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CAS No. : | 1113-59-3 | MDL No. : | |
Formula : | C3H3BrO3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | PRRZDZJYSJLDBS-UHFFFAOYSA-N |
M.W : | 166.96 | Pubchem ID : | 70684 |
Synonyms : |
Bromopyruvic acid;Hexokinase II Inhibitor II, 3-BP;NSC 62343;NSC 11731;β-Bromopyruvic acid;3-BP;Hexokinase II Inhibitor II;3-Bromopyruvate
|
Num. heavy atoms : | 7 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.33 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 26.38 |
TPSA : | 54.37 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.99 cm/s |
Log Po/w (iLOGP) : | 0.26 |
Log Po/w (XLOGP3) : | 0.46 |
Log Po/w (WLOGP) : | 0.04 |
Log Po/w (MLOGP) : | -0.29 |
Log Po/w (SILICOS-IT) : | 0.27 |
Consensus Log Po/w : | 0.15 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -1.03 |
Solubility : | 15.5 mg/ml ; 0.0927 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.17 |
Solubility : | 11.3 mg/ml ; 0.0676 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.45 |
Solubility : | 59.0 mg/ml ; 0.353 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.82 |
Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P280-P305+P351+P338-P310 | UN#: | 3261 |
Hazard Statements: | H314 | Packing Group: | Ⅱ |
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 |
---|---|---|
73% | at 50℃; for 1.2 h; | EXAMPLE 32Preparation of Intermediate Compound 32AA mixture of 3-bromopyruvic acid (16.37 g, 98.05 mmol) in anhydrous dioxane (90 ml_) was treated with ethyl thioamidooxalate (13.08 g, 98.22 mmol) for 1.2 h at 50 0C, and was then concentrated at 50 0C to yield a dry yellow solid. The crude product was dissolved in saturated sodium bicarbonate (150 mL) and water (150 mL). This solution was extracted with ethyl acetate (6 x 400 mL). The aqueous EPO <DP n="136"/>layer was then acidified to pH 2 with concentrated aqueous HCI (21 ml_), resulting in the formation of a heavy precipitate. This suspension was extracted with ethyl acetate (5 x 500 ml_). These extracts were pooled, dried with sodium sulfate, filtered, concentrated, and dried for about 15 hours under vacuum to yield compound 32A as a red-brown solid (14.36 g, 73percent yield) which was used without further purification. |
62.8% | at 60℃; for 16 h; | 3-Bromo-2-oxopropanoic acid and ethyl amino(thioxo)acetate in THF (100 ml) were stirred at 60°C for 16 h. The reaction mixture was reduced in vacuo to give an orange solid. The solid was triturated with E0, filtered and dried in vacuo to give the titled compound (4.54 g, 62.8percent) as a colourless solid. 1 H-NMR (DMSO-d6, 500 MHz): d[ppm]= 13.40 (s, 1 H), 8.77 (s, 1 H), 4.40 (q, J = 7.1 Hz, 2H), 1 .35 (t, J = 7.1 Hz, 3H) HPLCMS (ESI+): [m/z]: 201.90 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28.9% | Stage #1: at 20 - 30℃; for 4 h; Stage #2: for 4 h; Reflux |
Step 1 ethyl imidazo[1,2-c]pyrazine-3-carboxylate Pyrazin-2-amine 4a (1 g, 10 mmol) was dissolved in 50 mL of ethylene glycol dimethyl ether, followed by addition of 50 mL of methanol and 3-bromo-2-oxo-propionate (2.30 g, 12 mmol). After stirring for 4 hours at room temperature, the reaction mixture was cooled to 0° C. and stirred for 30 minutes until a solid precipitated. The reaction mixture was filtered, and the filter cake was washed with ether (10 mL*3). The solid was dissolved in 50 mL of anhydrous ethanol and the solution was refluxed for 4 hours. The reaction mixture was concentrated under reduced pressure, added with 100 mL of dichloromethane, washed successively with saturated sodium carbonate solution (40 mL) and saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain ethyl imidazo[1,2-a]pyrazine-3-carboxylate 14a (0.55 g, yield 28.9percent) as a brown solid. MS m/z (ESI): 192.1 [M+1] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 127; 2-((3-methoxyquinolin-6-yl)methyl)-6-phenylpyridazin-3(2H)-one <n="172"/>(1) S-Hydroxy--iodoquinoline^-carboxylic acid. Iodoindoline-2,3-dione (50 g, 183 mmol) was dissolved in a hot solution containing potassium hydroxide (82 g, 1465 mmol) and water (250 mL). The homogeneous solution precipitated out completely 5 min. Enough ethanol (30 mL) was added to redissolve the reaction mixture. After cooled to rt and mechanically stirred, <strong>[1113-59-3]3-bromo-2-oxopropanoic acid</strong> hydrate (47 g, 256 mmol) was added portionwise , causing temperature to rise (> 80 C). After the addition, the reaction mixture was cooled to rt and continued to stir for 3 days. The reaction mixture was treated with saturated solution OfNaHSO3 (sodium bisulfite, 12 g, 115.32 mmol) in order to prevent the development of color in the product. The resulting mixture was then acidified to pH=2 using concentrated HCl. After stirred for Ih, the yellow solid that was formed in the solution mixture was collected by filtration. The solid was washed with water and suspended in water with SO2 bubbling in the solution. After 30 minutes the solid again was separated by filtration. This wet solid was suspended in water, stirred, and dissolved by gradual addition of solid Na2CO3. The solution was treated with a saturated solution OfNaHSO3 and filtered. The filtrate was <n="173"/>acidified to pH=2 using concentrated HCl. The solid was collected by filtration and was washed with water. It was resuspended in water, and again filtered. The solid was suspended in EtOH, separated by filtration, and air dried to afford the desired product (brown solid, 22.0 g). MS (ESI pos. ion) m/z (M+l): 316.2. Calc'd exact mass for Ci0H6INO3: 315.06. 1H NMR (300 MHz, DMSO-d6) delta ppm 7.65 - 7.72 (m, 1 H) 7.75 - 7.84 (m, 1 H) 8.70 (s, 1 H) 8.81 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52.8% | A solution of 5-methoxyindoline-2,3-dione (15 g, 85 mmol) in water (150 ml) was treated with KOH (38.0 g, 677 mmol) and heated at 80C until it completely dissolved. The reaction mixture was cooled and treated with <strong>[1113-59-3]bromopyruvic acid</strong> (18.94 g, 113 mmol) and stirred at RT for 5d. The reaction mixture was treated with NaHSC^ (3.0 g) and slowly acidified with concentrated HC1. The solid product (9.8 g, 44.7 mmol, 52.8% yield) separating out was filtered washed thoroughly with water, dried in the oven at 70C under vacuum overnight and used in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | Example 43A 6-bromo-3-hydroxyquinoline-4-carboxylic Acid A solution of 5-bromoisatin (2.26 g, 10 mmol) and potassium hydroxide (4.48 g, 80 mmol) in water (10 mL) was warmed until the materials were dissolved then cooled to room temperature, treated with <strong>[1113-59-3]bromopyruvic acid</strong> (2.3 g, 14 mmol), stirred for 6 days, adjusted to pH<7 with concentrated HCl, and filtered. The solid was washed with water and ethanol and dried to provide the desired product (1.5 g, 58%). MS (DCI/NH3) m/e 269 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 1: To a solution of cyclohexane-1,3-dione (S5-SM, 88 g, 786 mmol) in aqueous potassium hydroxide (45 g, 800 mmol) in an ice bath, was added a freshly prepared solution of<strong>[1113-59-3]bromopyruvic acid</strong> (131.5 g, 787 mmol) in methanol (400 mL). After the removal of most of the methanol at 30 C in vacuo, water (800 mL) was added. The pH of the resulting solution was adjusted from 2 to 0.2 with concentrated hydrochloric acid and the mixture was heated under reflux at 90-100 C for 2 hrs. After cooled in an ice bath, the crystalline product was filtered off and dried to give S5-1. ?H NMR (300 MHz, CDC13) oe 13.173 (s, 1H), 8.416 (s, 1H), 2.978-2.936(m, 2H), 2.613-2.493 (m, 2H), 2.182-2.119 (m, 2H); LC-MS (ESI): 179 [M-H]. | ||
Step 1: To a solution of cyclohexane-l,3-dione (S5-SM, 88 g, 786 mmol) in aqueous potassium hydroxide (45 g, 800 mmol) in an ice bath, was added a freshly prepared solution of <strong>[1113-59-3]bromopyruvic acid</strong> (131.5 g, 787 mmol) in methanol (400 mL). After the removal of most of the methanol at 30 C in vacuo, water (800 mL) was added. The pH of the resulting solution was adjusted from ~ 2 to 0.2 with concentrated hydrochloric acid and the mixture was heated under reflux at 90-100 C for 2 hrs. After cooled in an ice bath, the crystalline product was filtered off and dried to give S5-1. 1H NMR (300 MHz, CDC13) delta 13.173 (s, 1H), 8.416 (s, 1H), 2.978-2.936 (m, 2H), 2.613-2.493 (m, 2H), 2.182-2.119 (m, 2H); LC-MS (ESI): 179 [M-H]". |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
