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CAS No. : | 623-47-2 | MDL No. : | MFCD00009184 |
Formula : | C5H6O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | FMVJYQGSRWVMQV-UHFFFAOYSA-N |
M.W : | 98.10 | Pubchem ID : | 12182 |
Synonyms : |
|
Num. heavy atoms : | 7 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.4 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 25.6 |
TPSA : | 26.3 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.22 cm/s |
Log Po/w (iLOGP) : | 1.84 |
Log Po/w (XLOGP3) : | 0.96 |
Log Po/w (WLOGP) : | 0.26 |
Log Po/w (MLOGP) : | 0.79 |
Log Po/w (SILICOS-IT) : | 0.5 |
Consensus Log Po/w : | 0.87 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.92 |
Solubility : | 11.8 mg/ml ; 0.12 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.1 |
Solubility : | 7.8 mg/ml ; 0.0795 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.36 |
Solubility : | 42.7 mg/ml ; 0.436 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.13 |
Signal Word: | Danger | Class: | 3 |
Precautionary Statements: | P501-P240-P210-P233-P243-P241-P242-P264-P280-P370+P378-P337+P313-P305+P351+P338-P362+P364-P303+P361+P353-P332+P313-P403+P235 | UN#: | 3272 |
Hazard Statements: | H225-H315-H319-H335 | Packing Group: | Ⅲ |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | at 20 - 30℃; for 4 h; | a. 1H-Pyrazole-3-carboxylic acid ethyl ester (Intermediate 74a) A solution of ethyl propiolate (10.0 g, 0.10 mol) in THF (67 mL) was treated dropwise with (trimethylsilyl)diazomethane (51 mL, 0.10 mol) maintaining the temperature between 20-30° C. with ice bath cooling. The mixture was stirred at RT for 4 h then treated cautiously with water (250 mL) with cooling in an ice bath. The organics were evaporated in vacuo and the resulting precipitate was collected by filtration, washed with water and dried at RT in vacuo to give the title compound (13.5 g, 94percent). LCMS (Method 3): Rt 2.22 min, m/z 141 [MH+]. |
94% | at 20 - 30℃; for 4 h; | A solution of ethyl propiolate (10.0 g, 0.10 mol) in THF (67 mL) was treated drop wise with (trimethylsilyl)diazo methane (51 mL, 0.10 mol) maintaining the temperature between 20-30 °C with ice bath cooling. The mixture was stirred at RT for 4h then treated cautiously with water (250 mL) with cooling in an ice bath. The organics were evaporated in vacuo and the resulting precipitate was collected by filtration, washed with water and dried at RT in vacuo to give the title compound (13.5 g, 94percent). LCMS (Method 3): Rt 2.22 min, m/z 141 [MH+]. |
90% | at 20 - 30℃; for 3 h; | Example 15, Step A[00152] To a solution of ethyl propiolate (30 g, 306 mmol) in THF (200 mL) was added dropwise trimethylsilyldiazomethane (153 mL, 2M in hexanes, 306 mmol) at 20-30°C with ice bath cooling (delayed exotherm observed). The reaction mixture was stirred for 3 hours at r.t. Water was then added (750 mL) and the organic solvents evaporated. The white precipitate was filtered and dried under vacuum to afford compound 15b (38.5 g, 90percent) as a white solid. |
90% | at 20℃; for 3 h; | Example 15.[00151] Example 15 presents the preparation of Cmpd 15, N-(5-fluoropyrimidin-2-yl)- 6,7-dihydro-4H-pyrazolo[4',3':5,6]oxepino[4,3-d][1 ,3]thiazol-2-amine (Table II,Compound No. 15). Cmpd 15Example 15, Step A[00152] To a solution of ethyl propiolate (30 g, 306 mmol) in THF (200 ml.) was added dropwise trimethylsilyldiazomethane (153 ml_, 2M in hexanes, 306 mmol) at 20-30°C with ice bath cooling (delayed exotherm observed). The reaction mixture was stirred for 3 hours at r.t. Water was then added (750 mL) and the organic solvents evaporated. The white precipitate was filtered and dried under vacuum to afford compound 15b (38.5 g, 90percent) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With 2,2'-azobis(isobutyronitrile); iodine; tetrabutylammonium periodite In dichloromethane at 20℃; for 10 h; Irradiation; Inert atmosphere | General procedure: N-Hydroxy-1-phenylmethanesulfonamide (0.2 mmol), n-Bu4NIO4 (0.2 mmol), I2 (0.1 mmol) and AIBN (10percent) were added to a 25 mL roundbottom flask. A solution of the alkene (excess) or alkyne (0.2 mmol) in anhydrous CH2Cl2 (2 mL) was injected via a syringe and the mixture was stirred under visible-light irradiation for 10 h at r.t. The mixture was diluted with CH2Cl2 (10 mL) and washed with saturated aqueous NaCl (2 10 mL), dried over Na2SO4 and concentrated under reduced pressure. Purification was accomplished by column chromatography on silica gel H with petroleum ether/ethyl acetate (20:1) as the eluent to give the pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With sodium hydrogencarbonate In water at 20℃; | INTERMEDIATE 54 - PREPARATION OF ethyl S-phenylisoxazole-δ-carboxylate. ; A mixture of ethyl propriolate (0.657 ml 6.43 mmol), (E)-N-hydroxybenzimidoyl chloride (0.500 g; 3.21 mmol) and sodium bicarbonate (0.818 g; 9.64 mmol) in a mixture of ethyl acetate (16 ml.) and water (1 ml.) was stirred at room temperature, overnight. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent 5 to 80percent dichloromethane in heptane) to furnish 0.295 g (42percent) of ethyl 3-phenylisoxazole-5- carboxylate.ESI/APCI(+): 218 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
