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CAS No. : | 619-21-6 | MDL No. : | MFCD00039575 |
Formula : | C8H6O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | UHDNUPHSDMOGCR-UHFFFAOYSA-N |
M.W : | 150.13 | Pubchem ID : | 12077 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 38.79 |
TPSA : | 54.37 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) : | -5.97 cm/s |
Log Po/w (iLOGP) : | 0.87 |
Log Po/w (XLOGP3) : | 1.76 |
Log Po/w (WLOGP) : | 1.2 |
Log Po/w (MLOGP) : | 0.97 |
Log Po/w (SILICOS-IT) : | 1.36 |
Consensus Log Po/w : | 1.23 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -2.15 |
Solubility : | 1.06 mg/ml ; 0.00706 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.52 |
Solubility : | 0.454 mg/ml ; 0.00302 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -1.7 |
Solubility : | 2.99 mg/ml ; 0.0199 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.0 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With thionyl chloride; at 0 - 20℃; for 12h;Inert atmosphere; | To a solution of 4-formylbenzoic acid or 3-formylbenzoic acid (1.0 g, 6.67 mmol) in methanol (15 mL) was added SOCl2 (1.5 mL, 20.00 mmol) at 0 C. The mixture was stirred at ambient temperature for 12 h, and then concentrated. Saturated NaHCO3 solution was added to adjust the pH to 7?8. The aqueous layer was extracted with ethyl acetate. The combined extracts was washed with brine, dried over anhydrous Na2SO4 and evaporated in vacuo to give methyl 4-formylbenzoate and methyl 3-formylbenzoate (0.8 g, 76percent), respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With ammonium acetate; acetic acid; at 90℃; for 5h; | General procedure: An aromatic aldehyde (5 mmol) was dropped into a solution ofammonium acetate (12 mmol) in dry nitromethane (10 mL) andacetic acid (20 mL) at 90 C with stirring. The mixture was thenrefluxed for 5 h, and the mixture was poured into water andextracted with ethyl acetate (3 50 mL). The extracts werewashed with a saturated NaCl solution, dried over Na2SO4, filteredand evaporated under reduced pressure. The residue was recrystallizedfrom methanol or purified by column chromatography onsilica gel (ethyl acetate/petroleum ether) to afford the target2-nitrovinyl benzene derivative. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With piperidine; pyridine; at 20℃; for 1h;Resolution of racemate; | 1 was synthesised via Knoevenagel-Doebner-condensation from 1 eq. 3-formyl benzoic acid and 1.2 eq. malonic acid in pyridine(0.1 eq. of piperidine as a catalyst).1?3 The reaction mixture was stirred for 1 h at RT, followed by reflux until the formation of CO2 ceased. After cooling, the reaction was quenched by amixture of ice and conc. hydrochloric acid. The resulting white crystals were washed withwater and dried in vacuo. The raw product was dissolved in ether and treated with sodium bisulfite to remove the remaining aldehyde starting material.4 The ether was removed by vacuum evaporation and the resulting pale yellow crystals were dried in vacuo. 1 was received in 97percent yield (according to 1H- and 13C-NMR (>95percent), NMR data are in accordancewith published data5). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride; In N-methyl-acetamide; toluene; | a) Preparation of 3-Formylbenzoyl chloride A mixture of 3-formylbenzoic acid (84 grams (g), 0.558 moles), thionyl chloride (80.5 g, 0.71 moles), and dimethylformamide (3 milliliters (ml)), in toluene (500 ml) was slowly warmed to 70 C. and stirred at that temperature for 2 hours. The toluene was eliminated in the rotavap to yield 97.7 g of 3-formylbenzoyl used in the next step as such. | |
With thionyl chloride; In toluene; for 1h;Heating / reflux; | 3-Formylbenzoic acid (0.10 g, 0.67 mmol) was dissolved in toluene (7 mL). Thionyl chloride (0.80 g, 6.7 mmol) was added thereto, and the mixture was heated under reflux for 1 hour. The reaction solution was concentrated, and the residue was dissolved in tetrahydrofuran (5 mL). The resulting solution was added dropwise to a solution of triethylamine (69 mg, 0.68 mmol) and hexahydro-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazin-3-one (0.20 g, 0.68 mmol) in tetrahydrofuran (3 mL) at 0C, and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with water and then extracted with ethyl acetate. The organic layer was sequentially washed with 1 N hydrochloric acid, an aqueous saturated sodium hydrogen carbonate solution, water and saturated brine, and dried over magnesium sulfate. The solid was filtered off, and the filtrate was concentrated. The residue was purified with silica gel column chromatography (hexane: ethyl acetate = 1: 1 to ethyl acetate), and the fractions were collected and concentrated. The residue was collected by filtration and washed with diisopropyl ether to obtain the title compound (0.19 g, yield 66%). Melting point 174-176C. 1H NMR (CDCl3) delta 2.30 (1H, br s), 3.06 (2H, br s), 3.60-3.69 (1H, m), 3.89 (1H, br s), 4.49-4.52 (2H, m), 7.26-7.65 (12H, m), 7.91 (1H, s), 7.97-8.00 (1H, m), 10.06 (1H, s). | |
With thionyl chloride; In toluene; for 2h;Inert atmosphere; Reflux; | Thionyl chloride (4.9 mL, 66.7 mmol, 10.0 equiv) was addedto a suspension of 3-formylbenzoic acid (1.0 g, 6.7 mmol, 1.0 equiv)in dry toluene (50 mL) under argon. This was stirred at reflux for2 h, and it turned from a suspension to a solution and was thenallowed to cool to rt. The toluene and excess thionyl chloride wasremoved under vacuum. This crude mixture was dissolved indry CH2Cl2 (30 mL) and 2-amino-2-methyl-propanol (1.3 mL,13.3 mmol, 2.0 equiv) was slowly added dropwise at 0 C. Thiswas stirred for 5 h and then filtered and concentrated to provide adull yellow oil. This residue was purified by column chromatographywith CHCl3/EtOH (98:2) as eluent to afford pure 26.White solid.Yield: 1.04 g, 77% over two steps. |
1.04 g | With thionyl chloride; In toluene; for 2h;Reflux; Inert atmosphere; | 4.1.3.1. 3-Formyl-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzamide(26). Thionyl chloride (4.9 mL, 66.7 mmol, 10.0 equiv) was addedto a suspension of 3-formylbenzoic acid (1.0 g, 6.7 mmol, 1.0 equiv)in dry toluene (50 mL) under argon. This was stirred at reflux for2 h, and it turned from a suspension to a solution and was thenallowed to cool to rt. The toluene and excess thionyl chloride wasremoved under vacuum. This crude mixture was dissolved indry CH2Cl2 (30 mL) and 2-amino-2-methyl-propanol (1.3 mL,13.3 mmol, 2.0 equiv) was slowly added dropwise at 0 C. Thiswas stirred for 5 h and then filtered and concentrated to provide adull yellow oil. This residue was purified by column chromatographywith CHCl3/EtOH (98:2) as eluent to afford pure 26.White solid.Yield: 1.04 g, 77% over two steps. 1H NMR(500 MHz, CDCl3): d 10.06(s, 1H, OC-H), 8.20 (t, 1H, J = 1.5 Hz, Ar), 8.06 (ddd, 1H, J = 7.7 Hz,J = 1.8 Hz, J = 1.3 Hz, Ar), 8.01 (td, 1H, J = 7.6 Hz, 1.4 Hz, Ar), 7.63(t, 1H, J = 7.7 Hz, Ar), 6.37-6.48 (m, 1H, COANH), 4.41-4.54 (m,1H, OH), 3.72 (s, 2H, CH2), 1.45 (s, 6H, 2 CH3). 13C NMR(125 MHz, CDCl3): d 191.9 (OC-H), 167.3 (C OANH), 136.8,136.3, 133.5, 133.1, 129.9, 127.8 (Ar), 70.8 ((CH3)2ACACH2), 57.1(CH2), 25.0 (2 CH3). MS (ES) m/s: C12H14O3N calculated [MH]+220.0974, actual [MH]+ 220.0970. |
With thionyl chloride; In toluene; at 60℃; for 4h; | <strong>[619-21-6]3-Carboxybenzaldehyde</strong> (609 mg, 4.05 mmol) in thionyl chloride (4 ml) and toluene (4 ml)was heated at 60 C for 4 h before solvents were evaporated. | |
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at -20℃; for 0.0833333h;Inert atmosphere; | To a separate dry round bottom flask under argon containing DMF (2 77 ml, 36 0 mmol) in Et2O (100 ml) at OX, oxalyl chloride (3.14 ml. 36 0 mmol) was added with constant stirring Gas evolution ceased in ca 5 minutes, and a colourless precipitate formed Ether was evaporated under vacuum, and to the solid salt so obtained was added DCM (60 ml) The suspension was cooled to - 20C and 3-formyl-benzoiotac acid (5 4 g, 36,0 mmol) was added at once In less than 5 minutes, all of the material went in solution, indicating that 3-formyl- benzoylchloride has formed. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | General procedure: Step A: 3-(azetidine-1-carbonyl) benzaldehyde (8a)To a solution of 3-formyl-benzoic acid 6 (150 mg, 1 mmol) inDMF (5 mL) was added azetidine (68 mg, 1.20 mmol) and the solutionwas stirred for 30 min at 25 C. Then the solution was treatedwith HOBT (202 mg, 1.50 mmol) and EDCI (383.4 mg, 2 mmol). Thereaction was stirred at 25 C for 4 h. After the reaction was completed,the mixture was added water and EtOAc. The organic layerwas washed with 1 M NaOH, 1 M HCl then brine and was driedover anhydrous sodium sulfate (Na2SO4). Then solvent wasremoved under reduced pressure. The residual solid was purifiedby silica gel column chromatography using petroleum ether-ethylacetate (4:1 to 2:1) to give white solid (130 mg). 69percent yield. | |
76% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In DMF (N,N-dimethyl-formamide); at 25℃; for 18.25h; | D. 3-(Piperidine-1-carbonyl)-benzaldehyde. To a solution of 3-formyl-benzoic acid (2.0 g, 13 mmol) in DMF (130 mL) was added piperidine (1.25 g, 14.7 mmol), and the resulting solution was stirred at 25° C. for 15 min. The solution was treated with HOBt (2.7 g, 20 mmol) and EDCI (3.8 g, 20 mmol), and the reaction mixture was stirred at 25° C. for 18 h. The mixture was partitioned with H2O (250 mL) and EtOAc (300 mL), and the organic layer was washed with 1 M NaOH (100 mL), 1 M HCl (100 mL) then brine (100 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to provide a colorless oil (2.21 g, 76percent). MS (ESI): mass calculated for C13H15NO2, 217.11; m/z found, 218.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 10.04 (s, 1H), 7.94-7.90 (m, 2H), 7.68-7.57 (m, 2H), 3.73 (br s, 2H), 3.34 (br s, 2H), 1.70-1.54 (m, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With N-Bromosuccinimide; sulfuric acid; at 60℃; for 2.25h; | 3-Formylbenzoic acid (10 g, 71.9 mmol)was taken up in concentrated H2SO4 (100 mL) and heated to60 °C. To the mixture was added N-bromosuccinimide (134 g, 75.5 mmol) in threeportions each in 15 min. After 2 h the reaction was complete as determined byLCMS analysis, and the reaction mixture was poured into crushed ice (1000 g) toprecipitate the solids. The precipitated solids were filtered, washed withwater (40 mL), and finally dried under high vacuum to give 5-bromo-3-formylbenzoic acid (15 g, 91percent);1H NMR (D6-DMSO): d13.71 (s br, 1 H), 10.06 (s, 1 H), 8.41 (t, J= 1.4 Hz, 1 H), 8.32-8.30 (m, 2 H). |
76.6% | With N-Bromosuccinimide; sulfuric acid; at 20℃; for 3.16667h; | Into a round bottom flask were combined 3-formylbenzoic acid (10.0 g, 66.6 mmol) and sulfuric acid (653 g, 6.66 mol). N-Bromosuccinimide (14.23 g, 79.9 mmol) was added portion wise over a 10 minute period and the reaction was stirred at room temperature for 3 h upon which the mixture was poured over ice. The white precipitate that formed was filtered, washed with cold water (5 x 100 mL), and recrystallized from water-ethanol to afford the title compound as a white solid (12.98 g, 76.6percent). LC-MS: 227.0 [M-I]-; 1H NMR (400 MHz, DMSO-d6): 10.05 (s, IH), 8.40 (t, IH, J = 1.5 Hz), 8.3 (d, 2H, J = 1.5 Hz). |
With N-Bromosuccinimide; sulfuric acid; at 60℃; for 2.75h; | A solution of 3-formyl-benzoic acid (10.8 g) in H2SO4 (100 mL) is warmed to 60°C before lambda/-bromo-succinimide (13.4 g, 75.5 mmol) was added in 3 portions every 15 min. After complete addition, stirring was continued for 2 h at 600C. The mixture is poured onto 1000 g of ice. The precipitate that formed was collected, washed with water and dried under high vacuum to give 3-formyl-5-bromo-benzoic acid as a white powder (15.1 g). LC-MS*: tR = 0.39 min, [M+H]+ = 227.03. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In nitrobenzene; at 160℃; for 30h; | 0.87 g 3-carboxybenzaldehyde and 0.866 g <strong>[3537-14-2]2,3-diamino-5-nitropyridine</strong> in 50 ml nitrobenzene were heated to 160 C. for 30 hrs. The mixture was cooled to room temperature and 200 ml ethyl acetate and 100 ml ethyl ether were added. The precipitated product was collected by filtration and dried. Yield 1.135 g |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Example 5; Stage 1 - Preparation of 3-[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]benzoic acid; <strong>[619-21-6]3-Carboxybenzaldehyde</strong> (25g, 0.167mol) and K2CO3 (69g, 0.499mol) were added to water (25OmL) and cooled to 0-50C. Trimethyl phosphonoacetate (32.3mL, 0.2mol) was charged dropwise maintaining the reaction temperature below 15°C. The reaction was warmed and stirred at RT for 17h. The mixture was acidified to pH ~ 1 , filtered and dried in vacuo to afford the product as an off-white solid (37.25g, >100percent - slightly wet). 1H NMR (300MHz, CD3OD) delta: 8.23 (1 H, s), 8.06 (1 H, d, J=7.8Hz), 7.86 (1 H1 d, J=7.5Hz), 7.75 (1 H, d, J=15.9Hz), 6.61 (1 H, d, J=16.2Hz), 7.54 (1 H, t), 3.81 (3H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In methanol; for 2.0h;Heating / reflux; | To a mixture of 3-formylbenzoic acid (500 mg) andp-toluenesulfonylmethyl isocyanide (715 mg) in methanol (20 mL) was added potassium carbonate (1.38 g) and the mixture was heated under reflux for 2 hours. After evaporation of solvent, the residue was partitioned between ethyl acetate and water. The aqueous layer was separated and acidified with IN hydrochloric acid. The resulting precipitates were collected and washed with water, methanol and ether to give3- (1, 3-oxazol-5-yl) benzoic acid as a colorless amorphous powder (484 mg). 3- (1, 3-Oxazol-5-yl) benzoic acid NMR (DMSO-d6, delta) : 7.63 (1H, t, J=8Hz), 7.84 (1H, s), 7.89-8. 02 (2H, m), 8.25 (1H, m), 8.50 (1H, s), 13.22 (1H, br) MS (ESI+) : m/z 188 (M-H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Combinatorial reaction / High throughput screening (HTS); | Libraries were prepared in a single compound per well format. Stock solutions of all aldehydes (0.5 M) and aryloxyamines (0.4 M) were prepared in DMSO. A Gilson 215 Liquid Handler equipped with a 1 mL syringe, 1.1 mL tubing, and a 13 mm I.D. probe was used to distribute all solutions into a 96 well (2 mL volume) polypropylene plate at a rate of 0.3 mL/min. To make 0.5 mL of a 0.1 M solution of each oxime ether, 100 muL (0.05 mmol, 1 eq.) of aldehyde, 156 muL (0.63 mmol, 1.25 eq.) of aryloxyamine, and 244 muL of 0.164 M acetic acid, were distributed to each well of the plate. The plate was covered and agitated for 24 h at room temperature using a dual action shaker. The reactions were diluted to 720 muM in DMSO and analyzed by LC-MS to determine yield, purity, and identity. Compounds were stored frozen at -20 C. after synthesis. Reaction yield was determined using the integrated value of aldehyde that remained in the reaction mixture. Calibration curves of all aldehydes were made and the yield of each oxime ether was calculated assuming all the aldehyde that reacted quantitatively formed oxime ether; i.e. if 5% of aldehyde remained in the reaction mixture the yield of oxime ether would be 95%. Yields ranged from 98-100% and >95% purity in all wells. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.99 g (90%) | With hydrogenchloride; sodium hydrogencarbonate; N-ethyl-N,N-diisopropylamine; In dichloromethane; N,N-dimethyl-formamide; | (d) To a solution of 5.00 g (33.26 mmol) 3-formylbenzoic acid in dichloromethane at 0 C. was added oxalyl chloride (3.48 mL, 39.92 mmol) and DMF (0.01 mL). The reaction was stirred for 3 h at 25 C., and then concentrated to dryness. The residue (2.1 g, 12.45 mmol) was dissolved in dichloromethane (30 mL) and 4-isopropyl-3-methylaniline-HCl (2.55 g, 13.70 g) added, followed by diisopropylethylamine (4.48 mL). After stirring for 2 h, the solution was washed with sat. sodium bicarbonate (2*20 mL) and 1N HCl (2*20 mL) and the organic layer dried over sodium sulfate and concentrated to dryness. The residue was purified on silica gel (3:1 hexane:ethyl acetate) to provide 2.99 g (90%) of 3-formyl-N-(4-isopropyl-3-methylphenyl)benzamide, G-1d, as a off-white solid: 1H NMR (300 MHz, CDCl3) delta10.12 (s, 1H), 8.60-8.58 (m, 1H), 8.38-8.36 (m, 1H), 8.21-8.15 (m, 2H), 8.07-8.04 (m, 1H), 7.93 (br s, 1H), 7.71-7.67 (m, 1H), 7.44 (br s, 1H), 7.27-7.24 (s, 1H), 3.15-3.10 (m, 1H), 2.35 (s, 3H),), 1.23 (d, 6H, J=6.7 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | 1-[2-(Methylamino)ethyl]piperidin-4-yl biphenyl-2-ylcarbamate (1.00 g, 2.83 mmol) was dissolved in dichloromethane (20 mL), 3-formylbenzoic acid (425 mg, 2.83 mmol), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluroniumhexafluorophosphate (1.08 g, 2.83 mmol) and diisopropylethylamine (1.48 mL, 8.49 mmol) were added under ice cooling, and the mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. After the reaction was completed, a saturated aqueous sodium hydrogencarbonate solution was added, and ethyl acetate was further added to separate the layers. The resulting organic layer was separated, washed with saturated sodium chloride solution, and then dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:methanol, 10:1, v/v) to give the title compound (1.54 g; yield, 100percent) as a colorless oily substance. 1H HMR (CDCl3, 400 MHz) : delta1.5-3.7 (15H, m), 6.6 (1H, s), 7.0-7.1 (1H, m), 7.1-7.2 (2H, m), 7.3-7.4 (3H, m), 7.4-7.5 (2H, m), 7.5-7.6 (1H, m), 7.7-7.8 (1H, m), 7.9-8.0 (2H, m), 10.0 (1H, s). | |
98% | With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; N,N-dimethyl-formamide; at 20℃; | Preparation 7A Alternately, the title compound was prepared by acylation of 3-acetylbenzoic acid with biphenyl-2-ylcarbamic acid 1-(2-methylaminoethyl)piperidin-4-yl ester, which then underwent oxidation, followed by an N-acylation step. <strong>[619-21-6]3-carboxybenzaldehyde</strong> (4.07 g, 27.11 mmol, 1 eq), HATU (10.307 g, 27.11 mmol, 1 eq) and biphenyl-2-ylcarbamic acid 1-(2-methylaminoethyl)piperidin-4-yl ester (9.58 g, 27.11 mmol, 1 eq; prepared as described in Preparation 6) were dissolved in a solution of DCM (100 mL) and DMF (10 mL). DIPEA (14 mL, 81.33 mmol, 3 eq) was added portionwise and the solution was allowed to stir at room temperature. The reaction mixture was concentrated under vacuum, yielding a yellow oil (34.1 g). The crude oil was dissolved in DCM and washed with H2O:brine (3*, 200 mL) and with brine (1*). The organic layer was concentrated under vacuum to afford biphenyl-2-ylcarbamic acid 1-{2-[(3-formylbenzoyl)methylamino]ethyl}piperidin-4-yl ester as a yellow foam (13.165 g, 98percent): |