hydrogenchloride; In water; at 30 - 40℃; for 9h; | All starting materials can be obtained from commercial sources, for example. The major components include 3-bromo-2-oxopropionate, ethanol, methanol, concentrated hydrochloric acid (HCl), and sodium carbonate (Na2CO3, or alternatively sodium bicarbonate NaHCO3). Similar to the preparation of Glycolycin, the principal chemical reaction to produce E-Glycolycin or M-Glycolycin is also the esterification of 3-bromo-2-oxopropionate by proper alcohols. Esterification of 3-bromo-2-oxopropionate by ethanol produces E-Glycolycin, whereas esterification of 3-bromo-2-oxopropionate by methanol generates M-Glycolycin. There are at least five specific steps each in the preparation of E-Glycolycin or M-Glycolycin: (1) Place 1 mole of 3-bromo-2-oxopropionate solid (167 grams) in each reaction chamber; (2) Add 2 moles of pure ethanol (for E-Glycolycin preparation) or methanol (for M-Glycolycin preparation) to the respective reaction chamber; the excess molar amount of alcohols favors the chemical reaction toward fully utilization of 3-bromo-2-oxopropionate with favorable yield of E-Glycolycin of M- Glycolycin; (3) Add a small amount of concentrated hydrochloric acid to each chamber as the catalyst for the esterification reaction, heat the chamber to 4O0C, and let the reaction continue under constant stirring. After 60 min, cool to 3O0C, and let the reaction continue for additional 8 hours with constant stirring; (4) After the reaction is completed, cool the reaction products to 0°C with an ice-bath, add solid Na2CO3 (or NaHCO3) in the amount only sufficient to neutralize the added HCl. Do not use excess Na2CO3 (or NaHCO3) or add water, since excess Na2CO3 (or NaHCO3) or the presence of water facilitates hydrolysis of the ester products; (5) Evaporate off the excess alcohol under low pressure with proper vacuum but without heating. Alternatively, E- Glycolycin stored with the excess ethanol -2O0C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | In 1,4-dioxane; for 1h;Heating / reflux; | A solution of N-Fmoc-thiourea (5.96 g, 20 mmol) in dioxane (40 mL) was treated with <strong>[1113-59-3]bromopyruvic acid</strong> (3.34 g, 20 mmol). The reaction mixture was refluxed for 1 hour then the precipitated solids were recovered by filtration and washed with diethyl ether (3×20 mL) to afford N-Fmoc-2-aminothiazole-4-carboxylic acid (7.1 g, 97%) as a white solid. EL-HRMS: Obs. Mass, 366.0679. Calcd. Mass, 366.0674 (M+). |
97% | In 1,4-dioxane; | EXAMPLE 2 Preparation of N-Fmoc-2-aminothiazole-4-carboxylic acid. A solution of N-Fmoc-thiourea (5.96 g, 20 mmol) in dioxane (40 mL) was treated with <strong>[1113-59-3]bromopyruvic acid</strong> (3.34 g, 20 mmol). The reaction mixture was refluxed for 1 h, then the precipitated solids were recovered by filtration and washed with diethyl ether (3*20 mL) to afford N-Fmoc-2-aminothiazole-4-carboxylic acid (7.1 g, 97%) as a white solid: EI-HRMS m/e calcd for C19H14N2O4S (M+) 366.0674, found 366.0679. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 5 Preparation of 2- [(6-bromo-3 -quinolinyl)oxy] -N-( 1 , 1 -dimethylethyl)butanamide (Compound 37) Step A: Preparation of 6-bromo-3-quinolinol A solution of potassium hydroxide (39.60 g, 707.0 mmol) in water (200 mL) at 50 C was treated with 5-bromoisatin (10.00 g, 44.2 mmol) in one portion. After 1.5 h the reaction temperature had decreased to 20 C. The resulting mixture was treated with <strong>[1113-59-3]bromopyruvic acid</strong> (20.69 g, 123.9 mmol) and stirred at 20 C for 6 days. The mixture was treated with concentrated aqueous hydrochloric acid to decrease the pH to 4. The resulting precipitate was collected on a coarse frit glass funnel and washed with ethanol then water. The remaining solid was air dried over 18 h affording 13.0 g of a yellow solid, which was suspended in nitrobenzene (200 mL) and heated to 200 C. The mixture was stirred for ten minutes as rapid evolution of carbon dioxide was observed. The solution was filtered hot to remove a tan solid which was discarded. As the filtrate cooled to 20 C a solid precipitated. The solid was collected, washed with hexanes and allowed to air dry, affording the title compound as a light brown solid (5.30 g). .H NMR (DMSO-d6) delta 8.57 (s, 1H), 8.04 (s, 1H), 7.80 (d, 1H), 7.55 (d, 1H), 7.43 (s, 1H). | ||
A solution of potassium hydroxide (39.60 g, 707.0 mmol) in water (200 mL) at 50 C was treated with 5-bromoisatin (10.00 g, 44.2 mmol) in one portion. After 1.5 h the reaction temperature had decreased to 20 C. The resulting mixture was treated with <strong>[1113-59-3]bromopyruvic acid</strong> (20.69 g, 123.9 mmol) and stirred at 20 C for 6 days. The mixture was treated with concentrated aqueous hydrochloric acid to decrease the pH to 4. The resulting precipitate was collected on a coarse frit glass funnel and washed with ethanol then water. The remaining solid was air dried over 18 h affording 13.0 g of a yellow solid, which was suspended in nitrobenzene (200 mL) and heated to 200 C. The mixture was stirred for ten minutes as rapid evolution of carbon dioxide was observed. The solution was filtered hot to remove a tan solid which was discarded. As the filtrate cooled to 20 C a solid precipitated. The solid was collected, washed with hexanes and allowed to air dry, affording the title compound as a light brown solid (5.30 g)..H MR (DMSO-d6) delta 8.57 (s, 1H), 8.04 (s, 1H), 7.80 (d, 1H), 7.55 (d, 1H), 7.43 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | In 1,4-dioxane; at 80℃; for 2h; | A suspension of compound 68 (2.1 g, 18 mmol) and 3-<strong>[1113-59-3]bromopyruvic acid</strong> (3.0 g, 18 mmol) in dioxane (180 mL) was heated to 80C. Upon reaching 80 C the mixture became clear, and soon thereafter the product started to precipitate as a white solid. After 2 h of heating, the reaction mixture was cooled to rt and the precipitate was filtered off and collected. This yielded pure title product (4.4 g, 94 %). |
94% | Example 26 2-(Isopropylamino)-1,3-thiazole-4-carboxylic acid hydrobromide (26) A suspension of compound 25 (2.1 g, 18 mmol) and 3-<strong>[1113-59-3]bromopyruvic acid</strong> (3.0 g, 18 became clear, and soon thereafter, the product started to precipitate as a white solid. After 2 h of heating, the reaction mixture was cooled to RT and the precipitate was filtered off and collected. This yielded pure title product 26 (4.4 g, 94 %). | |
94% | In 1,4-dioxane; | Example 20 2-(Isopropylamino)-1,3-thiazole-4-carboxylic acid hydrobromide (20) A suspension of compound 19 (2.1 g, 18 mmol) and 3-<strong>[1113-59-3]bromopyruvic acid</strong> (3.0 g, 18 mmol) in dioxane (180 ml) was heated to 80C. Upon reaching 80C, the mixture became clear and soon thereafter the product started to precipitate as a white solid. After 2 h of heating, the reaction mixture was cooled to room temperature and the precipitate was filtered off and collected. This yielded pure title compound 20 (4.4 g, 94%). |
94% | In 1,4-dioxane; at 80℃; for 2h; | A suspension of compound 9 (2.1 g, 18 mmol) and 3-<strong>[1113-59-3]bromopyruvic acid</strong> (3.0 g, 18 mmol) in dioxane (180 mL) was heated to 80 C. Upon reaching 80 C. the mixture became clear, and soon thereafter the product started to precipitate as a white solid. After 2 h of heating, the reaction mixture was cooled to rt and the precipitate was filtered off and collected. This yielded pure title compound (4.4 g, 94%). |
94% | In 1,4-dioxane; at 80℃; for 2h; | Example 58 2-(Isopropylamino)-1,3-thiazole-4-carboxylic acid hydrobromide (58) A suspension of compound 57 (2.1 g, 18 mmol) and 3-<strong>[1113-59-3]bromopyruvic acid</strong> (3.0 g, 18 mmol) in dioxane (180 mL) was heated to 80 C. Upon reaching 80 C. the mixture became clear, and soon thereafter the product started to precipitate as a white solid. After 2 h of heating, the reaction mixture was cooled to rt and the precipitate was filtered off and collected. This yielded pure title compound (4.4 g, 94%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | In ethanol at 60℃; for 1h; | 1.S A mixture of 12.9 g (54.6 mmol) [4- (trifluoromethoxy) phenyl]-thiourea, and 9.3 g (55.7 mmol) bromopyruvic acid in 70 ml ethanol was heated to 60 °C for 1 h. The precipitate was filtered off and washed with small portions of cold ethanol to yield after drying 8.9 g (53 %) of the title compound as crystalline solid. MS (m/e): 303.1 (M-H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | In ethanol; at 60℃; for 1h; | A mixture of 7.8 g (36 mmol) 1- (4-chloro-3-methoxyphenyl)-thiourea, and 6.2 g (36 mmol) <strong>[1113-59-3]bromopyruvic acid</strong> in 80 ml ethanol was heated to 60 C for 1 h. The precipitate was filtered off and washed with small portions of cold ethanol to yield after drying 10.0 g (98 %) of the title compound as crystalline solid. MS (m/e): 283.1 (M-H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran at 20℃; for 135h; Microwave irradiation; | Rink amide resin (0. 627 g,0. 