Structure of 2896-98-2
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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CAS No. : | 2896-98-2 |
Formula : | C5H9NOS |
M.W : | 131.20 |
SMILES Code : | O=C1NCCSCC1 |
MDL No. : | MFCD11111966 |
InChI Key : | YBUWZZKYXPWDGO-UHFFFAOYSA-N |
Pubchem ID : | 286337 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 8 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.8 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 1.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 38.54 |
TPSA ? Topological Polar Surface Area: Calculated from |
54.4 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.22 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
-0.1 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
-0.14 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.1 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.58 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.53 |
Log S (ESOL):? ESOL: Topological method implemented from |
-0.59 |
Solubility | 33.7 mg/ml ; 0.257 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-0.59 |
Solubility | 33.7 mg/ml ; 0.257 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.28 |
Solubility | 6.84 mg/ml ; 0.0521 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
No |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-7.17 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.08 |
* 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 |
---|---|---|
74% | With sodium carbonate; p-toluenesulfonyl chloride; In water; acetone; at 60℃; for 16h; | To a solution of compound 2 (1.0 g, 7.6 mmol) in acetone/H2O (20 mL/20 mL) was added TsC1 (2.16 g, 11.4 mmol) and Na2CO3 (1.2 g, 23.2 mmol). The resulting mixture was stirred at 60 C. for 16 hours. The mixture was concentrated to remove solvents. The residue was extracted with EA (20 mL×3). The organic layer was dried over Na2SO4, filtered, the filtrates were concentrated to give compound 3 (740 mg, 74%) as white solid. |
60% | With polyphosphoric acid; at 115℃; for 0.25h; | The mixture of dihydro-2H-thiopyran-4(31])-one oxime (4.01 g, 0.03 mol) in polyphosphoric acid was heated at 115 D for 1 5mm, and cooled to rt, ice-water was added, then the mixture was extracted with EtOAc 5 times. The combined organic layer was dried over Na2504 and concentrated under vacuum to give 2.4 g product as brown solid in 60% yield. ?H-NMR (400 IVIFIz, CDC13) : 6.79 (brs, 1H), 3.63 (m, 2H), 2.94 (m, 2H), 2.74 (m, 4H). |
With sodium carbonate; p-toluenesulfonyl chloride; In water; acetone; at 60℃; for 16h; | To a solution of compound 2 (1.0 g, 7.6 mmol) in acetone/H2O (20 mL/20 mL) was added TsCl (2.16 g, 11.4 mmol) and Na2CO3 (1.2 g, 23.2 mmol). The resulting mixture was stirred at 60 C. for 16 hours. The mixture was concentrated to remove solvents. The residue was extracted with EA (20 mL×3). The organic layer was dried over Na2SO4, filtered, the filtrates were concentrated to give compound 3 (740 mg, 74%) as white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | To a mixture of tetrahydrothiopyran-4-one (5.14 g) and conc. hydrochloric acid (20 mL) was added sodium azide (4.31 g) under ice-cooling. The reaction mixture was stirred at room temperature for 4 hrs., and sodium carbonate was added. The mixture was diluted with iced water and extracted with chloroform. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give 1,4-thiazepan-5-one as crystals (3.62 g, yield 62%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 120-121C. | |
(Ref: J. Org. Chem. 1960, 25, 1953-1956.) To a stirred solution of tetrahydrothiopyran-4-one 1 (10 g, 86 mmol) in cone. HCl (43 mL) cooled to 0 0C is added sodium azide (8.4 g, 129 mmol) portionwise over 30-60 min, (note: gas evolution). When the addition is complete the reaction mixture is stirred at RT for 4 h.The mixture is cooled to 0 0C and solid Na2CO3 is added portionwise (note: gas evolution), plus water to dissolve the salts, until the solution is alkaline ~pH 9. The alkaline solution is diluted with DCM (200 mL), the phases are seperated and the aqueous layer is extracted with DCM (3 x 100 mL). The combined organic layers are EPO <DP n="24"/>dried over MgSOphi filtered and concentrated to a low volume (-20 mL), petroleum ether is added and the solid is collected by filtration and dried to afford the title compound as a white solid: 1H NMR (400 MHz, DMSO) delta 7.52 (s, IH), 3.39 (m, 2H), 2.63 (m, 2H), 2.58 (m, 4H); MS-APCI (m/z+-) 131.9 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 4h; | To a solution of <strong>[2896-98-2]1,4-thiazepan-5-one</strong> (2.07 g, 15.7 mmol) in dry THF was added LiA1H4 (0.66 g, 17.3 mmol) at OD, then the mixture was stirred at rt for 4h. H20 (0.7 mL), 15% NaOH (0.7 mL) and H20 (2.1 mL) were added to the reaction in successively. The mixture was filtrated to give 1.77 g product in 96% yield.?H-NIVIR (400 IVIFIz, CDC13) : 3.07 (m, 2H), 2.98 (m, 2H), 2.75 (m, 4H), 1.93 (m, 2H). |