98% | With N-ethyl-N,N-diisopropylamine; HATU; In DCM; N,N-dimethyl-formamide; at 20℃; | Preparation 7A Alternately, the title compound was prepared by acylation of 3-acetylbenzoic acid with biphenyl-2-ylcarbamic acid 1-(2-methylaminoethyl)piperidin-4-yl ester, which then underwent oxidation, followed by an N-acylation step. <strong>[619-21-6]3-carboxybenzaldehyde</strong> (4.07 g, 27.11 mmol, 1 eq), HATU (10.307 g, 27.11 mmol, 1 eq) and biphenyl-2-ylcarbamic acid 1-(2-methylaminoethyl)piperidin-4-yl ester (9.58 g, 27.11 mmol, 1 eq; prepared as described in Preparation 6) were dissolved in a solution of DCM (100 mL) and DMF (10 mL). DIPEA (14 mL, 81.33 mmol, 3 eq) was added portionwise and the solution was allowed to stir at room temperature. The reaction mixture was concentrated under vacuum, yielding a yellow oil (34.1 g). The crude oil was dissolved in DCM and washed with H2O:brine (3*, 200 mL) and with brine (1*). The organic layer was concentrated under vacuum to afford biphenyl-2-ylcarbamic acid 1-{2-[(3-formylbenzoyl)methylamino]ethyl}piperidin-4-yl ester as a yellow foam (13.165 g, 98percent): This aldehyde was oxidized to N-{2-[4-(biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]ethyl}-N-methylisophthalamic acid using sulfamic acid (3.95 g, 40.65 mmol, 1.5 eq) and NaClCO2 (4.6 g, 40.65 mmol, 1.5 eq, dissolved in 20 mL of H2O) in glacial acetic acid (35 mL) at 0° C. for 40 minutes and at room temperature for 1 hour. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With hydrogenchloride; sodium tris(acetoxy)borohydride; acetic acid; In 1,4-dioxane; methanol; diethyl ether; dichloromethane; sodium hydrogencarbonate; | A. N-[(2,3-dichlorophenyl)methyl]-N-((3-methoxycarbonyl)-phenylmethyl)-amine, hydrochloride Acetic acid (0.57 mL, 10 mmol) was added to a solution of 3-carboxybenzaldehyde (1.0 g, 6.7 mmol) and <strong>[39226-95-4]2,3-dichlorobenzylamine</strong> (1.3 mL, 10 mmol) in dichloromethane (33 mL). The mixture was stirred for 1 hour, sodium triacetoxyborohydride (2.1 g, 10 mmol) was added and the solution was stirred for 16 hours and concentrated under vacuum. The residue was dissolved in methanol (50 mL), the solution was cooled to 0C, and anhydrous HCl was bubbled into the mixture. The solution was warmed to room temperature, heated to reflux for 6 hours and concentrated under vacuum. The residue was dissolved in 10% NaHCO3 (50 mL) and the aqueous solution was extracted with ethyl acetate (3 X 100 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated under vacuum. The residue was dissolved in diethyl ether (20 mL), treated with 4M HCl in dioxane (5 mL), and the solid was filtered. The solid material was washed with diethyl ether (3 X 10 mL) and dried under vacuum to afford Compound A (1.95 g, 81%) as a white solid. MS:(M+H)+ 324. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 241 3-[(2-Methoxy-5-phenylcarbamoyl-phenylamino)-methyl]-benzoic acid The title compound has been made using the procedure of Example 50, but using 3-amino-4-methoxy-N-phenyl benzamide and 3-carboxybenzaldehyde as starting materials, which are commercially available from Aldrich; m.p. 210-212 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With benzotriazol-1-ol; diisopropyl-carbodiimide; In dichloromethane; at 20℃; | Example 60: 3-(5-Oxo-4,5,6,7,8,9-hexahydro-2H-1,2,7,9-tetraazabenz[f]inden-4-yl)-N-(4-trifluoromethoxy-benzyl)-benzamide; compound with trifluoro-acetic acid Preparation of the aldehyde: to a solution of 300 mg of 3-carboxybenzaldehyde (2 mmoles) and 382 mg of <strong>[93919-56-3]4-(trifluoromethoxy)benzylamine</strong> (2 mmoles) in 5 ml of DCM is successively added 540 mg of 1-hydroxybenzotriazole (HOBt) (4 mmoles) and 0.63 mg of diisopropylcarbodiimide (DIC) (4 mmoles). The reaction mixture is stirred overnight at room temperature and then poured into 20 ml of 10% KH2SO4 solution. The mixture is extracted with twice 15 ml of ethyl acetate. The combined organic phases are washed with 20 ml of water, 20 ml of brine, dried over MgSO4 and evaporated giving 670 mg of 3-formyl-N-(4-trifluoromethoxy-benzyl)-benzamide (yield=85%). ([M+H]+): 324). Ret. Time: 5.24 min (gradient 5 to 85 % acetonitrile in 7 min). |
Yield | Reaction Conditions | Operation in experiment |
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59% | General procedure: Step A: 3-(azetidine-1-carbonyl) benzaldehyde (8a)To a solution of 3-formyl-benzoic acid 6 (150 mg, 1 mmol) inDMF (5 mL) was added azetidine (68 mg, 1.20 mmol) and the solutionwas stirred for 30 min at 25 C. Then the solution was treatedwith HOBT (202 mg, 1.50 mmol) and EDCI (383.4 mg, 2 mmol). Thereaction was stirred at 25 C for 4 h. After the reaction was completed,the mixture was added water and EtOAc. The organic layerwas washed with 1 M NaOH, 1 M HCl then brine and was driedover anhydrous sodium sulfate (Na2SO4). Then solvent wasremoved under reduced pressure. The residual solid was purifiedby silica gel column chromatography using petroleum ether-ethylacetate (4:1 to 2:1) to give white solid (130 mg). 69percent yield. | |
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 15h; | Compound 52: (3-(5-(2-methoxyphenyl)-1H-pyrazol-3-yl)phenyl)(morpholino)methanone 3-Formylbenzoic acid (450 mg) was reacted with morpholine (313 mg), EDCI-HCl (864 mg), triethylamine (1.3 ml), and HOBt-hydrate (689 mg) in dichloromethane (10 ml) for 15 hours at room temperature. The reaction mixture was diluted with water and extracted with dichloromethane. The extract was washed with brine, dried over Na2SO4, and concentrated in vacuo to give Compound 51. Compound 51 was reacted with tosylhydrazine (559 mg) in acetonitrile (5 ml) at room temperature for 3 hours. 5N NaOH (0.6 ml) was added and the mixture was stirred at room temperature for 15 min. Then, 2-methoxyphenylacetylene (0.79 g) was added and the resulting mixture was stirred at 50° C. for 48 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The extract was washed with brine, dried over Na2SO4, and concentrated in vacuo. Purification by HPLC afforded the title Compound 52 as a pale yellow solid (87 mg). 1H NMR (400 MHz, DMSO-d6) delta 3.32-3.78 (m, 8H) 3.93 (s, 3H) 7.01-7.09 (m, 1H) 7.16 (d, J=7.83 Hz, 1H) 7.23 (s, 1H) 7.31-7.40 (m, 2H) 7.51 (t, J=7.71 Hz, 1H) 7.80 (dd, J=7.71, 1.64 Hz, 1H) 7.87 (s, 1H) 7.94 (d, J=8.08 Hz, 1H). [M+H] calc'd for C21H21N3O3, 364; found, 364. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | (00341] Commercially available 3-formylbenzoic acid (15.0 g, 0.1 mol) and commercially available 4'-hydroxy-3'-methylacetophenone (15.0 g, 0.1 mol) were dissolved in 150 mL of methanol and 50 mL of water. The solution was cooled with an ice-water bath, to which was added potassium hydroxide (28.0 g, 0.5 mol). The reaction mixture was stirred overnight. The resulted mixture was poured on to 600 mL of ice-water, acidified to pH = 4 - 5 with 1 N HCl, filtered, washed with water (200 mL), methanol (100 mL) and dried in the air. 19 g (67%) of a yellowish solid was obtained. 1H NMR (400 MHz, DMSOd6): delta 13.18 (br, IH), 10.39 (s, I H), 8.38 (s, I H), 8.15 (m, IH), 7.95 (m, 4H), 7.75 (d, IH), 7.60 (m, IH), 6.95 (d, IH), 2.20 (s, 3H). MS (EI): 283 (MH+). | |
67% | With potassium hydroxide; In methanol; water; | Step 1; (E)-3-(3-(4-hydroxy-3-methylphenyl)-3-oxoprop-1-enyl)benzoic acid; 3-Formylbenzoic acid (15.0 g, 0.1 mol, Aldrich) and 4'-hydroxy-3'-methylacetophenone (15.0 g, 0.1 mol, Indofine) was dissolved in 150 mL of methanol and 50 mL of water. The solution was cooled with an ice-water bath, to which was added potassium hydroxide (28.0 g, 0.5 mol). The reaction mixture was stirred overnight. The resulted mixture was poured on to 600 mL of ice-water, acidified to pH=4-5 with 1 N HCl, filtered, washed with water (200 mL), methanol (100 mL) and dried in the air. 19 g (67%) of a solid was obtained as the desired (E)-3-(3-(3-(4-hydroxy-3-methylphenyl)-3-oxoprop-1-enyl)phenoxy)acetic acid. 1H NMR (400 MHz, DMSO-d6): 13.18 (br, 1H), 10.39 (s, 1H), 8.38 (s, 1H), 8.15 (m, 1H), 7.95 (m, 4H), 7.75 (d, 1H), 7.60 (m, 1H), 6.95 (d, 1H), 2.20 (s, 3H). MS (EI) for C17H14O4: 283 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
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86.3% | To a solution of acetophenone derivative 2 (13 g, 71.8 mmol) in methanol (150 mL) was added 10N aq. NaOH (23 mL) and stirred at rt for 15 min. <strong>[619-21-6]3-Carboxybenzaldehyde</strong> (10.77 g, 71.8 mmol) was added to the stirred solution and refluxed for 12 h. The reaction progress was monitored by TLC for the disappearance of the starting material 2. The reaction mixture was cooled to rt and neutralized with 10N aq. HCl (23 mL), resulting in the formation of a precipitate. The precipitate was filtered, washed with water and dried in vacuo to obtain the crude product. Recrystallization of the crude product from methanol-water (95:5) resulted in the pure product 3 as a yellow solid (19.41 g, 86.3percent). TLC: Rf = 0.31 (CH2Cl2/EtOAc 90:10). m.p. 253-254 °C. 1H NMR (400 MHz, DMSO-d6) delta 6.84 (d, J = 2.2 Hz, 1H), 7.07 (dd, J = 8.8 Hz, 1H), 7.26 (d, J = 16.4 Hz, 1H), 7.46 (d, J = 16.3 Hz, 1H), 7.57 (t, J = 7.7 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 8.04 (d, J = 7.6 Hz, 1H), 8.19 (d, J = 9.2, 1H), 8.23 (s, 1H), 12.32 (s, 2H, exchangeable with D2O). | |
