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CAS No. : | 205985-98-4 | MDL No. : | MFCD00216528 |
Formula : | C10H9ClO3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | DMVAIJCMWPNOKV-UHFFFAOYSA-N |
M.W : | 212.63 | Pubchem ID : | 735887 |
Synonyms : |
|
Num. heavy atoms : | 14 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.2 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 52.55 |
TPSA : | 43.37 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.1 cm/s |
Log Po/w (iLOGP) : | 1.71 |
Log Po/w (XLOGP3) : | 2.11 |
Log Po/w (WLOGP) : | 2.09 |
Log Po/w (MLOGP) : | 1.88 |
Log Po/w (SILICOS-IT) : | 2.58 |
Consensus Log Po/w : | 2.07 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.54 |
Solubility : | 0.612 mg/ml ; 0.00288 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.65 |
Solubility : | 0.474 mg/ml ; 0.00223 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.45 |
Solubility : | 0.0754 mg/ml ; 0.000355 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.58 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P302+P352-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | General procedure: Method A:16,17 A two-necked round-bottomed flask equipped with a reflux condenser and a magnetic stir bar was charged with the 2-bromobenzoic acid (20mmol) and freshly distilled methanol (25mL). The solution was heated in a hot water bath, conc. H2SO4 (8mmol) was added slowly and the reaction mixture was refluxed for 24h. After cooling to room temperature around half of the amount of the solvent was removed in vacuo and the residue was partitioned between water (50mL) and diethyl ether (70mL). The organic layer was separated and washed with saturated NaHCO3 (2×50mL), water (50mL) and brine (50mL), dried over anhydrous MgSO4 and the volatiles were removed under reduced pressure. The crude product thus obtained was purified by flash chromatography on silica gel to afford the alkyl-2-halobenzoate. (0023) In a two-necked round-bottomed flask equipped with a reflux condenser and a magnetic stir bar the alkyl 2-halobenzoate (22.5mmol) was dissolved in freshly distilled dry THF (30mL) under argon. The solution was cooled to 0C using an ice bath and NaH (60% in mineral oil, 15mmol) was added portionwise. After stirring for 15min a solution of the alkyl acetate (15mmol) in dry THF (30mL) was added dropwise to the reaction mixture at 0C. The mixture was warmed up, stirred at room temperature for 2h and heated under reflux for 24h. After cooling to room temperature around half of the amount of the solvent was removed in vacuo and the reaction mixture was diluted with toluene (50mL). The resulting mixture was washed with 2N HCl (50mL), saturated NH4Cl (50mL), dried over anhydrous MgSO4 and the volatiles were removed under reduced pressure. The crude product was purified by flash column chromatography on silica gel to afford the alkyl 3-(2?-halophenyl)-3-oxo-propanoate 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With bis(1,5-cyclooctadiene)diiridium(I) dichloride; C38H37FeN2P; potassium tert-butylate; hydrogen; In methanol; at 20℃; under 15001.5 Torr; for 24h;Glovebox; | The invention has wide substrate suitability,According to the reaction conditions in Example 3,Many substrates can participate in the reaction,High yield and high enantioselectivity to obtain the beta-hydroxyester product II of the chiral center,In a glove box filled with nitrogen,[Ir(COD)Cl] 2 (0.34 mg, 0.0005 mmol) andThe chiral P,N,N ligand L1 (0.64 mg, 0.0011 mmol) was dissolved in anhydrous methanol (3.0 mL).Stir at room temperature for 1 hour.Substrate methyl benzoylacetate I-a (178 mg, 1.0 mmol) was addedAnd t-BuOK (5.6 mg, 0.05 mmol),Put it in a high pressure reactor,Hydrogen replacement 3 times,Then pass hydrogen to 20 atmospheres,The reaction was carried out for 24 hours at room temperature.Slowly release hydrogenThe solvent was removed and the product was isolated on a silica gel column to give the product methyl 3-hydroxy-3-phenylpropionate II-a. 96% yield, 92% ee. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bis(1,5-cyclooctadiene)diiridium(I) dichloride; (SC,SC,RFC)-1-(diphenylphosphino)-2-[1-N-((4S)-4-tert-butyl-2-oxazolinyl-2-ylmethyl)ethyl]ferrocene; potassium tert-butylate; hydrogen; In methanol; at 20℃; under 7500.75 Torr; for 12h;Autoclave; | General procedure: In a nitrogen-filled glovebox, a stainless steel autoclave was charged with [Ir(cod)Cl]2 (3.4 mg, 0.05 mmol) and (Sc,Rp,Sc)-L3 (6.1 mg, 0.11 mmol) in 1.0 mL of dry MeOH. After stirring for 1h at room temperature, a solution of the substrates 1 (1.0 mmol) and t-BuOK (5.6 mg, 0.05 mmol) in 2.0 mL of MeOH was added to the reaction mixture, and then the hydrogenation was performed at room temperature under an H2 pressure of 10 bar for 12 h. The solvent was then evaporated and the residue was purified by flash column chromatography to give the corresponding hydrogenation product, which was analyzed by chiral HPLC to determine the enantiomeric excesses. | |
With bis(1,5-cyclooctadiene)diiridium(I) dichloride; (S)-N-(((S)-4-(tert-butyl)-4,5-dihydrooxazol-2-yl)methyl)-1-(2-(diphenylphosphino)phenyl)ethanamine; potassium tert-butylate; hydrogen; In methanol; at 20℃; under 7500.75 Torr; for 12h;Glovebox; | General procedure: In a nitrogen-filled glovebox, a stainless steel autoclave was charged with [Ir(cod)Cl]2 (3.4 mg, 0.005 mmol) and (S,S)-L4 (4.9 mg, 0.011 mmol) in 1.0 mL of dry MeOH. After stirring for 1h at room temperature, a solution of the substrates 3 (1.0 mmol) and t-BuOK (5.6 mg, 0.05 mmol) in 2.0 mL of MeOH was added to the reaction mixture, and then the hydrogenation was performed at room temperature under an H2 pressure of 10 bar for 12 h. The solvent was then evaporated and the residue was purified by flash column chromatography to give the corresponding hydrogenation product, which was analyzed by chiral HPLC to determine the enantiomeric excesses. | |
With bis(1,5-cyclooctadiene)diiridium(I) dichloride; (S)-N-(((S)-4-(tert-butyl)-4,5-dihydrooxazol-2-yl)methyl)-1-(2-(diphenylphosphino)phenyl)ethanamine; potassium tert-butylate; hydrogen; In methanol; at 20℃; under 15201.0 Torr;Glovebox; Autoclave; | General procedure: In a glove box filled with nitrogen, [Ir(COD)Cl] 2 (0.34 mg, 0.0005 mmol) and chiral P,N,N-ligand L1 (0.51 mg, 0.0011 mmol) was dissolved in anhydrous methanol (3.0 mL). Stir at room temperature for 1 hour. The substrate methyl benzoylacetate Ia (178 mg, 1.0 mmol) and t-BuOK (5.6 mg, 0.05 mmol) were added, placed in a high pressure autoclave, hydrogen was replaced 3 times, and then hydrogen was introduced to 20 atmospheres. The reaction was carried out at room temperature for 24 hours. The hydrogen gas was slowly released, and the solvent was removed, followed by separation on a silica gel column to give the product, methyl 3-hydroxy-3-phenylpropanoate II-a. L1 to L5 of the ligand, the remaining 22 to give the product 3-hydroxy-3-phenyl-propionic acid methyl ester II-a, 96% yield, 82% ee same embodiment. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
at 125℃; for 20h;Heating / reflux; | [00412] Methyl 2-chlorobenzoyl acetate (lg, 4.7 mmol) and urea (0.282 g, 4.7 mmol) were taken into a sealed tube and heated at 125 C for 20 hours. The reaction was cooled to room temperature and ethanol was added to the reaction mixture. The solid was filtered to afford 0.14 g of the desired product. HPLC (Rt 3.336 MINS., 95% purity). MS (ES+): m/e 221.1 (M-H); 223.1 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.5% | With sodium hydride; In toluene; for 16h;Reflux; | O-chloroacetophenone (l0 g, 64.7 mmol) was dissolved in toluene (250 mL) and stirred with sodium hydride(Mass fraction 60%, 2.59 g, 64. 7 mmol) and dimethyl carbonate (5. 83 g, 64. 7 mmol) were added and heated to reflux for 16 hours. (200 mL), extracted with ethyl acetate (200 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound compound (13 g). & Lt; RTI ID = 0.0 & gt; , Yield 94. 5%) |
Ca. 81% | With sodium carbonate; In toluene; at 120℃;Sonication; | In a 250 mL round bottom flask, 1-(2-chlorophenyl)ethan-1-one (5 g, 0.032 mol), dimethyl carbonate (3.4g, 0.038mol), toluene (100 mL) and sodium carbonate (6.7 g, 0.064 mol), after sonication, the temperature was raised to 120 C, and the reaction was completed. The reaction solution was cooled to room temperature, and then poured into 500 mL of petroleum ether. Stir to an oil. The oil was dissolved in dichloromethane, and an appropriate amount of NaOH solution was added and mixed. Washed three times with saturated brine, dried over anhydrous sodium sulfate, spin dry to give a yellow oil. The yield is about 81.0%. |
