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CAS No. : | 634-97-9 | MDL No. : | MFCD00005219 |
Formula : | C5H5NO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | WRHZVMBBRYBTKZ-UHFFFAOYSA-N |
M.W : | 111.10 | Pubchem ID : | 12473 |
Synonyms : |
|
Num. heavy atoms : | 8 |
Num. arom. heavy atoms : | 5 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 27.75 |
TPSA : | 53.09 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.37 cm/s |
Log Po/w (iLOGP) : | 0.7 |
Log Po/w (XLOGP3) : | 0.85 |
Log Po/w (WLOGP) : | 0.71 |
Log Po/w (MLOGP) : | -0.36 |
Log Po/w (SILICOS-IT) : | 0.82 |
Consensus Log Po/w : | 0.54 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -1.46 |
Solubility : | 3.85 mg/ml ; 0.0346 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.55 |
Solubility : | 3.14 mg/ml ; 0.0283 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.92 |
Solubility : | 13.4 mg/ml ; 0.12 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.07 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | at 0 - 35℃; for 24.5 h; | To a solution of pyrrole-2-carboxylic acid (1) (16.65 g, 0.15 mol)in 10 mL of MeOH was added 50 mL of SOCl2 dropwise within30 min at 0 C. Subsequently, the reaction mixture was stirred at35 C for 24 h. Then, the solvent was evaporated in vacuo, andthe residue was purified by column chromatography using ethylacetate/petroleum ether as eluent, giving intermediate 2 as a whitesolid, yield 85percent, mp: 72–73 C. |
79% | With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In DMF (N,N-dimethyl-formamide) at 20 - 60℃; for 72 h; | Example 36-1 Preparation for methyl 1H-pyrrole-2-carboxlate A suspension of 1H-pyrrole-2-carboxylic acid (5.5g, 49.5mmol), WSCI*HCl (12.2g, 63.6mmol), HOBt (8.4g, 62.2mmol), methanol (7.0g, 218mmol) and 4-dimethylaminopyridine (3.0g, 24.5mmol) in dimethylformamide (60ml) was stirred for 70 hours at room temperature and for 2 hours at 60°C. To the reaction mixture was added an aqueous 5percent potassium hydrogensulfate solution and the mixture was extracted with ethyl acetate/toluene (1/1).. The organic layer was washed with an aqueous saturated sodium hydrogencarbonate solution, and an aqueous saturated sodium chloride solution, and dried over magnesium sulfate.. The solvent was removed and the residue was purified with silica gel chromatography (hexane:ethyl acetate=5:13:1) to give the subject compound (4.88g, 79percent).1H NMR (CDCl3, 400 MHz) δ 9. 08 (brs, 1 H), 6. 90 - 6. 98 (m, 2 H), 6.25 - 6.29 (m, 1 H), 3.86 (s, 3 H). |
65% | With chloro-trimethyl-silane In methanol at 20℃; | Method I Synthesis of 5-tert-Butyl-3-(3-p-tolyl-ureido)-1H-pyrrole-2-carboxylic acid methyl ester. (Example 24) [Show Image] Step 1; Chlorotrimethylsilane (17.9 mL, 141 mmol, 2.5 equiv) is added in one portion to a solution of pyrrole-2-carboxylic acid (6.28 g, 56.5 mmol) in dry methanol (100 mL) under N2 at rt. After stirring overnight, the reaction mixture is concentrated in vacuo, redissolved in dichloromethane, washed with water, dried (Na2SO4) and concentrated to give 4.62 g of methyl pyrrole-2-carboxylate as a tannish semi-crystalline solid (65percent), which was used without further purification. 1H NMR (CDCl3) d 9.3 (br s, 1H), 6.96 (br m, 1H), 6.92 (br m, 1H), 6.29 (br q, 1H), 3.86 (s, 3H). |
65% | at 20℃; | To a solution of pyrrole-2-carboxylic acid (6.28 g, 56.5 mmol) in anh. MeOH (100 mL) under N2 at room temp. was added TMSCl (17.9 mL, 141 mmol, 2.5 equiv) in one portion. After stirring overnight, the reaction mixture was concentrated under reduced pressure, redissolved in CH2Cl2, washed with water, dried (Na2SO4) and concentrated to give methyl pyrrole-2-carboxylate as a tannish semi-crystalline solid (4.62 g, 65percent): 1H NMR (CDCl3) δ 3.86 (s, 3H), 6.29 (br q, 1H), 6.92 (br m, 1H), 6.96 (br m, 1H), 9.30 (br s, 1H). This material was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With potassium hydroxide; sodium tetrahydroborate; air In methanol at 20℃; for 37h; | |
92% | Stage #1: 2-pyrrole aldehyde With sodium hydroxide; silver(l) oxide In methanol; water at 20℃; for 1h; Inert atmosphere; Stage #2: With hydrogenchloride In diethyl ether; water at 0℃; Inert atmosphere; | |
87% | With sodium chlorite In acetonitrile 1.) 10 deg C, 2 h, 2.) RT, 3 h; |
85% | Stage #1: 2-pyrrole aldehyde With sodium hydroxide; silver(l) oxide In methanol; water at 20℃; for 1h; Stage #2: With hydrogenchloride In diethyl ether; water | 1 Example 1 - Synthetic Schemes for Compound 5; Synthesis of pyrrole-2-carboxylic acid; [102] Pyrrole-2-carboxaldehyde (10.0 g, 105 mmol) was dissolved in 50 mL of methanol and then diluted by 500 mL of distilled water. Fresh silver oxide (48.3 g, 210 mmol) and sodium hydroxide (8.5 g, 212 mmol) were added to the pyrrole-2-carboxaldehyde solution.After the reaction mixture was stirred for 1 hour at room temperature, the precipitate was filtered off and washed with hot water. The combined filtrates and washings were extracted with diethyl ether (500 mL) and then acidified at 0 0C with 37% hydrochloric acid. The solution was extracted with diethyl ether (200 mL x 4). The combined organic extract was dried over magnesium sulfate. The solvent was evaporated under reduced pressure to yield 9.9 g of pyrrole-2-carboxylic acid (85% yield). |
85% | Stage #1: 2-pyrrole aldehyde With sodium hydroxide; silver(l) oxide In methanol; water at 20℃; for 1h; Stage #2: With hydrogenchloride; water at 0℃; | 1.1 Example 1 - Synthetic Scheme of ss-6; 1) Synthesis of pyrrole-2-carboxylic acid (shown in FIG.4); [0062] Pyrrole-2-carboxaldehyde (10.0 g, 105 mmol) was dissolved in 50 mL of methanol then diluted by 500 mL of distilled water. Fresh silver oxide (48.3 g, 210 mmol) and sodium hydroxide (8.5 g, 212 mmol) were added. The reaction mixture was then stirred for one hour at root temperature. The precipitate was filtered off and washed with hot water. The combined filtrates and washings were extracted with diethyl ether (500 mL) and then acidified at 0 0C with 37% hydrochloric acid. The solution was extracted with diethyl ether (200 mL X 4). The combined organic extract was dried over magnesium sulfate. The solvent was evaporated under reduced pressure to obtain pyrrole-2-carboxylic acid [634-97-9] (9.9 g, 85% yield). |
With alkaline potassium permanganate solution at 40 - 50℃; | ||
With alkali metal bromate; sulfuric acid; mercury(II) diacetate; acetic acid at 24.85℃; Eexp, ΔH(excit.), ΔG(excit.), ΔS(excit.); | ||
With silver(l) oxide | ||
With sulfuric acid; quinolinium dichromate(VI); acetic acid In water at 39.85℃; for 48h; | ||
With sulfuric acid; quinolinium dichromate(VI); acetic acid In water at 39.85℃; for 48h; | ||
With silver(l) oxide In ethanol for 1h; Reflux; | 5.2.1.1. Synthesis procedures for compounds 1-5 1H-Pyrrole-2-carboxylic acid 2 was synthesized through an improved procedure referencing to literature [16]: To a suspension of sliver oxide was added 1 in ethanol. After stirring for 1 h at reflux (It is failed to get compound 2 when the mixture was stirred for 10 h at room temperature according to the literature [16]), the precipitate was filtered out and washed with hot water. The combined filtrate and washings were acidified with concentrated hydrochloride acid at room temperature and extracted with ethyl acetate, drying (MgSO4) and removal the ethyl acetate under vacuum to give the crude 2. | |
With quinolinium dichromate In water; acetic acid at 49.84℃; for 48h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane | |
93% | With oxalyl dichloride In toluene for 4h; | 10 Example 10; 3-{2-[(lH-Pyrrole-2-carbonyl)-amino]-benzoylamino}-thieno[2,3-c]pyrazole-l,5- dicarboxylic acid 5-tert-butyl ester 1-ethyl ester; To a suspension of pyrrole-2-carboxilic acid (1 g, 9 mmol) in toluene (7 ml) oxalyl chloride (2.28 mL, 27 mmol) and a catalytic amount of DMF were added. After 4 hours the reaction was complete. The solvent was removed under vacuum and the residue was stripped twice with toluene. The acyl chloride was isolated as brownish solid (1.086 g, 93 %). To the solution of 3-(2-amino-benzoylamino)-thieno[2,3-c]pyrazole-l,5-dicarboxylic acid 5-tert-butyl ester 1-ethyl ester (600 mg, 1.393 mmol) and DIEA (0.595 mL, 3.482 mmol) in DCM (15 mL) at 0 °C, pyrrole-2-carbonyl chloride (361 mg, 2.786 mmol) was added portionwise under stirring. The mixture was allowed to reach room temperature. After 3.5 hours the mixture was diluted with DCM (30 mL) and washed with water (2x50 mL), dried over Na2SO4 and evaporated under vacuum. Treatment with DCM and methanol afforded the product as white solid. The filtrate was purified over silica gel (eluant dichloromethane/methanol 95/5) yielding 460 mg (63 %) of the product. LC-MS: Rt 8.33; [M+H]+ 524; By operating in an analogous way and by reacting 3-(2-amino-benzoylamino)- thieno[2,3-c]pyrazole-l,5-dicarboxylic acid 5-tert-butyl ester 1-ethyl ester with the appropriate acyl chloride derivative, the following compounds were thus prepared: 3-{2-[(5-Methyl-isoxazole-4-carbonyl)-amino]-benzoylamino}-thieno[2,3-c]pyrazole- 1,5-dicarboxylic acid 5-tert-butyl ester 1-ethyl ester, [M+H]+ 540; 3-{2-[(Tetrahydro-pyran-4-carbonyl)-amino]-benzoylamino}-thieno[2,3-c]pyrazole-l,5- dicarboxylic acid 5-tert-butyl ester 1-ethyl ester, [M+H]+ 543; EPO 3 - {2- [(5-Methyl- 1 H-pyrazole-3 -carbonyl)-amino] -benzoylamino} -thieno[2,3 - c]pyrazole-l,5-dicarboxylic acid 5-tert-butyl ester 1 -ethyl ester, [M+H]+ 539; |
93% | With oxalyl dichloride; N,N-dimethyl-formamide In toluene for 4h; Inert atmosphere; | The oxalyl chloride (9.2 mL, 110 mmol, 3.0 equiv.) and a catalytic amount of DMF were added to a suspension of pyrrole-2-carboxilic acid (4.0g, 36 mmol, 1.0 equiv.) in toluene (15 ml). After 4 hours the reaction was complete. The solvent was removed under vacuum and the residue was stripped twice with toluene. The pyrrole-2-carbonyl chloride was isolated as brownish solid (4.34 g, 93%). To the solution of N-Boc-L-allo-threonine benzyl ester (3.10 g, 10 mmol, 1.0 equiv.) and DIPEA (4.4 mL, 25 mmol, 2.5 equiv.) in DCM (100 mL) at 0 oC, pyrrole-2-carbonyl chloride (2.6 g, 20 mmol, 2.0 equiv.) was added portionwise under stirring. The mixture was allowed to reach room temperature. After 4 hours the mixture was diluted with DCM (100 mL) and washed with water (2*100 mL), saturated brine (2*100 mL) and dried over Na2SO4 and evaporated under vacuum. The crude product was purified by column chromatography, eluting with 20% EtOAc/petroleum ether to afford N-Boc-3-(pyrrole-2-carbonyloxy)-L-allo-threonine benzyl ester as a yellow solid (2.13 g, 53%). |
With thionyl chloride | ||
With chloroform; phosphorus(V) chloride | ||
With oxalyl dichloride; N,N-dimethyl-formamide In benzene Ambient temperature; | ||
With thionyl chloride In dichloromethane at 40℃; | ||
With thionyl chloride; N,N-dimethyl-formamide In toluene at 60℃; for 1h; | ||
With oxalyl dichloride | ||
With thionyl chloride for 18h; Ambient temperature; | ||
With potassium hydroxide | ||
With oxalyl dichloride | ||
With thionyl chloride In pyridine; N,N-dimethyl-formamide at 20℃; for 1.5h; | ||
Stage #1: pyrrole-2-carboxyl acid With triethylamine In 1,2-dimethoxyethane at 20℃; for 0.25h; Stage #2: With thionyl chloride In 1,2-dimethoxyethane at 20℃; for 0.5h; | ||
With phosphorus(V) chloride In dichloromethane at 20℃; for 2h; | ||
With thionyl chloride for 0.5h; Heating; | ||
With thionyl chloride In toluene at 70℃; for 2.5h; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In benzene | ||
With thionyl chloride In dichloromethane at 20℃; for 20h; | ||
With thionyl chloride In <i>N</i>-methyl-acetamide | R.1.i Synthesis of methyl 3-(pyrrol-2-ylcarbonylamino)propionate (1) i) A 0.2 ml amount of dimethylformamide and 19.6 ml of thionyl chloride were dropwise added under room temperature to a 100 ml toluene suspension of 20 g of pyrrole-2-carboxylic acid. The mixture was stirred at 60° C. for 2 hours, then the solvent was distilled off under reduced pressure and the residue was dried under reduced pressure to obtain crude crystals of pyrrole-2-carbonyl chloride. | |
With oxalyl dichloride; N,N-dimethyl-formamide In toluene at 20℃; | 14 EXAMPLE 14 (2H-Pyridin-1-yl)(1H-pyrrol-2-yl)methanone 20 Pyrrolic acid (1.11 g, 10.0 mmol, 1 equiv.) is suspended in toluene (20 ml) under argon. Oxalyl chloride (2 ml, 23.0 mmol, 2.3 equiv.) is rapidly added dropwise and then one drop of DMF is added, which brings about the evolution of gas and dissolution of the product. After leaving overnight at ambient temperature, the reaction medium is concentrated under reduced pressure and dried using pump vacuum for 2 h. The acid chloride thus obtained is taken up in dichloromethane (10 ml) and introduced into a two-necked flask under argon. Pyridine (0.8 ml, 10.0 mmol, 1 equiv.) is added to this solution. After 1 h at ambient temperature, the precipitate formed is dried. It is taken up in methanol (10 ml) and cooled to -78° C., and NaBH4 (0.19 g, 5.0 mmol, 0.5 equiv.) is added. The reaction medium is stirred at the same temperature for 30 min, and then it is poured onto ice-cold water (50 ml) and extracted with diethyl ether (2*50 ml). The organic phase is dried over magnesium sulfate and then concentrated under reduced pressure. The residue is purified by chromatography on a column of alumina gel eluted with dichloromethane. The dihydropyridine 20 is obtained with a yield of 39% (0.68 g). 1H NMR (300 MHz, CDCl3): δ=9.70 (bs, 1H), 7.08 (d, J=7.6 Hz, 1H, H2), 6.99 (m, 1H, H5'), 6.67 (m, 1H, H3'), 6.30 (m, 1H, H4'), 5.98 (m, 1H, H4), 5.70 (m, 1H, H5), 5.38 (dd, J=7.6 and 7.6 Hz, 1H, H3); 13C NMR (75.5 MHz): 149.9 (C7), 127.5 (C2), 124.3 (C2'), 122.6 (C5'), 122.4 (C3), 120.4 (C5), 114.6 (C4), 110.1 (C4'), 107.3 (C5), 44.8 (C6); MS(ESI+): 175.1 [M+H+]; 197.0 [M+Na]; 215.0 [M+K]. | |
With oxalyl dichloride In dichloromethane at 20℃; | 9 A solution of lH-pyrrole-2-carboxylic acid (0.8 g, 7.2 mmol) in dry dichloromethane (10 mL), oxalyl chloride (5.8 mL, 68.5 mmol) and two drops of N,N-dimethylformamide was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, the residue dissolved in dry dichloromethane (10 mL) and added to a solution of 3-(2-amino-benzoylamino)-5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-5,6- dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester (2.5 g, 4.8 mmol), N,N- diisopropylethylamine (4 eq., 3.3 mL, 19.6 mmol) in dry dichloromethane (60 mL). The reaction mixture was stirred at room temperature overnight, washed with IN HCl (50 mL), saturated sodium hydrogenocarbonate (50 mL), brine (50 mL) and dried over sodium sulfate. The solvent was removed under vacuum and the crude residue purified by flash chromatography on silica gel, using hexane-ethyl acetate 6:4 as eluant, yielding the title compound as colourless solid (2.6 g, 88% yield). IH-NMR (400 MHz), δ (ppm, DMSOtZ6): 11.84 (s, IH), 11.09 (s, IH), 10.89 (s, IH), 8.32 (d, J=8.24 Hz, IH), 7.81 (d, bs, J=7.94 Hz, IH), 7.70-7.59 (m, 4H), 7.29 (m, IH), 7.02 (m, IH), 6.84 (m, IH), 6.22 (m, IH), 4.71 (s, 2H), 4.38 (q, J=7.02 Hz, 2H), 1.68 (s, 6H), 1.31 (t, J=7.02 Hz, 3H | |
