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CAS No. : | 33301-41-6 | MDL No. : | MFCD00159216 |
Formula : | C17H19NO3S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | MSVZMUILYMLJCF-UHFFFAOYSA-N |
M.W : | 317.40 | Pubchem ID : | 2758716 |
Synonyms : |
|
Num. heavy atoms : | 22 |
Num. arom. heavy atoms : | 12 |
Fraction Csp3 : | 0.29 |
Num. rotatable bonds : | 5 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 89.87 |
TPSA : | 54.99 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -6.3 cm/s |
Log Po/w (iLOGP) : | 2.79 |
Log Po/w (XLOGP3) : | 2.72 |
Log Po/w (WLOGP) : | 2.81 |
Log Po/w (MLOGP) : | 2.51 |
Log Po/w (SILICOS-IT) : | 2.09 |
Consensus Log Po/w : | 2.58 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.6 |
Solubility : | 0.0806 mg/ml ; 0.000254 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.53 |
Solubility : | 0.094 mg/ml ; 0.000296 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -4.93 |
Solubility : | 0.00371 mg/ml ; 0.0000117 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 3.05 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302 | Packing Group: | N/A |
GHS Pictogram: |
* 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 |
---|---|---|
100% | With triethylamine In dichloromethane at 0℃; for 2 h; | Methanesulfonic acid 1-benzhydryl-azetidin-3-yl ester (12) (Scheme 5, step 8). To a solution of 1-benzhydryl-azetidin-3-ol (15.0 g, 62.7 mmol) in dry CH2Cl2 (1 mL) at 0° C. (ice-water bath) under nitrogen was added dry Et3N (25 mL, 94.0 mmol). To this was then added a solution of methanesulfonyl chloride (5.8 mL, 75.2 mmol) in dry CH2Cl2 (50 mL) dropwise via pressure equalizing addition funnel. Upon complete addition, the cooling bath was removed and the mixture was stirred for 2 h. The heterogeneous mixture was treated with H2O (70 mL), the layers were separated and the aqueous layer was extracted with CH2Cl2 (2.x.100 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated to leave a clear, colorless oil. Upon addition of hexanes (100 mL) the viscous oil product solidified and was collected by vacuum filtration. Drying under high vacuum provided 19.7 g (100percent yield) of 12 as a colorless solid. |
100% | With triethylamine In dichloromethane at 20℃; for 1 h; | Step 1: l-Benzhydrylazetidin-3-yl methanesulfonateTriethylamine (870 ml, 62.67 mmol) and mesyl chloride (390 μΙ_, 50.13 mmol) were successively added to a solution of l-benzhydrylazetan-3-ol (1.0 g, 41.78 mmol) in dichloromethane (10 mL) at room temperature. The reaction mixture was stirred for 1 hour and then diluted by addition of water (20 mL). The aqueous phase was separated and extracted with dichloromethane (2 x 40 mL). The combined organic phases were washed with a saturated solution of sodium chloride (40 mL), dried over sodium sulfate, filtered and concentrated to dryness. The title compound was obtained as a yellow solid (1.5 g, 100percent).*H NMR (CDCI3, 400 MHz) : δ (ppm) : 7.41-7.19 (m, 10H), 5.12 (q, J = 6 Hz, 1H), 4.41 (s, 1 H), 3.68-3.66 (m, 2H), 3.23-2.21 (m, 2H), 2.99 (s, 3H). |
100% | With triethylamine In dichloromethane at 0 - 20℃; for 1 h; | Example 38 1-Benzhydrylazetidin-3-yl methanesulfonate A mixture of 1-benzhydrylazetidin-3-ol (20.0 g, 83.68 mmol) and Et3N (12.68 g, 125.52 mmol) in DCM (200 mL) at 0° C., MsCl (11.447 mg, 100.41 mmol) was added in portions and the resulting solution was stirred at RT for 1 h. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford the desired product (26.526 g, 100percent yield). |
100% | With triethylamine In dichloromethane at 0 - 20℃; for 1 h; | A mixture of 1-benzhydrylazetidin-3-ol (20.0 g, 83.68 mmol) and Et3N (12.68 g, 125.52 mmol) in DCM (200 mL) at 0°C, MsC1 (11.447 mg, 100.41 mmol) was added in portions and the resulting solution was stirred at RT for 1 h. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer wasdried over anhydrous Na2504, filtered and concentrated in vacuo to afford the desired product (26.526 g, 100percent yield). |
