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CAS No. : | 646-07-1 | MDL No. : | MFCD00002803 |
Formula : | C6H12O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | FGKJLKRYENPLQH-UHFFFAOYSA-N |
M.W : | 116.16 | Pubchem ID : | 12587 |
Synonyms : |
Isocaproic Acid
|
Num. heavy atoms : | 8 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.83 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 32.73 |
TPSA : | 37.3 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.01 cm/s |
Log Po/w (iLOGP) : | 1.55 |
Log Po/w (XLOGP3) : | 1.41 |
Log Po/w (WLOGP) : | 1.51 |
Log Po/w (MLOGP) : | 1.27 |
Log Po/w (SILICOS-IT) : | 0.76 |
Consensus Log Po/w : | 1.3 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.85 |
Log S (ESOL) : | -1.25 |
Solubility : | 6.52 mg/ml ; 0.0562 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.8 |
Solubility : | 1.85 mg/ml ; 0.0159 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.83 |
Solubility : | 17.1 mg/ml ; 0.147 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.0 |
Signal Word: | Danger | Class: | 6.1 |
Precautionary Statements: | P280-P312 | UN#: | 2810 |
Hazard Statements: | H311-H315 | Packing Group: | Ⅲ |
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 |
---|---|---|
66% | Stage #1: With thionyl chloride In tetrachloromethane at 25 - 65℃; for 0.5 h; Stage #2: With N-Bromosuccinimide; hydrogen bromide In tetrachloromethane; water at 85℃; Stage #3: at 0℃; |
Preparation of 2-bromo-4-methyl-pentanoic acid methyl ester: A solution of 4-methyl-pentanoic acid (50 g, 0.43 mol) in carbon tetrachloride (200 mL) at 25° C. was treated with thionyl chloride (125 mL, 1.72 mol). The reaction was then heated to 65° C. and stirred for 30 min. After this time, the reaction was removed from the heat and was then treated with N-bromosuccinimide (100 g, 0.56 mol), carbon tetrachloride (200 mL) and a 48percent aqueous hydrogen bromide (40 drops). The reaction was then heated to 85° C. and stirred overnight. After this time, the reaction was cooled to 0° C. and carefully quenched with methanol (150 mL) until no further gas evolution was observed. The mixture was then filtered and washed with hexanes. The dark solution was concentrated in vacuo. The remaining liquid was then partitioned between water (300 mL) and hexanes (3.x.300 mL). The combined organics were washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, rinsed and concentrated in vacuo. The obtained residue was distilled in vacuo to afford 2-bromo-4-methyl-pentanoic acid methyl ester as colorless oil (60 g, 66percent); 1H NMR (300 MHz, CDCl3): δ 4.28 (t, 1H, J=7.5 Hz), 3.77 (s, 3H), 1.90 (t, 2H, J=7.5 Hz), 1.78-1.71 (m, 1H), 0.93 (dd, 6H, J1=14.1 Hz, J2=6.6 Hz). GC-MS: 209 [M]+, tR=5.50 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With palladium 10% on activated carbon; W(OTf)6; hydrogen; at 100℃; under 760.051 Torr; for 12h; | Specific methods are as follows: propiolactone was added (0.36g, 5mmol), palladium on carbon (10%, 26.5mg, 0.025mmol, 0.5mol%) in the reactor and W (OTf)6(107.8mg, 0.1mmol, 2mol%). A hydrogen balloon connected to the top of the reactor, and the reactor was purged with hydrogen gas atmosphere. Hydrogen atmosphere at normal pressure, the reaction was stirred at 135 deg.] C after 12h, detected by gas, gamma- valerolactone complete conversion of starting material, and only n-valeric acid. The method carried out as follows completion of the hydrogenation reaction of the ring-opening reaction system separation, to obtain the desired product n-valeric acid: The reaction was completed reaction mixture was dissolved with methylene chloride, filtered to remove the palladium on carbon catalyst and W (OTf)699% yield measured propionic acid, purity of the product was 99%. NMR data for the product using the embodiment of the present invention is the NMR identified the product as follows:The specific reaction procedure and operation method were the same as in Example 27 except that the reaction temperature was changed to 100 C, the yield was 95%, and the purity of the product was 99%. The product was subjected to nuclear magnetic identification using the manner described in the present invention, and the NMR data of the product were as follows: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With dihydrogen peroxide at 90℃; for 6h; | |
With potassium permanganate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With lithium aluminium tetrahydride In tetrahydrofuran at 20℃; for 2h; Inert atmosphere; | |
88% | With lithium aluminium tetrahydride In diethyl ether | |
With lithium aluminium tetrahydride; diethyl ether |
Multi-step reaction with 2 steps 1: diethyl ether 2: lithium alanate; diethyl ether | ||
Multi-step reaction with 2 steps 1: calcium chloride; aqueous hydrochloric acid 2: sodium; ethanol | ||
Multi-step reaction with 2 steps 1: sulfuric acid / 3 h / Reflux 2: methanol; lithium borohydride / tetrahydrofuran; diethyl ether / 3 h / Inert atmosphere; Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With thionyl chloride In DMF (N,N-dimethyl-formamide); hexnes at 25 - 75℃; for 2.41667h; Industry scale; | |
87.3% | With thionyl chloride | 11.A Compounds of Formula (HH) A. To 4-methylpentanoic acid (25 g, 0.215 mmol) in a 25° C. water bath, thionyl chloride (20.4 mL, 1.3 g) was slowly added. Then the mixture was heated at 50° C. under argon for 3 hours (until the evolution of gas had stopped). The crude reaction mixture was distilled at atmospheric pressure to give 4-methylpentanoyl chloride (25.3 g, 87.3%), b.p. 143° C. |
87.3% | With thionyl chloride | 11.A Compounds of Formula (Fa) 11A. To 4-methylpentanoic acid (25 g, 0.215 mmol) in a 25° C. water bath, thionyl chloride (20.4 mL, 1.3 g) was slowly added. Then the mixture was heated at 50° C. under argon for 3 hours (until the evolution of gas had stopped). The crude reaction mixture was distilled at atmospheric pressure to give 4-methylpentanoyl chloride (25.3 g, 87.3%), b.p. 143° C. |
87.3% | With thionyl chloride | 13.A Compounds of formula (HH) A. To 4-methylpentanoic acid (25 g, 0.215 mmol) in a 25° C. water bath, thionyl chloride (20.4 mL, 1.3 g) was slowly added. Then the mixture was heated at 50° C. under argon for 3 hours (until the evolution of gas had stopped). The crude reaction mixture was distilled at atmospheric pressure to give 4-methylpentanoyl chloride (25.3 g, 87.3%), b.p. 143° C. |
78% | With thionyl chloride In chloroform for 2h; Heating / reflux; | |
68% | With thionyl chloride for 2h; Heating; | |
With thionyl chloride | ||
With phosphorus(V) chloride | ||
With anhydrous zinc chloride; phosphorus trichloride | ||
With thionyl chloride | ||
With thionyl chloride for 3h; Heating; | ||
With thionyl chloride a) below 30 deg C, b) reflux, 1 h; | ||
With thionyl chloride 1) room temperature, 3 h; 2) reflux, 2.5 h; | ||
With thionyl chloride for 0.5h; Heating; | ||
With thionyl chloride at 80℃; for 5h; | ||
With oxalyl dichloride at 20℃; | ||
With thionyl chloride at 50℃; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In hexane | ||
With thionyl chloride In benzene for 6h; Heating; | ||
With thionyl chloride In dichloromethane at 20℃; | 1 Preparation 14-Methylpentanoyl ChlorideIsocaproic acid (10.0 g, 86.1 mmol) was dissolved in methylene chloride (30.0 mL, 468.0 mmol), and thionyl chloride (18.8 mL, 258 mmol) was added. The mixture was stirred at room temperature overnight, then rotovaped to provide the title compound, which was used immediately in the next reaction. | |
With thionyl chloride In dichloromethane at 20℃; | 5 4-Methylpentanoyl Chloride Preparation 5 4-Methylpentanoyl Chloride Thionyl chloride (4.8 mL, 66.4 mmol) was added to a solution of isocaproic acid (2.6 g, 22.1 mmol) in DCM (10 mL, 156 mmol) at room temperature and was stirred overnight. Thionyl chloride was removed in vacuo to give the crude title compound (2.9 g) as a colorless oil. | |
With thionyl chloride for 2h; Heating; | ||
With thionyl chloride for 1.5h; Heating / reflux; | 30 A mixture of 4-methyl valeric acid (15 g, 129.1 mmol) and thionyl chloride (10.8 ml, 148 mmol) is heated at reflux for 90 minutes. The excess thionyl chloride is distilled under reduced pressure, then the residue is taken up in 48 ml of bromobenzene. After cooling to 0° C., anhydrous aluminum chloride (13.8 g, 103.5 mmol) is added to the solution. The mixture is stirred at ambient temperature for 80 hours, then treated with the addition of iced water, then with 20 ml of concentrated HCl. The organic phase is separated and the aqueous phase extracted by Et2O. The recombined organic phases are washed successively with water then with a solution saturated with sodium chloride, dried on MgSO4, filtered and concentrated under reduced pressure. The residue is purified either by a) distillation (approximately 80° C./0.01 mm) or b) chromatography on a silica gel (pentane 100% then pentane/ethyl acetate 10/1) followed by filtration, water wash and drying, to yield 20.337 g (62%, not optimized) of a colorless solid. Analyses identical to the literature. | |