With oxalyl dichloride at 0 - 50℃; | 2 Oxalyl chloride (6.7 g; 53 mmol) under nitrogen was cooled to 0-50C, and0.5 g of Pyrrole-2-carboxylic acid (4 mmol) was added. The reaction mixture was allowed to reach room temperature and heated to 500C and stirred at this temperature, until the reaction was finished (controlled by TLC). The reaction mixture was cooled to room temperature and evaporated to an oil, the residue was washed with toluene and dried. The product was used as such in the next reaction. | |
With thionyl chloride at 20℃; for 12h; | ||
With thionyl chloride for 2h; Inert atmosphere; Reflux; | ||
With thionyl chloride In benzene at 60℃; for 2h; Inert atmosphere; | ||
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; | 5.2.1.4. Synthetic procedures for target compounds 3a-r, 2a, 2g, 2r, 4a, 4g, 4r, 5a, 5g, 5r General procedure: To a solution of compound 3 (0.40 g, 1.5 mmol) in dry CH2Cl2 (15.0 mL) 0.5 mL oxalyl choride was added and stirred. 10 min later, two drops of dry DMF was added to the above solution. The mixture was stirred overnight at room temperature. Then the dark solution was evaporated under vacuum to get the 4,5-dibromo-1H-pyrrole-2-carbonyl chloride. | |
With thionyl chloride In toluene at 70℃; for 2h; Inert atmosphere; | Prop-2-enyl 1H-pyrrole-2-carboxylate (1b). A solution of 1H-pyrrole-2-carboxylic acid (2.29 g, 20.6 mmol) and SOCl2 (14.2 mL, 88.1 mmol) in toluene (20 mL) was stirred in an atmosphere of N2 for 2 h at 70 °C. Volatile components were removed by distillation (1013 mbar, 77 and 111 °C) to leave a dark oily residue. This material was dissolved in CH2Cl2 (15 mL) and treated with a solution of prop-2-en-1-ol (1.20 g, 20.6 mmol) in pyridine (15 mL). The reaction mixture was stirred for 20 min at 23 °C. After pouring the mixture in ice water (25 mL), the organic layer was separated and kept. The aqueous layer was extracted with Et2O (3 × 75 mL). Combined organic layer and extracts were washed with 2 m aq. HCl (40 mL), and dried (MgSO4). The solvent was removed under reduced pressure (20 mbar, 40 °C), to afford an oily residue, which was purified by column chromatography [petroleum ether/AcOEt = 3:1 (v/v)]. Yield: 1.40 g (9.27 mmol, 45 %). | |
With oxalyl dichloride at 50℃; for 1h; Inert atmosphere; | ||
With oxalyl dichloride In dichloromethane for 2.5h; | 7.a PREPARATION 7 1-amino-N-o-tolyl-1H-pyrrole-2-carboxamide a) N-o-tolyl-1H-pyrrole-2-carboxamide 15.0 g (135 mmol) of 1H-pyrrol 2-carboxylic acid (purchased from Aldrich, cat. no. P7,360-9) were suspended in a mixture of DMF (1.2 mL) and dichloromethane (150 mL). To this solution, 18 mL (207 mmol) of oxalyl chloride in dichloromethane (105 mL) were added dropwise over 30 minutes. The reaction was stirred two hours and then concentrated under reduced pressure to dryness. The residual black oil was redissolved in dichloromethane (150 mL) and a solution of 15.9 g (148 mmol) of o-toluidine in dichloromethane (16 mL) was added dropwise. The reaction was stirred overnight then the solution was washed with a saturated aqueous solution of sodium bicarbonate. The organic phase was concentrated in vacuo. The product was purified by flash chromatography (30% AcOEt in hexane) to give 15.45 g (100% yield) of the title compound. LRMS (m/z): 201 (M+1)+. | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane for 1.5h; | 1 To a solution of lH-pyrrole-2-carboxylic acid (8 equivalents) in dichloromethane was added oxalyl dichloride (7.5 equivalents) and a drop of catalytic N,N-dimethylformamide. After 1.5 hours, the resulting acid chloride was slowly added to Compound 8 (1 equivalent) in dichloromethane and pyridine (2:1 ratio) until starting material was consumed as verified by LC/MS. The solution was diluted with saturated aqueous ammonium chloride solution and dichloromethane. The layers were separated and the aqueous layer was extracted with dichloromethane. The organics were dried over magnesium sulfate, filtered, and the solvent was removed in vacuo. The residue was brought up in dichloromethane and diethyl ether (1 :2.5 ratio) and the resulting solid was filtered and washed with diethyl ether to give Compound 103 (9 mg, 79% yield) as a white solid. 1H-NMR (400 MHz, MeOD) δ 8.78 (s, 1H), 8.30 (m, 1H), 8.46 (m, 1H), 7.17 (q, 1H), 7.06-7.01 (m, 2H), 6.91 (s, 1H), 6.71-6.67 (m, 1H), 6.26 (m, 1H), 6.01 (s, 2H). | |
With oxalyl dichloride; N,N-dimethyl-formamide In tetrahydrofuran at 20℃; for 0.5h; | 51 N-[4-(2,4-difluorophenoxy)-3-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol- 1 -yl)phenyl]- 1H-pyrrole-2-carboxamide 1H-pyrrole-2-carboxylic acid (18.10 mg, 0.163 mmol) in tetrahydrofliran (2 mE) was treated with oxalyl dichioride (0.024 mE, 0.271 mmol) and one drop of dimethylformamide. The reaction mixture was stirred at room temperature for 30 minutes and concentrated. The residue was azeotroped with toluene and dissolved in tetrahydrofuran (2 mE). Example 45b (50 mg, 0.136 mmol) and triethylamine (0.07 6 mE, 0.543 mmol) were added and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was partitioned with ethyl acetate and watet The organic layer was washed with brine, dried with anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 1-2% methanol in dichloromethane) to afford the title compound (40 mg, 64%). ‘H NMR (300 MHz, DMSO-d5) ö 11.66 (s, 1H) 11.36 (s, 1H) 9.80 (s, 1H) 7.88 (d, J=2.38 Hz, 1H) 7.60 (dd, J8.93, 2.58 Hz, 1H) 7.32-7.46 (m, 1H) 7.02-7.08 (m, 3H) 6.93-6.98 (m, 1H) 6.86 (d, J=8.73 Hz, 1H) 6.13-6.20 (m, 1H) 2.64 (t, J=5.95 Hz, 2H) 2.43 (s, 3H) 2.24-2.34 (m, 2H) 1.82-1.94 (m, 2H). MS (ESI+) mlz 462 (M+H). | |
With oxalyl dichloride; N,N-dimethyl-formamide In tetrahydrofuran at 20℃; for 0.5h; | 51 N-[4-(2,4-difluorophenoxy)-3-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H- isoindol-l-yl)phenyl]-lH-pyrrole-2-carboxamide Example 51. N-[4-(2,4-difluorophenoxy)-3-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H- isoindol-l-yl)phenyl]-lH-pyrrole-2-carboxamide. lH-pyrrole-2-carboxylic acid (18.10 mg, 0.163 mmol) in tetrahydrofuran (2 mL) was treated with oxalyl dichloride (0.024 mL, 0.271 mmol) and one drop of dimethylformamide. The reaction mixture was stirred at room temperature for 30 minutes and concentrated. The residue was azeotroped with toluene and dissolved in tetrahydrofuran (2mL). Example 45b (50 mg, 0.136 mmol) and triethylamine (0.076 mL, 0.543 mmol) were added and the reaction mixture was stirred at roomtemperature for 30 minutes. The reaction mixture was partitioned with ethyl acetate and water. The organic layer was washed with brine, dried with anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 1-2% methanol in dichloromethane) to afford the title compound (40 mg, 64%). 1H NMR (300 MHz, DMSO-d6) δ 11.66 (s, 1 H) 11.36 (s, 1 H) 9.80 (s, 1 H) 7.88 (d, J=2.38 Hz, 1 H) 7.60 (dd, J=8.93, 2.58 Hz, 1 H) 7.32 - 7.46 (m, 1 H) 7.02 - 7.08 (m, 3 H) 6.93 - 6.98 (m, 1 H) 6.86 (d, J=8.73 Hz, 1 H) 6.13 - 6.20 (m, 1 H) 2.64 (t, J=5.95 Hz, 2 H) 2.43 (s, 3 H) 2.24 - 2.34 (m, 2 H) 1.82 - 1.94 (m, 2 H). MS (ESI+) m z 462 (M+H)+. | |
200 mg | With Dichloromethyl methyl ether In chloroform for 3h; Reflux; | 5.1 Preparation of 1H-pyrrole-2-carbonyl chloride To a solution of 1H-pyrrole-2-carboxylic acid (200 mg, 1.80 mmol) in CHCl3 (5 ml), dichloromethyl methyl ether (3.8 g, 3 ml, 33.05 mmol) was added, and the mixture was refluxed for 3 hours. The mixture was allowed to warm to RT and the solvent evaporated under reduced pressure. The crude was taken up with chloroform and evaporated to dryness (*3) to give 1H-pyrrole-2-carbonyl chloride (Int. 19) (200 mg, 1.54 mmol). MS/ESI+129.00 [MH]+ |
200 mg | With Dichloromethyl methyl ether In chloroform for 3h; Reflux; | 5.1 Step 1: Preparation of lH-pyrrole-2-carbonyl chloride (Intermediate 19) Step 1: Preparation of lH-pyrrole-2-carbonyl chloride (Intermediate 19) To a solution of lH-pyrrole-2-carboxylic acid (200 mg, 1.80 mmol) in CHCI3 (5 ml), dichloromethyl methyl ether (3.8 g, 3 ml, 33.05 mmol) was added, and the mixture was refluxed for 3 hrs. The mixture was allowed to warm to RT and the solvent evaporated under reduced pressure. The crude was taken up with chloroform and evaporated to dryness (x3) to give lH-pyrrole- 2-carbonyl chloride (Int. 19) (200 mg, 1.54 mmol). MS/ESI+ 129.00 [MH]+ |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 1h; | 251 A mixture of 1H-pyrrole-2-carboxylic acid (0.018 g, 0.164 mmol), oxalyl chloride (0.035 g, 0.274 mmol) and dimethylformamide (1 drop) in dichloromethane (3 mL) was stirred at ambient temperature for 1 hour. The solvent was evaporated under reduced pressure and the residue treated with toluene (2 mL) and then evaporated under reduced pressure. The residue was dissolved in dichloromethane (2 mL) and was then added to a solution of Example 225C (0.040 g, 0.137 mmol) and triethylamine (0.055 g, 0.547 mmol) in dichloromethane (3 mL). The reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (C I 8, CH3CN/water (0.1%TFA), 0-100%) to afford the title compound (0.035 g, 66%). 1H NMR (500 MHz, DMSO-d6) δ 10.64 (s, 1H), 9.85 (s, 1H),7.90 (d, J = 2.75 Hz, 1H), 7.82 (d, J = 2.75 Hz, 1H), 7.76 (dd, J = 8.85, 2.75 Hz, 1H), 7.60 (dd, J = 9.31 , 2.59 Hz, 1H), 7.29-7.33 (m, 2H), 6.97-7.01 (m, 3H), 6.97-6.98 (m, 1H), 6.89 (d, J = 7.63 Hz, 2H), 6.38 (d, J = 9.46 Hz, 1H), 6.17-6.19 (m, 1H), 3.44 (s, 3H). MS (ESI+) m/z 386.1 (M+H)+. 252 | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane for 2.5h; | 3.a 1 -Amino-N-o-tolyl-1H-pyrrole-2-carboxamide A/-o-Tolyl-1 W-pyrrole-2-carboxamide1 /-/-Pyrrol 2-carboxylic acid (15 g, 135 mmol) was suspended in a mixture of 1.2 mL DMF and 150 mL dichloromethane. To this suspension, oxalyl chloride (18 mL, 203 mmol) dissolved in 105 mL dichloromethane was added dropwise over 30 minutes. The reaction was stirred two hours and then concentrated under reduced pressure. The residue oil was re-dissolved in 150 mL dichloromethane and o-toluidine (15.9 g, 148 mmol) dissolved in 16 mL dichloromethane (16 mL) was added dropwise in the reaction mixture. The reaction was stirred overnight. The mixture was washed with a saturated aqueous solution of sodium bicarbonate and the organic phase was dried, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane-ethyl acetate 0% to 30%) to give 15.45 g (100% yield) of the title compound | |
With thionyl chloride for 2.5h; Reflux; | 27 3-Chloro-N,N-diox -4-(lH-pyrrole-2-amido)anilinium To lH-pyrrole-2-carboxylic acid (0.3g, 2.7 mmol) was added in one portion thionyl chloride (10 mL). The mixture was heated at reflux for 2.5 h. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was dissolved in dichloromethane (5 mL) and placed under a N2 atmosphere. A solution of 2-chloro-4- nitroaniline (0,52g, 3 mmol) and triethylamine (0.3g, 3 mmol) in dichloromethane (15 mL) was added dropwise at ambient temperature. The resulting mixture was stirred at ambient temperature for 18 h. To the reaction mixture was added water (50 mL) and dichloromethane (50 mL) and the mixture was stirred at ambient temperature for 15 min. The phases were separated. To the aqueous phase was added water (50 mL) and this was extracted twice with dichloromethane. The combined organic phase was dried over MgS04, filtered and concentrated to a small volume. Silica gel was added and the mixture was concentrated in vacuo. The residue was transferred to a pre-column and purified by chromatography using a gradient as follows: initially hexanes, then the eluent was modified to 30% hexane in dichloromethane over a 10 min. period, and kept at 30% hexane in dichloromethane for the remainder of the separation. Fractions containing the pure component at f= 0.17 (TLC-silica gel-30% hexane/dichioromethane) were combined and concentrated in vacuo to yield 102 mg of a pale yellow solid. The crude product was dissolved is hot MeOH (75 mL), diluted with water slowly until turbid (-30 mL) and let stand at ambient temperature. The resulting solid was filtered, washed with water and air dried to give 70.2 mg (9.8%) of 3-chloro-N,N- dioxo-4-(lH~pyrrole-2-amido)anilinium as an off-white solid. 1H-pyrrole-2-carboxylic acid | |
With oxalyl dichloride In N,N-dimethyl-formamide; toluene at 20℃; for 2h; Inert atmosphere; | ||
With oxalyl dichloride at 50℃; for 1h; Inert atmosphere; | N-(4-([1,4'-bipiperidine]-1'-carbonyl)-2-chlorophenyl)-1H-pyrrole-2-carboxamide 40 1H-Pyrrole-2-carboxylic acid (23 mg, 0.21 mmol) dissolved in oxalyl chloride (100 μL, 1.17 mmol) and the white solution was heated to 50 °C for 1 hour. The residual oxalyl chloride was evaporated to yield 1H-pyrrole-2-carbonyl chloride as a pink solid. The crude material was redissolved in dry dichloromethane (300 μL) and cooled to 0 °C. Triethylamine (28 μL, 0.205 mmol) and o-chloroaniline 21 (56 mg, 0.17 mmol) were then added and the solution rapidly turned orange. The reaction was allowed to warm to room temperature and stir overnight. As no reaction was observed to have occurred at this point, a catalytic quantity of N,N-dimethylaminopyridine was added to the reaction mixture and the solution was allowed to continue to stir at room temperature. After 4 hours product formation was detected, and while o-chloroaniline remained, the reaction was quenched with water (10 mL). The aqueous phase was separated and extracted with dichloromethane (3 x 3 mL). The organic fractions were combined, dried over anhydrous magnesium sulfate, and the solvent evaporated to yield a colourless, cloudy resin. The crude material was purified by reverse phase chromatography (1:3 v:v (10% aqueous ammonia in methanol):water) - 2:3:1 v:v (10% aqueous ammonia in methanol:water:methanol) to yield a colourless resin 40 (10 mg, 0.024 mmol, 14%). | |
100 %Spectr. | With 1-chloro-1-(dimethylamino)-2-methyl-1-propene In chloroform-d1 at 20℃; Inert atmosphere; | 4.2. General procedures for the reaction of a-haloenamines with oxyacids and alcohols General procedure: Reactions were performed under dry argon atmosphere under magnetic stirring. In procedure A, the alcohol was introduced through a syringe into a 0.5-1 M solution of the α-haloenamine (usually 1.1 equiv) in freshly dried chloroform or dichloromethane or the corresponding deuterated solvents. The reactions were quite exothermic. When performed on a preparative scale, the alcoholwas added at 0 °C, and then the mixture was left at room temperaturefor 0.5-3 h. In procedure B, the α-haloenamine was introduced into a solution of alcohol in the same solvents at 0 °C. It was shown that both procedures gave identical results. In few cases involving the preparation of unstable halides, the halogenation was effected at lower temperature (see Scheme 3) for up to 4 h. Yields were determined after removal of the solvent either by 1H NMR using an added standard (usually benzene or toluene) or by GLC. In some cases the halides were purified by distillation or flash chromatography. The isolated yields were always very close to those measured by NMR or GLC. Most of the halogenation products obtained in this study were known compounds: their spectroscopic properties have been shown to be identical to those reported in the literature and will therefore not been reported here. |