48% | With sodium hydride; In toluene; mineral oil; for 0.5h;Reflux; | General procedure: In a dry two neck flask equipped with a reflux condenser and rubber septum and a stir bar, NaH (60% wt in mineral oil, 4.0 g, 100 mmol) was suspended in toluene (8 mL) and dimethylcarbonate (9.1 g, 100 mmol, 2.5 eq) was added. The mixture was heated to reflux and acetophenone (4.8 g, 40 mmol, 1.0 eq) in toluene (20 mL) was added dropwise. The reaction mixture was stir for 0.5 h when hydrogen evolution had ceased.The suspension was cooled to 0 C, diluted with EtOAc (150 mL) and carefully quenched with MeOH (10 mL), followed by H2O, and then acidified to pH < 5 using 1N HCl. The organic layer is separated and then washed with H2O (200 mL) then brine (100 mL), and dried over MgSO4, and concentrated in vacuo. The resulting biphasic liquid was partitioned between MeCN (20 mL) and hexanes (10 mL) and then washed with hexanes (25 mL x 2) and concentrated in vacuo to give the beta-ketoesters. Dicarbonyl compound (6mmol) was dissolved in MeOH (6 mL) and then cooled in a brine-ice bath. Then, 30% KOH in MeOH (6 mL) solution was added dropwise an the mixture was allowed to stir for 2 minutes after which a solution of iodobenzene diacetate (6 mmol) was added dropwise and the resulting mixture was allowed to stir for 1 hr and then poured onto icewater (100 mL). The suspension is then extracted with CH2Cl2 (50 mL x 3). The combined extracts were dried over MgSO4, filtered through Buchner funnel, then concentrated in vacuo to approximately one third of the original volume. The ylide was slowly precipitated using Et2O and/or hexanes, and cooled to 0 C and isolated by filtration. |
Example 4: Synthesis of 3-(2-chlorophenyl)-6-(2,4-difluoro-phenoxy)-lH-pyrazolo- [3,4-d]pyrimidine following the procedure of Scheme II; Step 1. Preparation of 3-( 2-chlorophenyl)-3-oxo-propionic acid, methyl ester.; To a suspension of sodium hydride (30.8 g, 770 mmol, 60% in oil) in benzene (275 mL) and dimethyl carbonate (50 mL) was slowly added a solution of 2-chloro-acetophenone (40 mL, 308 mmol) in dimethyl carbonate (28 mL) via an addition funnel. The reaction mixture was then slowly and cautiously heated to 600C [Note: reaction is exothermic: ice bath cooling may be necessary to control the reaction] . After stirring for 15 min, the reaction mixture was stirred at 111 0C for one hour. The mixture was next cooled to ambient temperature and methanol was added to destroy excess sodium hydride. The material was poured onto a cold solution of aqueous hydrochloric acid (10%, 308 mL) in ice (300 mL). The resulting mixture was diluted with ether (250 mL). The organic layer was separated and washed with water (350 mL). The aqueous layer was extracted with ether (250 mL). The ether layers were combined, dried (magnesium sulfate), filtered and concentrated to give a crude oil. Purification via distillation under vacuum provided the product as a pale, clear oil (53.6 g; B.P. = 120-121 C, (M+H)+=213). | ||
With sodium hydride; In benzene; at 60 - 111℃; for 1.25h; | To a suspension of sodium hydride (30.8 g, 770 mmol, 60% in oil) in benzene (275 mL) and dimethyl carbonate (50 mL) was slowly added a solution of 2-chloro-acetophenone (Aldrich) (40 mL, 308 mmol) in dimethyl carbonate (28 mL) via an addition funnel. The reaction mixture was then slowly and cautiously heated to 60 C. [Note: reaction is exothermic: ice bath cooling may be necessary to control the reaction]. After stirring for 15 minutes, the reaction mixture was stirred at 111 C. for one hour. The mixture was next cooled to ambient temperature and methanol was added to destroy excess sodium hydride. The material was poured onto a cold solution of aqueous hydrochloric acid (10%, 308 mL) in ice (300 mL). The resulting mixture was diluted with ether (250 mL). The organic layer was separated and washed with water (350 mL). The aqueous layer was extracted with ether (250 mL). The ether layers were combined, dried (magnesium sulfate), filtered and concentrated to give a crude oil. Purification via distillation under vacuum provided the product as a pale, clear oil (53.6 g; B.P.=120-121 C., (M+H)+=213). | |