With thionyl chloride In dichloromethane at 20℃; | 14 Preparation 14. (S)-2-Acetylsulfanylmethyl-4-methvlpentanoic Acid. 4-Methylpentanoyl chloride was prepared as follows. Isocaproic acid (10.0 g, 86.1 mmol) was dissolved in methylene chloride (30.0 mL, 468.0 mmol), and thionyl chloride (18.8 mL, 258 mmol) was added. The mixture was stirred at room temperature overnight, then rotovaped to provide the title compound, which was used immediately in the next reaction.(Sj-4-Benzyl-2-oxazolidinone (15.1 g, 85.0 mmol) was dissolved in THF (200 mL, 2.5 mol), cooled at -78 °C under nitrogen, and stirred for 10 minutes. 1.6 M of n- butyllithium in hexane (53.1 mL) was added dropwise and stirred for 15 minutes. 4- Methylpentanoyl chloride (12.6 g, 93.5 mmol) was added dropwise, stirred for 30 minutes at -78 °C, then warmed to 0 °C for 2 hours. 150 mL of saturated NaHCO3 was added and the mixture was warmed to room temperature for 30 minutes. The mixture was extracted with DCM, washed with Na2CO3 (5%) and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. Excess oxazolidinone was removed using hexanes to provide 14.5 g of product.This product (14.5 g, 46.3 mmol) was dissolved in DCM (151 mL, 2.4 mol) and stirred at 0 °C under nitrogen. 1 M titanium tetrachloride in DCM (48.6 mL) was added and stirred for 15 minutes. DIPEA (8.9 mL, 51.0 mmol) was added dropwise at 0 °C and the mixture was stirred for 75 minutes. 1,3,5-Trioxane (4.6 g, 51.0 mmol) in DCM (30 mL) was then added. After 10 minutes a second equivalent of 1 M titanium tetrachloride in DCM (48.6 mL) was added and the mixture stirred at 0 0C for 5 hours. The reaction was then quenched with 250 mL of saturated ammonium chloride. Water and DCM were added, the aqueous phase was extracted twice more with DCM. The organic layers were combined, dried over MgSO4, filtered and concentrated. This material was purified by silica gel chromatography (0-60% EtOAc:hexanes) to provide 13.9 g of product.This product (13.9 g, 40.8 mmol) was dissolved in THF (200 mL, 2 mol) and stirred at 0 °C. 9 M hydrogen peroxide in water (46.3 mL) was added, followed by dropwise addition of 1.5 M lithium hydroxide monohydrate in water (54.4 mL). The mixture was then warmed to room temperature and stirred for 2.5 hours. Potassium hydroxide (4.58 g, 81.6 mmol) was then added and the mixture was heated at 60 °C for 30 minutes and then cooled at room temperature. To this was added a solution of sodium sulfite (10 g in 200 mL water) followed by water and chloroform (200 mL of each). The aqueous layer was extracted twice more with CHCl3 (150 mL), acidified and extracted with EtOAc. The organic layer was then washed with saturated aqueous NaCl, dried over MgSO4, filtered, and rotovaped to provide 5.4 g of product.Triphenylphosphine (19.5 g, 74.3 mmol) was dissolved in THF (200 mL, 2 mol) and cooled at 0 °C. Diisopropyl azodicarboxylate (14.6 mL, 74.3 mmol) was added dropwise and the mixture stirred for 10 minutes at 0 °C. The product (5.4 g, 37.1 mmol) and thioacetic acid (8.0 mL, 111 mmol) were dissolved in THF (20 mL) and added dropwise to the mixture. After the addition, the mixture was removed from the ice bath and stirred at room temperature. The mixture was stirred for 3.5 hours, concentrated to approximately a third of the volume, and then partitioned between EtOAc and saturated NaHCO3. The organic layer was extracted three times more with saturated NaHCO3 and the combined aqueous extracts were washed twice with CHCl3, acidified with IN HCl and extracted three times with EtOAc. The organic layer was washed with saturated aqueous NaCl, dried over MgSO4, filtered, and rotovaped to provide the title compound. | |
With pivaloyl chloride; triethylamine In tetrahydrofuran at -30℃; for 1.5h; | ||
With oxalyl dichloride In dichloromethane at 20℃; for 18h; | 11 4-Methylvaleric acid (4.30mmol, 0.543mL, 0.5g) was stirred in dichloromethane(5ml_) at O0C. Oxalyl chloride (21.52mmol, 1.848mL, 2.73g) was added. The reaction mixture allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was concentrated under vacuum to give the intermediate 4-methylpentanoyl chloride. A mixture of 4-methylpentanoyl chloride (1.564mmol, 0.211 g), (4-amino-3- fluorophenyl)(4-(4-(1 ,1 ,1 ,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazin-1- yl)methanone (1.043mmol, 0.5g) and triethylamine (2.086mmol, 0.29OmL, 0.21 1g) were stirred in dichloromethane at O0C for 1 hour. The reaction mixture was washed with water, dried over sodium sulfate, concentrated under vacuum and purified by silica chromatography (eluting with a solvent gradient from dichloromethane to 5% methanol / dichloromethane) to afford the title compound (54mg). MS (ESI) m/z 578.3 [M+H]+ | |
With thionyl chloride In dichloromethane for 1h; Reflux; | ||
With thionyl chloride In Carbon tetrachloride at 65℃; for 0.5h; | 9 Example 9 2-(2,3-Dioxo-2,3-dihydro-indol-1-yl)-4-methyl-pentanoic acid pyridin-2-ylamide A solution of 4-methyl-pentanoic acid (23.23 g) in carbon tetrachloride (20 mL) was treated with thionyl chloride (58.0 mL) and heated at 65° C. for 30 min. The reaction mixture was then removed from the oil bath and a mixture of N-bromosuccinimide (42.8 g) and a 48% aqueous hydrobromic acid solution (20 drops) in carbon tetrachloride (100 mL) was added dropwise. The resulting mixture was then heated at 70° C. for 10 min and then 85° C. for 3 h. After this time, the reaction was cooled to 0° C. in an ice bath and then treated dropwise with methanol (50 mL). The mixture was then filtered through a celite plug to remove the insoluble material and the filterate concentrated in vacuo. The residue was then dissolved in pentane (400 mL) and washed with water (400 mL) and the aqueous layer was then extracted with pentane (400 mL). The organic layers were then combined and dried over sodium sulfate, filtered and the filterate concentrated in vacuo. The crude material was purified using flash column chromatography (silica gel, 5% ethyl acetate/hexanes) to afford 2-bromo-4-methyl-pentanoic acid methyl ester (21.75 g, 52%) as a colorless oil. | |
With pivaloyl chloride; triethylamine In tetrahydrofuran at -20℃; for 1h; | (R)-4-Benzyl-3-(4-methylpentanoyl)oxazolidin-2-one (12): To a cooled solution of 4-methyl-pentanoic acid in dry THF (2 g 17.24 mmol, 1 eq) at -20 °C were added 2.1 mL (17.2 mmol, 1eq.) of pivaloyl chloride and 5.99 mL (43.1 mmol, 2.5 eq.) of triethylamine. After stirring for 1h at -20 ˚C, LiCl (1.08 g, 25.86 mmol, 1.5 eq.) and (R)-4-benzyloxazolidine-2-one 10 (3.03 g,17.2 mmol, 1 eq.) were added to it. The resulting mixture was stirred at -20 ˚C for 1h and then at 0 ˚C for 2h. After completion, the reaction mixture was quenched with sat. aq. NH4Cl. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The organic layer was dried over MgSO4 and the solvent was removed in vacuo. The residue was purified by column chromatography (EtOAc/ Hexane, 5:95) to give the compound 12 in 78% (3.697 g) yield as colourless liquid. [α]20D - 46 (c = 0.5); 1HNMR (300 MHz, CDCl3): δ 7.38-7.18 (5H, m), 4.72-4.63 (1H, m), 4.24-4.11 (2H, m), 3.32 (1H, dd, J = 3.7, 3.0 Hz), 3.06-2.84 (2H, m), 2.82-2.70 (1H, m), 1.73-1.50 (3H, m), 0.94 (6H, d, J = 6.7 Hz); 13C NMR (75 MHz, CDCl3): δ 173.5, 153.3, 135.2, 129.3, 128.8, 127.1, 66.0, 55.0, 37.8, 33.5, 33.0, 27.5, 22.2. IR (KBr): vmax 3451, 2957, 1783, 1700, 1200, 702 cm-1; ESI-MS: m/z 276 [M+H]+. | |
With thionyl chloride at 25℃; for 2h; Reflux; | ||
With thionyl chloride | ||
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 23℃; for 4h; | ||
With oxalyl dichloride In dichloromethane at 20℃; | ||
1 g | With thionyl chloride at 60℃; for 3h; Inert atmosphere; | 100.C A solution of 4-methylpentanoic acid (2.5 g, 21.52 mmol) in thionyl chloride (6.4 g, 53.8 mmol) under nitrogen atmosphere was heated at 60 °C for 3 h. The reaction mixture was cooled and the volatile organics were removed under reduced pressure. The oily residue so obtained was subjected to fractional distillation under atmospheric pressure. The distillation afforded a fraction at 155 °C, 4- methylpentanoyl chloride (1 g, 7.43 mmol) as a colorless oil. To a solution of 2-bromo-4-(oxazol-5-yl)aniline (900 mg, 3.76 mmol) in dichloroethane (30 mL) cooled to 0 °C under a nitrogen atmosphere was added DIPEA (1.45 g, 11.28 mmol). To this solution, 4-methylpentanoyl chloride (606 mg, 4.512 mmol) was added dropwise and stirring continued for 16 h at rt. The reaction was quenched by addition of saturated aqueous ammonium chloride (25 mL). The mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of ethyl acetate in hexanes to afford N-(2-bromo-4-(oxazol-5- yl)phenyl)-4-methylpentanamide (350 mg, 1.042 mmol, 28% yield) as a light brown solid. LCMS (ESI) m/e 337.0, 339.0 (Br pattern) [(M+H)+, calcd for Ci5Hi8BrN202, 337.05]; LC/MS retention time (method B): tR = 1.90 min. |
With oxalyl dichloride In dichloromethane at 20℃; | ||
With thionyl chloride Reflux; | ||
With oxalyl dichloride In dichloromethane at 20℃; for 3h; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 1h; Inert atmosphere; | General procedure: To the solution of carboxylic acid 10-13 (2.43 mM) in dry CH2Cl2 (5.5 mL) that had been pre-cooledto 0 C, were gradually added the catalytic amount of DMF (1-2 drop) and oxalyl chloride (7.29 mM).The resulting mixture was stirred for 5 min at 0 C and then at room temperature for a further 55 min.Subsequently the solvent was evaporated under vacuum and the crude product was used further. | |
With thionyl chloride for 2h; Inert atmosphere; Schlenk technique; Reflux; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; | Synthesis of compound 6b General procedure: Cyclopropyl acetic acid (1.00 g, 9.98 mmol) was taken in 35.0 mL of dry CH2Cl2 at 0 C and catalytic amount of DMF (1 drop) was added. The solution was stirred and treated with oxalyl chloride (0.9 mL, 10.40 mmol) dropwise. The resulting mixture was stirred overnight slowly warming to room temperature. After 12 hours, the solvent was evaporated in rotavapor minimizing exposure to air to yield the crude acid chloride. The crude product thus obtained was immediately used for the next step without further purification. A solution of (R)-4-benzyloxazolidin-2-one (1.32 g, 7.50 mmol) in 30.0 mL of dry THF was cooled to -78 oC under argon atmosphere, and treated with dropwise addition of n-BuLi (4.46 mL, 1.68 M in Hexanes, 7.50 mmol). The resulting mixture was stirred for 20 minutes at the same temperature, and a solution of acid chloride (obtained above) in 45.0 mL of dry THF was slowly added via cannula. The reaction was stirred at -78 oC for 30 minutes and at 0 oC for 1.5 hours. TLC examination revealed complete conversion of the starting material. The mixture was then quenched with saturated solution of NH4Cl and extracted with EtOAc (2 x 20 mL). The aqueous layer was further extracted with EtOAc and the combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography using hexanes-EtOAc: 8:2 to afford the title compound. Physical and spectral properties of compounds 6a [3] and 6e [4] are in agreement with the literature. | |
With thionyl chloride for 3h; Schlenk technique; Inert atmosphere; Reflux; | ||
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 20℃; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0℃; for 3h; Inert atmosphere; | ||
