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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
1H-pyrazole is an endogenous metabolite.
Synonyms: Pyrazole
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Surveying the scope of aromatic decarboxylations catalyzed by prenylated-flavin dependent enzymes
Anushree Mondal ; Pronay Roy ; Jaclyn Carrannatto ; Prathamesh M. Datar ; Daniel J. DiRocco ; Katherine Huntera and E. Neil G. Marsh
Abstract: The prenylated-flavin mononucleotide-dependent decarboxylases (also known as UbiD-like enzymes) are the most recently discovered family of decarboxylases. The modified flavin facilitates the decarboxylation of unsaturated carboxylic acids through a novel mechanism involving 1,3-dipolar cyclo-addition chemistry. UbiD-like enzymes have attracted considerable interest for biocatalysis applications due to their ability to catalyse (de)carboxylation reactions on a broad range of aromatic substrates at otherwise unreactive carbon centres. There are now ∼35[thin space (1/6-em)]000 protein sequences annotated as hypothetical UbiD-like enzymes. Sequence similarity network analyses of the UbiD protein family suggests that there are likely dozens of distinct decarboxylase enzymes represented within this family. Furthermore, many of the enzymes so far characterized can decarboxylate a broad range of substrates. Here we describe a strategy to identify potential substrates of UbiD-like enzymes based on detecting enzyme-catalysed solvent deuterium exchange into potential substrates. Using ferulic acid decarboxylase (FDC) as a model system, we tested a diverse range of aromatic and heterocyclic molecules for their ability to undergo enzyme-catalysed H/D exchange in deuterated buffer. We found that FDC catalyses H/D exchange, albeit at generally very low levels, into a wide range of small, aromatic molecules that have little resemblance to its physiological substrate. In contrast, the sub-set of aromatic carboxylic acids that are substrates for FDC-catalysed decarboxylation is much smaller. We discuss the implications of these findings for screening uncharacterized UbiD-like enzymes for novel (de)carboxylase activity.
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CAS No. : | 288-13-1 |
Formula : | C3H4N2 |
M.W : | 68.08 |
SMILES Code : | N1N=CC=C1 |
Synonyms : |
Pyrazole
|
MDL No. : | MFCD00005234 |
InChI Key : | WTKZEGDFNFYCGP-UHFFFAOYSA-N |
Pubchem ID : | 1048 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335-H412 |
Precautionary Statements: | P261-P273-P305+P351+P338 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With potassium carbonate In acetonitrile at 20℃; | A mixture of 4-nitrobenzyl bromide (0.500 g, 2.31 mmol), lH-pyrazole (0.362 g, 5.23 mmol), and potassium carbonate (0.704 g, 5.09 mmol) in acetonitrile (30 mL) was stirred at rt overnight. After this time, the mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate) to afford the title compound (0.380 g, 76percent) as a white solid. MW = 203.20. ]H NMR (CDC13, 500 MHz) δ 8.21-8.19 (m, 1H), 8.19-8.16 (m, 1H),7.61- 7.57 (m, 1H), 7.48-7.44 (m, 1H), 7.32-7.28 (m, 2H), 6.35 (t, / = 2.1 Hz, 1H), 5.44 (s, 2H); APCI MS m/z 204 [M + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With nitric acid; acetic anhydride; In acetic acid; at 55℃;Cooling with ice; Flow reactor; High pressure; | The acetic anhydride and fuming nitric acid are slowly mixed in an ice water bath at a volume ratio of 5.5:1 to obtain a nitrating agent, and the nitratingagent and the pyrazole acetic acid solution are respectively delivered to the microchannel reactor through a high-pressure constant-flow pump with precise flow control. The twoinlets control the molar ratio of nitric acid to pyrazole to be 1.1:1. At 45-70 °C, the two liquids are instantaneously mixed in the microchannel reactorand reacted. The reaction solution is poured into crushed ice and filtered. It was washed with ice water and dried under vacuum to give N-nitropyrazole; theflow rate of the acetic acid solution of the pyrazole was 0.1 mL/min.The yield and purity of N-nitropyrazole are shown in Table 1 and Figure 2. |