With thionyl chloride In N,N-dimethyl-formamide for 3h; Reflux; Inert atmosphere; Schlenk technique; | ||
With thionyl chloride at 70℃; for 0.5h; | 3 [00100] To a small vial was added 2-pyrrole-2-carboxylic acid (0.200 g, 1.82 mmol) and 1.5 mL of SOC12, and the resulting solution was heated to 70°C for 0.5 hrs. SOC12 was removed under reduced pressure to yield a reddish brown solid. The material was redissolved in 2 mL of toluene, and 0.248 g (2.18 mmol) of 3,4-dihydropyran-2H-pyran-2- methanol was added along with 1 mL of triethylamine. This mixture was heated to 60°C and allowed to stir for 24 hours. A white precipitate developed, which was filtered, and the resulting solvent was removed from the supernatant to yield a brown oil. The brown oil was flashed through a silica gel column (1:3 EtOAC/hexanes) to yield the title compound (115 mgs, 35-40%) as a white solid. ‘H NMR data (CDC13): 1H, 9.20 ppm; 2H, 6.92 ppm; 1H, 6.38 ppm; 1H, 6.2 ppm; 1H, 4.75 ppm; 2H, 4.20ppm; 1H, 4.05 ppm; 4H, 2.2-1.75 ppm. | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 4h; Inert atmosphere; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0℃; for 0.5h; | 30 A solution [OF TIN (IV)] chloride (3.72 g, 5 mmol) in benzene (10 mL) was added dropwise to a mixture of 2-chloronicotinoyl chloride (2.02 g, 11 mmol) and 1H-pyrrole-2- carboxylic acid ethyl ester (0.73 g; prepared as discussed below) in dry benzene (12 mL) at [0] [°C.] The reaction was allowed to warm up slowly to room temperature and stirred 4 hours. The reaction was concentrated, the residue was dissolved in ethyl acetate and washed with brine, dried and concentrated to give 1.53 g [OF 5-(2-CHLORO-PYRIDINE-3-CARBONYL)-LH-PYRROLE-] 2-carboxylic acid ethyl ester as a brown solid. 1H-pyrrole-2-carboxylic acid ethyl ester was prepared as follows: to a solution of [LH-PYRROLE-2-CARBOXYLIC] acid (10 mmol; Aldrich, Milwaukee, WI) in DCM (15 mL) was added oxalyl chloride (10 mmol) and 3 drops of DMF at [0° C.] The solution was stirred at [0° C] for 30 minutes to form [LH-PYRROLE-2-CARBONYL] chloride. Ethanol was added and the mixture was stirred at room temperature for 30 minutes. The mixture was concetrated to afford 1-carboxylic acid ethyl ester. A mixture of 5-(2-chloro-pyridine-3-carbonyl)-1H-pyrrole-2-carboxylic acid ethyl ester (0.5 g) and hydrazine hydrate (0.7 g) in ethanol was heated at 80 [°C] for 24 hours. The resulted precipitate was collected by vacuum filtration, washed with water and dried to give 80 mg of the titled compound. [MS 77L/Z 227] [M-1]. | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; | 32 To a solution of [1H-PYRROLE-2-CARBOXYLIC] acid (1 g, 9 mmol) (Aldrich, Milwaukee, WI) in DCM (15 mL) was added oxalyl chloride [(1.] [1] mL) and DMF (3 drops). The mixture was stirred at room temperature resulting in [LH-PYRROLE-2-CARBONYL] chloride. Methylamine (30 mmol) was then added to the acid chloride and the mixture was stirred at room temperature. The reaction was diluted with ethyl acetate, washed with brine (2x), [NAHC03,] dried and concentrated to give [LH-PYRROLE-2-CARBOXYLIC] acid methylamide. To a mixture of [1H-PYRROLE-2-CARBOXYLIC] acid methylamide (430 mg, 3.5 mmol) and 2-chloronicotinoyl chloride (0.6 g, 3.4 mmol) in benzene (15 mL) at [0 °C] was added a dropwise solution of tin (IV) chloride (1.6 g) in benzene (5 mL). The mixture was allowed to warm up slowly to room temperature and stirred for 4 hours. The reaction was diluted with ethyl acetate, washed with water, brine, dried and concentrated to give 320 mg (35%) of 5- (2- [CHLORO-PYRIDINE-3-CARBONYL)-LH-PYRROLE-2-CARBOXYLIC] acid methylamide. [IHNMR] (400 MHz, DMSO-d6) 8 12.42 (br s, 1H, NH), 8.76 (s, 1H), 8.38 (m, [1H,] NH), 7.98 (d, 1H), 7.52 (m, 1H), 6.76 (s, 1H), 6.58 (s, 1H), 2.76 (d, 3H, [CH3).] [MS M/Z 262] [M-1]. A mixture [OF 5-(2-CHLORO-PYRIDINE-3-CARBONYL)-LH-PYRROLE-2-CARBOXYLIC] acid methylamide (320 mg, 1.2 mmol) and hydrazine hydrate (2 mL) in ethanol (20 mL). The mixture was heated to at [80 °C] for 48 hours. The precipitate was collected by vacuum filtration, washed with ethanol and water, dried to give [80] mg (27%) of the titled compound. [IHNMR] (400 MHz, [DMSO-D6)] [6] 13.71 (s, 1H, NH), 11.51 (br s, 1H, [NH),] 8.54 (d, 1H), 8. 49 (d, J= [8] Hz, 1H), 8.17 (m, [1H,] NH), 7.23 (m, 1H), 6.81 (m, 2H), 2.76 (d, [J= 5] Hz, 3H). MS mlz 240 [M-1]. | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 3h; | Synthesis of different aromatic chain substitutedchloride 6 General procedure: A five or six membered aromatic carboxylic acid 5 wasdissolved in CH2Cl2 with dropping three drop DMF. 1.5times the amount of oxalylchloride was cautiously addedinto the reaction solution at 0 °C. After stirring at ambienttemperature for 3 h, the reaction mixture was concentratedunder reduced pressure to give the corresponding acidchloride intermediate 6. The remaining acid chloride weresynthesized according to the method described above with ayield of 83-92%. | |
With oxalyl dichloride; N,N-dimethyl-formamide In tetrahydrofuran at 0℃; for 1.5h; Inert atmosphere; | General Method for Synthesis of Intermediate Acid Chlorides General procedure: To the acid (1 eq) in 1 mL of THF and 1 drop of DMF at 0°C, oxalyl chloride (1.2 eq) was added. The reaction was stirred under nitrogen for 1.5 hours and then the solution was concentrated. The acid chloride was continued to the next step. | |
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 3h; | 1H-pyrrole-2-carbonyl chloride (8A) To a solution of 1H-pyrrole-2-carboxylic acid (8)(0.3 g) in DCM (15 mL) was added oxalyl chloride (0.28 mL) and a drop of DMF at 0 °C . The resulting clear solution was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure. The solvent was distilled off under reduced pressure from the reaction mixture, and the residue was subjected to an azeotropic distillation treatment with toluene. The crude product of lH-2-pyrrolecarbonyl chloride (0.35g) was obtained as a brown crystalline product which was used directly in the next step. | |
With thionyl chloride for 2h; Reflux; | 1 Example 1:Synthesis of Ligand L At room temperature,Methyl 1H-pyrrole-2-carboxylate (1.25 g, 10 mmol) in MeOHAqueous KOH (2.24 g, 40 mmol) was added to the solution and stirred for 7 h.After the reaction is completed, add 0.5M HCl to the solution pH=8 and extract it.After filtration and concentration in vacuo, 1H-pyrrole-2-carboxylic acid was obtained.Dissolve 1H-pyrrole-2-carboxylic acid in SOCl 2 (20 mL) and reflux for 2 h.The solvent was removed in vacuo to give 1H-pyrrole-2-acid chloride.Pyrazole (0.68 g, 10 mmol), 1H-pyrrole-2-acid chloride, at 0°C,Et3N (1.5 g) was stirred in Et20 for 2 h. The resulting mixture is concentrated,Column chromatography on silica gel (hexane:Ethyl acetate 6:1) gave pale yellow solid ligand L (1.35 g, overall yield 85%). | |
With thionyl chloride at 80℃; Inert atmosphere; | 6.1.1. Preparation of acid chlorides General procedure: Using a typical scale of 2.0 mmol, the appropriate aryl carboxylicacid (2.0 mmol) was added to a small round-bottomed flask, which was flushed with N2(g). SOCl2 (3 mL, 41.4 mmol) was added afterwhich the reaction mixture was refluxed, with stirring, at 80 °C andleft overnight to ensure complete conversion. The reaction mixturewas cooled and excess SOCl2 was completely removed underreduced pressure. The crude acid chloride was then used as a reagentfor subsequent reactions. | |
With oxalyl dichloride at 0 - 50℃; | 2 Oxalyl chloride (6.7 g; 53 mmol) under nitrogen was cooled to 0-50C, and 0.5 g of Pyrrole-2-carboxylic acid (4 mmol) was added. The reaction mixture was allowed to reach room temperature and heated to 5O0C and stirred at this temperature, until the reaction was finished (controlled by TLC). The reaction mixture was cooled to room temperature and evaporated to an oil, the residue was washed with toluene and dried. The product was used as such in the next reaction. | |
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 20℃; | 6 Pyrrole 2-carboxylic acid (0.284 g, 0.00255 mol) was dissolved in dichloromethane (DCM, 30 ml_). A few drops of anhydrous dimethyl formamide (DMF) were added following the drop-wise addition of oxalyl chloride (0.0153 g, 1.34 ml_). After stirring overnight at room temperature, the solvent was removed under vacuum and the mixture was taken up with toluene and evaporated to dryness (twice). This was newly dissolved in dichloromethane (DCM, 25 ml_) and a solution made up of 3-(2-Amino- benzoylamino)-1 H-furo[3,2-c]pyrazole-5-carboxylic acid (1 -methyl-1 -phenyl-ethyl)- amide (286 mg, 0.71 1 mmol), pyridine (4.27 mmol, 0.731 ml_) and diisopropyethylamine (10.6 mmol, 0.858 ml_) in dichloromethane (DCM, 30 ml_) was added drop-wise. The mixture was stirred at room temperature overnight. Then, it was diluted with dichloromethane, washed respectively with a saturated solution of sodium bicarbonate, with brine with water, and then dried over sodium sulphate. The organic solvent was next evaporated to dryness and the crude taken up with toluene and evaporated to dryness. The crude was then dissolved in a 10 % solution of triethylamine (TEA) in methanol and stirred at 50 0C for two hours and at room temperature overnight. The mixture was then evaporated to dryness and the residue purified by flash column chromatography on silica gel (eluting with dichloromethane- methanol 46/4). The material isolated was triturated with ethyl ether furnishing 1 10 mg of the title compound. [M+H]+ 497;1H NMR (400 MHz, DMSO-D6) D ppm 1.69 (s, 6 H) 6.06 - 6.21 (m, 1 H) 6.77 - 6.89 (m, 1 H) 6.94 - 7.05 (m, 1 H) 7.15 - 7.26 (m, 2 H) 7.27 - 7.36 (m, J=12.44 Hz, 3 H) 7.36 - 7.46 (m, 2 H) 7.56 - 7.70 (m, 1 H) 8.08 (d, 1 H) 8.25 (s, 1 H) 8.63 (d, 1 H) 1 1.19 (s, 1 H) 1 1.83 (s, 1 H) 1 1.89 - 12.01 (m, 1 H) 12.65 (s, 1 H). | |
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 1.25h; Cooling; | ||
With thionyl chloride In dichloromethane at 0 - 5℃; for 5h; | 4 Example 4Preparation of N-1-naphthyl- (2-pyrrolyl) -formamide (compound of formula II) Put 46.7g (0.42mol) of 2-pyrrolecarboxylic acid and 100ml of dichloromethane into the reaction bottle, stir, cool to 0-5 ° C, slowly add 60g (0.5mol) of dichlorosulfoxide, stir the reaction for 5 hours, and reduce the pressure Evaporate to dryness, add 200ml of dichloromethane and stir to dissolve to obtain acid chloride solution, and set aside.Put 50g (0.35mol) of 1-naphthylamine (the compound of structural formula III), 70.7g (0.7mol) of triethylamine, and 200ml of dichloromethane in another reaction flask, stir, add the prepared acid chloride solution dropwise, and monitor to After the reaction of the raw materials is complete, slowly add 500ml of water, separate the layers, wash the organic layer to neutrality, and evaporate to dryness under reduced pressure.Crystallization from methanol gave 75.9 g of (2-pyrroliyl) -1-naphthylamine, yield 92.0%, HPLC purity: 99.1%. | |
With thionyl chloride In dichloromethane for 4h; Inert atmosphere; Reflux; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In toluene at 65℃; for 1h; Schlenk technique; Inert atmosphere; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 2h; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With bromine In acetic acid at 60℃; for 1h; | |
94% | With bromine In acetic acid at 60℃; for 1h; | |
87% | Stage #1: pyrrole-2-carboxyl acid With bromine; acetic acid In chloroform at 20 - 50℃; for 5h; Stage #2: With water; potassium carbonate In chloroform | 5 4,5-dibromo-1H-pyrrole-2-carboxylic acid (11). Pyrrole-2-carboxylic acid 10 (1.00 g, 9.00 mmol), was dissolved in anhydrous chloroform (10 mL) and glacial HOAc (2 mL). To the resulting cloudy solution was slowly added bromine (0.971 mL, 18.9 mmol) at room temperature and once addition was complete the reaction was heated to 50° C. for 5 h. After cooling to ambient temperature the reaction was partitioned between water (30 mL) and chloroform (40 mL). The organic layer was rinsed with water (2*30 mL) and 10% K2CO3 (40 mL). The K2CO3 extract was then washed with chloroform (2*20 mL) and acidified to pH=3 with an aqueous solution of 4N HCl. The precipitate was collected by vacuum filtration and the filter cake rinsed with water (15 mL) to afford the target compound 11 (2.10 g, 87%) as a white solid: 1H NMR (400 MHz, DMSO-d6) δ 12.80 (bs, 1H), 6.82 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 160.43, 125.37, 116.73, 106.50, 98.70; HRMS (FAB) calcd for C5H3Br2NO (M+) 266.8531, found 266.8525. _ |
87% | Stage #1: pyrrole-2-carboxyl acid With bromine; acetic acid In chloroform at 20 - 50℃; for 5h; Stage #2: With water; potassium carbonate In chloroform Stage #3: With hydrogenchloride; water In chloroform | 4 4,5-dibromo-1H-pyrrole-2-carboxylic acid (11). Pyrrole-2-carboxylic acid 10 (1.00 g, 9.00 mmol), was dissolved in anhydrous chloroform (10 mL) and glacial HOAc (2 mL). To the resulting cloudy solution was slowly added bromine (0.971 mL, 18.9 mmol) at room temperature and once addition was complete the reaction was heated to 50° C. for 5 h. After cooling to ambient temperature the reaction was partitioned between water (30 mL) and chloroform (40 mL). The organic layer was rinsed with water (2×30 mL) and 10% K2CO3 (40 mL). The K2CO3 extract was then washed with chloroform (2×20 mL) and acidified to pH= 3 with an aqueous solution of 4N HCl. The precipitate was collected by vacuum filtration and the filter cake rinsed with water (15 mL) to afford the target compound 11 (2.10 g, 87%) as a white solid: 1H NMR (400 MHz, DMSO-d6) δ 12.80 (bs, 1H), 6.82 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 160.43, 125.37, 116.73, 106.50, 98.70; HRMS (FAB) calcd for C5H3Br2NO (M+) 266.8531, found 266.8525. |
With bromine; acetic acid | 5.2.1.1. Synthesis procedures for compounds 1-5 4,5-Dibromo-1H-pyrrole-2-carboxylic acid 3 and 3,4,5-tribromo-1H-pyrrole-2-carboxylic acid 4 were synthesized referencing to the literature [7] and [9]. When the bromine was 3 equivalents of the 2 in HOAc and the reaction time was prolonged. Compound 2 could be fully converted to the crude product 4 which could be also obtained from compound 3 reacting with the equivalent of bromine in HOAc. The crude 4 was then recrystallized in the solution of ethanol/water to give the pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: pyrrole-2-carboxyl acid With potassium hydroxide In dimethyl sulfoxide Stage #2: benzyl bromide In dimethyl sulfoxide at 20℃; for 1h; Further stages.; | |
95% | With potassium carbonate In N,N-dimethyl-formamide 1.) 15 min, 2.) 29 h; | |
84% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 2.5h; |
52% | Stage #1: pyrrole-2-carboxyl acid With potassium hydroxide In dimethyl sulfoxide Inert atmosphere; Stage #2: benzyl bromide In dimethyl sulfoxide at 20℃; for 3h; | 52.1 Step 1. To a solution of lH-pyrrole-2-carboxylic acid (1.15 g, 10.3 mmol) in DMSO (20 mL) was added potassium hydroxide (567 mg, 10.1 mmol) under argon. After attiring for 5-10 minutes, benzyl bromide (1.29 mL, 10.8 mmol) was added. The mixture was stirred at room temperature for 3 hours. The mixture was poured onto water, and was extracted with dichloromethane (2 x). The extract was washed with water (2 x), dried (Na2S04), and concentrated. Purification by flash column chromatography (9: 1 hexane/EtOAc) gave benzyl lH-pyrrole-2-carboxylate (1.1 g, 52% yield) as a white solid. 1H NMR (300 MHz, (1044) Chloroform-d) d 9.17 (bs, 1H), 7.50 - 7.29 (m, 5H), 7.03 - 6.91 (m, 2H), 6.33 - 6.23 (m, 1H), 5.33 (s, 2H). |
8.23 g (90%) | With triethylamine In hexane; dichloromethane; ethyl acetate; N,N-dimethyl-formamide | 98.a a a 1H-Pyrrole-2-carboxylic acid benzyl ester Lit. J. Org. Chem., 44:975 (1979). To a stirred solution of 5.0 g (45.0 mmol) pyrrole-2-carboxylic acid and 31.3 ml (225 mmol) triethylamine in 100 ml DMF was added dropwise 26 ml (225 mmol) benzyl bromide and stirring continued for 72 h at room temperature. The reaction mixture was then concentrated in vacuo and the residue resuspended in dichloromethane and washed twice with saturated sodium bicarbonate solution and twice with water, and the aqueous phases back-extracted with dichloromethane. The combined organic extracts were dried over sodium sulphate and concentrated in vacuo. Flash chromatography (25% EtOAc in hexane) afforded 8.23 g (90%) of the title compound as a yellow oil. MS m/e (%): 201 (M+, 33), 94 ([M-OBn]+, 22), 91 (Bn+, 100). |
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 18h; | 18 Intermediate 18: 1 H-Pyrrole-2,5-dicarboxylic acid monobenzyl ester; To a stirred solution of 1 H-pyrrole-2-carboxylic acid (1 .1 1 g, 10 mmol) in DMF (15 ml_) is added potassium carbonate (2.07 g, 15 mmol) and (bromomethyl)benzene (1 .80 g, 10.50 mmol). After stirring the mixture at room temperature for 18 hours, water is added and the mixture is extracted three times with ethyl acetate. The combined organic layers are washed with water and brine then is dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue is purified by flash chromatography (heptane/ethyl acetate =5:1 ) to give 1 H-pyrrole-2-carboxylic acid benzylester.Next, To a stirred solution of 1 H-pyrrole-2-carboxylic acid benzylester (2.0 g, 9.94 mmol) in 1 ,2-dichloroethane (15 ml_) at 5 0C is sequentially added DMF (1 .12 g, 15.31 mmol) and phosphoryl trichloride (2.35 g, 15.31 mmol). After the addition, the mixture is heated to 50 0C and stirred for an hour. Water is added and the mixture is extracted with ethyl acetate (3x). The combined organic layers are washed with water and brine then is dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue is purified by flash chromatography (heptane/ethyl acetate =3:1 ) to give 5-formyl-1 H-pyrrole-2- carboxylic acid benzyl ester; HPLC Retention time 1 .64 minutes (condition C): MS 230.3 (M+1 ).Next, to a stirred solution of 5-formyl-1 H-pyrrole-2-carboxylic acid benzyl ester (1.10 g, 4.80 mmol) in acetone (10OmL) is added a solution of potassium permanganate (1.52 g, 9.60 mmol) in 150 mL acetone/water (1 :1 ) dropwise and the mixture is stirred for three hours. The mixture is poured into a solution of 200 mL of 10% NaHSOβ in 1 N HCI and the mixture is extracted three times with ethyl acetate. The combined organic layers are washed with water and brine then is dried over magnesium sulfate. The solvent is removed under reduced pressure to give the title compound; HPLC Retention time 0.88 minutes (condition C): MS 244.3 (M -1 ). | |
With triethylamine In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 24h; | B Method B: General method for the synthesis of acylation reagents [00128] To a solution of pyrrole-2-carboxylic acid (2.0 g, 18 mmol, 1.0 eq.) in a (1:1) mixture of dry DMF/THF (60 mL) was added Et3N (12.6 mL, 90 mmol, 5.0 eq.) followed at rt by benzyl bromide (90 mmol, 10 mL, 5.0 eq.), the resulting white suspension was vigorously stirred at rt for one day. The reaction was poured into a mixture of Et20 and a saturated aqueous solution of NaHCO3 (5OmL), the aqueous layer was extracted with Et20 (2xlOOmL) and EtOAc (lOOmL). The combined organic layers were washed with brine dried over Na2SO4, filtered and concentrated. Chromatography on Si02 with gradient from pure petroleum ether to EtOAc/petroleum ether: 10/90: gave the protected pyrrole as a white solid. | |
With triethylamine In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 24h; | To a solution of pyrrole-2-carboxylic acid (2.0 g, 18 mmol, 1.0 eq.) in a (1 :1) mixture of dry DMF/THF (60 mL) was added Et3N (12.6 mL, 90 mmol, 5.0 eq.) followed at rt by benzyl bromide (90 mmol, 10 mL, 5.0 eq.), the resulting suspension was vigorously stirred at rt for one day. The reaction was poured into a mixture of Et20 and a saturated aqueous solution of NaHCOs (50mL), the aqueous layer was extracted with Et20 (2xl00mL) and EtOAc (lOOmL). The combined organic layers were washed with brine dried over Na2S04, filtered and concentrated. Chromatography on Si02with gradient from pure petroleum ether to EtO Ac/petroleum ether: 10/90: gave the protected pyrrole as a solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With thionyl chloride; at 0 - 35℃; for 24.5h; | To a solution of pyrrole-2-carboxylic acid (1) (16.65 g, 0.15 mol)in 10 mL of MeOH was added 50 mL of SOCl2 dropwise within30 min at 0 C. Subsequently, the reaction mixture was stirred at35 C for 24 h. Then, the solvent was evaporated in vacuo, andthe residue was purified by column chromatography using ethylacetate/petroleum ether as eluent, giving intermediate 2 as a whitesolid, yield 85%, mp: 72-73 C. |
79% | With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In DMF (N,N-dimethyl-formamide); at 20 - 60℃; for 72h; | Example 36-1 Preparation for methyl 1H-pyrrole-2-carboxlate A suspension of 1H-pyrrole-2-carboxylic acid (5.5g, 49.5mmol), WSCI·HCl (12.2g, 63.6mmol), HOBt (8.4g, 62.2mmol), methanol (7.0g, 218mmol) and 4-dimethylaminopyridine (3.0g, 24.5mmol) in dimethylformamide (60ml) was stirred for 70 hours at room temperature and for 2 hours at 60C. To the reaction mixture was added an aqueous 5% potassium hydrogensulfate solution and the mixture was extracted with ethyl acetate/toluene (1/1).. The organic layer was washed with an aqueous saturated sodium hydrogencarbonate solution, and an aqueous saturated sodium chloride solution, and dried over magnesium sulfate.. The solvent was removed and the residue was purified with silica gel chromatography (hexane:ethyl acetate=5:13:1) to give the subject compound (4.88g, 79%).1H NMR (CDCl3, 400 MHz) delta 9. 08 (brs, 1 H), 6. 90 - 6. 98 (m, 2 H), 6.25 - 6.29 (m, 1 H), 3.86 (s, 3 H). |
65% | With chloro-trimethyl-silane; In methanol; at 20℃; | Method I Synthesis of 5-tert-Butyl-3-(3-p-tolyl-ureido)-1H-pyrrole-2-carboxylic acid methyl ester. (Example 24) [Show Image] Step 1; Chlorotrimethylsilane (17.9 mL, 141 mmol, 2.5 equiv) is added in one portion to a solution of pyrrole-2-carboxylic acid (6.28 g, 56.5 mmol) in dry methanol (100 mL) under N2 at rt. After stirring overnight, the reaction mixture is concentrated in vacuo, redissolved in dichloromethane, washed with water, dried (Na2SO4) and concentrated to give 4.62 g of methyl pyrrole-2-carboxylate as a tannish semi-crystalline solid (65%), which was used without further purification. 1H NMR (CDCl3) d 9.3 (br s, 1H), 6.96 (br m, 1H), 6.92 (br m, 1H), 6.29 (br q, 1H), 3.86 (s, 3H). |
65% | With chloro-trimethyl-silane; at 20℃; | To a solution of pyrrole-2-carboxylic acid (6.28 g, 56.5 mmol) in anh. MeOH (100 mL) under N2 at room temp. was added TMSCl (17.9 mL, 141 mmol, 2.5 equiv) in one portion. After stirring overnight, the reaction mixture was concentrated under reduced pressure, redissolved in CH2Cl2, washed with water, dried (Na2SO4) and concentrated to give methyl pyrrole-2-carboxylate as a tannish semi-crystalline solid (4.62 g, 65%): 1H NMR (CDCl3) delta 3.86 (s, 3H), 6.29 (br q, 1H), 6.92 (br m, 1H), 6.96 (br m, 1H), 9.30 (br s, 1H). This material was used in the next step without further purification. |
With hydrogenchloride; | General scheme for synthesis of pyrroles.; Commercially available 2-carboxypyrrole was esterified under acidic conditions to yield a methyl ester. The pyrrole was alkylated using potassium carbonate, followed by ester hydrolysis to give the acid. The acid was converted to an amide using oxalyl chloride and the appropriate amine.; Synthesis of ENMD-1537: N-(6-aminohexyl)-l-(2-methylpropyl)-2-pyrrolecarboxamide.; Target was prepared by converting 2-carboxyacid pyrrole to the methyl ester, and alkylating the N with isobutyl bromide. The ester was hydrolyzed and the resulting acid was converted to an amide using oxalyl chloride and N-Boc-l,6-diaminohexane. Boc deprotection yielded the target. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With silver trifluoroacetate; triethylamine In acetonitrile at 50℃; for 5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With diethyl cyanophosphonate; triethylamine In N,N-dimethyl-formamide for 20h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: pyrrole-2-carboxyl acid With n-butyllithium In tetrahydrofuran; hexane at -20℃; for 1h; Stage #2: 4-fluoro-3-chlorobenzenesulfonyl chloride In tetrahydrofuran; hexane at -20 - 20℃; for 20h; Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; Inert atmosphere; | |
90% | With dmap; dicyclohexyl-carbodiimide at 20℃; for 12h; | |
90% | With sulfuric acid at 100℃; for 12h; Sealed tube; |
90% | With sulfuric acid at 100℃; for 12h; | |
53% | Stage #1: pyrrole-2-carboxyl acid With trichloroisocyanuric acid; triphenylphosphine In dichloromethane at 0℃; for 0.75h; Stage #2: ethanol With triethylamine In dichloromethane at 20℃; for 1h; | |
With sulfuric acid for 5h; Reflux; | - General synthetic procedure for the preparation of hydrazides R1-CO-NHNH2 General procedure: To a solution of the acid R1-CO2H in EtOH was added concentrated H2SO4 (2 equiv.) and the reaction mixture was refluxed for 5 h. After cooling to room temperature, water was added and the solution was neutralized with Na2CO3. The aqueous phase was extracted twice with EtOAc. The organic phases were combined, dried over MgSO4, filtered and evaporated under vacuum to yield the ethyl ester, which was used without necessity of purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; dicyclohexyl-carbodiimide In tetrahydrofuran; dichloromethane at 20℃; for 96h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With caesium carbonate In N,N-dimethyl-formamide at 25℃; for 16h; | 1.a; 3 To a solution of lH-pyrrole-2-carboxylic acid (1.5 g, 14 mmol) in N,N- dimethylformamide (50 mL) at 25 0C was added cesium carbonate (4.8 g, 14.7 mmol) and allyl bromide (1.34 mL, 15.4 mmol) and stirred for 16 h. The reaction mixture was treated with saturated aqueous ammonium chloride solution and diethyl ether (20 mL). The layers were separated and the aqueous layers were extracted with diethyl ether (3 x 100 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to afford the crude desired product, lH-pyrrole-2- carboxylic acid allyl ester (1.6 g, 10.6 mmol, 76% yield) as a yellow oil, which was used in the next step without further purification. 1H νMR (400 MHz, CDCl3) δ 4.77 (IH, m), 5.35 (IH, dd, J1 = 10.4 Hz, J2 = 1.2 Hz), 5.39 (IH, dd, J1 = 16.8 Hz, J2 = 1.6 Hz), 6.26 (IH, m), 5.96 (IH, m), 6.94 (2H, m), 9.2 (IH, bs). |
62% | With dmap; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide In dichloromethane at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.42 g (82%) | In dichloromethane; N,N-dimethyl-formamide; | 2(R,S)-Benzyl-4-oxo-4-(1H-pyrrol-2-yl)-butryric acid Method 7 General Experimental: Pyrrole-2-carboxylic acid (27.0 mmol, 3.00 g) in CH2Cl2 (100 ml) was treated with oxalyl chloride (54.0 mmol, 4.70 ml) and DMF (1 drop), then heated to reflux for 1 h, then concentrated under reduced pressure. The residue was diluted with CH2Cl2 (100 ml) and pyridine (6.50 ml), and treated with O,N-dimethyl-hydroxylamine hydrochloride (27.0 mmol, 2.65 g), then held at room temperature overnight. The resulting solution was diluted with ethyl acetate (250 ml), washed with 10% aqueous citric acid (2*30 ml), saturated aqueous sodium bicarbonate (2*30 ml), then brine (2*30 ml). The organics were concentrated under reduced pressure. Purification of the residue by silica gel chromatography provided 3.42 g (82%) of 1H-pyrrole-2-carboxylic acid methoxy-methyl amide. 1H NMR (CDCl3) delta6.90-6.80 (1H, m), 6.79-6.60 (1H, m), 6.18 (1H, dd, J=3.7, 1.3), 3.81 (3H, s), 3.01 (3H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.92 g (34.4%) | With N-ethyl-N,N-diisopropylamine; In hexane; dichloromethane; | a. (Pyrrole-2-carbonyl)-N-(benzyl)glycine-t-butyl Ester. To a suspension containing 3.00 g (27.0 mmol) of pyrrole-2-carboxylic acid in 75 mL of anhydrous dichloromethane under a nitrogen atmosphere at 0 C. was added 6.96 g (27.0 mmol) of BOPCl and 14.1 mL (81.0 mmol) of DIEA. After stirring for 30 minutes, 5.97 g (27.0 mmol) of N-(benzyl)gylcine-t-butyl ester was added and the reaction allowed to warm to room temperature overnight. The reaction was diluted with ethyl acetate and washed with a 5% potassium hydrogensulfate, saturated sodium bicarbonate solution and brine. The organic phase was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient of 100% hexane to 60% hexane/ethyl acetate to afford 2.92 g (34.4%) of the title compound as a white solid. FAB MS [M+H] m/z Calcd: 315, Found: 315. |
2.92 g (34.4%) | With N-ethyl-N,N-diisopropylamine; In hexane; dichloromethane; | a. (Pyrrole-2-carbonyl)-N-(benzyl)glycine-t-butyl ester. To a suspension containing 3.00 g (27.0 mmol) of pyrrole-2-carboxylic acid in 75 mL of anhydrous dichloromethane under a nitrogen atmosphere at 0 C. was added 6.96 g (27.0 mmol) of BOPCl and 14.1 mL (81.0 mmol) of DIEA. After stirring for 30 minutes, 5.97 g (27.0 mmol) of N-(benzyl)gylcine-t-butyl ester was added and the reaction allowed to warm to room temperature overnight. The reaction was diluted with ethyl acetate and washed with a 5% potassium hydrogensulfate, saturated sodium bicarbonate solution and brine. The organic phase was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient of 100% hexane to 60% hexane/ethyl acetate to afford 2.92 g (34.4%) of the title compound as a white solid. FAB MS [M+H]m/z Calcd: 315, Found: 315. |
