Structure of 669008-26-8
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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. : | 669008-26-8 |
Formula : | C4H9NO2S |
M.W : | 135.18 |
SMILES Code : | O=S(C1(C)CC1)(N)=O |
MDL No. : | MFCD11501466 |
InChI Key : | ATJVVVCODTXRAE-UHFFFAOYSA-N |
Pubchem ID : | 21889814 |
GHS Pictogram: |
![]() |
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 | 1.0 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 30.94 |
TPSA ? Topological Polar Surface Area: Calculated from |
68.54 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.43 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
-0.33 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.85 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-0.89 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
-0.27 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
-0.04 |
Log S (ESOL):? ESOL: Topological method implemented from |
-0.4 |
Solubility | 53.3 mg/ml ; 0.394 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-0.65 |
Solubility | 30.4 mg/ml ; 0.225 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-0.62 |
Solubility | 32.4 mg/ml ; 0.24 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 |
-7.36 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 |
2.0 |
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) |
2.4 |
* 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 |
---|---|---|
79% | To a solution of lR-tert-butoxycarbonylamino-2S-vinyl-cyclopropanecarboxylic acid (2.3 g, 10.1 mmol) in THF (40 mL) was added CDI (1.80 g, 11.6 mmol) and was heated to 85 °C for 30 min. After let cool to rt, the reaction mixture was treated with 1-methyl-cyclopropanesulfonam (1.64 g, 12.1 mmol) and DBU (3.08 g, 20.2 mmol). After stirring at rt for 16 h, the reaction was diluted with EtOAc (160 mL) and washed with 2x25 mL IN HC1. The combined aqueous layer was extracted with 1x50 mL EtOAc. The combined organic layer was washed with H20 (50 mL), brine, dried over MgS04 and concentrated to a light yellow solid product (2.75 g, 79percent). The product was used as crude. MS m/z 367 (M+Na). | |
74.2% | General procedure: Step 2: tert-butyl ((lR,2S)-l-(((l-methylcyclopropyl)sulfonyl)carbamoyl)-2- vinylcyclopropyl)carbamate A round-bottom flask was charged with the carboxylic acid product of step 1 (2 g, 8.80 mmol) and Iota,Gamma-carbonyldiimidazole (2.141 g, 13.20 mmol). Dry THF (44.0 ml) was added under anhydrous conditions and the mixture was heated (oil bath at 85°C) for 2 hours with exclusion of moisture. The mixture was cooled to room temp and a solution of 1- methylcyclopropane-1 -sulfonamide (2.379 g, 17.60 mmol) in dry THF (10 mL) was added followed by l,8-diazabicyclo[5.4.0]undec-7-ene (2.63 ml, 17.60 mmol). The mixture was heated (oil bath at 75°C) overnight. The reaction mixture was treated with aq 1M HC1 (20 mL) and water (50 mL). The product was extracted into ethyl acetate (400 mL). Upon separation, the organic layer was washed with aq 1M HCl/water (1 :2, 80 mL), and brine (80 mL), dried over magnesium sulfate, filtered and concentrated in rotavap. The residue was purified on a gold cap RediSep® (120 g) silica gel column (gradient: 0 to 25percent ethyl acetate in dichloromethane) to give the the title compound (2.25 g, 6.53 mmol, 74.2 percent yield) as a white powder. | |
74.2% | A round-bottom flask was charged with the carboxylic acid product of step 1 (2 g, 8.80 mmol) and 1,1?-carbonyldiimidazole (2.141 g, 13.20 mmol). Dry THF (44.0 ml) was added under anhydrous conditions and the mixture was heated (oil bath at 85° C.) for 2 hours with exclusion of moisture. The mixture was cooled to room temp and a solution of 1-methylcyclopropane-1-sulfonamide (2.379 g, 17.60 mmol) in dry THF (10 mL) was added followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (2.63 ml, 17.60 mmol). The mixture was heated (oil bath at 75° C.) overnight. The reaction mixture was treated with aq 1M HCl (20 mL) and water (50 mL). The product was extracted into ethyl acetate (400 mL) Upon separation, the organic layer was washed with aq 1M HCl/water (1:2, 80 mL), and brine (80 mL), dried over magnesium sulfate, filtered and concentrated in rotavap. The residue was purified on a gold cap RediSep® (120 g) silica gel column (gradient: 0 to 25percent ethyl acetate in dichloromethane) to give the title compound (2.25 g, 6.53 mmol, 74.2percent yield) as a white powder. |
