Structure of 170384-29-9
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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. : | 170384-29-9 |
Formula : | C8H15NO3 |
M.W : | 173.21 |
SMILES Code : | C(C)(C)(C)OC(NCC(C)=O)=O |
MDL No. : | MFCD10698678 |
InChI Key : | OZGMUQGCAFEQOX-UHFFFAOYSA-N |
Pubchem ID : | 357955 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H412 |
Precautionary Statements: | P273 |
Num. heavy atoms | 12 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.75 |
Num. rotatable bonds | 5 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 45.28 |
TPSA ? Topological Polar Surface Area: Calculated from |
55.4 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.07 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.68 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.1 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.53 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.53 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.98 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.01 |
Solubility | 16.8 mg/ml ; 0.0972 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.42 |
Solubility | 6.58 mg/ml ; 0.038 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.57 |
Solubility | 4.68 mg/ml ; 0.027 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 |
Yes |
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 |
-6.87 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) |
1.91 |
* 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 |
---|---|---|
61% | With dipyridinium dichromate; In N,N-dimethyl-formamide; at 0 - 23℃; for 16h;Inert atmosphere; | To a solution of PDC (68.9 g, 183 mmol) in DMF (50 mL) was added 45 (16.0 g, 92.0 mmol) in DMF (42 mL) at 0 C. The reaction was allowedto stir for 16 h while warming to 23 C. The reaction mixture waspoured over a plug of Celite with Et2O, quenched with brine (200 mL),and diluted with Et2O (700 mL). The combined Et2O layers werewashed with aq NH4Cl (2 × 200 mL), H2O (2 × 200 mL), and brine(2 × 200 mL), dried (MgSO4), filtered, and concentrated to give Boc-aminoacetone 42 as a yellow oil; yield: 10.6 g (61.0 mmol, 61%). |
52% | With sulfur trioxide pyridine complex; triethylamine; In dichloromethane; dimethyl sulfoxide; for 6h; | 2.24 g (12.7 mmol) of (2-hydroxy-propyl)-carbamic acid t-butyl ester obtained in the above step (1) was dissolved in 30 mL of dichloromethane, and then 3.6 mL (25.7 mmol) of triethylamine was dropwise added. To the resulting solution, was added a solution of 6.05 g (19 mmol) of 50% pyridine sulfur trioxide which was dissolved in 15 mL of dimethylsulf oxide. After 6 hours, 200 mL of ethyl acetate was added thereto and the reaction solution was washed with water, then an organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, then the residue was purified by column chromatography to give 1.15 g (6.64 mmol) of the title compound in a yield of 52%.[376] NMR: 1H-NMR(CDCl3) delta 5.2O(1H, brs), 4.05~4.00(2H, m), 2.17(3H, s), 1.43(9H, s)[377] Mass(EI) 174(M++.) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | a) Preparation of 1-amino-propan-2-one hydrochloride To the solution of Boc-glycine Weinreb amide (10 g, 46 mmol) in dry THF (tetrahydrofuran) (100 mL) was slowly added 1.4 M methyl magnesium chloride in toluene/THF (72 mL, 100 mmol) at -15 C. to -5 C. under N2. After addition, the mixture was stirred at room temperature for over night. After adding aqueous 1.0N HCl solution (115 mL) at 0 C., the product was extracted with ethyl acetate (150 mL). The organic layers were successively washed with water (150 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 0-30% ethyl acetate in hexane in 30 min) afforded (2-oxo-propyl)-carbamic acid tert-butyl ester (6.99 g, 88%) as colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | General procedure: This procedure has been adapted from the following article: J. Am. Chem. Soc., 2014, 136(30), pp 10777-10782.To a solution of ketone 17b, 18b or 19b (1.00 equiv) in anhydrous MeOH (5.00 M) at 0Cwas slowly added a solution of ammonium (7 N in MeOH, 1 mL per mmol of ketone). After 3hat 0C, a suspension of hydroxylamine-O-sulfonic acid (1.1 equiv) in anhydrous MeOH (11.0M) was added. The reaction was stirred at r.t. overnight. The mixture was concentrated andanhydrous MeOH was added. The suspension was filtered and the filtrate was concentrated.Anhydrous MeOH (1.40 M) was added and cooled down 0C. Anhydrous Et3N (1.60 equiv)was added, followed by a portionwise addition of I2 (0.40 equiv). After 10 min at 0C, thereaction was diluted with EtOAc. The organic layer was washed with a HCl solution (1N), anaqueous solution of Na2S2O3 (10 % wt), dried over Na2SO4, filtered and concentrated. Thecrude product was purified by silica gel column chromatography to give the desiredcompound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With hydrogenchloride; In 1,4-dioxane; for 12h; | To (2-oxo-propyl)-carbamic acid tert-butyl ester (6.99 mg, 40.4 mmol) was added 4 N HCl in dioxane (120 mL). After stirring 12 h and removal of the solvent, ether was added. The solid was collected by filtration and washed with ether and dried to give 1-amino-propan-2-one hydrochloride (4.51 g, 100%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With benzoic acid; In benzene; at 80℃; for 3h; | 500 mg (2.88 mmol) of (2-oxo-propyl)-carbamic acid t-butyl ester obtained in the above step (2) was dissolved in 8 mL of benzene, and then 1.45 g (4.33 mmol) of methyl (triphenyl phosphoranilidene) acetate and 35 mg (0.28 mmol) of benzoic acid was added thereto. The reaction solution was heated to 80C for 3 hours. The solvent was distilled off under reduced pressure, then the residue was purified by column chromatography to give 54 mg (6.64 mmol) of the title compound in a yield of 23% and 301 mg (1.31 mmol) of the trans compound in a yield of 45%.