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CAS No. : | 40611-79-8 | MDL No. : | MFCD02179575 |
Formula : | C7H7NO3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | MIBDQVZPRVDXQP-UHFFFAOYSA-N |
M.W : | 153.14 | Pubchem ID : | 640310 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 5 |
Fraction Csp3 : | 0.14 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 37.46 |
TPSA : | 59.16 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) : | -6.98 cm/s |
Log Po/w (iLOGP) : | 1.29 |
Log Po/w (XLOGP3) : | 0.36 |
Log Po/w (WLOGP) : | 0.61 |
Log Po/w (MLOGP) : | -0.57 |
Log Po/w (SILICOS-IT) : | 1.39 |
Consensus Log Po/w : | 0.62 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.15 |
Solubility : | 10.7 mg/ml ; 0.07 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.17 |
Solubility : | 10.4 mg/ml ; 0.0681 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.62 |
Solubility : | 3.71 mg/ml ; 0.0242 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.69 |
Signal Word: | Warning | Class: | |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | |
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 |
---|---|---|
48.18% | at 0 - 20℃; | To the stirred solution of methyl 1H-pyrrole-2-carboxylate (0.9 g, 7.19 mmol) in DMF (4.2 g, 57.52 mmol) at 0 00, POOl3 (5.5 g, 35.96 mmol) was added. The reaction mixture was stirred at 10 00 for 30 mm at room temperature over night. The reaction mixture was quenched with sodium hydroxide solution and extracted using ethyl acetate dried over anhydrous Na2SO4. The crude mixture of products was purified by column chromatography to yield the title compound polar spot (0.53 g, 48.18percent) as a pale yellow solid. LCMS: (M-H) = 152.1; 1H NMR: (DMSO-d6, 300MHz) 6 12.73 (5, 1H), 7.76 (5, 1H), 7.82-7.83 (d, 1H), 7.14 (5, 2H), 3.81 (5, 3H). Intermediate 12a: Methyl 5-formyl-1H-pyrrole-2-carboxylate was formed along with11 a. Upon separation of 11 a and 1 2a, intermediate 1 2a obtained (0.5 g, 45.45percent) asa pale yellow solid. LOMS: (M-H) = 152.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.72% | Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.25 h; Stage #2: at 20℃; for 0.5 h; |
To a solution of methyl 4-formyl-1H-pyrrole-2-carboxylate (0.15 g, 098 mmol) in DMF(4 mL) at 0 00 NaH (0.047 g (95percent), 1.96 mmol) was added and stirred at 0 00 for 15mm. Then methyl iodide (0.208 g, 1 .47 mmol) was added to it and stirred at roomtemperature for 30 mm. The reaction mixture was quenched with water and extractedusing ethyl acetate dried over anhydrous Na2SO4 and concentrated to yield the title compound (0.16 g, 95.72percent) as a pale brown solid. LCMS: (M+H) = 168.1; 1H NMR:(DMSO-d6, 300MHz) 69.71(s, 1H), 7.91(s, 2H), 7.22-7.23 (d, 2H), 3.92 (5, 3H), 3.78 (5, 3H). |
95.72% | Stage #1: With sodium hydroxide In N,N-dimethyl-formamide at 0℃; for 0.25 h; Stage #2: at 20℃; for 0.5 h; |
To a solution of methyl 4-formyl-1H-pyrrole-2-carboxylate (0.15 g, 098 mmol) in DMF(4 mL) at 0 00 NaOH (0.047 g (95percent), 1 .96 mmol) was added and stirred at 0 00 for15 mm. Then methyl iodide (0.208 g, 1 .47 mmol) was added and stirred at roomtemperature for 30 mm. The reaction mixture was quenched with water and extractedusing ethyl acetate dried over anhydrous Na2SO4 and concentrated to yield the titlecompound (0.16 g, 95.72percent) as a pale brown solid. LOMS: (M+H) = 168.1; 1H NMR:(DMSO-d6, 300MHz) 6 9.71 (5, 1 H), 7.91 (5, 2H), 7.22-7.23 (d, 2H), 3.92 (5, 3H), 3.78 (5, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With aluminium trichloride In dichloromethane | |
50% | With aluminum (III) chloride In dichloromethane at 0℃; | |
With aluminum (III) chloride; nitromethane In DCE |
In CH2Cl2:CH3NO2 | 6 Synthesis of E6 Methyl 4-formyl-1H-pyrrole-2-carboxylate (3). To a solution of 2 (4.50 g, 36.0 mmol) in CH2Cl2:CH3NO2 (1:1, 40 mL) at -40° C., was added AlCl3 (12.48 g, 93.6 mmol) followed by α,α-dichloromethyl methyl ether (4.15 mL, 46.8 mmol). The resulting mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was slowly poured onto ice (10.00 g) and allowed to warm to room temperature. The aqueous phase was extracted with CH2Cl2 (3*50 mL). The combined organic layer was dried over anhydrous MgSO4, filtered and concentrated to give 3 as a dark brown solid (3.40 g, 62%). 1H NMR (400 MHz, CDCl3) δ 10.32 (bs, 1H), 9.83 (s, 1H), 7.59 (d, J=1.6 Hz, 1H), 7.30 (s, 1H), and 3.88 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 186.07, 161.71, 129.15, 127.71, 124.99, 114.56, and 52.34. | |