311 mg | With isopentyl nitrite In butanone at 20 - 65℃; | General procedure: To a solution of the appropriate aldoxime (1.2 mmol, 1.0 equiv) in ethyl methyl ketone (10 mL) was added appropriately substituted alkyne (1.32 mmol, 1.1 equiv) followed by alkyl nitrite 4 (1.32 mmol,1.1 equiv). After 5 min stirring at r.t., the turbid reaction mixture became a clear solution and the reaction mixture was stirred at 65 °C until the aldoxime had been consumed. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (EtOAc–n-hexane, 1:9 v/v) to afford the desired compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49.1% | Stage #1: at 20℃; for 1 h; Cooling with ice Stage #2: at -10 - 45℃; for 17 h; |
Methyl 2-mercaptoacetate (4.31 mL, 47.1 mmol) was added to MeOH (94 mL) and cooled in an ice bath. Following, sodium hydride (3.39 g, 85 mmol) was slowly added and the reaction was stirred for 1 hour at room temperature. The reaction was cooled to -10 C and ethyl propiolate (5.01 mL, 48.0 mmol) was slowly added. The reaction was stirred at 0 °C for 1 hour, room temperature for 1 hour, and heated to 45 °C for three hours. (0342) Following, the reaction was heated for 12 hours at 35 °C. All reaction solvent was evaporated and the reaction was redissolved in water, neutralized to pH 7, and extracted 10 times with 3: 1 chloroform/IPA. The organic extracts were combined, evaporated, and dissolved in EtOAc. The EtOAc/reaction mixture was filtered through a pad of silica and washed with EtOAc. The organic was collected and condensed to generate methyl 3- hydroxythiophene-2-carboxylate (3.66 g, 49.1percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | at 140℃; Flow reactor | On a Vapourtec R2+/R4 flow system equipped with three PTFA reactor coils (a 10 mL) and a 250 psi back pressure regulator, ethyl propiolate and trimethylsilyl azide were injected via 2 mL loops. The flow rate was set to 0.5 mL/min, with a residence time of 1.5 h. The system was heated to 140 °C. Injections were performed every 40 min. The solvent used was acetonitrile. The total mixture coming out of the reactor was collected. In total, 5 injections were performed. The mixture was collected, and acetonitrile removed in vacuo (the collector of the rotary evaporator was filled with sat. aq. NaHC03 to quench any potentially formed HN3). The remaining solid was dissolved in EtOAc, and the organic phase washed with brine (3x), dried over Na2S04, filtered, and evaporated. The crude product was stirred in a minimal amount of Et20, filtered, and dried, to give the title compound (8.65 g, 81percent) as a white solid. MS (ESI): m/z = 142.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | at 110℃; Inert atmosphere | A solution of 1H-pyrazol-3-ylamine (7 g, 84.24 mmol, 1 .00 equiv) and ethyl prop-2-ynoate (50 mL) in dioxane ( 1 0 g, 1 21 equiv) was stirred under nitrogen overnight at 110 "C. The reaction mixture was cooled to rt and the precipitated product was collected by filtration to give 4 g (36percent) of the title compound as a light brown solid 1H NMR (300 MHz, DMSO-d6) δ 12.04 (s, 1H), 8.41 -8.44 (m, 1H), 7.71 (d. J = 18 Hz, 1H), 5.88 (d, J = 8. 1Hz, 1H), 5.77 (m, 1H) |
36% | at 110℃; Inert atmosphere | A solution of 1H-pyrazol-3-ylamine (7 g, 84.24 mmol, 1 .00 equiv) and ethyl prop-2-ynoate (50 mL) in dioxane ( 1 0 g, 1 21 equiv) was sti rred under nitrogen overnight at 1 1 0 "C. The reaction mixture was cooled to rt and the precipitated product was collected by filtration to give 4 g (36percent) of the title compound as a light brown sol id1HNMR ( 300 MHz, DMSO-d6) δ 1 2.04 (s, 1H), 8.41 -8.44 (m, 1H), 7.71 (d. J = 18 Hz, 1H ), 5.88 (d, J = 8. 1Hz, 1H), 5.77 (m, 1H) |
36% | at 110℃; Inert atmosphere | A solution of 1H-pyrazol-3-ylamine (7 g, 84.24 mmol, 1 .00 equiv) and ethyl prop-2-ynoate (50 mL) in dioxane ( 1 0 g, 1 21 equiv) was stirred under nitrogen overnight at 110 "C. The reaction mixture was cooled to rt and the precipitated product was collected by filtration to give 4 g (36percent) of the title compound as a light brown solid 1H NMR (300 MHz, DMSO-d6) δ 12.04 (s, 1H), 8.41 -8.44 (m, 1H), 7.71 (d. J = 18 Hz, 1H), 5.88 (d, J = 8. 1Hz, 1H), 5.77 (m, 1H) |