With hydrogenchloride; sodium hydroxide; In methanol; | (E)-3-(3-(5-Hydroxy-2-nitrophenyl)-3-oxoprop-1-enyl)benzoic acid 1-(5-Hydroxy-2-nitrophenyl)ethanone, 13 g (0.0718 mole) was dissolved in 150 ml of methanol and placed in 500 ml round-bottomed flask. To this 23 ml (3 equiv.) of 10 N NaOH was added and allowed to stir at room temperature for 15 mins, followed by addition of 10.77 g (0.0718 mole) of <strong>[619-21-6]3-carboxybenzaldehyde</strong>. Reaction mixture was refluxed for 12 hrs and monitored on TLC. The reaction mixture was allowed to cool and neutralized with 23 ml of 10 N HCl, resulting in the formation of a precipitate. The precipitate was filtered, washed thoroughly with water and allowed to dry, to give 21.2 g of crude product. Recrystallization from methanol-water (5percent) resulted in 19.4 g (86.3percent) of pure product, m.p. 253-254° C., TLC (90percent CH2Cl2: 10percent EtOAc) Rf=0.306. MS: m/z 313 (M+), 296, 284, 268, 250, 163 (base peak), 150, 135, 131, 120, 107, 92, 91, 77, 65, 51. IR: 3408 and 3215 cm-1 (-OH), 1702 cm-1 (alpha, beta unsaturated ketone C=O), 1627 cm-1 (aromatic carboxylic acid C=O), 1575 and 1332 cm-1 (aromatic nitro). 1H-NMR (DMSO-d6, delta ppm): a: 6.84, d, 1H, J=2.2 Hz; b: 7.07, dd, 1H, Jbh=8.8; c: 7.26, d, 1H, Jcd=16.4 Hz; d: 7.46, d, 1H, Jdc=16.3 Hz; e: 7.566, t, 1H, J=7.7 Hz; f: 7.99, d, 1H, Jfb=8 Hz; g: 8.04, d, 1H, Jge=7.6 Hz; h: 8.19, d, 1H, Jhe=9.2; i: 8.23, s, 1H; j: 12.32 (exchangeable with D2O), s, 2H. 13C-NMR (DMSO-d6, delta ppm): C1: 114.73, C2: 116.82, C3: 127.27, C4: 127.72, C5: 129.30, C6: 129.90, C7: 131.35, C8: 131.64, C9: 132.30, C10: 134.51, C11: 137.38, C12: 139.06, C13: 144.28, C14: 163.45, C15: 166.84, C16: 192.77. Anal.: Calc. for C16H11NO6: C, 61.35; H, 3.54; N, 4.47. Found: C, 61.06; H, 3.54; N, 4.41. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | To a stirred mixture of 3-formylbenzoic acid (450 mg, 3 mmol) in anhydrous dichloromethane (20 mL) was added triethylamine (758 mg, 7.5 mmol), 1-hydroxybenzotriazole (466 mg, 3.45 mmol), followed by 1-ethyl-3-(3-dimethylamino propyl) carbodiimide hydrochloride (629 mg, 3.45 mmol). After the addition, the mixture was stirred at room temperature for 40 mins. Then the mixture was cooled to 0° C. and cyclopropyl(piperazin-1-yl)methanone hydrochloride (629 mg, 3.3 mmol) was added in portion-wise. After the addition, the mixture was allowed to stir at room temperature overnight. The mixture was diluted with dichloromethane (50 mL), washed with saturated citric acid (100 mL.x.2), followed by saturated sodium bicarbonate (100 mL.x.2), brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give 3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)benzaldehyde (810 mg, yield 94percent) as a light yellow oil. 1H-NMR (400 MHz, CDCl3) delta (ppm): 0.79-0.85 (m, 2H), 1.00-1.04 (m, 2H), 1.73-1.76 (m, 1H), 3.47-3.77 (m, 8H), 7.62-7.66 (t, J=7.6 Hz, 1H), 7.70-7.72 (d, J=7.6 Hz, 1H), 7.95-7.98 (m, 2H), 10.1 (s, 1H); LC-MS (ESI) m/z: 287 (M+1)+ | |
94% | Example 28A3-(4-(Cyclopropanecarbonyl)piperazine- 1 -carbonyl) benzaldehyde[00555] To a stirred mixture of 3-formylbenzoic acid (450 mg, 3 mmol) in anhydrous dichloromethane (20 mL) was added triethylamine (758 mg, 7.5 mmol), 1 -hydroxybenzotriazole (466 mg, 3.45 mmol), followed by l-ethyl-3-(3-dimethylamino propyl) carbodiimide hydrochloride (629 mg, 3.45 mmol). After the addition, the mixture was stirred at room temperature for 40 mins. Then the mixture was cooled to 0 °C and cyclopropyl(piperazin- 1 -yl)methanone hydrochloride (629 mg, 3.3 mmol) was added in portion- wise. After the addition, the mixture was allowed to stir at room temperature overnight. The mixture was diluted with dichloromethane (50 mL), washed with saturated citric acid (100 mL*2), followed by saturated sodium bicarbonate (100 mL*2), brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give 3-(4-(cyclopropanecarbonyl)piperazine-l -carbonyl) benzaldehyde (810 mg, yield 94percent ) as a light yellow oil. H-NMR (400 MHz, CDC13) delta (ppm): 0.79-0.85 (m, 2H), 1.00-1.04 (m, 2H), 1.73- 1.76 (m, 1H), 3.47-3.77 (m, 8H), 7.62-7.66 (t, J= 7.6 Hz, 1H), 7.70-7.72 (d, J= 7.6 Hz, 1H), 7.95- 7.98 (m, 2H), 10.1 (s, 1H); LC-MS (ESI) m/z: 287 (M+l)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | To a solution of 3-formylbenzoic acid (750 mg, 5 mmol) in anhydrous dichloromethane (15 mL) was added triethylamine (1.263 g, 12.5 mmol), 1-hydroxybenzotriazole (0.743 g, 5.5 mmol), followed by 1-ethyl-3-(3-dimethylamino propyl)carbodiimide hydrochloride (1.05 g, 5.5 mmol). After the addition, the mixture was stirred at room temperature for 40 mins. Then the mixture was cooled to 0° C. and 2-methyl-1-(piperazin-1-yl)propan-1-one hydrochloride (1.06 g, 5.5 mmol) was added portionwise. After the addition, the mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane (50 mL), washed with saturated sodium bicarbonate (50 mL.x.2), 10percent citric acid (50 mL), brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to give 3-(4-isobutyrylpiperazine-1-carbonyl)benzaldehyde (1.44 g, yield 95percent) as a gum. 1H-NMR (400 MHz, CDCl3) delta (ppm): 1.13-1.14 (d, J=6.8 Hz 6H), 2.80 (s, 1H), 3.46-3.80 (m, 8H), 7.62-7.66 (t, J=7.6 Hz, 1H), 7.69-7.71 (d, J=7.6 Hz, 1H), 7.94 (s, 1H), 7.96-7.99 (dd, J1=7.6 Hz, J2=1.2 Hz, 1H), 10.06 (s, 1H); LC-MS (ESI) m/z: 289(M+1)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With piperidine; In pyridine; at 100℃; for 18h;Inert atmosphere; | Example 11(E)-3-(3-ethoxy-3-oxoprop-1-enyl)benzoic acid (S-5)To a flask was added 3-formylbenzoic acid (1.5 g, 10 mmol), 3-ethoxy-3-oxopropanoic acid (2.0 g, 15 mmol), piperidine (0.08 mL, 0.81 mmol), and pyridine (4 mL) at roomtemperature. The reaction mixture was heated to 100 0C for 18 h under a steady flow of nitrogen gas, cooled to room temperature, and poured into 2 M aqueous HCl (100 mL). The resulting mixture was cooled to 0 0C and filtered. The filter cake washed with acetonitrile (2 x 10 mL), and dried in vacuo. Cinnamyl ester S-5 (2.20 g, 100percent) was isolated as a white solid and carried on to hydrazine formation without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With piperidine; acetic acid; In ethanol; at 150℃; for 0.333333h;Microwave irradiation; | General procedure: To a suspension of thiazolidine-2,4-dione, 2-thioxothiazolidin-4-one or 2-iminothiazolidin-4-one (1.00 mmol) and benzaldehyde (1.00 mmol) in absolute ethanol (5 mL) in a 10 mL process vial, glacial acetic acid (0.10 mmol) and piperidine (0.10 mmol) were added. The vial was sealed, placed in a microwave reactor and heated at 150 °C for 20 min (max. power 30 W). The reaction mixture was cooled and the precipitate filtered off and dried. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With piperidine; acetic acid; In ethanol; at 150℃; for 0.333333h;Microwave irradiation; | General procedure: To a suspension of thiazolidine-2,4-dione, 2-thioxothiazolidin-4-one or 2-iminothiazolidin-4-one (1.00 mmol) and benzaldehyde (1.00 mmol) in absolute ethanol (5 mL) in a 10 mL process vial, glacial acetic acid (0.10 mmol) and piperidine (0.10 mmol) were added. The vial was sealed, placed in a microwave reactor and heated at 150 °C for 20 min (max. power 30 W). The reaction mixture was cooled and the precipitate filtered off and dried. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Example 13C3-(4-Isobutyrylpiperazine- 1 -carbonyl)benzaldehyde[00513] To a solution of 3-formylbenzoic acid (750 mg, 5 mmol) in anhydrous dichloromethane (15 mL) was added triethylamine (1.263 g, 12.5 mmol), 1 -hydroxybenzotriazole (0.743 g, 5.5 mmol), followed by l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.05 g, 5.5 mmol). After the addition, the mixture was stirred at room temperature for 40 mins. Then the mixture was cooled to 0 °C, and 2 -methyl- 1 -(piperazin- 1 -yl)propan- 1 -one (1.06 g, 5.5 mmol) was added portionwise. After the addition, the mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane (50 mL), washed with saturated sodium bicarbonate (50 mL*2), 10percent citric acid (50 mL), brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to give 3-(4- isobutyrylpiperazine- 1 -carbonyl)benzaldehyde (1.44 g, yield: 95percent) as a gum. LC-MS (ESI) m/z: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With sodium azide; In water; for 1h;Reflux; | General procedure: A mixture of p-tolualdehyde (0.5 g, 4.2 mmol), phenylsulfonyl acetonitrile 6 (0.75 g, 4.2 mmol) and sodium azide (0.4 g, 6.25 mmol) in water (15 mL) was stirred under reflux for 1 h. The resulting mixture was then cooled to 5 °C, the solid obtained was filtered and washed with water (50 mL) to afford pure 7a (0.73 g, 95percent yield) as a white crystals; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With sodium azide; triethylamine hydrochloride; In N,N-dimethyl-formamide; at 70℃; for 6h; | General procedure: To a mixture of p-tolualdehyde (0.5 g, 4.2 mmol), methyl cyanoacetate (0.41 g, 4.2 mmol) and Et3N*HCl (1.43 g, 10.4 mmol) in DMF (12 mL) was added sodium azide (0.81 g, 12.5 mmol). The mixture was then stirred at 70 °C for 10 h. Following, to the reaction mixture was added water (50 mL), 10percent HCl solution (2 mL) at room temperature and extracted with ethyl acetate (2 .x. 75 mL). The combined organic phases were washed with water (3 .x. 100 mL), brine solution (1 .x. 100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was subjected to column chromatography with dichloromethane/methanol (99.5/0.5) as eluent to obtain the desired 4a (0.585 g, 65percent yield) as a white solid; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With sodium tris(acetoxy)borohydride; In tetrahydrofuran; at 20℃; | To a suspension of the previous compound (10g, 46.9 mmol) in anhydrous THF (100 mL) was added 3-formylbenzoic acid (7.74g, 51 .6 mmol, 1 .1 eq) and the mixture was stirred at 50 °C for 15 min. Then a white slurry solution of NaBH(OAc)3 (29.8g, 141 mmol, 3eq) in THF (60 mL) was added to the mixture, stirred at room temperature overnight and concentrated to dryness. Finally the residue is purified by C18 column chromatography to give intermediate 6 (8g, 49percent) as a brown powder. |