In CH2Cl2:CH3NO2 | 8 Synthesis of E6b Methyl 4-formyl-1H-pyrrole-2-carboxylate (3). To a solution of 2 (4.50 g, 36.0 mmol) in CH2Cl2:CH3NO2 (1:1, 40 mL) at -40° C., was added AlCl3 (12.48 g, 93.6 mmol) followed by ∝,∝-dichloromethyl methyl ether (4.15 mL, 46.8 mmol). The resulting mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was slowly poured onto ice (10.00 g) and allowed to warm to room temperature. The aqueous phase was extracted with CH2Cl2 (3*50 mL). The combined organic layer was dried over anhydrous MgSO4, filtered and concentrated to give 3 as a dark brown solid (3.40 g, 62%). 1H NMR (CDCl3) δ 10.32 (bs, 1H), 9.83 (s, 1H), 7.59 (d, J=1.6 Hz, 1H), 7.30 (s, 1H), and 3.88 (s, 3H); 13C NMR (CDCl3) δ 186.07, 161.71, 129.15, 127.71, 124.99, 114.56, and 52.34. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48.18% | With trichlorophosphate at 0 - 20℃; | 11a Intermediate 11a: Methyl 4-formyl-1 H-pyrrole-2-carboxylate To the stirred solution of methyl 1H-pyrrole-2-carboxylate (0.9 g, 7.19 mmol) in DMF(4.2 g, 57.52 mmol) at 000, POOl3 (5.5 g, 35.96 mmol) was added. The reaction mixture was stirred at 10 00 for 30 mm and at room temperature over night. The reaction mixture was quenched with sodium hydroxide solution and extracted usingethyl acetate dried over anhydrous Na2SO4. The crude product was purified by column chromatography to yield the title compound polar spot (0.53 g, 48.18%) as a pale yellow solid. LCMS: (M-H) = 152.1; 1H NMR: (DMSO-d6, 300MHz) 6 12.73 (5, 1H), 7.76 (5, 1H), 7.82-7.83 (d, 1H), 7.14 (5, 2H), 3.81 (5, 3H). |
With trichlorophosphate Multistep reaction; | ||
With trichlorophosphate at 20℃; for 16h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48.18%; 45.45% | With trichlorophosphate; at 0 - 20℃; | To the stirred solution of methyl 1H-pyrrole-2-carboxylate (0.9 g, 7.19 mmol) in DMF (4.2 g, 57.52 mmol) at 0 00, POOl3 (5.5 g, 35.96 mmol) was added. The reaction mixture was stirred at 10 00 for 30 mm at room temperature over night. The reaction mixture was quenched with sodium hydroxide solution and extracted using ethyl acetate dried over anhydrous Na2SO4. The crude mixture of products was purified by column chromatography to yield the title compound polar spot (0.53 g, 48.18%) as a pale yellow solid. LCMS: (M-H) = 152.1; 1H NMR: (DMSO-d6, 300MHz) 6 12.73 (5, 1H), 7.76 (5, 1H), 7.82-7.83 (d, 1H), 7.14 (5, 2H), 3.81 (5, 3H). Intermediate 12a: Methyl 5-formyl-1H-pyrrole-2-carboxylate was formed along with11 a. Upon separation of 11 a and 1 2a, intermediate 1 2a obtained (0.5 g, 45.45%) asa pale yellow solid. LOMS: (M-H) = 152.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With dmap; N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With dmap In acetonitrile for 2.5h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride In tetrahydrofuran | ||
With sodium hydride In tetrahydrofuran |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With sodium chlorite; sodium dihydrogenphosphate; dihydrogen peroxide In acetonitrile | |
88% | With potassium permanganate In water; acetone at 20℃; | |
66% | With potassium permanganate In water; acetone at 20℃; for 16h; | 5-(methoxycarbonyl)-1H-pyrrole-3-carboxylic acid (2a) To a solution of methyl 4-formyl-1H-pyrrole-2-carboxylate (1.0 g, 6.535 mmol) in Acetone (10 mL) was added dropwise a solution of KMnO4 (1.0320 g, 6.535 mmol) in H2O (10 mL). The reaction mixture was stirred at r.t. for 16 h. The mixture was concentrated in vacuo and extracted with ether (10 mL, 2 times). The aqueous layer was acidified with 1 N aq. HCl to pH ~2-3 and extracted with ethyl acetate (20 mL, 3 times). The combined organic layers were washed with brine (15 mL), dried over Na2SO4 and filtered. The solution was concentrated in vacuo to give the product 2a (732730 mg, 66 %) as an off-white solid. LC-MS (M+H)+ =170.0 |
Stage #1: methyl 4-formyl-1H-pyrrole-2-carboxylate With potassium permanganate; water In acetone at 20℃; for 4h; Stage #2: With hydrogenchloride In water | 5.ii (ii) 1H-Pyrrole-2,4-dicarboxylic acid 2-methyl ester :; To a solution of 4-formyl-1H-pyrrole-2-carboxylic acid methyl ester (589 mg) in acetone/water (50 mL, 1 :1) was added a solution of KMnO4 in acetone/water (70 mL, 1 :1) dropwise within one hour. The mixture was stirred for 3h at RT whereupon it was poured into a solution of NaHSO3 (10% in 1N HCl, 100 mL). The resulting mixture was extracted with ethyl acetate. The combined organic phases were washed with water and extracted with 2N aqueous K2CO3 solution. The basic aqueous phase was acidified with 2N HCl and extracted with ethyl acetate The combined organic phases were dried (MgSO4) and concentrated in vacuo to provide 1H-pyrrole-2,4-dicarboxylic acid 2-methyl ester (530 mg) which was used directly in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: KHMDS / tetrahydrofuran / 0 °C 1.2: tetrahydrofuran / 20 °C 2.1: H2 / Pd/C / methanol / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: KHMDS / tetrahydrofuran / 0 °C 1.2: tetrahydrofuran / 20 °C 2.1: H2 / Pd/C / methanol / 20 °C 3.1: 67 percent / NaH / dimethylformamide / 65 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: KHMDS / tetrahydrofuran / 0 °C 1.2: tetrahydrofuran / 20 °C 2.1: H2 / Pd/C / methanol / 20 °C 3.1: 67 percent / NaH / dimethylformamide / 65 °C 4.1: 47 percent / NaH / acetonitrile / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 88 percent / KMnO4 / acetone; H2O / 20 °C 2: 94 percent / TMSCl / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 50 percent 2: 80 percent / NaH / tetrahydrofuran | ||