65% | Carbonyldiimidazole (1.75 g, 1.3 eq.) was added to a solution of compound 32B (1.89 g, 1 eq.) in anhydrous THF (20 mL) at room temperature. The reaction mixture was refluxed for 2 hrs and allowed to cooled down to room temperature. Methyl cyclopropyl sulfonamide (1.68 g, 1.5 eq.) and DBU (1.68 g, 1.5 eq.) were then added at 0 0C and the mixture was stirred at room temperature for 16 hrs.Solvent was removed in vacuo and the residue was dissolved in EtOAc, washed sequentially with IN HCl and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to yield compound 32Ca as a white powder in 65percent yield. 1H NMR (CDCl3, 400 MHz) delta (ppm) 1.01-1.05 (m, 2H), 1.25-1.28 (m, 2H), 1.35-1.40 (m, 2H), 1.45 (s, 9H), 1.50 (s, 3H), 1.77-1.80 (m, IH), 4.90(d, J= 10.60 Hz, IH), 5.04 (d, J= 17.32 Hz, IH), 5.42 (m, IH). | |
58% | To a solution of <strong>[159622-10-3](1R,2S)-1-(tert-butoxycarbonylamino)-2-vinylcyclopropanecarboxylic acid</strong> (25 g, 110 mmol) in THF (300 mL) was added CDI (205 g, 127 mmol) and the reaction mass was heated at 85° C. for 1 h. The reaction mass was cooled to rt and to this reaction mass was added 1-methylcyclopropane-1-sulfonamide (17.7 g, 131 mmol) followed by DBU (33.2 mL, 33.5 mmol). The reaction mixture was stirred at rt for 18 h. The solvent was evaporated under reduced pressure and the residue was diluted with water and acidified to pH ?2 by using aq. 1.5 N HCl solution. The precipitated solid was isolated via filtration and washed with water to get desired compound (22 g, 58percent) as off-white solid. 1H NMR (400 MHz, DMSO-d6) delta ppm 11.01-11.17 (m, 1H), 7.17-7.33 (m, 1H), 5.35-5.51 (m, 1H), 5.18-5.29 (m, 1H), 4.99-5.09 (m, 1H), 2.21 (s, 1H), 1.69 (dd, J=7.78, 5.27 Hz, 1H), 1.40 (d, J=3.01 Hz, 14H), 1.20 (dd, J=9.29, 5.27 Hz, 1H), 0.82-0.96 (m, 2H). MS: MS m/z 343 (M++1). | |
Step 4: tert-butyl [(lR,2S)-2-ethenyl-l~[(l-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl] carbamate; To a solution of (li?,2<S)-l-[(ter/-butoxycarbonyl)amino)-2- ethenylcyclopropanecarboxylic acid (4.35 g, 19.1 mmol) in THF (75 mL), carbonyldiimidazole (4.0 g, 24.88 mmol) was added, and the solution was then heated to reflux for 1 hour. The mixture was then cooled to T, and the product from step 3 (4.35 g, 19.14 mmol) was then added followed by DBU (4.0 mL, 26.8 mmol). After stirring for 20 hours, 1 N HC1 was added until acidic, and the mixture was extracted with EtO Ac 2x. The combined organic layers were dried over Na2S04, and the solvent was removed in vacuo. 1 : 1 EtOAc/hexanes (100 mL) was then added, and the resulting solid was filtered. The filtrate was concentrated and the 1 : 1 EtOAc hexanes was added again to produce more solid. The combined solids were dried to yield the title compound as a solid (5 g). LCMS (ES+) m/z 289.3 ((M-/-Bu) +H)+. | ||
With hydrogenchloride; 1,8-diazabicyclo[5.4.0]undec-7-ene; 1,1'-carbonyldiimidazole; In tetrahydrofuran; | Preparation of tert-butyl ((1R,2S)-1-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamate To a solution of <strong>[159622-10-3](1R,2S)-1-(tert-butoxycarbonylamino)-2-vinylcyclopropanecarboxylic acid</strong> (25 g, 110 mmol) in THF (300 mL) was added CDI (205 g, 127 mmol) and the reaction mass was heated at 85° C. for 1 h. The reaction mass was cooled to rt and to this reaction mass was added 1-methylcyclopropane-1-sulfonamide (17.7 g, 131 mmol) followed by DBU (33.2 mL, 33.5 mmol). The reaction mixture was stirred at rt for 18 h. The solvent was evaporated under reduced pressure and the residue was diluted with water and acidified to pH ?2 by using aq. 1.5 N HCl solutions. The precipitated solid was isolated via filtration and washed with water to get desired compound (22 g, 58percent) as off-white solid. 