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CAS No. : | 503-74-2 | MDL No. : | MFCD00002726 |
Formula : | C5H10O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | GWYFCOCPABKNJV-UHFFFAOYSA-N |
M.W : | 102.13 | Pubchem ID : | 10430 |
Synonyms : |
3-Methylbutanoic acid;Delphinic acid;Isobutyl formic acid;β-methylbutyric acid;Isopentanoic acid;3-Methylbutyric acid
|
Chemical Name : | 3-Methylbutanoic acid |
Num. heavy atoms : | 7 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.8 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 27.92 |
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) : | -6.1 cm/s |
Log Po/w (iLOGP) : | 1.35 |
Log Po/w (XLOGP3) : | 1.16 |
Log Po/w (WLOGP) : | 1.12 |
Log Po/w (MLOGP) : | 0.89 |
Log Po/w (SILICOS-IT) : | 0.35 |
Consensus Log Po/w : | 0.98 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -1.07 |
Solubility : | 8.65 mg/ml ; 0.0847 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.54 |
Solubility : | 2.96 mg/ml ; 0.029 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.41 |
Solubility : | 40.1 mg/ml ; 0.393 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.0 |
Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P210-P264-P273-P280-P301+P330+P331-P303+P361+P353-P304+P340+P310-P305+P351+P338+P310-P312-P363-P370+P378-P403+P235-P405-P501 | UN#: | 3265 |
Hazard Statements: | H227-H303-H314-H402 | Packing Group: | Ⅱ |
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 |
---|---|---|
46% | Stage #1: With N-ethyl-N,N-diisopropylamine In dichloromethane for 3 h; Stage #2: With piperidine In N,N-dimethyl-formamide for 0.1 h; |
General procedure: 4.2 General procedure A: resin loading (0026) Solid phase peptide synthesis was conducted manually in a sinter-fitted polypropylene syringe. 2-Chlorotritylchloride (CTC) resin was preswelled in DCM (mL) for 15min and drained. The first amino acid in 0.4M DIPEA/DCM was added and the mixture was agitated for 3h. After draining the solvent, any free 2-CTC resin linkers were capped by treatment of the resin with a solution of 17:2:1 DCM/MeOH/DIPEA (3×3mL×5min), and subsequently with a solution of 8:1:1 DMF/DIPEA/acetic anhydride (2×3mL×10min). The resin was finally washed with DCM (2×3mL×1min), DMF (2×3mL×1min), DCM (2×3mL×1min) and DMF (2×3mL×1min). 4.3 General procedure B: Fmoc deprotection (0027) The resin was agitated with a solution of 10percent piperidine inDMF (2×3mL×3min) and subsequently washed with DMF(3×3mL×1min), DCM (3×3mL×1min), DMF (5×3mL×1min). The deprotected solutions were combined and diluted appropriately (100-fold for 0.05mmol resin loading). The resin loading was estimated by measuring the absorbance of the piperidine-fulvene adduct with 10percent piperidine in DMF as a reference (λ=301nm; ε=7800M−1cm−1). 4.4 General procedure C: peptide coupling with HBTU (0028) A solution was prepared of the appropriate Fmoc-protected amino acid (3 equiv. relative to resin loading) and HBTU (2.9 equiv. relative to resin loading) in minimum amount of DMF. DIPEA (6 equiv. relative to resin loading) was added and the resin was agitated for 1.5h. The resin was then drained and washed with DMF (3×3mL×1min), DCM (3×3mL×1min) and DMF (5×3mL×1min). 4.5 General procedure D: peptide coupling with HATU (0029) A solution was prepared of the appropriate Fmoc-protected amino acid (3 equiv. relative to resin loading) and HATU (2.9 equiv. relation to resin loading) in minimal DMF. DIPEA (6 equiv. relation to resin loading) was added to the solution and the mixture was immediately added to the resin and agitated. Reaction times were altered based on the residue being coupled: Phe(NMe) and Ala (2×2h); Thr and Sta (1×2h); Asn, Leu, D-Val and L-Val (2×2h); DMVal (3×3h). Once the reaction was complete, the resin was drained and washed with DMF (3×3mL×1min), DCM (3×3mL×1min) and DMF (3×3mL×1min). 4.6 General procedure E: peptide coupling with DIC (0030) A solution was prepared of the appropriate Fmoc-protected amino acid (1.5 equiv. relative to resin loading), HOBt (1.5 equiv. relative to resin loading) and DIC (1.5 equiv. relative to resin loading) in minimal DMF. This solution was stirred for 20min, then added to the resin and agitated overnight. The resin was drained and washed with DMF (3×3mL×1min), DCM (3×3mL×1min) and DMF (5×3mL×1min). Double coupling of the next amino acid after the coupling of the fluorinated amino acid was applied. 4.7 General procedure F: resin cleavage (0031) After the last Fmoc deprotection, the resin was washed with DMF (3×3mL×1min) and DCM (3×3mL×1min) then dried in vacuo. The resin was agitated with a solution of 95:2.5:2.5 TFA/TIS/H2O (3mL) for 2h. The resin was drained and washed with the same TFA mixture above (2×3mL×1min). The combined cleavage solutions were concentrated under a stream of nitrogen. Diethyl ether was added and the supernatant was decanted (3×). The residue was then dried in vacuo to provide the crude linear peptide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With oxalyl dichloride; In dichloromethane; at 0 - 50℃;Inert atmosphere; | General procedure for acyl chloride precursorsRgammaClDichloromethane and the respective carboxylic acid are put under argon in a Schlenk flask. Oxalyl chloride is slowly added at 00C under stirring and cooling with ice. Afterwards, the reaction mixture is stirred at 500C external oil bath temperature for 12h. Then, excessive oxalyl chloride and solvent are removed in vacuum. The crude material is employed without further purification in the subsequent synthesis. | |
With thionyl chloride; In tetrachloromethane; at 80℃; for 0.666667h; | 21.8 ml (35.7 g; 0.3 mol) of thionyl chloride were added dropwise to a stirred solution of 11 ml (10.2 g; 0.1 mol) <strong>[503-74-2]isovaleric acid</strong> in 20 ml tetrachloromethane.The reaction mixture was heated for 40 min at 80 C, then cooled down and diluted with 15 ml of tetrachloromethane. 23.9 g (0.12 mol) of N-bromosuccinimide and 15 drops of 40% aqueous solution of HBr were applied. After 10 min of heating at 70 C, and 90 min at 85 C, the solvent and the excess of SOCl2 were removed under reduced pressure. The residue was suction filtered,the solid was washed several times with tetrachloromethane and the solvent was removed from the combined filtrate as before.The obtained 2-bromo-3-methylbutanoyl chloride was used in the next step of the reaction without further purification. | |
With oxalyl dichloride; In chloroform; at 70℃; | General procedure: To a solution of succinic acid (100.0 mg)in anhydrous chloroform at room temperaturewas added 2M oxalyl chloridesolution in anhydrous chloroform(11 ml). The reaction mixture was stirred for 48 h at 70?C and then concentrated invaccum. |
With thionyl chloride; In dichloromethane; for 1h;Reflux; | To a solution of 3-methylbutanoic acid (0.050 g, 0.494 mmol) and thionyl chloride (0.180 ml, 2.469 mmol) in methylene chloride (1.500 ml) was heated to reflux for 1 h then concentrated. A solution of the residue in ethyl acetate (1.5 ml) was added to a solution of 4-chloro-3-hydrazinyl-5-(4- phenylpiperidin-l-yl)pyridazine (0.15 g, 0.494 mmol) in ethyl acetate (1.5 ml), THF (3 ml), and saturated sodium bicarbonate (3 ml) was stirred for 16 h. The reaction was diluted with ethyl acetate and water. The ethyl acetate layer was washed with water and concentrated to give N'-(4-chloro-5-(4-phenylpiperidin-l-yl)pyridazin-3- yl)-3-methylbutanehydrazide as a brown oil. LCMS: Rt = 0.82 min, (M+H)+ = 388.15. The material was used without purification | |
With oxalyl dichloride; In dichloromethane; N,N-dimethyl-formamide; at 0 - 20℃; for 4h; | To a stirred solution of <strong>[503-74-2]isovaleric acid</strong> (0.90 g, 8.85 mmol) in DCM (20 mL) was added 0.1 mL of N,N-Dimethylformamide. The solution was cooled to 0C, followed by the addion of oxalyl chloride (1.45 g, 1 1.5 mmol). The reaction mixture was warmed to room temperature and stirred for 4.0 h. Then the solution was evaporated to remove the solvent at below 50C. The residue and azetidine-3-carbonitrile hydrochloride (0.94 g, 7.96 mmol) were dissolved in 20 mL DCM. The solution was cooled to -20C, followed by the addion of DIPEA (3.83 mL, 26.55 mmol). The reaction mixture was warmed to room temperature and stirred overnight. The resultant was quenched by addition of saturated aqueous NaHC03. The mixture was extracted with DCM (3 X 100 mL), and the combined extracts were washed with brine, dried by Na2S04 and filtered, concentrated under vacuum at below 40C. The crude product was purified by flash chromatography (20% Petrolium ether/ethyl acetate) to give 833 mg of Compound 9a (Yield: 63%) as a light yellow oil. [M+H] found 167. | |