2.92 g (34.4%) | With N-ethyl-N,N-diisopropylamine; In hexane; dichloromethane; | a. (Pyrrole-2-carbonyl)-N-(benzyl)glycine-t-butyl ester. To a suspension containing 3.00 g (27.0 mmol) of pyrrole-2-carboxylic acid in 75 mL of anhydrous dichloromethane under a nitrogen atmosphere at 0 C. was added 6.96 g (27.0 mmol) of BOPCl and 14.1 mL (81.0 mmol) of DIEA. After stirring for 30 minutes, 5.97 g (27.0 mmol) of N-(benzyl)gylcine-t-butyl ester was added and the reaction allowed to warm to room temperature overnight. The reaction was diluted with ethyl acetate and washed with a 5% potassium hydrogensulfate, saturated sodium bicarbonate solution and brine. The organic phase was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient of 100% hexane to 60% hexane/ethyl acetate to afford 2.92 g (34.4%) of the title compound as a white solid. FAB MS [M+H] m/z Calcd: 315, Found: 315. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride In ethanol; chloroform; N,N-dimethyl-formamide; toluene | 1.1 1-[(1-Benzyl-5-ethoxycarbonyl)pyrrol-3-yl]-3-hydroxy-3-(1H-1,2,4-triazol-3-yl)-propenone (Compound No. I-1) (1) To pyrrole-2-carboxylic acid (2.2 g, 20 mmol) were added at room temperature thionylchloride (2 ml, 27.4 mmol) and DMF (0.5 ml). The mixture was heated at 50° C. for 30 minutes. An excess of thionyl chloride was evaporated under reduced pressure. The residue was dissolved in toluene (5 ml) and evaporated under reduced pressure again. This procedure was performed three times. After that, the residue was dissolved in chloroform (10 ml), and the solution was added dropwise at room temperature to ethanol (20 ml) and stirred for 30 minutes. The reaction mixture was concentrated. The residue was chromatographed on silica gel (hexane:ethylacetate=1:1 v/v). The fraction of the objective was concentrated to give 2-ethoxycarbonylpyrrole (2.9 g) as an oil quantitatively. NMR(CDCl3) δ: 1.36(3H, t, J=7.0 Hz), 4.33(2H, q, J=7.0 Hz), 6.22-6.31(1H, m), 6.89-6.98(2H, m), 9.20(1H, brs). | |
Multi-step reaction with 2 steps 1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 20 °C 2: dichloromethane / 0.5 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.92 g (34.4%) | With N-ethyl-N,N-diisopropylamine; In hexane; dichloromethane; | a. (Pyrrole-2-carbonyl)-N-(benzyl)glycine-t-butyl ester. To a suspension containing 3.00 g (27.0 mmol) of pyrrole-2-carboxylic acid in 75 mL of anhydrous dichloromethane under a nitrogen atmosphere at 0 C. was added 6.96 g (27.0 mmol of BOPCl and 14.1 mL (81.0 mmol) of DIEA. After stirring for 30 minutes, 5.97 g (27.0 mmol) of N-(benzyl)glycine-t-butyl ester was added and the reaction allowed to warm to room temperature overnight. The reaction was diluted with ethyl acetate and washed with a 5% potassium hydrogensulfate, saturated sodium bicarbonate solution and brine. The organic phase was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient of 100% hexane to 60% hexane/ethyl acetate to afford 2.92 g (34.4%) of the title compound is a white solid. FAB MS [M+H] m/z Calcd: 315, Found: 315. |
2.92 g (34.4%) | With N-ethyl-N,N-diisopropylamine; In hexane; dichloromethane; | a. (Pyrrole-2-carbonyl)-N-(benzyl)glycine-t-butyl Ester To a suspension containing 3.00 g (27.0 mmol) of pyrrole-2-carboxylic acid in 75 mL of anhydrous dichloromethane under a nitrogen atmosphere at 0 C. was added 6.96 g (27.0 mmol of BOPCl and 14.1 mL (81.0 mmol) of DIEA. After stirring for 30 minutes, 5.97 g (27.0 mmol) of N-(benzyl)glycine-t-butyl ester was added and the reaction allowed to warn to room temperature overnight. The reaction was diluted with ethyl acetate and washed with a 5% potassium hydrogensulfate, saturated sodium bicarbonate solution and brine. The organic phase was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient of 100% hexane to (60% hexane/ethyl acetate to afford 2.92 g (34.4%) of the title compound is a white solid. FAB MS [M+H] m/z Calcd: 315, Found: 315. |
2.92 g (34.4%) | With N-ethyl-N,N-diisopropylamine; In hexane; dichloromethane; | a. (Pyrrole-2-carbonyl)-N-(benzyl)glycine-t-butyl ester To a suspension containing 3.00 g (27.0 mmol) of pyrrole-2-carboxylic acid in 75 mL of anhydrous dichloromethane under a nitrogen atmosphere at 0 C. was added 6.96 g (27.0 mmol of BOPCl and 14.1 mL (81.0 mmol) of DIEA. After stirring for 30 minutes, 5.97 g (27.0 mmol) of N-(benzyl)glycine-t-butyl ester was added and the reaction allowed to warm to room temperature overnight. The reaction was diluted with ethyl acetate and washed with a 5% potassium hydrogensulfate, saturated sodium bicarbonate solution and brine. The organic phase was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient of 100% hexane to 60% hexane/ethyl acetate to afford 2.92 g (34.4%) of the title compound is a white solid. FAB MS [M+H] m/z Calcd: 315, Found: 315. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; for 8.5h; | 1 Synthesis of Compound 1; CONEt2 Compound 1[103] Pyrrole-2-carboxylic acid (10.0 g, 90 mmol) was dissolved in 250 mL of dichloromethane. N,N'-Dicyclohexylcarbodiimide (DCC) (20.4 g, 99 mmol), 4-dimethyl- aminopyridine (DMAP) (2.2 g, 18 mmol) and diethylamine (10.2 mL, 99 mmol) were added subsequently at 0 0C under an Argon atmosphere. The reaction mixture was stirred at 0 0C for 30 minutes then stirred at room temperature for 8 hours. After the solution was diluted with dichloromethane and the solid was filtered off, the filtrate was washed by diluted hydrochloric acid, followed by saturated sodium bicarbonate solution. The organic layer was dried over Na2SO4 and then the solvent was evaporated under reduced pressure. The residue was purified by column chromatography using 35% EtOAc in n-hexane as diluent to obtain 10.5 g of Compound 1 as a white solid (70% yield). |
70% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; for 8.5h; Inert atmosphere; | |
70% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; for 8.5h; | 1.2 2) Synthesis of iV,iV-diethyl-lH"-pyrrole-2-carboxamide (ss-1) (shown in FIG. 4); [0063] Pyrrole-2-carboxylic acid (10.0 g, 90 mmol) was dissolved in 250 mL of dichloromethane. DCC (λζiV'-dicyclohexylcarbodiimide) (20.4 g, 99 mmol), DMAP (4-dimethyl-aminopyridine) (2.2 g, 18 mmol) and diethylamine (10.2 mL, 99 mmol) were added subsequently at 00C under an Argon atmosphere. The reaction mixture was stirred at 00C for 30 mins then stirred at root temperature for 8 hours. The solution was diluted with dichloromethane and the solid was filtered off. The filtrates were washed by diluted hydrochloric acid, followed by saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate and then the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel EPO (eluent: ethyl acetate/n-hexane=l/2) to obtain λζiV-diethyl-lH-pyrrole-2-carboxaniide as a white solid (10.5 g, 70% yield), mp 78.6 - 79.9 0C; 1H NMR (300 MHz, CDCl3): δ 10.1 (br, IH), 6.94 - 6.88 (m, IH), 6.57 - 6.51 (m, IH), 6.26 - 6.21 (m, IH), 3.95 -3.86 (m, 4H)3 1.31 - 1.24 (m, 6H); 13C NMR (75.5 Hz, CDCl3): δ 161.9, 120.7, 111.3, 110.1, 109.5, 41.9, 13.4; IR (CH2Cl2) 3442, 2981, 2937, 1716, 1600 cm'1; LRMS (EI) m/z (%) 166 (M+; 100); HRMS (EI): calcd for C9H14N2O: 166.1106, Found: 116.1106. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 2h; | 9 Example 9Synthesis of l'-methylpiperidine-4'-spiro-2-6-(lH-pyrrol-2-carboxamido)-2H- benzopyran l'-methylpiperidine-4'-spiro-2-6-amino-2H-benzopyran (30mg, 0.13mmol), prepared by using a method same as in the above Example 1 (a)-(f), was dissolved in dichloromethane (3mL), added with lH-pyrrol-2-carboxylic acid(16mg, 0.14mmol)/ EDC(37mg, 0.20mmol), DMAP(1.6mg, 0.013mmol), and the mixture was stirred at normal temperature for 2 hours. Upon completion of the reaction, the resultant was diluted with dichloromethane, washed with water, its organic layer was dried with anhydrous magnesium sulfate, filtered and distilled under reduced pressure, then the resultant was purified with silica gel column chromatography (methanol: dichloromethane, 1:10 v/v), and obtained V- methylpiperidine-4'-spiro-2-6-(lH-pyrrol-2-carboxamido)-2H-benzopyran (29mg, 70%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | Stage #1: 2,4,6-trifluorobenzoyl chloride With aluminum (III) chloride In dichloromethane at 20℃; for 0.25h; Inert atmosphere; Stage #2: pyrrole-2-carboxyl acid In dichloromethane at 20℃; for 1.16667h; | B To a 12OmL dichloromethane solution of 2,4,6-trifluorobenzoyl chloride (4.3g, 0.022mol) was added AICI3 (8.8g, 0.066mol) under N2 at room temperature. After stirring for 15min, IH- pyrrole-2-carboxylic acid (2.4g, 0.022mol) was added in small portions over a lOmin period.Stirring continued at room temperature for 1 hr, then the reaction mixture was treated with dropwise addition of ice-water (2OmL) andlN HCl to adjust pΗ to 1. After stirring for another30min, the reaction mixture was extracted with AcOEt (3x30 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give the title compound (5.8g, 97% yield). 1H-NMR (500MHz, CDCl3): δ 12.48 (br.s, 1H), 7.48 (s,1H), 7.28-7.38 (m, 2H), 6.83 (s, 1H). |
97% | Stage #1: 2,4,6-trifluorobenzoyl chloride With aluminum (III) chloride In dichloromethane at 20℃; for 0.25h; Inert atmosphere; Stage #2: pyrrole-2-carboxyl acid In dichloromethane at 20℃; for 1.16667h; Stage #3: With hydrogenchloride; water In dichloromethane | 1.B Step B: 4~(2,4J6-trifluorobenzoyl)-lH-pyrrole-2-carboxylic acid To a 12OmL DCM solution of 2,4,6-trifluorobenzoyl chloride (4.3g, 0.022mol) was added AlCl3 (8.8g, O.Omol) under N2 at room temperature. After stirring for 15min, IH- pyrrole-2-carboxylic acid (2.4g, 0.022rnol) was added in small portions over a lOmin period. After stirring at room temperature for 1 hr, the reaction mixture was treated with dropwise addition of ice- water (2OmL) and IN HCl to adjust pH to 1, stirred for another 30min, extracted with EtOAc (3x30 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO^ filtered and concentrated to give the title compound (5.8g, 97% yield). .H- NMR (500MHz5 CDCl3): δ 12.48 (br.s, 1H), 7.48 (s, 1H), 7.28-7.38 (m, 2H), 6.83 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.7% | With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; diisopropyl-carbodiimide In dichloromethane at 25℃; Inert atmosphere; | 3 3. Coupling step A [00187] To a stirred solution of acid RiCOOH (1 equivalent), HOBt (2.1 equivalents), and amine 1-1 (1 equivalent) in 9: 1 CH2C12:DIEA at 25 0C was added DIC (2 equivalents) and the mixture was stirred overnight. After quenching with water, the reaction was added to a separatory funnel and washed 3 times with CH2Cl2. The organic layers were combined, and washed with saturated aqueous brine solution. The organic layer was dried over MgSO4, and concentrated in vacuo to yield 1-2. The crude material was then subjected to flash chromatography to give pure 1-2 as a white solid (79-93 % yield). [00188] N-(3-bromo-4-methoxyphenethyl)-lH-pyrrole-2-carboxamide [00189] 1H NMR (400 MHz, DMSO-d6) δ 9.31 (br s, IH), 7.42 (d, J= 2.0, IH), 7.12 (dd, J- 2.0, 8.4 Hz, IH), 6.92 (m, IH), 6.84 (d, J= 8.4 Hz, IH), 6.44 (s, IH), 6.22 (m, IH), 5.85 (m, -->IH), 3.89 (s, 3H), 3.63 (q, J= 6.8 Hz, 2H), 2.82 (t, J= 7.2 Hz, 2H). 13C NMR (100 MHz, DMSO-d6) δ 161.4, 154.5, 133.4, 231.4, 128.7, 125.7, 121.8, 112.0, 111.6, 109.0, 77.3, 76.9, 76.7, 56.2, 40.5, 34.7. HRMS (Q-TOF): m/z calc for Ci4Hi5BrN2O2 [M + H]: 323.0395; found 323.0408. 84.7 % yield. |
With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; diisopropyl-carbodiimide In dichloromethane at 20℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With N-ethyl-N,N-diisopropylamine; HATU In tetrahydrofuran at 0 - 20℃; | 100.H To a solution of the product from Step G (1.0 g, 3.2 mmol) in tetrahydrofuran (15 mL) is added pyrrole 2-carboxylic acid (360 mg, 3.2 mmol), 2-{7-aza-l//-benzotriazole-l - ylj-. , 1,3,3-tetramethyluronium hexaflυorophosphate (1.84 g, 4.8 mmol), and NN- diisopropylethylamine (1.67 mL, 10.0 mmol) at 0 °C. The resulting mixture is stirred for 16 hours at room temperature. The mixture is diluted with water and extracted twice with ethyl acetate. The combined organic phase is dried over Νa2SO4, filtered, and the solvent is removed in vacuo. The crude material is purified via silica gel chromatography using 2% methanol/dichloromethane as eluent to give the desired product as a white solid (1.1 g, 70%). MS: 367.1 (M+Η+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | Stage #1: pyrrole-2-carboxyl acid With oxalyl dichloride; N,N-dimethyl-formamide In 1,2-dichloro-ethane at 20℃; for 3h; Stage #2: N,N-Dimethylhydrazine With 4-methyl-morpholine In 1,2-dichloro-ethane at 20℃; for 3h; Cooling with ice; | 102 To a solution of pyrrole-2-carboxylic acid (4.366 g, 39.3 mmol) in 1,2-dichloroethane (40 ml) were added oxalyl chloride (3.77 ml, 43.2 mmol) and N,N-dimethylformamide (0.01 ml), and the mixture was stirred at room temperature for 3 hr. The reaction solvent was evaporated under reduced pressure, and the residue was dissolved in 1,2-dichloroethane (40 ml). N,N-Dimethylhydrazine (3.30 ml, 43.2 mmol) and N-methylmorpholine (5.62 ml, 51.1 mmol) were added under ice-cooling, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was washed with water, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give an acylhydrazine compound pyrrole-2-carboxylic acid N',N'-dimethylhydrazide (4.75 g, 31.0 mmol, yield 79%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With 2-chloro-4,4,5,5-tetramethyl-1,3,2-dioxaphospholane; triethylamine In chlorobenzene at 20 - 130℃; for 14h; chemoselective reaction; | |
