow oil.Yield: 222.3 g (89.6 %, purity: 91.9 area% H PLC)HPLC (Method A): Rt = 5.3 mm.MS (ESI pos): m/z = 241 [M-OH]?H-NMR (500MHz, DMSO-d6): oe [ppm]= 1.12 (s, 6H), 1.78 (t, 2H), 2.50 (s, 3H), 4.20 (t, 2H), 4.47 (br s, 1H), 7.56 (d, 2H), 7.87 (d, 2H).This procedure was carried out at a technical scale using 1.5 kg of (IX). Nine batches were produced. An overview is given in the table below. |
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