With thionyl chloride; at 80℃; for 6h; | A 100-mL round-bottom flask was charged with 3-methylbutanoic acid (500 mg, 4.90 mmol) and thionyl chloride (20 mL). The resulting solution was stirred for 6 h at 80 C in an oil bath and then concentrated under vacuum to afford 3-methylbutanoyl chloride (510 mg, 86%) as yellow oil, which was directly used into next step without any purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With 1-methyl-3-(4-sulfonylbutyl)-1H-imidazol-3-ium trifluoromethanesulfonate; at 96 - 100℃; for 6h; | General procedure: A mixture of amine (0.02 mol), acetic acid (0.025 mol, 1.5 mL) and [BMIM(SO3H)][OTf] (50 mol %) was charged in an oven-dried round bottom flask and the reaction mixture was refluxed on an oil bath. Progress of the reaction was monitored by TLC and by GC-MS. After completion of reaction, the reaction mass was cooled at room temperature and poured into ice water. The crystals of N-acylated product so obtained were filtered, washed with of cold ethanol-water mixture (10-15 mL) and dried. The purity of all the products was checked by TLC and GC, and all the pure products were characterized by IR, GC-MS/LC-MS, 1HNMR and 13CNMR. The filtrate (water + ethanol + IL) was set aside for recovery and reuse of the IL. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | 3-Methylbutanoic acid (6.00 g, 58.7 mmol, 1.00 equiv) and N-methylmorpholine (6.42 g,63.4 mmol, 1.08 equiv) were dissolved in 1,2-dimethoxyethane (300 mL) at 0 C. Then,isobutylchloroformiate (8.66 g, 63.4 mmol, 1.08 equiv) was added dropwise. The reaction mixture was stirred for 15 min at 0 C. Afterwards, an aqueous ammonia solution (25%; 26.0 mL, 386 mmol, 6.57 equiv) was added dropwise. Now, the reaction mixture was stirred at 0 C rt. After 14 h, the reaction was terminated by adding HCl (1.0 M). The aqueouslayer was extracted with EtOAc (4×). The combined organic layers were washed withHCl (0.1 M) and subsequently dried over MgSO4, filtered and concentrated under reduced pressure. Amide 13 (4.14 g, 40.8 mmol, 70%) was isolated as a colourless solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | A solution of lithium diisopropylamide (?LDA?) (100 mL, 0.2 M) at 0 C. was treated (dropwise) with an <strong>[503-74-2]isovaleric acid</strong> solution (10.80 mL, 0.098 M) in 35 nL of anhydrous THF. The reaction solution was stirred for 30 more minutes upon completion of the addition of the <strong>[503-74-2]isovaleric acid</strong>. The reaction solution, which was a dark-red color, was treated with a solution of 2-iodopropane (29.4 mL, 0.294 M) and hexamethylphosphoramide (?HMPA?) (25.6 mL, 0.15 M) at 0 C. under static nitrogen (pale-yellow color). The reaction solution was stirred for 3 more hours until it warmed up to room temperature. The reaction mixture was quenched with a saturated solution of NH4Cl and transferred into a separatory funnel using brine (200 mL) and diethyl ether (300 mL). The reaction mixture was equilibrated and the aqueous layer was removed. The aqueous layer was extracted an additional time with diethyl ether (300 mL). The combined organic extracts were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to afford a yellow-orange liquid, which solidified upon standing at room temperature. This crude material was triturated with 50 mL of hexane to afford 2.9 grams of an off-white solid (21% yield). This material was determined to be 100% pure by GC/MS. 1H NMR gave signals consistent with the product's structure and indicated greater than 98% purity. The off-white solid (3.65 g, 25.3 mmol) described above was dissolved in dichloromethane (75 mL) and DMF (0.3 mL) and was treated with oxalyl chloride (2.5 mL, 28 mmol) at 0 C. under static in-house nitrogen to afford an intermediate acid chloride of the off-white solid. The reaction solution was stirred at room temperature overnight under nitrogen. The excess oxalyl chloride was removed under reduced pressure. Ammonia (gas) was bubbled through a solution of the acid chloride in anhydrous dichloromethane (100 mL) at 5 C. for 15 minutes. The reaction mixture was stirred overnight at room temperature under static house-nitrogen. The white precipitate (ammonium chloride) was filtered and washed with dichloromethane (100 mL). The filtrate and wash solution were combined and washed with water, 1.0 M HCl, a saturated solution of sodium bicarbonate and, a brine solution and were dried over magnesium sulfate, filtered, and evaporated under reduced pressure. The resulting white solid was triturated with a chilled solution of diethyl ether and hexane (50/50) to afford 970 mg of Compound KK as white flakes (34% yield). This material was determined to be 100% pure by GC/MS. 1H NMR gave signals consistent with the product's (Compound KK's) structure and indicated greater than 98% purity. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Add 15 mL of tetrahydrofuran to a 100 mL Leica bottle.10 mL of a solution of 2.0 mol/L lithium diisopropylamide in tetrahydrofuran, and then 1.1 mL (10.0 mmol) of <strong>[503-74-2]isovaleric acid</strong> represented by Formula A-1 was added dropwise at -15C, and the reaction was conducted for 1 hour, followed by addition of 1.04 mL ( 12.0 mmol) allyl bromide, naturally return to room temperature, continue the reaction for 1 hour, with a mass fraction of 10% hydrochloric acid to adjust the pH value of 1-2, 20 mL of petroleum ether was added for extraction, and then were respectively used 15mL mass fraction of 10% hydrochloric acid, The mixture was washed with water and brine, and the organic layers were combined and dried over anhydrous sodium sulfate. The organic solvent was removed under reduced pressure to obtain 1.2 g of 2-isopropyl-4-enovaleric acid represented by the formula D in a yield of 86%. as follows: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a suspension of S-chloro-delta-carboxypyridazine ethyl ester 6 (1.86 g, 10 mmol) in distilled water (30 mL) /so-butyl carboxylic acid (2.1 mL, 2.25 mmol), cone. H2SO4 (0.8 mL, 15 mmol) and AgNtheta3 (169 mg, 1 mmol) were added at room temperature. The mixture was heated at 65-75 0C and a solution of NH4S2O8 (3.4 g, 15 mmol) in distilled water (10 mL) was added drop-wise in 10-15 minutes. The reaction was stirred for additional 30 minutes at 70-75 0C, then poured in ice, neutralized with a 30% aqueous solution of NH4OH and immediately extracted twice with dichloromethane. The collected organic layers were dried over magnesium sulfate, the solvent removed under reduced pressure and the crude material purified by flash chromatography to give 1.13 g of regioisomer 3 and 564 mg of regioisomer 4.Ethyl-6-chloro-5-/so-butylpyridazine-3-carboxylate 3: Rf - 0.49 (Hexane/AcOEt = 70:30). <n="26"/>Ethyl-6-chloro-4-/so-butylpyridazine-3-carboxylate 4: Rf = 0.55 (Hexane/AcOEt = 70:30). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | /7-cyanopyridine (8.00 g, 76.8 mmol) was added to a 1:1 mixture of chlorobenzene/water (1.5 L) in a 2 L round-bottom flask. Isovaleric acid (21.74 g, 212.8 mmol), (NH4^S2O8 (34.40 g, 150.7 mmol), trifluoroacetic acid (8.78 g, 77.0 mmol) and AgNO3 (1.040 g, 6.1 mmol) were added and the heterogeneous mixture was vigorously stirred and refluxed for 2 h. The reaction was cooled down to 0 0C and 8 M NaOH was added slowly until pH 9-10. The mixture was filtered through Celite and extracted with EtOAc (x3). The combined organic extracts were dried with MgStheta4 and the solvent removed in vacuo. The dark-brown oil was purified via flash chromatography (1:4 EtOAc/Hexane) to give a brown oil (6.538 g, 54 %); 1H NMR (400 MHz, CDCl3): delta 0.95 (d, J= 6.8 Hz, 6H), 2.13 (m, IH), 2.73 (d, J= 6.8 Hz, 2H), 2.37 (m, 2H), 8.73 (m, IH); 13C NMR (100 MHz, CDCl3): D 22.3, 29.1, 47.3, 116.8, <n="33"/>120.4, 122.4, 125.0, 150.2, 163.3; HRMS-EI (tn/z): [MH-H+] calcd for [C I0H13N2f, 161.1079; found, 161.1073. | |
