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CAS No. : | 2199-51-1 | MDL No. : | MFCD01365811 |
Formula : | C9H13NO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | QWSFDUPEOPMXCV-UHFFFAOYSA-N |
M.W : | 167.21 | Pubchem ID : | 137481 |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 5 |
Fraction Csp3 : | 0.44 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 46.81 |
TPSA : | 42.09 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.12 cm/s |
Log Po/w (iLOGP) : | 2.07 |
Log Po/w (XLOGP3) : | 1.69 |
Log Po/w (WLOGP) : | 1.81 |
Log Po/w (MLOGP) : | 1.02 |
Log Po/w (SILICOS-IT) : | 2.5 |
Consensus Log Po/w : | 1.82 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.05 |
Solubility : | 1.48 mg/ml ; 0.00888 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.19 |
Solubility : | 1.08 mg/ml ; 0.00647 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.86 |
Solubility : | 0.233 mg/ml ; 0.00139 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.79 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-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 |
---|---|---|
77.3% | With hydrogenchloride In water; isopropyl alcohol at 25 - 50℃; Industry scale | Step (ii): Preparation of 2,4-dimethyI-lH-pyrroIe-3-carboxyIic acid ethyl ester(πi)Into a 10-L four necked round-bottomed flask equipped with a mechanical stirrer, a thermometer pocket, gas bubbler and an air condenser, were charged 3,5-dimethyl-lH- pyrrole-2,4-dicarboxylic acid 2-tertiary butyl ester 4-ethyl ester (II) (1.5 Kg; 5.6 mole), isopropyl alcohol 4.5 L and stirred while Cone. HCl (2.2 L) was charged with the aid of addition funnel at 25-30° C. After addition, the temperature of the reaction mixture was raised to 45-50° C and maintained at this temperature until the gas evolution completely ceases. The reaction was monitored by TLC and the solution cooled to 25-30° C and quenched in a carboy containing ice water under stirring. The product was isolated by filtration and dried at 50° C.Dry Weight: 721.3 g Yield: 77.3percent HPLC purity: >96percent |
77.3% | With hydrogenchloride In isopropyl alcohol at 25 - 50℃; | Into a 10-L four necked round-bottomed flask equipped with a mechanical stirrer, a thermometer pocket, gas bubbler and an air condenser, were charged 3,5-dimethyl-1H-pyrrole-2,4-dicarboxylic acid 2-tertiary butyl ester 4-ethyl ester (II) (1.5 Kg; 5.6 mole), isopropyl alcohol 4.5 L and stirred while Conc. HCl (2.2 L) was charged with the aid of addition funnel at 25-30oC. After addition, the temperature of the reaction mixture was raised to 45-50oC. and maintained at this temperature until the gas evolution completely ceases. The reaction was monitored by TLC and the solution cooled to 25-30oC. and quenched in a carboy containing ice water under stirring. The product was isolated by filtration and dried at 50oC. Dry Weight: 721.3 g Yield: 77.3percent HPLC purity: >96percent |
68% | With hydrogenchloride In ethanol; water for 4 h; Reflux | 1 g of 2-tert-butyl-4-ethyl 3,5-dimethyl-1H-pyrrole-2,4-dicarboxylate was added to 10 mL of ethanol, and 1.9 mL of 10 M hydrochloric acid was slowly added and refluxed for 4 h. Cool to room temperature, concentrate, extract with EA, wash with water, dry over anhydrous Na2SO4, column chromatography(PE: EA = 8:1) gave 428 mg of pale yellow solid, yield 68percent. |
20% | With sulfuric acid In ethanol; water at 65℃; for 4 h; | Step Id. Ethyl 2,4-dimethyl-lH-pyrrole-3-carboxylate (Compound 106)A solution of 105 (12 g, 45 mmol ) in ethanol (325 mL) was treated with 1 MH2SO4 (240 mL). The solution was stirred at 65°C for 4 h, and then cooled to room temperature and evaporated most of ethanol, extracted with dichloromethane. The organic layer was combined and dried with MgSO4. After removal of the solvent, the crude product 506 (3 g, 40percent) was obtained. The crude product was purified by column chromatography (silica gel, elution 10/1 petroleum/ethyl acetate) to obtain brown solid product 106 (1.5 g, 20percent). LCMS: m/z 168(M+1), 1H NMR(DMSO-^6) δ2.10(s, 3H), 2.35(s, 3H), 4.13(q, 2H), 6.37(s, IH), 10.85( s, IH). |