Multi-step reaction with 2 steps 1: NaH / tetrahydrofuran 2: 1.) NaH / 1.) THF, 0 deg C; 2.) THF, -10 deg C, 5 min |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 50 percent 2: 80 percent / NaH / tetrahydrofuran 3: 30 percent / LiHMDS / tetrahydrofuran / -78 °C | ||
Multi-step reaction with 3 steps 1: NaH / tetrahydrofuran 2: 1.) NaH / 1.) THF, 0 deg C; 2.) THF, -10 deg C, 5 min 3: 65 percent / LiHMDS / tetrahydrofuran / 0.25 h / -70 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 50 percent 2: 80 percent / NaH / tetrahydrofuran 3: 30 percent / LiHMDS / tetrahydrofuran / -78 °C 4: CH2Cl2 / 0 °C | ||
Multi-step reaction with 4 steps 1: NaH / tetrahydrofuran 2: 1.) NaH / 1.) THF, 0 deg C; 2.) THF, -10 deg C, 5 min 3: 65 percent / LiHMDS / tetrahydrofuran / 0.25 h / -70 °C 4: CH2Cl2 / 24 h / 0 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: methyl 4-formyl-1H-pyrrole-2-carboxylate; Ethoxysulfonyl-acetic acid With piperidine In pyridine Stage #2: With hydrogen | 2 Example 2 Synthesis of Dyes A2-12 In addition to the two previously described variations, the dyes H2 and 12 present a third modification with respect to dyes H and) : a shortening of the sulfonate side chain from a three to a two carbon tether. This adjustment is made by substituting pyrroles 68 and 71 to pyrroles 47 and 54 respectively in the synthesess of H and 1. The syntheses of fragments 68 and 71 are illustrated in Scheme 11. The synthesis of Pyrrole 68 starts with the known pyrrole-3-carboxaldehyde 4. (Bray, B. L. ; et [AL.,] [ (1990) J. ORG. CHEM. , 55,6317). COUPLING OF 4 WITH THE KNOWN ETHOXYSULFONYL-ACETIC ACID (KING, J. F.] and Gill, Manjinder S. (1996) J. Org. Chem.; 61 (21), 7250) and subsequent catalytic hydrogenation of the resulting olefin leads to intermediate 66. Formylation of 66 into 67 is carried out under the Vilsmeier-Haack conditions. At this point the stage is set for the Doebner coupling of formyl pyrrole 67 with mono ethyl malonate to generate 68. The synthesis of 71 starts with the known ester 69. Treatment of 69 under the conditions described above leads to ester 70, which is subsequently reduced to the corresponding alcohol and protected to yield 71. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N,N-dimethyl-formamide; trichlorophosphate; In dichloromethane; at 0 - 20℃; for 0.5h;Heating / reflux; | Example 5 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-4-(perhydro-1,4-oxazepine-4-carbonyl)-1H-pyrrole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide (i) 4-Formyl-1H-pyrrole-2-carboxylic acid methyl ester and 5-formyl-1H-pyrrole-2-carboxylic acid methyl ester: Both formyl-pyrrole derivatives were prepared adopting a procedure described by C. Schmuck,Tetrahedron2001, 57, 3063: To DMF (1.61 g) was added POCl3 (3.37 g) dropwise under Ar at 0C. The mixture was allowed to warm to RT after which it was diluted with DCM (11 mL). A solution of 1H-pyrrole-2-carboxylic acid methyl ester (2.51 g) in DCM (11 mL) was added dropwise. The mixture was refluxed for 30 min whereupon it was cooled to 10 C and quenched with a solution of potassium acetate (10.8 g) in water (28 mL). The phases were separated and the aqueous layer was extracted with MTBE. The combined organic phases were washed with saturated aqueous K2CO3 solution and concentrated in vacuo. The residue was purified by flash column chromatography on silica (ethyl acetate / heptane 1:5) to yield 4-formyl-1H-pyrrole-2-carboxylic acid methyl ester (589 mg) and 5-formyl-1H-pyrrole-2-carboxylic acid methyl ester (1.60 g) as solids. | |
With N,N-dimethyl-formamide; trichlorophosphate; In 1,2-dichloro-ethane; at 0℃; for 1.33333h;Heating / reflux; | 2.1.) Synthesis of Methyl 4-oxo-l,4,5,6-tetrahydrocyclopenta[6]pyrrole-2-carboxylate2.1. a) Synthesis of 5-formyl-l H-pyrrole-2-carboxylic acid methyl ester [0300] To 1,2-dichloroethane (40 mL) was added DMF (13.6 mL, 176 mmol). The mixture was cooled to 0 0C and phosphorus oxychloride (16.4 mL, 176 mmol) was added dropwise over 5 min. The resulting solution was stirred for 15 min. To the solution at 0 0C was added dropwise methyl lH-pyrrole-2-carboxylate (20 g, 160 mmol) in dichloroethane (80 mL) (about 1 h). The cooling bath was removed, and the reaction mixture was heated to reflux for about Ih and was then cooled to rt. EtOAc (250 mL) in ice water (400 mL) was added and the organic layer was separated. The aqueous layer was neutralized with NaHCO3 solution, and then extracted with EtOAc (4 x 100 mL). The organic layer and the combined organic extracts were washed with dilute NaHCO3 solution, brine, dried (Na2SO4) and filtered. Silica gel was added, the solvent removed and the silica gel-imbedded material was purified by flash chromatography (0-50% EtO Ac/Heptane) to afford a major product, methyl 5-formyl- lH-pyrrole-2-carboxylate (16.3 g) and a minor product, methyl 4-formyl-lH-pyrrole-2- carboxylate (6.94 g). Combined yield: 23.3 g (95 %).