75.7% | With lithium aluminium tetrahydride; In tetrahydrofuran; at 60℃; for 2h; | To a suspension of LiAlH4 (200 mg, 5.2 mmol) in THF (5 mL) was added compound 3 (370 mg, 2.8 mmol). The mixture was stirred at 60 C. for 2 hours. The reaction was quenched with H2O (0.2 mL), dried over Na2SO4, filtered, and the filtrates were concentrated to give desired compound 4 (250 mg, 75.7%) as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) 6=3.08-3.02 (m, 1H), 2.99-2.92 (m, 1H), 2.89-2.82 (m, 1H), 2.81-2.66 (m, 5H), 2.00-1.85 (m, 2H) |
(Ref: J. Org. Chem. 1960, 25, 1953-1956.) To a stirred solution of 1,4- thiazepan-5-one (9.16 g, 70 mmol) in THF (271 mL) at 0 0C is added dropwise over20 min LAH (IM in THF, 70 mL, 70 mol). The reaction mixture is stirred at 0 0C for 10 min and then warmed to RT, stirring is continued for 2 h. The reaction mixture is quenched with careful successive addition of H2O (2.5 mL), 5N aqeous NaOH (2.5 mL) and H2O (9 mL). A thick gel like precipitate formed. The reaction mixture is filtered through a small pad of Celite, and the filter cake is washed with ether (300 mL). The filtrate is concentrated to afford the title compound as an oil, which is used immediately in the next reaction. 1H NMR (400 MHz, DMSO) delta 2.89 (t, 2H), 2.84 (t, 2H), 2.69 (t, 2H), 2.59 (t,2H), 1.78 (m, 2H). |
2.63 g (98%) | With sodium hydroxide; LiAlH4; In tetrahydrofuran; water; | To a solution of <strong>[2896-98-2]1,4-thiazepan-5-one</strong> (3.0 g) in distilled THF (90 mL) cooled to 0 C. is added dropwise a solution of LiAlH4 in THF (1M solution, 22.9 mL). The mixture is stirred at room temperature for 2 h. The reaction is quenched by successive addition of water (2 mL), 15% NaOH (2 mL) and water (2 mL). The reaction mixture is filtered to remove the aluminum salt that had precipitated. The filtrate was dried (Na2SO4), filtered, and concentrated to obtain 2.63 g (98%) of 1,4-thiazepane as a yellow residue. Physical characteristics are as follows: 1H NMR (300 MHz, CDCl3) delta3.07, 2.96, 2.75, 1.92. |
With sodium hydroxide; In tetrahydrofuran; water; | Step 2. Lithium aluminum hydride (5.5 mL of a 1M solution in THF) is added dropwise to a stirred solution of <strong>[2896-98-2]hexahydro-5-oxo-1,4-thiazepine</strong> (721.5 mg) in dry THF (21 mL) cooled to 0 C. The reaction mixture is stirred at 0 C. for 10 min, then at room temperature for 4 h. The reaction mixture is quenched by careful successive addition of water (0.2 mL), 5N aqueous NaOH (0.2 mL) and water (0.74 mL). The reaction mixture becomes very thick and gel-like. The reaction mixture is diluted with ether (50 mL) and filtered through a pad of celite. The filter cake is washed with ether (100 mL). The filtrate is concentrated to afford 616.6 mg of 1,4-hexahydrothiazepine which is used immediately in the next step. | |
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 4.16667h; | Step 2.. lithium aluminum hydride (5.5 ML of a 1M solution in THF) is added dropwise to a stirred solution of <strong>[2896-98-2]hexahydro-5-oxo-1,4-thiazepine</strong> (721.5 mg) in dry THF (21 ML) cooled to 0 C. The reaction mixture is stirred at 0 C. for 10 min, then at room temperature for 4 h.. The reaction mixture is quenched by careful successive addition of water (0.2 ML), 5 N aqueous NaOH (0.2 ML) and water (0.74 ML).. The reaction mixture becomes very thick and gel-like.. The reaction mixture is diluted with ether (50 ML) and filtered through a pad of celite.. The filter cake is washed with ether (100 ML).. The filtrate is concentrated to afford 616.6 mg of 1,4-hexahydrothiazepine which is used immediately in the next step. | |
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 0.5h; | To a mixture of lithium aluminum hydride (2.31 g) and tetrahydrofuran (100 mL) was added a solution of <strong>[2896-98-2]1,4-thiazepan-5-one</strong> (4.0 g) in'tetrahydrofuran (30 mL) with stirring under ice-cooling and the mixture was stirred at room temperature for 30 min. 2N Sodium hydroxide was added to the reaction mixture until aluminum hydroxide precipitated, and the solid was filtered off. The filtrate was concentrated until the liquid amount became half, and di-tert-butyl dicarbonate (7.32 g) was added dropwise with stirring under ice-cooling. The mixture was stirred at room temperature for 2 hrs., and the reaction mixture was concentrated, diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and tert-butyl 1,4-thiazepan-4-carboxylate was obtained as a colorless oil (6.00 g, yield 91%) from a fraction eluted with ethyl acetate-hexane (1:4,volume ratio). NMR(CDCl3) delta:1.46(9H, s), 1.92-2.10(2H, m), 2.60-2.76(4H, m), 3.50-3.68(4H, m). | |