752 mmol, 1.20 mmol/g) was suspended and allowed to swell for 10 minutes in 4 mLof N, N-dimethylformamide (DMF). Phenylacetic acid (0.15 g, 1.1 mmol) and triethylamine (0.21 mL, 1.5 mmol) were then added to the reaction mixture.0- (7- Azabenzotriazol-1-yl)-N,N,N', N'-tetramethyluronium hexafluorophosphate (HATU, 0.46 g, 1.2 mmol) was added and the reaction mixture was swirled for two hours, filtered, and washed withDMF and dichloromethane. The resin was then suspended in 5 mL of toluene and 2,4-bis- (4- methoxyphenyl)-1, 3-dithia-2,4-diphosphetane-2, 4-disulfide (Lawesson's Reagent, 0.93 g, 2.3 mmol) was added to the suspension. The reaction mixture was then swirled for 2 hours at65 C, filtered, and washed with DMF and dichloromethane. The resin (0.50 g, 0.60 mmol) was then allowed to swell in 5 mL of tetrahydrofuran for 10 minutes and bromopyruvic acid (0.060 g, 0.36 mmol) was added to the reaction mixture. The mixture was then subjected to microwave irradiation for 20 minutes at135 C, and followed by filtration to yield crude 2-benzyl-thiazole-4- carboxylic acid. MSnilz calc. 219.0, found (ESI); 220.2(M+HF). Retention time 2.38 minutes. The crude acid was dissolved in 2 mL of acetonitrile containing triethylamine (0.0836 mL, 0.600 mmol) and2- (3, 4-dimethoxy-phenyl)-ethylamine (0.0332 mL, 0.200 mmol).0- (7-Azabenzotriazol-1-yl)-N, N, N',N'-tetramethyluronium hexafluorophosphate (0.0836 g, 0.220 mmol) was added and the solution was allowed to stir for 16 hours. The reaction mixture was then purified by reverse-phase preparative liquid chromatography to yield (0.011 g, 0.029 mmol, 4.8 %) a colorless oil. MSSz calc.382. 1, found (ESI); 383.2(M+H+) Retention time 2.97 minutes NMR (400 MHz, CD3CN)oS 2.85 (t, J = 7.0 Hz, 2H), 3.53-3. 65 (m, 2H), 3.78 (s, 3H), 3.80 (s, 3H), 4.33 (s, 2H), 6.78-6. 91 (m, 3H), 7.29-7. 42 (m,5H), 7.52 (s, 1H), 7.92 (s, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In ethanol; at 20℃; for 18h;Heating / reflux; | 2-(1H-Pyrrolo[2,3-b]pyridin-3-yl)-thiazole-4-carboarylic acid:; A mixture of 1H-pyrrolo[2,3-b]pyridine-3-carbothioic acid amide (2.53 g, 14.37 mmol), <strong>[1113-59-3]bromopyruvic acid</strong> (2.4 g, 14.37 mmol) in ethanol (50 mL) was refluxed for 2 h. The solution was left at room temperature for 16 h and precipitated solid was filtered to give 2-(lH-pyrrolo[2,3-b ]pyridin-3-yl)-thiazole-4-carboxylic acid (3.5 g, 100%) as a yellow solid MS 246 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; | EXAMPLE 2 3-(Bromomethyl)-2(1H)-Quinoxalinone O-phenylenediamine (1.0 g., 0.0092 mol.) was dissolved in tetrahydrofuran (50 ml.) and 3-bromopyruvic acid (1.7 g., 0.0102 mol.) added. The reaction mixture was stirred at room temperature for one hour, during which time the product precipitated as a yellow solid. The product was collected by filtration and crystallized from methylene chloride. (0.91 g., m.p. 221-223 (dec.) 41%) Analysis Calc'd for: C9 H7 ON2 Br: C, 45.21; H, 2.95; N, 11.71; Br, 33.43. Found: C, 45.38; H, 2.82; N, 12.04; Br, 33.57. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | With sodium acetate; In methanol; at 20℃; for 5h; | 1.7 g (10.0 mmol) of 3-bromo-2-oxopropionic acid was dissolved in 50 mL of methanol, then 1.6 g (20.0 mmol) of anhydride sodium acetate and 1.1 g (10 mmol) of propyloxyamine hydrochloride were added thereto, followed by stirring for 5 hours at room temperature. The solvent was removed, and ethyl acetate was added thereto, followed by washing with 1 N HCl. An organic layer was dried over anhydrous magnesium sulfate and filtered off, and then solvent was removed and the residue was recrystallized with hexane/ethyl acetate (10/1) to obtain 76 g of the title compound in a yield of 34%.NMR: 1H-NMR(CDCl3) delta 4.14(4H, m), 4.19(2H, s), 1.69~1.64(2H, m), 0.93(3H, 8Hz)Mass(EI) 224, 226(M++1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
> 95% | With Dichloromethyl methyl ether; at 20 - 50℃; for 2.5h; | 1, 1-Dichlorodimethyl ether (2.5g. 21 ,74 mmol) was added slowly to solid Bromopyruvic acid (1) while maintaining the temperature below 2.0C. The resulting slurry was slowly heatedto 5WC and stIrred lix 2.5 it The. clear solution was cooled and the excess of dichlorodim.ethyi ether was concentrated under vacuum to obtain 3-bromopyruvic chloride (2) in greater than 95%yield. |
With Dichloromethyl methyl ether; at 20 - 50℃; for 2.16667h; | 3-Bromopyruvic acid'hydratc (3.34 g, 20 mmol) was placed in a flask and 1,1- dichloromethyl methyl ether (3.7 mL, 20 mmol) was added at 20C. The mixture was heated to 500C with stirring and a clear solution was obtained in 10 minutes. Heating was continued for 2 h. Solvent was removed under high vacuum to give 3-bromopyruvic chloride (6 g, 90% pure by 1H NMR) and the compound was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | In 1,4-dioxane; for 2h;Heating / reflux; | Step 1. 2-Phenyl-thiazole-4-carboxylic acid A solution of thiobenzamide (Aldrich; 1.37 g, 10 mmol) and 3-bromopyruvic acid (1.67 g, 10 mmol) in dioxane (50 mL) was heated at reflux for 2 hrs. The solution was concentrated in vacuo. Water (50 mL) was added. The resulting solid was filtered and triturated with ether to give a white solid (2.0 g, 99%). |
0.8 g | In 1,4-dioxane; at 110℃; for 2h; | To a solution of 1-1 (1.0 g, 7.3 mmol) and 3-bromopyruvic acid (1.2 g, 7.3 mmol) in 1,4-dioxane (50 mL). The reaction mixture was stirred at 110 C. for 2 hours. The mixture was quenched with ice water (100 mL), extracted with EtOAc, washed with brine, dried with anhydrous Na2SO4, filtered and concentrated to give the crude product. The crude product was purified by silica gel chromatography eluted to give product 1-2 (0.8 g, 53.5). MS m/z [ESI]: 206.0 [M+1]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | In 1,4-dioxane; at 50℃; for 1.2h; | EXAMPLE 32Preparation of Intermediate Compound 32AA mixture of 3-bromopyruvic acid (16.37 g, 98.05 mmol) in anhydrous dioxane (90 ml_) was treated with ethyl thioamidooxalate (13.08 g, 98.22 mmol) for 1.2 h at 50 0C, and was then concentrated at 50 0C to yield a dry yellow solid. The crude product was dissolved in saturated sodium bicarbonate (150 mL) and water (150 mL). This solution was extracted with ethyl acetate (6 x 400 mL). The aqueous EPO <DP n="136"/>layer was then acidified to pH 2 with concentrated aqueous HCI (21 ml_), resulting in the formation of a heavy precipitate. This suspension was extracted with ethyl acetate (5 x 500 ml_). These extracts were pooled, dried with sodium sulfate, filtered, concentrated, and dried for about 15 hours under vacuum to yield compound 32A as a red-brown solid (14.36 g, 73% yield) which was used without further purification. |
62.8% | In tetrahydrofuran; at 60℃; for 16h; | 3-Bromo-2-oxopropanoic acid and ethyl amino(thioxo)acetate in THF (100 ml) were stirred at 60C for 16 h. The reaction mixture was reduced in vacuo to give an orange solid. The solid was triturated with E0, filtered and dried in vacuo to give the titled compound (4.54 g, 62.8%) as a colourless solid. 1 H-NMR (DMSO-d6, 500 MHz): d[ppm]= 13.40 (s, 1 H), 8.77 (s, 1 H), 4.40 (q, J = 7.1 Hz, 2H), 1 .35 (t, J = 7.1 Hz, 3H) HPLCMS (ESI+): [m/z]: 201.90 [M+H]+ |
41% | In tetrahydrofuran; at 20℃; for 12h;Inert atmosphere; | Ethyl thiooxamate (1.0 Kg, 7.52 mol) was added portion-wise to a solution of 2- bromopyruvic acid (1.38 Kg, 8.27 mol) in THF (4 L) over 20 min while the reaction was cooled with water bath. The reaction mixture was stirred for 12 h at room temperature. The reaction mixture was filtered to remove solid. The filtrate was concentrated to dryness to afford crude compound 70-1 (1.8 kg). The crude 70-1 was triturated with EtOAc/hexane/H20 (1 :3 :2, 6 L), filtered, and the solid was further triturated with EtO Ac/hexane (1 :8, 3 L), filtered, and the solid was dissolved in DCM (6 L), dried over anhydrous Na2S04, concentrated to afford compound 70-1 (617 g, 41% yield based on ethyl thiooxamate) as light yellow solid. 1H NMR (400 MHz, CDCI3): d 8.79 (s, 1H), 4.38-4.46 (q, J= 7.2 Hz, 2H), 1.3-1.38 (t, J= 7.2 Hz, 3H). |
A mixture of 3-bromopyruvic acid (16.4 g, 98.0 mmol) in anhydrous dioxane (90 mL) was treated with ethyl thioamidooxalate (13.1 g, 98.2 mmol). The reaction flask was immersed in an oil-bath preheated to 50 C, and within minutes the solution was fully homogenous. The reaction was stirred for 1.5 h at 50 C, and was then concentrated at 50 C to provide a dry yellow solid. The crude product was dissolved in saturated sodium bicarbonate (150 mL) and water (150 mL). This solution was extracted with ethyl acetate (6 x 400 mL) and the organic extracts were discarded. The aqueous layer was then acidified to pH 2 with 21 mL of concentrated aqueous HCI, resulting in a change to a dark red color and the formation of a heavy precipitate. This suspension was then extracted with ethyl acetate (5 x 500 mL). These extracts were combined, dried over sodium sutfate, filtered and concentrated in vacuo to provide Compound 3A as a red-brown solid (14.4 g, 73%). | ||
In 1,4-dioxane; at 50℃; for 1.5h;Inert atmosphere; | To a 3-neck, 200 mL round bottom flask under nitrogen was added 3-bromo-2-oxopropanoic acid (5 g, 30 mmol) and anhydrous 1,4-dioxane (50 mL). To this mixture was added ethyl 2-amino-2-thioxoacetate (4.1 g, 31 mmol) and the mixture heated at 50 C. for 1.5 h. The reaction was concentrated to dryness, the residue was dissolved in saturated aqueous NaHCO3 (100 mL) and water (100 mL), and the aqueous solution extracted with ethyl acetate (4 ×100 mL). The aqueous layer was acidified to pH 2 with concentrated HCl. After precipitate formation (20 min) the aqueous mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to dryness to give the title compound as a red solid, which was used in next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