[0301] Methyl 5-formyl-l/f-pyrrole-2-carboxylate: 1H NMR (400 MHz, CDCl3) delta ppm: 3.93 (s, 3 H), 6.95 (d, J= 2.39 Hz, 2 H), 9.68 (s, 1 H), 9.82 (br s, 1 H); LCMS- MS (ESI+) 153.9 (M+H). <n="96"/>[0302] Methyl 4-formyl-lH-pyrrole-2-carboxylate: 1H NMR (400 MHz, CHLOROFORM-J) delta ppm: 3.91 (s, 3 H), 7.32 (dd, J= 2.29, 1.61 Hz, 1 H), 7.57 (dd, J= 3.32, 1.51 Hz, 1 H), 9.55 (br s, 1 H), 9.86 (s, 1 H); LCMS- MS (ESI+) 153.8 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With sodium chloride; lithium diisopropyl amide In tetrahydrofuran; water | S.11 Synthesis of methyl 4-methoxyvinylpyrrole-2-carboxylate SYNTHESIS EXAMPLE 11 Synthesis of methyl 4-methoxyvinylpyrrole-2-carboxylate Into a solution of 200 g (0.58 mol) of methoxymethyltriphenylphosphonium chloride in 1.5 liter of tetrahydrofuran, was added dropwise 220 ml of a tetrahydrofuran solution (2.01 mol concentration) containing 0.44 mol of lithium diisopropylamide under stirring and cooling with ice. After one-hour stirring at room temperature, 400 ml of a tetrahydrofuran solution of 57.6 g (0.38 mol) of methyl 4-formylpyrrole-2-carboxylate was added to the mixture at 5° to 8° C. under cooling with ice. The reaction was carried out for one hour at room temperature, and the reaction mixture was added with water and extracted with ethyl acetate. The organic layer was collected, washed with a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate and evaporated to obtain a residue. The residue was purified by a silica-gel column chromatography (eluent:ethyl acetate/hexane=1/4) to obtain 34.4 g of methyl 4-methoxyvinylpyrrole-2-carboxylate as a mixture of E-isomer and Z-isomer. The yield was 50%. NMR (CDCl3) δ: 3.63 (s, E-isomer), 3.76 (s, Z-isomer), 3.85 (3H, s), 5.20 (d, Z-isomer, J=6.5 Hz), 5.68 (d, E-isomer, J=13 Hz), 6.01 (d, Z-isomer), 6.82 (2H, m), 7.00 (1H, m), 7.17 (1H, m), 9.10 (1H, broad s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With n-butyllithium; sodium chloride In tetrahydrofuran; hexane | 47 Preparation of methyl 4-(1-cis-tridecenyl)pyrrole-2-carboxylate (Compound No.73 in Table 1) EXAMPLE 47 Preparation of methyl 4-(1-cis-tridecenyl)pyrrole-2-carboxylate (Compound No.73 in Table 1) A ca. 15% solution (18.5 ml) of n-butyllithium in hexane was added dropwise at -50° C. to a tetrahydrofuran suspension (95 ml) of 16.0 g (31.4 mmol) of dodecyltriphenylphosphonium bromide described in Chemistry and Industry (London) p. 1086, 1958. The temperature was raised to room temperature and the mixture was stirred for 30 minutes. The temperature was again lowered to -50° C. To the mixture was added dropwise a tetrahydrofuran solution (50 ml) of 2.4 g (15.7 mmol) of methyl 4-formylpyrrole-2-carboxylate described in Bulletin de la Societe Chimique de France, p. 283, 1972. The mixture was stirred for 1 hour, diluted with water, extracted with ethyl acetate, washed with an aqueous saturated solution of sodium chloride and dried over anhydrous magnesium sulfate. After removing the solvent under reduced pressure, the residue was purified by subjecting it to column chromatography over silica gel (eluent: ethyl acetate/hexane=1/7) to obtain 3.11 g (65% yield) of methyl 4-(1-cis-tridecenyl)pyrrole-2-carboxylate, m.p. 51°-52° C. IR (KBr) cm-1: 3300, 2930, 1685. NMR (CDCl3) δ: 0.88 (3H, t), 1.29 (18H, m), 2.29 (2H, m), 3.86 (3H, s), 5.50 (1H, m), 6.17 (1H, m), 6.93 (2H, m). |
14% | With n-butyllithium In ethanol; hexane | 49 Preparation of methyl 4-(1-trans-tridecenyl)pyrrole-2-carboxylate (Compound No.73 in Table 1) EXAMPLE 49 Preparation of methyl 4-(1-trans-tridecenyl)pyrrole-2-carboxylate (Compound No.73 in Table 1) To a tetrahydrofuran suspension (200 ml) of 32 g (62.7 mmol) of dodecyltriphenylphosphonium bromide was added dropwise 40 ml of a ca. 15% solution of n-butyllithium in hexane under ice-cooling. After stirring the reaction mixture for 30 minutes, the temperature was dropped to -78° C. A tetrahydrofuran solution (100 ml) of 4.8 g (31.4 mmol) of methyl 4-formylpyrrole-2-carboxylate was then added dropwise. After stirring for 1 hour, 190 ml of ethanol was further added thereto dropwise. The reaction mixture was stirred for 1.5 hour at -78° C., and for another 12 hours while the temperature was gradually raised to room temperature. The resulting mixture was diluted with water, extracted with ethyl acetate, washed with aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After removing he solvent under reduced pressure, the residue was purified by subjecting it to column chromatography (eluent: ethyl acetate/hexane=1/10) and by recrystallizing twice from hexane to obtain 1.30 g (14% yield) of methyl 4-(1-trans-tridecenyl)pyrrole-2-carboxylate, m.p. 65°-67° C. IR (KBr) cm-1: 3350, 2940, 1690. NMR (CDCl3) δ: 0.88 (3H, t), 1.32 (18H, m), 2.12 (2H, m), 3.85 (3H, t), 5.95 (1H, s), 6.18 (1H, d), 6.83 (1H, m), 6.95 (1H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26.2%; 57.8% | 4.2.a) Synthesis of (Z) -methyl 4-(3-tert-butoxy-3-oxoprop-l-enyl)-lH-pyrrole-2-carboxylate and (E)-methyl 4-(3-tert-butoxy-3-oxoprop-l-enyl)-lH-pyrrole-2-carboxylate [0367] Methyl 5-formyl-lH-pyrrole-2-carboxylate (16.3 g) and its regioisomer methyl A- formyl-lH-pyrrole-2-carboxylate (6.94 g) were obtained (combined yield of 95percent) from a Vilsmeier formylation of lH-pyrrole-2-carboxylic acid methyl ester via exhaustive extraction of the neutralized aqueous layer with EtOAc to provide a better recovery of the more polar A- <n="115"/>formyl isomer [see, e.g., Charkraborty, T. K. et al., Tetrahedron Lett. 2006, 47: 4631 and Denmark, S. E.; Matsuhashi, H. J. Org. Chem. 2002, 67: 3479].[0368] To a suspension of NaH (0.54 g, 13.58 mmol; 60percent dispersed in oil) in THF (30 mL) at 0 0C was added <strong>[59159-39-6](tert-butoxycarbonylmethyl)triphenylphosphonium bromide</strong> (6.2 Ig, 13.585 mmol) as a solid in three portions. The cooling bath was removed and the mixture was stirred at rt for 30 min before cooling to 0 0C. Methyl 4-formyl-lH-pyrrole-2- carboxylate (1.6 g, 10.45 mmol) in THF (10 mL) was added dropwise over 10 min. The cooling bath was removed, and the reaction mixture was stirred at rt for about 12 h. The crude product was dried onto silica gel and was purified by flash chromatography (0-20percent EtO Ac/Heptane) to afford two isomeric compounds:[0369] (Z)-methyl 4-(3-tert-butoxy-3-oxoprop-l-enyl)-lH-pyrrole-2-carboxylate (0.81 g, 26.2 percent) as a white solid; 1H NMR (400 MHz, CDCl3) delta ppm 1.52 (s, 9 H), 3.87 (s, 3 H), 5.65 (d, J= 12.59 Hz, 1 H), 6.67 (d, J= 12.64 Hz, 1 H), 7.25 (dd, J= 2.54, 1.56 Hz, 1 H), 7.97 (dd, J= 3.10, 1.44 Hz, 1 H), 9.14 (br s, 1 H); LCMS- MS (ESI+) 195.7 (M-56). [0370] (^-methyl 4-(3-tert-butoxy-3-oxoprop-l-enyl)-lH-pyrrole-2-carboxylate (1.8 g, 57.8 percent) as a white solid; 1H NMR (400 MHz, CDCl3) delta ppm 1.52 (s, 9 H), 3.88 (s, 3 H), 6.12 (d, J= 15.86 Hz, 1 H), 7.08 (m, 1 H), 7.14 (dd, J= 3.03, 1.56 Hz, 1 H), 7.49 (d, J= 15.86 Hz, 1 H), 9.22 (br s, 1 H); LCMS- MS (ESI+) 195.8 (M-56). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: methyl Pyrrole-2-carboxylate; Vilsmeier reagent In N,N-dimethyl-formamide at 20℃; for 16h; Stage #2: With sodium hydroxide In water; N,N-dimethyl-formamide at 0℃; | 29 To a solution of methyl 1 H-pyrrole-2-carboxylate (35 g) in DMF (80 ml_) a solution of Vilsmeier reagent (synthesized as follow: phosphorus (III) oxychloride (85.12g) adding drop wise at 0 0C to DMF (40.88 g), then the solution was warmed to rt and stirred for 30 min) in DMF (20 ml_) was added at rt and the reaction mixture was stirred for 16h. NaOH 4N solution was added slowly at 0 0C under stirring to the reaction mixture until pH=7, filtrated and washed several times with EA. The filtrate was extracted with EA for three times and the collected organic phase was washed with water, brine, dried over Na2SO4 and concentrated under vacuum. The crude product was combined with one other batch of crude product obtained with the same procedure starting from methyl 1 H-pyrrole-2- carboxylate (15 g). The collected crude was purified by FC on silica gel to give the title compound (32 g) as yellow solid.1H NMR (400 MHz, DMSO-d6) δ:3.77 (3H, s), 7.09 (1 H, s), 7.77 (1 H, s), 9.71 (1 H, s), 12.6- 12.7 (1 H,b). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In acetonitrile at 20℃; for 1h; Inert atmosphere; | ||
With potassium carbonate In acetonitrile at 20℃; for 1h; | 30 To a solution of methyl 4-formyl-1 H-pyrrole-2-carboxylate(10 g, P29) in acetonitrile (100 ml_) K2CO3 (27.6 g) and 2-bromo-1-(3-methoxyphenyl)ethanone (14.9 g) were added and the suspension was stirred for 1 h at room temperature. The reaction mixture was diluted with EA (100ml), washed with water (three times) and brine, dried, filtrated and concentrated under vacuum to give the title compound(19.10 g) as yellow solid.1H NMR (400 MHz, DMSO-d6), δ: 3.64 (3H, s), 3.81 (3H, s), 5.96 (2H, s), 7.295 (2H, m), 7.49 (2H, m), 7.62 (1 H, d), 7.89 (1 H, s), 9.74 (1 H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In acetonitrile at 20℃; for 1h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In acetonitrile at 20℃; for 1h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In acetonitrile at 20℃; for 1h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In acetonitrile at 20℃; for 1h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In acetonitrile at 20℃; for 1h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In acetonitrile at 20℃; for 1h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In CH2Cl2:CH3NO2 | 4 Synthesis of E4 Methyl 4-formyl-1H-pyrrole-2-carboxylate (3). To a solution of 2 (4.50 g, 36.0 mmol) in CH2Cl2:CH3NO2 (1:1, 40 mL) at -40° C., was added AlCl3 (12.48 g, 93.6 mmol) followed by α,α'-dichloromethyl methyl ether (4.15 mL, 46.8 mmol). The resulting mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was slowly poured onto ice (10.00 g) and allowed to warm to room temperature. The aqueous phase was extracted with CH2Cl2 (3*50 mL). The combined organic layer was dried over anhydrous MgSO4, filtered and concentrated to give 3 as a dark brown solid (3.40 g, 62%). 