78% | Fuming nitric acid (3.3 mL) was added dropwise to a stirred solution of pyrazole (4.5 g, 66 mmol) in glacial acetic acid (14.1 mL) that had been cooled to ?10 °C using an ice-salt bath. A voluminous precipitate was formed. Acetic anhydride (9.45 mL) was added dropwise and the resultant mixture was stirred at ambient temperature for 1.5 h. The mixture was poured onto ice and was neutralized with potassium carbonate. The precipitate was isolated by filtration. The yield of the obtained white solid of N-nitropyrazole is 78percent. | |
The 4-arnino-l-methyl-lH-pyrazole used as a starting material was prepared as follows :-4-Nitropyrazole is available commercially from the N.D. Zelinsky Institute, Organic Chemistry, Leninsky prospect 47, 117913 Moscow B-334, Russia. The compound may also be 5 prepared as follows :-Fuming nitric acid (9.5 ml) was added dropwise to a stirred solution of pyrazole (13.6 g) in glacial acetic acid (51 ml) that had been cooled to -10°C using an ice-salt bath. A voluminous precipitate was formed. Acetic anhydride (27 ml) was added dropwise and the resultant mixture was stirred at ambient temperature for 2.5 hours. The mixture was poured10 onto ice and the acidity of the mixture was reduced to pEta5 by the addition of potassium carbonate. The precipitate was isolated by filtration. The resultant solid was dissolved in water and the aqueous solution was extracted with diethyl ether. The organic solution was dried over magnesium sulphate and filtered. Petroleum ether (b.p. 60-80°C, 50 ml) was added to the filtrate which was concentrated by evaporation to a volume of about 50 ml. A precipitate15 formed which was isolated by filtration. This solid was believed to be 1-nitropyrazole(20.6 g); 1H NMR: (DMSOd6) 6.71 (s, IH), 7.88 (s, IH), 8.81 (s, IH). |
4-Nitropyrazole is available commercially from the N.D. Zelinsky Institute, Organic Chemistry, Leninsky prospect 47, 117913 Moscow B-334, Russia. The compound may also be prepared as follows :- s Fuming nitric acid (9.5 ml) was added dropwise to a stirred solution of pyrazole(13.6 g) in glacial acetic acid (51 ml) that had been cooled to -100C using an ice-salt bath. A voluminous precipitate was formed. Acetic anhydride (27 ml) was added dropwise and the resultant mixture was stirred at ambient temperature for 2.5 hours. The mixture was poured onto ice and the acidity of the mixture was reduced to pH5 by the addition of potassium 0 carbonate. The precipitate was isolated by filtration. The resultant solid was dissolved in water and the aqueous solution was extracted with diethyl ether. The organic solution was dried over magnesium sulphate and filtered. Petroleum ether (b.p. 60-80°C, 50 ml) was added to the filtrate which was concentrated by evaporation to a volume of about 50 ml. A precipitate formed which was isolated by filtration. This solid was believed to be S 1-nitropyrazole (20.6 g); 1H NMR: (DMSOd6) 6.71 (s, IH), 7.88 (s, IH), 8.81 (s, IH). The compound may be explosive and should be handled cautiously. | ||
With nitric acid; acetic anhydride; acetic acid; at -10 - 25℃; for 2.5h; | Fuming nitric acid (9.5 ml) was added drop wise to a stirred solution of pyrazole (13.6 g) in glacial acetic acid (51 ml) that had been cooled to -1O0C using an ice-salt bath. A voluminous precipitate was formed. Acetic anhydride (27 ml) was added dropwise and the resultant mixture was stirred at ambient temperature for 2.5 hours. The mixture was poured onto ice and the acidity of the mixture was reduced to pH5 by the addition of potassium carbonate. The precipitate was isolated by filtration. The resultant solid was dissolved in water and the aqueous solution was extracted with diethyl ether. The organic solution was dried over magnesium sulphate and filtered. Petroleum ether (b.p. 60-80°C, 50 ml) was added to the filtrate which was concentrated by evaporation to a volume of about 50 ml. A precipitate formed which was isolated by filtration. This solid was believed to be 1-nitropyrazole (20.6 g); 1HNMR: (DMSOd6) 6.71 (s, IH), 7.88 (s, IH), 8.81 (s, IH). | |
