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CAS No. : | 16369-05-4 | MDL No. : | MFCD00004730 |
Formula : | C5H13NO | Boiling Point : | - |
Linear Structure Formula : | NH2CH(CH(CH3)2)CH2OH | InChI Key : | - |
M.W : | 103.16 | Pubchem ID : | - |
Synonyms : |
|
Num. heavy atoms : | 7 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 1.0 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 30.02 |
TPSA : | 46.25 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.93 cm/s |
Log Po/w (iLOGP) : | 1.54 |
Log Po/w (XLOGP3) : | 0.0 |
Log Po/w (WLOGP) : | -0.04 |
Log Po/w (MLOGP) : | 0.23 |
Log Po/w (SILICOS-IT) : | -0.21 |
Consensus Log Po/w : | 0.3 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.35 |
Solubility : | 46.3 mg/ml ; 0.449 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.52 |
Solubility : | 31.0 mg/ml ; 0.3 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.15 |
Solubility : | 73.4 mg/ml ; 0.711 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.0 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P264-P271-P280-P302+P352-P304+P340+P312-P305+P351+P338-P332+P313-P337+P313-P403+P233-P405-P501 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | 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 |
---|---|---|
62% | With sodium hydroxide In tetrahydrofuran; water | EXAMPLE 2 A dry, 12-liter glass reaction vessel equipped as described in Example 1 was charged with 900 grams (7.7 moles) of valine and 2.5 liters of tetrahydrofuran. Using the procedure described in Example 1, boron trifluoride diethyl etherate (1.05 liters, 8.5 moles) was added followed by 0.85 liter (8.5 moles) of borane-dimethyl sulfide at reflux. The addition took 8 hours and heating was continued for an additional 3 hours following the addition. The reaction mixture was then hydrolyzed with 0.75 liter of tetrahydrofuran/water followed by 24.6 moles of sodium hydroxide as an aqueous solution. The product was isolated as described in Example 1 giving 494 grams (62percent yield) of 2-amino-3-methyl-1-butanol, bp 78°-79°C at 8 mm, n20D 1.4543, purity by glc analysis: 97percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tetrahydroborate; In tetrahydrofuran; | C. Synthesis of 2-amino-3-methyl-1-butanol Valine methyl ester (0.1 mol) is dissolved in dry THF, and NaBH4 (0.035 mol) is then added slowly. The reaction mixture is stirred at room temperature for about 4 hours, and the colorless solid is purified by the procedure described in part (A). | |
With sodium tetrahydroborate; In tetrahydrofuran; | C. Synthesis of 2-amino-3-methyl-1-butanol STR22 Valine methyl ester (0.1 mol) is dissolved in dry THF, and NaBH4 (0.035 mol) is then added slowly. The reaction mixture is stirred at room temperature for about 4 hours, and the colorless solid is purified by the procedure described in part (A). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; sodium tetrahydroborate; sulfuric acid; In tetrahydrofuran; methanol; diethyl ether; | 1. 2-Amino-3-methyl-butan-1-ol To a stirred suspension of NaBH4 (1.136 g; 29.9 moles) in THF (12 L) is added DL-valine (1.4 Kg; 11.95 moles). The flask is immersed in an ice-water bath, and a solution of concentrated H2SO4 (1,325 g; 14.94 moles; 1.25 eq.) in diethyl ether (total volume of 2.4 L) is added dropwise at such a rate as to maintain the reaction mixture below 20 C. (addition time ~10 hours). Stirring of the reaction mixture is continued at room temperature overnight, and methanol (1.5 L) is added carefully to destroy excess BH3. The mixture is stirred for 3 hours at room temperature and then concentrated. 5 L NaOH (8 L; 5 M sol.) is added and the mixture is distilled. The solvent that distills below 100 C. is removed. The mixture is then heated at reflux for 3 hours. The turbid aqueous mixture is cooled and extracted with CH2Cl2 (2*5 L) and dried over MgSO4. Evaporation of the solvent gives crude product which is purified via vacuum distillation (90-95 C./10-15 mmHg) yielding 724 g (59%) of pure 2-Amino-3-methyl-butan-1-ol (a). | |
With sodium tetrahydroborate; iodine; In tetrahydrofuran; at 0 - 65℃; for 16h; | To a mixture of 2-amino-3-methylbutanoic acid (15 g, 128 mmol), and NaBH4 (19.5 g, 512 mmol) in THF (200 mL) was added ?2 (32 g, 128 mmol, dissolved in 100 mL of THF)dropwise at 0 C. The reaction mixture was stirred at 65 C for 16 h, quenched with MeOH (100 mL) and concentrated in vacuo. The white residue was dissolved in 225 mL of 20% aqueous KOH and stirred for 3 h at RT, extracted with EA (100 mL x 3), and the organic phases dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo to afford 2-amino-3-methylbutan-1-ol (7 g, 50 %) as an oil. LC-MS m/z: 118.1 [M+H]1 Purity (214 nm): 90%; tR= 0.34 min |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94%Chromat. | With oxygen; copper dichloride; In water; at 100℃; under 30003.0 Torr; for 4h;Autoclave; Green chemistry; | General procedure: In a typical experiment the glass vial was charged with a dou-bled distilled water solution (5.0 mL) of substrate (amine or aminol) (4 mmol), catalyst (CuCl2, 0.40 mmol), which appeared transparentand deep blue colored. The vial was introduced into the autoclave which was sealed, purged and charged with O2(0.6 MPa) and CO upto a total pressure of 4 MPa. Under these conditions, the substrate should be deemed the limiting reagent, also taking into account the head space of the autoclave and the stoichiometry of the carbony-lation process [Eq. (1)].The mixture was heated at 100C and allowed to react for 4 h.After this time, the autoclave was cooled at room temperature and then the residual gas was evacuated Identification of reaction products was performed via GC-MS bycomparison of their MS spectra with those reported in the litera-ture (and with the help of NIST database). A complete list of massspectral data of the major reaction products, including by-products,was reported into the supplementary material section. Quantitativeanalysis of reaction mixture was accomplished by GC-MS usingbutanone as an external standard. Conversions and yields were reported in Tables 1-3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 8% 2: 57% | With lithium perchlorate In methanol Ambient temperature; electrochemical oxidation; acetic acid buffer, pH ca. 4.5; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 3h; | Diisopropylethyl amine (17.4 ml, 134 mmol) was added a solution of (DL)-<strong>[16369-05-4]valinol</strong> (9.85 g, 95 mmol) in methylene chloride (100 ml).. The reaction mixture was cooled to 0 C., treated with a solution of p-toluoyl chloride (12.8 ml, 91 mmol) in methylene chloride (50 ml) and then allowed to warm to room temperature.. After stirring for 3 hours, excess aqueous sodium hydroxide solution was added and the reaction was transferred to a separatory funnel.. The organic layer was separated and the aqueous layer washed with one portion of methylene chloride.. The combined organic layers were washed with water and brine, dried over magnesium sulfate and concentrated in vacuo.. Chromatography eluding with 25% ethyl acetate in hexanes, followed by 50% ethyl acetate in hexanes gave N-p-toluoyl <strong>[16369-05-4]valinol</strong> (18.04 g). | |
