Structure of 5835-79-0
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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. : | 5835-79-0 |
Formula : | C8H17NO2 |
M.W : | 159.23 |
SMILES Code : | OCCCCN1CCOCC1 |
MDL No. : | MFCD03211280 |
InChI Key : | URFFPMJFOHTCLI-UHFFFAOYSA-N |
Pubchem ID : | 16641259 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H319 |
Precautionary Statements: | P305+P351+P338 |
Num. heavy atoms | 11 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 1.0 |
Num. rotatable bonds | 4 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 47.51 |
TPSA ? Topological Polar Surface Area: Calculated from |
32.7 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.1 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
-0.08 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
-0.29 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.02 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.12 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.57 |
Log S (ESOL):? ESOL: Topological method implemented from |
-0.51 |
Solubility | 48.9 mg/ml ; 0.307 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-0.15 |
Solubility | 111.0 mg/ml ; 0.7 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.1 |
Solubility | 12.7 mg/ml ; 0.0798 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) |
Yes |
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 |
-7.33 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) |
1.58 |
* 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 |
---|---|---|
35% | EXAMPLE 3; l -(4-Hydroxybutyl)morpholine was prepared as follows. In a 250 mL flask was mixed morpholine (65.5 g, 750 mmol), 4-chlorobutanol (27.2 g, 250 mmol), sodium iodide (3.8 g, 25 mmol) and 75 mL of dioxane. The reaction was heated to reflux. <n="76"/>After 2 days the reaction was allowed to cool to ambient temperature. Solvent was removed by rotary evaporation leaving a brown oil. The oil was dissolved in 100 mL of 2N NaOH, extracted with EtOAc and dried over Na2SO4. After filtration of the drying agent solvent was removed in vacuo leaving an orange oil. The oil was distilled (90 0C, 1 mm Hg), leaving 1 - (4-hydroxylbutyl)morpholine ( 13.9 g, 87 mmol, 35 % yield) as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
B. Similarly prepared by use of the appropriate secondary amines and the appropriate omega-haloalcohols are the following N,N-disubstituted aminoalcohols: 4-(4-morpholinyl)butanol; 4-(1-piperidinyl)butanol; 4-(1-pyrrolidinyl)butanol; 4-(N,N-diphenylamino)butanol; 4-(N,N-dimethylamino)butanol; ... |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | Into a 100 mL flask fitted with a Dean-Stark trap were added l -(4- hydroxybutyl)- morpholine ( 13.2 g, 83 mmol), 4-(pivalamido)butanoic acid (1 1.1 g, 59 mmol), p-toluencsulfonic acid ( 1.1 g, 5.9 mmol) and 55 mL of toluene. The reaction was heated to reflux. Conversion was periodically checked by HPLC (ELSD) and after 7 days -80% conversion was observed. The reaction was allowed to cool to ambient temperature, was poured into saturated NaHCO3, extracted with EtOAc (2 x 250 mL), washed with saturated NaI lCO3 and water and dried over Na2SO4. After filtration of the drying agent solvent was removed in vacuo at 90 0C leaving 7 g of the product (see reaction below) (21 mmol, 36 % yield; >99 % pure by HPLC) as a brown oil. The spectra for the product of this reaction are shown in FlGs 13- 16. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Neat DMSO (2.7 mL, 37.8 mmol) was added to a -78 0C CH2Cl2 solution (25 mL) of oxalyl chloride (2.6 mL, 30.3 mmol). After 10 min at -78 0C a CH2Cl2 solution (25 mL) solution of 4-(4-morpholinyl)-l-butanol (2.4 g, 15.1 mmol) was added. After 10 min at -78 0C neat triethylamine (8.4 mL, 60.5 mmol) was added, stirred for 10 min at -78 0C, then allowed to warm to 0 0C and stirred for an additional 30 min. The resulting white suspension was poured into diethyl ether and the suspension was filtered. The filtrate was concentrated and purified by column chromatography to afford 2.2 g of the title compound, as a brown liquid (2.23 g, 94%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: General Procedure C Preparation of Mono-Esters of Fumaric Acid Coupling Reaction of Morpholin-4-ylalkyl-1-ol with Fumaric Acid [0429] [0430] Fumaric acid (1.0 eq.) is dissolved in an inert solvent such as dichloromethane (DCM), N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), or N,N-dimethylacetamide (DMA, DMAc) (ca. 3 mL/mmol) and the solution is treated with 1.0-1.5 eq. of a carbodiimide dehydration agent such as 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDAC, EDC), N,N-diisopropylcarbodiimide (DIC), N,N-dicyclohexyl-carbodiimide (DCC) at a temperature from ca. 0 C. (ice bath) to room temperature. The mixture is then reacted with a solution of an appropriately functionalized of morpholin-4-ylalkyl-1-ol (1.0-1.5 eq.) in the same solvent. Optionally, a catalytic or stoichiometric amount of 4-(N,N-dimethylaminopyridine (DMAP) is added to the mixture at a temperature from ca. 0° C. to room temperature. When the amine is in a salt form, an equimolar amount of an organic tertiary base, such as triethylamine (TEA), or diisopropylethylamine (DIEA) may be added to free the amine base prior to the coupling step. The reaction mixture is stirred for 4 to 12 hours at room temperature. Optionally the organic solvents are removed under reduced pressure using a rotary