With thionyl chloride In dichloromethane at 20℃; Inert atmosphere; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 25℃; for 3h; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; | ||
With oxalyl dichloride In tetrahydrofuran at 0℃; | ||
With thionyl chloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 2h; Inert atmosphere; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 2h; Inert atmosphere; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 4h; Cooling with ice; Inert atmosphere; | ||
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 2h; Inert atmosphere; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 4h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | Preparation of 2-bromo-4-methyl-pentanoic acid methyl ester: A solution of 4-methyl-pentanoic acid (50 g, 0.43 mol) in carbon tetrachloride (200 mL) at 25 C. was treated with thionyl chloride (125 mL, 1.72 mol). The reaction was then heated to 65 C. and stirred for 30 min. After this time, the reaction was removed from the heat and was then treated with N-bromosuccinimide (100 g, 0.56 mol), carbon tetrachloride (200 mL) and a 48% aqueous hydrogen bromide (40 drops). The reaction was then heated to 85 C. and stirred overnight. After this time, the reaction was cooled to 0 C. and carefully quenched with methanol (150 mL) until no further gas evolution was observed. The mixture was then filtered and washed with hexanes. The dark solution was concentrated in vacuo. The remaining liquid was then partitioned between water (300 mL) and hexanes (3×300 mL). The combined organics were washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, rinsed and concentrated in vacuo. The obtained residue was distilled in vacuo to afford 2-bromo-4-methyl-pentanoic acid methyl ester as colorless oil (60 g, 66%); 1H NMR (300 MHz, CDCl3): delta 4.28 (t, 1H, J=7.5 Hz), 3.77 (s, 3H), 1.90 (t, 2H, J=7.5 Hz), 1.78-1.71 (m, 1H), 0.93 (dd, 6H, J1=14.1 Hz, J2=6.6 Hz). GC-MS: 209 [M]+, tR=5.50 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 23℃; | |
63% | With dmap; N-ethyl-N,N-diisopropylamine; diisopropyl-carbodiimide In chloroform at 25℃; for 24h; | |
1.98 g | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 23℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | Stage #1: (4S)-4-isopropyl-1,3-oxazolidin-2-one With n-butyllithium In tetrahydrofuran at -78℃; Inert atmosphere; Stage #2: 4-Methylpentanoic acid With pivaloyl chloride; triethylamine In tetrahydrofuran at 0℃; Inert atmosphere; | |
70% | Stage #1: (4S)-4-isopropyl-1,3-oxazolidin-2-one With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5h; Stage #2: 4-Methylpentanoic acid With pivaloyl chloride; triethylamine In tetrahydrofuran at 0℃; for 0.5h; Stage #3: In tetrahydrofuran; hexane at 20℃; for 2h; | |
Stage #1: 4-Methylpentanoic acid With triethylamine; isobutyl chloroformate In tetrahydrofuran at 0℃; for 0.333333h; Stage #2: (4S)-4-isopropyl-1,3-oxazolidin-2-one With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1h; | 21 4.1.21. (S)-4-Isopropyl-3-{3-(thiophen-2-yl)propanoyl}oxazolidin-2-one 30 General procedure: To 2-thiophene-propionic acid 28 (5.23 g, 33.5 mmol) in THF (60 mL) were added Et3N (5.6 mL, 40 mmol) and isobutylchloroformate (5.0 mL, 36.8 mmol) at 0 °C. After stirring for 30 min, the mixture was added to the lithio-(4S)-4-isopropyl-2-oxazolidinone, prepared by dropwise addition of n-BuLi (14.2 mL, 36.8 mmol, 2.6 mol/L in hexane) to (4S)-4-isopropyl-2-oxazolidinone (4.76 g, 36.8 mmol) in THF (60 mL) at -78 °C, and the mixture was stirred for 1 h. The reaction was quenched with saturated aqueous NaHCO3 and the whole was extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane/EtOAc = 5:1) to yield 30 (3.68 g, 97%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With triethylamine In acetonitrile at 20℃; for 16h; | |
With triethylamine In dichloromethane at 20℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
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93% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
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71% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In DMF (N,N-dimethyl-formamide) at 20℃; | 27 Example 27; Synthesis of N-(1H-indazol-5-yl)-4-methylpentanamide To a solution of 5-aminoindazole (1.00 g, 7.51 mmol) in N,N-dimethylformamide (15 ml) were added 4-methylvaleric acid (960 mg, 8.26 mmol), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide monohydrochloride (1.72 g, 9.01 mmol), hydroxybenzotriazole (1.12 g, 8.26 mmol) and triethylamine (1.7 ml, 12.0 mmol), and the resulting mixture was stirred overnight at room temperature. Then, the reaction solution was cooled to 0°C and a 1N-aqueous sodium hydroxide solution was added thereto, followed by extraction with chloroform. The organic layer was washed with water and then a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was dissolved in a mixture of diethyl ether and methanol, followed by adding thereto hexane. The solid precipitated was collected by filtration and dried under reduced pressure to obtain N-(1H-indazol-5-yl)-4-methylpentanamide (1.24 g, 71%). Melting point: 215-216°C (decomp.) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With boron trifluoride diethyl etherate; trifluoroacetic anhydride In toluene at 50 - 55℃; for 2h; | |
78% | With boron trifluoride diethyl etherate; trifluoroacetic anhydride In toluene at 50 - 55℃; for 2h; Inert atmosphere; | |
77% | With boron trifluoride diethyl etherate; trifluoroacetic anhydride In toluene at 20 - 55℃; for 2h; Inert atmosphere; | 1 Embodiment 1 In 500 ml three port in the reaction bottle, the flowability of the magnetic force of a suitable, with argon balloon is provided with a thermometer and the three-way. The reaction bottle-side vacuum pumping uses heating blowing heating, replacement of argon three times. Through the injector into the 220 ml anhydrous toluene. Sequentially adding furan 24 ml (335mmol, 1 . 3equiv), 4-methyl valeric acid (33 ml, 258mmol, 1.0equiv). Under stirring at room temperature by adding trifluoroacetic anhydride 44 ml (1.1equiv) boron trifluoride ether and 3.3 ml (10mmol %). The elevated temperature of the oven is kept at 50-55 °C reaction 2h. The reaction bottle placed in the ice-water bath, is added in batches 150 ml mass fraction 21% the Na2CO3and in solution. Separation, the organic phase is filtered through diatomaceous earth, anhydrous sodium sulfate for drying. By reduced pressure distillation to remove the solvent. The concentrated solution is distilled under reduced pressure through the oil pump (oil to be temperature 100 °C, distillation head temperature is 68-78 °C). Got about 33g colorless liquid, yield 77%. |
With trifluoroborane diethyl ether; trifluoroacetic anhydride In toluene | 2.A Preparation of 5-diethylphosphono-2-[(1-oxo)alkyl]furans and 6-diethylphosphono-2-[(1-oxo)alkyl]pyridines Step A. A solution of furan (1.3 mmole) in toluene was treated with 4-methyl pentanoic acid (1 mmole), trifluoroacetic anhydride (1.2 mmole) and boron trifluoride etherate (0.1 mmole) at 56° C. for 3.5 h. The cooled reaction mixture was quenched with aqueous sodium bicarbonate (1.9 mmole), filtered through a celite pad. Extraction, evaporation and distillation gave 2-[(4-methyl-1-oxo)pentyl]furan as a brown oil (bp 65-77° C., 0.1 mm Hg). | |
With trifluoroborane diethyl ether; trifluoroacetic anhydride In toluene | 2.A Step A. Step A. A solution of furan (1.3 mmole) in toluene was treated with 4-methyl pentanoic acid (1 mmole), trifluoroacetic anhydride (1.2 mmole) and boron trifluoride etherate (0.1 mmole) at 56° C. for 3.5 h. The cooled reaction mixture was quenched with aqueous sodium bicarbonate (1.9 mmole), filtered through a celite pad. Extraction, evaporation and distillation gave 2-[(4-methyl-1-oxo)pentyl]furan as a brown oil (bp 65-77° C., 0.1 mm Hg). | |
With boron trifluoride diethyl etherate; trifluoroacetic anhydride In toluene at 56℃; for 3.5h; | 2.A Preparation of 5-diethylphosphono-2-[(1-oxo)alkyl]furans and 6-diethylphosphono2-[(1-oxo)alkyl]pyridines Step A. A solution of furan (1.3 mmole) in toluene was treated with 4-methyl pentanoic acid (1 mmole), trifluoroacetic anhydride (1.2 mmole) and boron trifluoride etherate (0.1 mmole) at 56° C. for 3.5 h.. The cooled reaction mixture was quenched with aqueous sodium bicarbonate (1.9 mmole), filtered through a celite pad.. Extraction, evaporation and distillation gave 2-[(4-methyl-1-oxo)pentyl)furan as a brown oil (bp 65-77° C., 0.1 MmHg). | |
With boron trifluoride diethyl etherate; trifluoroacetic anhydride In toluene | 10.A Step A Step A. A solution of furan (1.3 mmole) in toluene was treated with 4-methyl pentanoic acid (1 mmole), trifluoroacetic anhydride (1.2 mmole) and boron trifluoride etherate (0.1 mmole) at 56°C for 3.5 h. The cooled reaction mixture was quenched with aqueous sodium bicarbonate (1.9 mmole), filtered through a celite pad. Extraction, evaporation and distillation gave 2-[(4-methyl-1-oxo)pentyl]furan as a brown oil (bp 65 - 77 C, 0.1 mmHg). | |