Fuming nitric acid (9.5 ml) was added drop wise to a stirred solution of pyrazole (13.6 g) in glacial acetic acid (51 ml) that had been cooled to -10°C using an ice-salt bath. A voluminous precipitate was formed. Acetic anhydride (27 ml) was added dropwise and the resultant mixture was stirred at ambient temperature for 2.5 hours. The mixture was poured onto ice and the acidity of the mixture was reduced to rhoH5 by the addition of potassium carbonate. The precipitate was isolated by filtration. The resultant solid was dissolved in water and the aqueous solution was extracted with diethyl ether. The organic solution was dried over magnesium sulphate and filtered. Petroleum ether (b.p. 60-800C, 50 ml) was added to the filtrate which was concentrated by evaporation to a volume of about 50 ml. A precipitate formed which was isolated by filtration. This solid was believed to be1-nitropyrazole (20.6 g); 1H NMR: (DMSOd6) 6.71 (s, IH), 7.88 (s, IH), 8.81 (s, IH). The compound may be explosive and should be handled cautiously. | ||
The compound may also be prepared as follows:- Fuming nitric acid (9.5 ml) was added dropwise to a stirred solution of pyrazole (13.6 g) in glacial acetic acid (51 ml) that had been cooled to -10° C. using an ice-salt bath. A voluminous precipitate was formed. Acetic anhydride (27 ml) was added dropwise and the resultant mixture was stirred at ambient temperature for 2.5 hours. The mixture was poured onto ice and the acidity of the mixture was reduced to pH5 by the addition of potassium carbonate. The precipitate was isolated by filtration. The resultant solid was dissolved in water and the aqueous solution was extracted with diethyl ether. The organic solution was dried over magnesium sulphate and filtered. Petroleum ether (b.p. 60-80° C., 50 ml) was added to the filtrate which was concentrated by evaporation to a volume of about 50 ml. A precipitate formed which was isolated by filtration. This solid was believed to be 1-nitropyrazole (20.6 g); 1H NMR: (DMSOd6) 6.71 (s, 1H), 7.88 (s, 1H), 8.81 (s, 1H). The compound may be explosive and should be handled cautiously. | ||
With nitric acid; acetic anhydride; acetic acid; at 25℃; for 0.5h; | Freshly prepared acetyl nitrate (HNO3, 1.8 mL, d = 1.54 g cm?3 and acetic anhydride, 4.2 mL) was added to pyrazole (1.0 g) dissolved in acetic acid (2.8 mL) at 25 °C. After stirring for 30 min the reaction mixture was poured into water. The crude yield after washing with water and drying was 1.4 g (84percent). m.p. 91?92 °C. FT-IR (KBr, cm?1): 1617, 1320 (N?NO2). 1H NMR (DMSO-d6) delta: 8.65 (d, 1H, 5-H), 7.80 (s, 1H, 3-H), 6.73 (m, 1H, 4-H). EI-MS: m/z 113 (M+·). Anal. Calcd for C3H3N3O2 (113.08): C, 31.83; H, 2.67; N, 37.26. Found: C, 32.88; H, 2.62; N, 37.43. | |
With nitric acid; In acetic anhydride; acetic acid; at 20 - 30℃; for 2.5h; | A 100mL one-neck flask equipped with a magnetic stirrer was added 5g of compound 1 and 15mL acetic acid, stirred, to give a clear solution. Under ice bath 3.5mL of fuming nitric acid was slowly added dropwise to the mixed solution, maintaining vigorous stirring, the reaction temperature does not exceed 30 deg. C. 10mL acetic anhydride was added to the mixture, after the addition, the mixture immediately became cloudy, to give a white turbid liquid. After the addition it was stirred at room temperature, until the solution became clear, about 2.5h. After completion of the reaction, the solution was slowly poured into 100mL crushed ice and with vigorous stirring, potassium carbonate was added portionwise until the mixture was neutral, white precipitate was filtered to give 5.6g of white powdery crystals, the filtrate was extracted with ethyl acetate, the combined organic phase was dried over anhydrous sodium sulfate, the solvent was removed by rotary evaporation to give pale yellow crystals 1.3490g, total crude was 6.9490g, yield 91.9percent recrystallized from benzene. Weigh three 100mg compound 2 into thick-walled pressure bottle, gradually heated to 160 deg. C, 180 deg. C, 200 deg. C, the reaction at this temperature for 1 ~ 3h to obtain compound 3, the results shown in Table 1. | |