49% | To a suspension of the previous compound (10 g, 46.9 mmol) in anhydrous THF (100 mL) was added 3-formylbenzoic acid (7.74 g, 51.6 mmol, 1.1 eq) and the mixture was stirred at 50° C. for 15 min. Then a white slurry solution of NaBH(OAc)3 (29.8 g, 141 mmol, 3 eq) in THF (60 mL) was added to the mixture, stirred at room temperature overnight and concentrated to dryness. Finally the residue is purified by C18 column chromatography to give intermediate 6 (8 g, 49percent) as a brown powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With sodium tris(acetoxy)borohydride; In tetrahydrofuran; at 20℃; | To a suspension of the previous compound (900 mg, 3.55 mmol) in anhydrous THF (10 mL) was added 3-formylbenzoic acid (587 mg, 3.91 mmol, 1 .1 eq) and the mixture was stirred at 50 °C for 15 min. Then a white slurry solution of NaBH(OAc)3 (2.2 g, 10.66 mmol, 3eq) in THF (6 mL) was added to the mixture, stirred at room temperature overnight and concentrated to dryness. Finally the residue is purified by C18 column chromatography to give intermediate 12 (670 mg, 49percent) as a brown powder. |
49% | To a suspension of the previous compound (900 mg, 3.55 mmol) in anhydrous THF (10 mL) was added 3-formylbenzoic acid (587 mg, 3.91 mmol, 1.1 eq) and the mixture was stirred at 50° C. for 15 min. Then a white slurry solution of NaBH(OAc)3 (2.2 g, 10.66 mmol, 3 eq) in THF (6 mL) was added to the mixture, stirred at room temperature overnight and concentrated to dryness. Finally the residue is purified by C18 column chromatography to give intermediate 12 (670 mg, 49percent) as a brown powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37.2% | To a solution of Intermediate 4 (10 g x 2, 0.0379 mol x 2) in DCE (400 mL x 2) was added Et3N (9.2 g x 2, 0.0910 mol x 2) and MgS04 (20 x 2, 0.139 mol x 2), and stirred for 0.5 h at 30 °C. 3- formylbenzoic acid (6.26 g x 2, 0.0417 mol x 2) and AcOH (5.46 g x 2, 0.0910 mol x 2) was added. The reaction mixture was stirred at 30 °C for 0.5 hours. NaBH(OAc)3 (24.1 g x 2, 0.1 137 mol x 2) was added and the reaction mixture was stirred at 30 °C overnight. TLC (methylene dichloride : methanol = 10:1 ) showed the reaction was complete. The reaction mixture was filtered. The filtered cake was washed with CH2CI2, the filtrate was washed with brine, dried over Na2S04 and concentrated in vacuo, and purified by preparative HPLC to give Intermediate 5 (10.2 g, 37.2percent) as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With 4-methyl-morpholine; dmap; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 20℃; for 16h; | To a solution of 3-formylbenzoic acid (600mg, 3.99 mmol) in DCM (12mL) were added tert-butyl piperazine-l-carboxylate (818.8mg, 4.40 mmol), HATU (1.82g, 4.80 mmol), NMM (l.lmL, 9.99mmol), and DMAP (49 mg, 0.39 mmol) at 0°C. Reaction was stirred at RT for 16h. TLC analysis indicated complete consumption of starting material. The reaction mixture was diluted with DCM and washed with water. Organic layer was separated and dried over Na2SC>4 and concentrated. Column chromatography of crude material afforded pure product tert-butyl 4-(3-formylbenzoyl)piperazine-l-carboxylate as off-white solid (990mg, 78percent). NMR: delta (, 400 MHz, CDC13): 1.45 (9H, s), 3.2-4.0 (8H, m), 7.60 (1H, t, J=7.6Hz), 7.66 (1H, d, J=7.6Hz), 7.90 (1H, s), 7.94 (1H, d, J=7.6Hz), 10.03 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With 4-methyl-morpholine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 16h; | To a solution of 3-formylbenzoic acid 20 (O.lg, 0.819 mmol) in DMF (2mL) were added glysine ethyl ester (0.13g, 0.98 mmol), HATU (0.37g, 0.98 mmol), and NMM (0.2g, (2.04 mmol). The reaction mixture was stirred at RT for 16h. The reaction was monitored by LCMS. The reaction mixture was concentrated and column chromatographed to afford ethyl 2-(3-formylbenzamido)acetate 35 (146 mg). Yield: 76percent. LCMS (254nm): [M+H]+ 235.95 (96.35percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With sodium tris(acetoxy)borohydride; acetic acid; In tetrahydrofuran; at 20℃; | General procedure: Method B: To a solution of 21 (0.150 g, 0.244 mmol) in THF (10 mL), the corresponding benzaldehyde (0.268 mmol), CH3COOH (0.014 mL, 0.244 mmol) and Na(OAc)3BH (0.103 g, 4.88 mmol) were added, and the reaction mixture was stirred overnight at room temperature. To quench the reaction, saturated aqueous NaHCO3 (10 mL) was used, and the water phase was extracted with EtOAc (3 10 mL), washed with brine (20 mL) and dried with Na2SO4. Thecrude residue was purified by flash chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37.2% | To a solution of Intermediate 4 (10 g*2, 0.0379 mol*2) in DCE (400 mL*2) was added Et3N (9.2 g*2, 0.0910 mol*2) and MgSO4 (20*2, 0.139 mol*2), and stirred for 0.5 h at 30° C. 3-formylbenzoic acid (6.26 g*2, 0.0417 mol*2) and AcOH (5.46 g*2, 0.0910 mol*2) was added. The reaction mixture was stirred at 30° C. for 0.5 hours. NaBH(OAc)3 (24.1 g*2, 0.1137 mol*2) was added and the reaction mixture was stirred at 30° C. overnight. TLC (methylene dichloride:methanol=10:1) showed the reaction was complete. The reaction mixture was filtered. The filtered cake was washed with CH2Cl2, the filtrate was washed with brine, dried over Na2SO4 and concentrated in vacuo, and purified by preparative HPLC to give Intermediate 5 (10.2 g, 37.2percent) as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With sodium cyanoborohydride; toluene-4-sulfonic acid; In methanol; dichloromethane; at 25℃; for 24h;Inert atmosphere; | General procedure: To a preformed solution of amine (1 equivalence) and aldehyde (1.2 equivalence) in anhydrous dichloroethane or methanol (1.0 M) was added p-TSA (1.1 equivalence) followed by NaBH3CN (1.1 equivalence) over a period of 5 minutes at room temperature. The reaction mixture was magnetically stirred at room temperature under the nitrogen atmosphere. After completion of the reaction (monitored by TLC), reaction mixture was diluted with ethyl acetate (20 mL) and quenched with water (10 mL), extracted with ethyl acetate (3 x 20 mL), the organic layer was washed with water (20 mL), dried over Na2SO4. The solvent was removed under reduced pressure to give the crude reaction mixture which was purified by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41.6% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 8h; | Step 1: Synthesis of 3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4- (difluoromethoxy)phenyl)-2-((S)-3-(3-formylbenzoyl)thiazolidine-2-carbonyloxy)ethyl)pyridine 1-oxide (Intermediate 14)3,5 -dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((S)-thiazolidine-2-carbonyloxy)ethyl)pyridine 1-oxide (mt 4, 208 mg, 0.389 mmol), 3- formylbenzoic acid (87 mg, 0.583 mmol), EDC (149 mg, 0.777 mmol) and DMAP (57.0 mg, 0.466 mmol) were dissolved in DMF (2m1). The reaction was stirred at RT for 8 hrs to achieve completion. The reaction mixture was diluted with HC1 iN, and the precipitate was filtered, washed with HC1 iN, dissolved in DCM and extracted with HC1 iN,Na2CO3 sat and brine . The organic phase was dried over Na2504 and concentrated under vacuum to give 3,5 -dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4- (difluoromethoxy)phenyl)-2-((S)-3-(3 -formylbenzoyl)thiazo lidine-2-carbonyloxy)ethyl)pyridine 1-oxide (108 mg, 0.162 mmol, 41.6 percent yield). The compound was used in the next step without any further purification.MS/ESI 667.08 [MH] + |
41.6% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 8h; | 3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((S)-thiazolidine-2-carbonyloxy)ethyl)pyridine 1-oxide (Int 4, 208 mg, 0.389 mmol), 3-formylbenzoic acid (87 mg, 0.583 mmol), EDC (149 mg, 0.777 mmol), and DMAP (57.0 mg, 0.466 mmol) were dissolved in DMF (2 ml). The reaction was stirred at RT for 8 hours to achieve completion. The reaction mixture was diluted with HCl 1N, and the precipitate was filtered, washed with HCl 1N, dissolved in DCM and extracted with HCl 1N, Na2CO3 sat and brine. The organic phase was dried over Na2SO4 and concentrated under vacuum to give 3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((S)-3-(3-formylbenzoyl)thiazolidine-2-carbonyloxy)ethyl)pyridine 1-oxide (108 mg, 0.162 mmol, 41.6percent yield). The compound was used in the next step without any further purification. MS/ESI+ 667.08 [MH]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 21h; | A solution of (S)-3 ,5 -dichloro-4-(2-(3 ,4-dimethoxyphenyl)-2-hydroxyethyl)pyridine 1-oxide (0.688 g, 2 mmol), 3-formylbenzoic acid (0.300 g, 2mmo 1), N-(3 -dimethylaminopropyl)-N?-ethylcarbodiimide hydrochloride (0.767 g, 4mmol) and 4-(dimethylamino)pyridine (0.122 g, 1 mmol) in anhydrous DCM (30 mL)was stirred at RT for 21 h. The reaction mixture was partitioned between saturatedaqueous NaHCO3 (20 mL) and DCM (10 mL) and filtered through a phase separator. The solvent was removed in vacuo and the crude material was purified by silica gel column chromatography eluting with 1:1 DCM:EtOAc to afford the title compound as an off-white solid (0.863 g, 9 1percent). ?H NMR (400 MHz, CDC13): oe 10.08 (s, 1 H), 8.54 (t, J = 1.7 Hz, 1 H), 8.27 (dt, J = 7.8,1.5 Hz, 1 H), 8.14 (s, 2 H), 8.09 (dt, J = 7.7, 1.5 Hz, 1 H), 7.63 (t, J = 7.7 Hz, 1 H), 7.05(dd, J = 8.2, 2.1 Hz, 1 H), 7.00 (d, J = 2.1 Hz, 1 H), 6.87 (d, J = 8.3 Hz, 1 H), 6.33 (dd, J =9.7, 4.6 Hz, 1 H), 3.92 (s, 3 H), 3.88 (s, 3 H), 3.76 (dd, J = 14.0, 9.8 Hz, 1 H), 3.39 (dd, J= 14.0, 4.6 Hz, 1 H). LCMS (Method 1): [MH+] = 476 at 3.55 mm. |
91% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 21h; | A solution of (S)-3 ,5 -dichloro-4-(2-(3 ,4-dimethoxyphenyl)-2-hydroxyethyl)pyridine 1-oxide (0.688 g, 2 mmol), 3-formylbenzoic acid (0.300 g, 2 mmo 1), N-(3 -dimethylaminopropyl)-N?-ethylcarbodiimide hydrochloride (0.767 g, 4mmol) and 4-(dimethylamino)pyridine (0.122 g, 1 mmol) in anhydrous DCM (30 mL) was stirred at RT for 21 hours. The reaction mixture was partitioned between saturated NaHCO3 (20 mL) and DCM (10 mL) and filtered through a phase separator cartridge. The cartridge was washed thoroughly with DCM and the solvent was removed in vacuo. The crude material was purified by silica gel column chromatography eluting with 1:1DCM:EtOAc to afford the title compound as an off-white solid (0.863 g, 9 1percent). 1H NMR (400 MHz, CDC13): oe 10.08 (s, 1 H), 8.54 (t, J = 1.7 Hz, 1 H), 8.27 (dt, J= 7.8, 1.5 Hz, 1 H), 8.14 (s, 2 H), 8.09 (dt, J = 7.7, 1.5 Hz, 1 H), 7.63 (t, J = 7.7 Hz, 1 H),7.05 (dd, J = 8.2, 2.1 Hz, 1 H), 7.00 (d, J = 2.1 Hz, 1 H), 6.87 (d, J = 8.3 Hz, 1 H), 6.33(dd, J = 9.7, 4.6 Hz, 1 H), 3.92 (s, 3 H), 3.88 (s, 3 H), 3.76 (dd, J = 14.0, 9.8 Hz, 1 H),3.39 (dd, J = 14.0, 4.6 Hz, 1 H). LCMS (Method 1): [MH+] = 476 at 3.55 mm. |
91% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 21h; | Intermediate 2. (S)-3,5-dichloro-4-(2-(3,4-dimethoxyphenyl)-2-((3-formylbenzoyl)oxy)ethyl)pyridine 1-oxide (I-2) A solution of (5)-3,5-dichloro-4-(2-(3,4-dimethoxyphenyl)-2-hydroxyethyl)-pyridine 1-oxide (0.688 g, 2 mmol), 3-formylbenzoic acid (0.300 g, 2 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.767 g, 4 mmol) and 4-(dimethylamino)pyridine (0.122 g, 1 mmol) in anhydrous DCM (30 mL) was stirred at RT for 21 hours. The reaction mixture was partitioned between saturated NaHCO3 (20 mL) and DCM (10 mL) and filtered through a phase separator cartridge. The cartridge was washed thoroughly with DCM and the solvent was removed in vacuo. The crude material was purified by silica gel column chromatography eluting with 1:1 DCM:EtOAc to afford the title compound as an off-white solid (0.863 g, 91percent). 1H NMR (400 MHz, CDCl3): delta 10.08 (s, 1H), 8.54 (t, J=1.7 Hz, 1H), 8.27 (dt, J=7.8, 1.5 Hz, 1H), 8.14 (s, 2H), 8.09 (dt, J=7.7, 1.5 Hz, 1H), 7.63 (t, J=7.7 Hz, 1H), 7.05 (dd, J=8.2, 2.1 Hz, 1H), 7.00 (d, J=2.1 Hz, 1H), 6.87 (d, J=8.3 Hz, 1H), 6.33 (dd, J=9.7, 4.6 Hz, 1H), 3.92 (s, 3H), 3.88 (s, 3H), 3.76 (dd, J=14.0, 9.8 Hz, 1H), 3.39 (dd, J=14.0, 4.6 Hz, 1H). LCMS (Method 1): [MH+]=476 at 3.55 min. |
91% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 21h; | A solution of (5)-3,5-dichloro-4-(2-(3,4-dimethoxyphenyl)-2- hydroxyethyl)pyridine 1 -oxide (described in the co-pending international application n. PCT/EP2013/075526 as Compound I 32/A) (0.688 g, 2 mmol), 3-formylbenzoic acid (0.300 g, 2 mmol), ^-(S-dimethylaminopropy^-N'-ethylcarbodiimide hydrochloride (0.767 g, 4 mmol) and 4-(dimethylamino)pyridine (0.122 g, 1 mmol) in anhydrous DCM (30 mL) was stirred at RT for 21 h. The reaction mixture was partitioned between saturated aqueous NaHC03 (20 mL) and DCM (10 mL) and filtered through a phase separator. The solvent was removed in vacuo and the crude material was purified by silica gel column chromatography eluting with 1 : 1 DCM:EtOAc to afford the title compound as an off-white solid (0.863 g, 91percent). NMR (400 MHz, CDC13): delta 10.08 (s, 1 H), 8.54 (t, J = 1.7 Hz, 1 H), 8.27 (dt, J = 7.8, 1.5 Hz, 1 H), 8.14 (s, 2 H), 8.09 (dt, J = 7.7, 1.5 Hz, 1 H), 7.63 (t, J = 7.7 Hz, 1 H), 7.05 (dd, J = 8.2, 2.1 Hz, 1 H), 7.00 (d, J = 2.1 Hz, 1 H), 6.87 (d, J = 8.3 Hz, 1 H), 6.33 (dd, J = 9.7, 4.6 Hz, 1 H), 3.92 (s, 3 H), 3.88 (s, 3 H), 3.76 (dd, J = 14.0, 9.8 Hz, 1 H), 3.39 (dd, J = 14.0, 4.6 Hz, 1 H). LCMS (Method 1): [MH+] = 476 at 3.55 min. |
91% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 21h; | A solution of (15)-2-(3,5-dichloro-l-oxido-pyridin- l-ium-4-yl)- l-(3,4- dimethoxyphenyl)ethanol, obtained as described in the co-pending international application WO 2014/086849 page 58, (688 mg, 2 mmol), 3-formylbenzoic acid (300 mg, 2 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (767 mg, 4 mmol) and 4-dimethylaminopyridine (122 mg, 1 mmol) in anhydrous DCM (30 mL) was stirred at room temperature for 21 hours. The reaction mixture was partitioned between saturated aqueous NaHC03 solution (20 mL) and DCM (10 mL) and filtered through a phase separator cartridge. The cartridge was washed thoroughly with DCM and the solvent was removed in vacuo. The crude material was purified by silica gel column chromatography eluting with 50percent EtOAc in DCM to afford the title compound as an off-white solid (863 mg, 91percent>).NMR (400 MHz, CDC13): delta 10.08 (s, 1 H), 8.54 (t, J = 1.7 Hz, 1 H), 8.27 (dt, J = 7.8, 1.5 Hz, 1 H), 8.14 (s, 2 H), 8.09 (dt, J = 7.7, 1.5 Hz, 1 H), 7.63 (t, J = 7.7 Hz, 1 H), 7.05 (dd, J = 8.2, 2.1 Hz, 1 H), 7.00 (d, J = 2.1 Hz, 1 H), 6.87 (d, J = 8.3 Hz, 1 H), 6.33 (dd, J = 9.7, 4.6 Hz, 1 H), 3.92 (s, 3 H), 3.88 (s, 3 H), 3.76 (dd, J = 14.0, 9.8 Hz, 1 H), 3.39 (dd, J = 14.0, 4.6 Hz, 1 H). LCMS (Method 1): [MH+] = 476 at 3.55 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 14h;Inert atmosphere; | According to the literature,15 3-formylbenzoic acid (751 mg, 5.00 mmol) was dissolved in DMF (50 mL), and K2CO3 (1.4 g, 10.0 mmol) and EtI (1.6 g, 10.0 mmol) were added to this solution. The reaction mixture was stirred at 60 °C under N2 atmosphere for 14 h. The resulting solution was quenched with sat. aq NH4Cl (20 mL), extracted with EtOAc (3 × 50 mL) and dried (anhyd MgSO4). After filtration, the solvents were evaporated in vacuo. The crude product was purified by flash column chromatography on silica gel (i-hexane/EtOAc, 96:4 to9:1) yielding ethyl 3-formylbenzoate as a white solid (561 mg, 63percent). 1H NMR (400 MHz, CDCl3): delta = 10.11 (s, 1 H), 8.59 (s, 1 H), 8.29 (d, J =7.6 Hz, 1 H), 8.11 (d, J = 7.6 Hz, 1 H), 7.65 (t, J = 7.6 Hz, 1 H), 4.46 (q, J =7.0 Hz, 2 H), 1.44 (t, J = 7.0 Hz, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sodium tetrahydroborate; In ethanol; at 0℃; | In a one-neck round bottom flask, <strong>[619-21-6]3-carboxybenzaldehyde</strong> 9 (1.5 g, 10 mmol) was added.Ethanol was used as a solvent, and NaBH4 (0.57 g, 15 mmol) was added portionwise at 0 C.After the reaction is completed, it is quenched by the addition of a saturated ammonium chloride solution, and after concentration, acidified with 1 M HCl.Extract three times with ethyl acetate and combine the organic phases.Wash twice with saturated sodium chloride solution and dry over anhydrous sodium sulfate.After concentration, a pale yellow liquid 10 was obtained in a yield of 95%. |
93% | With [Ir(2,2':6',2'?-terpyridine)(1,10-phenanthroline)Cl](PF6)2; sodium formate; In ethanol; water; at 100℃; for 0.666667h;Microwave irradiation; | General procedure: An aldehyde (1 mmol),sodium formate (4.5 eq), and catalyst (0.2 mol%) were taken in70% ethanol in water (4 mL) in a microwave vial and vortexed togenerate a homogenous solution. The mixture was heated in MWat 100 C using 150W of irradiation. Reaction progress was monitored by TLC. If complete conversion took place, the reaction colorturns to emerald green (color disappears after sometime) from paleyellow, and byproduct Na2CO3 precipitates. The Na2CO3 solid wasremoved by decanting the supernatant. The solid was washed withethyl acetate (20 mL). The combined decanted solution waswashed with water (5.0 mL), followed by brine solution (5.0 mL),dried over Na2SO4, filtered, and evaporated to dryness to affordthe desired alcohol as a pale-yellow liquid or off-white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With pyrrolidine; In ethanol; at 100℃; for 0.25h;Microwave irradiation; | General procedure: A catalytic amount of pyrrolidine (0.001 mmol) was added into a stirred ethanol solution (5 mL) containing 28a (1 mmol) and the appropriate aldehydes (1.2 mmol). The reaction was irradiated with microwaves (CEM, Discover) at 100 °C for 15 min. The crude product precipitated with cooling. (For mixtures PMR data for major isomer is presented). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | To a solution of 3-formylbenzoic acid (22.5 mg, 0.15 mmol) in DMF (3 mL) were added EDCIHCl (57 mg, 0.3 mmol, 2 eq.), HOBt (41 mg, 0.3 mmol, 2 eq.). The mixture was stirred at r.t. for 30 min, then N-(4-aminobutyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (5b, 71 mg, 0.158 mmol, 1.05 eq) and N, N-diisopropylethylamine (29 mg, 0.2 mmol, 2 eq) were added. The resulting mixture was stirred at r.t. for 24 hrs. The reaction mixture was diluted with ethyl acetate (50 mL), washed with brine (5 × 20 mL), dried over sodium sulfate, and concentrated in vacuo. The crude product (102 mg) was purified by column chromatography (ethyl acetate/petroleum ether = 3/1) to give compound 14as white foam (63 mg, 72percent). 1H NMR (400 MHz, CDCl3) delta 10.08 (s, 1H, CHO), 8.36 (t, J = 1.5 Hz, 1H), 8.18 (dt, J = 7.6, 1.3 Hz, 1H) 8.01 (dt, J = 7.6, 1.3 Hz, 1H), 7.62 (t, J = 7.7 Hz, 1H), 7.43 (d, J = 2.0 Hz, 1H), 7.34 ? 7.24 (m, 4H), 7.14 ? 7.00 (m, 4H), 3.59 (q, J = 6.5 Hz, 2H), 3.51 (q, J = 6.6 Hz, 2H), 2.37 (s, 3H), 1.81 ? 1.71 (m, 4H). 13C NMR (101 MHz, CDCl3) delta 191.80 (+, CHO), 166.34 (PhCONH), 163.32 (PhCONH), 144.96, 143.34, 136.63, 136.20, 136.04, 135.81, 135.16, 133.33, 133.11, 132.00, 130.95 (2 signals overlapped), 130.64, 130.50, 129.50, 129.08 (2 signals overlapped), 128.50, 128.06, 127.28, 117.88, 40.12 (CH2), 38.46 (CH2), 28.01 (CH2), 26.23 (CH2), 9.57 (CH3 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With ammonium acetate; In toluene; at 125℃; for 0.333333h;Microwave irradiation; | General procedure: The intermediate 3 (1 equiv), substituted benzaldehydes (1 equiv) and ammonium acetate (2 equiv) in toluene (4 ml) were irradiated on microwave at 125 C, 220 W for 20 min. The solvent was evaporated on vacuo and crude mixture was purified on silica gel CC yielded compounds 4, 4a-t. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With water; palladium diacetate; potassium carbonate; at 20℃; under 760.051 Torr; for 5h; | General procedure: A 25-mL flask was charged with Pd(OAc)2 (1.2 mg, 0.005 mmol), 1-iodo-4-nitrobenzene (1a, 127.0 mg, 0.5 mmol), K2CO3 (141.0 mg, 1.0 mmol), H2O (0.5 mL), and PEG 400 (2.0 mL); the flask was subjected to standard cycles (3 ×) of evacuation and back-filling with dry and pure CO. The mixture was stirred at r.t. for the indicated time. The mixture was poured into sat. aq NaCl (15 mL), acidified to pH 3 with 3 M aq HCl, and extracted with EtOAc (3 × 15 mL). The solvent was removed from the combined organic phases on a rotary evaporator. The crude product was purified by column chromatography (silica gel, PE?EtOAc?HCO2H, 25:1:1) to afford 2a as a light yellow solid; yield: 75mg (90percent); mp 238.0?239.3 °C. 1H NMR (400 MHz, DMSO-d6): delta = 13.68 (br s, 1 H), 8.30 (d, J = 8.0 Hz,2 H), 8.14 (d, J = 8.0 Hz, 2 H). 13C NMR (100 MHz, DMSO-d6): delta = 165.9, 150.0, 136.4, 130.7, 123.8. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76.3% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 40℃; for 6h; | The compound of formula 6-2 (methyl4-((5-(piperidin-4-yl)- 1 H-pyrrolo[2,3-blpyridin- 1 -yI)methyl)benzoate) (1.000 g, 2.862 mmol), 3-formylbenzoic acid (0.859 g, 5.724 mmol), 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (1.097 g, 5.724 mmol), 1-hydroxybenzotriazole hydrate (0.773 g, 5.724 mmol), and N,N-diisopropylethylamine (1.0 13 mL, 5.724 mmol) were dissolved in N,N-dimethylformamide (10 mL) at 40°C, and the solution was stirred at the same temperature for 6 hours, and then cooled to room temperature. After completion of the reaction, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (Si02, 40 g cartridge; methanol / methylene chloride = from 0percent to 10percent) to afford the desired compound of formula 15-1 (1.051 g, 76.3percent) as a yellow liquid.Step 2: Synthesis of methyl |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.2% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 16h; | [20821 Step 1: Synthesis of (E?)-methyl3-(4-(((25.6R?)-4-(3-formylbenzoyl)-2.6-dimethylpiperazin- 1 -yl)methyl)phenyl)acrylat e[20831 (E)-methyl 3-(4-(((25 ,6R)-2,6-dimethylpiperazin- 1 -yl)methyl)phenyl)acrylate (formula 17-1, 0.300 g, 1.040 mmol), 3-formylbenzoic acid (0.172 g, 1.144 mmol), EDCI (0.399 g, 2.08 1 mmol), HOBt (0.3 19 g, 2.08 1 mmol) and DIPEA (0.921 mL, 5.201 mmol) were dissolved in methylene chloride (3 mL) at room temperature, and the solution was stuffed at the same temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the concentrate was purified by column chromatography (silicon dioxide, 4 g cartridge; ethyl acetate hexane = from 30 percent to 40 percent) and concentrated to afford the desired compound (0.386 g, 88.2 percent) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With water; sodium hydroxide; In methanol; at 20℃; for 24h; | A solution of 4percent (w/v) sodium hydroxide (34 mmol) was added to a suspension of 3-formylbenzoic acid (17 mmol) and 1-(5-methyl-2-furyl)ethanone (17 mmol) in methanol (100 ml). The mixture was stirred at room temperature for 24 h and acidified with concentrated hydrochloric acid to a pH of 1-2. The precipitate that formed was filtered, rinsed with water and recrystallised from methanol to afford 7i. 5.1.1.1. 3-[(1E)-3-(5-methylfuran-2-yl)-3-oxoprop-1-en-1-yl]benzoicacid (7i). Yield 68percent; Pale yellow crystals; mp 191.7-194.1 °C (methanol); 1H NMR (600 MHz, DMSO-d6) d 13.20 (br s, 1H, OH),8.33 (br s, 1H, H-20), 8.07 (br d, J 7.8 Hz, 1H, H-60), 7.98 (dt, J 1.4,7.7 Hz, 1H, H-40), 7.82 (d, J 3.5 Hz, 1H, H-300), 7.75 (d, J 16.0 Hz,1H, H-7 or H-8), 7.71 (d, J 16.0 Hz, 1H, H-7 or H-8), 7.57 (t,J 7.7 Hz, 1H, H-50), 6.42 (dd, J 1.1, 3.5 Hz, 1H, H-400), 2.40 (s, 3H,CH3).13C NMR (151 MHz, DMSO-d6) d 175.6 (C-1), 167.0 (acid C]O),158.8 (C-500), 151.8 (C-200), 141.2 (C-3), 135.0 (C-10), 132.8 (C-60), 131.6 (C-30), 131.0 (C-40), 129.2 (C-20 , C-50), 123.1 (C-2), 121.9 (C-300), 109.6 (C-400), 13.8 (CH3). EI-HRMS m/z: calcd for C15H12O4, 256.07356, found 256.07292; Purity (HPLC): 100percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | 8-Hydroxyjulolidine (1.4 g, 7.2 mmol) and 3-formyl benzoic acid (500 mg, 3.6 mmol) are mixed with 60percent aqueous sulfuric (40 mE) and stirred at 150° C. for 24 hours under air atmosphere. The reactionmixture is addedto ice (100 g), after which 60percent NaOH is careffilly added to pH 6-7, precipitating the crude product. The crude product is extracted between DCM and watet The organic phase is separated, and washed with brine. The organic solvent is removed and the final products are dried by evaporating with EtOH and toluene 5 times to yield 1.7 g 3-acid product (94percent yield). Purity as determined by HPEC is 95percent. MS (ESI) [M+]=491. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With ammonium hydroxide; potassium hydroxide; In ethanol; at 20℃; for 48h; | A mixture of <strong>[619-21-6]3-carboxybenzaldehyde</strong> (0.74g, 4.93 mmol),3-acetylpyridine(1.19g, 9.87mmol), KOH (0.8g,14mmol),NH3*H2O (20mL) and ethanol (150mL)were put into a flask(250 mL). The reaction solution was stirring for 2 days at room temperature, after that pH was adjusted to 5.0 with HCl (aq,conc.). Finally, the white product was obtained after vacuum filtration, water and ethanol washing, air drying and grinding.Yield 1.44g,83percent (base on<strong>[619-21-6]3-carboxybenzaldehyde</strong>). Anal.Calcd.(percent) for C22H15N3O2 : C,74.78;H,4.28;N,11.89percent.Found:C,74.56;H,4.04;N, 11.74percent. IR (KBr, cm-1): 3417(s),3238(s),2065(w),1639(s),1618(s),1402(s), 1130(m),619(m),484(w). HRMS(ESI): m/z [MH] calcd fo rC22H15N3O2: 354.1237; found: 354.1239. 1HNMR (400MHz,DMSO-d6): delta 9.62 (s,2H),8.94(d, J8.0 Hz,2H),8.78 (s,2H),8.55(s,1H),8.49(s,2H),8.33(d, J8.0 Hz,1H),8.09(d, J7.6Hz,1H),7.70?7.78(m,3H). 13C NMR(400MHz,DMSO-d6): delta 169.23,152.54,151.98,150.12,149.43,137.89,134.82,134.72,133.12,130.76,130.56,129.12,124.10,118.13. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | General procedure: To the magnetically stirred solution of 17 (232 mg, 2 mmol) in HOAc (7 mL), was added NaOAc (500 mg, 6 mmol). After 15 min 3,4-dimethoxybenzaldhyde (16a, 400 mg, 2.4 mmol) was added and the reaction mixture was heated under reflux for 72 h. The HOAc was removed under reduced pressure and the resultant solid was washed successively with water, methanol and EtOAc to obtain the desired products as solid. 10.2.1.9 5-(3-Carboxybenzylidene)-2-iminothiazolidin-4-one (14i) Yellow solid; mp > 200 C; 218 mg, 44% yield; IR (neat) numax = 3278, 3110, 2764, 2413, 1874, 1682, 1641, 1602 cm-1; 1H NMR (400 MHz, CD3SOCD3) delta 9.51 (br s, 1H) 9.21 (s, 1H), 8.51 (s, 1H), 7.97 (d, J = 7.60, 1H), 7.84 (d, J = 7.48, 1H), 7.64 (s, 1H), 7.62-7.60 (m, 1H); 13C NMR (100 MHz, CD3SOCD3): delta 180.65, 175.85, 167.26, 134.97, 134.91, 132.12, 130.97, 130.44, 130.07, 129.32, 128.38; HRMS (ESI-TOF): m/z calculated for C11H8N2O3S [M+H]+, 249.0334; found 249.0328. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61.2% | With potassium hydroxide; In ethanol; at 20℃; | 3-formyl-benzoic acid (150 mg, 1 mmol) and intermediate 2 obtained in Example 3 (257 mg, 1.2 mmol) were dissolved in absolute ethanol, and then KOH (772 mg, 12 mmol) was added. The reaction mixture was stirred at room temperature until 3-formyl-benzoic acid disappeared as monitored by TLC. The mixture was adjusted to pH=4 by iM of hydrochloric acid. The absolute ethanol was removed by rotary evaporation and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and rotary evaporated. The final product compound 20 was isolated by colunm chromatography as a yellow solid, yielded 61.2percent; ?H NMR (400 MHz, CDC13), oe 13.14 (s, iH), 8.01 (d, J=iO.8 Hz, iH), 7.89 (dd, J=9.2, 4.6 Hz, iH), 7.78 (d, J=7.2 Hz, iH), 7.73-7.69 (m, 2H), 7.64 (dd, J=7.7, 5.3 Hz, iH), 7.58 (d, J=9.8 Hz, iH), 7.54 (s, iH), 7.48-7.41 (m, 2H), 7.36 (d, J=i6.i Hz, iH), 7.22 (s, iH),7.16 (d, J=i5.i Hz, iH), 6.87 (d, J=i5.4 Hz, iH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With 1,4-dihydropyridine; trifluoroacetic acid; In dichloromethane; at 40℃; for 12h;Inert atmosphere; Molecular sieve; | General procedure: To the solution of amines 9a (60 mg, 0.28 mmol) and substituted benzaldehydes 16a (36 mg, 0.24 mmol) in DCM (3 mL) added DHP (83.5 mg, 0.33 mmol) and molecular sieve (840.2 mg). Trifluoroacetic acid (17.6 mkL, 0.24 mmol) was added to the suspension dropwise and the mixture was stirred at 40 C for 12 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The solid produced was purified through the column chromatography on silica gel to afford the titled compound 2a(53 mg, 64percent) as a brown solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With diludine; trifluoroacetic acid; In dichloromethane; at 20 - 40℃; for 10h;Molecular sieve; | Compound 9 (0.03 g, 0.14 mmol) was added with 4 mL of CH2Cl2,3-formyl-benzoic acid (0.03 g, .21 mmol)And dihydropyridine ester (0.05 g, 0.20 mmol)A catalytic amount of 4A molecular sieves and trifluoroacetic acid (0.003 mL, 0.03 mmol) were added at room temperature with stirring,Heating to 40 reaction 10h, TLC detection reaction is complete.The filtrate was purified by distillation under reduced pressure and purified by silica gel column chromatography (CH2Cl2: CH3OH = 10: 1) to give 10b (0.026 g, yield 54percent) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | To a stirred solution of 3-formylbenzoic acid (0.50 g, 3.3 mmol) in DMF (7 mL) was added DIPEA (0.61 mL, 3.5 mmol) and HATU (1.5 g, 4.0 mmol) and the mixture stirred at room temperature for 15 minutes. 4,4-Diethoxybutan-l -amine (0.43 g, 2.68 mmol) was added and the- stirring continued for a further five hours. The reaction mixture was diluted and washed sequentially with aqueous 1M sodium hydroxide, aqueous 2M sodium hydroxide and brine. The organic phase was dried over magnesium sulfate, filtered and the filtrate evaporated at reduced pressure to afford the title compound (0.72 g, 93percent). 