100% | With triethylamine In dichloromethane for 1.5 h; Cooling with ice | Example 8 N-(4-{4-[3-(4-hydroxymethylpiperidin-1-yl)azetidin-1-yl]phenylamino}-6-methoxypyridin-3-yl)acetamide (8a) 1-benzhydrylazetidin-3-yl methanesulfonate 1-Benzhydrylazetidin-3-ol (30.0 g, 125 mmol) was dissolved in methylene chloride (240 mL), triethylamine (26 mL, 0.19 mol) was added and, under ice-cooling, methanesulfonyl chloride (11.6 mL, 150 mmol) was added, and the mixture was stirred for 1.5 hr. Water (100 mL) was added, two layers were separated, and the organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title object compound as a pale-yellow powder (40.1 g, yield 100percent). 1H-NMR (CDCl3, 400 MHz) δ: 2.99 (3H, s), 3.15-3.23 (2H, m), 3.59-3.68 (2H, m), 4.39 (1H, s), 5.10 (1H, quintet, J=5.8 Hz), 7.16-7.22 (2H, m), 7.24-7.30 (4H, m), 7.36-7.41 (4H, m). |
98% | With triethylamine In dichloromethane at 0℃; for 1 h; | A solution of methanesulfonyl chloride (115 g, 1.01 mol) in CH2Cl2 (500 mL) was added dropwise to a solution of 1-benzhydrylazetidin-3-ol (Intermediate 31, 200 g, 0.84 mol) and triethylamine (119 g, 1.17 mmol) in CH2Cl2 (2 L) at 0°C, and the mixture was stirred at 0°C for1h. The reaction was quenched by the addition of aqueous NaHCO3. The phases were separated and the aqueous solution was extracted with CH2Cl2 (3 x 500 mL). The combined organic solutions were dried (Na2SO4) and concentrated in vacuo to give the title compound (260 g, 98percent) as a white solid. |
91% | With N-ethyl-N,N-diisopropylamine In dichloromethane at -20 - 20℃; | To a stirred solution of l-benzhydrylazetidin-3-ol (4.0 g, 16.7 mmol, CAS 18621-17-5) in CH2CI2 (40 mL) was added N,N-diisopropylethylamine (14.6 mL, 83.6 mmol). The reaction mixture was cooled to -20 °C, followed by addition of methanesulfonyl chloride (1.95 mL, 25.1 mmol). After 30 min, the reaction mixture was allowed to warm to room temperature and stirred for further 16 hours. The mixture was diluted with CH2CI2 and the organic phrase washed with aqueous citric acid, aqueous NaHC03 then brine. Organic layers were collected, dried (Na2S04) and concentrated in vacuo to afford the title compound (4.85g, 91 ) as an orange solid. MS (ISP): 318.5 ([M+H]+). |
65% | Stage #1: With pyridine In dichloromethane at 0℃; Inert atmosphere Stage #2: at 20℃; for 2 h; Inert atmosphere |
Step 2To a suspension of l-benzhydrylazetidin-3-ol [93] (5.0 g, 2 mmol) in DCM (50 ml), pyridine (8.26ml, 10 mmol) were slowly added at 0°C under inert atmosphere. After the addition was complete, the suspension dissolved was stirred at 0 °C for 20 min, then methane sulphonyl chloride (2.5 ml, 15 mmol) was added to the solution and stirred at RT for 2 h. The progress of the reaction was monitored by TLC. Reaction mixture was quenched with water (150 ml) and extracted with DCM (500 ml x 2). The DCM layer was washed with brine (100 ml x 2), dried over anhydrous Na2S04 and evaporated to yield a yellow gel. The product was purified by column chromatography over 100-200 silica mesh using 1percent MeOH:DCM as eluent to give 1 - benzhydrylazetidin-3-yl methane sulfonate [94] as a white solid(4.3gm,65percent).ESIMS: 318.1 (M+ + 1) |
56.7% | at -20℃; for 61 h; | (Production Example 81) 1-Benzhydryl-3-(methanesulfonyloxy)azetidine A suspension of 1-benzhydrylazetidin-3-ol (15.0 g) in pyridine (100 ml) was cooled to -20 °C under a nitrogen atmosphere, and methanesulfonyl chloride (6.33 ml) was added dropwise thereto. The reaction mixture was stirred under a nitrogen atmosphere at -20 °C for 1 hr, then in a water bath for 2.5 days. The reaction mixture was partitioned after addition of water and ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, water and brine, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. To the residue were added ethanol (10 ml) and hexane (50 ml) to suspend precipitated crystals. The crystals were collected by filtration and washed with hexane. This was dried under aeration at room temperature to provide the titled compound as pale yellow crystals (5.943 g, 44.8 percent). The filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate = 2:1, 1:1, then heptane:ethyl acetate:methanol = 50:50:1, 40:60:1, then ethyl acetate:methanol = 100: 1). Fractions containing the target compound were concentrated to provide the titled compound as pale yellow crystals (1.58 g, 11.9 percent). 1H-NMR Spectrum (CDCl3) δ (ppm): 2.99 (3H, s), 3.18-3.21 (2H, m), 3.62-3.66 (2H, m), 4.40 (1H, s), 5.11 (1H, m), 7.18-7.22 (2H, m), 7.26-7.31 (4H, m), 7.39 (4H, d, J = 7.2 Hz). |