32.5% | With ammonium persulfate; sulfuric acid; silver nitrate; In water; at 100℃; for 3h; | Step 1: Synthesis of2-isobutylpyridine-4-carbonitrile (2) [0185] To a suspension of 4-cyano pyridine (1) (30 g, 0.288 mol, 1 equiv.) in water (210 mL), concentrated sulfuric acid (15.3 mL, 0.288 mol, 1 equiv.) was added dropwise maintaining the temperature at 20-25 C. After formation of a clear solution, AgN03 (4.9 g, 0.028 mmol, 0.0001 equiv.) followed by <strong>[503-74-2]isovaleric acid</strong> (160 mL, 1.47 mol, 5 equiv.) were added in to the reaction mixture. A white hazy solution formed. Ammonium peroxydisulfate (66 g, 0.288 mol, 1 equiv.) dissolved in water (90 mL) was then added. A black clear solution formed. The reaction mixture was then heated to reflux at 100 C for 3 h. The reaction was monitored by TLC. After completion, the reaction mixture was basified (pH = 7-8) using a saturated solution of sodium bicarbonate, and extracted with EtOAc (3x750 mL). The extracts were combined and were washed with brine (3x300 mL) and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure and the crude product was purified by column chromatography (silica gel: 100-200) using 0-6 % EtOAc in hexane as eluant to afford 2- isobutylpyridine-4-carbonitrile (2) (15 g (32.5 % yield)) as a pale yellow liquid. 1H NMR (400 MHz, Chloroform-;/): delta (ppm): 8.78 - 8.63 (m, 1H), 7.41 - 7.27 (m, 2H), 2.72 (d, J= 7.2 Hz, 2H), 1.35 - 1.23 (m, 1H), 0.94 (d, J= 6.6 Hz, 6H). |
32.5% | With ammonium peroxydisulfate; sulfuric acid; silver nitrate; In water; at 20 - 100℃; for 3h; | To a suspension of 4-cyano pyridine (1) (30 g, 0.288 mol, 1 equiv.) in water (210 mL), concentrated sulfuric acid (15.3 mL, 0.288 mol, 1 equiv.) was added dropwise maintaining the temperature at 20-25 C. After formation of a clear solution, AgNO3 (4.9 g, 0.028 mmol, 0.0001 equiv.) followed by <strong>[503-74-2]isovaleric acid</strong> (160 mL, 1.47 mol, 5 equiv.) were added in to the reaction mixture. A white hazy solution formed. Ammonium peroxydisulfate (66 g, 0.288 mol, 1 equiv.) dissolved in water (90 mL) was then added. A black clear solution formed. The reaction mixture was then heated to reflux at 100 C. for 3 h. The reaction was monitored by TLC. After completion, the reaction mixture was basified (pH=7-8) using a saturated solution of sodium bicarbonate, and extracted with EtOAc (3*750 mL). The extracts were combined and were washed with brine (3*300 mL) and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure and the crude product was purified by column chromatography (silica gel: No.100-200) using 0-6% EtOAc in hexane as eluant to afford 2-isobutylpyridine-4-carbonitrile (2) (15 g (32.5% yield)) as a pale yellow liquid. 1H NMR (400 MHz, Chloroform-d): delta (ppm): 8.78-8.63 (m, 1H), 7.41-7.27 (m, 2H), 2.72 (d, J=7.2 Hz, 2H), 1.35-1.23 (m, 1H), 0.94 (d, J=6.6 Hz, 6H). |
32.5% | With ammonium peroxydisulfate; sulfuric acid; silver nitrate; In water; at 20 - 100℃; for 3h; | To a suspension of 4-cyano pyridine (1) (30 g, 0.288 mol, 1 equiv.) in water (210 mL), concentrated sulfuric acid (15.3 mL, 0.288 mol, 1 equiv.) was added dropwise maintaining the temperature at 20-25 C. After formation of a clear solution, AgNO3 (4.9 g, 0.028 mmol, 0.0001 equiv.) followed by <strong>[503-74-2]isovaleric acid</strong> (160 mL, 1.47 mol, 5 equiv.) were added in to the reaction mixture. A white hazy solution formed. Ammonium peroxydisulfate (66 g, 0.288 mol, 1 equiv.) dissolved in water (90 mL) was then added. A black clear solution formed. The reaction mixture was then heated to reflux at 100 C. for 3 h. The reaction was monitored by TLC. After completion, the reaction mixture was basified (pH=7-8) using a saturated solution of sodium bicarbonate, and extracted with EtOAc (3*750 mL). The extracts were combined and were washed with brine (3*300 mL) and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure and the crude product was purified by column chromatography (silica gel: No.100-200) using 0-6% EtOAc in hexane as eluant to afford 2-isobutylpyridine-4-carbonitrile (2) (15 g (32.5% yield)) as a pale yellow liquid. 1H NMR (400 MHz, Chloroform-d): delta (ppm): 8.78-8.63 (m, 1H), 7.41-7.27 (m, 2H), 2.72 (d, J=7.2 Hz, 2H), 1.35-1.23 (m, 1H), 0.94 (d, J=6.6 Hz, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With enzyme Novozym 435; In toluene; at 40℃; | To a stirred solution [OF RACEMIC 4- [4-DIMETHYLAMINO-1- (4-FLUORO-PHENYL)-1-HYDROXY-] [BUTYL]-3-HYDROXYMETHYL-BENZONITRILE] (0,29 mmol, 100 mg) and vinylbutyrate (0,29 mmol, [37 L)] in anhydrous toluene (2,925 ml) is added Novozymes 435, (0,2 mg) and 1,1 eq. Carboxylic acid. The reaction is heated to 40 degrees celcius and followed by HPLC. The enzyme is filtered off and washed with a small amount of toluene. The combined organic phases are evaporated in vacuo and subsequently analyzed on super critical fluid chromatography. Result is shown in table 19. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.2% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; dichloromethane; at 10 - 20℃; for 12h;Inert atmosphere; | To a cooled solution of compound 10 (1 g, 3.82 mmol) in dichloromethane (12 mL) and tetrahydrofuran (8 mL) was sequentially added <strong>[503-74-2]isovaleric acid</strong> (0.47 g, 4.59 mmol), EDC.HCl (1.17 g, 6.11 mmol) and 4-(dimethylamino)pyridine (20 mg) at 10 C and stirred at room temperature for 12 h. The reaction mixture was quenched with ice cold water, separated organic layer and again extracted aqueous layer with dichloromethane. Combined organic layer was washed with brine solution, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to obtain crude solid. Obtained crude solid was purified by flash column chromatography over silica gel 60 (230-400 mesh) using 5% methanol: dichloromethane as eluent to afford 1.1 g (83.2%) of (+/-)-SPF32629B as colorless solid. Rf = 0.3 (5% Methanol:Dichloromethane); mp 129-132 C; IR (KBr pellet): numax 3461, 1742, 1688, 1639 cm-1; 1HNMR (400 MHz CDCl3): delta 14.24 (1H, brs, D2O exchangeable COOH), 13.51 (1H, brs, D2O exchangeable OH), 10.1 (1H, brs, D2O exchangeable CONH), 7.42-7.34 (5H, m), 6.63 (1H, s), 6.22 (1H, s), 2.34 (2H, d, J 7.2 Hz), 2.15-2.09 (1H, m), 0.94 (6H, d, J 6.8 Hz); 13CNMR (100 MHz, CDCl3): delta 174.94 (C), 171.83 (C), 171.35 (C), 165.93 (C), 151.07 (C), 134.75 (C), 129.82 (CH), 129.34 (2CH), 127.21 (2CH), 101.35 (CH), 96.84 (C), 72.67 (CH); 42.95 (CH2); 25.69 (CH); 22.28 (CH3); 22.26 (CH3); MS (ESI) m/z 344.20 (M-H)-; LCMS (ES) m/z calcd for C18H18NO6 [M-H]-: 344.36, found: 344.2; Develosil ODS MG-3 (4.6 × 33 mm), mobile phase: A: 0.1% Aq. HCOOH, B: 0.1% HCOOH (Acetonitrile:Methanol (50:50)), T/%B: 0/30, 4/90, 10/90, 10.1/30; flow rate: 1 mL/min, diluent: acetonitrile; UV: 301 nm, RT = 4.61, purity = 98.72%; HPLC-column used: eclipse XDB-C18 (4.6 × 150 mm) 5 mu, mobile phase: A: 0.1 M formic acid; B: methanol; T/%B: 0/50, 8/90, 15/90, 15.1/50; flow rate: 1.0 mL/min, diluent: (A:ACN,1:1); UV: 303 nm; RT = 9.13; purity = 99.12%. Chiral HPLC-column used: chiral PAK-AD-H (4.6 × 250 mm), 5 mu, mobile phase: A: 0.1%TFA in n-hexanes, B: ethanol (70:30), isocratic; flow rate: 0.7 mL/min, diluent: ethanol, run time: 25 min, UV: 304 nm, RT = 8.69 and 12.57. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In methanol; dichloromethane; at 10 - 20℃; for 16h;Inert atmosphere; | To a cooled solution of compound 6 (1.8 g, 8.28 mmol) in a mixture of tetrahydrofuran:dichloromethane (1:2, 30 mL) was sequentially added <strong>[503-74-2]isovaleric acid</strong> (1.04 g, 10.12 mmol), EDC.HCl (2.64 g, 13.81 mmol) and 4-(dimethylamino)pyridine (25 mg) at 10 C and stirred at room temperature for 16 h. The reaction mixture was quenched with ice cold water, separated organic layer and again extracted aqueous layer with dichloromethane. Combined organic layer was washed with brine solution, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to obtain crude solid. Obtained crude solid was purified by flash column chromatography over silica gel 60 (230-400 mesh) using 6% methanol: dichloromethane as eluent to afford 2.1 g (84%) of 1 as colorless solid. Rf = 0.5 (10% Methanol:Dichloromethane); mp 127-130 C; IR (KBr pellet): numax 3492 (br), 1759, 1652, 1611 cm-1; 1H NMR (400 MHz, CDCl3): delta 9.2 (brs, D2O exchangeable CONH and OH), 7.34 (5H, s), 6.62 (1H, s), 5.97 (1H, d, J 1.6 Hz), 5.88 (1H, s, D2O exchangeable pyridine 3-CH), 2.32-2.30 (2H, m), 2.14-2.08 (1H, m), 0.92-0.91 (6H, dd, J 1 Hz, 6.6 Hz); 13C NMR (100 MHz, CDCl3): delta 171.84 (C), 169.98 (C), 165.78 (C), 146.11 (C), 135.93 (C), 129.11 (CH), 128.9 (2CH), 127.18 (2CH), 101.84 (CH), 98.45 (CH), 72.78 (CH), 43.09 (CH2), 25.64 (CH), 22.29 (CH3), 22.27 (CH3); MS (ESI) m/z 300.1 [M-H]-; Anal. calcd for: C17H19NO4: C, 67.76; H, 6.36; N, 4.65, Found: C, 67.9; H, 6.173; N, 4.551; LCMS (ES) m/z calcd for C17H18NO4, [M - H]-: 300.33, found: 300.2; m/z calcd for C17H20NO4, [M + H]+: 302.14, found: 302; Column used: Develosil ODS MG-3 (4.6 × 33 mm), Mobile Phase: A: 0.1% Aq. HCOOH, B: 0.1% HCOOH (Acetonitrile:MeOH (50:50)), T/%B: 0/30, 4/90, 8/90, 8.1/30; flow rate: 1 mL/min, diluent: acetonitrile; UV: 283 nm, RT = 3.63, purity = 98.56%; HPLC-Column used: Eclipse-XDB-C18 (4.6 × 150 mm), 5 mu; mobile phase: A: 0.1% Aq. HCOOH; B: methanol; T/%B: 0/30, 8/90, 15/90, 15.1/30; flow rate: 1.0 mL/min, diluent: acetonitrile; UV: 285 nm; RT = 8.741; purity = 99.04%, Chiral HPLC: racemic mixture; Column used: Chiral PAK-AD-H (4.6 × 250 mm), 5 mu, Mobile Phase: A:B: n-hexane:isopropanol (90:10), isocratic; flow rate: 0.7 mL/min, diluent: ethanol, run time: 30 min, UV: 206 nm, RT = 9.99 and 12.57. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With sodium cyanoborohydride; In methanol; at 20℃;Inert atmosphere; | General procedure: The amine (0.04-0.05 mmol) and an aldehyde (1.2-1.6eq. for monoalkylation, and 3-4 eq. for dialkylation) were dissolved in CH3OH (5 mL), and then NaBH3CN (2-4 eq. for monoalkylation, and 5-7 eq. for dialkylation) was added. The mixture was then stirred at room temperature until the disappearance of the starting material by TLC. At this point, the solution was diluted with EtOAc, washed with satd aqueous NaHCO3, and extracted with more EtOAc.The combined organic layers were then washed with brine, dried (Na2SO4), and filtered. After removal of the solvent, the residue was purified by column chromatography to give the corresponding products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With sodium cyanoborohydride; acetic acid; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere; | General procedure: The amine (0.04-0.05 mmol) and an aldehyde (2.5-3eq.) were dissolved in DMF (5 mL) containing 1% acetic acid, and then NaBH3CN (5-7 eq.) was added.The mixture was stirred at room temperature until the disappearance of the starting material by TLC. The resulting solution was then diluted with EtOAc, washed with satd aqueous NaHCO3, and extracted with more EtOAc. The combined organic layers were then washed with brine, dried (Na2SO4), and filtered. After removal of the solvent, the residue was purified by column chromatography to give the corresponding products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.9 mg | General procedure: The chlorosilyl resin was swollen in dry DCM (20 mL) under argon atmosphere. A solution of imidazole (1.16 g, 17.0 mmol) and diol 5 (10.7 g, 16.8 mmol) in DCM (20 mL) was subsequently added. The mixture was vortexed overnight at room temperature using a Burrell wrist-action shaker. The loaded resin was washed with DCM (3 × 75 mL) and dried overnight under vacuum to provide 7.3 g of resin 6 (loading of 0.40 mmol/g). IR (KBr): nu 3442 (OH, alcohol), 1702 (C=O, carbamate) cm-1. The free diol 5 (8.7 g) was easily recovered after flash chromatography using EtOAc/hexanes (1:1) as eluent. A solution of piperidine in DCM (20% v/v) (70 mL) was added to resin 6 (7.3 g, 0.4 mmol/g) and the suspension was vortexed using a Burrell wrist-action shaker for 1 h at room temperature. The resin was then filtered and washed successively with DCM (5 × 75 mL) and MeOH (5 × 75 mL), and finally dried overnight to provide 6.5 g of Fmoc deprotected resin. The resin was divided into portions (1.80 g, 0.4 mmol/g in a 50 mL peptide flask). To each portion was added a solution of the appropriate amino acid (Fmoc-l-proline-OH (2.5 g, 7.5 mmol), Fmoc-d-proline-OH (2.5 g, 7.5 mmol), Fmoc-l-phenylalanine-OH (2.9 g, 7.5 mmol), Fmoc-d-phenylalanine-OH (2.9 g, 7.5 mmol) or Fmoc-l-tetrahydro-isoquinoline-3-carboxylic acid (3.0 g, 7.5 mmol), benzotriazole-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate (PyBOP) (3.9 g, 7.5 mmol) and N-hydroxybenzotriazole (HOBt) (1.0 g, 7.5 mmol) in DMF (25 mL) under argon atmosphere. Diisopropylethylamine (DIPEA) (2.6 mL, 15 mmol) was added to the suspensions and the peptide flasks were vortexed with a Burrell wrist-action shaker for 5 h at room temperature. The resins were then filtered and washed successively with DCM (5 × 25 mL) and MeOH (5 × 25 mL), and finally dried overnight to give the resins 7. The coupling reaction was repeated a second time in each case in order to ensure complete coupling. A solution of piperidine in DCM (20% v/v) (70 mL) was added to resin 6 (7.3 g, 0.4 mmol/g) and the suspension was vortexed using a Burrell wrist-action shaker for 1 h at room temperature. The resin was then filtered and washed successively with DCM (5 × 75 mL) and MeOH (5 × 75 mL), and finally dried overnight to provide 6.5 g of Fmoc deprotected resin. The resin was divided into portions (1.80 g, 0.4 mmol/g in a 50 mL peptide flask). To each portion was added a solution of the appropriate amino acid (Fmoc-l-proline-OH (2.5 g, 7.5 mmol), Fmoc-d-proline-OH (2.5 g, 7.5 mmol), Fmoc-l-phenylalanine-OH (2.9 g, 7.5 mmol), Fmoc-d-phenylalanine-OH (2.9 g, 7.5 mmol) or Fmoc-l-tetrahydro-isoquinoline-3-carboxylic acid (3.0 g, 7.5 mmol), benzotriazole-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate (PyBOP) (3.9 g, 7.5 mmol) and N-hydroxybenzotriazole (HOBt) (1.0 g, 7.5 mmol) in DMF (25 mL) under argon atmosphere. Diisopropylethylamine (DIPEA) (2.6 mL, 15 mmol) was added to the suspensions and the peptide flasks were vortexed with a Burrell wrist-action shaker for 5 h at room temperature. The resins were then filtered and washed successively with DCM (5 × 25 mL) and MeOH (5 × 25 mL), and finally dried overnight to give the resins 7. The coupling reaction was repeated a second time in each case in order to ensure complete coupling. To each of the resin-bound derivatives 8 was added 2 mL of an acid solution of 2 M methanolic HCl (AcCl + MeOH) in DCM (20:80, v/v) and the resulting suspensions were vortexed at 600 rpm for 1 h. DCM (1 mL) was added and the suspensions were filtered and the recovered filtrate was neutralized with 0.5 mL of 10% aqueous NaHCO3 (pH 8). The biphasic solution was filtered using a phase separator syringe (Biotage) and the resulting organic solution evaporated under reduced pressure. The 12 (3 × 4) crude amide compounds of library A (Table 2 ) were purified by filtration over a silica gel plug (10 mL) using EtOAc/hexanes (1:1) (15 mL) and then EtOAc (20 mL). In another experiment, the 28 (4 × 7) amide compounds of library B (Table 3 ) were evaporated to dryness and judged sufficiently pure by TLC and 1H NMR analyses for direct screening on HL-60 cells. All members of libraries A and B were analyzed by TLC, 1H NMR and LRMS. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 21h;Inert atmosphere; | General procedure: Tryptamine 3 was dissolved in CH2Cl2, and then 1.1 equiv. acid, 1.1 equiv. EDC, and 1.1 equiv. HOBt were added sequentially at room temperature. The reaction was stirred at room temperature until the starting material was completely consumed. The reaction was diluted with CH2Cl2 (EA for4a), worked up with water. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (EA/nHx =1:6 for 4a; EA/nHx = 1:9 for 4d) to give compounds 4a and 4d. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