1H NMR (400 MHz, DMSO-d6) delta ppm 11.01-11.17 (m, 1H), 7.17-7.33 (m, 1H), 5.35-5.51 (m, 1H), 5.18-5.29 (m, 1H), 4.99-5.09 (m, 1H), 2.21 (s, 1H), 1.69 (dd, J=7.78, 5.27 Hz, 1H), 1.40 (d, J=3.01 Hz, 14H), 1.20 (dd, J=9.29, 5.27 Hz, 1H), 0.82-0.96 (m, 2H). MS:MS m/z 343 (M++1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31 g | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃; for 36h; | Preparation of Intermediate A10. Step 1 . Preparation of A10-1 : A solution of A9-1 (25 g, 100 mmol) and 1 - methylcyclopropane-1 -sulfonamide (prepared according to Example 1 .2 of International Patent Publication No. WO 2008/064066, p. 47; 15g, 1 10 mmol) in DCM (330 mL) was treated with DMAP (24.4 g, 200 mmol) followed by slow addition of EDC (38.3 g, 200 mmol) at 0 C. After addition was completed, the mixture stirred vigorously at 0 C and allowed to warm rt over 36 h. The reaction was diluted with EtOAc (300 mL). The organic layer was washed with 10% citric acid (3X30 mL) and sat. NaHCOs (2X20 mL). The combined aqueous washes were extracted once with EtOAc. The combined organic layers were washed with brine (2X25 mL), dried over anhydrous Na2SO , filtered and concentrated in vacuo. After trituration with hexane/EtOAc (10/1 ), acyl sulfonamide A10-1 (31 g) was obtained as a white solid. |
The acid 54 (10.0 g, 39.8 mmol, 1.0 equiv.), 1-methylcyclopropane-1-sulfonamide 55 (6.49 g, 48.0 mmol, 1.20 equiv), and HATU (17.86 g, 47.0 mmol, 1.18 equiv) were charged to a 250 ml, flask followed by 120 mL of acetonitrile. Then 2,6-lutidine (5.5 mL, 51.5 mmol, 1.29 equiv.) was added dropwise maintaining an internal temperature below 25 C. The solution was stirred for 30 minutes and then cooled to 10 C. DMAP (19.45 g, 159.2 mmol, 4.0 equiv) was added in several portions over 6 minutes maintaining an internal temperature below 15 C. The resulting slurry was stirred overnight at 20 C. The reaction was filtered and the solids were washed with 30 mL of IPAc. IPAc (76 mL) was added to the filtrate and the solution washed with 20 wt % phosphoric acid (3×80 mL), 2 wt % phosphoric acid (1×80 mL), and water (5×80 mL). The IPAc solution of 56 was used directly in the next reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; 1,8-diazabicyclo[5.4.0]undec-7-ene; 1,1'-carbonyldiimidazole; In tetrahydrofuran; | Preparation of tert-butyl((1R,2S)-1-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamate To a solution of <strong>[159622-10-3](1R,2S)-1-(tert-butoxycarbonylamino)-2-vinylcyclopropanecarboxylic acid</strong> (25 g, 110 mmol) in THF (300 mL) was added CDI (205 g, 127 mmol) and the reaction mass was heated at 85° C. for 1 h. The reaction mass was cooled to rt and to this reaction mass was added 1-methylcyclopropane-1-sulfonamide (17.7 g, 131 mmol) followed by DBU (33.2 mL, 33.5 mmol). The reaction mixture was stirred at rt for 18 h. The solvent was evaporated under reduced pressure and the residue was diluted with water and acidified to pH?2 by using aq. 1.5 N HCl solution. The precipitated solid was isolated via filtration and washed with water to get desired compound (22 g, 58percent) as off-white solid. 1H NMR (400 MHz, DMSO-d6) delta ppm 11.01-11.17 (m, 1H), 7.17-7.33 (m, 1H), 5.35-5.51 (m, 1H), 5.18-5.29 (m, 1H), 4.99-5.09 (m, 1H), 2.21 (s, 1H), 1.69 (dd, J=7.78, 5.27 Hz, 1H), 1.40 (d, J=3.01 Hz, 14H), 1.20 (dd, J=9.29, 5.27 Hz, 1H), 0.82-0.96 (m, 2H). MS: MS m/z 343 (M++1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | Carbonyldiimidazole (1.75 g, 1.3 eq.) was added to a solution of compound 6 (1.89 g, 1 eq.) in anhydrous THF (20 mL) at room temperature. The reaction mixture was refluxed for 2 hrs and allowed to cooled down to room temperature. Methyl cyclopropyl sulfonamide (1.68 g, 1.5 eq.) and DBU (1.68 g, 1.5 eq.) were then added at 0 °C and the mixture was stirred at room temperature for 16 hrs. Solvent was removed in vacuo and the residue was dissolved in EtOAc, washed sequentially with 1N HCl and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to yield compound 7a as a white powder in 65percent yield. 1H NMR (CDCl3, 400 MHz) delta (ppm) 1.01-1.05 (m, 2H), 1.25-1.28 (m, 2H), 1.35-1.40 (m, 2H), 1.45 (s, 9H),1.50 (s, 3H), 1.77-1.80 (m, 1H), 4.90(d, J = 10.60 Hz, 1H), 5.04 (d, J= 17.32 Hz, 1H), 5.42 (m, 1H). |
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