General procedure: O-chloroacetophenone (3.0 g, 0.155 mol) was added to toluene (20 mL) under the condition of ice water and stirred for 30 min. Dimethyl carbonate (5.2 g, 0.210 mol) was added, and then reacted at 120 C for 4 h. The mixed system was adjusted to pH = 6 with glacial acetic acid in water and extracted with CH2Cl2. The organic phase was dried over Na2SO4 and concentrated to give methyl 3-(2-chlorophenyl)-3-oxopropanoate as a light yellow oily liquid. Methyl 3-(2-chlorophenyl)-3-oxopropanoate (2.66 g, 0.175 mol) and DMF-DMA (1.88 g, 0.361 mol) were added to toluene (25 mL) and stirred at 120 C for 10 h. The reaction mixture was poured into water and extracted with CH2Cl2 to give methyl 2-(2-chlorobenzoyl)-3-(dimethylamino)acrylate as brown oily liquid. Methyl 2-(2-chlorobenzoyl)-3-(dimethylamino)acrylate (3.2 g, 0.267 mol), p-fluoroaniline (1.9 g, 0.111 mol) were added to NMP, and stirred at 100 C for 3 h. K2CO3 (2.1 g, 0.361 mol) was added and the temperature was raised to 150 C to reacte for 12 h. The reaction solution was filtered, and isopropyl alcohol (5 mL) and petroleum ether (5 mL) was add to filtrate to give 1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate as a yellow solid, which was dissolved to 1,4-dioxane (15 mL) and H2O (15 mL) and added NaOH (0.6 g, 0.146 mol). The mixture was reacted at 100 C for 2 h, and then concentrated. NaCl (aq) was added, and adjusted to pH = 4 with HCl (37.5%). Yellow solid of 1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid was obtained through filter, which was stirred in SOCl2 at 80 C for 1 h to give 1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carbonyl chloride as a yellow viscous oil. 4-((1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)-3-fluoroaniline were synthesized according our previously reported procedures in Ref. 14. Reaction of aromatic amine with acyl chloride catalyzed by DIPEA in CH2Cl2 to give crude product, which was purified by chromatography on silica gel using MeOH/CH2Cl2 to afford compound 34 as white solid. Yield: 59%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic anhydride; at 20 - 130℃; | To a flask containing 3-(2-chlorophenyl)-3-oxo-propionic acid, methyl ester (20 g, 94 mmol) was added triethylorthoformate (37.5 mL, 225.6 mmol) and acetic anhydride (63 mL, 667 mmol). The resulting mixture was heated to 130 C. with stirring for a total of 2 hours, then stirred over night at room temperature. The reaction mixture was concentrated under reduced pressure to provide a crude oil, which was used directly in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | at 60℃; for 16h; | A solution of methyl 3- (2-chlorophenyl) -3-oxopropionate (5 g, 23.5 mmol) was dissolved in N, N-dimethylformamide di acetal (100 mL), extracted with ethyl acetate (100 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a compound (4. lg, & lt; RTI ID = 0.0 & gt; Yield 65%). |
at 20 - 60℃; for 3h; | Step 1: methyl 2-(2-chlorobenzoyl)-3-(dimethylamino)acrylate A solution of <strong>[205985-98-4]methyl 3-(2-chlorophenyl)-3-oxopropanoate</strong> (5.00 g, 23.5 mmol) was dissolved in DMF-DMA (9.4 mL, 70 mmol). The reaction mixture was allowed to stir at rt for 2 h, at 60 C. for 1 h, and then allowed to cool to rt. Water was added and the mixture was extracted with EtOAc. The organic solutions were combined, dried over MgSO4, filtered and concentrated to give methyl 2-(2-chlorobenzoyl)-3-(dimethylamino)acrylate (6.02 g, 96%), which was used without purification in the next step. LCMS (FA): m/z=268 (M+H). | |
at 20℃; for 336h; | A mixture of <strong>[205985-98-4]methyl 2-chlorobenzoylacetate</strong> (Acros; 266 mg, 1.25 mmol) and N,N-dimethylformamide dimethylacetal (161 mg, 1.35 mmol) was stirred at rt under N2 for 2 weeks. The reaction was then concentrated in vacuo and the residue was adsorbed on silica gel and chromatographed. Elution with 3:1 EtOAc/hexanes afforded 193 mg of the title compound as a yellow solid. |
2.87 g | at 120℃; for 5h; | Add intermediate a (3.78 g, 1.43 mol)120 C in 10 mL DMA-DMFCarry out the reaction under the conditions,After stirring the reaction 5.h,Add an appropriate amount of saturated brine,Extracted with dichloromethane,The organic layer was dried over anhydrous sodium sulfate.Concentration gave an oily liquid (2.87 g). |