60% | With copper(l) iodide; methyl ethynyl ketone In acetonitrile at 80℃; for 4h; | 9 4.2. A typical procedure for synthesis of N-[(4-methylphenyl)sulfonyl]benzamide (11a) General procedure: To a solution of benzoic acid (9a, 61mg, 0.5mmol), TsN3 (5a, 148mg, 0.75mmol) and CuI (9.6mg, 0.05mmol) in MeCN (3mL) was added but-3-yn-2-one (8a, 51mg, 0.75mmol). After the mixture was stirred at 80°C for 4h (monitored by TLC), the solvent was removed. The residue was purified by a flash chromatography [silica gel, 1 % MeOH and 20 % EtOAc in petroleum ether (60-90°C)] to give 124 mg (90 %) of product 11a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: pyrrole-2-carboxyl acid With oxalyl dichloride In dichloromethane for 2.5h; Stage #2: <i>o</i>-toluidine In dichloromethane | 7.a a) W-o-Tolyl-1 W-pyrrole-2-carboxamide15.0 g (135 mmol) of 1 /-/-pyrrol 2-carboxylic acid (purchased from Aldrich, cat. no. P7, 360-9) were suspended in a mixture of DMF (1.2 mL) and dichloromethane (150 mL). To this solution, 18 mL (207 mmol) of oxalyl chloride in dichloromethane (105 mL) were added dropwise over 30 minutes. The reaction was stirred two hours and then concentrated under reduced pressure to dryness.The residual black oil was redissolved in dichloromethane (150 mL) and a solution of 15.9 g (148 mmol) of o-toluidine in dichloromethane (16 mL) was added dropwise. The reaction was stirred overnight then the solution was washed with a saturated aqueous solution of sodium bicarbonate. The organic phase was concentrated in vacuum. The product was purified by flash chromatography (30% AcOEt in hexane) to give 15.45 g (100% yield) of the title compound.LRMS (m/z): 201 (M+1 )+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | Stage #1: pyrrole-2-carboxyl acid With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 1h; Stage #2: 5-(5-amino-2-phenoxyphenyl)-1-methylpyridin-2(1H)-one With triethylamine In dichloromethane at 20℃; for 2h; | 251 Example 251 N-[3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-phenoxyphenyl]-1H-pyrrole-2-carboxamide Example 251 N-[3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-phenoxyphenyl]-1H-pyrrole-2-carboxamide [1069] A mixture of 1H-pyrrole-2-carboxylic acid (0.018 g, 0.164 mmol), oxalyl chloride (0.035 g, 0.274 mmol) and dimethylformamide (1 drop) in dichloromethane (3 mL) was stirred at ambient temperature for 1 hour. The solvent was evaporated under reduced pressure and the residue treated with toluene (2 mL) and then evaporated under reduced pressure. The residue was dissolved in dichloromethane (2 mL) and was then added to a solution of Example 225C (0.040 g, 0.137 mmol) and triethylamine (0.055 g, 0.547 mmol) in dichloromethane (3 mL). The reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (C18, CH3CN/water (0.1% TFA), 0-100%) to afford the title compound (0.035 g, 66%). 1H NMR (500 MHz, DMSO-d6) δ 10.64 (s, 1H), 9.85 (s, 1H), 7.90 (d, J=2.75 Hz, 1H), 7.82 (d, J=2.75 Hz, 1H), 7.76 (dd, J=8.85, 2.75 Hz, 1H), 7.60 (dd, J=9.31, 2.59 Hz, 1H), 7.29-7.33 (m, 2H), 6.97-7.01 (m, 3H), 6.97-6.98 (m, 1H), 6.89 (d, J=7.63 Hz, 2H), 6.38 (d, J=9.46 Hz, 1H), 6.17-6.19 (m, 1H), 3.44 (s, 3H). MS (ESI+) m/z 386.1 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | Stage #1: pyrrole-2-carboxyl acid With 4-methyl-morpholine; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate In dichloromethane at 20℃; for 0.5h; Stage #2: tert-butyl 2-amino-4-(3-aminophenyl)-1H-imidazole-1-carboxylate In dichloromethane at 35℃; for 24h; | 2.6. General procedure E. Synthesis of Compounds 7a, 7b, 9, 11, 12a, 12b, 14, 16a-c, 24, 25, 27, 29 and 31 (with 7a as an Example). To a suspension of pyrrole-2-carboxylic acid (122 mg, 1.09 mmol) and TBTU (380 mg, 1.18 mmol) in dichloromethane (5 mL) N-methylmorpholine (0.501 mL, 4.56 mmol) was added, and the mixture stirred at rt for 0.5 h upon which a clear solution formed. Compound 4a (250 mg, 0.91 mmol) was added and the mixture stirred at 35 °C overnight. The solvent was evaporated in vacuo, the residue dissolved in ethyl acetate (30 mL), and washed successively with water (2 × 10 mL), saturated aqueous NaHCO3 solution (2 × 10 mL), and brine (1 × 10 mL). The organic phase was dried over Na2SO4, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash column chromatography using ethyl acetate/petroleum ether or dichloromethane/methanol as an eluent, to afford 7a. |
Stage #1: pyrrole-2-carboxyl acid With 4-methyl-morpholine; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate In dichloromethane at 20℃; for 0.5h; Stage #2: tert-butyl 2-amino-4-(3-aminophenyl)-1H-imidazole-1-carboxylate In dichloromethane at 35℃; for 24h; | General procedure: To a suspension of 5-methoxy-indole-2-carboxylic acid (251 mg, 1.31 mmol) and TBTU (456 mg, 1.42 mmol) in dichloromethane (5 mL), N-methylmorpholine (0.601 mL, 5.47 mmol) was added and the mixture stirred at rt for 0.5 h upon which a clear solution formed. Compound 3 (300 mg, 1.09 mmol) was added and the mixture stirred at 35 °C for 24 h. The solvent was evaporated in vacuo, the residue dissolved in ethyl acetate (30 mL) and washed successively with water (2 × 10 mL), saturated aqueous NaHCO3 solution (2 × 10 mL) and brine (1 × 10 mL). The organic phase was dried over Na2SO4, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash column chromatography using ethyl acetate/petroleum ether or dichloromethane/ methanol as an eluent, to afford 5f (305 mg, 62% yield) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | Stage #1: pyrrole-2-carboxyl acid With 4-methyl-morpholine; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate In dichloromethane at 20℃; for 0.5h; Stage #2: tert-butyl 4-(3-aminophenyl)-2-(methylamino)-4,5-dihydro-1H-imidazole-1-carboxylate In dichloromethane at 35℃; for 24h; | 2.6. General procedure E. Synthesis of Compounds 7a, 7b, 9, 11, 12a, 12b, 14, 16a-c, 24, 25, 27, 29 and 31 (with 7a as an Example). General procedure: To a suspension of pyrrole-2-carboxylic acid (122 mg, 1.09 mmol) and TBTU (380 mg, 1.18 mmol) in dichloromethane (5 mL) N-methylmorpholine (0.501 mL, 4.56 mmol) was added, and the mixture stirred at rt for 0.5 h upon which a clear solution formed. Compound 4a (250 mg, 0.91 mmol) was added and the mixture stirred at 35 °C overnight. The solvent was evaporated in vacuo, the residue dissolved in ethyl acetate (30 mL), and washed successively with water (2 × 10 mL), saturated aqueous NaHCO3 solution (2 × 10 mL), and brine (1 × 10 mL). The organic phase was dried over Na2SO4, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash column chromatography using ethyl acetate/petroleum ether or dichloromethane/methanol as an eluent, to afford 7a. |
Stage #1: pyrrole-2-carboxyl acid With 4-methyl-morpholine; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate In dichloromethane at 20℃; for 0.5h; Stage #2: tert-butyl 4-(3-aminophenyl)-2-(methylamino)-4,5-dihydro-1H-imidazole-1-carboxylate In dichloromethane at 35℃; for 24h; | General procedure: To a suspension of 5-methoxy-indole-2-carboxylic acid (251 mg, 1.31 mmol) and TBTU (456 mg, 1.42 mmol) in dichloromethane (5 mL), N-methylmorpholine (0.601 mL, 5.47 mmol) was added and the mixture stirred at rt for 0.5 h upon which a clear solution formed. Compound 3 (300 mg, 1.09 mmol) was added and the mixture stirred at 35 °C for 24 h. The solvent was evaporated in vacuo, the residue dissolved in ethyl acetate (30 mL) and washed successively with water (2 × 10 mL), saturated aqueous NaHCO3 solution (2 × 10 mL) and brine (1 × 10 mL). The organic phase was dried over Na2SO4, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash column chromatography using ethyl acetate/petroleum ether or dichloromethane/ methanol as an eluent, to afford 5f (305 mg, 62% yield) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.2% | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 24h; | 1 General procedure B. EDC/HOBt-promoted coupling General procedure: A solution of 1,3-diaminopropan-2-ol (0.500 g, 5.55 mmol),carboxylic acid (10.56 mmol) and HOBt (1.80 g,13.34 mmol) in DMF(8 mL) was prepared and the pH adjusted to 8 with N-methylmorpholine.The solution was cooled to 0 C, then EDCHCl (2.60 g,13.34 mmol) and dichloromethane (2 mL) were added and thereaction mixture stirred overnight at room temperature. The solventwas evaporated in vacuo and the oily residue dissolved in ethylacetate (50 mL) and washed successively with saturated aqueousNaHCO3 solution (3 20 mL) and brine (20 mL). The organic phasewas dried over Na2SO4, filtered and the solvent evaporated underreduced pressure.4.1.5.1 N,N'-(2-Hydroxypropane-1,3-diyl)bis(1H-pyrrole-2-carboxamide) (7e) Prepared from 1,3-diaminopropan-2-ol (0.500 g, 5.55 mmol) and 1H-pyrrole-2-carboxylic acid (1.173 g, 10.56 mmol) according to the general procedure B. Yield: 1.234 g (81.2%); yellowish amorphous powder; IR (KBr) ν 3300, 1619, 1570, 1527, 1407, 1327, 1208, 1130, 1103, 1085, 1040, 996, 837, 772, 743, 604 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 3.26 (t, 4H, J = 5.9 Hz, 2* CH2), 3.69-3.75 (m, 1H, CH), 5.15 (br s, 1H, OH), 6.09 (dd, 2H, J1 = 2.5 Hz, J2 = 3.6 Hz, Ar-H), 6.80 (dd, 2H, J1 = 1.4 Hz, J2 = 3.6 Hz, Ar-H), 6.86 (dd, 2H, J1 = 1.4 Hz, J2 = 2.5 Hz, Ar-H), 8.05 (t, 2H, J = 5.9 Hz, CONH), 11.47 (s, 2H, NH) ppm; MS (ESI+): m/z (%) = 277 ([M + H]+, 100). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | With 4-methyl-morpholine; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate In N,N-dimethyl-formamide at 0 - 20℃; for 6h; Inert atmosphere; | (E)-N-(3-(2-amino-1H-imidazol-4-yl)allyl)-1H-pyrrole-2-carboxamide (2a) General procedure: The corresponding carboxylic acid (0.36 mmol), TBTU (137 mg, 0.414 mmol) and N-methylmorpholine (0.08 mL, 0.72 mmol) were dissolved in dry dimethylformamide (2 mL) and stirred under argon at rt for 1 h. The prepared mixture was added dropwise to a stirred solution of compound 1 (50 mg, 0.36 mmol) and N-methylmorpholine (0.08 mL, 0.72 mmol) in dry dimethylformamide (1 mL) at 0 °C. After 1 h, the mixture was warmed to rt and stirred under argon for 5 h. The solvent was evaporated under reduced pressure, and the residue was purified by flash column chromatography using dichloromethane/methanol saturated with NH3 (6:1) as an eluent. |
With 4-methyl-morpholine; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate In N,N-dimethyl-formamide at 20℃; for 6h; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | Stage #1: pyrrole-2-carboxyl acid With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine In dichloromethane at 20℃; for 0.5h; Stage #2: 4-(3-aminophenyl)-1-benzyl-1H-imidazol-2-amine In dichloromethane at 20℃; for 18h; | 3.4.7. N-(3-(2-Amino-1-benzyl-1H-imidazol-4-yl)phenyl)-1H-pyrrole-2-carboxamide (15) To a suspension of pyrrole-2-carboxylic acid (77 mg, 0.69 mmol) in dichloromethane (30 mL) were added triethylamine (0.192 mL, 1.38 mmol) and TBTU (244 mg, 0.76 mmol) and the mixture stirred at rt for 0.5 h upon which an opalescent solution formed. Compound 14 (190 mg, 0.69 mmol) was added and the mixture stirred at rt for 18 h. The reaction mixture was diluted with dichloromethane (20 mL) and washed with saturated aqueous NaHCO3 solution (2 × 30 mL) and brine (1 × 40 mL). The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography using dichloromethane/methanol as an eluent, to afford 15 (see Supplementary Information, Figure S21) (105 mg, 41% yield) as an off-white solid; mp 229-232 °C; IR (KBr) ν = 3370 (N-H), 3066 (C-H), 1646 (C=O), 1606, 1570, 1545, 1496, 1454, 1437, 1364, 1308, 1202, 1169, 1130, 1068, 993, 896, 884, 823, 790, 725 cm-1. 1H NMR (DMSO-d6) δ 5.02 (s, 2H, CH2), 5.69 (s, 2H, NH2), 6.15-6.18 (m, 1H, Ar-H), 6.95-6.98 (m, 1H, Ar-H), 7.03 (s, 1H, Ar-H), 7.08-7.12 (m, 1H, Ar-H), 7.21 (t, 1H, 3J = 7.8 Hz, Ar-H), 7.26-7.32 (m, 4H, 4 × Ar-H), 7.35-7.40 (m, 2H, 2 × Ar-H), 7.54-7.58 (m, 1H, Ar-H), 7.94-7.97 (m, 1H, Ar-H), 9.70 (s, 1H, NH) 11.60 (br s, 1H, NH); 13C NMR (DMSO-d6) δ 47.20, 108.84, 110.73, 111.29, 115.37, 117.14, 118.45, 122.30, 126.18, 127.35, 127.44, 128.34, 128.52, 135.40, 135.49, 137.76, 139.34, 149.52, 158.99; MS (ESI) m/z (%) = 358.2 (MH+, 100). HRMS for C21H20N5O: calculated, 358.1668; found, 358.1661. HPLC: Phenomenex Luna 5 μm C18 column (4.6 mm × 150 mm); mobile phase: 10%-90% of MeOH in TFA (0.1%) in 20 min; flow rate: 1.0 mL/min; injection volume: 10 μL; retention time: 16.868 min (97.4% at 254 nm, 96.9% at 280 nm). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | Stage #1: pyrrole-2-carboxyl acid With 2,4,6-trimethyl-pyridine; bis(trichloromethyl) carbonate In tetrahydrofuran at 20℃; for 0.166667h; Inert atmosphere; Stage #2: (S)-allyl 2-(allyloxy)-4-(2-(allyloxy)-4-(4-(2-(4-aminobenzamido)-3-cyanopropanamido)benzamido)-3-methoxybenzamido)-3-methoxybenzoate With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 12h; | Compound 14 BTC (1 .15 eq, 0.100 mmol, 30 mg) was dissolved in dry THF (5 ml) under an atmosphere of argon.1 H-pyrrole-2-carboxylic acid (3.5 eq, 0.305 mmol, 29 mg) was added. syn-Collidine (8 eq, 0.700 mmol, 0.092 ml) was slowly added via syringe and the white suspension was stirred at room temperature for 10 min. The amine (1 eq, 0.087 mmol, 70 mg) and DIPEA (10 eq, 0.872 mmol, 0.150 ml) were added via syringe. The reaction mixture was stirred for 12 h at room temperature and quenched by the addition of water. After removing the organic solvent under reduced pressure the aqueous phase was extracted with EtOAc (3 x 50 ml). The organic phase was washed with saturated NaHC03 solution (2 x 50 ml), aqueous HCI solution (5 %, 2 x 50 ml), water (1 x 50 ml) and brine (1 x 50 ml). After drying over Na2S04 and filtration, the solvent was removed under reduced pressure. Column chromatography (CHCI3:MeOH; 1 .8 % MeOH) yielded the product as an orange solid (54 mg, 69 %). The solid (1 eq, 0.058 mmol, 56 mg) and phenylsilane (8 eq, 0.466 mmol, 0.057 ml) were dissolved in dry THF under an atmosphere of argon and exclusion of light. Pd[P(Ph)3]4 (0.5 eq, 0.029 mmol, 34 mg) was added and the mixture was stirred 12 h at room temperature. After adding 3 drops of acetic acid the solvent was removed under reduced pressure. The product was isolated after preparative HPLC purification as a white powder (17 mg, 38 %). H-NMR (DMSO-ds, 400 MHz): δ [ppm] 3.07 (m, 1 H), 3.16 (m, 1 H), 3.77 (s, 3H), 3.91 (s, 3H), 4.99 (m, 1 H), 6.18 (m, 1 H), 7.00 (m, 1 H), 7.12 (m, 1 H), 7.58 (t, J = 9.1 Hz, 2H), 7.80 (m, 3H), 7.88 (m, 4H), 7.99 (d, J = 8.9 Hz, 2H), 8.06 (d, J = 8.9 Hz, 1 H), 9.02 (d, J = 7.5 Hz, 1 H), 9.71 (s, 1 H), 9.99 (s, 1 H), 10.58 (s, 1 H), 1 1 .18 (s, 1 H), 1 1 .54 (s, 1 H). HR-MS: [M-H]- calculated: 774.2154 [M-H]- found: 774.2153 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | To 1H-pyrrole-2-carboxylic acid (CAS 634-97-9, 0.8 g, 7.20 mmol) dissolved in THF (30 mL) was added n-butyl lithium (1.6 M in hexane, 9.90 mL, 15.84 mmol) dropwise under 5-10 mm at -20C. The mixture was stirred for 1 h, before <strong>[141337-26-0]4-chloro-2-fluorobenzenesulfonyl chloride</strong> (CAS 141337-26-0, 2.062 g, 9.00 mmol) dissolved in THE (3 mL) was added under 5-10 mm at-20C. The mixture was stirred at rt overnight and then diluted with ethyl acetate, washedtwice with 2 M aq. HCI and brine, dried over MgSO4 and solvent evaporated to give thecrude, which was re-crystallized from 40 mL isopropanol/water 1:1 to give 1-(4-chloro-2- fluorophenylsulfonyl)-1H-pyrrole-2-carboxylic acid (1.6 g, 59 %).1H NMR (400 MHz, DMSO-d6) 5 ppm 6.46 (t, 1 H) 7.10 (dd, 1 H) 7.61 (m, 1 H) 7.73 - 7.83 (m, 2 H) 8.02 (t, 1 H) 12.89 (br. s., 1 H).MS (ESI) m/z 301.7 [M-1] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 0 - 20℃; for 6.5h; | 3.7 General procedure for synthesis of opened derivatives 2a-i General procedure: To a solution of diamine derivative 3a (100mg) in DCM (10mL) at 0°C, were added HOBt (1.1equiv.), EDCI (1.1equiv.) and Et3N (1.1equiv.) and the resulting mixture was stirred at 0°C for 30min. The solution was then stirred at rt for 6h (monitoring by TLC). The solution was washed with saturated NaHCO3 aqueous solution (3×30mL). The organic layers were combined, dried over Na2SO4, filtered and the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane and filtered through alumina gel using sintered glass Buchner funnel. The solvent was removed in vacuo to afford pure opened derivatives 2a-i. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0 - 20℃; for 20h; Inert atmosphere; | General procedure for synthesis of compounds 9c-g General procedure: N-Cbz piperazine (0.55 g, 2.48 mmol, 1 eq) and carboxylic acid 8c-g (2.48 mmol, 1 eq) were dissolved in dry DMF (10 mL), the reaction mixture flushed with argon and cooled to 0 °C. N-methyl morpholine (NMM; 7.44 mmol,3 eq), hydroxybenzotriazole hydrate (HOBt; 2.98 mmol,1.2 eq) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride HCl salt (EDC; 3.22 mmol, 1.3 eq) were slowly added. The reaction mixture was stirred under argon atmosphere for 5 h at 0 °C and an additional 15 h at room temperature. DMF was evaporated under reduced pressure and the residue redissolved in dichloromethane (10 mL).The dichloromethane phase was washed with H2O (1 x 10 mL), a 1 M HCl solution (3 x 10 mL), saturated aqueous NaHCO3 solution (3 9 10 mL), brine (1 x 20 mL), dried over Na2SO4, filtered, and the solvent evaporated under reduced pressure. The crude product was purified by flash column chromatography using ethyl acetate/hexane solvents as eluents to afford compounds 9c-g. |