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59% | In tetrahydrofuran; at 20℃; for 4h; | 3-Bromopuruvic acid (2.94 g, 17.6 mmol) was added to a stirred solution of 1,1-dimethyl-thiourea (1.87 g, 17.6 mmol) in dry THF (60 mL). The reaction mixture was stirred at rt for 4 hrs. The precipitate that had formed was filtered off, washed with cold THF and dried on high vacuum. LC-MS showed the product peak. The product was obtained as a white solid (2.64 g, 59%). |
59% | In tetrahydrofuran; at 20℃; for 96h; | Example 69 2-Dimethylamino-thiazole-4-carboxylic acid *HBr (69) 3-Bromopuruvic acid (2.94 g, 17.6 mmol) was added to a stirred solution of N,N-di-methyl-thiourea (1.87 g, 17.6 mmol) in dry THF (60 mL). The reaction mixture was stirred at rt for 4 hrs. The precipitate that had formed was filtered off, washed with cold THF and dried on high vacuum. LC-MS showed the product peak. The title compound was obtained as a white solid (2.64 g, 59%). |
Yield | Reaction Conditions | Operation in experiment |
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In acetonitrile; at 85℃; for 12h;Sealed tube; | 8-Bromo-imidazo[l,2-alpha]pyridine-2,5-dicarboxylic acid 5-methyl ester: -amino-S-bromo-pyridine^-carboxylic acid methyl ester (1 eq.) is dissolved in acetonitrile (0.2 M). To this solution is added 3 -bromopyruvic acid (1.1 eq.). The reaction is stirred at 85 0C in a sealed tube for 12 h and then cooled to room temperature. The resulting solid is collected and washed with acetonitrile to provide a yellow brown solid, m/z 379 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
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In acetonitrile; at 85℃; for 12.0h;Sealed tube; | -amino-S-bromo-pyridine^-carboxylic acid methyl ester (1 eq.) is dissolved in acetonitrile (0.2 M). To this solution is added 3-bromopyruvic acid (1.1 eq.). The reaction is stirred at 85 0C in a sealed tube for 12 h and then cooled to room temperature. The resulting solid is collected and washed with acetonitrile to provide a yellow brown solid, m/z 301 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
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80% | In N,N-dimethyl-formamide; at 20 - 80℃; for 1h; | Step C.1 : Preparation of the 2-[(3-chlorophenyl)aminol-1 ,3-thiazole-4-carboxylic acid:<strong>[1113-59-3]3-bromo-2-oxopropanoic acid</strong> (5,080 g) is dissolved in DMF (5,5 ml). A solution of 3-chloro-phenyl- thiourea (4,870 g) in DMF (4 ml) is added at room temperature. After stirring at 800C for 1 hour, a precipitate is present in the reaction mixture. After cooling down and adding water, this precipitate is filtered, washed with water, Et20 then dried with MgSO4. The desired compound 2-[(3- chlorophenyl)amino]-1 ,3-thiazole-4-carboxylic acid is obtained (yield: 80%). |
Yield | Reaction Conditions | Operation in experiment |
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48% | Stage #1: 5-chloro-2,3-diaminopyridine; bromopyruvic acid In N,N-dimethyl-formamide at 125℃; for 0.333333h; Automated synthesizer; Stage #2: cyclohexylamine With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 75℃; for 0.166667h; Automated synthesizer; |
Yield | Reaction Conditions | Operation in experiment |
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50% | Stage #1: methyl 2-aminoisonicotinate; bromopyruvic acid In N,N-dimethyl-formamide at 125℃; for 0.333333h; Automated synthesizer; Stage #2: cyclohexylamine With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 75℃; for 0.166667h; Automated synthesizer; |
Yield | Reaction Conditions | Operation in experiment |
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With hydrogenchloride; potassium hydroxide; In methanol; water; | Step 1: 2-(4-Hydroxyphenyl)-1,3-thiazole-4-carboxylic Acid 4-Hydroxybenzenecarbothioamide (1.53 g, 10 mmol) and potassium hydroxide (1.50 g, 26.8 mmol) were dissolved in a mixture of 60 ml of water and 15 ml of methanol. A solution of bromopyruvic acid (1.67 g, 10 mmol) in 10 ml of methanol was added dropwise at room temperature. The resulting mixture was heated to reflux for 1.5 h, cooled to room temperature, poured into 100 ml of water and adjusted with 0.2N HCl solution to pH2. The mixture was placed in a refrigerator for 15 h. The title compound was obtained by filtration as a brown solid. 1H NMR (400 MHz, DMSO-d6) delta ppm 6.82 (d, 2H), 7.78 (d, 2H), 8.37 (s, 1H), 10.05 (s, 1H), 13.00 (s, 1H). | |
With hydrogenchloride; potassium hydroxide; In methanol; water; | Step 1: 2-(4-Hydroxyphenyl)-1,3-thiazole-4-carboxylic Acid 4-Hydroxybenzenecarbothioamide (1.53 g, 10 mmol) and potassium hydroxide (1.50 g, 26.8 mmol) were dissolved in a mixture of 60 ml of water and 15 ml of methanol. A solution of bromopyruvic acid (1.67 g, 10 mmol) in 10 ml of methanol was added dropwise at room temperature. The resulting mixture was heated to reflux for 1.5 h, cooled to room temperature, poured into 100 ml of water and adjusted with 0.2N HCl solution to pH2. The mixture was placed in a refrigerator for 15 h. The title compound was obtained by filtration as a brown solid. 1H NMR (400 MHz, DMSO-d6) delta ppm 6.82 (d, 2H), 7.78 (d, 2H), 8.37 (s, 1H), 10.05 (s, 1H), 13.00 (s, 1H). | |
With potassium hydroxide; In methanol; water; at 20℃; for 1.5h;Reflux; | 4-Hydroxybenzenecarbothioamide (1.53 g, 10 mmol) and potassium hydroxide (1.50 g, 26.8 mmol) were dissolved in a mixture of 60 ml of water and 15 ml of methanol. A solution of bromopyruvic acid (1.67 g, 10 mmol) in 10 ml of methanol was added dropwise at room temperature. The resulting mixture was heated to reflux for 1.5 h, cooled to room temperature, poured into 100 ml of water and adjusted with 0.2N HCl solution to pH2. The mixture was placed in a refrigerator for 15 h. The title compound was obtained by filtration as a brown solid. |
Yield | Reaction Conditions | Operation in experiment |
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97% | In acetonitrile; at 80℃; for 2h; | (Example 33a) 2-[4-(ethoxycarbonyl)-1H-pyrazol-1-yl]methyl}-1,3-thiazole-4-carboxylic acid [Show Image] To a solution (9 mL) of the compound (2.0 g, 9.38 mmol) obtained in Example 1b in acetonitrile was added <strong>[1113-59-3]3-bromo-2-oxopropanoic acid</strong> (1.9 g, 11.3 mmol), and the mixture was stirred at 80C for 2 hr. The resulting crystals were collected by filtration and washed with hexane to give the title compound (2.56 g, 97%) as pale-brown crystals. 1H NMR (400 MHz, DMSO-d6) delta ppm 1.27 (3 H, t, J=7.1 Hz), 4.23 (2 H, q, J=7.1 Hz), 5.80 (2 H, s), 7.97 (1 H, s), 8.43 (1 H, s), 8.57 (1 H, s) LCMS (ESI+) M+H+: 282. |
Yield | Reaction Conditions | Operation in experiment |
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84% | In acetonitrile; at 20℃; | Synthesis 343-(lmino(3-methyl-4-oxo-3,4-dihydroimidazo[5, 1 -d][1 ,2,3,5]tetrazin-8-yl)methylthio)-2- oxopropanoic acidTo a solution of 3-<strong>[1113-59-3]bromopyruvic acid</strong> (1.388 g; 8.3 mmol) in dry acetonitrile (20 mL) was added 3-methyl-4-oxo-3,4-dihydroimidazo[5, 1 -d][1 ,2,3,5]tetrazine-8-carbothioamide (1.000 g; 4.8 mmol). The mixture was stirred at room temperature overnight, and then concentrated under reduced pressure. The residue was washed with DCM (3 x 15 mL) and diethyl ether (2 x 20 mL) and the pale yellow solid (1.20 g; 84%) was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
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67% | With sulfuric acid;Inert atmosphere; | Trimethyl orthoformate (3 equiv) and sulfuric acid (0.25 equiv) were used to dissolve <strong>[1113-59-3]bromopyruvic acid</strong> (1 equiv) under argon. The mixture is stirred overnight for less than 24 h. Acid work-up was done by extracting with 10% aqueous hydrochloric acid. After back extraction of aqueous layers with methylene chloride and/or ethyl acetate, the organic layers were combined, dried over sodium sulfate, filtered, and concentrated in vacuo. |
Yield | Reaction Conditions | Operation in experiment |
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85% | With sodium azide; In dimethyl sulfoxide; at 20℃; for 2.66h; | [248] Synthesis of ammonium (£)-2-(2-(4-(3,4-dichlorophenyl)thiazol-2-yl)hydrazono)-3-(4- (pyridin-2-yl)- 1 H- 1 ,2,3 -triazol- 1 -yl)propanoate : KY-767-batch-A (E)-KY-767; [249] Synthesis of 3-azido-2-oxopropanoic acid: KY-740 <strong>[1113-59-3]3-bromo-2-oxopropanoic acid</strong> (1.66 gr, 10 mmol) was added to a solution of sodium azide (0.715 gr, 11 mmol) in DMSO (20 ml) which was prepared by stirring the sodium azide in DMSO at room temperature for 40 min. the mixture reaction was stirred for 2h at room temperature. It was quenched with water (50 ml). The mixture was extracted with Et20 ( 3 XI 00ml). The combined organic layers were washed with water, dried with Na2S04, filtered, and concentrated in vacuo. Yield 1.1 gr (85%). 'HNMR (400 MHz, DMSO-d6) delta 6.3 (s, 2H). 13C-NMR 6 113.52, 136.31, 165.3. |