1H NMR (400 MHz, CDCl3) δ 10.32 (brs, 1H), 9.83 (s, 1H), 7.59 (m, 1H), 7.30 (s, 1H), and 3.88 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 186.07, 161.71, 129.15, 127.71, 124.99, 114.56, and 52.34. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethyl acetate | 2 Synthesis of E2 Methyl (2-bromo-5-(2-phenyl-1H-indole-6-carbonyl)thiophen-3-yl)acetate (4). To a solution of 3 (25 mg, 0.05 mmol) in EtOAc (5 mL) was added stannous chloride dihydrate (58 mg, 0.26 mmol). The resulting mixture was refluxed for one hour under N2. The reaction mixture was poured onto ice (5 g), and basified with a saturated NaHCO3 solution to pH 8. The white milky mixture was filtered through a Celite pad to remove tin oxides. The organic layer from the filtrate was dried over MgSO4, filtered, and then concentrated in vacuo. MPLC purification (Hex:EtOAc/4:1) of the crude product gave the desired intermediate methyl (2-bromo-5-(3-amino-4-(phenylethynyl)benzoyl)thiophen-3-yl)acetate as a yellow foam (21 mg, 90%). 1H NMR (400 MHz, CDCl3) δ 7.55 (m, 2H), 7.50 (s, 1H), 7.48 (d, J=1.6 Hz, 1H), 7.38 (m, 3H), 7.17 (m, 2H), 4.40 (brs, 2H), 3.73 (s, 3H), and 3.66 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 186.7, 170.3, 148.1, 143.4, 138.1, 135.9, 135.1, 132.4, 131.8, 129.0, 128.7, 122.9, 122.8, 118.8, 114.5, 112.3, 97.6, 85.3, 52.6, and 35.0; HRMS-ESI calcd C22H16BrNO3S [M+Na] 475.9926, found 475.9923. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethyl acetate | 1 Synthesis of E1f To a solution of 3 (450 mg, 0.71 mmol) in EtOAc (10 mL) was added stannous chloride dihydrate (642 mg, 2.84 mmol). The resulting mixture was refluxed for one hour under N2. The reaction mixture was then poured onto ice (5 g), and basified with a saturated NaHCO3 solution to pH 8. The white milky mixture was filtered through a Celite pad to remove tin oxides. The organic layer from the filtrate was dried over MgSO4, filtered, and then concentrated in vacuo. MPLC purification (Hex:EtOAc/4:1) of the crude product gave the desired intermediate benzyl 4-((2-amino-4-(5-bromo-4-(2-ethoxy-2-oxoethyl)thiophene-2-carbonyl)phenyl)ethynyl)benzoate as a yellow foam (450 mg, 95%). 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J=8.0 Hz, 2H), 7.60 (d, J=8.0 Hz, 2H), 7.51-7.36 (m, 7H), 7.22-7.18 (m, 2H), 5.38 (s, 2H), 4.18 (q, J=7.2 Hz, 2H), 3.64 (s, 2H), and 1.27 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 186.72, 169.84, 166.01, 148.31, 143.21, 138.58, 136.12, 136.05, 135.39, 132.55, 131.71, 130.02, 129.98, 128.90, 128.62, 128.51, 127.71, 122.93, 118.70, 114.66, 111.47, 96.66, 88.41, 67.21, 61.63, 53.75, 35.32, and 14.44. | |
In ethyl acetate | 7 Synthesis of E1c To a solution of 3 (450 mg, 0.71 mmol) in EtOAc (10 mL) was added stannous chloride dihydrate (642 mg, 2.84 mmol). The resulting mixture was refluxed for one hour under N2. The reaction mixture was poured onto ice (5 g), and basified with saturated NaHCO3 solution to pH 8. The white milky mixture was filtered through a Celite pad to remove tin oxides. The organic layer from the filtrate was dried over MgSO4, filtered, and then concentrated in vacuo. MPLC purification (Hex:EtOAc/4:1) of the crude product gave the desired intermediate benzyl 4-((2-amino-4-(5-bromo-4-(2-ethoxy-2-oxoethyl)thiophene-2-carbonyl)phenyl)ethynyl)benzoate as a yellow foam (450 mg, 95%). 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J=8.0 Hz, 2H), 7.60 (d, J=8.0 Hz, 2H), 7.51-7.36 (m, 7H), 7.22-7.18 (m, 2H), 5.38 (s, 2H), 4.18 (q, J=7.2 Hz, 2H), 3.64 (s, 2H), and 1.27 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 186.72, 169.84, 166.01, 148.31, 143.21, 138.58, 136.12, 136.05, 135.39, 132.55, 131.71, 130.02, 129.98, 128.90, 128.62, 128.51, 127.71, 122.93, 118.70, 114.66, 111.47, 96.66, 88.41, 67.21, 61.63, 53.75, 35.32, and 14.44. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethyl acetate | 3 Synthesis of E3 Ethyl 2-(2-bromo-5-(2-phenyl-1H-indole-6-carbonyl)thiophen-3-yl)acetate (4). To a solution of 3 (1.37 g, 2.75 mmol) in EtOAc (50 mL) was added stannous chloride dihydrate (2.5 g, 11.08 mmol). The resulting mixture was refluxed for 1 hour under N2. The reaction mixture was poured into a saturated NaHCO3 solution (50 mL) and extracted with EtOAc (150 mL). The organic layer was washed with aqueous NaHCO3 solution (3*30 mL), dried over MgSO4, filtered, and then concentrated in vacuo. MPLC purification (Hex/EtOAc 4:1) of the residue gave the desired intermediate ethyl (2-bromo-5-(3-amino-4-(phenylethynyl)benzoyl)-thiophen-3-yl)acetate as a yellow foam (1.28 g, 100%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: potassium carbonate / methanol 2: AlCl3 / CH2Cl2:CH3NO2 | ||