36% | at 110℃; Inert atmosphere | 0217] Step 1. 4H-Pyrazolor 5-alpyrimidin-5-one. A solution of lH-pyrazol-3-ylamine (7 g, 84.24 mmol, 1.00 equiv) and ethyl prop-2-ynoate (50 mL) in dioxane (10 g, 1.21 equiv) was stirred under nitrogen overnight at 110 °C. The reaction mixture was cooled to rt and the precipitated product was collected by filtration to give 4 g (36percent) of the title compound as a light brown solid. 1H NMR (300 MHz, DMSO-J6) δ 12.04 (s, 1H), 8.41-8.44 (m, 1H), 7.71 (d, J = 1.8 Hz, 1H), 5.88 (d, J = 8.1 Hz, 1H), 5.77 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | at 110℃; Inert atmosphere | [0209] Step 1. 4H-Pyrazolo[1,5-alpyrimidin-5-one. A solution of 1H-pyrazol-3-ylamine (7 g, 84.24 mmol, 1.00 equiv) and ethyl prop-2-ynoate (50 mL) in dioxane (10 g, 1.21 equiv) was stirred under nitrogen overnight at 110 °C. The reaction mixture was cooled to rt and the precipitated product was collected by filtration to give 4 g (36percent) of the title compound as a light brown solid. ‘H NMR (300 MHz, DMSO-d6) ö 12.04 (s, 1H), 8.41-8.44 (m, 1H), 7.71 (d, J= 1.8 Hz, 1H), 5.88 (d, J= 8.1 Hz, 1H), 5.77 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | Stage #1: With mesitylenesulfonylhydroxylamine In dichloromethane at 0℃; for 2 h; Stage #2: With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 18 h; |
General procedure: These were made using MSH or DNPH as detailed below, unless otherwise stated. A fresh solution of MSH23 in CH2Cl2 (1 equiv) was added to the substituted pyridine (1 equiv) in CH2Cl2 (10 mL) at 0 °C. After 2 h, the solvent was removed in vacuo. Alternatively, a solution of DNPH12 (1 equiv) and the substituted pyridine (1 equiv) in MeCN (40 mL) was heated at 40 °C for 18 h. The solvent was removed in vacuo. The method continues by taking the residue from either method in dry DMF (8 mL), and then ethyl propiolate (1 equiv) and K2CO3 (2 equiv) were added, and the suspension stirred at room temperature for 18 h. The reaction mixture was diluted with water and extracted twice with EtOAc. The combined organic phases were washed three times with water then with brine, dried (Na2SO4) and the solvent removed in vacuo. Chromatography (eluting with a hexanes: EtOAc gradient, unless otherwise stated) gave the pyrazolo[1,5-a]pyridine. |
53% | Stage #1: With mesitylenesulfonylhydroxylamine In dichloromethane at 0℃; for 2 h; Stage #2: With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 18 h; |
Step 2.1 : A fresh solution of O-(mesitylsulfonyl)hydroxylamine in CH2CI2 (6.0 ml_, 0.44 mol L"1, 2.6 mmol) [T. Eichenberger et al., HeIv. Chim. Acta 1986, 69(6), 1521] was added to 4-methylpyridine (1: X = Me) (248 mg, 2.66 mmol) in CH2CI2 (10 mL) at 0 0C. After 2 h, the solvent was removed in vacuo. The residue was taken up in dry DMF (8 mL), then ethyl propiolate (0.25 mL, 2.5 mmol) and K2CO3 (450 mg, 3.26 mmol) were added, and the suspension stirred at room temperature for 18 h. The reaction mixture was diluted with water and extracted twice with EtOAc. The combined organic phases were washed three times with water then with brine, dried (Na2SO4) and the solvent removed in vacuo. Chromatography (eluting with hexanes: EtOAc 97:3 to 95:5 to 9:1) gave ethyl 5-methyl- pyrazolo[1 ,5-a]pyridine-3-carboxyIate (4: X = Me) as a pale brown solid (175 mg, 53percent). 1H NMR δ (400 MHz, CDCI3) 8.39 (d, J 7.1 Hz, 1 H)1 8.34 (s, 1H), 7.93 (s, 1H), 6.76 (dd, J 7.1 , 1.9 Hz, 1 H), 4.38 (q, J 7.1 Hz, 2H), 2.47 (s, 3H), 1.41 (t, J 7.1 Hz, 3H). LCMS (APCI+) 205 (MH+, 100percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | for 24 h; Reflux | Propiolic acid (310 μL, 5 mmol; Alfa Aesar, Ward Hill, Mass.; catalog No. A13245) was dissolved in 13 mL of ethanol, giving a colorless solution, to which concentrated sulfuric acid (139 μL, 2.5 mmol) was added. The resulting mixture was heated to reflux for 24 h, and then treated with 13 mL of water before being extracted with dichloromethane (10 mL; three times). The combined organic layers were washed with water (10 mL; three times) and brine (10 mL), and then dried over anhydrous Na2SO4 (Thermo Fisher Scientific, Pittsburgh, PA; catalog No. S421-3). Removal of the solvent under vacuum afforded the product as a light yellow color oil (177 mg, 36percent yield). 1H NMR (400 MHz, CDCl3, δ): 4.26 (q, 3JH-H=7.1 Hz, CH2, 2H), 2.92 (s, C≡CH, 1H), 1.33 (t, 3JH-H=7.2 Hz, CH3, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With triphenylphosphine In tetrahydrofuran; benzene | But-2-ynyloxy-benzene To a solution of 6.14 g (23.40 mmol) of triphenylphosphine dissolved in 100 mL of benzene and 50 mL of THF was added 1.75 mL (23.40 mmol) of 2-butyn-1-ol. After five minutes 2.00 g (21.28 mmol) of the phenol, dissolved in 10 mL of THF, was added to the reaction followed by 3.69 mL (23.40 mmol) of diethyl azodicarboxylate. The resulting reaction mixture was stirred for 18 h at room temperature and then concentrated in vacuo. The residue was chromatographed on silica gel eluding with ethyl acetate/hexanes (1:10) to provide 2.18 g (70percent) of the desired propargylic ether as a clear liquid. EI Mass Spec: 146.0 M+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With triphenylphosphine In tetrahydrofuran; benzene | EXAMPLE 5 5-Bromo-3-methyl-2-[methyl-(4-prop-2-ynyloxy-benzenesulfonyl)-amino]-benzoic acid methyl ester To a solution of 0.317 g (1.208 mmol) of triphenylphosphine dissolved in 5 mL of benzene and 2 mL of THF was added 0.070 mL (1.208 mmol) of propargyl alcohol. After five minutes 0.500 g (1.208 mmol) of the product of Example 4, dissolved in 2 mL of THF, was added to the reaction followed by 0.190 mL (1.208 mmol) of diethyl azodicarboxylate. The resulting reaction mixture was stirred for 18 h at room temperature and then concentrated in vacuo. The residue was chromatographed on silica gel eluding with ethyl acetate/hexanes (1:10) to provide 0.389 g (71percent) of the desired propargylic ether as a white solid. Electrospray Mass Spec: 451.8 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | Stage #1: With silver(I) nitrite In acetone at 20℃; for 0.0833333 h; Stage #2: With N-Bromosuccinimide In acetone at 20℃; for 2 h; |