Yield | Reaction Conditions | Operation in experiment |
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54% | In 1,4-dioxane; at 100℃; | [00736] To a solution of <strong>[1113-59-3]bromopyruvic acid</strong> (2.0 g, 11.98 mmol) in anhydrous 1, 4-dioxane (20 ml) was added ethyl amino(thioxo)acetate (1.60 g, 11.98 mmol) and stirred at 100 C overnight. The reaction mixture was cooled to room temperature, basified with saturated NaHC03 solution and extracted with EtOAc (2 x 20 ml). The organic extracts were discarded. The aqueous extracts were then acidified to pH 3/4 using 5M aq HCl solution and extracted with EtOAc (2 x 50 ml). The organic extracts were dried over sodium sulfate and concentrated in vacuo to afford the title compound (1.34 g, 54%) as an orange powder. [00737] Method B: LC-MS m/z = 201.85 [M + H]+; RT = 0.80 min. |
In 1,4-dioxane; for 5h;Reflux; | Bromopyruvic acid (22.7 g, 135.33 mmol) was added to a solution of ethyl 2-amino-2- thioxoacetate (Intermediate W, 18 g, 135.3 mmol) in dioxane (200 mL) and refluxed for 5 h. After completion the reaction mixture was poured into water (200 mL), the residue was basified with sat NaHC03 and extracted with EtOAc (2 x 250 mL). The aqueous layer was acidified with 2N HC1 and extracted with EtOAc (2 x 250 mL). The combined extracts were washed with water (250 mL), brine (250 mL), dried over anhydrous Na2S04, filtered and evaporated to afford 2-(ethoxycarbonyl)thiazole-5-carboxylic acid (13 g crude). The crude was carried to next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
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In 1,4-dioxane; for 24h;Reflux; | Step B : Preparation of the HBr salt of 6-(trifluoromethyl)imidazo[ 1 ,2-a]pyrimidine-2- carboxylic acidThe product of Step A (1.0 g, 6.1 mmol) was added to a solution of bromopyruvic acid (1.025 g, 6.134 mmol) in dioxane (30 mL), and the reaction mixture was heated at reflux for 24 hours. The dioxane was removed under reduced pressure to give 798 mg of the title compound. .H NMR ((CD3)2SO) delta 9.67 (s, 1H), 8.99 (s, 1H), 8.49 (s, 1H), 5.98 (br s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
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28.9% | Step 1 ethyl imidazo[1,2-c]pyrazine-3-carboxylate Pyrazin-2-amine 4a (1 g, 10 mmol) was dissolved in 50 mL of ethylene glycol dimethyl ether, followed by addition of 50 mL of methanol and 3-bromo-2-oxo-propionate (2.30 g, 12 mmol). After stirring for 4 hours at room temperature, the reaction mixture was cooled to 0 C. and stirred for 30 minutes until a solid precipitated. The reaction mixture was filtered, and the filter cake was washed with ether (10 mL*3). The solid was dissolved in 50 mL of anhydrous ethanol and the solution was refluxed for 4 hours. The reaction mixture was concentrated under reduced pressure, added with 100 mL of dichloromethane, washed successively with saturated sodium carbonate solution (40 mL) and saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain ethyl imidazo[1,2-a]pyrazine-3-carboxylate 14a (0.55 g, yield 28.9%) as a brown solid. MS m/z (ESI): 192.1 [M+1] |
Yield | Reaction Conditions | Operation in experiment |
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78% | General procedure: To a hot air dried round bottomed flask, containing a solution of isothiocyanate(2.0 mmol) and DMF (5 mL), amidine/guanidine (2.0 mmol) was added at20-25 C temperature and the solution was stirred for 2-3 h. To the abovesolution, halomethylene compound (2.0 mmol) in DMF (5 mL) was added atambient temperature and it was further maintained for 8-24 h with stirring (inthe case of chloro compounds, reaction was warmed to 40-45 C). Progress ofthe reaction was monitored by TLC using ethyl acetate/hexane (2:8). After thecompletion of reaction, the reaction mixture was poured into ice. Upon stirring,precipitate was observed (in the case of no precipitation, reaction mass wasextracted with either dichloromethane or ethyl acetate) which were collectedthrough Buchner funnel. These precipitates were then dissolved in eitherdichloromethane or ethyl acetate and dried over anhydrous magnesium sulfateand concentrated under reduced pressure. The residues were further subjectedto purification either by chromatography or by treating with hexane and/orether to give the pure compounds (4a-t). |
Yield | Reaction Conditions | Operation in experiment |
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With potassium hydroxide In methanol; water for 0.5h; | 150.150A Example 150A 4-oxo-4,7-dihydro-5H-spiro[1-benzofuran-6,1′-cyclobutane]-3-carboxylic acid To a solution of spiro[3.5]nonane-6,8-dione (CAS221342-48-9) (9.36 g, 61.5 mmol) in water (50 mL) was added potassium hydroxide (4.49 g, 80 mmol). The reaction was cooled in an ice bath, and then a solution of 3-bromo-2-oxopropanoic acid (10.27 g, 61.5 mmol) in methanol (50 mL) was added dropwise over 30 minutes. The mixture was concentrated under reduced pressure, and the residue was acidified with 37% HCl and heated to reflux overnight. The mixture was cooled and then extracted with CH2Cl2 (3×200 mL). The combined CH2Cl2 layers were concentrated and purified by chromatography on silica gel eluting with CH2Cl2. Precipitation from methanol provided the titled compound. 1H NMR (400 MHz, CDCl3) δ ppm 13.12 (s, 1H), 8.08 (s, 1H), 3.08 (s, 2H), 2.80 (s, 2H), 2.06-1.94 (m, 6H) | |
With potassium hydroxide In methanol; water for 0.5h; | 150.150A Example 150A 4-oxo-4,7-dihydro-5H-spiro[1-benzofuran-6,1'-cyclobutane]-3-carboxylic acid Example 150A 4-oxo-4,7-dihydro-5H-spiro[1-benzofuran-6,1'-cyclobutane]-3-carboxylic acid To a solution of spiro[3.5]nonane-6,8-dione (CASNo.221342-48-9) (9.36 g, 61.5 mmol) in water (50 mL) was added potassium hydroxide (4.49 g, 80 mmol). The reaction was cooled in an ice bath, and then a solution of 3-bromo-2-oxopropanoic acid (10.27 g, 61.5 mmol) in methanol (50 mL) was added dropwise over 30 minutes. The mixture was concentrated under reduced pressure, and the residue was acidified with 37% HCl and heated to reflux overnight. The mixture was cooled and then extracted with CH2Cl2 (3*200 mL). The combined CH2Cl2 layers were concentrated and purified by chromatography on silica gel eluting with CH2Cl2. Precipitation from methanol provided the titled compound. 1H NMR (400 MHz, CDCl3) δ ppm 13.12 (s, 1H), 8.08 (s, 1H), 3.08 (s, 2H), 2.80 (s, 2H), 2.06-1.94 (m, 6H). |
Yield | Reaction Conditions | Operation in experiment |
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In tetrahydrofuran; at 0 - 20℃; for 4h; | To a solution of <strong>[1683-85-8]<strong>[1683-85-8]5-fluoropyrimidin-2-amin</strong>e</strong> 86-a (3.17 g, 28.0 mmol) in DMF (14 mL) at 0 C. was added bromopyruvic acid (7.73 g, 53.4 mmol). The reaction mixture was stirred for 2 hours at 0 C. and then for 2 days at room temperature. The reaction was diluted with acetone; precipitate formed and intermediate 86-b.HBr was collected by filtration as a beige solid. |
Yield | Reaction Conditions | Operation in experiment |
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46% | General procedure: The first reaction, the formation of imidazo[1,2-a]pyridine-2-carboxylic acid, was carried out in a 1000 muL reactor (glasschip) at 100 C. The acid exiting the first reactor was combinedwith EDC/HOBt/DIPEA (1:1:1, 0.5 M, DMA) in a T-mixer.The synthesis of amidoxime (ArCN/NH2OH·HCl/DIPEA(1.1:1:3), 0.4 M, DMA) was achieved by placing a secondreactor (250 muL glass chip) in a heated silicone oil bath at100 C. This stream was next introduced into a third reactor andmixed with the stream exiting from the T-mixer at 150 C. Thestream exiting the third chip was collected after passing throughthe back pressure regulator. This reaction was carried out with aback pressure of 4.0 bar. The reaction mixture was mixed withexcess water and extracted three times with dichloromethane.The combined organic layers were washed with brine, driedover magnesium sulfate, filtered, and concentrated and the residue was purified via automated flash chromatography(SiO2) to afford the desired product (CombiFlash Rf, 12g flashcolumn). The solvent gradient was 90% hexane to 50% ethylacetate over 15 min at a flow rate of 15 mL/min. |
Yield | Reaction Conditions | Operation in experiment |
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32% | General procedure: The first reaction, the formation of imidazo[1,2-a]pyridine-2-carboxylic acid, was carried out in a 1000 muL reactor (glasschip) at 100 C. The acid exiting the first reactor was combinedwith EDC/HOBt/DIPEA (1:1:1, 0.5 M, DMA) in a T-mixer.The synthesis of amidoxime (ArCN/NH2OH·HCl/DIPEA(1.1:1:3), 0.4 M, DMA) was achieved by placing a secondreactor (250 muL glass chip) in a heated silicone oil bath at100 C. This stream was next introduced into a third reactor andmixed with the stream exiting from the T-mixer at 150 C. Thestream exiting the third chip was collected after passing throughthe back pressure regulator. This reaction was carried out with aback pressure of 4.0 bar. The reaction mixture was mixed withexcess water and extracted three times with dichloromethane.The combined organic layers were washed with brine, driedover magnesium sulfate, filtered, and concentrated and the residue was purified via automated flash chromatography(SiO2) to afford the desired product (CombiFlash Rf, 12g flashcolumn). The solvent gradient was 90% hexane to 50% ethylacetate over 15 min at a flow rate of 15 mL/min. |