With triethylamine; In dichloromethane; at 0 - 20℃; | Step 13 To a solution of <strong>[16369-05-4]valinol</strong> (DL, 5.0 g, 0.048 mol) in 200 ML of CH2Cl2 in the presence of Et3N (18.4 ML, 3eq.) at 0 C. was added 4-methyl-benzoyl chloride (7.1 ML, 1.1 eq.) in 50 ML of CH2Cl2 dropwise.After the addition was complete, the mixture was stirred at rt overnight.It was then quenched with water, and the organic layer was extracted with CH2Cl2, washed with NaCl (sat.), dried over Na2SO4 and concentrated.Column purification with 2/2/6 of acetone/CH2Cl2/hexane gave 7.8 g of white solid N-(1-hydroxymethyl-2-methyl-propyl)-4-methyl-benzamide (M+: 221). | |
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 3h; | Step 5 diisopropylethyl amine (17.4 ML, 134 mmol) was added a solution of (DL)-<strong>[16369-05-4]valinol</strong> (9.85 g, 95 mmol) in methylene chloride (100 ml).. The reaction mixture was cooled to 0 C, treated with a solution of p-toluoyl chloride (12.8 ML, 91 mmol) in methylene chloride (50 ML) and then allowed to warm to room temperature.. After stirring for 3 h, excess aqueous sodium hydroxide solution was added and the reaction was transferred to a separatory funnel.. The organic layer was separated and the aqueous layer washed with one portion of methylene chloride.. The combined organic layers were washed with water and brine, dried over magnesium sulfate and concentrated in vacuo.. Chromatography eluding with 25% ethyl acetate in hexanes, followed by 50% ethyl acetate in hexanes gave N-p-toluoyl <strong>[16369-05-4]valinol</strong> (18.04 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With zinc(II) chloride In various solvent(s) for 24h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridinium p-toluenesulfonate; In toluene; at 110℃; for 45h; | To a solution of 3-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid 3-chlorobenzylamide (1.20 g) obtained in the previous step in toluene (120 ml) were added pyridinium p-toluenesulfonate (815 mg) and 2-amino-3-methylbutanol (702 mg)'and the mixture was stirred at 110 C. for 15 hr. 2-Amino-3-methylbutanol (833 mg) was added and the mixture was further stirred at 110 C. for 30 hr. The solvent was evaporated from the reaction mixture, saturated aqueous sodium carbonate solution (30 ml) was added and the mixture was extracted twice with chloroform. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (ethyl acetate-chloroform:methanol=10:1) to give a crude product containing N-(3-chlorobenzyl)-3-benzyloxy-1-(1-hydroxymethyl-2-methylpropyl)-4-oxo-1,4-dihydropyridine-2-carboxamide as a main component. The total amount of this crude product was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; sulfuric acid; In tetrahydrofuran; diethyl ether; | (1) Synthesis of the Chiral Ionic Liquid 4-(S)-Isopropyl-2.3-dimethyl-oxazoliniumtetrafluoroborate 117 g (1 mol) L-valine are suspended with 100 g (2.5 mol) sodium borhydride in 1000 ml THF and cooled to 0 C. A solution of 66 ml (1.25 mol) sulphuric acid in 150 ml diethyl ether is added with stirring, such that the temperature of the reaction mixture remains below 20 C. When addition is complete the whole is heated to room temperature and stirred for 12 h. To destroy excess diborane 100 ml methanol are added. The reaction mixture is concentrated on the rotation evaporator to around 500 ml and 1000 ml 5N sodium hydroxide solution added. The solvents are distilled to 100 C., then cooked for 3 h under reflux. The solution is extracted with dichloromethane, and the dichloromethane is removed under vacuum. The valinol yield is 86.5 g (84%). | |
With sodium hydroxide; sulfuric acid; In tetrahydrofuran; diethyl ether; | (2) Synthesis of the Chiral Ionic Liquid 3-Butyl4-(S)-isopropyl-2-methyl-oxazoliniumtetrafluoroborate 117 g (1 mol) L-valine are suspended with 100 g (2.5 mol) sodium borhydride in 1000 ml THF and cooled to 0 C. A solution of 66 ml (1.25 mol) sulphuric acid in 150 ml diethyl ether is added with stirring, such that the temperature of the reaction mixture remains below 20 C. When addition is complete the whole is heated to room temperature and stirred for 12 h. To destroy excess diborane 100 ml methanol are added. The reaction mixture is concentrated on the rotation evaporator to around 500 ml and 1000 ml 5N sodium hydroxide solution added. The solvents are distilled to 100 C., then cooked for 3 h under reflux. The solution is extracted with dichloromethane, and the dichloromethane is removed under vacuum. The valinol yield is 86.5 g (84%). | |
With sodium hydroxide; sulfuric acid; In tetrahydrofuran; diethyl ether; | (3) Synthesis of the Chiral Ionic Liquid 3-Butyl-4-(S)-isopropyl-2-methyloxazoliniumhexafluorophosphate 117 g (1 mol) L-valine are suspended with 100 g (2.5 mol) sodium borhydride in 1000 ml THF and cooled to 0 C. A solution of 66 ml (1.25 mol) sulphuric acid in 150 ml diethyl ether is added with stirring, such that the temperature of the reaction mixture remains below 20 C. When addition is complete the whole is heated to room temperature and stirred for 12 h. To destroy excess diborane 100 ml methanol are added. The reaction mixture is concentrated on the rotation evaporator to around 500 ml and 1000 ml 5N sodium hydroxide solution added. The solvents are distilled to 100 C., then cooked for 3 h under reflux. The solution is extracted with dichloromethane, and the dichloromethane is removed under vacuum. The valinol yield is 86.5 g (84%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic acid; In water; | 20 g (0.194 mol) <strong>[16369-05-4]valinol</strong> are dissolved with 11.64 g (0.194 mol) acetic acid in 60 ml toluol and cooked for 24 h under reflux in the water separator. After cooling the solution is extracted with 10% hydrochloric acid. The aqueous phase is neutralized with 40% sodium hydroxide solution and extracted with diethyl ether. The organic phase is dried via Na2SO4 and the solvent removed. Distillation (112 C.) produces 19.2 g (78%) 4-(S)-isopropyl-2-methyloxazoline as a colourless oil. | |