[381] NMR: 1H-NMR(CDCl3) delta 5.77(1H, s), 5.17(1H, brs), 4.16(2H, d, J=6.4Hz),3.69(3H, s), 2.05(3H, s), 1.44(9H, s)[382] Mass(EI) 230(M++.) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In diethyl ether; at 20℃; for 2h; | In a 100 mL round-bottomed flask was tert-butyl (2- oxopropyl)carbamate (451 mg, 2.60 mmol) in diethyl ether (8 mL) to give a colorless solution. Allylmagnesium bromide (5.73 mL, 5.73 mmol) was slowly added at rt. The mixture was stirred at rt for 2 h and was quenched with saturated NH4C1 solution. The layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated to a tan oil (crude 580 mg, 100%). Crude 1H NMR indicated the desired product: 1H NMR (500 MHz, Chloroform- d) 5 5.88 (ddt, J = 17.6, 10.3, 7.5 Hz, 1H), 5.22 - 5.08 (m, 2H), 4.93 (s, 1H), 3.15 (d, J = 6.3 Hz, 2H), 2.38 (s, 1H), 2.26 (ddt, J = 7.4, 2.3, 1.1 Hz, 2H), 1.46 (s, 9H), 1.18 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | In 5,5-dimethyl-1,3-cyclohexadiene; for 4h;Reflux; Inert atmosphere; | To a solution of Boc-amino acetone3 17 (4.21 g, 24.3 mmol) in xylenes (24 mL) was added 2,2,6-trimethyl-4H-1,3-dioxin-4-one 18 (7.1 mL, 48.6 mmol). The reaction was heated to reflux (130 C) for 4 h, was cooled to 23 C and concentrated under reduced pressure to afford crude beta-ketoamide. Purification by flash column chromatography (CH2Cl2:Et2O 90:10) provided mixed fractions of beta-ketoamide and alpha,beta-unsaturated lactam 19. alpha,beta-Unsaturated lactam 19 was isolated (1.37, 24%) as a yellow oil. The mixed fractions were re-subjected to flash column chromatography (CH2Cl2:Et2O 90:10) which provided alpha,beta-unsaturated lactam 19 (1.78 g, 31%) for a combined yield of 3.15 g (55%) of a yellow oil. To a solution of alpha,beta-unsaturated lactam 19 (1.40 g, 6.0 mmol) in toluene (120 mL) was added DIBAL-H in hexanes (12 mL, 1.0 M solution, 12 mmol) at -78 C. The reaction was stirred for 4 h, quenched with EtOAc (10 mL)and Rochelle?s salt (20 mL) at -78 C, and allowed to warm to 23 C while stirring vigorously overnight. The solution was diluted with CH2Cl2 (300 mL) and poured over Celite. The organic extracts were separated and washed with brine (60 mL), dried over Na2SO4, decanted, and concentrated under reduced pressure. Purification by flash column chromatography (hexanes:EtOAc 40:60) delivered allylic alcohol (408 mg, 28%) as an orange oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; for 72h; | The free base of 2-(aminomethyl)-4-(tert-butyl)-6-(6-(trifluoromethyl)pyridin-3-yl)phenol hydrochloride (Example 64), was prepared by partitioning the hydrochloride salt (560 mg, 1.55 mmol) between ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic phase was separated, dried (Na2SO4), filtered and the solvent removed under reduced pressure. The residue was redissolved in a solution of <strong>[170384-29-9]tert-butyl (2-oxopropyl)carbamate</strong> in ethanol (5 mL) and stirred for three days. Sodium borohydride (290 mg, 7.75 mmol) was added portionwise and the reaction mixture stirred at room temperature for one hour. The reaction was quenched with saturated aqueous ammonium chloride solution (1 mL) and the reaction mixture partitioned between ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic phase was separated, dried (Na2SO4), filtered and the solvent was removed under reduced pressure. The residue was purified using flash chromatography on silica eluting with a solvent gradient of 0-100% ethyl acetate in hexanes to give tert-butyl (2-((5-(tert-butyl)-2-hydroxy-3-(6-(trifluoromethyl)pyridin-3-yl)benzyl)amino)propyl)carbamate (500 mg, 67%) as a white solid. The carbamate (500 mg, 1.04 mmol) was dissolved in methylene chloride (20 mL) and trifluoroacetic acid (10 mL) added and the reaction was stirred for 16 h. The solvent was removed under reduced pressure, the residue azeotroped twice with toluene (20 mL) and then redissolved in a 1:1 mixture of methylene chloride and trifluoracetic acid (40 mL) and stirred at room temperature for four hours. The solvent was removed under reduced pressure, the residue azeotroped twice with toluene (20 mL) and the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic phase was separated, dried (Na2SO4), filtered and the solvent removed under pressure. The residue was purified using flash chromatography on silica eluting with a solvent gradient of 0 to 100% of (89% methylene chloride, 10% methanol and 1% ammonium hydroxide) in methylene chloride. The purified residue was dissolved in a 1.25 M hydrochloric acid solution in ethanol, the solution stood for 10 minutes, and then the solvent removed under reduced pressure and the residue triturated with diethyl ether to give 2-(((1-aminopropan-2-yl)amino)methyl)-4-(tert-butyl)-6-(6-(trifluoromethyl)pyridin-3-yl)phenol dihydrochloride (150 mg, 32% yield) as a white solid. |
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