Yield | Reaction Conditions | Operation in experiment |
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44% | General procedure: The first reaction, the formation of imidazo[1,2-a]pyridine-2-carboxylic acid, was carried out in a 1000 muL reactor (glasschip) at 100 C. The acid exiting the first reactor was combinedwith EDC/HOBt/DIPEA (1:1:1, 0.5 M, DMA) in a T-mixer.The synthesis of amidoxime (ArCN/NH2OH·HCl/DIPEA(1.1:1:3), 0.4 M, DMA) was achieved by placing a secondreactor (250 muL glass chip) in a heated silicone oil bath at100 C. This stream was next introduced into a third reactor andmixed with the stream exiting from the T-mixer at 150 C. Thestream exiting the third chip was collected after passing throughthe back pressure regulator. This reaction was carried out with aback pressure of 4.0 bar. The reaction mixture was mixed withexcess water and extracted three times with dichloromethane.The combined organic layers were washed with brine, driedover magnesium sulfate, filtered, and concentrated and the residue was purified via automated flash chromatography(SiO2) to afford the desired product (CombiFlash Rf, 12g flashcolumn). The solvent gradient was 90% hexane to 50% ethylacetate over 15 min at a flow rate of 15 mL/min. |
Yield | Reaction Conditions | Operation in experiment |
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59% | General procedure: The first reaction, the formation of imidazo[1,2-a]pyridine-2-carboxylic acid, was carried out in a 1000 muL reactor (glasschip) at 100 C. The acid exiting the first reactor was combinedwith EDC/HOBt/DIPEA (1:1:1, 0.5 M, DMA) in a T-mixer.The synthesis of amidoxime (ArCN/NH2OH·HCl/DIPEA(1.1:1:3), 0.4 M, DMA) was achieved by placing a secondreactor (250 muL glass chip) in a heated silicone oil bath at100 C. This stream was next introduced into a third reactor andmixed with the stream exiting from the T-mixer at 150 C. Thestream exiting the third chip was collected after passing throughthe back pressure regulator. This reaction was carried out with aback pressure of 4.0 bar. The reaction mixture was mixed withexcess water and extracted three times with dichloromethane.The combined organic layers were washed with brine, driedover magnesium sulfate, filtered, and concentrated and the residue was purified via automated flash chromatography(SiO2) to afford the desired product (CombiFlash Rf, 12g flashcolumn). The solvent gradient was 90% hexane to 50% ethylacetate over 15 min at a flow rate of 15 mL/min. |
Yield | Reaction Conditions | Operation in experiment |
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55% | General procedure: The first reaction, the formation of imidazo[1,2-a]pyridine-2-carboxylic acid, was carried out in a 1000 muL reactor (glasschip) at 100 C. The acid exiting the first reactor was combinedwith EDC/HOBt/DIPEA (1:1:1, 0.5 M, DMA) in a T-mixer.The synthesis of amidoxime (ArCN/NH2OH·HCl/DIPEA(1.1:1:3), 0.4 M, DMA) was achieved by placing a secondreactor (250 muL glass chip) in a heated silicone oil bath at100 C. This stream was next introduced into a third reactor andmixed with the stream exiting from the T-mixer at 150 C. Thestream exiting the third chip was collected after passing throughthe back pressure regulator. This reaction was carried out with aback pressure of 4.0 bar. The reaction mixture was mixed withexcess water and extracted three times with dichloromethane.The combined organic layers were washed with brine, driedover magnesium sulfate, filtered, and concentrated and the residue was purified via automated flash chromatography(SiO2) to afford the desired product (CombiFlash Rf, 12g flashcolumn). The solvent gradient was 90% hexane to 50% ethylacetate over 15 min at a flow rate of 15 mL/min. |
Yield | Reaction Conditions | Operation in experiment |
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35% | General procedure: The first reaction, the formation of imidazo[1,2-a]pyridine-2-carboxylic acid, was carried out in a 1000 muL reactor (glasschip) at 100 C. The acid exiting the first reactor was combinedwith EDC/HOBt/DIPEA (1:1:1, 0.5 M, DMA) in a T-mixer.The synthesis of amidoxime (ArCN/NH2OH·HCl/DIPEA(1.1:1:3), 0.4 M, DMA) was achieved by placing a secondreactor (250 muL glass chip) in a heated silicone oil bath at100 C. This stream was next introduced into a third reactor andmixed with the stream exiting from the T-mixer at 150 C. Thestream exiting the third chip was collected after passing throughthe back pressure regulator. This reaction was carried out with aback pressure of 4.0 bar. The reaction mixture was mixed withexcess water and extracted three times with dichloromethane.The combined organic layers were washed with brine, driedover magnesium sulfate, filtered, and concentrated and the residue was purified via automated flash chromatography(SiO2) to afford the desired product (CombiFlash Rf, 12g flashcolumn). The solvent gradient was 90% hexane to 50% ethylacetate over 15 min at a flow rate of 15 mL/min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | General procedure: The first reaction, the formation of imidazo[1,2-a]pyridine-2-carboxylic acid, was carried out in a 1000 muL reactor (glasschip) at 100 C. The acid exiting the first reactor was combinedwith EDC/HOBt/DIPEA (1:1:1, 0.5 M, DMA) in a T-mixer.The synthesis of amidoxime (ArCN/NH2OH·HCl/DIPEA(1.1:1:3), 0.4 M, DMA) was achieved by placing a secondreactor (250 muL glass chip) in a heated silicone oil bath at100 C. This stream was next introduced into a third reactor andmixed with the stream exiting from the T-mixer at 150 C. Thestream exiting the third chip was collected after passing throughthe back pressure regulator. This reaction was carried out with aback pressure of 4.0 bar. The reaction mixture was mixed withexcess water and extracted three times with dichloromethane.The combined organic layers were washed with brine, driedover magnesium sulfate, filtered, and concentrated and the residue was purified via automated flash chromatography(SiO2) to afford the desired product (CombiFlash Rf, 12g flashcolumn). The solvent gradient was 90% hexane to 50% ethylacetate over 15 min at a flow rate of 15 mL/min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | General procedure: The first reaction, the formation of imidazo[1,2-a]pyridine-2-carboxylic acid, was carried out in a 1000 muL reactor (glasschip) at 100 C. The acid exiting the first reactor was combinedwith EDC/HOBt/DIPEA (1:1:1, 0.5 M, DMA) in a T-mixer.The synthesis of amidoxime (ArCN/NH2OH·HCl/DIPEA(1.1:1:3), 0.4 M, DMA) was achieved by placing a secondreactor (250 muL glass chip) in a heated silicone oil bath at100 C. This stream was next introduced into a third reactor andmixed with the stream exiting from the T-mixer at 150 C. Thestream exiting the third chip was collected after passing throughthe back pressure regulator. This reaction was carried out with aback pressure of 4.0 bar. The reaction mixture was mixed withexcess water and extracted three times with dichloromethane.The combined organic layers were washed with brine, driedover magnesium sulfate, filtered, and concentrated and the residue was purified via automated flash chromatography(SiO2) to afford the desired product (CombiFlash Rf, 12g flashcolumn). The solvent gradient was 90% hexane to 50% ethylacetate over 15 min at a flow rate of 15 mL/min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | General procedure: The first reaction, the formation of imidazo[1,2-a]pyridine-2-carboxylic acid, was carried out in a 1000 muL reactor (glasschip) at 100 C. The acid exiting the first reactor was combinedwith EDC/HOBt/DIPEA (1:1:1, 0.5 M, DMA) in a T-mixer.The synthesis of amidoxime (ArCN/NH2OH·HCl/DIPEA(1.1:1:3), 0.4 M, DMA) was achieved by placing a secondreactor (250 muL glass chip) in a heated silicone oil bath at100 C. This stream was next introduced into a third reactor andmixed with the stream exiting from the T-mixer at 150 C. Thestream exiting the third chip was collected after passing throughthe back pressure regulator. This reaction was carried out with aback pressure of 4.0 bar. The reaction mixture was mixed withexcess water and extracted three times with dichloromethane.The combined organic layers were washed with brine, driedover magnesium sulfate, filtered, and concentrated and the residue was purified via automated flash chromatography(SiO2) to afford the desired product (CombiFlash Rf, 12g flashcolumn). The solvent gradient was 90% hexane to 50% ethylacetate over 15 min at a flow rate of 15 