The 4-amino-l -ethyl- lH-pyrazole used as a starting material was prepared as follows :; -4-Nitropyrazole is available commercially from the N.D. Zelinsky Institute, Organic Chemistry, Leninsky prospect 47, 117913 Moscow B-334, Russia. The compound may also be prepared as follows :; -Fuming nitric acid (9.5 ml) was added drop wise to a stirred solution of pyrazole (13.6 g) in glacial acetic acid (51 ml) that had been cooled to -100C using an ice-salt bath. A voluminous precipitate was formed. Acetic anhydride (27 ml) was added dropwise and the resultant mixture was stirred at ambient temperature for 2.5 hours. The mixture was poured onto ice and the acidity of the mixture was reduced to pH5 by the addition of potassium carbonate. The precipitate was isolated by filtration. The resultant solid was dissolved in water and the aqueous solution was extracted with diethyl ether. The organic solution was dried over magnesium sulphate and filtered. Petroleum ether (b.p. 60-80°C, 50 ml) was added to the filtrate which was concentrated by evaporation to a volume of about 50 ml. A precipitate formed which was isolated by filtration. This solid was believed to be 1-nitropyrazole (20.6 g); 1H NMR Spectrum: (DMSOd6) 6.71 (s, IH), 7.88 (s, IH), 8.81 (s, IH). | ||
4-Nitropyrazole is available commercially from the N.D. Zelinsky Institute, Organic Chemistry, Leninsky prospect 47, 117913 Moscow B-334, Russia. The compound may also be prepared as follows :-; Fuming nitric acid (9.5 ml) was added drop wise to a stirred solution of pyrazole (13.6 g) in glacial acetic acid (51 ml) that had been cooled to -10°C using an ice-salt bath. A voluminous precipitate was formed. Acetic anhydride (27 ml) was added dropwise and the resultant mixture was stirred at ambient temperature for 2.5 hours. The mixture was poured onto ice and the acidity of the mixture was reduced to peta5 by the addition of potassium carbonate. The precipitate was isolated by filtration. The resultant solid was dissolved in water and the aqueous solution was extracted with diethyl ether. The organic solution was dried over magnesium sulphate and filtered. Petroleum ether (b.p. 60-800C, 50 ml) was added to the filtrate which was concentrated by evaporation to a volume of about 50 ml. A precipitate formed which was isolated by filtration. This solid was believed to be 1-nitropyi-azole (20.6 g); 1H NMR Spectrum: (DMSOd6) 6.71 (s, IH), 7.88 (s, IH), 8.81 (s, IH). The compound may be explosive and should be handled cautiously. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile; at 50℃; | Pyrazole (0.185 g, 2.7 mmol) was taken up in MeCN (9 ml) and added to N-Boc-D-serine [beta]-lactone (Vederas, Arnold, Kalantar, J.Am.Chem. Soc. 1985, 107, 7105) (0.5 g) in MeCN (12 ml) followed by stirring overnight at 50[deg.] C. Solvent was removed in vacuo to yield a crude oil (630 mg) that was taken up in methanol and transferred to a Bond Elut PSA column. The column was washed with methanol prior to elution with 4% TFA/THF which afforded the subtitle compound (280 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;copper(l) iodide; D-Prolin; In dimethyl sulfoxide; at 100℃; for 3.0h;Inert atmosphere; | Reference Example 11b; 1H-Pyrazole (0.14 g), potassium carbonate (0.46 g), D-proline (38 mg), and copper(I) iodide (32 mg) were added to a dimethyl sulfoxide (5 mL) solution of <strong>[890315-72-7]tert-butyl 4-bromo-2-nitrobenzoate</strong> (0.50 g), followed by stirring under a nitrogen atmosphere at 100 C. for 3 hours. After cooling the reaction mixture to room temperature, ethyl acetate and water were added thereto, and the insoluble substance was removed by filtration. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride sequentially, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 100-80% hexane/ethyl acetate] to obtain 0.20 g of tert-butyl 2-nitro-4-(1H-pyrazol-1-yl)benzoate as a white solid.1H-NMR (CDCl3) delta: 1.57 (9H, s), 6.56 (1H, dd, J=2.6, 1.8 Hz), 7.79 (1H, d, J=1.8 Hz), 7.88 (1H, d, J=8.5 Hz), 7.95 (1H, dd, J=8.5, 2.1 Hz), 8.01 (1H, d, J=2.6 Hz), 8.15 (1H, d, J=2.1 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With potassium carbonate; In toluene; for 10h;Reflux; | 6.2 Synthesis of 1-(2,4,6-trimethylbenzyl)-1H-pyrazole, L1a A mixture of pyrazole (0.27 g; 4.00 mmol), 2,4,6-trimethylbenzyl bromide (2.13 g; 10.0 mmol) and K2CO3 (1.80 g, 13.0 mmol) was refluxed 10 h in toluene (10 mL). Following the completion of the process, the mixture was cooled to room temperature, filtered and all volatiles of filtrate were removed. The residue was crystallized from hexane to give colourless solid upon cooling to -20 C. Yield: 1.89 g, 92%; mp: ca. 20 C. 1H NMR (400 MHz, CDCl3): delta 7.52 (d, J=1.95 Hz, 1H, HPz-H), 7.01 (d, J=2.34 Hz, 1H, HPz-H), 6.91 (s, 2H, Ar-H), 6.16 (t, J=2.15 Hz, 1H, HPz-H), 5.33 (s, 2H, CH2-Ar), 2.28 (s, 9H, Ar-CH3). 