20% | With sulfuric acid; water In ethanol at 65℃; for 4 h; | A solution of 105 (12 g, 45 mmol) in ethanol (325 niL) was treated with 1 M H2SO4 (240 rnL). The solution was stirred at 65°C for 4 h, and then cooled to room temperature and evaporated most of ethanol, extracted with dichloromethane. The organic layer was combined and dried with MgSO4. After removal of the solvent, the crude product 506 (3 g, 40percent) was obtained. The crude product was purified by column chromatography (silica gel, elution 10/1 petroleum/ethyl acetate) to obtain brown solid product 106 (1.5 g, 20percent). LCMS: m/z 168(M+1), 1H NMR(DMSO-J6) δ2.10(s, 3H), 2.35(s, 3H), 4.13(q, 2H), 6.37(s, IH), 10.85( s, IH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.5% | Inert atmosphere | 4-(Ethoxycarbonyl)-3,5-dimethyl-1H-pyrrole-2-carboxylic acid (7, 5.0 g, 25.0 mmol) was heated in a flask to 200-210 °C with an oil bath for 12 min. The reactant gradually melted with accompanying production of carbon dioxide. The heating was removed when there was no more gas evolving. The reaction was allowed to cool down to r.t. and then dried under vacuum to afford 8 as a pale-gray solid (3.90 g, 98.5 percent), m.p. 75-76 °C (lit. 74-76 °C [17]), yield 90.0 percent (lit. [13]). Rf = 0.73 (eluent: chloroform/methanol, v/v = 10:1). |
53% | for 1.5 h; Heating | 35,5-dimethyl-4-ethoxycarbonyl--1H- pyrrole-2-carboxylic acid (9.5g, 0.045mol) was heated to a molten state reaction 1.5h, cooled to room temperature, dissolved in dichloromethane, filtered and the filtrate dried over anhydrous sodium sulfate, and concentrated. Column chromatography with petroleum ether: ethyl acetate = 10:1 (V / V) as eluent to give dark red crystals (4.0g, 53percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With hydrogenchloride In <i>N</i>-methyl-acetamide; (2S)-N-methyl-1-phenylpropan-2-amine hydrate; dichloromethane; trichlorophosphate | Dimethylformamide (322 g) and dichloromethane (3700 mL) were cooled in an ice bath to 4° C. and phosphorus oxychloride (684 g) was added with stirring. Solid 2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (670 g) was slowly added in aliquots over 15 minutes. The maximum temperature reached was 18° C. The mixture was heated to reflux for one hour, cooled to 10° C. in an ice bath and 1.6 L of ice water was rapidly added with vigorous stirring. The temperature increased to 15° C. 10 N Hydrochloric acid (1.6 L) was added with vigorous stirring. The temperature increased to 22° C. The mixture was allowed to stand for 30 minutes and the layers allowed to separate. The temperature reached a maximum of 40° C. The aqueous layer was adjusted to pH 12-13 with 10 N potassium hydroxide (3.8 L) at a rate that allowed the temperature to reach and remain at 55° C. during the addition. After the addition was complete the mixture was cooled to 10° C. and stirred for 1 hour. The solid was collected by vacuum filtration and washed four times with water to give 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (778 g, 100percent yield) as a yellow solid. 1H-NMR (DMSO-d6) δ 1.25 (t, 3H, CH3), 2.44, 2.48 (2*s, 2*3H, 2*CH3), 4.16 (q, 2H, CH2), 9.59 (s, 1H, CHO), 12.15 (br s, 1H, NH). MS m/z 195 [M+1]. |