With trifluoroborane diethyl ether; trifluoroacetic anhydride In toluene | 2.A Step A. Step A. A solution of furan (1.3 mmole) in toluene was treated with 4-methyl pentanoic acid (1 mmole), trifluoroacetic anhydride (1.2 mmole) and boron trifluoride etherate (0.1 mmole) at 56° C. for 3.5 h. The cooled reaction mixture was quenched with aqueous sodium bicarbonate (1.9 mmole), filtered through a celite pad. Extraction, evaporation and distillation gave 2-[(4-methyl-1-oxo)pentyl]furan as a brown oil (bp 65-77° C., 0.1 mmHg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In DMF (N,N-dimethyl-formamide) at 20℃; for 64h; | 78 Example 78; 5-Fluoro-N-[cis-4-(4-methyl-pentanoylamino)-cyclohexyl]-2-(3-methylsulfanyl- PHENOXY)-NICOTINAMIDE; N- (CIS-4-AMINO-CYCLOHEXYL)-5-FLUORO-2- (3-METHYLSULFANYL-PHENOXY)-NICOTINAMIDE hydrochloride (100mg, 0. 243MMOL) was dissolved in dimethylformamide (1ml) and triethylamine (100µl, 0. 729MOL) was added followed by 4-METHYLPENTANOIC acid (37µl, 0. 291 MMOL), 1- (3-DIMETHYLAMINOPROPYL)-3-ETHYLCARBODIIMIDE HYDROCHLORIDE (56mg, 0. 291mmol) and 1-hydroxybenzotriazole (39mg, 0. 291MOL). The reaction was stirred under nitrogen at room temperature for 64h and the solvent was removed under reduced pressure. The residue was partitioned between sat. sodium bicarbonate solution (5ML) and ethyl acetate (10ML) and the aqueous phase was extracted with ethyl acetate (3X10ML). The combined organic extracts were washed with water (2X5ML), brine (5ML), dried over MgS04 and the solvent was removed under reduced pressure. The residue was triturated with diethylether (5ML) to give 5- FLUORO-N- [CIS-4- (4-METHYL-PENTANOYLAMINO)-CYCLOHEXYL]-2- (3-METHYLSULFANYL-PHENOXY)- nicotinamide (114MG) as a white solid. 1H NMR (400MHZ, CDCI3) : A = 8. 36-8.40 (1H, dd), 8. 05-8. 07 (1H, d), 7.98-8. 03 (1H, d), 7.37-7. 42 (1H, t), 7. 15-7.19 (1H, d), 7.04 (1H, s), 6.88-6. 92 (1H, d), 5.12-5. 19 (1H, d), 4. 18-4. 25 (1H, brs), 3.85-3. 94 (1H, m), 2.50 (3H, s), 2.09-2. 14 (2H, t), 1.70-1. 83 (6H, m), 1.44-1. 60 (3H, 2xm, partially masked by solvent), 1.32-1. 43 (2H, m), 0.87- 0.93 (6H, d) ppm. LRMS (electrospray) : M/Z [M+H] + 474. Anal. Found C, 63.15 ; H, 6.78 ; N, 8.83. C25H32FN303S requires C, 63.40 ; H, 6.81 ; N, 8.87%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With dicyclohexyl-carbodiimide In tetrahydrofuran at 20℃; | 5.B B. A mixture of [1-(6-Aminopyridazin-3-yl)piperidin-4-yl]phenylmethanone(0.115 g, 0.380 mmol) and 4-methylpentanoic acid (0.090 g, 0.775 mmol) in the presence of Λ/,/V'-dicyclohexylcarbodiimide (0.116 g, 0.562 mmol) in THF (20 mL) was stirred at ambient temperature overnight. The solvent was evaporated and the residue was purified by column chromatography. Further purification by recrystallization from ethyl acetate and methanol afforded the title compound as a white powder in 71% yield (0.108 g). 1H NMR (300 MHz, CDCI3) δ 9.12 (br., s, 1H), 8.31 (d, J = 9.8 Hz, 1 H), 8.02- 7.98 (m, 2H), 7.16 (t, J = 8.6 Hz, 2H), 7.07 (d, J = 9.8 Hz, 1 H), 4.33 (dt, J = 3.3 and EPO 13.3 Hz1 2H), 4.09 (br., s, 2H), 3.50-3.40 (m, 5H), 3.12 (dt, J = 3.3 and 13.3 Hz, 2H), 2.52-2.49 (m, 2H), 0.93 (d, J = 6.6 Hz, 6H). MS (ES+) m/z 399.1 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With perchloric acid In acetic acid tert-butyl ester | 1 tert-Butyl 4-Methylvalerate EXAMPLE 1 tert-Butyl 4-Methylvalerate A solution of 4-methylvaleric acid (25 g) in tert-butyl acetate (538 ml) is treated with perchloric acid (2.7 ml) then stirred at ambient temperature for 1.5 h. This is subsequently poured into water (350 ml) containing NaOH (50 g) and the tert-butyl ester is isolated by ether extraction as a pale yellow oil (24.90 g; 68% yield). NMR (CDCl3) δ 0.88(d, J=6 Hz,6H), 1.45(m,12H), 2.20 (t, J=7.5 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 5.81 g of <strong>[19763-90-7]3,4-dichlorophenylhydrazine hydrochloride</strong> was mixed 11.57 g of 4,4-dimethylbutyric acid, and the resulting mixture was sufficiently stirred to obtain a transparent solution, after which 7.64 g of n-butanol was added. The mixed solution was stirred with treating at 110 C. for 1 hour. The reaction solution was cooled to room temperature, diluted with water, and neutralized with a 1N aqueous sodium hydroxide solution. The aqueous phase was extracted with ethyl acetate, and the ethyl acetate phase was washed with distilled water and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was removed by distillation and the oily substance thus obtained was purified by a silica gel column chromatography and a silica gel thin-layer chromatography to obtain 0.28 g of methyl 4,5-dichloroindole-3-acetate and 0.395 g of n-butyl 5,6-dichloroindole-3-acetate. | ||
In sodium hydroxide; | With 5.81 g of <strong>[19763-90-7]3,4-dichlorophenylhydrazine hydrochloride</strong> was mixed 11.57 g of 4,4-dimethylbutyric acid, and the resulting mixture was sufficiently stirred to obtain a transparent solution, after which 7.64 g of n-butanol was added. The mixed solution was stirred with treating at 110C for 1 hour. The reaction solution was cooled to room temperature, diluted with water, and neutralized with a IN aqueous sodium hydroxide solution. The aqueous phase was extracted with ethyl acetate, and the ethyl acetate phase was washed with distilled water and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was removed by distillation and the oily substance thus obtained was purified by a silica gel column chromatography and a silica gel thin-layer chromatography to obtain 0.28 g of methyl 4,5-dichloroindole-3-acetate and 0.395 g of n-butyl 5,6-dichloroindole-3-acetate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With 4-methyl-morpholine; hydrogenchloride; benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate In N,N-dimethyl-formamide | 207 Methyl (2R)-3-(((2R)-1-(2-cyclohexylacetyl)pyrrolidin-2-yl)methylthio)-2-(4-methylpentanoylamino)propionate (207) Example 207 Methyl (2R)-3-(((2R)-1-(2-cyclohexylacetyl)pyrrolidin-2-yl)methylthio)-2-(4-methylpentanoylamino)propionate (207) To a solution of 60 mg (0.175 mmol) of methyl (2R)-3-(((2R)-1-(2-cyclohexylacetyl)pyrrolidin-2-yl)methylthio)-2-aminopropionate (200) in 3 ml of DMF, were added 20 mg (0.175 mmol) of 4-methylvaleric acid, 100 mg (0.193 mmol) of PyBOP and 0.023 ml (0.210 mmol) of N-methylmorpholine, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture, 1N hydrochloric acid was added and the resulting mixture was extracted with ethyl acetate. Organic layers were combined, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (silica gel; hexane/ethyl acetate = 2/1) to obtain 36 mg of methyl (2R)-3-(((2R)-1-(2-cyclohexylacetyl)pyrrolidin-2-yl)methylthio)-2-(4-methylpentanoylamino)propionate (207) (yield: 38%). LR-MS (m/z): 440 (M+) 1H-NMR (300MHz, CDCI3, δppm): 0.88(6H, dd, J= 1.5, 6.3 Hz), 1.48-1.97(18H, m), 2.10(2H, d, J= 6.6 Hz), 2.16-2.35(3H, m), 2.86-3.01(2H, m), 3.09(1H, dd, J= 6.9, 17.4 Hz), 3.37-3.61(2H, m), 3.73-3.76(3H, m), 4.19(1H, s), 4.81-4.87(1H, m), 7.06(1H, d, J= 7.5 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 96h; | 29 Example 29: λH1 -r(3,4-dichlorophenyl)methyll-1 H-pyrazol-4-yl}-2-(4- methylpentanoyl)-1 ,2,3,4-tetrahydro-6-isoquinolinecarboxamide; A solution of N-{1-[(3,4-dichlorophenyl)methyl]-1 H-pyrazol-4-yl}-1 ,2,3,4-tetrahydro-6- isoquinolinecarboxamide hydrochloride (Example 1 ) (105 mg, 0.24 mmol), 4- methylpentanoic acid (40 μl_, 0.32 mmol), HOBt (40 mg, 0.29 mmol), EDCI (55 mg, 0.29 mmol) and triethylamine (100 μl_, 1.3 mmol) in dichloromethane (5 ml.) was stirred at room temperature for 4 days. The reaction mixture was washed with a 1 N sodium hydroxide aqueous solution then dried over sodium sulphate. After filtration and evaporation under reduced pressure, the residue was purified by flash column chromatography eluting with a gradient DCM 100% to DCM/MeOH: 94/6 to give the title compound as colourless oil (75 mg, 63%). HRMS calculated for C26H28CI2N4O2 (M+H)+ 499.1667, found: 499.1659, Rt: 3.12 min |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With diethyl cyanophosphonate; triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 16.5h; | 13 General procedure for the synthesis of acyl Meldrum's acids General procedure: Method B: Adapted from the procedure of Srensen et al..14 Meldrum’s acid (1equiv) and corresponding acid (1equiv) were dissolved in DMF, and cooled to 0°C. To this solution was added diethyl cyanophosphonate (1.1equiv) and triethylamine (3.1equiv) drop wise. The mixture was allowed to stir at 0°C for 30min followed by 16h at room temperature. The reaction was quenched with 2M hydrochloric acid and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, and dried over sodium sulfate. The solution was filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography using a gradient from 5% to 10% ethyl acetate in hexane, 1% acetic acid to yield acyl Meldrum’s acids (11f-i, k, m, n, o). |
Stage #1: cycl-isopropylidene malonate; 4-Methylpentanoic acid With dmap In dichloromethane at -5℃; for 0.5h; Inert atmosphere; Stage #2: With dicyclohexyl-carbodiimide In dichloromethane at -5 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 24h; | 9 EXAMPLE 9 Synthesis of 4-methyl-1-[4-(3-thiophen-2-yl[1,2,4]oxadiazol-5-yl)piperid-1-YL]pentan-1-one (Compound 25) 86 mg (2 eq.) of 4-methylvaleric acid, 141 mg (2 eq.) of 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (EDCI) and 207 μl (4 eq.) of triethylamine were dissolved in 2 ml of dichloromethane. 100 mg (1 eq.) of 4-(3-thiophen-2-yl[1,2,4]oxadiazol-5-yl)piperidinium hydrochloride were then added to the reaction medium, which was then stirred at room temperature for 24 hours. The reaction medium was evaporated under reduced pressure and the residue was taken up in 20 ml of ethyl acetate. The organic phase was washed with aqueous 1N sodium hydroxide solution (3*30 ml), with aqueous 1N hydrochloric acid solution (3*30 ml) and with saturated aqueous NaCl solution (30 ml) and then dried over MgSO4 and concentrated under reduced pressure to give 102 mg (83%) of the expected compound. 1H NMR (CDCl3): δ=7.72 (dd, J=3.7 Hz J=1.2 Hz, 1H), 7.45 (dd, J=5.1 Hz J=1.2 Hz, 1H), 7.09 (dd, J=5.1 Hz J=3.7 Hz, 1H), 4.46 (m, 1H), 3.89 (m, 1H), 3.19 (m, 2H), 2.90 (m, 1H), 2.3 (t, J=8 Hz, 2H), 2.10 (m, 2H), 1.84 (m, 2H), 1.49 (m, 3H), 0.86 (d, J=6.4 Hz, 6H) 13C NMR (CDCl3): δ=180.87, 171.86, 164.30, 129.58, 129.32, 128.19, 127, 98, 44.55, 40.73, 34.35, 34.21, 31.37, 29.27, 27.91, 22.39 MS: m/z 334 (M+H+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; | A-82-1 Example A-824-(2-Chloro-5-methylphenylcarbamoyl)-3-[4-cyclopropyl-5-(3-isobutylcyclobutyl)isoxazol-3-yl]butanoic acid(A-82-1) 4-Methyl-1-piperidin-1-ylpentan-1-one 4-Methylvaleric acid (238 g) and DMF (833 mL) were mixed. After an addition of piperidine (233 mL), HOBt.H2O (361 g) and WSC.HCl (452 g) to the mixture at ice temperature, the resulting mixture was stirred at RT overnight. To the reaction was added water (1000 mL) at ice temperature and the resulting mixture was extracted with toluene (500 mL×2). The organic layer was washed with aqueous 10 w/v % sodium carbonate (500 mL+300 mL) and water (500 mL×2). The organic layer was concentrated in vacuo to give the title compound (414.29 g) as a crude product. | |