Reaction Step 1. Synthesis of ethyl 3-bromopropiolate Silver nitrite (1.72 g, 10.2 mmol, 0.1 eq) was added to a solution of ethyl propiolate (10.00 g, 102 mmol, 1.0 eq) in acetone (200 mL) at room temperature. The resulting reaction mixture was stirred for 5 min, then NBS (20.0 g, 112 mmol, 1.1 eq) was added and the reaction mixture stirred for 2 h at room temperature. After completion of the reaction (monitored by TLC, 5percent ethyl acetate-hexane Rf=0.55), the reaction mixture was filtered through a celite pad, washing with acetone. The filtrate was concentrated under reduced temperature (25-30° C.) to afford an oil. |
58% | Stage #1: With silver(I) nitrite In acetone at 20℃; for 0.0833333 h; Stage #2: With N-Bromosuccinimide In acetone at 20℃; for 2 h; |
Silver nitrite (1.72 g, 10.2 mmol, 0.1 eq) was added to a solution of ethyl propiolate (10.00 g, 102 mmol, 1.0 eq) in acetone (200 mL) at room temperature. The resulting reaction mixture was stirred for 5 min, then NBS (20.0 g, 112 mmol, 1.1 eq) was added and the reaction mixture stirred for 2h at room temperature. After completion of the reaction (monitored by TLC, 5percent ethyl acetate-hexane, Rf = 0.55), the reaction mixture was filtered through a celite pad, washing with acetone. The filtrate was concentrated under reduced temperature (25– 30 °C) to afford an oil. The crude product was purified by flash column chromatography on silica gel (100-200 mesh), eluting with 10percent diethyl ether in hexanes to afford ethyl 3- bromopropiolate (10.0 g, 58percent) as a yellow oil. LCMS m/z = 176.91 (M+1). |
58% | Stage #1: With silver(I) nitrite In acetone at 20℃; for 0.0833333 h; Stage #2: With N-Bromosuccinimide In acetone at 20℃; for 2 h; |
Reaction step 1. Synthesis of e propiolate Silver nitrite (1.72 g, 10.2 mmol, 0.1 eq) was added to a solution of ethyl propiolate (10.00 g, 102 mmol, 1.0 eq) in acetone (200 mL) at room temperature. The resulting reaction mixture was stirred for 5 min, then NBS (20.0 g, 112 mmol, 1.1 eq) was added and the reaction mixture stirred for 2h at room temperature. After completion of the reaction (monitored by TLC, 5percent ethyl acetate-hexane, Rf = 0.55), the reaction mixture was filtered through a celite pad, washing with acetone. The filtrate was concentrated under reduced temperature (25– 30 °C) to afford an oil. The crude product was purified by flash column chromatography on silica gel (100-200 mesh), eluting with 10percent diethyl ether in hexanes to afford ethyl 3-bromopropiolate (10.0 g, 58percent) as a yellow oil. LCMS m/z = 176.91 (M+1). |
58% | Stage #1: With silver nitrate In acetone for 0.0833333 h; Stage #2: With N-Bromosuccinimide In acetone at 20℃; for 2 h; |
Silver nitrite (1.72 g, 10.2 mmol, 0.1 eq) was added to a solution of ethyl propiolate (10.0 g, 102 mmol, 1.0 eq) in acetone (200 mE) at room temperature. The resulting reaction mixture was stirred for 5 mm, then N135 (20.0 g, 112 mmol, 1.1 eq) was added and the reaction mixture stirred for 2 hr at room temperature. After completion of the reaction (monitored by TEC, 5percent ethyl acetate-hexane, R1=0. 55), the reaction mixture was filtered through a celite pad, washing with acetone. The filtrate was concentrated under reduced temperature (25-30° C.) to afford an oil. The crude product was purified by flash column chromatography on silica gel (100-200 mesh), eluting with 10percent diethyl ether in hexanes to afford ethyl 3-bromopropiolate (10.0 g, 58percent) as a yellow oil. ECMS mlz=176.91 (M+1). |
58% | Stage #1: With silver(I) nitrite In acetone at 20℃; for 0.0833333 h; Stage #2: With N-Bromosuccinimide In acetone at 20℃; for 2 h; |