156 mg | With HATU; N,N`-dimethylethylenediamine; In N,N-dimethyl-formamide; at 20℃; for 3h; | Example 37 4- ( (4-Chlorobenzyl) oxy) -1- ( 2-isobutyl-l-methyl-lH- benzimidazol-6-yl) pyridin-2 (1H) -one A) 6-Bromo-2-isobutyl-l-methyl-lH-benzimidazole To a solution of 5-bromo-N1-methylbenzene-l, 2-diamine (159 mg) , isovaleric acid (0.087 ml) and N,N- diisopropylethylamine (0.41 ml), in DMF (2 ml) was added HATU (316 mg) at room temperature. The mixture was stirred at room temperature under a dry atmosphere (CaCl2 tube) for 3 h. After evaporation of the mixture, the residue was purified by . NH silica gel column chromatography (hexane/EtOAc) . The resulting residue was stirred in AcOH (2.0 ml) at 80C for 1 h. After evaporation, the residue was purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (156 mg) as a pale yellow solid. MS (ESI+) : [M+H]+ 268.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | The amino acid N(im)-trityl-D-histidine (353 mg, 0.9 mmol,1.0 equiv.) was dissolved in dichloromethane followed by the addition oftriethylamine (3.5 equiv.) and trimethylsilylchloride (3.5 equiv). After 2 hours ofgentle reflux, the mixture was ready to be used for in situ coupling to the anhydrideof the carboxylic acid. Thus, <strong>[503-74-2]isovaleric acid</strong> (60 mg, 0.59 mmol, 1.0 equiv) wasseparately dissolved in THF and maintained at -20 oC using an ice-salt bath. N-methyl morpholine(1.2 equiv) was then added followed by the addition of ethyl chlorofomate (1.0 equiv). After 15minutes to 20 minutes at -20 oC, the bis-TMS amino acid reaction mixture was added directly to theanhydride solution and left stirring at room temperature overnight. After 8 hours, the reaction mixturewas concentrated in vacuo. The residue obtained was first partitioned and washed between aqueoussat. NaHCO3 and n-hexane. The hexane layer was discarded and the aqueous was acidified with citricacid, and then extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine,dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified by silica gelcolumn chromatography to give the desired N-acylated amino acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.5% | Charge 3-methylbutanoic acid (106.36 g), toluene (800 ml) and triethylamine (126.46 g) into a 3-neck flask (R1). Heat R1 to 90 C. Add a solution of DPPA (289.3 g) in toluene (400 ml) slowly (Care: N2 released). Stir R1 at 90 C. for 30-60 mins, then cool to 20-30 C. In a separate flask (R2) charge benzyl 2-aminoacetate hydrochloride (200 g), triethylamine (150.54 g), and toluene (1000 ml) and stir at 20-30 C. for 1-2 hours. Add the R1 mixture into R2 drop wise slowly via addition funnel at 20-30 C. and stir for 1-2 hours. Slowly add the reaction mixture to water (2000 ml) with vigorous stirring. Separate the organic and extract the aqueous layer with EtOAc (2×1000 ml). Combine the organic layers and wash with 1 N hydrochloric acid (1000 ml), then 7% NaHCO3 aq (1000 ml), then water (1000 ml), then 15% brine (1000 ml). Concentrate under reduced pressure. Slurry the residue with heptane (1000 ml) then filter the solid. Dry the filter cake under reduced pressure below 40 C. to give benzyl 2-(isobutylcarbamoylamino)acetate (218 g; 98.1% assay; 81.5% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.1% | Charge 3-methylbutanoic acid (106.36 g), toluene (800 ml) and triethylamine (126.46 g) into a 3-neck flask (R1). Heat R1 to 90 C. Add a solution of DPPA (289.3 g) in toluene (400 ml) slowly (Care: N2 released). Stir R1 at 90 C. for 30-60 mins, then cool to 20-30 C. In a separate flask (R2) charge benzyl 2-aminoacetate hydrochloride (200 g), triethylamine (150.54 g), and toluene (1000 ml) and stir at 20-30 C. for 1-2 hours. Add the R1 mixture into R2 drop wise slowly via addition funnel at 20-30 C. and stir for 1-2 hours. Slowly add the reaction mixture to water (2000 ml) with vigorous stirring. Separate the organic and extract the aqueous layer with EtOAc (2×1000 ml). Combine the organic layers and wash with 1 N hydrochloric acid (1000 ml), then 7% NaHCO3 aq (1000 ml), then water (1000 ml), then 15% brine (1000 ml). Concentrate under reduced pressure. Slurry the residue with heptane (1000 ml) then filter the solid. Dry the filter cake under reduced pressure below 40 C. to give benzyl 2-(isobutylcarbamoylamino)acetate (218g; 98.1% assay; 81.5% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | 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; | 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 |
---|---|---|
83.3% | General procedure: The relevant carboxylicacids (1.1 equiv) were activated with O-(benzotriazol-1-yl)-N,N,N?,N?-tetramethyluronium tetrafluoroborate (TBTU; 1.1 equiv) in the presenceof N-ethyl-N,N-diisopropylamine (DIEA; 2.0 equiv) in N,N-dimethylformamide (DMF; 2 mL) for 20 min at 0 C. Then, a solutionof 7 (for compounds 9b-i) or 8 (for compounds 10b-i) (1 equiv) in DMF (2 mL) was added, and the reaction was allowed to proceedat RT for 24 h. CH2Cl2 (25 mL) was added to the reaction mixture,and the resulting solution was washed three times with 5% aqueous Na2CO3 (30 mL), dried with anhydrous Na2SO4 and filtered. The solvent was evaporated under reduced pressure (rotatory evaporator),and the crude residue was purified by liquid chromatography on a silica gel column with CH2Cl2/MeOH 4:1 (v/v) as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.3% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 1h; | General procedure: A solution of compound 17 (1 equiv) and various carboxylic acid (1.2 equiv) in dried DCM was treated with EDC.HCl (1.2 equiv) and TEA (1.5 equiv). After 1 h, the resulting mixture was treated with saturated aq. NH4Cl (10 mL). The organic phase was extracted with DCM (3 x 10 mL), and combined organic phase was dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (CHCl3/MeOH 50:1, v/v) to afford 18a-18m and 19a-19m. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 0 - 20℃; for 2h; | 1-[2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl]piperazine (300 mg, 0.97 mmol) in dichloromethane (5 ml) of 1-(3-dimethylaminopropyl propyl)-3-ethylcarbodiimide hydrochloride (210mg, 1.07mmol), <strong>[503-74-2]isovaleric acid</strong> (110mg, 1.07mmol), triethylamine (150 mg, 1.46 mmol) was added at 0 C., and stirred for 2 hours at room temperature. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography and purified by (elution solvent ethyl acetate / n-hexane = 1/1) to give the title compound as a brown oil (the yield 320 mg, 84% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | The 0.1mmol Compound 5 was dissolved in 1mL of dichloromethane was added at 0C 0.12mmol 3,3- dimethyl propionic acid with 0.05mmol 4-dimethylaminopyridine, stirring 10min, was added 0.2 mmol of dicyclohexyl carbodiimide imido amine, stirred at room temperature overnight. 5mL ethyl acetate was added 5mL of water and stirred for stratification, the organic phase was washed 3 times with saturated NaCl solution, dried over anhydrous Na2SO4Dried, the solvent was distilled off under reduced pressure to give a yellow oil. The yellow oil was dissolved in 1ml of tetrahydrofuran and water mixed solvent (8: 2), was added 0.5mL of glacial acetic acid, stirredat room temperature 8h, extracted with ethyl acetate, the organic phase was washed 3 times with saturated NaCl solution, dried over anhydrous Na 2SO 4Dried, the solvent was distilled off under reducedpressure to give a yellow oil. By silica gel column chromatography (petroleum ether:ethyl acetate = 10: 1) to give Compound 3 as a yellow oil (88% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With dmap; dicyclohexyl-carbodiimide; In dichloromethane; N,N-dimethyl-formamide; at 0℃; for 0.5h; | General procedure: General procedure for the preparation of compounds 37-39.The opportune alcohol 35b-c, (25mg, 0.07 mmol), acid (lOjiL, 0.07 mmol), N,N?25 dicyclohexylcarbodiimide (22mg, 0.llmmol), and DMAP (3mg, 0.Olmmol),were stirred at 0Cfor 30 mm. in a mixture of CH2C12 lOmL and DMF 2mL. After that time, the reaction mixture was allowed to reach r.t. and stirred for 12h. The solvent was then removed at reduced pressure, EtOAc was added and the mixture was washed with 5% LiC1 aq. Solution, dried over anhydrous Na2504, and concentrated in vacuo. The residue was purified by flashchromatography on silica gel with the opportune eluent.2-(1-(4-(3-(o-tolyl)ureido)phenyl)- 1H- 1 ,2,3-triazol-4-yl)ethyl 3-methylbutanoate (37). (Purification eluent: DCM-methanol 98:2). Yield 74% white solid.1H NMR (400 MHz, CDC13-oe 7.72 (s, 1H), 7.56-7.48 (m, 5H), 7.25-7.23 (m, 3H), 7.17-7.14 (m, 2H), 6.61 (s, 1H), 4.4 1-4.38 (t, J=6.6 Hz, 2H), 3.14-3.11 (t, J6.6 Hz, 2H), 2.28 (s, 3H), 2.18-2.16 (d, J=7.6 Hz, 2H),0.92-0.89 (d, J=6.8 Hz, 6H) ppm. 13C NMR (100 MHz, CDC13): oe 173.05, 153.62, 144.95,139.21, 136.93, 135.65, 136.19, 132.73, 132.18, 131.54, 131,00, 127.53, 126.98, 126.62,125.34, 121.28, 120.30, 119.94, 62.75, 43.32, 25.57, 22.45, 17.88 ppm. MS (ESI): m/z 420 [M5 H]-, 456 [M+Cl] |