mL/min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | General procedure: The first reaction, the formation of imidazo[1,2-a]pyridine-2-carboxylic acid, was carried out in a 1000 muL reactor (glasschip) at 100 C. The acid exiting the first reactor was combinedwith EDC/HOBt/DIPEA (1:1:1, 0.5 M, DMA) in a T-mixer.The synthesis of amidoxime (ArCN/NH2OH·HCl/DIPEA(1.1:1:3), 0.4 M, DMA) was achieved by placing a secondreactor (250 muL glass chip) in a heated silicone oil bath at100 C. This stream was next introduced into a third reactor andmixed with the stream exiting from the T-mixer at 150 C. Thestream exiting the third chip was collected after passing throughthe back pressure regulator. This reaction was carried out with aback pressure of 4.0 bar. The reaction mixture was mixed withexcess water and extracted three times with dichloromethane.The combined organic layers were washed with brine, driedover magnesium sulfate, filtered, and concentrated and the residue was purified via automated flash chromatography(SiO2) to afford the desired product (CombiFlash Rf, 12g flashcolumn). The solvent gradient was 90% hexane to 50% ethylacetate over 15 min at a flow rate of 15 mL/min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | General procedure: The first reaction, the formation of imidazo[1,2-a]pyridine-2-carboxylic acid, was carried out in a 1000 muL reactor (glasschip) at 100 C. The acid exiting the first reactor was combinedwith EDC/HOBt/DIPEA (1:1:1, 0.5 M, DMA) in a T-mixer.The synthesis of amidoxime (ArCN/NH2OH·HCl/DIPEA(1.1:1:3), 0.4 M, DMA) was achieved by placing a secondreactor (250 muL glass chip) in a heated silicone oil bath at100 C. This stream was next introduced into a third reactor andmixed with the stream exiting from the T-mixer at 150 C. Thestream exiting the third chip was collected after passing throughthe back pressure regulator. This reaction was carried out with aback pressure of 4.0 bar. The reaction mixture was mixed withexcess water and extracted three times with dichloromethane.The combined organic layers were washed with brine, driedover magnesium sulfate, filtered, and concentrated and the residue was purified via automated flash chromatography(SiO2) to afford the desired product (CombiFlash Rf, 12g flashcolumn). The solvent gradient was 90% hexane to 50% ethylacetate over 15 min at a flow rate of 15 mL/min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | General procedure: The first reaction, the formation of imidazo[1,2-a]pyridine-2-carboxylic acid, was carried out in a 1000 muL reactor (glasschip) at 100 C. The acid exiting the first reactor was combinedwith EDC/HOBt/DIPEA (1:1:1, 0.5 M, DMA) in a T-mixer.The synthesis of amidoxime (ArCN/NH2OH·HCl/DIPEA(1.1:1:3), 0.4 M, DMA) was achieved by placing a secondreactor (250 muL glass chip) in a heated silicone oil bath at100 C. This stream was next introduced into a third reactor andmixed with the stream exiting from the T-mixer at 150 C. Thestream exiting the third chip was collected after passing throughthe back pressure regulator. This reaction was carried out with aback pressure of 4.0 bar. The reaction mixture was mixed withexcess water and extracted three times with dichloromethane.The combined organic layers were washed with brine, driedover magnesium sulfate, filtered, and concentrated and the residue was purified via automated flash chromatography(SiO2) to afford the desired product (CombiFlash Rf, 12g flashcolumn). The solvent gradient was 90% hexane to 50% ethylacetate over 15 min at a flow rate of 15 mL/min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | The <strong>[1113-59-3]bromopyruvic acid</strong> (11.7 g) was dissolved in dichloromethane (100 mL)Transferred to a 300 mL sealed tube,Tert-butanol (8. 8 mL) was added,Cool to _40 C and slowly add concentrated H2S04 (1.9 mL)Isobutyl (40 mL),After sealing, move to rt for 4 days.Cooled to -40 C,Open the seal,The solution was poured into 100 mL of saturated NaHOVK solution,After the gas is finished,Dichloromethane (100 mL x 3)Combine organic phase,Brine Wash the organic phase to neutral,Anhydrous MgS04 dry.Filtered and concentrated to give a yellow oily liquid 11. 08g,With triphenylphosphine (52. 2 mmol, 13. 68 g),Tetrahydrofuran (450 mL) was added to the reactor,60 C oil bath for 2 h. After cooling, the excess solvent is removed under reduced pressure,Dichloromethane (60 mL) was added,Water (90 mL),Aqueous potassium hydroxide solution (2 M, 26 mL),At room temperature after vigorous stirring 30min after the liquid,The aqueous phase was extracted with dichloromethane (50 mL x 3)Combine organic phase,Saturated sodium chloride solution to wash the organic phase,Anhydrous MgS04 dry.filter,After concentration, 100 mL of ether was added,Stirring,The resulting solid was filtered,After vacuum drying,To give 11. 73 g of a pale yellow solid as shown in Figure 12,Yield 58%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With potassium hydroxide; In methanol; at 0 - 40℃; for 1.5h;Inert atmosphere; | To the reactor was added 4-chlorobenzaldehyde (lOOmmol, 14. lg), MeOH (22 mL) under nitrogen atmosphere,Pyruvate (lOOmmol, 8.8 g),Move to 0 C low temperature reaction bath,A solution of K0H (100 mmol, 5.6 g) in MeOH (25 mL) was added dropwise with stirring,About 30min plus finished.Plus,Add K0H (50mmol, 2.8g), move to 40 C oil bath stirring lh,A large amount of yellow solid appears.After the reaction, the reaction was stirred overnight at 0 C.The next day, the resulting yellow solid was filtered through a Buchner funnel,Cold MeOH (lOOmL) rinse,After draining,Continue to dry with oil chestnut,To give 17. lg of the product as shown in the yellow solid, 7-e, in 69% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With potassium hydroxide; In methanol; at 0 - 40℃; for 1.5h;Inert atmosphere; | 4-Bromobenzaldehyde (lOOmmol, 18.5 g), MeOH (10 mL) was added to the reactor under a nitrogen atmosphere,Pyruvate (lOOmmol, 8.8 g),Move to 0 C low temperature reaction bath,A solution of K0H (100 mmol, 5.6 g) in MeOH (25 mL) was added dropwise with stirring,About 30min plus finished.After adding, add K0H (50mmol, 2.8g),Move to 40 C oil bath stirring lh,A large amount of yellow solid appears.After the reaction, the reaction was stirred overnight at 0 C.The next day,The resulting yellow solid was filtered through a Buchner funnel,Cold MeOH (lOOmL) rinse,After drying, continue to dry with oil chestnut,To give the product as a yellow solid of 7-f 24. 0 g,Yield 82% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With potassium hydroxide; In methanol; at 0 - 40℃; for 1.5h;Inert atmosphere; | To the reactor was added 4-methylbenzaldehyde (lOOmmol, 12.0 g) under nitrogen atmosphere,MeOH (lOmL),Pyruvate (lOOmmol, 8.8 g),Move to 0 C low temperature reaction bath,A solution of Kappa0H (lOOmmol, 5.6 g) in Me0H (25 mL) was added dropwise with stirring,About 30min plus finished.After adding, add K0H (50mmol, 2.8g), Moved to 40 C oil bath stirring lh,A large amount of yellow solid appears.After moving to 0 C the reaction bath was stirred overnight.The next day, the resulting yellow solid was filtered through a Buchner funnel, washed with cold Mu0Eta (100 mL), dried,To give the product as shown in the yellow solid form 7-i 19. 8 g,Yield 87% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | In ethanol; at 70℃; for 1h; | General procedure: A mixture of (E)-3-phenylprop-2-enethioamide (9) (0.082 g, 0.5 mmol) and 2-bromoacetophenone (0.099 g, 0.5 mmol) in ethanol (1.5 mL) was stirred at 70 0C for 1 h. The solvent was removed in vacuo and the crude product was extracted with EtOAc. The resulting solution was washed successively with satd. aq. NaHCO3 and water, and dried (anhydr. Na2SO4), and the solvent was removed in vacuo. The crude product was purified using column chromatography on silica gel G60, eluting with hexane-EtOAc (3:2) to give, as a yellowish, fluffy solid, 4-phenyl-2-styrylthiazole (4a) (0.109 g, 82.6%) |