Reaction Step 1 Synthesis of ethyl 3-bromopropiolate Silver nitrite (1.72 g, 10.2 mmol, 0.1 eq) was added to a solution of ethyl propiolate (10.00 g, 102 mmol, 1.0 eq) in acetone (200 mL) at room temperature. The resulting reaction mixture was stirred for 5 min, then NBS (20.0 g, 112 mmol, 1.1 eq) was added and the reaction mixture stirred for 2 h at room temperature. After completion of the reaction (monitored by TLC, 5percent ethyl acetate-hexane, Rf=0.55), the reaction mixture was filtered through a celite pad, washing with acetone. The filtrate was concentrated under reduced temperature (25-30° C.) to afford an oil. The crude product was purified by flash column chromatography on silica gel (100-200 mesh), eluting with 10percent diethyl ether in hexanes to afford ethyl 3-bromopropiolate (10.0 g, 58percent) as a yellow oil. LCMS m/z=176.91 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | at -78 - 20℃; for 5 h; | To a solution of liquid NH3 (50 ml.) at -78°C was added dropwise ethyl 2-propynoate (1 1 g, 0.11 mol). The mixture was stirred at -78°C for 2 hours, then for 3 hours at room temperature. The remaining residue was concentrated under vacuum to give the title compound which was used in the next step without further purification (8 g, quantitative yield). |
74% | at -10℃; for 1 h; Inert atmosphere | Ethyl propiolate (4.0 mL, 40 mmol) was added to aqueous ammonia (25percent w/w; 130 mL) at −10 °C and the reaction was stirred at −10 °C (1 h). The reaction mixture was poured onto ethyl acetate (100 mL) and the layers were separated. The aqueous phase was extracted with ethyl acetate (4 x 100 mL) and the combined organic extracts were dried over MgSO4. The solvent and unreacted ethyl propiolate were removed in vacuo to give the crude title compound (2.02 g, 74percent) as an off-white solid, which was used without further purification. |
72% | With ammonium hydroxide In water at 0℃; for 5.5 h; | Propynamide: To a solution of 30 mL of water and 9.19 g (135 mmol) ammonia (25-28 wt percent) is added dropwise 9.81 g (100 mmol) ethyl propiolate at 0° C. for 30 minutes. The mixture was stirred for 5 h at 0° C., then acetic acid (3 mL) was added. The mixture was stirred for another 10 minutes and saturated with NaCl, followed by extraction with ethyl acetate (3×40 mL). The combined organic phase was washed with saturated aqueous solution of NaHCO3 (20 mL), dried over Na2SO4, and removed by rotary evaporation to give product (5.0 g, yield 72percent, purity 99percent by GC). 1H NMR (400 MHz, DMSO-d6) δ 8.07 (1H, s), 7.61 (1H, s), 4.05 (1H, s). |
72% | With ammonia In water at 0℃; for 5.5 h; | To a solution of 30 mL of water and 9.19 g (135 mmol) ammonia (25-28 wt percent) is added dropwise 9.81 g (100 mmol) ethyl propiolate at 0 °C for 30 mins. The mixture was stirred for 5 h at 0 °C, then acetic acid (3 mL) was added. The mixture was stirred for another 10 mins and saturated with NaCI, followed by extraction with ethyl acetate (3 χ 40 mL). The combined organic phase was washed with saturated aqueous solution of NaHC03 (20 mL), dried over Na2S04, and removed by rotary evaporation to give product (5.0 g, yield 72percent, purity 99percent by GC).1H NMR (400 MHz, DMSO-d6) δ 8.07 (1 H, s), 7.61 (1 H, s), 4.05 (1 H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | Stage #1: With copper(l) iodide; caesium carbonate In tetrahydrofuran at 20℃; for 0.0833333 h; Inert atmosphere Stage #2: at 35℃; Inert atmosphere |
a) (4-Chloro-phenyl)-propynoic acid ethyl ester (Va) Under argon atmosphere, a four neck flask was charged with 1-chloro-4-iodo-benzene (130.0 g, 0.55 mol), bis(triphenylphosphine) palladium(II) chloride (7.57 g, 10.8 mmol, 2 mol percent), copper(I) iodide (4.19 g, 22.0 mmol, 4 mol percent) and dry THF (1.4 l). At r.t., cesium carbonate (355.3 g, 1.09 mol, 2 eq.) was added over 5 min. Afterwards propynoic acid ethyl ester (111.3 ml, 1.09 mol, 2 eq.) was added, and the reaction mixture was stirred overnight at 35° C. An additional portion of propynoic acid ethyl ester (11.1 ml, 0.11 mol, 0.2 eq.) was added, and the reaction was stirred for another 3 h at 35° C. The reaction mixture was evaporated to dryness, and the residue was taken up in toluene (0.5 l) and heptane (1 l). The resulting suspension was stirred at 40° C. for 1 h and filtered over celite. The filtrate was concentrated, and the product purified by silica gel filtration (toluene/heptane 1:2) to yield 72.6 g (61percent) of Va as a light yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46.3% | for 0.416667 h; Heating | General procedure: A mixture of aromatic aldehyde (0.05 mol), ethyl propiolate (0.10 mol), amine (0.05 mol), and 5.0 mL of acetic acid was heated in a steam bath for 25 min [16, 17]. The product was crystallized from methanol : water, 4 : 1 and then recrystallized from acetone : hexane, 1 : 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | at 120 - 122℃; for 12 h; | A solution of 3a,4,5,6-tetrahydro-3-oxo-3H-pyrrolo[1,2-c][1,2,3]oxadiazol-7-ium ylide (13.5 g, 0.107 mole, crude, from example 4) and ethyl propiolate (15.8 g, 16.3 ml, 0.16 mole) in dry N,N-dimethylformamide (50 ml) is stirred and heated to 120-122° C. under a nitrogen atmosphere for a period of 12 hours. The reaction is monitored for completion by HPLC [Prodigy ODS3 4.6.x.150 mm column, with a 10 minutes gradient from 90:10 to 10:90 water/acetonitrile with 0.02percent trifluoroacetic acid. Retention times under these conditions were: 2.6-2.7 min for ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate (the desired, more polar isomer) and 2.8-2.9 min for ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylate (the less polar, undesired isomer). The UV detector was set at 215 nm, because at 254 nm the two isomers absorbed very differently, and the undesired isomer was almost undetectable). The mixture is then evaporated to a dark syrup under oil pump vacuum using a bath temperature up to 50° C. The ratio of the esters in the dark syrup is determined by NMR, as 2.13 to 1 in favor of the desired ester, ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate. The dark syrup is diluted with toluene and the solution is applied to a column of silica gel (500 mL) prepacked in hexanes by washing onto the column with hexanes. Elution is with hexanes-ethyl acetate mixture (4:1) followed by hexanes-ethyl acetate (1:1). Fractions are monitored by HPLC (same conditions as above). Fractions that contained both esters are combined and chromatographed once more. Fractions containing only ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate are combined and concentrated to give 11 g (57percent) of the pure ester as white crystals, m. p. 41-43° C. Similarly, 6.5 g (33.7percent) of ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylate is obtained as white crystals, m.p. 35-37° C. |
41% | at 120 - 125℃; for 8 - 11 h; | The 3a,4,5,6-Tetrahydro-3-oxo-3H-pyrrolo[1,2-c][1,2,3]oxadiazol-7-ium ylide (971 g, 7.70 mol, made as in example 2) and 1,2-diethoxyethane (DEE, 2913 mL) are charged to a multinecked 12 L round bottom flask, is equipped with a water cooled condenser, and purged with nitrogen. The stirred solution is heated to 120-125° C. under a nitrogen atmosphere and ethyl propiolate (971 g, 9.90 mol) is added dropwise over a period of 3 hours (carbon dioxide evolution). The reaction is held at 120-125° C. for about 5 hours until the conversion is >99percent (<1percent of residual 3a,4,5,6-tetrahydro-3-oxo-3H-pyrrolo[1,2-c][1,2,3]oxadiazol-7-ium ylide, by GC-MS analysis). The mixture is then concentrated under oil pump vacuum using a rotary evaporator with a bath temperature up to 70° C. to a residue. About 1.5 kg of toluene is then added to the residue and the mixture is concentrated once more. A dark oil is obtained [1218 g, 46.9percent strength, (HPLC) in 41percent (real yield of ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate, from crude 3a,4,5,6-tetrahydro-3-oxo-3H-pyrrolo[1,2-c][1,2,3]oxadiazol-7-ium ylide]. [TABLE-US-00001] Ratio of 2- Ylide, Ester to 3- Addition Hold 3, Product 2-Ester Ester Time Time starting Crude 2-Ester percent Yield by GC-MS Solvent Temp° C. (hours)* (hours)** (g) (g) Wt percent (crude to real) (Area percent) DEE 120-125 3 5 971 1218 46.9 41 58/42 DEE 120-125 3 6.2 1400 1988 48.2 47 60/37 DEE 120-125 3 8 827 1075 45.5 42 57/40 *Addition time is the time taken to add the reagent, ethyl propiolate. **Hold time is the time the reaction is allowed to run beyond the addition time. The total reaction time is the sum of the addition time and the hold time. |
42 %Chromat. | at 120 - 125℃; for 5 h; | To 3a,4,5,6-Tetrahydro-3-oxo-3H-pyrrolo[1,2-c][1,2,3]oxadiazol-7-ium Ylide (29.3 g, 0.232 mol prepared as in example 2) and chlorobenzene (97.2 g) under a nitrogen atmosphere at 120-125° C. is added dropwise ethyl propiolate (29.3 g, 0.299 mol) over a period of about 2 hours (carbon dioxide evolution). The reaction is held for about 3 hours until the conversion is >99percent (<1percent residual according to GC-MS analysis). The GC-MS ratio of the desired isomer, ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate, to the undesired isomer, ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylate, is 59/41 The mixture is then washed with water (50 mL). The organic phase is concentrated under oil pump vacuum up to a bath temperature of about 70° C. to afford a residue as a dark oil [39.1 g, 45.3percent strength (HPLC) in ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate, 42percent (real yield of 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate from crude 3a,4,5,6-tetrahydro-3-oxo-3H-pyrrolo[1,2-c][1,2,3]oxadiazol-7-ium ylide)]. The oil is characterized by HPLC, NMR. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | at 80℃; for 23 h; | A mixture of 3,5-dichloro-6-methyl-[1 ,4]oxazin-2-one (45.5 g, 253 mmol) and ethyl propiolate (74.4 g, 758 mmol) in toluene (135 mL) is stirred under nitrogen at 80 0C for 23 h. The reaction is then cooled down to room temperature and the solvents are removed by rotary evaporation. The residue is treated with hexanes (400 mL), and the somewhat cloudy solution is decanted from a dark red residue containing undesired impurities. The hexanes are removed by rotary evaporation. The crude is then cooled to 0 0C, and the flask is swirled occasionally until the crude oil solidifies. The solid is then washed with small amounts of pentane. The cooled filtrate is filtered again, resulting in removal of additional yellow solid, which is the undesired regioisomer (16 g). The filtrate is then concentrated down to dryness by rotary evaporation and purified by silica gel chromatography (9:1 heptane / dichloromethane) to yield a clear liquid which solidifies upon standing (15.4 g, 65.8 mmol, 26percent). MS(ESI) m/z 234.16 (M+1 ). 1H NMR (400 MHz, CDCI3) δ ppm 7.55 (s, 1 H), 4.39 (q, J=7.07 Hz, 2 H), 2.53 (s, 3 H), 1.39 (t, J=7.14 Hz, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | Stage #1: With sodium hydroxide; hydroxylamine hydrochloride In ethanol; water at 20℃; for 48 h; |