74% | With dmap; dicyclohexyl-carbodiimide; In dichloromethane; N,N-dimethyl-formamide; at 0 - 20℃; | General procedure: The opportune alcohol 35b-c, (25mg, 0.07 mmol), acid (lOjiL, 0.07 mmol), N,N?dicyclohexylcarbodiimide (22mg, 0.1 lmmol), and DMAP (3mg, 0.0 lmmol),were stirred at 0C for 30 mm. in a mixture of CH2C12 lOmL and DMF 2mL. After that time, the reaction mixturewas allowed to reach r.t. and stirred for 12h. The solvent was then removed at reduced pressure, EtOAc was added and the mixture was washed with 5% LiC1 aq. Solution, dried over anhydrous Na2504, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel with the opportune eluent. 2-(1-(4-(3-(o-tolyl)ureido)phenyl)- 1H- 1 ,2,3-triazol-4-yl)ethyl 3-methylbutanoate (37).(Purification eluent: DCM-methanol 98:2). Yield 74% white solid.1H NMR (400 MHz, CDC13- d): oe 7.72 (s, 1H), 7.56-7.48 (m, 5H), 7.25-7.23 (m, 3H), 7.17-7.14 (m, 2H), 6.61 (s, 1H), 4.41- 4.38 (t, J=6.6 Hz, 2H), 3.14-3.11 (t, J6.6 Hz, 2H), 2.28 (s, 3H), 2.18-2.16 (d, J=7.6 Hz, 2H),0.92-0.89 (d, J=6.8 Hz, 6H) ppm. 13C NMR (100 MHz, CDC13): oe 173.05, 153.62, 144.95,139.21, 136.93, 135.65, 136.19, 132.73, 132.18, 131.54, 131,00, 127.53, 126.98, 126.62,125.34, 121.28, 120.30, 119.94, 62.75, 43.32, 25.57, 22.45, 17.88 ppm. MS (ESI): m/z 420 [MH]-, 456 [M+Cl] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82.0% | General procedure: To a solution of acid (0.65 mmol) in DMF (10 mL) atroom temperature was added BOP reagent (0.28 g, 0.65 mmol), followed by TEA(0.18 mL, 1.29 mmol). The mixture was stirred for 0.5 h before compound 30 (0.2g, 0.43 mmol) was added. Then the resulting solution was stirred at room temperature for 12 h. The aqueous solution was poured into 100 mL water and white precipitated solid was filtered off, washed with water, and dried to afford products 31-36, 37B-42B and 43-44. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Under ice-cooling conditions,The intermediate s5 (38.4 mg, 0.15 mmol) was dissolved in 10 ml of toluene, triphenylphosphine (184 mg, 0.75 mmol) and <strong>[503-74-2]isovaleric acid</strong> (46 mul, 0.45 mmol) were added, stirred for 10 minutes and diethylazodicarboxylate And the mixture was stirred at room temperature for 30 minutes. The organic solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to give 50 mg of a colorless oil. Yield92%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With 1-(2-(methylamino)ethyl)-3-phenylthiourea; In toluene; at 80℃; for 16h; | 4.8 mg of compound 4 (0.023 mmol), used as a catalyst, and 11.7 mg <strong>[503-74-2]isovaleric acid</strong> (0.115 mmol) were added to a solution of compound 6 (26.2 mg, 0.115 mmol) in toluene (0.5 mL). The reaction was heated at 80 C. for 16 h. The crude product was purified by column chromatography (SiO2: EtOAc/n-hexane, 1:5; Rf 0.76), and 21.6 mg of compound 5mc (0.086 mmol, 75%) was obtained as a colorless solid. The compound 5mc is the same as the compound in Example 19, therefore, the description of compound 5mc is omitted. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | General procedure: At first, [Rh(COD)Cl]2 (2.4 mg, 0.0049 mmol), (S,S)-BDPP (5.7 mg, 0.013 mmol) and 1.0 mL DCE were added to a Schlenk tube under an argon atmosphere. Then ZnI2 (6.4 mg, 0.02 mmol)was added and the mixtures were stirred for 10 min. After thea ddition of Et3N (166 muL, 1.2 mmol) and oxabenzonorbornadiene (0.2 mmol), the mixtures were stirred for an additional 10 min.Then, a solution of carboxylic acid (1.0 mmol) in DCE (1.0 mL)was added, and the mixtures were stirred at 40 C under argon atmosphere with TLC monitoring until the complete consumption of oxabenzonorbornadiene. The reaction mixture was concentrated,and the residue was purified by chromatography on a silicagel column to afford the desired ring opening product. The enantiomeric excess value of the product was determined by HPLC ona chiral stationary phase. 4.2.13 (1S,2S)-1-Hydroxy-1,2-dihydronaphthalen-2-yl 3-methylbutanoate 3am White solid; 78% yield; 90% ee; mp 112-113 C; = +168 (c 0.208, CH2Cl2); 1H NMR (400 MHz, CDCl3): delta 7.55 (t, J = 8.2 Hz, 1H), 7.28-7.26 (m, 2H), 7.10 (t, J = 8.4 Hz, 1H), 6.51 (d, J = 9.8 Hz, 1H), 5.86 (dd, J = 10.0, 2.8 Hz, 1H), 5.63 (d, J = 9.1 Hz, 1H), 4.94 (d, J = 9.0 Hz, 1H), 2.47 (s, 1H), 2.26 (d, J = 7.4 Hz, 2H), 2.17-2.10 (m, 1H), 0.98 (d, J = 6.6 Hz, 6H); 13C NMR (CDCl3, 100 MHz): delta 173.52, 135.41, 131.61, 129.45, 128.34, 128.32, 126.73, 125.97, 125.63, 75.23, 72.01, 43.51, 25.85, 22.38; MS (ESI) calcd for C15H18O3 (M+): 246.1256; Found: 246.1260 (M+). The ee of 3am was determined by HPLC analysis using Daicel Chiralcel OD-H column (25 cm * 0.46 cm ID), conditions: n-hexane/i-PrOH = 90/10, 1.0 mL/min, 254 nm; tminor = 6.1 min, tmajor = 10.0 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With tetraethylammonium bromide; potassium carbonate; In dichloromethane; at 20℃;Molecular sieve; | General procedure: A mixture of glucosyl bromide 1 (1.03 g, 2.5 mmol), acid (5.0 mmol), K2CO3 (0.69 g, 5.0 mmol),TEAB (0.05 g, 0.25 mmol) and 4 A MS (0.25 g) in 35 mL DCM was stirred 24-48 h at room temperature.Next, the insoluble substances, made up of the slightly soluble potassium carboxylate, 4 A MS andother salts, were filtered off. The filtrate was washed with water, and the separated organic layer wasthen washed with 25% aqueous K2CO3 to removed any remaining potassium carboxylate. After dryingover MgSO4 and concentration in vacuo, the residue was purified via silica gel column chromatographyusing EtOAc/hexane or EtOAc/petroleum ether (1:10 to 1:1) as eluents to yield the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.8 eq of commercially available <strong>[204316-32-5]Fmoc-L-Dab(Alloc)-OH</strong> and DIEA (4 eq) are added to the resin in 2 mL DMF. The mixture is intermittently stirred manually during 1 hour. After that, 0.5 mL/g of MeOH are added to the reaction mixture to cap the remaining reactive points of resin. After 15 minutes, the solution is filtered off and the resin is washed thoroughly with DCM, DMF and MeOH. Fmoc removal is achieved by treating the resin with 20% piperidine in DMF (1 x 5', 1 x 10' and 1 x 15'). For the coupling of Fmoc-L-Ile-OH, 3 eq of the amino acid, 3 eq of the coupling agent TBTU and 6 eq of DIEA dissolved in a small amount of DMF and premixed for 2 minutes. After which, the mixture is added to the resin and the reaction is allowed to react for 90 minutes. To extent of the reaction is monitored using the Kaiser test. The Fmoc group is then removed by treatments with 20% piperidine in DMF (1 x 5', 1 x 10' and 1 x 15'). For the N-methylation of the amino group of the lle moiety, the free amino group is protected with ortho-nitro benzene sulfonyl chloride (4 eq) using collidine (10 eq) as a base in DMF, which are allowed to react with the resin for 30 minutes. Then, the resin is rinsed with DMF and DCM, and the protection step is repeated again under the same conditions. The extent of the protection is monitored using the Kaiser test. The N- methylation of the amino group is achieved by treating the resin with 3 eq of 7-methyl- l,5,7-triazabicyclo[4.4.0]dec-5-ene and 4 eq of para-nitrobencensulfonate in DMF for 30 minutes (3 treatments). Between treatments the resin is washed thoroughly with DMF and DCM. After the N-methylation of the lle amino group, the ortho-nitro benzene sulfonyl protecting group is removed by treating the resin with 10 eq of beta- mercaptoethanol and 5 eq of DBU (1 x 10' and 1 x 40'). The removal of the ortho-nitro benzene sulfonyl group is assessed using the chloranil test. After that, the Fmoc-L-Pro- OH moiety is attached, for that purpose 3 eq of the amino acid, 3 eq of the coupling agent TBTU and 6 eq of DIEA dissolved in a small amount of DMF and premixed for 2 minutes. After which, the mixture is added to the resin and the reaction is allowed to react for 90 minutes. The extent of the reaction is monitored using the Kaiser test. The Fmoc group is then removed by treatments with 20% piperidine in DMF (1 x 5', 1 x 10' and 1 x 15') and additional treatment with a mixture of piperidine/DBU/toluene/DMF (5:5:20:70) (1 x 5'). 