With acetic acid; In water; | 20 g (0.194 mol) <strong>[16369-05-4]valinol</strong> are dissolved with 11.64 g (0.194 mol) acetic acid in 60 ml toluol and cooked for 24 h under reflux in the water separator. After cooling the solution is extracted with 10% hydrochloric acid. The aqueous phase is neutralized with 40% sodium hydroxide solution and extracted with diethyl ether. The organic phase is dried via Na2SO4 and the solvent removed. Distillation (112 C.) produces 19.2 g (78%) 4-(S)-isopropyl-2-methyloxazoline as a colourless oil. | |
With acetic acid; In water; | 20 g (0.194 mol) <strong>[16369-05-4]valinol</strong> are dissolved with 11.64 g (0.194 mol) acetic acid in 60 ml toluol and cooked for 24 h under reflux in the water separator. After cooling the solution is extracted with 10% hydrochloric acid. The aqueous phase is neutralized with 40% sodium hydroxide solution and extracted with diethyl ether. The organic phase is dried via NaSO4 and the solvent removed. Distillation (112 C.) produces 19.2 g (78%) 4-(S)-isopropyl-2-methyloxazoline as a colourless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30.70 g (95.6%) | With triethylamine; In dichloromethane; | a. N-Benzyloxycarbonyl-L-<strong>[16369-05-4]Valinol</strong>. To a stirred solution of <strong>[16369-05-4]valinol</strong> (13.96 g, 0.14 mol) and triethylamine (18.87 mL, 0.14 mol) in 250 mL of dry methylene chloride cooled to 0 C. under a nitrogen atmosphere was added 19.3 mL (0.14 mol) of benzyl chloroformate dropwise over 20 min. After warming to RT overnight, the mixture was diluted with methylene chloride (100 mL) and washed with 1N HCl (2*), brine and dried with anhydrous magnesium sulfate. The resulting mixture was filtered and evaporated to give 30.70 g (95.6%) of N-benzyloxycarbonyl-<strong>[16369-05-4]valinol</strong> as a white solid: Rf =0.27 (silica gel; 1:1 hexane:ethyl acetate). Used without further purification. |
With sodium carbonate; In water; at 20℃; for 16h; | To a mixture of 2-amino-3-methylbutan-1-ol (7 g, 60 mmol), and Na2CO3 (22 g, 180 mmol) in H20 (100 mL) was added benzyl chloroformate (12 g, 66 mmol). The mixturewas stirred at RT for 16 h, and extracted with EA (50 mL x 3) and dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (EA:PE = 1:3) to afford benzyl 1-hydroxy-3-methylbutan-2- ylcarbamate (9 g, 65 %) as a white solid. LC-MS m/z: 238.1 [M+Hjt Purity (214 nm): 90%; tR = 1.62 min |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol | 1.G G. G. Preparation of 4 Methyl-5-(2-Propyl)-3-Morpholinone Treatment of valinol in basic ethanol with chloroacetyl chloride using the procedure of Surry, et. al., J. Am. Chem. Soc. (1955) 77, 633, gives 5-(2-propyl)-3-morpholinone. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With sodium hydroxide; In tetrahydrofuran; water; | EXAMPLE 2 A dry, 12-liter glass reaction vessel equipped as described in Example 1 was charged with 900 grams (7.7 moles) of valine and 2.5 liters of tetrahydrofuran. Using the procedure described in Example 1, boron trifluoride diethyl etherate (1.05 liters, 8.5 moles) was added followed by 0.85 liter (8.5 moles) of borane-dimethyl sulfide at reflux. The addition took 8 hours and heating was continued for an additional 3 hours following the addition. The reaction mixture was then hydrolyzed with 0.75 liter of tetrahydrofuran/water followed by 24.6 moles of sodium hydroxide as an aqueous solution. The product was isolated as described in Example 1 giving 494 grams (62% yield) of 2-amino-3-methyl-1-butanol, bp 78-79C at 8 mm, n20D 1.4543, purity by glc analysis: 97%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With sodium hydride; In tetrahydrofuran; at 20℃; | To a chilled (ice bath) suspension of 1.45 g (36.2 mmol) of sodium hydride in 40 mL of THF was added 1 mL (9.07 mmol) of 2-amino-3-methylbutan-l-ol in 10 mL of THF dropwise followed by 5.58 g (19.9 mmol) of <strong>[51527-73-2]2,4,6-trichlorobenzenesulfonyl chloride</strong> in several portions. The mixture stirred for 30 minutes in the ice bath then at room temperature overnight. The mixture was then poured into saturated aqueous ammonium chloride and extracted in two portions of ether. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified on silica gel (Combflash 40 gram column) eluting with EtOAc-hexanes (0-5%) to afford 1.35 g(45%) of 2-isopropyl-l-(2,4,6-trichlorobenzenesulfonyl)aziridine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | In toluene; at 115℃; for 42h; | Intermediate 1B.4-A: Benzyl ?raw^-6-(3-fluorophenyl)-2-isopropyl-2'-methyl-5-oxo-5,6-dihydro-l 'H- spirofimidazo? .5-alimidazole-7,4'-piperidine1-r-carboxylateStep A: Amination with aminoalcoholA neat solution of benzyl /ralpha«5-4-amino-l-(3-fluorophenyl)-7-methyl-2-oxo-l,3,8-triazaspiro[4.5]dec-3- ene-8-carboxylate (Intermediate 1B.3 previously described in International Patent Application WO2007/1 1833, 1.0 g, 2.4 mmol) in DL-2-amino-3-methyl-l-butanol (3.8 g, 36.5 mmol) was allowed to stir at 1150C for 18 h. Toluene (2 ml) was added to improve stirring, and the reaction was allowed to stir at 1 150C for an additional 24 h. The reaction was cooled to rt and diluted with EtOAc/hexanes. The resulting precipitate was isolated via filtration to afford benzyl /r°ws-l-(3-fluorophenyl)-4-[l- (hydroxymethyl)-2-methylpropyl]amino}-7-methyl-2-oxo-l,3,8-triazaspiro[4.5]dec-3-ene-8-carboxylate (83%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With sodium hydroxide; In tetrahydrofuran; at 20℃; for 24h;Cooling with ice; | To a magneticallystirred solution of valinol (4d, 2.0 