11.9% | at -20 - 0℃; for 61 h; | Water (7.2 ml) and sodium cyanate (3.48 g) were added to a solution of 1-benzhydryl-3-(methanesulfonyloxy)azetidine (7.52 g) in N,N-dimethylformamide (60 ml), followed by stirring at 65° C. for 9 hours. Water, sodium carbonate and ethyl acetate were added to the reaction mixture, which was partitioned. The aqueous layer was extracted with ethyl acetate. The organic layer was collected, washed with brine, and dried over anhydrous sodium sulfate. This was concentrated under reduced pressure, and the resultant crystals were suspended by addition of diethyl ether (10 ml). The crystals were collected by filtration, and washed with diethyl ether. This was dried under aeration to give the title compound (5.43 g, 92.3percent) as pale yellow crystals.1H-NMR Spectrum (CDCl3) δ (ppm): 3.20-3.31 (3H, m), 3.47 (2H, m), 4.36 (1H, s), 7.19-7.23 (2H, m), 7.26-7.30 (4H, m), 7.39 (4H, m). |
11.9% | at -20℃; Inert atmosphere | (Reference Example F-1) 1-Benzhydryl-3-(methanesulfonyloxy)azetidine A suspension of 1-benzhydrylazetidin-3-ol (15.0 g) in pyridine (100 ml) was cooled to -20 °C under a nitrogen atmosphere, and methanesulfonyl chloride (6.33 ml) was added dropwise thereto. The reaction mixture was stirred under a nitrogen atmosphere at -20 °C for 1 hr, then in a water bath for 2.5 days. The reaction mixture was partitioned after addition of water and ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, water and brine, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. To the residue were added ethanol (10 ml) and hexane (50 ml) to suspend precipitated crystals. The crystals were collected by filtration and washed with hexane. This was dried under aeration at room temperature to provide the titled compound as pale yellow crystals (5.943 g, 44.8 percent). The filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate = 2:1, 1:1, then heptane:ethyl acetate:methanol = 50:50:1, 40:60:1, then ethyl acetate:methanol = 100:1). Fractions containing the target compound were concentrated to provide the titled compound as pale yellow crystals (1.58 g, 11.9 percent). 1H-NMR Spectrum (CDCl3) δ (ppm): 2.99 (3H, s), 3.18-3.21 (2H, m), 3.62-3.66 (2H, m), 4.40 (1H, s), 5.11 (1H, m), 7.18-7.22 (2H, m), 7.26-7.31 (4H, m), 7.39 (4H, d, J = 7.2 Hz). |
5 g | With triethylamine In toluene at 0℃; for 1 h; | To a cooled solution of 1-Benzhhydrylazetidin-3-ol (3.5 g, 14.624 mmol, available from Manchester A10473) and triethylamine (4.07 ml, 29.25 mmol) in toluene (21 ml) Methanesulfonyl chloride (1.13 ml, 14.62 mmol) was added dropwise keeping the temperature at 0° C. The reaction mixture was stirred 1 h at 0° C. then the solid was filtered off and washed with toluene (2×5 ml). The yellow filtrate was evaporated in vacuo to afford the title compound (D19) (5g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With triethylamine In dichloromethane at 0 - 20℃; | C. Preparation of 1-(diphenylmethyl)azetidin-3-yl methanesulfonate (C49). Methanesulfonyl chloride (180 g, 1.57 mol) was added to a solution of C48 (360 g, 1.31 mol) and triethylamine (330 g, 3.26 mol) in dichloromethane (3 L) at 0° C. The reaction mixture was stirred at room temperature for 3 h, quenched with saturated aqueous sodium bicarbonate solution, then extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford C49. Yield: 360 g, 1.14 mol, 87percent. B. Preparation of 1-(diphenylmethyl)azetidin-3-yl methanesulfonate (C49). Compound C49 was prepared according to the procedure described in Preparation 1 to afford C49 as a yellow solid. Yield: 303 g, 0.96 mol, 91percent. 