3-methylbutanoic acid is coupled to the Pro moiety by adding to the resin 20 eq of the acid, 10 eq of the coupling regent DPCDI and 10 eq of the additive HO At. The reaction is stirred manually intermittently for 60 minutes. Then the reaction is filtered off and the resin is rinsed thoroughly with DMF and DCM. The extent of the reaction is monitored using the chloranil test. For the removal of the Alloc group, 10 eq of phenylsilane in DCM are added to the resin while N2 is bubbled through the mixture. Then, 0.1 eq of Pd(PPh3)4 are added maintaining the N2 bubbling while mixing everything well. Then the reaction vessel is sealed and shaken for 15 minutes. After this time, the reaction is filtered and the resin washed thoroughly. The same treatment is repeated two more times. After the last treatment, the resin is washed thoroughly with DCM, MeOH and DMF. For the coupling of the 3,5-difluorobenzoic acid on the side chain of the Dab moiety, 3 eq of said acid, 3 eq of TBTU and 6 eq of DIEA in DMF are added to the resin. The reaction is allowed to react for 60 minutes. After this time, the resin is washed with DMF and DCM and the extent of the reaction is monitored the Kaiser test. For the cleavage of the peptide, the resin is washed several times with DCM and dried by suction. The linear side-chain protected peptide is cleaved from the resin by adding a solution of HFIP/DCM (1 :4), the mixture is allowed to react for 15 min. Then the reaction mixture is filtered and the resin rinsed with HFIP/DCM. This cleavage procedure is repeated for a second time. All the filtrates are pooled and the solvent is evaporated under vacuum. The crude peptide is used for the formation of the hydroxamide in solution without prior purification. The peptide is dissolved in DCM. After which, 3.5 eq of 0-(2,4-dimethoxybenzyl)hydroxylamine, 5 eq of 4- methylmorpholine, 1.3 eq of the coupling agent EDC HCl and 1.3 eq of the additive HO At are added and the mixture is allowed to react under a N2 atmosphere overnight. The extent of the reaction is monitored using HPLC. Once the desired product is obtained, the mixture is washed with IN HC1, water and brine. The organic layer is dried over magnesium sulfate, filtered and evaporated. A mixture of TFA/water/TIS (95:2.5 :2.5) is added to the peptide crude and the mixture is lightly stirred during 2 hours. Afterwards, TFA is evaporated under a N2 flow, yielding example 5. The compound is purified using reverse-phase chromatography |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | General procedure: After compound 10 (175 mg, 0.5 mmol), HATU (248 mg, 0.65 mmol) was added to DMSO (3 mL) and stirred well, 10 drops of triethylamine was added and the solution was stirred for five minutes. Then 4-methoxy-benzoic acid (77 mg, 0.5 mmol) was added to the solution, stirred overnight at room temperature. Upon the completion of the reaction, the reaction mixture was added to 20 mL distilled water to give yellow precipitate. The yellow precipitate was filtered, washed, dried and then separated by column chromatography to give compound 2a, pale yellow solid, 80 mg, yield 33%. Compounds 2b-2g were prepared with protocols similar to the preparation of 2a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Isovaleric acid 131 (94 mul, 851 mumol) was dissolved in anhydrous dichloromethane (5.6 ml, 15 mM) and the solution was stirred at 0 C. under a nitrogen atmosphere.DMAP (10 mg, 85 mumol) was then added followed by DCC (88 mg, 425 mumol) and the reaction allowed to warm to room temperature over 2 hours.The resulting activated acid was coupled with Tuv (OH) -Tup-O allyl dipeptide124 (50 mg, 85 [mu] mol) and the reaction was stirred overnight,The UPLC / MS showed the conversion to the product. The reaction was then diluted with dichloromethane and washed with 0.1 M HClAll. After the aqueous layer was extracted twice with dichloromethane, the combined organic layers were dried over sodium sulfate, filtered, And concentrated to give the crude product which was subsequently purified by preparative HPLC to afford 52 mg (91%) & lt; RTI ID = 0.0 & gt;Of the BOC-Tuv (isovaleryloxy) -Tup-O-allyl product(2S, 4R) -allyl4- (2 - ((1 R, 3R) -3 - ((tert-Butoxycarbonyl)(Methyl) amino) -4-methyl-1-((3-methylbutanoyl) oxy) pentyl) thiazole-4-carboxamido) -2-methyl-5-phenylpentanoate(133) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With palladium 10% on activated carbon; W(OTf)6; hydrogen; at 180℃; 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 180 C, the yield 46%, the purity of the product is 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 |
---|---|---|
77% | General procedure: N-cyclohexyl-2-(N-phenylacetamido)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide (1) A 10-mL glass tube containing aniline (0.10 mL;0.55 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (116 mg;0.50 mmol), and 0.5 mL of methanol was first stirred for 5 min at room temperature. Then, acetic acid (0.03 mL; 0.55 mmol) and cyclohexylisocyanide(0.07 mL; 0.55 mmol) were added to the reaction mixture. Microwave irradiation was applied for 30 min (45 C, 150 W) under medium-speed magnetic stirring, andthe reaction mixture was concentrated and re-dissolved in dichloromethane. The crude solution was then washed with 1 M HCl(aq) and NaHCO3(aq), respectively.The organic solution was collected and dried over MgSO4 and concentrated invacuo. The concentrated material was placed under vacuum at 40 C for 8 h to afford the desired product in a 93 % yield (221.94 mg) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 24h; | General procedure: To a stirred solution of thiol 3 (0.50 mmol) and carboxylic acid (0.60 mmol) in anhydrous dichloromethane were added DCC (0.12 g, 0.60 mmol) and DMAP (31 mg, 0.25 mmol). After stirring overnight at room temperature, petroleum ether was added to the reaction mixture at 4 oC to facilitate precipitates. Then the solution was filtered, and concentrated in vacuum. The residue was purified by flash chromatography to afford thioesters 7a-7z as colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | General procedure: 4 mmol of carboxylic acid in toluene (5 vol) was added with sodium borohydride (2.5 mmol) in portions at 0-5C. To the mixture was added EnCat Ni 2.5 %. Gradually raise the temperature to 25-30 C. To the mixture was added 1 mmol secondary amine. Raise the temperature to 80 C. To the reaction mixture was added 1.5 mmol of sodiumborohydride in portions. The progress of the reaction was monitored by TLC. After the completion of reaction, reaction mixture was quenched with 1N HCl to pH 7 to 8 and separated organic solution washed with water. Solvent was distilled out under reduce pressure at 50 C. The product was isolated by crystallisation in isopropyl alcohol and conc. Hydrochloric acid followed by filtration and drying to yield (90-99 %) solid hydrochloride salt as product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; | General procedure: To a stirred solution of alcohol 2 (0.58 mmol) and carboxylic acid (0.70 mmol) in anhydrous dichloromethane (6.0 mL) were added DCC (0.14 g, 0.70 mmol) and DMAP (35mg, 0.29 mmol). After stirring overnight at room temperature, petroleum ether was added to the reaction mixture at 4C to facilitate precipitation. The solution was filtered and concentrated in vacuo. The residue was purified by flash chromatography to afford a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 12h; | General procedure: To a solution of compound 8 (0.3 mmol) in 5 mL DMF,R2-COOH (0.36 mmol), EDCI (0.45 mmol), HOBt(0.45 mmol), DIEA (0.6 mmol) was added and stirredovernight. The reaction mixture was evaporated undervacuum to give crude product, which was purified by columnchromatography on silica gel to give title compounds10b-10n. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; | 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 |
---|---|---|
93% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; | 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 |
---|---|---|
79% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; | 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 |
---|---|---|