g, 19.4 mmol) and 1 N NaOH (19.4 mL) inTHF (25 mL) in an ice bath, a solution of Boc2O (5.08 g, 23.3 mmol)in 15 mL of THF was added dropwise. The mixture reaction was stirred at roomtemperature for 24 h. Then, the solvent was evaporated under reduced pressureand the residue collected with EtOAc and washed with water and brine, dried (Na2SO4),and evaporated under vacuum to give 3.7 g of a white solid which wasrecrystalized from EtOAc/hexane to afford 2.85 g (73 %) of white crystals: mp 71-72 C; IR (KBr): 3419 (NH), 3274 (OH), 1683(CO); 1H NMR: delta 0.91 (d, J = 6.6Hz, 3H, CH3CHCH3),0.93 (d, J = 6.6 Hz, 3H, CH3CHCH3)1.42 (s, 9H, C(CH3)3),1.75-1.85 (m, 1H, CH(CH3)2),2.72-2.81 (m, 1H, exch D2O, OH), 3.35-3.45 (m, 1H, CH2CH),3.52-3.72 (m, 2H, CH2CH), 4.73 (d, J = 8.5 Hz, 2H,NH); 13C NMR: delta 18.7 (1C),19.7 (1C), 41.6 (1C), 28.6 (3C), 58.3 (1C), 64.3 (1C), 79.7 (1C), 157.1(1C); GC-MS (70 eV) m/z (%) 385 (M+ -31, 23), 57 (100); Anal.Calcd for (C10H21NO3): C, 59.08; H, 10.41; N,6.89. Found: C,59.54; H, 10.08; N, 6.98. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In pyridine; at 20℃; | Palmitic acid (0.5g, 1.95 mmol) dissolved in 5 ml of dry pyridine to which 1.2 equivalents of dry TEA, DCC (0.442g, 2.144mmol) and NHS (0.2467, g 2.144mmol). The reaction mixture was stirred at 24hr at room temperature for O.N.. Reaction progress was followed using TLC (5% MeOH /CHCl3) When the starting martial was fully converted to the active -NHS intermediate, Valinol (5) (0.20 Ig, 1.95mmol) or (0.197g, 1.95mmol) was added and the reaction was allowed to stand at room temperature for the time needed for completion. TLC (100% Eth.Ac). When the reaction was completed pyridine was removed under reduced pressure and the gum was dissolved in 20 ml DCM and purified on column chromatography using (Ethyl acetate: DCM; 1:1). Correct fractions were collected and volatiles were removed to dryness under reduced pressure to afford the desired product as white solid. <n="66"/>Pahnitoylvalinol; [Hexadecanoic acid (l-hydroxymethyl-2-methyl-propyl)-amide](37): Yield: 36.4%1H-NMR(CDCl3, delta ppm):5.59(s,lH),3.8(d,2H),3.7(q,lH)2.60(m,lH),2.24(t,2H),1.90(m,2H),1.63(m,2H),1.27(m,2 2 )0.97(q,6H),0.98(t,3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With diisopropylamine; at 70℃;sealed tube; | Example VI. Synthesis of 2-chloro-6-[4-isopropyl-2-(2-pyridyl)oxazolidin-3-yl]-4- (trifluoromethyl) pyridine-3-carbonitrile (Compound 12);.Step 1 : Preparation of 2-chloro-6- [ [ 1 -(hydroxymethyl)-2-methyl -propyl] amino] -4- (trifluoromethyl) pyridine-3-carbonitrile intermediate.; Neat 3-cyano-2,6-dichloro-4-trifluoromethylpyridine (0.641 g, 6 mmol) (Compound 14) was added by pipette at a dropwise rate over 3 minutes to 2-amino- 3-methyl-butan-l-ol (1.5 g, 6 mmol) (Compound 15). Di-isopropylamine (0.9 g, 7 mmol) was added after 10 minutes and the resultant mixture was heated in a sealed tube at 70 C for 30 minutes to selectively displace the chlorine at position 6 before quenching in ice-cold water and extracted with dichloromethane. Organic extracts were washed twice with water, dried over sodium sulfate and concentrated under reduced pressure. The residue was washed with diethylether and the resultant solid was used in the next step without further purification. 2-Chloro-6-[[l- (hydroxymethyl)-2-methyl -propyl] amino] -4-(trifluoromethyl) pyridine-3-carbonitrile (Compound 13) was isolated in 50 % yield. 1HNMR (CDCl3, 400 MHz) delta / ppm 6.66 (s, IH), 5.63 (br, IH), 4.09 (br, 0.7H), 3.81 (t, J = 4.5 Hz, 2.4 H), 2.01 (octet, J= 6.9 Hz, IH), 1.70 (br t, J= 4.9 Hz, 0.9 H), 1.03 (d, J= 6.7 Hz, 3H), 1.00 (d, J= 6.8 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | To a chilled (ice bath) suspension of 1.6 g (40.0 mmol) of sodium hydride (60% in mineral oil) in 25 mL of THF was added 1.03 g (9.98 mmol) of 2-amino-3-methylbutan-1-ol in 5 mL of THF dropwise. After the addition, 4.97 g (22.4 mmol) of 2-nitrobenzenesulfonyl chloride was added portionwise. The reaction was monitored by thin layer chromatography (ethyl acetate-hexanes, 3:7) and then poured into 50 mL of saturated aqueous ammonium and extracted with three 50 mL portions of ethyl acetate. The combined organic layers were washed with two 30 mL portions of saturated aqueous ammonium chloride, 30 mL of brine, four 25 mL portions of 2 N aqueous KOH, 30 mL of brine, two 25 mL portions of saturated aqueous ammonium chloride, dried over magnesium sulfate, treated with carbon (Norit A), filtered through CELITE filter aid, adsorbed onto silica gel and chromatographed on silica gel eluting with ethyl acetate-hexanes (2-10% gradient) to afford 1.35 g (50%) of 2-isopropyl-1-(2-nitrobenzenesulfonyl)aziridine as a yellow oil which solidified. To a solution of 120 mg (1.02 mmol) of indole in 4 mL of DMF was added 48 mg (1.20 mmol) of 60% sodium hydride in mineral oil. Once hydrogen evolution ceased, 270 mg (1.00 mmol) of 2-isopropyl-1-(2-nitrobenzenesulfonypaziridine was added. The reaction was monitored by thin layer chromatography (ethyl acetate-hexanes, 2:8). The mixture was diluted with 10 mL of saturated aqueous ammonium chloride and extracted with three 10 mL portions of ethyl acetate. The combined organic layers were washed with five 10 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated. The residue dissolved in dichloromethane and concentrated to near dryness and diluted with ether and then hexanes to afford 240 mg (62%) of the title compound as an orange solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | With triethylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 18h; | To a solution of 3-[(6,7-dimethoxy-2-oxo-1,2-dihydro-quinoline-3-carbonyl)-amino]-4-methyl-benzoic acid (0.1 g, 0.26 mmol) (from Example 18 supra) in DMF (5 mL) was added HATU (0.128 g, 0.34 mmol) (Aldrich), triethylamine (0.1 mL) (Aldrich) and 2-amino-3-methyl-butan-1-ol (0.04 mL, 0.34 mmol) (Aldrich). The reaction mixture was stirred at room temperature for 18 hours. Then, water (5 mL), saturated aqueous sodium bicarbonate solution (5 mL) and ethyl acetate (10 mL) were added. After mixing, the precipitate was filtered under vacuum and washed with ethyl acetate. The resulting solid was dried under air to provide 6,7-dimethoxy-2-oxo-1,2-dihydro-quinoline-3-carboxylic acid [5-(1-hydroxymethyl-2-methyl-propylcarbamoyl)-2-methyl-phenyl]-amide. (Yield 0.03 g, 25%). HR-MS (ES+) m/z Calculated for C25H30N3O6 ([M+H]+): 468.2129. Found: 468.2128. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With C29H44IrN5P2; potassium tert-butylate; In tetrahydrofuran; at 90℃; for 24h;Inert atmosphere; | General procedure: In a pressure tube (inner diameter 25.4 mm, length 20.3 cm, volume 38 ml) a magnetic stir bar, catalyst II (3 to 50 mmol), tetrahydrofuran (THF) (10 ml), secondary alcohol (20.0 mmol), amino alcohol (10.0 mmol) and KO-t-Bu (11.0 mmol) were combined in a dry nitrogen atmosphere using glove-box techniques. The pressure tube was closed with a silicone tube (inner diameter 7 mm, outer diameter 10 mm, length 30 cm) used as a semi-permeable membrane (for details see the Supplementary Information) and stirred at 90 C for 24 hours. The reaction mixture was cooled to room temperature and quenched by the addition of 2 ml of water. The layers were separated and the aqueous layer was extracted with Et2O (4 × 40 ml). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With copper(l) iodide; 2,2,6,6-tetramethylheptane-3,5-dione; caesium carbonate; In dimethyl sulfoxide; at 20℃; for 14h;Schlenk technique; Inert atmosphere; | General procedure: Into a flame dried Schlenk tube containing a magnetic stir bar was added aryliodide (1.0mmol), amino alcohol (1.1mmol), Cs2CO3 (652mg, 2.0mmol; or 977mg, 3.0mmol for entries 1-5 in Table 5, which employ ephedrine hydrochloride salt) and CuI (9.5mg, 0.05mmol). Under an atmosphere of argon, DMSO (2mL) and 2,2,6,6-tetramethylheptane-3,5-dione (21.0muL, 0.1mmol) or indole-2-carboxylic acid (0.1mmol) were added and the reaction mixture was stirred at room temperature for 14h. After addition of ethyl acetate (15mL) and brine (5mL), the organic layer was separated and the aqueous layer extracted with ethyl acetate (3×20mL). The combined organic layer was dried over anhydrous Na2SO4 before passing it through a short pad of silica gel. The filtrate was concentrated and purified via flash column chromatography to afford the corresponding arylated product |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | General procedure: We have adopted a synthetic route by analogy to other bis(oxazoline) ligands [19,20]. A 100-mL two-necked round bottom flask fixed with a reflux condenser was charged substituted dicyanobenzene (500 mg, 3.50 mmol), zinc triflate (5 mol%, 0.18 mmol, 0.060 g), and dry chlorobenzene (20.0 mL) under free oxygen and free-water conditions. The mixture was stirred for 5 min and then a solution of achiral 2-aminoalcohol (8.80 mmol) in dry chlorobenzene (5.0 mL) was added slowly. The reaction mixture was heated and refluxed at 135 C for 24 h. The solvent was removed under reduced pressure to give an oily residue which was dissolved in 25 mL of dichloromethane. The solution was extracted twice with 15 mL of water and the aqueous phase was washed with 15.0 mL of dichloromethane. The combined organic layers were dried with sodium sulfate and the solvent was removed under vacuum to give the crude oil. Further purification of the ligands was done by silica gel column chromatography (ether/dichloromethane 1/4). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | To the solution of N-methyl indole (200 mg, 1.52 mmol), Meldrum?s acid (220 mg, 1.52 mmol),phenyl acetaldehyde (183.68 mg, 1.52 mmol) in acetonitrile (2 mL), was added choline chlorideureaionic liquid (20mol%). The resultant mixture was stirred at 80 C. After 6hr, 3-methyl-2-(methylamino)butan-1-ol (234 mg, 2.28 mmol) was added and continued the heating. After 7hr,reaction completion was monitored by TLC which shows absence of starting material. Thereaction mixture was cooled to ambient temperature and diluted with water (2 mL). The contentswere extracted into ethyl acetate (6 x 3 mL). The organic layer was washed with brine solution (3mL), dried over anhydrous Na2SO4 and concentrated to residue. The residue was further purifiedby column chromatography (Pet ether and ethyl acetate system). The product collected in thegradient of 70-80 % v/v to obtain off-white solid (482 mg, 84%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | In acetonitrile; at 20℃; | General procedure: A mixture of chlorosulfonyl derivative (5) (100 mg, 0.29 mmol)and the appropriate amine (1.00 mmol) in anhydrous acetonitrile(10 ml) was stirred overnight at room temperature, after which the reaction mixture was concentrated under reduced pressure to afford crude sulfonamides, 6a-l as yellow solids. The residues were purified by crystallization from EtOH or by column chromatography on silica using a mixture of CH2Cl2:EtOH (25/1, v/v) as the eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With potassium carbonate; In water; toluene; for 0.333333h; | General procedure: Compounds 1, 3, 6, 8-13, and 15 were obtained by means of N-acylation[12,28]. In the reaction 0.015 mol of appropriate aminoalkanolsuch as (R,S)-2-aminopropan-1-ol for 1, (R,S)-1-aminopropan-2-ol for 3, (R,S)-2-aminobutan-1-ol for 6, (R,S)-1-aminobutan-2-ol for 8, 2-amino-2-methylpropan-1-ol for 9, 5-aminopropan-1-ol for 10, (R,S)-2-amino-3-methylbutan-1-ol for11, trans-D,L-2-aminocyclohexanol for 13, 4-hydroxypiperidine for15, or amino acid ester - methyl (R,S)-2-amino-3-methylbutanoatehydrochloride (for 12) was dissolved in 50 ml 5.5% solution of K2CO3. Then 10 mL toluene was added and the solution of 2.5 g(0.015 mol) trans-cinnamoyl chloride in 30 ml of toluene was being added dropwise for about 20 min while the reaction mixture was mixed on magnetic stirrer. The crude products were filtered formthe reaction mixture and washed with 20 ml of 5% K2CO3 and 50 mlof distilled water. The obtained compounds were dried and crystallizedwith a mixture of n-hexane and toluene (3:1 v/v). Trans-D,L-2-aminocyclohexanol for preparation of compound 13 was synthesized in reaction of cyclohexene oxide with 25% ammonia[29]. Other aminoalkanols and amino acid ester were purchased from the commercial supplier. 5.3.11 R,S-(2E)-N-(1-hydroxy-3-methylbutan-2-yl)-3-phenylprop-2-enamide (11) CAS: 1609486-26-1 [26] . White solid (yield 82%), m.p. 98-100 C. M = 233.31. Anal. C14H19NO2 calcd: C, 72.07; H, 8.21; N, 6.00. Found: C, 71.99; H, 8.05; N, 5.84. 1H-NMR (CDCl3, 300 MHz) ppm delta 0.99 (d, J = 5.4; 3H, CH3); 1.01 (d, J = 5.4; 3H, CH3); 1.97 (dq, J = 13.7; J = 6.9; CH(CH3)2); 2.53 (bs, 1H, OH); 3.70-3.83 (m, 2H, CH2-OH); 3.83-3.94 (m, 1H, NH-CH); 5.84 (d, J = 8.0; NH); 6.45 (d, J = 15.6; 1H, Ar-CH=CH); 7.31-7.42 (m, 3H, Ar-H); 7.45-7.56 (m, 2H, Ar-H); 7.65 (d, J = 15.6; 1H, Ar-CH=CH). IR: 3258; 3059; 2960; 1655; 1615; 1551. ESI-MS: 234.24 (C14H20NO2 [M + H]+). Rf = 0.60; RM0 = 2.219; miLogP = 2.247. |