Multi-step reaction with 2 steps 1: potassium carbonate / methanol 2: AlCl3 / CH2Cl2:CH3NO2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With hydroxylamine hydrochloride; potassium carbonate In water at 65℃; | 2.30 4.2.26 Methyl 5-((hydroxyimino)methyl)-1H-pyrrole-2-carboxylate (32a)35 General procedure: Methyl 5-formyl-1H-pyrrole-2-carboxylate (31a, 2.50 g, 16.3 mmol) was dissolved in water at 65 °C, and a solution of hydroxylamine hydrochloride (1.70 g, 24.5 mmol) and potassium carbonate (1.40 g, 10.1 mmol) in water (30 mL) was added dropwise. Upon cooling a white precipitate formed, which was filtered and recrystallized from water/ethyl acetate (3:1) to give the desired product in a 3:5 mixture of the two diastereomers as a white powder (1.56 g, 57%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: methyl 4-formyl-1H-pyrrole-2-carboxylate With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 0.5h; Stage #2: 5-acetoxymethyl-3,4-dimethylpyrrole-2-carbaldehyde In N,N-dimethyl-formamide; mineral oil at 30℃; for 18h; | |
75% | Stage #1: methyl 4-formyl-1H-pyrrole-2-carboxylate With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 0.5h; Stage #2: 5-acetoxymethyl-3,4-dimethylpyrrole-2-carbaldehyde In N,N-dimethyl-formamide; mineral oil at 30℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In tetrahydrofuran at -78 - 20℃; for 3h; | 12.1 Step 1 : Methyl 4-(cvclohexyl(hvdroxy)methyl)-1 H-pyrrole-2-carboxylate (12a) Step 1 : Methyl 4-(cvclohexyl(hvdroxy)methyl)-1 H-pyrrole-2-carboxylate (12a) Cyclohexylmagnesiumchloride (1 M in THF, 88.0 mL, 88.0 mmol) was added to a solution of methyl 4-formyl-1 H-pyrrole-2-carboxylate (3.06 g, 20.0 mmol) in THF (80 mL) at -78°C. The mixture was stirred at -78°C to rt for 3h, quenched with aq. NH4CI (aq.) and extracted with EA. The organic layer was washed with water then brine, dried by Na2S04, filtered and concentrated to give crude compound 12a (8.0 g, quant.) as a yellow solid. 1H-NMR (400 MHz, CDCI3) δ: 0.76-1.21 (m, 10H), 1.84-1.87 (m, 1 H), 3.78-3.85 (m, 1 H), 6.74-6.77 (m, 2H), 9.04 (d, J = 1.6 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | Stage #1: methyl 4-formyl-1H-pyrrole-2-carboxylate With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 0.5h; Stage #2: 5-acetoxymethyl-3,4-diethylpyrrole-2-carbaldehyde In N,N-dimethyl-formamide; mineral oil at 30℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | Stage #1: methyl 4-formyl-1H-pyrrole-2-carboxylate With sodium hydride In tetrahydrofuran; mineral oil at 20℃; for 0.5h; Stage #2: tert-butyl 5-acetoxymethyl-4-ethyl-3-methylpyrrole-2-carboxylate In tetrahydrofuran; mineral oil at 100℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.72% | To a solution of methyl 4-formyl-1H-pyrrole-2-carboxylate (0.15 g, 098 mmol) in DMF(4 mL) at 0 00 NaH (0.047 g (95%), 1.96 mmol) was added and stirred at 0 00 for 15mm. Then methyl iodide (0.208 g, 1 .47 mmol) was added to it and stirred at roomtemperature for 30 mm. The reaction mixture was quenched with water and extractedusing ethyl acetate dried over anhydrous Na2SO4 and concentrated to yield the title compound (0.16 g, 95.72%) as a pale brown solid. LCMS: (M+H) = 168.1; 1H NMR:(DMSO-d6, 300MHz) 69.71(s, 1H), 7.91(s, 2H), 7.22-7.23 (d, 2H), 3.92 (5, 3H), 3.78 (5, 3H). | |
95.72% | To a solution of methyl 4-formyl-1H-pyrrole-2-carboxylate (0.15 g, 098 mmol) in DMF(4 mL) at 0 00 NaOH (0.047 g (95%), 1 .96 mmol) was added and stirred at 0 00 for15 mm. Then methyl iodide (0.208 g, 1 .47 mmol) was added and stirred at roomtemperature for 30 mm. The reaction mixture was quenched with water and extractedusing ethyl acetate dried over anhydrous Na2SO4 and concentrated to yield the titlecompound (0.16 g, 95.72%) as a pale brown solid. LOMS: (M+H) = 168.1; 1H NMR:(DMSO-d6, 300MHz) 6 9.71 (5, 1 H), 7.91 (5, 2H), 7.22-7.23 (d, 2H), 3.92 (5, 3H), 3.78 (5, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: dmap; N-ethyl-N,N-diisopropylamine / dichloromethane / 2 h / 0 °C 2: n-butyllithium; diisopropylamine; N,N,N,N,N,N-hexamethylphosphoric triamide / tetrahydrofuran; hexane / 2.25 h / -100 - -78 °C 3: tetrachloromethane / 2 h / 150 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In toluene at 120℃; for 2h; Inert atmosphere; Sealed tube; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 48h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With caesium carbonate; sodium iodide In acetonitrile at 80℃; for 16h; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | Stage #1: methyl Pyrrole-2-carboxylate; dichloromethyl propyl ether With aluminum (III) chloride In nitromethane; dichloromethane at -15℃; for 2.16667h; Stage #2: With water In nitromethane; dichloromethane chemoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: methyl 4-formyl-1H-pyrrole-2-carboxylate With sodium hydride In tetrahydrofuran; mineral oil at 20℃; for 1h; Stage #2: 4-chlorobenzenesulfonyl chloride In tetrahydrofuran; mineral oil at 20℃; | |