92% | With boron trifluoride diethyl etherate; In 1,2-dichloro-ethane; at 20℃; for 6h;Inert atmosphere; | General procedure: To a solution of benzoic acid (0.12 g. 1.00 mmol) and 2-diphenylmethoxypyridine (0.39 g, 1.50 mmol) in DCE (4 mL) BF3OEt2 (0.028 g. 0.20 mmol) was added. The mixture was stirred at room temperature for 6h. The reaction mixture was extracted with ethyl acetate (2 x 10 mL), and then washed with water (10 mL), followed by brine (10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was then purified by flash column chromatography on silica gel with hexane-CH2Cl2 as eluent to afford the desired product 5a as a white solid (0.175 g, 95%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With caesium carbonate; In N,N-dimethyl-formamide; at 140℃; for 12h;Inert atmosphere; | General procedure: A carboxylic acid 1 or anhydride 5 (2 mmol), cyclic tertiary amine 2 or 6 (2 mmol), an aryl halide 3 (1 mmol), Cs2CO3 (1 mmol) and DMF (2 mL) were added to a 25-mL reaction vessel under nitrogen atmosphere. The reaction mixture was stirred at 140 C for 12 h (or 100 C for 24 h), and then cooled to room temperature. The mixture was poured into water and extracted with EtOAc (3 ×). The organic layer was dried over anhydrous Na2SO4. The obtained organic solution was concentrated and then purified by flash column chromatography on silica gel (EtOAc-petroleum ether, 1:10 to 1:1) to afford the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | General procedure: Isovaleric acid (4.4 equiv./equiv. ALC) and HOBt 85% (4.4 equiv./equiv. ALC) were dissolved in DMF (12.5 mml/ mmol ALC). The solution was cooled down to 0- 5 C in an ice-bath. At this temperature a solution of Dicyclohexylcarbodiimide (4.5 equiv./equiv. ALC) in DCM (5 ml/mmol ALC) was added dropwise within 30 min. the solution was kept at this temperature for another 10 min. Then Azithromycin (1 equiv.) was added in one portion. While stirring, the solution was allowed to come to room temperature within 2 h. Stirring was continued for another 2 h at 50 C. The reaction mixture was allowed to stand at RT for 12 h. A white precipitate was removed by suction. The solvent was evaporated completely at 12 mbar and 50 C. The residue was dissolved in DCM (12.5 mL/mmol ALC) and washed with water (7.5/mmol ALC). A small amount of a white precipitate was removed. Then the solution was treated with citric acid (25 mL/mmol ALC, 5 %). The aqueous phase was washed with DCM (5 ml/mmol ALC). NaOH 10 % was added until the aqueous phase was basic (pH 12) and was washed with DCM (2 x 10 ml/mmol ALC). After phase separation the organic phase was evaporated to dryness, products were obtained as white solids. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 25℃;Inert atmosphere; | General procedure: Compound 17, 18, 19, 20 were prepared according to the following general procedure. Compound 16 wasdissolved in CH2Cl2 (0.2 mL/3 mg of 16). DCC (4 eq.), carboxylic acid (4 eq.) and DMAP (2 eq.) were addedsequentially to the reaction mixture. Upon completion of the reaction determined by TLC analysis, the reactionmixture was purified directly via preparative TLC (1:2 EtOAc:Hexanes) to afford the corresponding C3 analog. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 48h; | General procedure: To a solution of the appropriate carboxylic acid (3.806mmol) in dry CH2Cl2(15 mL) was added thetetramicacid1(1.0 g; 3.46mmol), DMAP (0.6353 g; 5.2mmol) and DCC (0.8563 g; 4.15mmol). The mixture was stirred at room temperature for 48 h, filtered off and thedicyclohexylureaformed was washed with ethyl acetate (20 mL). The combined organic layers were successively washed with 5% KHSO4(3 x 20 mL), brine (20 mL) and dried over anhydrousNa2SO4.The solvent was removed under vacuum and to the formed crude oil was added cold acetone (15 mL) and stored at 4oCfor 24 h. Filtration followed by removal of solvent produced compounds2a-ias yellow to orange oils in good purities. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In acetonitrile; at 40℃; for 24h; | To a suspension of 6-(3-fluoro-4-(piperidin-4-ylmethoxy)phenyl-2H-benzo[ d] [ 1,3]oxathiole-3- oxide hydrochloride (0.5 g, 1.4 mmol) and 3-methylbutanoic acid (0.15 g, 1.5 mmol) in acetonitrile (15 mL) was added triethylamine (0.43 g, 4.2 mmol) and N-[(lH-1,2,3-benzotriazol-1- yloxy)(dimethylamino )methylene] -N-methylmethanaminium hexafluorophosphate (0.68 g, 1.8 mmol). The resulting solution was stirred at 40 c for 24 hours. Upon cooling, a precipitate was formed which was filtered off and dried to afford the title compound (0.4 g, 64 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9% | General procedure: The compounds were synthesized manually by SPPS following theFmoc/tert-butyl (Fmoc/tBu) strategy and using 2-chlorotrityl resin (IrisBiotech) in polypropylene syringes, each fitted with a polyethyleneporous disk. Solvents and soluble reagents were removed by suction.Prior to starting the synthesis, the resin was conditioned by swelling indichloromethane (DCM, 15 min) and washings with dimethylformamide(DMF, 3×30 s). The incorporation of hydroxylamine linker wasperformed by adding N-Fmoc-hydroxylamine (1.5 eq) and N,N-diisopropylethylamine(10 eq) to the resin in DCM for 24 h [50]. After this,the unreacted points of the resin were capped with methanol (0.8 mL/ gresin, 10 min). The Fmoc protecting groups were removed using 20%piperidine (Carlo Erba) solution in DMF (Carlo Erba) (2x1 min, 1x10min). The coupling reactions were performed in DMF using Fmocaminoacids (3 eq) and oxyma pure (3 eq, Iris Biotech) in the presenceof diisopropylcarbodiimide (3 eq) for 90 min. This mixture is known toproduce couplings with high efficiency and extremely low or null racemization[51]. The reaction was monitored by colorimetric tests: theKaiser colorimetric test [52] was used for the detection of primaryamines, while the chloranil test was used for secondary amines boundto the solid-phase [53]. The Alloc group was removed by adding phenylsilane(10 eq) and Pd(PPh3)4 (0.1 eq) in DCM (3×15 min). Peptideswere cleaved from the resin using 30% trifluoroacetic acid (TFA,Fluorochem) in DCM (3×15 min). After cleavage, filtrates and DCMwashes (3×5 min) were evaporated and lyophilized. The crude productobtained was purified by reverse-phase column chromatographyusing a Combi flash ISCO RF provided with dual ultraviolet detectionusing a high performance RediSep Rf Gold C18 column (Teledyne isco).The purity of the purified compounds was determined at lambda=220 nmby analytical HPLC (Waters Alliance 2695 separation module equippedwith a 2487 photodiode array detector, a Sunfire C18 column(100×4.6mm×5 mum, 100 A, Waters), and Empower software). Flowrate 1 mL/min, mobile phase H2O (0.036% TFA) and acetonitrile(0.045% TFA). Compound identity was assessed by analytical HPLC-MS(Waters Alliance 2695 separation module system equipped with aWaters 2998 photodiode array detector electrospray ionization (ESI)-MS micromass ZQ and a Sunfire C18 column (2.1×100mm×3.5 mum,100 A, Waters), and Masslynx software. Flow rate 0.3 mL/min, mobilephase H2O (0.1% formic acid (FA)) and acetonitrile (0.07% FA). Thepurity of all final compounds was 95% or higher, as measured by HPLC.The exact mass for compound 40 was measured in a LCT-Premier XE(Waters-Micromass) coupled to UPLC (Acquity, Waters). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.42% | Put 102 g (1 mol) of <strong>[503-74-2]isovaleric acid</strong>, 48 g (1.2 mol) of sodium hydroxide, and 192 g of water into the flask.Stir the temperature and control the temperature for 70 80 for 3 hours.First remove 106 g of water at normal pressure, and then put 600 g of toluene (including 400 g of toluene recovered in Example 2).The water was dehydrated with toluene to obtain a toluene suspension of sodium isovalerate.153 g of chloropropene (containing 60 g of chloropropene recovered in Example 2, 2 mol) and 5.1 g of tetrabutylammonium bromide were added to the toluene suspension of sodium isovalerate,The reaction was heated at reflux for 6-8 hours, and monitored by meteorological chromatography. When the chloropropene content in the reaction solution was basically unchanged, the reaction was ended.Dissolve and wash away the catalyst in the reaction solution and the sodium chloride produced by the reaction with the water extracted in step (1),It was washed again with pure water to obtain crude allyl isovalerate containing chloropropene and toluene.After the crude product is recovered from chloropropene and toluene, the product of allyl isovalerate is distilled under reduced pressure.The effective amount of the product is 135.5g, and the yield is 95.42%. |
Tags: 503-74-2 synthesis path| 503-74-2 SDS| 503-74-2 COA| 503-74-2 purity| 503-74-2 application| 503-74-2 NMR| 503-74-2 COA| 503-74-2 structure
A1173975[ 344298-81-3 ]
3-(Methyl-d3)butanoic-2,2,3,4,4,4-d6 acid
Reason: Stable Isotope
Precautionary Statements-General | |
Code | Phrase |
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P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
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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