100% | With hydrogenchloride In <i>N</i>-methyl-acetamide; (2S)-N-methyl-1-phenylpropan-2-amine hydrate; dichloromethane; trichlorophosphate | Dimethylformamide (322 g) and dichloromethane (3700 mL) were cooled in an ice bath to 4° C. and phosphorus oxychloride (684 g) was added with stirring. Solid 2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (670 g) was slowly added in aliquots over 15 minutes. The maximum temperature reached was 18° C. The mixture was heated to reflux for one hour, cooled to 10° C. in an ice bath and 1.6 L of ice water was rapidly added with vigorous stirring. The temperature increased to 15° C. 10 N Hydrochloric acid (1.6 L) was added with vigorous stirring. The temperature increased to 22° C. The mixture was allowed to stand for 30 minutes and the layers allowed to separate. The temperature reached a maximum of 40° C. The aqueous layer was adjusted to pH 12-13 with 10 N potassium hydroxide (3.8 L) at a rate that allowed the temperature to reach and remain at 55° C. during the addition. After the addition was complete the mixture was cooled to 10° C. and stirred for 1 hour. The solid was collected by vacuum filtration and washed four times with water to give 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (778 g, 100percent yield) as a yellow solid. 1H-NMR (DMSO-d6) δ1.25 (t, 3H, CH3), 2.44, 2.48 (2*s, 2*3H, 2*CH3), 4.16 (q, 2H, CH2), 9.59 (s, 1H, CHO), 12.15 (br s, 1H, NH). MS m/z 195 [M+1]. |
100% | With hydrogenchloride In <i>N</i>-methyl-acetamide; (2S)-N-methyl-1-phenylpropan-2-amine hydrate; dichloromethane; trichlorophosphate | Dimethylformamide (322 g) and dichloromethane (3700 mL) were cooled in an ice bath to 4° C. and phosphorus oxychloride (684 g) was added with stirring. Solid 2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (670 g) was slowly added in aliquots over 15 minutes. The maximum temperature reached was 18° C. The mixture was heated to reflux for one hour, cooled to 10° C. in an ice bath and 1.6 L of ice water was rapidly added with vigorous stirring. The temperature increased to 15° C. 10 N Hydrochloric acid (1.6 L) was added with vigorous stirring. The temperature increased to 22° C. The mixture was allowed to stand for 30 minutes and the layers allowed to separate. The temperature reached a maximum of 40° C. The aqueous layer was adjusted to pH 12-13 with 10 N potassium hydroxide (3.8 L) at a rate that allowed the temperature to reach and remain at 55° C. during the addition. After the addition was complete the mixture was cooled to 10° C. and stirred for 1 hour. The solid was collected by vacuum filtration and washed four times with water to give 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (778 g, 100percent yield) as a yellow solid. 1H-NMR (DMSO-d6) δ 1.25 (t, 3H, CH3), 2.44, 2.48 (2*s, 2*3H, 2*CH3), 4.16 (q, 2H, CH2), 9.59 (s, 1H, CHO), 12.15 (br s, 1H, NH). MS m/z 195 [M+1]. |
100% | With hydrogenchloride In <i>N</i>-methyl-acetamide; (2S)-N-methyl-1-phenylpropan-2-amine hydrate; dichloromethane; trichlorophosphate | Dimethylformamide (322 g) and dichloromethane (3700 mL) were cooled in an ice bath to 4° C. and phosphorus oxychloride (684 g) was added with stirring. Solid 2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (670 g) was slowly added in aliquots over 15 minutes. The maximum temperature reached was 18° C. The mixture was heated to reflux for one hour, cooled to 10° C. in an ice bath and 1.6 L of ice water was rapidly added with vigorous stirring. The temperature increased to 15° C. 10 N Hydrochloric acid (1.6 L) was added with vigorous stirring. The temperature increased to 22° C. The mixture was allowed to stand for 30 minutes and the layers allowed to separate. The temperature reached a maximum of 40° C. The aqueous layer was adjusted to pH 12-13 with 10 N potassium hydroxide (3.8 L) at a rate that allowed the temperature to reach and remain at 55° C. during the addition. After the addition was complete the mixture was cooled to 10° C. and stirred for 1 hour. The solid was collected by vacuum filtration and washed four times with water to give 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (778 g, 100percent yield) as a yellow solid. 1H-NMR (DMSO-d6) δ1.25 (t, 3H, CH3), 2.44, 2.48 (2*s, 2*3H, 2*CH3), 4.16 (q, 2H, CH2), 9.59 (s, 1H, CHO), 12.15 (br s, 1H, NH). MS m/z 195 μM+1]. |