1H NMR (400 MHz, CDCl3) δ 2.91 (s, 3H), 3.13 (m, 2H), 3.55 (m, 2H), 4.31 (s, 1H), 4.02 (m, 1H), 7.14 (m, 2H), 7.20 (m, 4H), 7.31 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | at 0 - 20℃; | [Referential Example 103]; (1-Benzhydrylazetidin-3-yl) methanesulfonate ; [] Under cooling with ice, methanesulfonyl chloride (0.68 mL) was added dropwise to 1-benzhydrylazetidin-3-ol (1.50 g) in pyridine (12 mL), followed by stirring at room temperature overnight. Ice-water was added to the reaction mixture, and the precipitated material was recovered by filtration, to thereby give the title compound (890 mg, 45percent). LC-MSm/z: 318(M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium iodide In 1,2-dimethoxyethane; water at 20℃; Reflux | Step 1: l-Benzhydryl-3-iodoazetidinePotassium iodide (530 mg, 3.14 mmol) was added to a solution of 1- benzhydrylazetidin-3-yl methanesulfonate (500 mg, 1.57 mmol) in a mixture of water (2.5 mL) and 1,2-dimethoxyethane (2.5 mL) at room temperature. The reaction mixture was then heated up to reflux and stirred for 3 hours. After cooling down to room temperature, the reaction mixture was diluted by addition of water (50 mL) and ethyl acetate (50 mL). The aqueous phase was separated and extracted with ethyl acetate (2 x 70 mL). The combined organic phases were washed with a saturated solution of sodium chloride (40 mL), dried over sodium sulfate, filtered and concentrated to dryness. The title compound was obtained as a yellow solid (550 mg, 100percent). LCMS (ESI-APCI) m/z 350.0 (M + H)+ |
62% | With potassium iodide In 1,2-dimethoxyethane; water | Preparation 21 1-Benzhydryl-3-iodoazetidine A solution of potassium iodide (60g, 0.361mol) in water (300ml) was added to a solution of 1-benzhydryl-3-methanesulphonyloxyazetidine (see WO-A-96/05193) (60g, 0.189mol) in 1,2-dimethoxyethane (600ml). The reaction mixture was heated under reflux for 2.5 hours. After this time, the reaction was cooled to room temperature and partitioned between ethyl acetate and dilute aqueous sodium carbonate solution. The organic layer was dried over Na2SO4, filtered and solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluding with diethyl ether. The product was recrystallized from diisopropyl ether to afford the title compound (41g, 62percent). 1H-NMR (CDCl3): δ = 7.10-7.50 (10H, m), 4.70 (1H, s), 4.40-4.50 (1H, m), 3.80-4.0 (2H, m), 3.40-3.60 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With ammonia In methanol | A. 1-Benzhydryl-azetidin-3-ylamine Ammonia gas was bubbled through a solution of methanesulfonic acid 1-benzhydryl-azetidin-3-yl ester (952.4 mg, 3 mmol) in MeOH (15 mL). After 2 hours, TLC showed the reaction to be complete. The title compound was obtained as a white solid (643.5 mg, 90percent) after removal of the solvent. MS: 239 (MH+); HPLC Rf: 3.54 min; HPLC purity: 98percent. |
84% | With ammonia In water; isopropyl alcohol at 50 - 71℃; for 3 h; | Preparation of Formula IV; The mesylate wet cake (838 g dry weight expected, 2.64 mol) (Example 1) was dissolved in isopropanol at 50°C. The solution was charged to a 2 gallon Parr reactor, followed by the addition of 28 wtpercent ammonium hydroxide under vacuum (10 vol of 28percent NH4OH and 15 vol of isopropanol). The Parr reactor was sealed, and heated to 71 °C for 3 h (38 - 40 psi pressure observed). The reaction was assayed by HPLC, and showed reaction completion. The reaction mixture was cooled to room temperature, discharged from the Parr reactor, and concentrated under vacuum. The product was extracted with isopropyl ether (8.4 L). The organic extract was concentrated to ~ 4 L under atmospheric pressure, and 159 g (1 eq.) of acetic acid was added, the mixture was stirred for 2 h, and the product (mono acetate salt) was collected by filtration. The solids were dried at 4O0C under vacuum to give 662 g of product (84percent yield). About 4percent of the Formula IV dimer was observed. 1H NMR (CD3OD, 400 MHz) 7.42-7.04 (m, 10 H), 4.44 (s, 1 H), 3.78-3.62 (m, 1 H), 3.43-2.36 (m, 2H), 3.03-2.99 (m, 2H), 1.93 (s, 3H). 13C NMR (CD3OD, 100 MHz) 176.2, 141.4, 128.3, 127.3, 127.2, 77.5, 58.3, 41.2, 22.2. |
70% | With ammonia In methanol; water; isopropyl alcohol at 70 - 75℃; for 3 h; | Example 3: Preparation of Formula IV; The reaction conditions were similar to Example 2, except that 10 volumes 7N ammonia in methanol was added under vacuum to 15 volumes isopropanol. The reaction was heated to 70-750C resulting in a pressure of 40-50 psi. After three hours, the reaction was nearly complete with a ratio of IV to its dimer of 94:6 by HPLC. The product was isolated by evaporation and recrystallized from isopropyl ether to give a 70percent yield. |
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