70% | Stage #1: methyl 4-formyl-1H-pyrrole-2-carboxylate With sodium hydride In tetrahydrofuran; mineral oil at 20℃; for 1h; Stage #2: 4-chlorobenzenesulfonyl chloride In tetrahydrofuran; mineral oil at 20℃; | 1.A Step A Synthesis of Methyl 1-(4-chlorobenzenesulfonyl)-4-formyl-1H-pyrrole-2-carboxylate (2a) Solution of pyrrole 1 (1.0 g, 6.5 mmol) in THF (15 mL) was slowly added to a suspension of NaH (0.36 g, 60% in mineral oil, 9.0 mmol) in THF (15 mL). The reaction mixture was then stirred for 1 h at r.t. followed by slow addition of p-ClPhSO2Cl (1.65 g, 7.8 mmol) in 15 mL of THF. Reaction mixture was then stirred at r.t. overnight followed by quenching with CH3COOH. After solvent was evaporated, the crude product was purified by column chromatography using hexane/EtOAc=7/3. Product 2a was isolated with the yield of 1.7 g, 70%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17%; 64% | Todry DMF (2.890 g, 39.6 mmol) cooled to 0C, POCl3(6.070 g, 39.6 mmol) was added for 15 min. The reactionmixture was stirred until complete crystallization(30 min). The mixture was heated to room temperature,and the resulting iminium salt was dissolved indry CH2Cl2 (20 mL) and cooled to -25C. A solutionof methyl-1H-pyrrol-2-carboxylate (5) (3.536 g,28.3 mmol) in CH2Cl2 (20 mL) was added via syringefor 1 h at 0C. The solution was brought to room temperatureand boiled for 30 min under stirring. Thereaction mixture was cooled to room temperature, anda saturated aqueous NaHCO3 solution was added upto pH 8-9 and refluxed for 15 min. The organic phasewas separated, and the aqueous phase was extractedwith Et2O (3 × 10 mL). The combined organic phasewas washed with a saturated aqueous NaCl solutionand dried over Na2SO4. The drying agent was filteredoff, and the solvent was removed under low pressure.Methyl-5-formyl-1H-pyrrol-2-carboxylate (6) (2.770 g,64%) was isolated by column chromatography on silicagel (PE-EtOAc 15 : 1-3 : 1) in the form of whitecrystals. Rf 0.37 (PE-EtOAc 65 : 35); mp 96.20C. Inaddition, a side product, methyl-4-formyl-1H-pyrrol-2-carboxylate was obtained (0.736 g, 17%). The spectralcharacteristics coincided with those reported inthe literature [7]. 1H NMR (CDCl3): 3.92 (s, 3 H),6.94 (m, 2 H), 9.67 (s, 1H), 9.88 (br s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate In N,N-dimethyl-formamide at 20℃; | 1 Procedure 4 -intermediate for A111 Methyl 4-formyl-1H-pyrrole-2-carboxylate (2 g,13 mmol,1 equiv) was dissolved in DMF (65 ml_), and CS2CO3 (6.37 g,19 mmol,1.5 equiv) and (bromomethyl)pyridine hydrobromide (3.3g,13 mmol,1.0 equiv) were added. The resulting reaction mixture was stirred at room temperature overnight. The next morning, the reaction mixture was diluted with water (20 ml_) and extracted with EtOAc (4 x 30ml_). The organic layer was dried over Mg2SC>4, filtered and concentrated in vacuo. The resulting crude product was purified via silica gel chromatography (25-100% EtOAc in hexanes) to yleld the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With (2S)-2-{diphenyl[(trimethylsilyl)oxy]methyl}pyrrolidine; benzoic acid In toluene at 40℃; for 72h; | Synthesis of 3a-r and 5a-j; General Procedure General procedure: Indole-3-carbaldehyde 1 or pyrrole-3-carbaldehyde 4 (0.15 mmol, 1.5 equiv), enone 2 (0.1 mmol, 1.0 equiv), catalyst C1 (6.5 mg, 0.02 mmol, 20 mol%), and acid A1 (2.5 mg, 0.02 mmol, 20 mol%) were dissolved in toluene (2.0 mL), and the mixture was stirred at 40 °C for the indicated time (24-72 h). After completion, the product was purified by flash chromatography on silica gel (EtOAc/petroleum ether = 1:10-1:3) to give product 3 or 5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42 % ee | With (S)-1-(3,5-bis(trifluoromethyl)phenyl)-3-(pyrrolidin-2-ylmethyl)thiourea; benzoic acid In toluene at 40℃; for 24h; Overall yield = 15 percent; | |
58 % ee | With (-)-(S)-α,α-diphenylpyrrolidine-2-methanol methyl(diphenyl)silyl ether; benzoic acid In toluene at 40℃; for 24h; Overall yield = 60 percent; |
Tags: 40611-79-8 synthesis path| 40611-79-8 SDS| 40611-79-8 COA| 40611-79-8 purity| 40611-79-8 application| 40611-79-8 NMR| 40611-79-8 COA| 40611-79-8 structure
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P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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