100% | With hydrogenchloride In <i>N</i>-methyl-acetamide; (2S)-N-methyl-1-phenylpropan-2-amine hydrate; dichloromethane; trichlorophosphate | Dimethylformamide (322 g) and dichloromethane (3700 mL) were cooled in an ice bath to 4° C. and phosphorus oxychloride (684 g) was added with stirring. Solid 2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (670 g) was slowly added in aliquots over 15 minutes. The maximum temperature reached was 18° C. The mixture was heated to reflux for one hour, cooled to 10° C. in an ice bath and 1.6 L of ice water was rapidly added with vigorous stirring. The temperature increased to 15° C. 10 N Hydrochloric acid (1.6 L) was added with vigorous stirring. The temperature increased to 22° C. The mixture was allowed to stand for 30 minutes and the layers allowed to separate. The temperature reached a maximum of 40° C. The aqueous layer was adjusted to pH 12-13 with 10 N potassium hydroxide (3.8 L) at a rate that allowed the temperature to reach and remain at 55° C. during the addition. After the addition was complete the mixture was cooled to 10° C. and stirred for 1 hour. The solid was collected by vacuum filtration and washed four times with water to give 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (778 g, 100percent yield) as a yellow solid. 1H-NMR (DMSO-d6) δ 1.25 (t, 3H, CH3), 2.44, 2.48 (2*s, 2*3H, 2*CH3), 4.16 (q, 2H, CH2), 9.59 (s, 1H, CHO), 12.15 (br s, 1H, NH). MS m/z 195 [M+1]. |
100% | With hydrogenchloride In <i>N</i>-methyl-acetamide; (2S)-N-methyl-1-phenylpropan-2-amine hydrate; dichloromethane; trichlorophosphate | Dimethylformamide (322 g) and dichloromethane (3700 mL) were cooled in an ice bath to 4° C. and phosphorus oxychloride (684 g) was added with stirring. Solid 2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (670 g) was slowly added in aliquots over 15 minutes. The maximum temperature reached was 18° C. The mixture was heated to reflux for one hour, cooled to 10° C. in an ice bath and 1.6 L of ice water was rapidly added with vigorous stirring. The temperature increased to 15° C. 10 N Hydrochloric acid (1.6 L) was added with vigorous stirring. The temperature increased to 22° C. The mixture was allowed to stand for 30 minutes and the layers allowed to separate. The temperature reached a maximum of 40° C. The aqueous layer was adjusted to pH 12-13 with 10 N potassium hydroxide (3.8 L) at a rate that allowed the temperature to reach and remain at 55° C. during the addition. After the addition was complete the mixture was cooled to 10° C. and stirred for 1 hour. The solid was collected by vacuum filtration and washed four times with water to give 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (778 g, 100percent yield) as a yellow solid. 1H-NMR (DMSO-d) δ 1.25 (t, 3H, CH3), 2.44, 2.48 (2*s, 2*3H, 2*CH3), 4.16 (q, 2H, CH2), 9.59 (s, 1H, CHO), 12.15 (br s, 1H, NH). MS m/z 195 [M+1]. |
90% | Stage #1: With trichlorophosphate In dichloromethane at 10 - 20℃; for 0.833333 h; Stage #2: at 5℃; for 1.5 h; Heating / reflux |