13C NMR (100 MHz, CDCl3): delta 139.8, 138.2, 129.6, 128.9, 128.1, 109.9, 105.4 (Ar-C, HPz-C), 50.1 (CH2-Ar), 19.8, 21.2 (Ar-CH3). IR, numax (CH2Cl2): 2989, 1650, 1613, 1463, 1383, 1313, 1254, 1134, 1091, 746 cm-1. Anal. Calcd for C13H16N2 (M=200.28): C, 77.96; H, 8.05; N, 13.19. Found: C, 78.01; H, 8.13; N, 13.29%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In toluene; at 74.0℃; under 217.522 Torr; for 12.0h; | A solution of 2-chloro-N-chloromethyl-2',6'-dimethylacetanilide, prepared in situ from 2,6- dimethyl-N-methylene benzamine (469 g, approx. 1 :7.5 w/w in cyclohexane/toluene) that was obtained from formaldehyde and 2,6-dimethylaniline (120.9 g, 997.9 mmol), and chloroacetyl chloride (1 12.8 g, 998.7 mmol, 1 .00 eq) in toluene (85 g) was evacuated to 290 mbar and heated to 74 C. A melt of pyrazole (71 .7 g, 1053.1 mmol, 1 .05 eq) was then metered in over a period of 6 hours, and the reaction mixture was then stirred for another 6 hours. The reaction mix- ture was then concentrated by distilling off the solvent (60 C, 100 mbar) to yield a solution of 264.4 g (62.0 wt%, 95 % yield based on 2,6-dimethylaniline) Metazachlor. The crystallization of Metazachlor was initiated by adding seed crystals to the concentrated reaction mixture which was then cooled to 0 C. Precipitated Metazachlor was filtered off, washed with cyclohexane and dried (215.0 g, > 96 % purity). The combined mother liquor and wash liquor were again concentrated and crystallized to yield further Metazachlor (41.0 g, > 96 % purity). The total yield across both crystallizations was 89 %. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82.1% | To a stirred solution of 0.34 g (50 mmol) of pyrazole in 50 ml of dimethylformamide under nitrogen atmosphere(50 mmol) of sodium hydride, stirred for several minutes, and then slowly added 1.07 g (50 mmol) of <strong>[7089-68-1]2-chloro-1,10-phenanthroline</strong>, refluxed for 72 h, cooled, cold water was added and the white The precipitate was recrystallized from ethanol to give 2-pyrazole-1,10-phenanthroline as a white crystal in a yield of 82.1percent. | |
With potassium carbonate; In N,N-dimethyl-formamide; for 72h;Reflux; | Synthesis of 2-(1H-pyrazol-1-yl)-1,10-phenanthroline: <strong>[7089-68-1]2-chloro-1,10-phenanthroline</strong> (2.13 g,10 mM), pyrazole (0.70 g, 10 mM), and potassium carbonate (1.50 g, 0.011 mM) weredissolved in 20mL of DMF. The mixture was refluxed for 24 h, then another batch ofpyrazole (0.34 g, 5.0 mM) and potassium carbonate (1.00 g, 7.2 mM) was added into theDMF solution and the reaction continued to reflux for another 48 h. After that, a fraction ofDMF was distilled out by vacuum and 40mL of ice water with crushed ice was added into the solution. The raw product then appeared and was separated by filtration. Then, theproduct was washed with ice water until the filtrate was neutral and the final product wasobtained by vacuum drying. 1H NMR (300MHz, CDCl3, 25 °C): delta = 9.19 (s, 2H), 8.40 (brs,2H), 8.28 (s, 1H), 7.82 (brs, 3H), 7.66 (s, 1H), 6.56 (s, 1H). HRMS (ESI): m/z calcd forC15H10N4+H+: 247.0978 [M+H+]; found: 247.0982. All other chemicals are analyticalgrade and used without purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With copper(l) iodide; In toluene; at 110℃; for 24h;Alkaline conditions; | Step b) [0224] The brominated triphenylene derivative (1 equivalent) is subsequently stirred with 5-10 mol % of CuI, 20 mol % of amine(N,N-dimethylcyclohexane-1,2-diamine or phenantroline), 1.0 equivalent of pyrazol and 2.1 equivalents of base (K2CO3, CsCO3 or NaOtBu) at 110 C. in toluene for 24 hours. [0225] Step c) [0226] The reaction product obtained in step b) is subsequently converted to the triphenylene derivative of the formula IIf in step c1), in step c2) or in step c3): [0227] c1) iPrMgCl.LiCl; HCl; c2) H2, NEt3, Pd(OH)2/C; c3) HCO2H, NEt3, P(oTol)3, Pd(OAc)2, DMF, 50 C., 24 h. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With aluminum tri-bromide; carbon tetrabromide; In neat (no solvent); at 15 - 20℃;Green chemistry; | General procedure: A mixture of the appropriate adamantane/norbornane (1 mmol), amine (1 mmol), AlBr3 (0.5 mmol) and CBr4 (0.5 mmol) was ground in a mortar and pestle at room temperature till the completion of reaction as indicated by TLC (5-10 min). The product of azole derivatives were purified by recrystallization from ethyl alcohol, and the other amine derivatives were purified by column chromatography using ethyl acetate and petroleum ether mixtures as the mobile phase. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With potassium carbonate; In N,N-dimethyl-formamide; at 115℃; for 3h;Inert atmosphere; | In a 250 mL round-bottom flask, <strong>[3107-19-5]1,3-dichloro-2-fluoro-5-nitrobenzene</strong> (1.5 g, 7.14 mmol, Eq:1.00), 1H-pyrazole (486 mg, 7.14 mmol, Eq: 1.00) and potassium carbonate (1.5 g, 10.9 mmol, Eq: 1.52) were combined with DMF (30 mL) to give a yellow suspension. This mixture washeated at 115 oc for three hours. The reaction mixture was cooled to room temperature. Thecooled mixture was poured into -100 mL of ice water. A cream-colored solid precipitated out. The precipitate was collected via vacuum filtration and air dried to provide 1-(2,6-dichloro-4- nitro-phenyl)-1H-pyrazole (1.73 g, 94%) as an off-white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With copper(l) iodide; caesium carbonate; trans-1,2-cyclohexanediamine; In N,N-dimethyl-formamide; at 0 - 125℃; for 0.25h;Microwave irradiation; | Intermediate 23: 5-Chloro-2-(lH-pyrazol-l-yl)<strong>[13421-00-6]benzoic acid</strong> To the solution of lH-pyrazole (1.5 g, 22.05 mmol ) in DMF (7.0 ml) was added cesium carbonate (7.16 g, 22.05 mmol), irans-N,N'-cyclohexyl-l,2-diamine (0.31 g, 2.20 mmol), copper(I) iodide (0.104 g, 0.55 mmol) and <strong>[13421-00-6]5-chloro-2-iodo<strong>[13421-00-6]benzoic acid</strong></strong> (3.11 g, 11.02 mmol ) at 0-10 C. The reaction was stirred at 125C for 15 min in microwave and then poured into water (100 ml) and extracted with ethyl acetate (100 ml x 3). The aqueous layer was acidified with dilute HC1 to pH 2 and extracted with ethyl acetate (100 ml x 3). The combined organic layer was washed with brine, dried over sodium sulphate and concentrated in vacuo. This was then purified by column chromatography (0-3% methanol / dichloromethane) to afford the title compound.1H NMR (400 MHz DMSO-d6): delta ppm 6.50-6.60 (m, 1H), 7.62-7.74 (m, 3H), 8.12-8.17 (m, 1H), 13.23 (s, 1H)MS ES+: 223, 225 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a suspension of sodium hydride (278 mg, 6.95 mmol, 60percent in oil) in DMF (10 mL) was added 1H-pyrazole (279 mg, 4.11 mmol) at RT and the resulting mixture stirred at RT for 0.5 h. 3-Chloropyrazine-2-carboxylic acid (500 mg, 3.16 mmol) was added and the mixture heated to 60°C for 2 h. After cooling to RT, water (20 mL) was added and the mixture extracted with 4.7percent MeOH in DCM (20 mL x 3). The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated in vacuo to give the title compound as a solid. LRMS m/z (M+H) 191.0 found, 191.0 required. | ||
To a suspension of sodium hydride (278 mg, 6.95 mmol, 60percent in oil) in DMF (10 mL) was added 1H-pyrazole (279 mg, 4.11 mmol) at RT and the resulting mixture was stirred at room temperature for 30 mins. 3-Chloropyrazine-2-carboxylic acid (500 mg, 3.16 mmol) wasadded and the mixture heated to 60 °C for 2 h. After cooled to RT, water (20 mL) was added and the mixture extracted with 4.7percent MeOH in DCM (20 mL x 3). The combined organic layers were washed with brine, dried over Na2504, filtered, and concentrated in vacuo to give the title compound. LRMS m/z (M+H) 191.0 found, 191.0 required. | ||