evaporator and the residue diluted with an appropriate extraction solvent such as diethyl ether (Et2O), methyl tert-butyl ether (MTBE), ethyl acetate (EtOAc), or others. Water is added to the reaction mixture, the aqueous phase was acidified using 1N hydrochloric acid until aqueous pH reaches to pH 2. After phase separation, the aqueous phase is extracted several times with the same solvent. The combined organic extracts are washed with water, brine, and dried over anhydrous magnesium sulfate (MgSO4). After filtration, the organic solvents are removed under reduced pressure using a rotary evaporator. If required, the crude reaction products are further purified by well-known purification techniques such as silica gel flash column chromatography (i.e., Biotage), mass-guided reversed-phase preparative HPLC/lyophilization, precipitation, or crystallization to yield the pure desired product. Example 15 (4-Morpholinobutyl)fumarate (39) [0471] t-butyl hydrogen fumarate (MHF) (0.2 mol) is activated with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDAC) (47.75 g, 0.25 mol) in 200 mL of dichloromethane (DCM) at ca. 0 C. 4-Morpholin-4ylbutyl-1-ol (31.8 g, 0.2 mol) and 4-N,N-dimethylaminopyridine (DMAP) (1 g, 0.008 mol) were added to the activated carboxylic acid. After work-up and isolation, the crude material is reacted with 50% vol-% trifluoroacetic acid in DCM. The free acid is purified by mass-guided preparative HPLC to afford the title compound (40). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0℃; | Example 16 Preparation of the MMF Prodrug Methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate Methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate Monomethyl fumarate (MMF) was reacted with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDAC) (1.2 eq) in dichloromethane (DCM) at ca. 0 C. 4-Morpholin-4-yl-butan-1-ol (1 eq) and 4-N,N-dimethylaminopyridine (DMAP) (catalytic amount) were added to the activated carboxylic acid. After the completion of the reaction, followed by the work-up of the reaction mixture, the title compound was isolated as a viscous-oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | Example 170 General Procedure 11 4-Morpholin-4-ylbutyl 4-[(5?-fluoro-2?-hydroxybiphenyl-3-yl)sulfonyl]amino}-2-hydroxybenzoate trifluoroacetate [0779] 4-[(5?-fluoro-2?-hydroxybiphenyl-3-yl)sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 16) (20 mg, 0.050 mmol) and thionyl chloride (18 mg, 0.15 mmol) in MeCN (2 mL) was stirred at room temperature for 20 minutes. The reaction mixture was concentrated to half the volume with a stream of nitrogen and a solution of <strong>[5835-79-0]4-morpholin-4-ylbutan-1-ol</strong> (40 mg, 0.25 mmol) in MeCN (1 mL) was added. The reaction mixture was stirred at room temperature for 3 days, and purified by preparative HPLC (acidic system). The title compound was obtained in 31% yield (10.2 mg). MS (ESI+) m/z 545 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane; at 20℃;Inert atmosphere; | General procedure: To a solution of 6-substituted pyridazinone 9 (0.5 mmol) in DMF (10 mL) was added Cs2CO3 (0.55 mmol). An appropriately substituted nitro benzyl chloride (0.52 mmol) was added and the resulting mixture was stirred at 40-50 C for 3 h, the solvent was removed under reduced pressure and the residue was dissolved in EtOAc (30 mL), which was then washed with brine (3 × 10 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product, 2-nitrobenzyl-6-substituted-pyridazin-3(2H)-one (10), was used in the next step without further purification. To a solution of 10 in 95 % ethanol (50 mL) was added acetic acid (10 mmol) followed by slow addition of iron powder (2 mmol). The resulting mixture was stirred for 5 h at 100 C. The mixture was then filtered through celite and the filter cake was washed with 95 % ethanol (3 × 15 mL). The combined ethanol filtrates were evaporated in vacuo and the residue was re-dissolved in ethyl acetate (30 mL). The organic layer was washed with brine (3 × 10 mL) and 2 M NaOH (10 mL) sequentially. The organic layer was dried over anhydrous Na2SO4, evaporated in vacuo to afford 2-aminobenzyl-6-substituted-pyridazin-3(2H)-one (11) as a yellow solid, which was used without further purification. To a stirred solution of 11 and triphosgene (1 mmol) in dry dichloromethane (5 mL) was added triethylamine (2 mmol) under nitrogen atmosphere. A solution of the corresponding alcohol (1 mmol) in dichloromethane (5 mL) was added 5-10 min later and the mixture was stirred at room temperature overnight, diluted with dichloromethane (15 mL) and washed with water (3 × 20 mL). The organic phases were separated, combined, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by using column chromatography to afford the corresponding product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; In chloroform; | General procedure: The syntheses of compounds 3-20 were carried out accordingto our previously reported method [17]. Briefly, at room temperature,the acid 2 (150 mg, 0.5 mmol) was acyl chlorinated withthionyl chloride (2.5 mL) and then esterized with various alcoholderivatives in chloroform. The reaction mixture was heated underreflux for 5 h to overnight, and cooled to room temperature. Thesolvent was evaporated under reduced pressure. The crude productwas purified by using silica gel column chromatography to give thetarget product. |
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