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; Cooling with ice; | F-499.F-499-1 F-499-1 4-Methyl-1-piperidine-1-ylpentan-1-one F-499-1 4-Methyl-1-piperidine-1-ylpentan-1-one (3154) (3155) 4-Methyl valerate (238 g) and DMF (833 mL) were mixed. To the mixture were added piperidine (233 mL), HOBt.H2O (361 g), and WSC.HCl (452 g) at ice temperature. The resulting mixture was stirred overnight at room temperature. To the reaction mixture was added water (1000 mL) at ice temperature. The resulting mixture was extracted with toluene (500 mL×2). The organic layer was washed with aqueous 10 w/v % sodium carbonate (500 mL+300 mL) and water (500 mL×2) in this order, and concentrated under reduced pressure to give the title compound (414.29 g) as a crude product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: 4-Methylpentanoic acid With 1-hydroxy-pyrrolidine-2,5-dione; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 2h; Cooling with ice; Stage #2: C39H38N6O6 In dichloromethane at 20℃; for 4h; | 1 Synthesis of VIIILeu 1.38 mL (10.9 mmol) of 4-methylvaleric acid was dissolved in 33 mL of dehydrated dichloromethane and 1.39 g (12.0 mmol) of N-hydroxysuccinic acid imide was added to the solution. Then, 2.37 g (11.5 mmol) of dicyclohexylcarbodiimide was also added to the solution while being cooled with ice and the solution was agitated at room temperature for 2 hours. The insoluble was removed by filtration and the filtered solution was added to the reaction mixture A. The reaction mixture was then agitated at room temperature for 4 hours. Subsequently, 5 mL of methanol was added to the solution, which was then agitated for 30 minutes. The reaction solution was diluted by dichloromethane and washed with water. The dichloromethane solution was concentrated under reduced pressure and the residue was purified by medium pressure chromatography (dichloromethane-ethanol 49:1→17:3). In this way, target product VIIILeu was obtained in an amount of 5.03 g (70%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53.3% | 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 dichloromethane at 20℃; | 168 Procedure for preparation of Compound 168: To a solution of compound 1 (15mg, 0.079mmol) and 3 (36mg, 0.095mmol), 4 (31mg, 0.237mmol) in DCM (3ml), then the compound 2 (11mg, 0.095mmol) was added, the mixture was stirred at r.t. overnight. The reaction was quenched by adding water and extracted with EA. The combine organic phases were washed by water, brine, dried over anhydrous Na2SO4 and concentrated to dryness. The residue was purified by pre- TLC to obtain the title compound Compound 168 (12.16mg, yield: 53.3%). LCMS: m/z, 289.2(M+H)+; 1H NMR (d-CDCl3, 400MHz): δ 8.53-8.55 (m, 1H), 7.61-7.65 (m, 1H), 7.41-7.44 (m, 1H), 7.20-7.25 (m, 1H), 3.79-4.32 (m, 2H), 3. 65-3.76 (m, 2H), 2.20-2.24 (m, 2H), 2.15-2.19 (m, 2H), 1.47-1.53 (m, 3H), 0.84-0.87 (m, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45.6% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; | 4.5. General Procedure for Preparation of Compounds(33-39) General procedure: The derivatives (33-39) were obtained by the reaction ofcaudatin (0.2 mmol) with an excess of acids (5 equiv) andDCC (5 equiv) in the presence of DMAP (0.8 equiv) wasstirred in CH2Cl2 at room temperature, which had the similartreatment process to preparation of compounds 2-31. Thecrude products were purified by chromatography with petroleumether/acetone (8:1 - 20:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.1% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; | 4.3. General Procedure A for Preparation of Derivatives(2-31) General procedure: The DCC (1.2 equiv) was added to the solution of caudatin(0.2 mmol), DMAP (0.2 equiv), and appropriate carboxylic acid (1.2 equiv) in anhydrous CH2Cl2 (8 mL) at 0 °C.The resulting mixture was stirred at room temperature until the starting material was not observed by TLC. The reaction mixture was filtered, and the residue was washed with CH2Cl2 (210 mL). Then, the CH2Cl2 solution was washed with 5% HCl (330 mL), saturated NaHCO3 (330 mL) and saturated NaCl (330 mL), respectively. Subsequently, the organic layer was dried by Na2SO4 and concentrated to dryness under reduced pressure. At last, the residue was purified by column chromatography over the silica gel with petroleum ether/acetone (60:40 - 95:5) to yield the pure target compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 16h; | S2.2. Synthesis of series IIIA (12a-12f) and series IVA (13a-13f): General procedure: The general synthesis of these inhibitors starts with an amide coupling between intermediate 2 and different carboxylic acids to give 10a-10f, or with different N-Boc-D-amino acids to give 11a-11f, using EDCI / HOAt in presence of DIEA (Scheme S2). The resulting amides were stirred with hydroxylamine hydrochloride and DIEA in anhydrous methanol for 16 h to form the corresponding hydroxyamidine. The hydroxyamidine were then used directly in the next step. The hydroxyamidine were stirred with acetic anhydride in acetic acid for 30-45 min. 10% Pd/C was then added and the mixture was hydrogenated. In case of products that have a Boc group, this protecting group was removed with 3 N methanolic HCl. The final products, 12a-12f and 13a-13f, were further purified using reverse-phase HPLC to a purity > 95%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With triethylamine; 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℃; | 6 EXAMPLE 6 SYNTHESIS OF 1-(4-(4-(6-AMINO-5-(5-(2,6-DICHLOROPHENYL)-1,3,4-OXADIAZOL-2- YL)PYRIDIN-3 -YL)- lH-PYRAZOL- 1 -YL)PIPERIDIN- 1 -YL)-4-METHYLPENTAN- 1 -ONE EXAMPLE 6 SYNTHESIS OF 1-(4-(4-(6-AMINO-5-(5-(2,6-DICHLOROPHENYL)-1,3,4-OXADIAZOL-2- YL)PYRIDIN-3 -YL)- lH-PYRAZOL- 1 -YL)PIPERIDIN- 1 -YL)-4-METHYLPENTAN- 1 -ONE To a mixture of 3-(5-(2,6-dichlorophenyl)-l,3,4-oxadiazol-2-yl)-5-(l- (piperidin-4-yl)-lH-pyrazol-4-yl)pyridin-2-amine (63.0 mg, 0.138 mmol), 4- methylpentanoic acid (0.021 mL, 0.166 mmol) and l-[bis(dimethylamino)methylene]- lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (78.7 mg, 99%, 0.20 mmol) dissolved in N,N-dimethylformamide (1.0 mL) was added triethylamine (0.039 mL, 0.276 mmol). The resulting mixture was stirred at ambient temperature overnight, and diluted with ethyl acetate (30 mL), washed with brine (2 x 30 mL), and dried over sodium sulfate. After filtration and removal of the solvent, the residue was purified by column chromatography eluted with dichloromethaneimethanohNlHLOH (from 200:6: 1 to 200:8:1) to afford the title compound as a yellow solid in 39% yield (30.0 mg). 1H NMR (400 MHz, CDC13): δ 8.38 (d, J= 2.4 Hz, 1H), 8.12 (d, J= 2.4 Hz, 1H), 7.73 (s, 1H), 7.64 (s, 1H), 7.51-7.49 (m, 3H), 6.86-6.60 (br s, 2H), 4.80-4073 (m, 1H), 4.40- 4.35 (m, 1H), 4.04-3.98 (m, 1H), 3.25-3.18 (m, 1H), 2.80-2.71 (m, 1H), 2.38-2.32 (m, 2H), 2.30-2.14 (m, 2H), 2.03-1.88 (m, 2H), 1.67-1.49 (m, 3H), 0.91 (d, J= 6.4 Hz, 6H). MS: (ES+): m/z 554.4, 555.3, and 556.3 (M + 1), 576.3, 577.3 and 578.3 (M + Na). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With 2-azidosulfonylbenzoic acid methyl ester; dipotassium peroxodisulfate; sodium hydrogencarbonate In water; acetonitrile at 85℃; for 4h; Schlenk technique; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | Stage #1: 4-Methylpentanoic acid; C30H34N2O4 With 3-hydroxy-3,4-dihydrobenzotriazine-4-one; diisopropyl-carbodiimide In N,N-dimethyl-formamide Stage #2: With trifluoroacetic acid In dichloromethane; N,N-dimethyl-formamide | 3 10084] Block 3. Yield 60%. 1H NMR (DMSO-d6, 400MHz) ö (two rotamers) 7.83 (d, J=7.6 Hz, 2H), 7.58-7.53 (m,2H), 7.36-7.26 (m, 5H), 7.24-7.09 (m, 5H). 4.13-4.06 (m,3H), 3.96-3.74 (m, 4H), 3.51-3.46 (m, 1H), 3.40-3.32 (m,1H), 3.38-3.11 (m, 1H), 2.78-2.72 (m, 1H), 2.67-2.56 (m,1H), 2.32-2.06 (m, 2H), 1.47-1.36 (m, 1H), 1.33-1.24 (m,2H), 0.80-0.7 1 (m, 6H). 13C NMR (DMSO-d6, 100 MHz) ö173.7, 156.1, 144.2, 141.1, 139.5, 139.1, 129.53, 129.46,128.4, 128.0, 127.4, 126.5, 126.3, 125.7, 125.6, 125.5, 120.5,120.5,65.8,65.8,51.5,51.0,47.0,38.3,34.3,34.1,30.9,30.9,27.6, 27.5, 22.8, 22.7. HR-ESI: [M+H]+ cad: 529.2697.found: 529.2700. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 20℃; | 1 SYNTHESIS OF 4-METHYLPENTANOIC ACID {6-[4-(2-TRIFLUOROMETHYLBENZOYL)-PIPERAZIN-1-YL]PYRIDAZIN-3-YL}AMIDE REFERENCE EXAMPLE 1 SYNTHESIS OF 4-METHYLPENTANOIC ACID {6-[4-(2-TRIFLUOROMETHYLBENZOYL)-PIPERAZIN-1-YL]PYRIDAZIN-3-YL}AMIDE To a stirred solution of [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethyl-phenyl)methanone (0.226 g, 0.645 mmol) in tetrahydrofuran (10.0 mL) was added 4-methylpentanoic acid (0.500 g, 4.30 mmol) followed by (3-dimethylaminopropyl)-ethyl carbodiimide (1.0 mL). The mixture was stirred at ambient temperature overnight. Water was added and the mixture was extracted with ethyl acetate. The combined organic layer was dried with Na2SO4, concentrated, and the residue was dissolved again in a small amount of ethyl acetate. The solid, which precipitated by dropwise addition of hexane was filtered off and dried in vacuum to give the title product (0.070 g) as a white solid in 24% yield. 1H NMR (300 MHz, CDCl3) δ 9.15, 8.36, 7.74, 7.63, 7.56, 7.36, 7.05, 4.03-3.98, 3.93-3.89, 3.69-3.62, 3.55-3.53, 3.33-3.31, 2.51, 1.63-1.61, 0.91. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 14h; | 37.C Part C. 5 -Bromo-2-(4-methylpentanamido)benzamide To a stirred solution of 2-amino-5-bromobenzamide (7.8 g, 0.036 mol), 4-methyl pentanoic acid (8.41 g, 0.O72mmol), and TBTU (17.46 g, 0.054 mol) in DMF (100 mL) was added DIPEA (25 mL, 0.154 mol) and the reaction mixture was stirred at room temperature for 14 h. The reaction mixture was diluted with water (100 mL)and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with aq. sodium bicarbonate solution (100 mL) and brine (100 mL). The organic layer was dried over sodium sulfate, and the volatiles were evaporated to dryness. The residue was purified by silica gel column chromatography using a gradient of 40% ethyl acetate in hexanes and the required fractions were collectedand volatiles were evaporated to give 5-bromo-2-(4-methylpentanamido)benzamide (7.0 g, 0.022 mol, 55% yield) as a brown solid. LCMS (ESI) m/e 313.0 (bromo pattern) [(M+H), calcd for C13H18BrN2O2, 313.05]; LC/MS retention time (LC/MS Method = Column - YMC PACK TMS (3X5Omm), 3.0 rim; Mphase A: 2%MeCN98%H20 - 10mM NH4OAc; Mphase B : 98%ACN - 2%H20 -10 mM NH4OAC;Flow: 1.2 mL/min)): ti = 2.12 mm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With dipotassium peroxodisulfate; silver nitrate In water; acetonitrile at 50℃; for 12h; Inert atmosphere; chemoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With dmap; dicyclohexyl-carbodiimide In toluene at 20 - 100℃; for 8h; Inert atmosphere; | IV Pogostone can also be derived, for the purposes of preparing the disclosed derivatives by flaming dried flask of commercially available 98% purity TAL (0.252 g, 2.0 mmol). Dried toluene (5 mL) can be added to this flask and stirred. To this suspension, DCC (0.413 g, 2.0 mmol) and DMAP (0.048 g, 0.4 mmol) may be added and stirred under argon. Then 4-methylpentanoic acid (0.25 mL, 2.0 mmol) may be added to this mixture and was stirred for 3 h at room temperature and was further stirred for 5 h at 100° C. After cooling to room temperature, the reaction mixture can be subjected to filtration. The filtrate can be washed twice with toluene (10 mL×2). The combined toluene solution can then be concentrated under reduced pressure to give the crude product, which was subjected to silica column chromatography (silica gel, hexane:EtOAc 10:1 as an eluent) to afford pogostone (0.429 g, 96%) as a yellow solid. |