With lithium aluminium tetrahydride; In tetrahydrofuran; at 60℃; for 2h; | To a suspension of LiAlH4 (200 mg, 5.2 mmol) in THF (5 mL) was added compound 3 (370 mg, 2.8 mmol). The mixture was stirred at 60 C. for 2 hours. The reaction was quenched with H2O (0.2 mL), dried over Na2SO4, filtered, and the filtrates were concentrated to give desired compound 4 (250 mg, 75.7%) as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) 6=3.08-3.02 (m, 1H), 2.99-2.92 (m, 1H), 2.89-2.82 (m, 1H), 2.81-2.66 (m, 5H), 2.00-1.85 (m, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With n-butyllithium; triethylamine; In 1,4-dioxane; hexane; | To a solution of 4-oximino-tetrahydrothiopyran (1.0 g, 7.6 mmol) in 20 mL of dry ether under nitrogen atmosphere at 0 C. was added n-butyllithium (5.0 mL of a 1.6 M solution in hexane, 8.0 mmol). The resulting white suspension was stirred at 0 C. for one hour at which point a solution of p-toluenesulfonyl chloride (1.52 g, 8.0 mmol) in 10 mL ether was added and the reaction mixture stirred for 4 h at 5 C. The solvent was removed in vacuo and then the residue was treated with 20 mL of 70% dioxane containing five drops of triethylamine and stirred for 24 h at room temperature. The solvent was removed in vacuo and the residue was extracted with methylene chloride. The methylene chloride layer was washed with water, saturated sodium chloride and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo and the product purified by flash column chromatography on silica gel eluted with hexane/ethyl acetate (7:3) to give 0.13 g of hexahydro-(1H)-1,4-thiazepin-5-one. 1 H NMR (500 MHz, CDCl3): delta6.92 (brs, 1H), 3.61 (m, 2H), 2.92(m, 2H), 2.74 (m, 2H), 2.70 (m, 2H). 13 C NMR (125 MHZ, CDCl3): delta177.76, 45.88, 40.95, 31.54, 24.61. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4.30 g (81%) | With sodium carbonate; In hydrogenchloride; water; | Preparation 34 1,4-Thiazepane To a stirred solution of tetrahydrothiopyran-4-one (4.74 g) in conc. HCl (20.7 mL) cooled to 0 C. is added portion-wise sodium azide (3.98 g, 61.2 mmol). After addition is complete, the reaction is stirred at room temperature for 4 h. Solid sodium carbonate is then added portion-wise until the solution was slightly alkaline (pH=9). Water is added during addition of sodium carbonate to dissolve the salt. The alkaline solution is diluted with CHCl3 (125 mL), and the phases are separated. The aqueous layer is extracted with CHCl3 (2*75 mL). The combined organic layers are dried (Na2SO4), filtered, and concentrated. The crude product is recrystallized from CH2Cl2/hexanes to afford 4.30 g (81%) of 1,4-thiazepan-5-one as a white solid. Physical characteristics are as follows: Mp 114-116 C.; 1H NMR (300 MHz, CDCl3) delta6.41, 3.66, 2.96, 2.76. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1 ,4-thiazepan-5-one (prepared as described in WO 2006/056875, 910 mg, 6.94 mmol) was dissolved in anhydrous THF (27 mL) and cooled to 0 C. LAH (1 M THF solution, 1.05 equiv., 7.28 mmol, 7.28 mL) was added dropwise over 10 minutes. Following the completion of LAH addition, the reaction was allowed to stir at 0 C for an additional 10 minutes at which point the cooling bath was removed and the reaction was stirred at room temperature for 2 hours. The reaction was carefully quenched by the sequential addition of H20 (0.3 mL) fol- lowed by 1 N aqueous NaOH (1.5 ml_). The resulting solids were removed by filtration through a celite plug followed by washing of the celite plug with Et20 (400 mL). The combined filtrate was concentrated to generate crude 1 ,4-thiazepane which was redissolved in DCM (70 mL). TEA (-1.2 equiv, 8.4 mmol, 1.2 mL) was added followed by di-tert-butyl di- carbonate (-1.05 equiv, 7.35 mmol, 1.604 g). The reaction mixture was allowed to stir at room temperature for 12 hours. The crude reaction mixture was concentrated and purified with silica gel flash column chromatography (0-30% ethyl acetate in hexanes) to afford the title compound as a clear oil, MS m/z 240.1 (M+Na+) (Method M). |
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