With potassium carbonate; In water; toluene; at 20℃; | In a250 ml Erlenmeyer flask a K2CO3 solution was prepared by dissolving 2.78 g (0.02 M) K2CO3 in 50 ml distilled water. Then 1.55 g (0.015 M) of (/?,S)-2-amino- 3-methylbutan-1-ol was added to the solution. Then 10 ml of toluene was added. The flask was placed on magnetic stirrer in room temperature. The solution of 2.5 g (0.015 M) frans-cinnamoyl chloride in 30 ml of toluene was being added dropwise for about 20 minutes. The reaction mixture was mixed constantly. After the reaction was completed, the reaction mixture was cooled down, the precipitate was filtered and washed with 20 ml of 5%K2C03and 50 ml of distilled water. Obtained compound was dried and crystallized with mixture i-hexane:toluene (3:1 v/v). Compound KM-626of the formula 1 was obtained (R1 : (f?,S)-2-amino-3- methylbutan-1-ol, R2:H). 1H NMR (delta, ppm,CDCI3 with internal standard TMS) (CDCI3): 0.99 (d, J=5.4; 3H, -CH3); 1.01 (d, J=5.4; 3H, -CH3); 1.97 (dqv, J=13.7; J=6.9; -CH(CH3)2); 2.53 (bs, 1 H, OH); 3.70-3.83 (m, 2H, -CH2.-OH); 3.83-3.94 (m, 1 H, -NH-CH); 5.84 (d, J=8.0; NH); 6.45 (d, J=15.6; 1 H, Ar-CH=CH-); 7.31-7.42 (m, 3H, Ar-H); 7.45-7.56 (m, 2H, Ar-H); 7.65 (d, J=15.6; 1 H, Ar-CH=CH-);ESI-MS [M+H] z calc./found234.14/234.24. Melting point: 98-100C, elemental analysis: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With C29H44IrN5P2; potassium tert-butylate; In tetrahydrofuran; at 90℃; for 24h;Inert atmosphere; | General procedure: In a pressure tube (inner diameter 25.4 mm, length 20.3 cm, volume 38 ml) a magnetic stir bar, catalyst II (3 to 50 mmol), tetrahydrofuran (THF) (10 ml), secondary alcohol (20.0 mmol), amino alcohol (10.0 mmol) and KO-t-Bu (11.0 mmol) were combined in a dry nitrogen atmosphere using glove-box techniques. The pressure tube was closed with a silicone tube (inner diameter 7 mm, outer diameter 10 mm, length 30 cm) used as a semi-permeable membrane (for details see the Supplementary Information) and stirred at 90 C for 24 hours. The reaction mixture was cooled to room temperature and quenched by the addition of 2 ml of water. The layers were separated and the aqueous layer was extracted with Et2O (4 × 40 ml). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With sodium carbonate; at 110℃; for 12h;Inert atmosphere; | General procedure: Corresponding chiral amino alcohol (100 mmol), 1,2-dibromoethane, (16.67 mmol) and Na2CO3 (16.67 mmol)were stirred at 110 8C for 12 h under Ar atmosphere. Themixture was cooled to room temperature and CHCl3(100 mL) was then added to the mixture and refluxed for1 h. The CHCl3 layer was separated from the solid phase.The remaining solid was re-extracted with CHCl3(3 25 mL). The combined CHCl3 layers were dried(Na2SO4) and evaporated. After the excess amino alcoholwas distilled at 165-175 8C/0.8 mmHg, the product waspurified by flash column chromatography on silica gel(eluent: ethyl acetate/n-hexane 1/2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide; at 20℃; for 16h;Inert atmosphere; Sealed tube; | General procedure: For the synthesis of the amide libraries 100 lM stock solutionsof the primary amines (Supporting information) in DMF were prepared.For that matter HCl salts were diluted using 4:1 DMF/0.5 MLiOH(aq.), double HCl salts accordingly in the ratio 3:2. A mixture of14.0 lL DMF, 10.0 lL NHS-ester solution (32.2 lM in DMF) and16.0 lL of the 100 lM amine stock solution (5 eq.) was preparedin a 96 well polypropylene plate, mixed, heat-sealed and left toreact overnight. After TLC analysis, the reactions were terminatedby the addition of 40 lL of 16.4 lM acetic acid in DMSO and storedat 78 C. The cell-based screening was executed without furtherpurification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide; at 20℃; for 16h;Inert atmosphere; Sealed tube; | General procedure: For the synthesis of the amide libraries 100 lM stock solutionsof the primary amines (Supporting information) in DMF were prepared.For that matter HCl salts were diluted using 4:1 DMF/0.5 MLiOH(aq.), double HCl salts accordingly in the ratio 3:2. A mixture of14.0 lL DMF, 10.0 lL NHS-ester solution (32.2 lM in DMF) and16.0 lL of the 100 lM amine stock solution (5 eq.) was preparedin a 96 well polypropylene plate, mixed, heat-sealed and left toreact overnight. After TLC analysis, the reactions were terminatedby the addition of 40 lL of 16.4 lM acetic acid in DMSO and storedat 78 C. The cell-based screening was executed without furtherpurification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In neat (no solvent); at 20℃; for 1h;Sonication; Green chemistry; | General procedure: In a 10-cm3 round-bottom flask a mixture of aldehyde(1 mmol) and aminoalcohol (1 mmol) was taken at roomtemperature and then triethyl phosphite (1 mmol) wasadded. Then reaction mixture was subjected to the ultrasonicationfor appropriate time. After completion of thereaction, as indicated by TLC, a 4:1 mixture of diethylether and n-hexane was added and the mixture was cooledto 6 C overnight. The product was finally filtered anddried. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With Candida antarctica B lipase Enzymatic reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