38% | With dmap; dicyclohexyl-carbodiimide In toluene at 20 - 70℃; for 21h; | 1 Example 1 Synthesis of (3- (4-Methylpentanoyl) -4-hydroxy-6-methyl-2H-pyran-2-one (1A)) 4-hydroxy-6-methyl-2-pyrone6.3 g (0.05 mol) is suspended in 100 ml of toluene at room temperature, N, N-dimethylaminopyridine1.22 g (0.01 mol), 11.6 g of isocaproic acid(0.1 mol) and 12.4 g (0.06 mol) of dicyclohexylcarbodiimide were sequentially added.After stirring this mixture at room temperature for 1 hour,The temperature was raised to 70 ° C., and heating and stirring were performed for 20 hours. After returning to 25 ° C,The resulting insoluble dicyclohexylurea is filtered off,The filtrate was washed once with 1 N hydrochloric acid and twice with 10% brine.The crude product was obtained by distilling off the solvent under reduced pressure from the obtained organic layer. Silica gel column chromatography of the crude productPurified using (hexane / ethyl acetate = 20/1),There were obtained 4.3 g (yield 38%) of 3- (4-methylpentanoyl) -4-hydroxy-6-methyl-2H-pyran-2-one. |
27.2% | With dmap; dicyclohexyl-carbodiimide In toluene at 20℃; for 1h; | 3.2. Chemical synthesis A mixture of 4-hydroxy-6-methyl-2-pyrone (14.1 g) and toluene (180 ml), DMAP (1.5 g),4-methylvaleric acid (8.95 g), and DCC (16.42 g) was added in a round-bottom flask andstirred at room temperature for 1 h. During the reaction, the mixture was stirred andheated to 80 °C and the detection was monitored by TLC. After completion of the reaction,the compound was cooled to room temperature and the liquid was collected by suctionfiltration using Buchner funnel. Toluene was used to wash the residue and the filtrate aswell as washing liquid was combined and washed by 1% hydrochloric acid and saturatedsodium chloride solution (2 × 100 ml). Two percent sodium hydroxide solution was usedfor extraction and the aqueous layer was adjusted to pH 2~3 which accompanied with theprecipitation of white crystal. The precipitate was extracted with EtOAc and the organiclayer dried over Na2SO4. Yellow oil (7.55 g), obtained under reduced pressure, was washedby large amount of hot sodium bicarbonate solution (500 ml) till the odor of isovaleric acidwore off. Upon recrystallization by n-hexane, PO was obtained as colorless crystal (5.33 g,yield 27.2%), the purity reached 98% by HPLC, and it showed the identical TLC behaviorwith the reference substance. The resulting compound was characterized by 1H NMR, 13CNMR, IR, and EI-MS. The spectral data are given below:3.2.1. 4-Hydroxy-6-methyl-3-(4-methylpentanoyl)-2H-pyran-2-one (PO)m.p. 32.5-33 °C, yield 27.2%; IR (KBr) νmax: 3462(C-OH), 3084 (C=CH), 2972 (C-H), 1757(C=O), 1658 (C=O), 1643 (C=C), 1457 (CH2), 1367 (CH3), 1198 (C-O-C) cm-1; 1H NMR(CDCl4, 300 MHz): δ 5.91(s), 3.04 (t, 2H, J = 1.6 Hz), 2.24 (s), 1.66-1.54 (m, 1H), 1.54-1.48(m, 2H), 0.91 (d, 6H, J = 6.5 Hz); 13C NMR (CDCl3, 100 MHz): δ 208.2, 181.3, 168.8, 160.9,101.5, 99.4, 39.7, 32.8, 27.8, 22.4, 20.6; EI-MS m/z: 222 [M-2] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With dmap; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In dichloromethane at 20℃; Inert atmosphere; | |
With dmap; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In dichloromethane at 20℃; for 12h; Inert atmosphere; Schlenk technique; | ||
With dmap; diisopropyl-carbodiimide In dichloromethane |
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; Inert atmosphere; | ||
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; | ||
With dmap; diisopropyl-carbodiimide In dichloromethane at 20℃; | Typical procedure for the preparation of NHPI esters General procedure: A 100 mL round-bottom flask was charged with 4-phenylbutanoic acid (1.64 g,10 mmol), N-hydroxyphthalimide (1.63 g, 10 mmol) and 4-dimethylaminopyridine(122 mg, 1.0 mmol). Dichloromethane (50 mL) was added and the mixture was stirred vigorously. N,N’-Diisopropylcarbodiimide (1.39 g, 11 mmol) was then added dropwise via syringe and the mixture was allowed to stir at room temperature until the carboxylic acid or the N-hydroxyphthalimide was fully consumed (monitored byTLC). The resulting mixture was filtered over Celite and rinsed with additional CH2Cl2 (10 mL × 3). The solvent was removed under reduced pressure, and the crude product was purified by column chromatography on silica gel with hexane/ethylacetate (20:1, v:v) as the eluent to give the pure product 1,3-dioxoisoindolin-2-yl 4-phenylbutanoate (1a) as a white solid. Yield: 2.72 g (88% yield). | |
With dmap; dicyclohexyl-carbodiimide In ethyl acetate at 20℃; Inert atmosphere; | (b) General procedure for synthesis of alkyl NHP esters [2] General procedure: To a 100 mL round bottom flask equipped with magnetic stir bar, N-Hydroxyphthalimide (1.63g,10.0 mmol), 4-dimethylaminopyridine (61mg, 0.5 mmol), N, N’-dicyclohexylcarbodiimide (2.06 g,12 mmol), carboxylic acid (12 mmol) was added and dissolved in ethyl acetate (40 mL). The mixtu rewas stirred for 30-180 minutes at room temperature. After completing the reaction, the solid wasseparated via vacuum filtration and the filtrate was washed by brine (10 ml) for three times. Theorganic layer was dried over Na2SO4 and the solvent was removed under reduced pressure. Thecrude product was purified by chromatography on a silica gel column (0 to 20% ethyl acetate/petroleum ether). | |
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; | 4. Preparation of N-hydroxyphthalimide ester[4] General procedure: In a 250 mL round bottom flask equipped with magnetic stir bar was added N-hydroxyphthalimide (1.63 g, 10 mmol, 1.0 equiv.), 4-dimethylaminopyridine (DMAP) (61mg, 0.5 mmol), dicyclohexylcarbodiimide (2.47 g, 12 mmol, 1.2 equiv.), CH2Cl2 (10 mL) and carboxylic acid (12 mmol, 1.2 equiv.). The mixture was stirred at room temperature for 0.5-3 h, during which time the reaction mixture became cloudy and a white solid precipitated from the solution. The white solid was removed via vacuum filtration and the filtrate was removed under reduced pressure. The crude product was purified by chromatography on a silica gel column (0 → 20% ethyl acetate/hexane). | |
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; | 4. Preparation of N-hydroxyphthalimide ester[4] General procedure: In a 250 mL round bottom flask equipped with magnetic stir bar was added N-hydroxyphthalimide (1.63 g, 10 mmol, 1.0 equiv.), 4-dimethylaminopyridine (DMAP) (61mg, 0.5 mmol), dicyclohexylcarbodiimide (2.47 g, 12 mmol, 1.2 equiv.), CH2Cl2 (10 mL) and carboxylic acid (12 mmol, 1.2 equiv.). The mixture was stirred at room temperature for 0.5-3 h, during which time the reaction mixture became cloudy and a white solid precipitated from the solution. The white solid was removed via vacuum filtration and the filtrate was removed under reduced pressure. The crude product was purified by chromatography on a silica gel column (0 → 20% ethyl acetate/hexane). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With ammonium cerium (IV) nitrate In neat (no solvent) at 160 - 165℃; for 2h; Microwave irradiation; Green chemistry; | General procedure General procedure: Amine (4.2 mmol), carboxylic acid (2 mmol), and catalyst (ceric ammonium nitrate) (2 mol%)were added to an empty flask equipped with a reflux condenser, at atmospheric pressure, placed ina microwave set to maintain a constant temperature in the range of 160-165 °C for a given time period(microwave power set up to 480 W but was smoothly and automatically controlled by the softwareto keep the target temperature constant). After 2 h, the reaction mixture was allowed to cool to roomtemperature, and subsequently, 25 mL of ethyl acetate were added. The organic phase was washedwith 3 x 15 mL of 2 M aqueous HCl, 3 x 15 mL saturated aqueous NaHCO3, and 3 x 15 mL of saturatedaqueous NaCl; dried over Na2SO4; filtered; and the solvent was removed under reduced pressure toobtain the pure product. The resulting products were characterized by 1H NMR, 13C NMR, andHRMS. |
With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl acetamide at 60℃; for 0.166667h; Flow reactor; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | Stage #1: 4-Methylpentanoic acid With thionyl chloride In dichloromethane at 20℃; for 2h; Stage #2: With ammonium hydroxide In dichloromethane at 20℃; for 0.5h; | 3 The synthesis of 4-methylpentanamide (0055-2). To a solution of compound 0055-1 (500 mg, 4.3 mmol) in DCM (20 mL) was added thionyl chloride (1.0 g, 8.6 mmol). The resulting reaction mixture was stirred for 2 h at rt and concentrated in vacuo , then added ammonium hydroxide (5 mL) and stirred at rt for another 0.5 h, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated, to give the desired product 0055-2 (240 mg, yield: 48%) as a white solid. |
Multi-step reaction with 2 steps 1: triethylamine / tetrahydrofuran / 1.08 h / 0 °C 2: ammonium hydroxide / tetrahydrofuran; water / 0 - 20 °C | ||