Yield | Reaction Conditions | Operation in experiment |
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89% | With triethylamine In acetonitrile at 100℃; for 3h; Sealed tube; Microwave irradiation; | 5,5-Dimethyl-4-oxo-2-(1H-pyrrol-2-yl)-4,5-dihydro-3-furancarbonitrile (3a); Typical Procedure a) To a stirred solution of 1H-pyrrole-2-carboxylic acid (1a; 111 mg, 1 mmol) and 4-hydroxy-4-methylpent-2-ynenitrile (2a; 131 mg, 1.2 mmol) in MeCN (5 mL) was added Et3N (101 mg, 1 mmol) dropwise over 1 min. The reaction mixture was irradiated with MW at 100 °C/1.2 atm for 3 h. The mixture was concentrated and the residue was washed with a mixture of pentane-acetone (3:1) to give the desired product 3a; yield: 179 mg (89%); light yellow crystals; mp 160-163 °C. b) Following the typical procedure for 3a, catalyst-free version (without Et3N), the product 3a was not obtained. c) Following the typical procedure for 3a, using 0.5 equiv of Et3N, product 3a was obtained (94 mg, 47%). d) Following the typical procedure for 3a, using 1 equiv of Bu3N, product 3a was obtained (129 mg, 64%). e) Following the typical procedure for 3a, using 1 equiv of DABCO, product 3a was obtained (161 mg, 80%). IR (KBr): 3431 (NH), 3152 (HC=C), 2218 (C≡N), 1702 (C=O), 1581, 1525 cm-1 (C=C). 1H NMR (400.1 MHz, CDCl3): δ = 1.52 (s, 6 H, CH3), 6.50 (m, 1 H, H-4′), 7.29 (m, 1 H, H-5′), 7.53 (m, 1 H, H-3′), 9.88 (br s, 1 H, NH). 13C NMR (100.6 MHz, CDCl3): δ = 23.1 (CH3), 81.3 (C-3), 90.9 (C-5), 113.2 (CN), 113.4 (C-4′), 120.2 (C-2′), 120.7 (C-3′), 128.0 (C-5′), 176.7 (C-2), 198.5 (C=O). Anal. Calcd for C11H10N2O2 (202.21): C, 65.34; H, 4.98; N, 13.85. Found: C, 65.62; H, 5.05; N, 13.47. |
Yield | Reaction Conditions | Operation in experiment |
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65% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; Inert atmosphere; | 1 General method for the preparation of (thieno[2,3-d]pyrimidin-4-yl)-hydrazides 25-36 General procedure: The aryl carboxylic acid (1.1 eq.) and TBTU (1.2) were suspended in anhydrous THF (11 mL/mmol eq.) at r.t. under N2 atmosphere. DiPEA (2.4 eq.) was then added dropwise to the reaction mixture,followed by the different (thieno[2,3-d]pyrimidin-4-yl)-hydrazine (8a-d or f-i) (1 eq.) dissolved in anhydrous THF (11 mL/mmol eq.). The mixture was stirred at r.t. for 4 h, then concentrated under vacuum. The residue was dissolved in EtOAc (30 mL/mmol eq.), washed with water (30 mL/mmol eq.), saturated NaHCO3 solution (30 mL/mmol eq.), and finally with brine (30 mL/mmol eq.). The organic phase was concentrated under vacuum after drying over MgSO4. The crude residue was purified by recrystallisation or flash column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
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76.5% | With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine In dichloromethane at 0 - 30℃; for 6h; | 4.1.6 General procedure for the synthesis of amide derivatives (15-20) General procedure: To a solution of 7-chloro-4-(piperazin-1-yl)quinoline (1mmol) in dry dichloromethane (3mL) was added triethyl amine (1.5mmol) and corresponding acid (1mmol) at 0°C. propylphosphonic anhydride (2mmol) was then added drop wise to the reaction mixture and the reaction mixture was stirred at 30° for 6h (monitored by TLC & LCMS for completion). The reaction mixture was washed with water (2mL), brine (2mL), dried over anhydrous sodium sulphate and evaporated in vacuo to give the desired product as mentioned below. |
Yield | Reaction Conditions | Operation in experiment |
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14% | The luteolin1(500mg, 1.74mmol) placed in 50ml round bottom flask, and dissolved in 20 ml of THF, added DMAP (488mg, 4mmol), stirred for 30min at 40 dropwise DCC (537mg, 2.61mmol), then stirred for 30min after adding pyrrole - 2- carboxylic acid (430mg, 4.5mmol) the reaction was continued at 40 24h.Join NH4After termination of the reaction Cl saturated solution 10ml, share THF layer, continue with CH2Cl2(10ml × 2) the aqueous layer was extracted, and the combined THF layers CH2Cl2The extract was dried over anhydrous Na2SO4Dried under reduced pressure to recover the solvent residue.The residue (10g) column chromatography through silica gel, chloroform - methanol (220: 1) to give compound7(Yellow amorphous powder, 70mg, 14% yield). |
Yield | Reaction Conditions | Operation in experiment |
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76% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 48h; | 3.1.3. General Procedure for the Synthesis of Compounds 4a-l General procedure: A mixture of the carboxylic acids derivative (2.4 mmol), 1.05 g of compound 3 (2.0 mmol),0.46 g of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (2.4 mmol), and 0.34 g of 1-hydroxybenzotriazole (2.4 mmol) were dissolved in 50 mL of dichloromethane and stirred for36-48 h at room temperature. The mixture was washed with saturated aqueous NaHCO3 and brine,and then dried with Na2SO4 overnight. The crude residue obtained was purified by silica gel columnchromatography (petroleum ether: ethyl acetate 1:1-1:4 v/v) to afford the desired compounds. |
Yield | Reaction Conditions | Operation in experiment |
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50% | With dicyclohexyl-carbodiimide In dichloromethane for 1h; Inert atmosphere; | |
50% | With dicyclohexyl-carbodiimide In tetrahydrofuran at 0℃; for 1h; Inert atmosphere; | tert-Bntyl i/aT-pyrrole-2-carboxylate (9). A solution of 7H-pyrrole-2-carboxylic acid (5.00 g, 45.0 mmol) in THF (120 mL) was treated with tert-BuOH (60 mL) followed by DCC (13.9 g, 67.6 mmol) at 0 °C under an argon atmosphere. After 1 h, the reaction mixture was filtered. The filtrate was concentrated and chromatographed [silica, hexanes/ethyl acetate (10: 1)] to afford a white solid (3.76 g, 50%): mp 91-93 °C; 1H NMR 51.47 (s, 9H), 6.22-6.25 (m, 1H), 6.82-6.85 (m, 1H), 6.90-6.92 (m, 1H), 9.23 (bs, 1H); I3C NMR 528.6, 81.0, 110.4, 112.4, 114.8, 160.9; ESI-MS obsd 168.1017, calcd 168.1019 [(M + H)+, M = C9H13N02]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 60% 2: 10% | With lithium tert-butoxide In N,N-dimethyl-formamide at 100℃; for 24h; | 7 [Example 7] Examples 7 to 9 1H-pyrrole was used as 1H-pyrrole, 5 times equivalent of lithium t-butoxide (LiO Bu) to 1H-pyrrole was used in Example 7, 1H- 3-fold equivalent of lithium t-butoxide (LiO Bu) was added to pyrrole and 1 time equivalent of lithium t-butoxide (LiO Bu) was charged in Example 9, In Example 9, the carboxylation product of the target product was obtained in the same manner as in Example 1 except that the reaction temperature was 60 ° C and methylation with methyl iodide was not performed. Submit CorrectionsCloseThe recovery rate of 1 H-pyrrole used as 1 H-pyrrole (including by-products) and the obtained carboxylation product pyrrole-1-carboxylate (monocarboxylated product; N-substituted product) and And the yield based on 1 H-pyrrole of 1 H-pyrrole-2-carboxylate (monocarboxylated product; 2-substituted product) were determined by NMR analysis. The results obtained are shown in Table 2 and the reaction formulas in Examples 7 to 9 are shown below |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.8% | Stage #1: pyrrole-2-carboxyl acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 1h; Stage #2: 2-(4-ethylpiperazin-1-yl)-4-methyl-6-aminoquinoline With triethylamine In dichloromethane at 20℃; for 24h; | 26 4.1.2.1 General procedures for the synthesis of compounds 18-46 General procedure: Aromatic carboxylic acid (1.11mmol), EDCI (213mg, 1.11mmol), HOBt (150mg, 1.11mmol) were added into 10ml DCM. The mixture was stirred at rt for 1h. Then Et3N (0.31ml, 2.22mmol) and intermediate 17 (200mg, 0.74mmol) were added. After stirring at rt for 24h, the reaction was washed with 2mol/L NaOH solution (20ml×3) and saturated NH4Cl solution (20ml×1), dried over anhydrous Na2SO4 and then concentrated. The residue was purified by normal phase column chromatography to afford the desired compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70.1% | With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at -8 - 40℃; for 19.5833h; | A solution of 1H-pyrrole-2-carboxylic acid (50.0 g, 450 mmol) in 500 mL oftetrahydrofuran was cooled to -5 to -8 C, followed by the addition of 2,2-dimethoxy-N- methylethanamine (64.4 g, 540 mmol) and diisopropylethylamine (171 mL, 128 mmol). The reaction mixture was stirred at this temperature, while propylphosphonic anhydride (315 g,495 mmol) was added dropwise over 20 minutes. After the addition, the reaction mixture was warmed to 23 C over 15 minutes. The reaction mixture was stirred for 1 hour at ambient temperature, and then heated to 40 C. After 18 hours at 40 C, the reaction mixture was cooled in an ice bath and diluted with 1000 mL of water and 500 mL of ethyl acetate. The organic layer was separated. The aqueous layer was back extracted three times with 250mL of ethyl acetate. The combined ethyl acetate layers were washed with 250 mL of water and 250 mL of brine. The resulting organic layer was reduced under house high vacuum with a jacket temperature of 30-40 C. After the volume was reduced by 50% to 850 mL, an additional 850 mL of heptane was added and the distillation continued under house high vacuum with ajacket temperature of 3 0-40 . Heptane (550 mL) was distilled off and the reaction mixture was cooled to 15 C. The product began to precipitate and then 500 mL of heptane was added to generate a slurry, which was heated to 3 0-40 C to remove all the solids that adhered to the vessel wall. The slurry was cooled to 25 C. An additional 500 mL ofheptane was added to thin out the slurry. The slurry was cooled in an ice bath and filtered at 0C. The solid was quickly washed with heptane, and then dried in the vacuum oven at 40 C overnight to give the title compound (63.6 g, 70.1% yield) as a fluffy, white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With sodium methylate In methanol for 24h; Inert atmosphere; Reflux; | 1.1-1 Synthesis of 1-1, 4-(cyclopent-1-en-1-yl)-1H-pyrrole-2-carboxylic acid A reflux condenser and a mechanical stirrer were placed in a 250 mL round bottom flask, and the entire system was purged with nitrogen. 1H-Pyrrol-2-carboxylic acid (1.21 g, 10.86 mmol) was added to a flask, followed by the addition of ΜeOH (15.5 mL). After stirring at room temperature for 10 minutes, cyclopentanone (2.88 mL, 32.58 mmol) was added. Methanol/sodium methoxide (25% w/w, 15.15 mL, 66.25 mmol) was added portionwise over 10 min. The mixture was then refluxed for 24 hours. After cooling to room temperature, water (23.31 mL) was added and methanol was removed under reduced pressure. The residual aqueous phase was acidified to pH = 1 with concentrated HCl (ca. 7 mL). The resulting pale yellow precipitate was collected by filtration, washed with water and dried under vacuum at 50 °C. Get the desired beige solid 4-(cyclopent-1-en-1-yl)-1Η-pyrrole-2-carboxylic acid (Compound 2), 1.91 g, yield 99% |
99% | In methanol at 20℃; for 24h; Inert atmosphere; Reflux; | 1.1-1 Synthesis of 1-1, 4-(cyclopent-1-en-1-yl)-1H-pyrrole-2-carboxylic acid A reflux condenser and a mechanical stirrer were placed in a 250 mL round bottom flask, and the entire system was purged with nitrogen. 1H-Pyrrol-2-carboxylic acid (1.21 g, 10.86 mmol) was added to a flask, followed by MeOH (15.5 mL). After stirring at room temperature for 10 minutes, cyclopentanone (2.88 mL, 32.58 mmol) was added. Methanol/sodium methoxide (25% w/w, 15.15 mL, 66.25 mmol) was added portionwise over 10 min. The mixture was then refluxed for 24 hours. After cooling to room temperature, water (23.31 mL) was added and methanol was evaporated. The residual aqueous phase was acidified to pH = 1 with cone. HCl (~7 mL). Light yellow precipitate collected by filtrationThe material was washed with water and dried under vacuum at 50 °C. Get the desired beige solid4-(cyclopent-1-en-1-yl)-1H-pyrrole-2-carboxylic acid (Compound 2), 1.91 g, yield 99%. |
99% | With sodium methylate In methanol at 20℃; for 24h; Inert atmosphere; Reflux; | 1.1-1 1-1Synthesis of 4-(cyclopent-1-en-1-yl)-1H-pyrrole-2-carboxylic acid A reflux condenser and a mechanical stirrer were placed in a 250 mL round bottom flask, and the entire system was purged with nitrogen. 1H-Pyrrol-2-carboxylic acid (1.21 g, 10.86 mmol) was added to a flask, followed by MeOH (15.5 mL). After stirring at room temperature for 10 minutes, cyclopentanone (2.88 mL, 32.58 mmol) was added.Methanol/sodium methoxide (25% w/w, 15.15 mL, 66.25 mmol) was added portionwise over 10 min. The mixture was then refluxed for 24 hours. After cooling to room temperature, water (23.31 mL) was added and methanol was evaporated.The residual aqueous phase was acidified to pH = 1 with cone. HCl (~7 mL). The resulting pale yellow precipitate was collected by filtration, washed with water and dried in vacuo.Get the desired beige solid4-(cyclopent-1-en-1-yl)-1H-pyrrole-2-carboxylic acid (Compound 2), 1.91 g, yield 99%. |
99% | With sodium hydroxide In methanol for 24h; Inert atmosphere; Reflux; | 1.1-1 1-1, Synthesis of 4-(cyclopent-1-en-1-yl)-1H-pyrrole-2-carboxylic acid A reflux condenser and a mechanical stirrer were placed in a 250 mL round bottom flask, and the entire system was purged with nitrogen. 1H-Pyrrol-2-carboxylic acid (1.21 g, 10.86 mmol) was added to a flask, followed by MeOH (15.5 mL). After stirring at room temperature for 10 minutes, cyclopentanone (2.88 mL, 32.58 mmol) was added. Methanol/sodium methoxide (25% w/w, 15.15 mL, 66.25 mmol) was added portionwise over 10 min. The mixture was then refluxed for 24 hours. After cooling to room temperature, water (23.31 mL) was added and methanol was evaporated. The residual aqueous phase was acidified to pH = 1 with conc.HCl (~7 mL). The resulting pale yellow precipitate was collected by filtration, washed with water and dried in vacuo at 50 . To give the desired off-white solid 4- (cyclopent-1-en-1-yl) lH-pyrrole-2-carboxylic acid (Compound 2), 1.91g, 99% yield. |