Step Ie. Ethyl 5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxylate (Compound 107)To a solution of DMF (2 g, 27 mmol) at 100C was added POCl3 (2.6 mL) in 10 mL of dichloromethane through the dropping funnel over a period of 30 min. After addition, the mixture was stirred for 20 min at room temperature. Dichloromethane (10 mL) was added into the mixture. When the internal temperature lowed to 5°C, a solution of compound 506 in dichloromethane (10 mL) was added through a dropping funnel to the stirred, cooled mixture over a period of 1 h, then the mixture was stirred at the reflux temperature for 30 min, the mixture was then cooled to30°C, a solution of sodium acetate (17 g, 125 mmol) in water (100 ml) was added. The reaction mixture was again refluxed for 30 min. then cooled to room temperature, the aqueous layer was extracted with dichloromethane (4x100 mL). The combined organic layer were washed with brine, dried and evaporated to give gray solid product 107 (4.42 g,90percent). LCMS: m/z 196(M+1), 1H NMR(DMSO-^6) δl.35 (t, J3H), 2.23 (s, 3H), 2.48 (s, 3H), 4.12 (q, 2H), 9.60 (s, IH), 10.58 (s, IH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: With trichlorophosphate In dichloromethane for 1.5 h; Reflux Stage #2: With sodium hydroxide In dichloromethane; water for 0.5 h; Reflux |
Anhydrous DMF (2.0 mL, 24.4 mmol) in a dry flask was precooled to 0 °C with a salt-ice bath, into which a solution of POCl3 (3.60 mL, 39.1 mmol) in anhydrous dichloromethane (8.2 mL) was added slowly dropwise. The temperature should be kept below 3 °C during the whole addition process. The reaction mixture was stirred for 0.5 h using an ice-bath before dropwise addition of solution of ethyl 2,4-dimethyl-1H-pyrrole-3-carboxylate (8) in anhydrous dichloromethane (10.0 mL, 2.27 mol/L). The mixture was heated under reflux for 1.5 h before evaporating the excess dichloromethane from the system. Aqueous sodium hydroxide (52.0 mL, 2.81 mol/L) was then added before further reflux for 0.5 h. While cooling to r.t., a large amount of pale-gray solid appeared from the system. The solid was filtrated and washed with a small amount of cold water, and dried under vacuum to afford 9 (4.5 g, 100 percent), m.p. 163-164 °C (lit. 166-167 °C [19]), yield 91.5 percent (lit. [13]). Rf = 0.71 (eluent: chloroform/methanol, v/v = 10:1). 1H NMR (400 MHz, CDCl3) δ: 10.71 (s, 1H, CHO), 9.61 (s, 1H, pyrrole-1-H), 4.31 (q, 2H, CH3CH2O), 2.58 (m, 6H, 2 x 9 (CH3)), 1.38 (t, 3H, J = 8.0 Hz, CH3CH2O). |
92% | Stage #1: at 0 - 50℃; |
Step (iii): Preparation of 5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxylic acid ethyl ester (IV):Into a 5-L four necked round-bottomed flask equipped with a mechanical stirrer, a thermometer pocket, addition funnel, air condenser and a nitrogen bubbler was charged dimethyl formamide (1.05 L). The solvent was cooled to 0° C. To this chilled solvent, phosphorous oxychloride (0.434 L) was charged at below 5° C. After addition, the temperature of the reaction mixture was slowly brought to 25-30° C. Then a solution of 2,4-dimethyl-lH-pyrrole-3-carboxylic acid ethyl ester (III) (0.7 Kg; 4.2 mole) dissolved in dimethyl formamide (1.05 L) was added drop-wise into the flask at 25-30° C. After addition, the temperature of the reaction mixture was brought to 50° C and maintained for 2-3 hours. The reaction was monitored by TLC. After maintenance, the reaction mixture was cooled to 25-30° C and quenched in a carboy containing ice-water. The pH of the solution was then adjusted to 12-13 using aq. KOH solution. After pH adjustment, the solution was stirred at 25-30° C and filtered and washed with water. The product was dried in a hot air oven at 60° C. Dry Weight: 0.753 Kg Yield: 92percent HPLC purity: >99.9percent |
92% | Stage #1: at 0 - 50℃; for 2 - 3 h; Stage #2: With potassium hydroxide In water at 25 - 30℃; |