200 mg | With N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16h; | To a solution of 4-bromo-2,6-dimethyl-7-oxo- 1 -((2-(trimethylsilyl)ethoxy)methyl) -6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylic acid (Intermediate D) (207 mg, 0.50 mmol) in DMF(10 mL) was added N-ethyl-N-isopropylpropan-2-amine (129 mg, 1.00 mmol), HATU (380 mg,1.00 mmol) and 2-amino-3-methylbutan-1-ol (103 mg, 1.00 mmol). The reaction was stirred atambient temperature for 16 h and then diluted with water (20 mL). The mixture was extractedwith EtOAc (3 x 20 mL) and the combined organic layers were washed with water (20 mL),brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude title compound (200 mg, 80% yield) as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With triethylamine; In acetonitrile; at 80℃; for 8h; | General procedure: 1,2-Aminoalcohols (2a, 2b, 2c,2d, 2e, 2f or 1-amino-2-indanol 2g, 5mmol) and Et3N (1.0ml) were added with stirring to the solution of diferrocenilcyclopropenilium tetrafluoroborates 1a or 1b (3mmol) in dry benzene, or acetonitrile, or CHCl3, or CH2Cl2 (70ml). After stirring for 3-12hat 20-80C, the volatiles were removed in vacuo; chromatography of the residue on Al2O3 (hexane-ether, 4:1), yield compounds 3a-f (Table1), and 5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With triethylamine; In benzene; at 79℃; for 10h; | General procedure: 1,2-Aminoalcohols (2a, 2b, 2c,2d, 2e, 2f or 1-amino-2-indanol 2g, 5mmol) and Et3N (1.0ml) were added with stirring to the solution of diferrocenilcyclopropenilium tetrafluoroborates 1a or 1b (3mmol) in dry benzene, or acetonitrile, or CHCl3, or CH2Cl2 (70ml). After stirring for 3-12hat 20-80C, the volatiles were removed in vacuo; chromatography of the residue on Al2O3 (hexane-ether, 4:1), yield compounds 3a-f (Table1), and 5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With zinc(II) chloride; In chlorobenzene; at 48℃; | Under anhydrous and anaerobic conditions,With 0.2720g zinc chloride as a catalyst,Weigh 2.0449g of acetylcarbamide and 8.1397g of 1.3275g (R) -<strong>[16369-05-4]valinol</strong>,Into 250mL two-necked flask,Add 100mL chlorobenzene as a solvent,After refluxing for 48 hours,Column chromatography,Elution with petroleum ether / dichloromethane (3/7)The first component collected will naturally volatilize,Was single crystal -4-isopropyl oxazolinyl-2-one; Elemental analysis data C6H11N02,Theoretical value: C: 55.80%;H: 8.58%; N: 10.84%; Found: C 55.79%; H 8 8.1%; N 10.53% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.2 mg | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 1h; | A solution of 150 mg intermediate 4, 100 mg 2-amino-3-methylbutan-1 -ol, 270 mg HATU and 0.25 mL ethyldiisopropylamine in 6 mL of DMF was stirred at room temperature for 1 hour. Then the reaction was quenched by water, and the mixture was extracted with ethylacetate. The organic phase was dried over sodium sulfate and evaporated to dryness. The residue was subjected to column chromatography (ethyl acetate / petroleum ether 1 : 1 ) to yield 66.2 mg 2- (3-fluorophenyl)-/V-(1 -hydroxy-3-methylbutan-2-yl)-6-(4-methylphenyl)-3-oxo-2,3- dihydropyridazine-4-carboxamide. 1H-NMR (300 MHz, DMSO-de): delta = 0.83-0.93 (m, 6H), 1 .93-2.00 (m, 1 H), 2.36 (s, 3H), 3.42- 3.45 (m, 1 H), 3.47-3.56 (m, 1 H), 3.82-3.87 (m, 1 H), 4.78-4.81 (t, 1 H), 7.32-7.41 (m, 3H), 7.53- 7.65 (m, 3H), 7.83-7.86 (m, 2H), 8.63 (s, 1 H), 9.42-9.45 (d, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With C18H28ClN4OPRu; potassium <i>tert</i>-butylate In toluene at 110℃; for 12h; Inert atmosphere; | |
71% | With C22H30ClN4OPRu; potassium <i>tert</i>-butylate In toluene at 110℃; for 12h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With C18H28ClN4OPRu; potassium <i>tert</i>-butylate In toluene at 110℃; for 12h; Inert atmosphere; | |
53% | With C22H30ClN4OPRu; potassium <i>tert</i>-butylate In toluene at 110℃; for 12h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22 mg | To a vial containing a solution of NN?-disuccinimidyl carbonate (44 mg, 1.1 equiv.) in DMF (1 mL), a solution of 3-[l -(azetidin-3 -ylsulfonyl)-4-piperidyl] - 1H-pyrrolo [2,3 - b]pyridine (compound of formula (1-2)) (50 mg, 1 equiv.) in DMF (1 mL) was added. Tothe resulting solution DIPEA (0.223 mL, 8.2 equiv.) was added and the reaction mixture stirred at RT for 15 mm. Then, 2-amino-3 -methyl-butan- 1 -ol (21 tL, 1.2 equiv.) was added and the reaction was shaken at 80 C for 1 h. Solvent was evaporated to dryness to give the crude product, which was purified by preparative LC-MS (ES mode, low pH method) to afford the expected racemic product (22 mg). LCMS: IVIW (calcd): 449.57; MS (ES, m/z):450.7 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With acetic acid; In ethanol; for 4h;Reflux; | To a mixture of 2-(2-(benzyloxy)-5 -chloro-4-methoxyphenyl)-4H-pyran-4-one (208 mg, 0.5 mmol) in AcOHIEtOH (10 mL, 2:3 ratio), D,L-<strong>[16369-05-4]valinol</strong> (76 mg, 0.75 mmol) was added and the contents were refluxed for 4h. The reaction mixture was concentrated under vacuum, and theresidue was purified by normal phase Si02 chromatography (0% to 10% MeOHICH2C12) to furnish ethyl 6-(2-(benzyloxy)-5 -chloro-4-methoxyphenyl)- 1 -(1 -hydroxy-3 -methylbutan-2-yl)-4- oxo-1,4-dihydropyridine-3-carboxylate as an orange solid, which was collected upon crystallization from methanol (30 mL) yielded ethyl 6-(2-(benzyloxy)-5-chloro-4- methoxyphenyl)- 1 -(1 -hydroxy-3 -methylbutan-2-yl)-4-oxo- 1 ,4-dihydropyri dine-3 -carboxylate asa white foam (125 mg, 50% yield, m/z: 500 [M+H] observed). ?H NMR (300 IVIFIz, CDC13):8.36 (s, 1 H), 7.63 (s, 1H), 7.40-7.28 (m, 5 H), 7.15 (d, J=3.0 Hz, 1H), 6.10 (d, J=3.0 Hz, 1 H),5.20 (bs, 2 H), 4.25 (q, J=2.0 Hz, 2 H), 3.95 (s, 3 H), 3.80-3.85 (m, 1H), 3.60-3.45 (m, 2H), 2.45-2.20 (m, 1H), 1.30 (t, J2.OHz, 3H), 0.95-0.92 (dd, J=2.2 &1.0 Hz, 3H) and 0.75-0.67 (dd, J=6.0& 2.2 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With acetic acid; In ethanethiol; at 100℃; for 8h; | To a mixture of ethyl 6-(2, 5 -dichloro-6-methoxypyridin-3 -yl)-4-oxo-4H-pyran-3 -carboxyl ate ( 138 mg, 0.402 mmol) in AcOH/EtOH (2:3, 10 mL) was added DL-<strong>[16369-05-4]valinol</strong> (62 mg, 0.6 mmol).The reaction was heated at 100 C for 8 h. The reaction mixture was concentrated under vacuum and the residue was purified by normal phase Si02 chromatography (0% to 10% MeOHICH2C12) to afford ethyl 2?, 5 ?-dichloro- 1 -(1 -hydroxy-3 -methylbutan-2-yl)-6?-methoxy-4-oxo- 1 ,4-dihydro- [2,3?