To a solution of 30 g (0.306 mol) of ethyl propiolate in 600 mL of ethanol, 85 g (1.223 mol) of hydroxylamine hydrochloride in 1.1 L of a 10percent sodium hydroxide solution were added in an argon atmosphere. The mixture was stirred at room temperature for 48 h, and then acidified to a pH = 2-3 by addition of concentrated hydrochloric acid. The reaction mixture was extracted three times with diethyl ether, and the combined extracts were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure. The residue was extracted with hot hexane, and then the solvent was evaporated under reduced pressure. 9.0 g (yield = 35percent) of a white crystalline solid corresponding to the title compound was obtained. Mass spectrum (m/e): 83 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78.5% | Stage #1: With triethylamine In toluene at 20℃; for 2 h; Stage #2: at 85℃; for 70 h; |
ii) 6-Hydroxy-5-methyl-nicotinic acid ethyl ester At RT, a solution of propionyl chloride (1.55 mL, 17.4 mmol) in 3.5 mL of toluene was added drop-wise to a solution of N-tert-butyldimethylsilyl isopropyl formimidate (3.51 g, 17.4 mmol) and triethylamine (12.2 mL, 87 mmol) in 10 mL of toluene. The resulting mixture was stirred at RT for 2 hours and then 10 mL of hexanes was added. The precipitate was removed by filtration and washed with hexanes (3 x 5 mL). The solution was concentrated in vacuo to afford a clear oil. This oil was solubilised in toluene (15 mL) and ethyl propiolate (1.2 mL, 11.6 mmol) was added. The resulting mixture was stirred at 85°C for 70 hours. The mixture was concentrated in vacuo and then diluted with HCI 2N. The aqueous phase was extracted with DCM. The organic phases were combined, dried over sodium sulfate and concentrated in vacuo to afford a crude yellow paste (3.5 g). The crude product was purified by flash chromatography over silica gel using Hexanes/EtOAc (75/25 to 0/100) as solvent gradient to afford 6-hydroxy-5-methyl-nicotinic acid ethyl ester (1.65 g, 78.5percent) as a yellow powder. (ES- MS: m/z 182.1 [M+H]+, tR 3.28 min (system 2)). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With methanol; [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane; copper(l) chloride; sodium t-butanolate In tetrahydrofuran at 20℃; for 24 h; Inert atmosphere | General procedure: CuCl (1.5 mg, 0.015 mmol), NaOt-Bu (2.9 mg, 0.03 mmol), and Xantphos ligand (8.7 mg, 0.015 mmol) were placed in an oven-dried Schlenk tube under nitrogen and THF (0.45 mL) were added. The reaction mixture was stirred for 30 min at room temperature and then bis(pinacolato)diboron (127 mg, 0.5 mmol) in THF (0.3 mL) was added. The reaction mixture was stirred for 10 min and α,β-acetylenic ester 2 (0.5 mmol) was added, followed by MeOH (40 μL, 1 mmol). The reaction tube was washed with further THF (0.2 mL), sealed, and stirred until no starting material was detected by TLC. The reaction mixture was filtered through a pad of Celite and concentrated. The product was purified by silica gel chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
850 mg | Stage #1: With potassium carbonate In N,N-dimethyl-formamide at 0℃; for 0.166667 h; Stage #2: at 20℃; for 16 h; |
To a solution of the product from step 1(1.50 g, 4.9 mmoi) in I)MF (2() mL) was added K2C03 (1.4 g, 98 mmoi). The mixture was stirred at ()°C for 10 minutes, then ethylpropiolate (480 mg, 4.9 mmoi) was added. The mixture was stirred at RT for i6hours, dilutedwith water and extracted with EtOAc (50 mL x 3). The combined organic layer was dried over sodium sulfate, filtered and concentrated in vaeuo. The residue was purified by PrepHPLC to give the title compound (850 mg) as yellow oil. LRMS m/z (M-f-H) 221.1 found, 221 .1 required. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
300 mg | With potassium carbonate In N,N-dimethyl-formamide for 0.166667 h; | Compound 64.3. Ethyl 5-bromopyrazolo[l,5-a]pyridine-3-carboxylate. Into a 250-mL three neck round-bottom flask, was placed a solution of l-amino-4-bromopyridin-l- ium iodide (compound 64.2, 15 g, -50percent purity, 24.9 mmol) in N.N-dimethylformamide (80 mL). Potassium carbonate (10.6 g, 76.7 mmol) was added portion-wise followed by the addition of ethyl propiolate (1 1.7 mL, 1 15 mmol) drop-wise over 10 min. The resulting mixture was stirred overnight at room temperature, then diluted with EtOAc (300 mL) and water (100 mL). The solids were removed by filtration and the organic layer was washed with brine (3 x 50 mL), dried (Na2S04), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1 : 10) as the eluent to yield the title compound as a brown solid (300 mg, 6percent). |