To a suspension of sodium hydride (60 wtpercent in mineral oil, 278 mg, 6.95 mmol) inDMF (10 mL) was added 1H-pyrazole (279 mg, 4.11 mmol) at RT and the resulting mixture wasstirred at RT for 30 mins. 3-Chloropyrazine-2-carboxylic acid (500 mg, 3.16 mmol) was addedand the mixture was heated at 60 °C for 2 h. After cooling to RT, water (20 mL) was added and the mixture was extracted with 5percent MeOH in DCM (20 mL x 3). The combined organic layers were washed with brine, dried over Na2504, filtered, and concentrated in vacuo to give the title compound as a solid. LRMS m/z (M+H) 191.0 found, 191.0 required. |
To a suspension of sodium hydride (278 mg, 6.95 mmol, 60percent in oil) in DMF (10 mL) was added lH"-pyrazole (279 mg, 4.11 mmol) and the resulting mixture stirred at room temperature for 30 mins. 3-Chloropyrazine-2-carboxylic acid (500 mg, 3.16 mmol) was added and the mixture was heated to 60 °C for 2 h. After cooling to room temperature, water (20 mL) was added and the mixture extracted with 5percent MeOH in DCM (3 x 20 mL). The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated in vacuo to give Intermediate E as a solid. LRMS m/z (M+H) 191.0 found, 191.0 required. | ||
To a suspension of sodium hydride (278 mg, 6.95 mmol, 60percent in oil) in DMF (10 mL) was added 1H-pyrazole (279 mg, 4.11 mmol) at RT and the resulting mixture stirred at room temperature for 30 mins. 3-Chloropyrazine-2-carboxylic acid (500 mg, 3.16 mmol) was added and the mixture heated to 60 oC for 2 h. After cooling to RT, water (20 mL) was added and the mixture extracted with 4.7percent MeOH in DCM (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the title compound as a solid. LRMS m/z (M+H) 191.0 found, 191.0 required. | ||
Intermediate Z 3-(lH-Pyrazol-l-yl)pyrazine-2-carboxylic acid Intermediate Z 3-(lH-Pyrazol-l-yl)pyrazine-2-carboxylic acid (Intermediate Z) To a suspension of sodium hydride (278 mg, 6.95 mmol, 60percent in oil) in DMF (10 mL) was added lH-pyrazole (279 mg, 4.11 mmol) at RT and the resulting mixture was stirred at room temperature for 30 mins. 3-Chloropyrazine-2-carboxylic acid (500 mg, 3.16 mmol) was added and the mixture heated to 60 °C for 2 h. After cooled to RT, water (20 mL) was added and the mixture extracted with 4.7percent MeOH in DCM (20 mL x 3). The combined organic layers were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo to give the title compound. LRMS m/z (M+H) 191.0 found, 191.0 required. | ||
To a suspension of sodium hydride (60 wtpercent in mineral oil, 278 mg, 6.95 mmol) in DMF (10 mL) was added IH-pyrazole (279 mg, 4.11 mmol) at RT and the resulting mixture was stirred at RT for 30 mins. 3-Chloropyrazine-2-carboxylic acid (500 mg, 3.16 mmol) was added and the mixture was heated at 60 °C for 2 h. After cooling to RT, water (20 mL) was added and the mixture was extracted with 5percent MeOH in DCM (20 mL x 3). The combined organic layers were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo to give the title compound as a solid. LRMS m/z (M+H) 191.0 found, 191.0 required. | ||
Step I: 3_( 1H-Pyrazol-1yl) irazine2carboxylic acid (intermediate P1To a suspension of sodium hydride (278 mg, 6.95 rnrnol, 60percent in oil) in DMF (10 mL) was added 1H-pyrazoie (279 mg, 4.11 mmol) at RT and the resulting mixture stirred at room temperature for 30 mins. 3-Chioropyrazine-2-carboxyiic acid (500 mg, 3.16 mmol) was added and the mixture heated to 60 °C for 2 h. After cooling to RI, water (20 mL) was added and the mixture extracted with 47percent MeOH in DCM (20 mL x 3). The combined organic layers werewashed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the title compound as a solid. LRMS mz M±Hj 191.0 found, 191,0 required. | ||