Multi-step reaction with 2 steps 1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2 h / 0 - 20 °C / Inert atmosphere 2: ammonium hydroxide / tetrahydrofuran / 12 h / 20 °C / Inert atmosphere |
Multi-step reaction with 2 steps 1: oxalyl dichloride / dichloromethane; N,N-dimethyl-formamide / 2 h / 0 - 20 °C / Inert atmosphere 2: ammonium hydroxide / tetrahydrofuran / 12 h / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With ammonium peroxydisulfate; [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine-N1,N1′]bis{3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-κN]phenyl-κC}iridium(III) hexafluorophosphate In dimethyl sulfoxide at 20℃; Irradiation; Inert atmosphere; | |
53% | With bis-[(trifluoroacetoxy)iodo]benzene In acetonitrile at 20℃; for 12h; Inert atmosphere; Irradiation; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In water; acetonitrile at 37℃; for 2.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | 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 tetrahydrofuran at 60℃; for 16h; | 49 Example 37- N-(6-(((1-(1-Methyl-1H-tetrazol-5-yl)-1H-benzo[d]imidazol-2- yl)oxy)methyl)pyridin-2-yl)acetamide 37 Following the procedure of Example 37, using the appropriate starting materials there were obtained the following Examples 38-51:; HATU (118 mg, 0.310 mmol) was added to a solution of picolinic acid (38 mg, 0.31 mmol), 6- (((1 -(1-methyl-i H-tetrazol-5-yl)- 1 H-benzo[d]im idazol-2-yl)oxy)methyl)pyridin-2-ami ne T (100 mg, 0.31 mmol) and N,N-diisopropylethylamine (270 mL, 1.6 mmol) in THF (1 mL). The reaction mixture was stirred for 16 h then was chromatographed on silica (12 g Puriflash cartridge) eluting with 40-100% EtOAc/ PE to give N-(6-(((1-(1-methyl-1H-tetrazol-5-yl)-1H- benzo[d]imidazol-2-yl)oxy)methyl)pyridin-2-yl)picolinamide 37 (97 mg, 73%) as a white solid. 1H NMR (500 MHz, ODd3) O 10.51 (5, 1H), 8.66 (ddd, J 4.7, 1.6, 0.9 Hz, 1H), 8.41 (d, J 8.0 Hz, 1H), 8.29 (dt, J= 7.8, 1.0 Hz, 1H), 7.93 (td, J= 7.7, 1.7 Hz, 1H), 7.80 (t, J= 7.9 Hz, 1H), 7.70-7.57 (m, 1H), 7.52 (ddd, J= 7.6, 4.8, 1.2 Hz, 1H), 7.35-7.28 (m, 2H), 7.27-7.24 (m, 1H),7.18 (5, 1H), 5.67 (5, 2H), 4.12 (5, 3H); LCMS (method A): 3.08 mm (428.1, MH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With dmap; dihydrogen peroxide; dicyclohexyl-carbodiimide In dichloromethane at -10℃; for 3h; | |
60% | Stage #1: 4-Methylpentanoic acid With dmap; dihydrogen peroxide In dichloromethane; water at 0℃; for 0.166667h; Inert atmosphere; Stage #2: With dicyclohexyl-carbodiimide In dichloromethane; water at 0℃; for 3h; Inert atmosphere; | |
With dmap; dihydrogen peroxide; dicyclohexyl-carbodiimide In dichloromethane; water at -15 - -10℃; for 15h; | Synthesis of alkyl diacyl peroxides General procedure: Diacyl peroxides were synthesized according to the reported literature.1,2 Diacyl peroxides have potentials to explode. Any diacyl peroxide involved in the reaction (as product or substrate) should be carried out with precautions. 4-Dimethylaminopyridine (DMAP, 0.224g, 0.6 mmol), acid (6 mmol), hydrogen peroxide (30 % v/v in H2O, 7.5 mmol) and CH2Cl2 were added to a 50 mL round bottom flask respectively. The reaction mixture was S5 cooled to -15 °C for about 10 min and dicyclohexylcarbodiimide (DCC, 6.72 mmol) was added. Then, the mixture was stirred at -10 to -15°C for 1.5 hours. The solution was filtered with petroleum ether and dried over MgSO4. After filtration the solvent was removed under reduced pressure at 10 to 15 °C. The residue (peroxide 2) was used without further purification. |
Stage #1: 4-Methylpentanoic acid With dmap; dihydrogen peroxide In dichloromethane for 0.166667h; Cooling; Inert atmosphere; Stage #2: With dicyclohexyl-carbodiimide In dichloromethane for 1.5h; Cooling; Inert atmosphere; | ||
With dmap; dihydrogen peroxide; dicyclohexyl-carbodiimide In dichloromethane at -15℃; for 1.5h; | (c) General procedure for synthesis of alkyl diacyl peroxides General procedure: To a solution of DMAP (122 mg, 1.0 mmol) in CH2Cl2 (8 mL)(cooled to -15 ), 30%hydrogen peroxide (1.13 mL, 10 mmol) and DCC (2.06 g, 10 mmol) was added. The mixture wasvigorously stirred and the acid 3 (9 mmol) was then added. After being stirred for 1.5 hours at-15 , n-pentane (50 mL) was added into the reaction solutionand the resulting mixture wasfiltered by flash chromatography (n-pentane/ethylacetate = 10/1, 100 mL). The solution wasconcentrated on a rotary evaporator under vacuum at 10-15 give the peroxide 4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; | 2 3.2. General experimental procedure General procedure: In a 20 or 40 mL reaction vial equipped with magnetic stir bar and Teflon-lined cap, a solution of the corresponding carboxylic acid (1.5 mmol, 3.0 eq) and DMAP (183.3 mg, 1.5 mmol, 3.0 eq) in anhydrous DMF (9.0 mL) was homogenized by stirring for 5-10min. EDCI·HCl (287.6mg, 1.5mmol, 3.0 eq) was added, and the resulting mixture was homogenized by stirring for 5-10 min. The corresponding 1,3-indandione (0.5mmol, 1.0 eq) was added, and the resulting mixture was resealed and stirred for 12-72h, monitoring by LCMS. When complete, workup method A, B, or C was used to isolate the final products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In tetrahydrofuran at -78 - 20℃; for 1.25h; Inert atmosphere; | a 4.18. (R)-4-(Tert-butoxy)-2-(cyclopentylmethyl)-4-oxobutanoic acid (42) General procedure: The title compd was prepared as per Scheme 2 (steps a-d). Steps a-b:To a solution of 3-cyclopentylpropanoic acid 30 (46.6 g, 0.33mol) in freshly distilled anhydrous THF (0.9M) was added triethylamine (52mL, 0.38mol), the mixture was cooled to -78 °C and pivaloyl chloride (41mL, 0.33 mol) was added dropwise, stirred for 15min at -78 °C then allowed to warm to rt and stirred for 1 h (white suspension forms). To asolution of (S)-4-benzyloxazolidin-2-one (59.2mg, 0.33 mol) in freshly distilled THF was added nBuLi (2.5M in THF, 134mL, 0.33mol) and the mixture stirred for 20 min at -78 °C whereupon it was added to the precooled (-78 °C) pivalic anhydride prepared in situ above. The result antmixture was stirred for 30min at -78 °C whereupon the reaction was allowed to reach rt by removing the cooling bath. Saturated aq NH4Cl (500mL) was then added and the aq phase extracted with EtOAc (2×200 mL). Combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The crude thus obtained was subjected to flash chromatographic purification using 20% EtOAc in petroleum etherto obtain 91 g (91%) (S)-4-benzyl-3-(3-cyclopentylpropanoyl)oxazolidin-2-one (34) as white solid. 1H NMR (CDCl3) δ: 7.43 - 7.12 (m, 5H), 4.67(ddt, J=10.2, 7.0, 3.4 Hz, 1H), 4.27 - 4.10 (m, 2H), 3.30 (dd, J=13.4,3.3Hz, 1H), 3.08 - 2.83 (m, 2H), 2.76 (dd, J=13.3, 9.6 Hz, 1H), 1.93 -1.42 (m, 10H), 1.20 - 1.04 (m, 2H). Step c: To a stirred solution of 34(95 g, 0.315 mol) in THF (0.08M) at-78 °C was added NaHMDS (1M inTHF, 410mL, 0.41 mol) dropwise over 1 h, whereupon tert-butyl bromoacetate (70 mL, 0.41mol) was added dropwise over 30 min at -78 °C. The cooling bath was then removed to allow the reaction to warm to rtand stirred overnight. The mixture was then cooled using an ice-bath and saturated aq NH4Cl added slowly (300mL), followed by water (100mL); then the aq phase was extracted with EtOAc (200 mL) and the combined organic extracts dried (Na2SO4), filtered and evaporated to dryness. The thus obtained crude was purified by flash chromatography using 5-30% EtOAc in petroleum ether gradient to obtain 73 g (56%) of tert-butyl (R)-4-((S)-4-benzyl-2-oxooxazolidin-3-yl)-3-(cyclopentylmethyl)-4-oxobutanoate (38) as white solid. Step d: To a stirred solution of 38 (73 g, 0.18mol) in 750mL THF/water (4:1, v/v) at 0 °C was added H2O2 (35% in water, 68mL, 0.7mol) dropwise over 15min. Stirring was continued for 10 min, then 1M aq LiOH (300mL, 0.35mol) was added dropwise over 15 min whereupon the mixture was allowed to warm to rt and stirred for 16 h till reaction deemed completed by LCMS. The reaction mixture was cooled using an ice-bath and a solution of sodium bisulfite (225 g, 1.8mol) in water (1 L) was added dropwise over 1 h. (Caution: slight exotherm during this addition) The bulk of THF was removed in vacuo and the thus obtained aq layer (pH∼12) was washed with Et2O (3×500 mL), cooled (ice-bath) and acidified to pH 1-2 with 6M HCl and extracted with EtOAc (5×500mL). The combined extracts dried (MgSO4), filtered and concentrated in vacuo to dryness to obtain the titlecompound, 42 (30 g, 65%) as pale yellow oil. 1H NMR (CDCl3) δ: 2.80 (td,J=8.5, 7.6, 4.4Hz, 1H), 2.60 (dd, J=16.4, 9.3 Hz, 1H), 2.39 (dd,J=16.4, 5.1 Hz, 1H), 1.96 - 1.65 (m, 5H), 1.49 (m, 4H), 1.43 (s, 9H),1.07 (m, 2H). | |
With lithium chloride at 0℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Stage #1: 4-Methylpentanoic acid With lithium diisopropyl amide In tetrahydrofuran; hexane at -15 - 0℃; Stage #2: With 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone In tetrahydrofuran; hexane at 0℃; for 0.5h; Stage #3: 1-iodo-propane In tetrahydrofuran; hexane at 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide; acetonitrile for 18h; | 19 Synthesis Example 19: MN1213 (Coupling by Method F) 1-Isobutyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (228 mg, 1.00 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide-HCl (EDC-HCl) (191 mg, 1.00 mmol), 4-dimethylaminopyridine (DMAP) (12 mg, 0.10 mmol), and hydroxybenzotriazole (HOBT) (51 mg, 0.33 mmol) were all dissolved in acetonitrile (1.25 mL), dimethylformamide (DMF) (5 mL), and diisopropylethylamine (DIEA) (200 μL, 1.20 mmol). 4-Methylvaleric acid (126 μL, 1.00 mmol) was added by syringe. The solution was stirred for 18 hrs. The result was diluted with EtOAc (100 mL), washed with sat. NaCl (2×50 mL), 1M citric acid (3×25 mL), sat. NaHCO3 (3×25 mL), and sat. NaCl (2×50 mL). The organic layer was dried (anhyd. Na2SO4), filtered, and evaporated under vacuum. The crude product was purified by silica gel chromatography: 5 fractions (200 mL each) consisting of 0%, 0.5%, 0.75%, 1%, and 2% MeOH in CH2Cl2. Fractions containing product were combined, the solvent was removed under vacuum yielding a solid (245 mg, 75.0% yield; TLC Rf=0.29 (2% MeOH in CH2Cl2); HPLC Rt=4.869 min). 