300 mg | With potassium carbonate In N,N-dimethyl-formamide at 20℃; | Compound 64.3. Ethyl 5-bromopyrazolo[l,5-]pyridine-3-carboxylate. Into a 250-mL three neck round-bottom flask, was placed a solution of l-amino-4-bromopyridin-l- ium iodide (compound 64.2, 15 g, -50percent purity, 24.9 mmol) in N,N-dimethylformamide (80 mL). Potassium carbonate (10.6 g, 76.7 mmol) was added portion-wise followed by the addition of ethyl propiolate (11.7 mL, 115 mmol) drop-wise over 10 min. The resulting mixture was stirred overnight at room temperature, then diluted with EtOAc (300 mL) and water (100 mL). The solids were removed by filtration and the organic layer was washed with brine (3 x 50 mL), dried ( a2S04), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1 : 10) as the eluent to yield the title compound as a brown solid (300 mg, 6percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3% | Stage #1: With mesitylenesulfonylhydroxylamine In N,N-dimethyl-formamide at 0 - 40℃; for 16 h; Stage #2: With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃; for 6 h; |
To a stirred solution of 4-bromopyridine (64.0 g, 40.5 mmol) in DME (200 mL) at 0 °0 was added O-(mesitylsulfonyl)hydroxylamine (80.0 g, 37.1 mmol) portion wise over a period of 20 mm. The resultant reaction mixture was allowed to warm to room temperature and maintained at 40°C for 16 h. The reaction mixture was cooled toO °0, diluted with DME (200 mL), K2003 (128 g, 92.7 mmol) followed by ethyl propiolate (43.07 mL, 42.5 mmol) were added and the resulting reaction mixture was stirred at rt for 6 h. The reaction mixture was poured on to ice-cold water, extracted with ethyl acetate (2 x 1000 mL). The ethyl acetate layer was washed with water, brine, dried over anhyd. Na2SO4 and concentrated. The crude compound was purified by column chromatography over silica gel (100—200 mesh) using a solvent gradient mixture of 7percent ethyl acetate in pet-ether to afford 3.5 g (3percent) of ethyl 5-bromopyrazolo[1 , 5-a]pyridine-3-carboxylate 94-1 as a light brown solid. ESI-LC/MS: m/z269.2 (M+H) & 271.2 [(M+2)+H]; R = 3.46 mm [Agilent [C with Ion trap Detector; Symmetry 018,3.5 pm, 4.6 X 75mm column; gradient of 50:50 H20 (0.1percent H000H): CH3CN (0.1percent H000H) to 10:90 H20 (0.1percent H000H):CH3CN (0.1percent H000H) in 4.0 mm and hold for 3.0 mm with flow rate of 1.0 mL/min]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21 g | With triethylamine In N,N-dimethyl-formamide at 20℃; for 48 h; | To a magnetically stirred white suspension of 1 -amino-3 -bromo-5 -methoxypyridin- 1 -ium 2,4,6-trimethylbenzenesulfonate (33.24 g, 82.42 mmol) in DMF (82 mL) at ambient temperature was added TEA (22.98 mL, 164.8 mmol), followed by drop-wise addition of ethyl propiolate (16.71 mL, 164.8 mmol). After vigorous stirring for 2 d, the reaction was slowly quenched via portion- wise addition to rapidly stirring ice water (820 mL). The mixture was stirred at ambient temperature for 10 mm and then vacuum filtered. Solids collected were rinsed with water and airdried, yielding the title compounds as an orange solid in an isomeric ratio of about 4:1 (by ‘H NMR) with the 6-Br isomer as the major isomer (21 g). The wet solid isomeric mixture (about 75percent w/w) was directly used in Step 3 without further purification. MS (apci) m/z = 298.9, 300.9 (M+H). Regioisomeric ratio was determined by MeO chemical shift in ‘H NMR (CDC13) 3.98 (6-Br isomer) vs. 3.83 (4-Br isomer). |
21 g | With triethylamine In N,N-dimethyl-formamide at 20℃; for 48 h; | Preparation of Ethyl 6-bromo-4-methoxypyrazolo|"l,5-a"|pyridine-3- carboxylate and Ethyl 4-bromo-6-methoxypyrazolo|"l,5-a"|pyridine-3-carboxylate. To a magnetically stirred white suspension of l-amino-3-bromo-5-methoxypyridin-l-ium 2,4,6- trimethylbenzenesulfonate (33.24 g, 82.42 mmol) in DMF (82 mL) at ambient temperature was added TEA (22.98 mL, 164.8 mmol), followed by drop-wise addition of ethyl propiolate (16.71 mL, 164.8 mmol). After vigorous stirring for 2 d, the reaction was slowly quenched via portion-wise addition to rapidly stirring ice water (820 mL). The mixture was stirred at ambient temperature for 10 min and then vacuum filtered. Solids collected were rinsed with water and air-dried, yielding the title compounds as an orange solid in an isomeric ratio of about 4: 1 (by MR) with the 6-Br isomer as the major isomer (21 g). The wet solid isomeric mixture (about 75percent w/w) was directly used in Step 3 without further purification. MS (apci) m/z = 298.9, 300.9 (M+H). Regioisomeric ratio was determined by MeO chemical shift in 1H MR (CDCh) δ 3.98 (6-Br isomer) vs. 3.83 (4-Br isomer). |
[ 762-21-0 ]
Diethyl acetylenedicarboxylate
Similarity: 0.88
[ 762-21-0 ]
Diethyl acetylenedicarboxylate
Similarity: 0.88
[ 762-21-0 ]
Diethyl acetylenedicarboxylate
Similarity: 0.88