99% | Stage #1: pyrrole-2-carboxyl acid In methanol at 20℃; for 0.166667h; Stage #2: cyclopentanone With sodium methylate In methanol for 24h; Reflux; | 1.1-1 Synthesis of 1-1, 4-(cyclopent-1-en-1-yl)-1H-pyrrole-2-carboxylic acid A 250 mL round bottom flask was equipped with a reflux condenser and a mechanical stirrer.And the entire system is purged with nitrogen.1H-pyrrole-2-carboxylic acid (1.21 g, 10.86 mmol) was added to the flask.Then MeOH (15.5 mL) was added.After stirring at room temperature for 10 minutes,Cyclopentanone (2.88 mL, 32.58 mmol) was added.Methanol/sodium methoxide (25% w/w, 15.15 mL, 6.25 mmol) was added portionwise over 10 min.The mixture was then refluxed for 24 hours.After cooling to room temperature,Water (23.31 mL) was added and the methanol was removed under reduced pressure.The residual aqueous phase was acidified to pH = 1 with cone. HCl (~7 mL).The resulting pale yellow precipitate was collected by filtration.It was washed with water and dried under vacuum at 50 °C. ,Get the desired beige solid 4-(cyclopent-1-en-1-yl)-1H-pyrrole-2-carboxylic acid (Compound 2), 1.91 g, yield 99%. |
99% | Stage #1: pyrrole-2-carboxyl acid In methanol at 20℃; for 0.166667h; Stage #2: cyclopentanone With sodium methylate In methanol for 24h; Reflux; | 1.1-1 Synthesis of 1-1, 4-(cyclopent-1-en-1-yl)-1H-pyrrole-2-carboxylic acid A 250 mL round bottom flask was equipped with a reflux condenser and a mechanical stirrer.And the entire system is purged with nitrogen.1H-pyrrole-2-carboxylic acid (1.21 g, 10.86 mmol) was added to the flask.Then MeOH (15.5 mL) was added.After stirring at room temperature for 10 minutes, cyclopentanone (2.88 mL, 32.58 mmol) was added.Methanol/sodium methoxide (25% w/w, 15.15 mL, 66.25 mmol) was added portionwise over 10 min. The mixture was then refluxed for 24 hours.After cooling to room temperature, water (23.31 mL) was added andThe methanol was removed under reduced pressure. The residual aqueous phase was acidified to pH = 1 with cone. HCl (~7 mL).The resulting pale yellow precipitate was collected by filtration.It was washed with water and dried under vacuum at 50 °C.The desired beige solid 4-(cyclopent-1-en-1-yl)-1H-pyrrole-2-Carboxylic acid (Compound 2), 1.91 g, yield 99%. |
Yield | Reaction Conditions | Operation in experiment |
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87% | Stage #1: pyrrole-2-carboxyl acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 1h; Inert atmosphere; Stage #2: (S)-2-{2-(methoxymethoxy)-1-[4-(phenylethynyl)phenyl]ethoxy}ethan-1-amine In dichloromethane at 0 - 20℃; for 16h; Inert atmosphere; | 17 4.2.17 (S)-N-(2-{2-(Methoxymethoxy)-1-[4-(phenylethynyl)phenyl]ethoxy}ethyl)-1H-pyrrole-2-carboxamide (26) Under N2 atmosphere, triethylamine (0.13mL, 93mg, 0.92mmol) and EDCIHCl (88mg, 0.46mmol) were added to a suspension of pyrrole-2-carboxylic acid (26mg, 0.23mmol) and HOBt (47mg, 0.35mmol) in dry dichloromethane (2mL). After stirring the reaction mixture for 1hat ambient temperature, a solution of 24 (150mg, 0.46mmol) in dry dichloromethane (1mL) was added at 0°C (ice bath). Afterwards, the ice bath was removed and the mixture was stirred at ambient temperature overnight. Then a saturated aqueous solution of ammonium chloride and water were added and the mixture was extracted with dichloromethane (3×). The combined organic layers were dried over sodium sulfate, filtered, and the solvent was removed in vacuo. The residue was purified by flash column chromatography (=2cm, h=17cm, cyclohexane/ethyl acetate=1:2, V=10mL) to give 26 as colorless oil (85mg, 0.20mmol, 87% yield). Rf= 0.28 (cyclohexane/ethyl acetate=1:2); specific rotation: [α]20D [α]D20 =+35.3 (2.6; CH2Cl2); 1H NMR (CDCl3): δ [ppm]=3.33 (s, 3H, OCH2OCH3), 3.50-3.61 (m, 2H, HNCH2CH2O (1H), HNCH2CH2O (1H)), 3.62-3.72 (m, 3H, HNCH2CH2O (1H), HNCH2CH2O (1H), OCHCH2O (1H)), 3.75 (dd, J=10.9/8.0Hz, 1H, OCHCH2O), 4.55 (dd, J=8.0/3.6Hz, 1H, OCHCH2O), 4.68 (d, J=6.9Hz 1H, OCH2OCH3), 4.70 (d, J=6.9Hz 1H, OCH2OCH3), 6.23-6.27 (m, 1H, 4′-Hpyrrole), 6.53-6.66 (m, 2H, 3′-Hpyrrole, CONH), 6.91-6.94 (m, 1H, 5′-Hpyrrole), 7.29-7.39 (m, 5H, 2′-H4-(phenylethynyl)phenyl, 6′-H4-(phenylethynyl)phenyl, 3″-Hphenyl, 5″-Hphenyl, 4″-Hphenyl), 7.48-7.56 (m, 4H, 3′-H4-(phenylethynyl)phenyl, 5′-H4-(phenylethynyl)phenyl, 2″-Hphenyl, 6″-Hphenyl), 9.53 (s br, 1H, 1′-Hpyrrole); 13C NMR (CDCl3): δ [ppm]=39.3 (1C, HNCH2CH2O), 55.5 (1C, OCH2OCH3), 68.4 (1C, HNCH2CH2O), 72.0 (1C, OCHCH2O), 81.8 (1C, OCHCH2O), 89.1 (1C, C≡C), 89.9 (1C, C≡C), 96.9 (1C, OCH2OCH3), 109.1 (1C, 3′-Cpyrrole), 110.0 (1C, 4′-Cpyrrole), 121.5 (1C, 5′-Cpyrrole), 123.3 (1C, Carom.), 123.4 (1C, Carom.), 126.1 (1C, 2′-Cpyrrole), 126.9 (2C, C-2′4-(phenylethynyl)phenyl, C-6′4-(phenylethynyl)phenyl), 128.49 (1C, C-4″phenyl), 128.50 (2C, C-3″phenyl, C-5″phenyl), 131.8 (2C, C-2″phenyl, C-6″phenyl), 132.0 (2C, C-3′4-(phenylethynyl)phenyl, C-5′4-(phenylethynyl)phenyl), 139.0 (1C, C-1′4-(phenylethynyl)phenyl), 161.2 (1C, CONH); IR (neat): [cm-1]=3248, 2928, 1632, 1732, 1558, 1512, 1408, 1312, 1107, 1034, 833, 752, 691; LCMS (m/z): [M+H]+ calcd for C25H27N2O4: 419.1965, found: 419.2006; HPLC (method 1): tR=22.4min, purity 99.3%. |
Yield | Reaction Conditions | Operation in experiment |
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75% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; | 1.1 1. Preparation of (3-Methyloxetan-3-yl)methyl 1H-pyrrole-2-carboxylate (1-1 1H-Pyrrol-5-carboxylic acid (111.1 mg, 1.0 mmol), DCC (309·5 mg, 1.5 mmol) and DMAP (183.3 mg, 1.5 mmol) were dissolved in dichloromethane (2 mL) Stir at room temperature for 5 minutes.(3-methyloxetan-3-yl) methanol (153.2 mg, 1.5 mmol) was slowly added to the reaction system by a syringe, and stirred at room temperature overnight.The reaction was completed by TLC, and the solvent was removed by concentration under reduced pressure.After adding methyl tert-butyl ether (5 mL), the mixture was stirred and filtered, and the filtered cake was washed with ethyl t-butyl ether.The crude product was purified by preparative TLC (ethyl acetate / petroleum ether (v/v) = 1/1)The fractions of Rf = 0.4 to 0.6 were collected to give Compound 1-1 (146 mg, yield: 75%). |
Yield | Reaction Conditions | Operation in experiment |
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77% | Stage #1: pyrrole-2-carboxyl acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0℃; for 0.166667h; Stage #2: 2-amino-1-(3,5-dibromo-4-methoxyphenyl)ethanol In dichloromethane at 0 - 20℃; for 12h; | 20. General procedure for amide synthesis C To a cooled (0 °C) solution of an appropriate carboxylic acid (1.2 equiv ) in anhydrous CH2Cl2 (3 mL) were added EDC·HCl (2.1 equiv) and HOBt (2.3 equiv ). The resulting solution was stirred at 0 °C for 10 min, and the amine (0.307 mmol) was added at 0 °C. The reaction mixture was warm to room temperature and stirred at room temperature until complete consumption of the starting material (monitored by T LC). The reaction mixture was diluted with CH2Cl2 (10 mL) was added and washed with saturated aqueous NaHCO3 solution (5 mL) and brine (5 mL), dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (60-120 mesh), (1-2 % MeOH in CH2 Cl2) to get the coupled ptoduct. |
Yield | Reaction Conditions | Operation in experiment |
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66% | General procedure: To a suspension of indole or pyrrole carboxylic acids 1a-h (1.0 mmol) in dry tetrahydrofuran (8mL) N,N?-dicyclohexylcarbodiimmide (1.5 mmol) was added portionwise, maintaining the temperature below 0C. After 20 minutes, 1-hydroxybenzotriazole (1.5 mmol) in dry tetrahydrofuran (4mL) was added, and the reaction was allowed to stir for additional 20 minutes. Finally, a suspension of desired amino ester hydrochloride (1.5 mmol) and triethylammine in dry tetrahydrofuran was prepared and added dropwise. The reaction mixtures were allowed to warm to room temperature. The progress of the reactions was monitored by TLC. The reaction mixture was filtrated in vacuo and the filtrate was diluted and extracted with EtOAc (3 × 50ml) and washed with 5% NaHCO3, 10% HCl, water, and finally with brine. The organic layers were dried with anhydrous sodium sulfate and evaporated in vacuo. The products were purified using column chromatography on silica gel (EtOAc/PE 80:20 as eluent) afford the indole carboxamides 3a-l and pyrrole carboxamides 3m-n. The spectroscopic data of compounds 3a-n are reported below. For known compounds 3a-b, g, m-n only 1H and 13C NMR are reported. |
Yield | Reaction Conditions | Operation in experiment |
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75% | With dihydrogen peroxide; potassium iodide In ethyl acetate at 20℃; for 4.5h; | 8 Example 1The preparation method of the N-acetyl derivative of the compound of formula (3a) includes the following steps: General procedure: Add N-acetyl indole 3-one (0.2mmol, 35mg), benzoic acid (0.6mmol, 73.2mg) to a 10mL single-necked bottle, and then add the oxidant H2O2 (1.5 equivalents, 30ul), KI (5mol%, 1.66 mg), 1 mL of ethyl acetate, reaction at room temperature for 5 h, the reaction is completed, silica gel column chromatography (petroleum ether: ethyl acetate 3: 1), the obtained crude product is added to a saturated sodium carbonate solution, extracted with ethyl acetate, and washed with water The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a white solid. NMR and GC-MS confirmed that it was N-acetyl 3-oxoindole derivative 3a. Yield: 85%; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.1% | With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; triethylamine In dichloromethane at 20℃; for 12h; | 12 N-(Benzo[d]isothiazol-3-yl)-1H-pyrrole-2-carboxamide(12) In dichloromethane solution (5mL) of benzo[d]isothiazol-3-amine (100mg, 0.67mmol)Add pyrrole-2-carboxylic acid (75.0mg, 0.67mmol),1-hydroxybenzotriazole (135.1mg, 1mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (191.7mg, 1mol) and triethylamine (202.3mg, 2mmol) ). React at room temperature for 12 hours.After the reaction, the reaction solution was filtered with suction, and the filtrate was extracted with dichloromethane (3×20 mL).Wash with saturated brine (10 mL). Combine the organic phases, dry with anhydrous sodium sulfate,The solvent was evaporated under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain the target product as a white solid (131.1 mg, 81.1%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 25℃; | 1.S5 S5, refer to the following synthetic route to synthesize compound 7 Dissolve 1 equivalent of compound 5 and 1.2 equivalent of compound 6 in N,N-dimethylformamide, add 2.5 equivalents of HATU and 2 equivalents of triethylamine, and react at room temperature (about 25°C). Follow-up monitoring by thin-layer chromatography, after the reaction is complete, a large amount of ice water is added to the reaction solution to precipitate out. After filtration, the precipitate was washed with water, and dried to obtain compound 7 with a yield of 78%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 16h; Inert atmosphere; | Synthesis of 1-((2,6,6-trimethylcyclohex-1-en-1-yl)methyl)-1H-pyrrole-2-carboxylic acid 86 PBr3 (0.3 mL, 2.9 mmol) was added to a stirred solution of 84 (2.00 g, 12.9 mmol) in a mixed solvent nhexane(7 mL)/Et2O (7 mL) at -20 under a N2 atmosphere. The mixture was stirred at this temperature for15 min., then filtered through a short pad of silica and eluted with a mixed solution of n-hexane/Et2O (1:3,v/v). The filtrate was concentrated to dryness to give 2-(bromomethyl)-1,3,3-trimethylcyclohex-1-ene 85 ascolourless oil (2.5 g, 89%) which was immediately used without further purification for the next reactionstage due to its instability. This residue was dissolved in dry DMF (20 mL), and Cs2CO3 (5.28 g, 16.20mmol) and pyrrole-2-carboxylic acid (0.90 g, 0.10 mmol) were added. The reaction was stirred at r.t. undera N2 atmosphere for 16 h, then diluted with water (30 mL) and extracted with EtOAc (3 x 50 mL). Thecombined organic extracts were washed with brine, dried over Na2SO4 and concentrated to dryness. Theresidue was co-evaporated multiple times with EtOAc to give the title compound as a light brown oil (1.80g, 92%). 1H-NMR (500 MHz, CDCl3), δ: 9.44 (bs, 1H), 6.87-6.82 (m, 2H), 6.17-6.15 (m, 1H), 4.72 (s, 2H), 1.94(t, J = 6.2 Hz, 2H), 1.63 (s, 3H), 1.58-1.53 (m, 2H), 1.41-1.38 (m, 2H), 0.97 (s, 6H) ppm. 13C-NMR (125 MHz,CDCl3), δ: 161.6, 136.2, 132.2, 123.1, 122.7, 115.2, 110.2, 60.8, 39.3, 34.1, 33.0, 28.4, 19.9, 19.2 ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 20h; Inert atmosphere; | 4.2.3 3-(1H-Pyrrole-2-carboxamido)propanoic acid (8) General procedure: To a solution of β-alanine methyl ester hydrochloride 2 (3.938g, 1 equiv.) in DCM (50mL) under nitrogen atmosphere was added pyrrole-2-carboxylic acid 4 (5g, 36mmol), followed by anhydrous DMAP (5.71g, 1.3 equiv.) and finally EDCI.HCl (12.42g, 1.8 equiv.). The reaction was allowed to stir at rt until the completion of the reaction (20h). To the reaction mixture, was added crushed ice and stirred continuously to obtain solid. The solid intermediate was filtered, exhaustively washed with water and the solid was dried under vacuum to obtain the desired ester intermediate 6 (pale yellow, 81%). This ester was dissolved in LiOH (3.5 equiv.), and THF (3 equiv.) was added, and the reaction mixture was allowed to stir for 30min at rt. After the completion of the reaction, the solvent was evaporated under vacuum and water was added. To this, 1N HCl was added slowly until acidic, and the precipitate was filtered and dried to obtain the acid 8 (71%). |
81% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 20h; Inert atmosphere; | 4.2.3 3-(1H-Pyrrole-2-carboxamido)propanoic acid (8) General procedure: To a solution of β-alanine methyl ester hydrochloride 2 (3.938g, 1 equiv.) in DCM (50mL) under nitrogen atmosphere was added pyrrole-2-carboxylic acid 4 (5g, 36mmol), followed by anhydrous DMAP (5.71g, 1.3 equiv.) and finally EDCI.HCl (12.42g, 1.8 equiv.). The reaction was allowed to stir at rt until the completion of the reaction (20h). To the reaction mixture, was added crushed ice and stirred continuously to obtain solid. The solid intermediate was filtered, exhaustively washed with water and the solid was dried under vacuum to obtain the desired ester intermediate 6 (pale yellow, 81%). This ester was dissolved in LiOH (3.5 equiv.), and THF (3 equiv.) was added, and the reaction mixture was allowed to stir for 30min at rt. After the completion of the reaction, the solvent was evaporated under vacuum and water was added. To this, 1N HCl was added slowly until acidic, and the precipitate was filtered and dried to obtain the acid 8 (71%). |
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