0.175 g | In ethanol; at 70℃; for 1h; | General procedure: A mixture of (E)-3-phenylprop-2-enethioamide (9) (0.082 g, 0.5 mmol) and 2-bromoacetophenone(0.099 g, 0.5 mmol) in ethanol (1.5 mL) was stirred at 70C for 1 h. The solvent was removed invacuo and the crude product was extracted with EtOAc. The resulting solution was washedsuccessively with satd. aq. NaHCO3 and water, and dried (anhydr. Na2SO4), and the solvent wasremoved in vacuo. The crude product was purified using column chromatography on silica gel G60,eluting with hexane-EtOAc (3:2) to give, as a yellowish, fluffy solid, 4-phenyl-2-styrylthiazole (4a) (0.109 g, 82.6%), |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With sulfuric acid; magnesium sulfate; In dichloromethane; at 20℃;Inert atmosphere; | The RB flask was charged with MgSO4 (2.88 g, 24 mmol) and 30 mL of dry DCM under argon atmosphere, after which concentrated H2SO4 (0.32 mL, 6 mmol) was added. After stirring for 5 min, 3-<strong>[1113-59-3]bromopyruvic acid</strong>, (3-BP) (3 g, 18 mmol) and 1-octanol (0.95 mL, 6 mmol) were added. The reaction mixture was stirred overnight at RT. The reaction was quenched by slow addition of water and then aq. NaHCO3 at 0 C. The organic layer was separated, the aqueous layer was washed with DCM (2*50 mL) and combined organic fractions were washed with brine (100 mL). The solvent was evaporated to give octyl 3-bromo-2-oxopropanoate as yellowish oil (1.54 g, 92%) or tetradecyl 3-bromo-2-oxopropanoate as a white solid (1.97 g, 91%). j0489] Tetradecyl 3-bromo-2-oxopropanoate: 1H NMR(400 MHz, CDC13, ppm): oe 0.87 (t, 3H, J=6 Hz, CH3),1.27-1.40 (m, 22H, 11xCH2), 1.70-1.76 (m, 2H, CH2),4.29-4.32 (m, 5H, OCH2, HrCH2); 13C NMR (400 MHz,CDC13, ppm): 14.10 (CH3), 22.67 (CH2), 25.69 (CH2),28.28 (CH2), 29.10 (CH2), 29.29 (HrCH2), 29.33 (CH2),29.42 (CH2), 29.51 (CH2), 29.56 (CH2), 29.63 (CH2),29.68 (CH2), 30.74 (CH2), 31.90 (CH2), 67.28 (OCH2),159.43 (C0), 184.63 (CrrrO). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With sulfuric acid; magnesium sulfate; In dichloromethane; at 20℃;Inert atmosphere; | The RB flask was charged with MgSO4 (2.88 g, 24 mmol) and 30 mL of dry DCM under argon atmosphere, after which concentrated H2SO4 (0.32 mL, 6 mmol) was added. After stirring for 5 min, 3-<strong>[1113-59-3]bromopyruvic acid</strong>, (3-BP) (3 g, 18 mmol) and 1-octanol (0.95 mL, 6 mmol) were added. The reaction mixture was stirred overnight at RT. The reaction was quenched by slow addition of water and then aq. NaHCO3 at 0 C. The organic layer was separated, the aqueous layer was washed with DCM (2*50 mL) and combined organic fractions were washed with brine (100 mL). The solvent was evaporated to give octyl 3-bromo-2-oxopropanoate as yellowish oil (1.54 g, 92%) or tetradecyl 3-bromo-2-oxopropanoate as a white solid (1.97 g, 91%). Octyl 3-bromo-2-oxopropanoate: 1H NMR (400 MHz, CDCl3, ppm): delta 0.87 (t, 3H, J=6 Hz, CH3), 1.22-1.40 (m, 10H, 5*CH2), 1.70-1.77 (m, 2H, CH2), 4.30 (t, 2H, J=8 Hz, OCH2), 4.32 (s, 2H, BrCH2); 13C NMR (400 MHz, CDCl3, ppm): 14.05 (CH3), 22.59 (CH2), 25.66 (CH2), 28.27 (CH2), 29.09 (2*CH2), 29.27 (BrCH2), 30.74 (CH2), 67.27 (OCH2), 159.40 (C=O), 184.64 (C=O). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sulfuric acid; magnesium sulfate; In dichloromethane; at 20℃; | Concentrated sulfuric acid (87 muL) was added to a suspension of magnesium sulfate (788 mg, 6.55 mmol) in dry dichloromethane (4 mL).1.64mmol),After stirring for half an hour at room temperature,3-<strong>[1113-59-3]bromopyruvic acid</strong> (410 mg, 2.46 mmol) and phenylethyl alcohol (0.2 mL, 1.64 mmol) were added separately.The reaction proceeds at room temperatureThe progress of the reaction was monitored by TLC and 1H-NMR.After the reaction is over,The reaction solution was diluted with dichloromethane.It is decompressed and filtered with a funnel covered with diatomaceous earth.The filtrate was washed with saturated saline to remove excess 3-bromopyruvate,Then dry with anhydrous sodium sulfate.Finally, the solvent is distilled off under reduced pressure.Vacuum drying gives 1,Orange liquidYield is 95% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; at 90℃; for 2h; | General procedure: 3,4-difluoroaniline (1.29 g, 10.0 mmol) was dissolved in hydrochloric acid. Ammonium thiocyanate (1.17 g, 15.4 mmol) in water was added and the mixture was stirred at 90C for 2 h. After reaction mixture was cooled to room temperature, and extracted with ethyl acetate, the organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo and then purified by silica gel chromatography. <strong>[19250-09-0]1-<strong>[19250-09-0](3,4-dichlorophenyl)thiourea</strong></strong> and trifluorobromoacetone (0.710 g, 3.72 mmol) were dissolved in ethanol (5 mL) and stirred at 90C for 2 h. After reaction mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to give compound 7 as a white crystal (0.130 g, 0.464 mmol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | In N,N-dimethyl-formamide at 20℃; for 96h; Inert atmosphere; | 4.9 General Method E. Synthesis of 2-substituted 6-arylimidazo[1,2-a]pyrimidines General procedure: To a solution of 6, 6a-c or 10 (1 eq) in DMF (0.1M) the appropriate bromo pyruvate reagent (2 eq) was added and the reaction mixture was stirred under Ar at r.t. for 4 days. For the ethyl ester derivatives, the reaction mixture was then poured into saturated NaHCO3, extracted with CH2Cl2, washed with water, and brine, dried over anhydrous MgSO4 and concentrated in vacuo. The esters were purified with flash column chromatography (eluent 30-40°C petrol/EtOAc, 3:1 to 1:1), followed by recrystallization from EtOH. For the acid derivatives, the reaction mixture was poured into saturated NaHCO3, adjusted to pH 8 and extracted with CH2Cl2. Then, the aqueous phase was adjusted to pH 3 with conc. HCl and extracted with iPrOH/CHCl3 (1:3 v/v), dried over Na2SO4 and concentrated in vacuo. The final products were obtained after recrystallization with EtOH. Representative spectra for cpds 8a-d follow. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1,4-dioxane; at 100℃; for 16h; | To a stirred solution of <strong>[69034-08-8]5-(trifluoromethyl)pyrimidin-2-amine</strong>(A36, 4.5 g, 27.60 mmol) in l,4-dioxane(80 mL) was added 3-bromo-2-oxopropanoic acid(A15, 6.87 g , 41.4 mmol .The reaction mixture was heated at 100 C for 16 h. After completion of reaction mixture was concentrated under reduced pressure. The crude product was triturated with ethyl acetate and dried to afford 6-(trifluoromethyl)imidazo[l,2-a]pyrimidine-2-carboxylic acid A37 and A38 as dark brown mixture Yield: 7.0 g,(crude). LC-MS m/z : 229.96[M-H] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a stirred solution of the mixture A37 and A38(3, 4.5 g, l9.4mmol) in methanol(100 mL) was added drop wise H2S04(10 mL) and the reaction mixture was stirred at 80 C temperature for l6h. After completion of reaction organic solvent was evaporated and the aqueous layer was basified with Sat.NaHCCL up to pH 8 to 9 and aqueous layer was extracted with 10% MeOH in DCM and then concentrated under reduced pressure. The obtained crude was purified by column chromatography using 10% methanol in dichloromethane as eluent to afford methyl 6-(trifluoromethyl)imidazo[l,2- a]pyrimidine-2-carboxylate 1-57 and 1-58 as pink solid Yield: 0.5 g,(10%). LC-MS m/z : 245.97[M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | CS2 (150muL, 2.45mmol) was added to a solution of benzylamine (15) (50muL, 0.49mmol) in CH3CN (0.50mL) at rt and after stirring for 60min a solution of <strong>[1113-59-3]bromopyruvic acid</strong> (82mg, 0.49mmol) in CH3CN (0.30mL) was added to the reaction mixture followed by addition of Et3N (140muL, 0.98mmol). Stirring was continued at rt and after 60min, the reaction mixture was diluted with H2O (5mL) and the pH was adjusted to 4 using a 2M HCl solution. The aqueous phase was extracted with EtOAc, the combined organic layer was dried and concentrated to yield a residue (126 mg). The residue was subjected to FCC - RP C-18 and eluted with H2O-CH3CN gradient (100:0 to 50:50) to yield 3-benzyl-2-thioxo-2,3-dihydrothiazole-4-carboxylic acid (16) in 45% yield (55mg). HPLC: tR=9.4min (method B). 1H NMR (500MHz, DMSO-d6): deltaH 7.95 (s, 1H), 7.30 (t, J=7.5 HZ, 2H), 7.24 (t, J=7.5Hz, 1H), 7.10 (d, J=7.5Hz, 1H), 5.85 (s, 2H). 13C NMR (125MHz, DMSO-d6): deltaC 188.8, 158.6, 136.2, 134.7, 128.4, 127.2, 126.6, 122.3, 50.1. LC-MS -ESI: m/z 252.1 [M+H]+; 249.9 [M-H]-. HR-MS-ESI m/z: calc. for C11H10NO2S2, 252.0147 [M+H]+, found m/z 252.0149 [M+H]+. UV (HPLC, CH3CN-H2O) lambdamax: 210, 330nm. FTIR (KBr) numax: 1750, 1420, 1346, 1048cm-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | In ethanol; at 80℃;Inert atmosphere; | General procedure: A mixture of the corresponding thiosemicarbazone [25] (1.0 eq.), the - haloketone (1.2 eq.),and dry ethanol (1 mL per 100 mg of thiosemicarbazone) was heated at reflux until the disappearanceof the thiosemicarbazide (4-10 h, checked by TLC, SiO2, petroleum ether:EtOAc 70:30). After that,the mixture was cooled to room temperature, and the precipitate was filtered o and washed withethanol: Water (80:20). The solid was crystallized from ethanol or ethanol:Water. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | In ethanol; at 80℃;Inert atmosphere; | General procedure: A mixture of the corresponding thiosemicarbazone [25] (1.0 eq.), the - haloketone (1.2 eq.),and dry ethanol (1 mL per 100 mg of thiosemicarbazone) was heated at reflux until the disappearanceof the thiosemicarbazide (4-10 h, checked by TLC, SiO2, petroleum ether:EtOAc 70:30). After that,the mixture was cooled to room temperature, and the precipitate was filtered o and washed withethanol: Water (80:20). The solid was crystallized from ethanol or ethanol:Water. |
Tags: 1113-59-3 synthesis path| 1113-59-3 SDS| 1113-59-3 COA| 1113-59-3 purity| 1113-59-3 application| 1113-59-3 NMR| 1113-59-3 COA| 1113-59-3 structure
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P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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