1H NMR (CDCl3, 0.003% v/v TMS, 400 MHz): δH 0.87-1.15 (12H, m), 1.5-1.83 (4H, m), 2.35-2.55 (2H, m), 2.65-2.90 (2H, m), 3.45-3.55 (1H, m), 4.05 (1H, dd), 5.85-5.90 (1H, m), 7.10 (1H, dd), 7.15 (1H, dd), 7.33 (1H, d), 7.45 (1H, d), 7.83 (1H, br s). This method was used in the synthesis of the following compounds: MN0580, MN1169, MN1172, MN1186, MN1189, MN1190, MN1194, MN1195, MN1220, MN1221, MN1222, MN1223, MN1224, MN1225, MN1226, MN1227, MN1228, MN1229, MN1230, MN1231, MN1232, MN1233, MN1234, MN1235, MN1236, MN1237, MN1238, MN1239, MN1240, MN1241, MN1242, MN1243, MN1244, MN1245, MN1246, MN1247, MN1248, MN1249, MN50, MN1251, MN1252, MN1253, MN1254, MN1255, MN1256, MN1257, MN1258, MN1259, MN1260, MN1261, MN1262, MN1263. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | 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℃; | N-(6-(((tert-Butyldimethylsilyl)oxy)methyl)pyridin-2-yI)-4-methylpentanamide N A solution of 6-[(teit-butyl(dimethyl)silyl)oxymethyl]pyridin-2-amine (400 mg, 1.68 mmol), 4-methylvaleric acid (0.253 mL, 2.01 mmol) and N,N-diisopropylethylamine (1.15 mL, 6.71mmol) in DMF (5 mL) was treated with HATU (957 mg, 2.52 mmol). The reaction mixture was stirred at RT overnight. It was then diluted with water and extracted into EtOAc (2 x 30 mL).The organics were washed with water (50 mL), brine (50 mL), dried (MgSO4) andconcentrated in vacuo. The residue was chromatographed on silica (40g Claricep cartridge)eluting with 20-60% EtOAc I PE to give N-(6-(((teit-butyldi methylsilyl)oxy)methyl)pyridin-2-yl)-4-methylpentanamide N (500 mg, 89%) as a pale yellow oil.1H NMR (500 MHz, ODd3) O 8.06 (d, J= 8.2 Hz, 1H), 7.83 (5, 1H), 7.71 (t, J= 7.9 Hz, 1H),7.22 (d, J = 7.5 Hz, 1 H), 4.69 (5, 2H), 2.43 -2.30 (m, 2H), 1.62 (d, J = 6.2 Hz, 2H), 1.28 -1.14 (m, 1H), 0.95 (5, 9H), 0.92 (d, J= 6.2 Hz, 6H), 0.11 (5, 6H); LCMS (method A) 4.32 mm(338.6, MH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; Inert atmosphere; | General procedure for the synthesis of monoacylated diamines. General procedure: In a typical procedure, alkanediamine (0.014 mol) was suspended in 20 ml DMF. Diisopropylethylamine (DIEA, 0.48 ml, 2.78 mmol) was added, followed by the appropriate carboxylic acid (1.39 mmol), 1-Hydroxybenzotriazole (HOBt, 380 mg, 2.78 mmol) and PyBOP (720 mg, 1.39 mmol). The reaction was allowed to proceed at room temperature 24-30 hours. DMF was then removed by evaporation under reduced pressure and the resultant residue was suspended in ethyl acetate and treated with an aqueous saturated solution of NaHCO3. Phases were separated and the aqueous one extracted with ethyl acetate. The organic layers were dried over magnesium sulfate and rotary evaporated to produce a crude yellow oil, which was purified by column chromatography (silica, CH2Cl2/MeOH 4:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With ammonium cerium (IV) nitrate In neat (no solvent) at 160 - 165℃; for 2h; Microwave irradiation; Green chemistry; | General procedure General procedure: Amine (4.2 mmol), carboxylic acid (2 mmol), and catalyst (ceric ammonium nitrate) (2 mol%)were added to an empty flask equipped with a reflux condenser, at atmospheric pressure, placed ina microwave set to maintain a constant temperature in the range of 160-165 °C for a given time period(microwave power set up to 480 W but was smoothly and automatically controlled by the softwareto keep the target temperature constant). After 2 h, the reaction mixture was allowed to cool to roomtemperature, and subsequently, 25 mL of ethyl acetate were added. The organic phase was washedwith 3 x 15 mL of 2 M aqueous HCl, 3 x 15 mL saturated aqueous NaHCO3, and 3 x 15 mL of saturatedaqueous NaCl; dried over Na2SO4; filtered; and the solvent was removed under reduced pressure toobtain the pure product. The resulting products were characterized by 1H NMR, 13C NMR, andHRMS. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With dmap; triethylamine; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 16h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69.9% | Stage #1: tert-butyl 6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ6,2,5-thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate With trifluoroacetic acid In dichloromethane for 1.5h; Stage #2: 4-Methylpentanoic acid With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 0.333333h; | 45.45A Example 45A: 5-[6-(benzyloxy)-8-fluoro-2-(4-methylpentanoyl)-1,2,3,4-tetrahydroisoquinolin- 7-yl]-1l6,2,5-thiadiazolidine-1,1,3-trione To a solution of tert-butyl 6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1l6,2,5- thiadiazolidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (50 mg, 0.102 mmol) in dichloromethane (2.0 mL) was added trifluoroacetic acid (118 mL, 1.53 mmol). After 90 minutes, the reaction mixture was directly concentrated, the substrate was suspended in dichloromethane (1.0 mL) and N,N-diisopropylethylamine (71.1 mL, 0.407 mmol) was added, resulting in a homogeneous solution. Subsequently, 2-(1H-benzotriazole-1-yl)-1,1,3,3- tetramethylaminium tetrafluoroborate (TBTU) (35.9 mg, 0.112 mmol) was added followed by 4- methylvaleric acid (13.0 mg, 0.112 mmol), and the reaction was stirred at room temperature. After 20 minutes, additional N,N-diisopropylethylamine (71.1 mL, 0.407 mmol) was dispensed. After 5 minutes, the reaction mixture was diluted with dichloromethane (2 mL), quenched with 1 M HCl (2 mL), and extracted into dichloromethane (2 × 2 mL). The combined organic extracts were washed with brine (1 × 2 mL), dried over sodium sulfate, filtered, and concentrated to give a yellow oil that was immediately purified by flash chromatography on silica gel [4 g SiO2, heptanes 95% acetone/heptanes, 18 mL/minute, monitor at 205 nm] to afford the title compound (35.0 mg, 0.071 mmol, 69.9% yield). MS (APCI+) m/z 490 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | 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 dichloromethane at 20℃; for 12h; | 2 Ethyl 4-(2-isopentyl-1H-benzo[d]imidazol-1-yl)thiophene-2-carboxylate (6m). To a solution of compound 5 (78.69 mg, 0.3 mmol) in anhydrous DCM (5 mL) were added 4-methylvaleric acid (45.31 μL, 0.36 mmol), HATU (114.07 mg, 0.3 mmol) and DIPEA (156.77 μL, 0.9 mmol). The reaction mixture was stirred at room temperature for 12 h. The mixture was diluted with water and extracted with DCM (3*10 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (20% EtOAc/hexanes) to obtain the N-acyl intermediate as a pale yellow solid (89 mg, 82%). MS (ESI-TOF) for C19H24N2O3S [M+H]+ calculated 361.1580; found, 361.1590. The N-acyl intermediate (72.09 mg, 0.2 mmol) was dissolved in acetic acid (2 mL) and stirred at 80° C. for 12 h. The solvent was removed under reduced pressure, and the crude material was purified by flash chromatography (20% EtOAc/hexanes) to obtain the desired product 6m as pale orange solid (61 mg, 89%). MS (ESI-TOF) for C19H22N2O2S [M+H]+ calculated 343.1475; found, 343.1468. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | With ammonium peroxydisulfate; silver nitrate In water; acetonitrile at 75℃; for 1h; | General Procedure A (silver-mediated radical decarboxylation general method) General procedure: carboxylic acid (2 equiv.) was added to a solution of menadione (1 equiv.) in CH3CN/H2O (3:1) and the mixture was heated to 75 °C. To this solution,AgNO3 (0.1 equiv.) was added followed by the slow addition of (NH4)2S2O8 (2.5 equiv.) in H2O (5 mL) over 10 min. The resulting mixture was stirred for a further 1 h. The mixture was cooled to room temperature (RT), extracted withCH2Cl2 and the organic extract washed with saturated NaHCO3 and H2O. The organic layer was dried over MgSO4, filtered and the solvent removed under reduced pressure to give the crude product, which was purified by flashchromatography (silica gel). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With ammonium peroxydisulfate; silver nitrate In water; acetonitrile at 75℃; for 1h; | General Procedure A (silver-mediated radical decarboxylation general method) General procedure: carboxylic acid (2 equiv.) was added to a solution of menadione (1 equiv.) in CH3CN/H2O (3:1) and the mixture was heated to 75 °C. To this solution,AgNO3 (0.1 equiv.) was added followed by the slow addition of (NH4)2S2O8 (2.5 equiv.) in H2O (5 mL) over 10 min. The resulting mixture was stirred for a further 1 h. The mixture was cooled to room temperature (RT), extracted withCH2Cl2 and the organic extract washed with saturated NaHCO3 and H2O. The organic layer was dried over MgSO4, filtered and the solvent removed under reduced pressure to give the crude product, which was purified by flashchromatography (silica gel). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | Stage #1: 4-Methylpentanoic acid With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; for 2h; Stage #2: Ethyl isocyanoacetate With lithium hexamethyldisilazane In tetrahydrofuran at 0 - 20℃; | Ethyl 5-(3-methylbutyl)-1 ,3-oxazole-4-carboxylate 4-methylpentanoicacid (1.00 g, 8.61 mmol) dissolved in 10 ml of THF was treated with 1 ,1 ,- carbonyl-diimidazole (1.68 g, 10.3 mmol) and stirred at room temperature. After 2 h ethyl isocyanoacetate (1.0 ml, 9.5 mmol), dissolved in 10 ml of THF, and a solution of lithium bis(trimethylsilyl)amide in THF (8.6 ml, 1 .0 M, 8.6 mmol) were added at 0°C. The mixture was allowed to warm to room temperature and stirred over night. The solvent was removed on a rotary evaporator. The residue was taken up with ethyl acetate and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate, filtered, Isolute was added and the solvent was evaporated on a rotary evaporator. The crude product was purified by column chromatography (Machine: Biotage Isolera One; column: Biotage SNAP Ultra 50 g; gradient: Cy/EE-gradient,6% EE - 50% EE; flow: 100 ml/min). Product containing samples were united and the solvents were removed on a rotary evaporator. 970 mg (100 % purity, 53 % yleld) of the title compound were obtained. LC-MS (Method 8): Rt = 0.99 min; MS (ESIpos): m/z = 212 [M+H]+ |
Tags: 646-07-1 synthesis path| 646-07-1 SDS| 646-07-1 COA| 646-07-1 purity| 646-07-1 application| 646-07-1 NMR| 646-07-1 COA| 646-07-1 structure
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H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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