To a suspension of sodium hydride (278 mg, 6.95 mmol, 60percent in oil) in DMF (10 mL) was added 1H-pyrazole (279 mg, 4.11 mmol) and the resulting mixture stirred at room temperature for 30 mins. 3-Chloropyrazine-2-carboxylic acid (500 mg, 3.16 mmol) was added and the mixture was heated to 60 °C for 2 h. After cooling to room temperature, water (20 mL) wasadded and the mixture extracted with 5percent MeOH in DCM (3 x 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give Intermediate D as a solid. LRMS mlz (M+H) 191.0 found, 191.0 required. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With caesium carbonate; In N,N-dimethyl-formamide; at 23℃; for 20h;Inert atmosphere; | Under N2 atmosphere, a solution of <strong>[456-24-6]2-fluoro-5-nitropyridine</strong> (0.71 g, 5.00 mmol, 1.00 equiv) was added to a mixture of ltf-pyrazole (0.51 g, 7.50 mmol, 1.50 equiv) and CS2CO3 (2.44 g, 7.50 mmol, 1.50 equiv) in DMF (25.0 mL, 0.300 M) and the reaction mixture was stirred at 5 23 °C for 20 h. The reaction mixture was poured to LiCl solution (100 mL) , extracted with EtOAc. The combined organic layers was dried (MgS04> , filtered and concentrated in vacuo. The residue was recrystalized from hexanes/EtOAc, to afford the title compound as a yellow solid (0.910 g, 4.78 mmol, 96percent yield). R/ = 0.77 (hexanes : EtOAc 10 5:1 (v/v) ) . FontWeight="Bold" FontSize="10" H NMR (700 MHz, (CD3)2SO, 25 °C, delta) : 9.29 (br. s., 1H) , 8.75 (d, J = 8.17 Hz, 1H) , 8.73-8.71 (m, 1H) , 8.12 (d, J = 9.04 Hz, 1H), 7.99-7.98 (m, 1H) , 6.72-6.70 (m, 1H) . 13C NMR (175 MHz, (CD3)2SO, 25 °C, delta) : 153.7, 145.0, 144.4, 142.3, 135.3, 128.5, 112.2, 110.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With hydrogenchloride; In 1,4-dioxane; at 120 - 130℃; for 1.75h;Microwave irradiation; Sealed tube; | Step 1: A 20 mL reaction vessel was charged with <strong>[552331-00-7]4-iodopyridin-2-amine</strong> (1.5 g, 6.8 mmol) and 1H-pyrazole(4.0 g, 58.9 mmol). Concentrated hydrochloric acid (1.5 ml) and 1,4-dioxane (1.5 mL) were added, and the reactionvessel was sealed. The mixture was irradiated in a microwave oven at 120 C for 45 min and then at 130 C for 60 min.The mixture was cooled to rt and then diethyl ether (6 ml) and ethanol (3 ml) were added. The mixture was sonicatedfor 10 min, and the solid was collected by filtration and washed with diethyl ether and n-hexane to give 4-(1H-pyrazol-1-yl)pyridin-2-amine hydrochloride (1.2 g, 90%) as a white solid. LCMS (ESI) m/z 161 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A solution of thionyl chloride (250 mmol) was added dropwise to a solution of <strong>[117724-63-7]2-methyl-4-trifluoromethylthiazole-5-carboxylic acid</strong> (100 mmol) in 1,2-dichloroethane (120 mL) at room temperature under stirring (150 mL). After the dropwise addition, the reaction was carried out under reflux for 4-6 hr, After removal of the solvent and excess of thionyl chloride, dichloromethane (150 mL) was added. Pyrazole (200 mmol) was added in portions and reacted at room temperature for 3-5 hr. The reaction solution was poured into ice water, the dichloromethane layer was separated and the aqueous phase was extracted twice with methylene chloride. The combined organic phases were dried over anhydrous sodium sulfate and the solvent was removed to give the title crude product 22.3 g, directly for the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.02 g | With copper(l) iodide; dimethylaminoacetic acid; caesium carbonate; In N,N-dimethyl acetamide; at 90℃; for 2.5h;Inert atmosphere; | Pyrazole (0.60 g), cesium carbonate (3.6 g), N,N-dimethylglycine (0.76 g), and copper iodide (I) (0.76 g) were added to an N,N-dimethylacetamide (20 ml) solution containing <strong>[25391-58-6]2-hydroxy-3-iodo-5-nitropyridine</strong> (2.00 g) in a nitrogen atmosphere, followed by stirring at 90C for 2.5 hours. The reaction solution was adjusted to room temperature, water and ethyl acetate were added, and an insoluble precipitate was removed. The pH was adjusted to pH 2 with the addition of 6M hydrochloric acid. Then, organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure. Ethyl acetate was added to the obtained residue, a solid precipitate was collected by filtration, and a green solid of 2-hydroxy-5-nitro-3-(1H-pyrazol-1-yl)pyridine (0.35 g) was thus obtained. Thereafter, the filtrate was collected, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 3:1 to 0:1), and a light green solid of 2-hydroxy-5-nitro-3-(1H-pyrazol-1-yl)pyridine (1.02 g) was thus obtained. MS (ESI m/z): 207 (M+H) RT (min): 0.94 |
Tags: 1H-pyrazole | Pyrazole | Pyrazoles | Heterocyclic Building Blocks | 288-13-1
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