Into a 5-L four necked round-bottomed flask equipped with a mechanical stirrer, a thermometer pocket, addition funnel, air condenser and a nitrogen bubbler was charged dimethyl formamide (1.05 L). The solvent was cooled to 0o C. To this chilled solvent, phosphorous oxychloride (0.434 L) was charged at below 5oC. After addition, the temperature of the reaction mixture was slowly brought to 25-30oC. Then a solution of 2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (III) (0.7 Kg; 4.2 mole) dissolved in dimethyl formamide (1.05 L) was added drop-wise into the flask at 25-30oC. After addition, the temperature of the reaction mixture was brought to 50oC. and maintained for 2-3 hours. The reaction was monitored by TLC. After maintenance, the reaction mixture was cooled to 25-30oC. and quenched in a carboy containing ice-water. The pH of the solution was then adjusted to 12-13 using aq. KOH solution. After pH adjustment, the solution was stirred at 25-30oC. and filtered and washed with water. The product was dried in a hot air oven at 60oC. Dry Weight: 0.753 Kg Yield: 92percent HPLC purity: >99.9percent |
90% | Stage #1: With trichlorophosphate In dichloromethane at 10 - 20℃; for 0.833333 h; Stage #2: at 5℃; for 1.5 h; Heating / reflux |
To a solution of DMF (2 g, 27 mmol) at 100C was added POCl3 (2.6 mL) in 10 mL of dichloromethane through the dropping funnel over a period of 30 min. After addition, the mixture was stirred for 20 min at room temperature. Dichloromethane(10 mL) was added into the mixture. When the internal temperature lowed to 5°C, a solution of compound 506 in dichloromethane (10 mL) was added through a dropping funnel to the stirred, cooled mixture over a period of 1 h, then the mixture was stirred at the reflux temperature for 30 min, the mixture was then cooled to30°C, a solution of sodium acetate (17 g, 125 mmol) in water (100 ml) was added.The reaction mixture was again refluxed for 30 min. then cooled to room temperature, the aqueous layer was extracted with dichloromethane (4x100 mL). The combined organic layer were washed with brine, dried and evaporated to give gray solid product 107 (4.42 g,90percent). LCMS: m/z 196(M+1), 1H NMR(DMSO-J6) δl.35 (t, J3H), 2.23 (s, 3H), 2.48 (s, 3H), 4.12 (q, 2H), 9.60 (s, IH), 10.58 (s, IH). |
84% | Stage #1: With trichlorophosphate In dichloromethane at 5℃; for 0.5 h; Stage #2: for 1.5 h; Reflux |
DMF (1.0ml) dropwise POCl 3 (1.88ml) in dichloromethane (4ml) solution, ice water bath temperature was cooled to 5 ° C, dropwise with stirring Bi 30min, was added dropwise 2,4-dimethyl -1H- pyrrole 3-carboxylate (2.0g, 12mmol) in dichloromethane (5ml) was dropwise Bi reflux 1.5h, concentrated under reduced pressure to dryness. Was added sodium hydroxide (3.1g) in water (27 ml of) the solution was stirred at reflux for 0.5h, cooled to room temperature, filtered, the filter cake was washed with water to give a tan solid (2.25g, 97percent). Recrystallized from ethanol to give white crystals (1.97g, 84percent). |
76% | Stage #1: With trichlorophosphate In 1,2-dichloro-ethane at 20℃; for 0.25 h; Stage #2: at 20 - 40℃; for 2.25 h; Stage #3: With sodium hydrogencarbonate In 1,2-dichloro-ethane at 40℃; for 1 h; |
Under ice bath conditions, 0.25 mL (2.625 mmol) of phosphorus oxychloride was slowly dropped into 0.20 mL (2.63 mmol) of DMF in dichloroethane solution.After the reaction mixture was stirred at room temperature for 15 min, 400 mg (2.39 mmol) of 2,4-dimethyl-H-pyrrole-3-carboxylic acid ethyl ester dichloroethane solution was slowly added dropwise, stirred at room temperature for 15 min and then heated to 40 ° C. After 2 h of reaction, cool to room temperature and add 12 mL of 1 M sodium bicarbonate solution.Heated at 40 ° C for 1 h, extracted with DCM, dried over anhydrous Na 2 SO 4 ,Column chromatography purification (PE: EA =8:1) gave 357 mg of light yellow solid, yield 76percent. |
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