'H NMR (400 MHz, DMSO-d6); delta 10.08 (s, 1H), 8.71 (dd, J=5.5, 5.5 Hz, 1H), 8.38 (s, 1H), 8.16 (d, J=7.8 Hz, 1H), 8.06 (d, J=7.7 Hz, 1H), 7.71 (dd, J=7.7, 7.7 Hz, 1H), 4.53 - 4.47 (m, 1H), 3.57 (ddd, J=7.0, 9.5, 14.1 Hz, 2H), 3.43 (ddd, J=7.1, 9.5, 14.1 Hz, 2H), 3.31 - 3.27 (m, 2H), 1.58 - 1.54 (m, 4H), 1.11 (dd, J=7.0, 7.0 Hz, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | General procedure: Step A: 3-(azetidine-1-carbonyl) benzaldehyde (8a)To a solution of 3-formyl-benzoic acid 6 (150 mg, 1 mmol) inDMF (5 mL) was added azetidine (68 mg, 1.20 mmol) and the solutionwas stirred for 30 min at 25 C. Then the solution was treatedwith HOBT (202 mg, 1.50 mmol) and EDCI (383.4 mg, 2 mmol). Thereaction was stirred at 25 C for 4 h. After the reaction was completed,the mixture was added water and EtOAc. The organic layerwas washed with 1 M NaOH, 1 M HCl then brine and was driedover anhydrous sodium sulfate (Na2SO4). Then solvent wasremoved under reduced pressure. The residual solid was purifiedby silica gel column chromatography using petroleum ether-ethylacetate (4:1 to 2:1) to give white solid (130 mg). 69percent yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | General procedure: Step A: 3-(azetidine-1-carbonyl) benzaldehyde (8a)To a solution of 3-formyl-benzoic acid 6 (150 mg, 1 mmol) inDMF (5 mL) was added azetidine (68 mg, 1.20 mmol) and the solutionwas stirred for 30 min at 25 C. Then the solution was treatedwith HOBT (202 mg, 1.50 mmol) and EDCI (383.4 mg, 2 mmol). Thereaction was stirred at 25 C for 4 h. After the reaction was completed,the mixture was added water and EtOAc. The organic layerwas washed with 1 M NaOH, 1 M HCl then brine and was driedover anhydrous sodium sulfate (Na2SO4). Then solvent wasremoved under reduced pressure. The residual solid was purifiedby silica gel column chromatography using petroleum ether-ethylacetate (4:1 to 2:1) to give white solid (130 mg). 69percent yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | General procedure: Step A: 3-(azetidine-1-carbonyl) benzaldehyde (8a)To a solution of 3-formyl-benzoic acid 6 (150 mg, 1 mmol) inDMF (5 mL) was added azetidine (68 mg, 1.20 mmol) and the solutionwas stirred for 30 min at 25 C. Then the solution was treatedwith HOBT (202 mg, 1.50 mmol) and EDCI (383.4 mg, 2 mmol). Thereaction was stirred at 25 C for 4 h. After the reaction was completed,the mixture was added water and EtOAc. The organic layerwas washed with 1 M NaOH, 1 M HCl then brine and was driedover anhydrous sodium sulfate (Na2SO4). Then solvent wasremoved under reduced pressure. The residual solid was purifiedby silica gel column chromatography using petroleum ether-ethylacetate (4:1 to 2:1) to give white solid (130 mg). 69percent yield. 1HNMR(500 MHz, CDCl3) d 10.05 (s, 1H), 8.13 (s, 1H), 7.97 (d, J = 7.6, 1H),7.92 (d, J = 7.7, 1H), 7.60 (d, J = 7.7, 1H), 4.35 (t, J = 7.5, 2H), 4.26 (t,J = 7.7, 2H), 2.42?2.34 (m, 2H). MS (ESI): Calcd for C11H12NO2 [M +H]+ 190.09, found 190.18. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With dipotassium hydrogenphosphate; [4,4?-bis(1,1-dimethylethyl)-2,2?-bipyridine-N1,N1?]bis [3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]iridium(III) hexafluorophosphate; triphenylphosphine; In dichloromethane; water; at 20℃;Inert atmosphere; Irradiation; | Firstly weighing (30.0 mg, 0.2 mmol),photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6(2.3 mg, 0 . 002 mmol), K2HPO4(7.0 mg, 0 . 04 mmol), and Ph3P (62.9 mg, 0 . 24 mmol) are added to a reaction tube, pumping air through the vacuum line three times, in the argon atmosphere, adding DCM/H2O (2.0 ml, 4:1 v/v), then carefully added (31.5 mg, 0.3 mmol), then put into 5 W blue LEDs lamp irradiation, react at room temperature for 36 - 60h. Add 20 ml water, and the DCM extraction (3x 10 ml) the aqueous phase, combined with the organic phase. The organic phase by absolute Na2SO4After drying and steaming and to remove the solvent, dry sample, column chromatography (300 - 400 item of chromatographic analysis silica gel) (petroleum ether - ethyl acetate) to obtain the product 29.2 mg, Yield 61%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With boron trifluoride diethyl etherate In 1,4-dioxane at 80℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With sodium cyanoborohydride; acetic acid; In methanol; at 20℃;Inert atmosphere; | General procedure: To a stirred solution of 30b (1.80 g, 5.94 mmol) and 4-carboxybenzaldehyde (0.885 g, 5.94 mmol) in MeOH (10 mL), fewdrops of glacial AcOH were added. Sodium cyanoborohydride (560 mg, 8.92 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with H2O then extracted with EtOAc. The combined organic layer was dried over anhydrous MgSO4 and concentrated under reducedpressure. The residue was purified by silica gel chromatography (EtOAc: n-hexane 1: 0.95 with 0.5% AcOH) to give compound 31b(1.76 g, yield 68%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.7% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 3h; | General procedure: To a solution of intermediate 14a (1g, 5.13mmol), 3-formylbenzoic acid (0.85g, 5.64mmol), and HATU (2.92g, 7.69mmol) in DMF (15mL) was added DIPEA (3.31g, 25.63mmol). The mixture was stirred at room temperature for 3h. After that time, the solution was poured into water. The precipitate was filtered off to give a residue, which was triturated with ether to give compound 15a (1.37g, 81.7%). It was obtained as a white solid. 1H NMR (600MHz, DMSO-d6) delta 10.09 (s, 1H), 8.13 (s, 1H), 8.06 (d, J=7.7Hz, 1H), 7.95 (d, J=7.8Hz, 1H), 7.75 (t, J=7.6Hz, 1H), 7.47 (dd, J=7.9, 5.9Hz, 5H), 7.41-7.36 (m, 1H), 7.32 (s, 1H), 7.13 (s, 1H), 4.05-3.98 (m, 2H), 3.15 (t, J=8.1Hz, 2H). ESI-MS m/z: 328.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Dissolve 3-formylbenzoic acid (1.0g, 6.7mmol), HATU (3.8g, 10.0mmol) and DIPEA (2.6g, 20.0mmol) in tetrahydrofuran (20mL), stir at room temperature for 0.5 hours, and add 4- Chloro-2- (trifluoromethyl) benzylamine (1.4 g, 6.7 mmol) was reacted at room temperature for 4 hours, and an appropriate amount of water was added, followed by extraction with ethyl acetate three times. The organic phases were combined and washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title compound (2.1 g, yield: 92%) in this step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With piperidine; In ethanol; for 5.0h;Reflux; | General procedure: A mixture of 2a-2n (0.38 mmol), aldehyde 3a-3p and 44 (or ketone 39-43) (0.42 mmol) and piperidine (37.5 µL, 0.38 mmol) in ethanol (3.0 mL) was refluxed for the given time as described individually. The reaction was monitored by TLC. The purification was performed in either of the following two methods. Purification 1. When the product is crystalized as solid during reaction, the reaction mixture was cooled to room temperature slowly. The precipitate is collected by using vacuum filtration with washing cold EtOH. The collected product was dried under low pressured vacuum to give a desired product. |
64% | With piperidine; In ethanol; for 5.0h;Reflux; | General procedure: A mixture of 2a-2n (0.38 mmol), aldehyde 3a-3p and 44 (or ketone 39-43) (0.42 mmol) and piperidine (37.5 µL, 0.38 mmol) in ethanol (3.0 mL) was refluxed for the given time as described individually. The reaction was monitored by TLC. The purification was performed in either of the following two methods. Purification 1. When the product is crystalized as solid during reaction, the reaction mixture was cooled to room temperature slowly. The precipitate is collected by using vacuum filtration with washing cold EtOH. The collected product was dried under low pressured vacuum to give a desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28.84% | With 1H-imidazole; dmap In N,N-dimethyl-formamide at 20℃; | 1.6.1 6.1 (S)-l -(benzyloxy)- l-oxopropan-2-yl 3 -formylbenzoate To a suspension of 3 -formylbenzoic acid (0.2 g, 1.33 mmol) in Acetonitrile (10 mL) was addedoxalyl dichloride (169.09 mg, 1.33 mmol, 115.81 uL) and DMF (0.01 mL). The mixture was stirred at 25 °C for 23 hr. Then benzyl (2S)-2- hydroxypropanoate (240.06 mg, 1.33 mmol) and N-ethyl-N-isopropyl-propan-2- amine (430.43 mg, 3.33 mmol, 580.10 uL) was added to the reation at 25 °C and the reaction mixture was sirred at 25 °C for 3h. This crude product was purifed by combi- flash (PE/EA=9/1) to get the product as a off-white solid (120 mg, yield 28.84%) LC-MS: (ESI) m/z: 335.1 [M+Na]+ |
28.84% | With 1H-imidazole; dmap In N,N-dimethyl-formamide at 20℃; | 1.6.1 6.1 (S)-l -(benzyloxy)- l-oxopropan-2-yl 3 -formylbenzoate To a suspension of 3 -formylbenzoic acid (0.2 g, 1.33 mmol) in Acetonitrile (10 mL) was addedoxalyl dichloride (169.09 mg, 1.33 mmol, 115.81 uL) and DMF (0.01 mL). The mixture was stirred at 25 °C for 23 hr. Then benzyl (2S)-2- hydroxypropanoate (240.06 mg, 1.33 mmol) and N-ethyl-N-isopropyl-propan-2- amine (430.43 mg, 3.33 mmol, 580.10 uL) was added to the reation at 25 °C and the reaction mixture was sirred at 25 °C for 3h. This crude product was purifed by combi- flash (PE/EA=9/1) to get the product as a off-white solid (120 mg, yield 28.84%) LC-MS: (ESI) m/z: 335.1 [M+Na]+ |
Tags: 619-21-6 synthesis path| 619-21-6 SDS| 619-21-6 COA| 619-21-6 purity| 619-21-6 application| 619-21-6 NMR| 619-21-6 COA| 619-21-6 structure
[ 19675-63-9 ]
4-(2-Carboxyvinyl)benzoic acid
Similarity: 0.97
[ 19675-63-9 ]
4-(2-Carboxyvinyl)benzoic acid
Similarity: 0.97
[ 50446-44-1 ]
5'-(4-Carboxyphenyl)-[1,1':3',1''-terphenyl]-4,4''-dicarboxylic acid
Similarity: 0.91
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