-bipyridine]-S-carboxylate as a white foam (100 mg, 58% yield, m/z: 429 [M+H]observed). ?H NMR (300 MHz, CDC13) 8.70 (s, 1H), 7.49 (s, 1H), 6.26 (s, 1H), 4.40-4.25 (m,2H), 4.15 (s, 3H), 4.00-3.95 (m, 2H), 3.25 (m, 1H), 2.45 (m, 1H), 1.37 (m, 3H) and 1.05-0.85 (m,6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25.3 mg | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 2h; | A solution of 100 mg intermediate 6, 33.2 mg 2-amino-3-methylbutan-1-ol, 184 mg HATU and125 mg ethyldiisopropylamine in 5 mL of DMF was stirred at room temperature for 2 hour.Then the reaction was quenched by water, and the mixture was extracted with ethylacetate.The organic phase was dried over sodium sulfate and evaporated to dryness. The residue wassubjected to RP-HPLC ((column: X-Bridge 018 5pm iOOx3Omm, mobile phase: acetonitrile Iwater (0.1 vol% formic acid)-gradient)) to yield 25.3 mg N-(1-hydroxy-3-methylbutan-2-yl)-6-(4-methylphenyl)-2-(1 -methyl-i H-pyrazol-4-yl)-3-oxo-2 ,3-d ihyd ropyridazine-4-carboxamide.1H-NMR: (400 MHz, 25C, Methanol-d4): 6 [ppm] = 1.00-i .07 (m, 6H); 2.02-2.13 (m, 1H); 2.41 (s, 3H); 3.67-3.75 (m, 2H); 3.95-4.01 (m+s, 4H); 7.34 (d, 2H); 7.88 (d, 2H); 8.15 (s, 1H); 8.49(s, 1H); 8.64 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1H-imidazole; In tetrahydrofuran; at 25℃; for 14h; | To a solution of compound 34.8 (1 g, 9.69 mmol, 1.06 mL, 1 eq) in THF (15 mL) was added IMIDAZOLE (2.64 g, 38.76 mmol, 4 eq) and TBDPSC1 (5.33 g, 19.38 mmol, 4.98mL, 2 eq). The mixture was stirred at 25 C for 14 hours. The reaction mixture was quenched by addition H20 50 mL at 25C, and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with saturated brine (25 mL x 1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. Compound 34.7 (4 g, crude) was obtained as a yellow oil, and the crude product was used into the next stepwithout further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | In acetonitrile; at 20℃; for 1h;Sealed tube; | <strong>[16369-05-4]valinol</strong> (258.0 mg, 2.5 mmol) was dissolved in acetonitrile (3 mL) in a 50 mL reaction flask.The reaction flask was sealed with a rubber stopper and CF3SO3CF3 (109.0 mg, 0.5 mmol)Dissolved in 2mL of acetonitrile and into the reaction bottle with a syringe.The mixed liquid was stirred at room temperature for 1 h, and after completion of the reaction, the reaction was quenched with 5 drops of water.The solvent was removed under reduced pressure using petroleum ether:Ethyl acetate = 5:1 (v / v) as the eluent, column chromatography to give the product:4-isopropyloxazolidin-2-one(White solid, 118.4 mg), Yield: 92%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | With triethylamine; In benzene;Inert atmosphere; Reflux; | General procedure: 1,2-Aminophenol 3a [or 3b-e, or 1,2-aminoalcohols 11a-e](2.5 mmol) and Et3N (1.0 mL) was added to a stirring solution of2,3-diferrocenyl-1-methylthiocyclopropenylium iodide 2 (3.0 mmol)in dry benzene (70 mL) under a nitrogen atmosphere. The reactionmixture was heated to refluxing conditions (6-8 h), the solventwas removed in vacuo and the residue was dissolved in dichloromethane(30 mL). The solution was mixed with (Al2O3, Brockmannactivity III) (20 g) and the solvent was evaporated in air. This materialwas placed on the top of a column with Al2O3 (the height ofalumina is ca. 20 cm) and the elution was performed first with hexaneand then with hexane-ether (3:1), hexane-dichloromethane(4:1) to afford compounds 4, 5a, 6a, 7a, 9a, 10a,b [or (4, 5b-e,6b-e, 7b-e, 8b-d, 9b-e, 10a,b), or (4, 12a-e, 13b-e, 14a-e+ 15a-e, 10a,b)]. cis-14a-e and trans-15a-e isomers were isolatedby thin-layer chromatography (TLC) on Al2O3 or silica in a solventsystem hexane-ether (4:1). The physicochemical characteristics ofcompounds 4, 5a-e, 6a-e, 8c,d and 12a-e were in accordance withthe literature data (See Supplementary material) [27-29]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 0 - 25℃; for 2h; | General procedure: Method B (Scheme S2): To a solution of 2-amino-1-phenylethan-1-ol (1.10 g, 8.0 mmol, 2 equiv.) and Et3N(1.66 mL, 12 mmol, 3 equiv.) in CH2Cl2 (20 mL) was added 2-bromo-1-(3,4-dimethoxyphenyl)ethan-1-one (1a,1.04 g, 4.0 mmol, 1 equiv.) slowly at 0 oC. The mixture was stirred at 25 oC for 2 h. Then CH2Cl2 (10 mL), Et3N(1.66 mL, 12 mmol, 3 equiv.) and (Boc)2O (8 mmol, 2 equiv.) were added to the mixture. The mixture was stirredat 25 oC for 16 h, then diluted by ethyl acetate (50 mL), and washed with water (50 mL) and brine (50 mL), anddried over Na2SO4. The organic phase was concentrated under vacuum. The residue was purified by silica gelflash chromatography (hexane: ethyl acetate = 60: 40) to obtain the product 3p. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With triethylamine In ethyl acetate at 0 - 20℃; for 32h; | N-(1-Hydroxy-3-methylbutan-2-yl)-4-iodobenzamide 2-Amino-3-methyl-1-butanol (316 mg, 3.30 mmol) was dissolved in ethyl acetate (20 mL), then triethyl amine (0.625 mL, 6.20 mmol) was added and the solution cooled in an ice bath. A solution of 4-iodobenzoyl chloride (799 mg, 3.0 mmol) in ethyl acetate (10 mL) was added dropwise, resulting in formation of a white precipitate. The reaction mixture was stirred at RT for 32 hours, then washed with aq. HCl (2.0 M; 2 × 15 mL) and aq. NaOH (2.0 M; 2 × 15 mL). The organic phase was dried over MgSO4, filtered and concentrated in vacuo, affording the title compound as a free-flowing, nonhygroscopic white solid (853 mg, 2.6 mmol, 84%). M.p. /°C: 130-132. IR (neat) νmax/cm-1: 3286, 2957, 2870, 1636, 1620, 1587, 1539, 1477, 1389, 1368, 1339, 1154, 1070, 1007, 978, 896, 876, 838, 798, 753, 720, 683, 624, 534, 479, 431. 1H NMR (400 MHz, DMSO-d6): δH 8.03 (d, J = 8.9 Hz, 1H), 7.83 (d, J = 8.1 Hz, 2H), 7.65 (d, J = 8.1 Hz, 2H), 4.48 (brs, 1H), 3.83-3.74 (m, 1H), 3.54-3.45 (m, 2H), 1.91 (hept, J = 6.8 Hz, 1H), 0.90 (d, J = 6.8 Hz, 3H), 0.86 (d, J = 6.8 Hz, 3H). 13C{1H} NMR (101 MHz, DMSO-d6): δC 165.7, 137.0, 134.5, 129.4, 98.3, 61.2, 56.8, 28.6, 19.7, 18.7. HRMS (ESI-, m/z) calcd for C12H15O2NI-: 332.1575 [M-H]-; found: 332.0156. |
Tags: 16369-05-4 synthesis path| 16369-05-4 SDS| 16369-05-4 COA| 16369-05-4 purity| 16369-05-4 application| 16369-05-4 NMR| 16369-05-4 COA| 16369-05-4 structure
[ 112245-13-3 ]
(S)-2-Amino-3,3-dimethylbutan-1-ol
Similarity: 0.95
[ 112245-09-7 ]
(R)-2-Amino-3,3-dimethylbutan-1-ol
Similarity: 0.95
[ 24629-25-2 ]
(2S,3S)-2-Amino-3-methylpentan-1-ol
Similarity: 0.90
[ 53448-09-2 ]
(R)-2-Amino-4-methylpentan-1-ol
Similarity: 0.86
[ 7533-40-6 ]
(S)-2-Amino-4-methylpentan-1-ol
Similarity: 0.86
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