In toluene; at 120℃; for 10h; | General procedure: O-chloroacetophenone (3.0 g, 0.155 mol) was added to toluene (20 mL) under the condition of ice water and stirred for 30 min. Dimethyl carbonate (5.2 g, 0.210 mol) was added, and then reacted at 120 C for 4 h. The mixed system was adjusted to pH = 6 with glacial acetic acid in water and extracted with CH2Cl2. The organic phase was dried over Na2SO4 and concentrated to give <strong>[205985-98-4]methyl 3-(2-chlorophenyl)-3-oxopropanoate</strong> as a light yellow oily liquid. Methyl 3-(2-chlorophenyl)-3-oxopropanoate (2.66 g, 0.175 mol) and DMF-DMA (1.88 g, 0.361 mol) were added to toluene (25 mL) and stirred at 120 C for 10 h. The reaction mixture was poured into water and extracted with CH2Cl2 to give methyl 2-(2-chlorobenzoyl)-3-(dimethylamino)acrylate as brown oily liquid. Methyl 2-(2-chlorobenzoyl)-3-(dimethylamino)acrylate (3.2 g, 0.267 mol), p-fluoroaniline (1.9 g, 0.111 mol) were added to NMP, and stirred at 100 C for 3 h. K2CO3 (2.1 g, 0.361 mol) was added and the temperature was raised to 150 C to reacte for 12 h. The reaction solution was filtered, and isopropyl alcohol (5 mL) and petroleum ether (5 mL) was add to filtrate to give 1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate as a yellow solid, which was dissolved to 1,4-dioxane (15 mL) and H2O (15 mL) and added NaOH (0.6 g, 0.146 mol). The mixture was reacted at 100 C for 2 h, and then concentrated. NaCl (aq) was added, and adjusted to pH = 4 with HCl (37.5%). Yellow solid of 1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid was obtained through filter, which was stirred in SOCl2 at 80 C for 1 h to give 1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carbonyl chloride as a yellow viscous oil. 4-((1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)-3-fluoroaniline were synthesized according our previously reported procedures in Ref. 14. Reaction of aromatic amine with acyl chloride catalyzed by DIPEA in CH2Cl2 to give crude product, which was purified by chromatography on silica gel using MeOH/CH2Cl2 to afford compound 34 as white solid. Yield: 59%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | a (2-Chloro-phenyl)-propynoic acid methyl ester The title compound was synthesised from commercially available 3-(2-chloro-phenyl)-3-oxo-propionic acid methyl ester using the procedure described in Example 32, step (b), in 71% yield. 1H NMR (CDCl3) delta7.53 (dd, 1H, J=1.6, 6.0 Hz), 7.36 (m, 1H), 7.30 (dt, 1H, J=1.6, 5.7 Hz), 7.19 (dt, 1H, J=1.3, 6.4 Hz), 3.78 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic anhydride; at 20 - 130℃; | Step 2. Preparation of 2-(2-chlorobenzoyl)-3-ethoxyacrylic add, ethyl ester.; To a flask containing 3-(2-chlorophenyl)-3-oxo-propionic acid, methyl ester (20 g, 94 mmol) was added triethylorthoformate (37.5 mL, 225.6 mmol) and acetic anhydride (63 mL, 667 mmol). The resulting mixture was heated to 1300C with stirring for a total of 2 hours, then stirred over night at RT. The reaction mixture was concentrated under re- duced pressure to provide a crude oil, which was used directly in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | General procedure: LiHMDS (10 mol) was added to the solution of beta-keto ester (10 mol) in THF (20 mL) at 0 C. After stirring at this temperature for 30 min LAH (20 mol, 1 M solution in THF) was added at 0 C and stirred at this temperature for 30 min. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with cold water (30 mol) and the resulting solid was filtered through Celite bed and washed with ethyl acetate (20 mL). Filtrate was dried over anhyd Na2SO4 and the crude product was purified by column chromatography to get the pure product. refText |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
188 mg | Step 1: Preparation of 5-chloro-7-(3-chlorophenyl)-2-methylpyrazolo[1,5-a]pyrimidine (Chemical Formula 71) 3-Methylpyrazol-5-amine (321 mg) and <strong>[205985-98-4]methyl 3-chlorophenyl-3-oxopropanoate</strong> (623 mg) are stirred overnight in a pyridine (10 mL) solvent at 95 C. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The extracted organic layer is washed with brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure. The remainder is dissolved in POCl3 (15 mL) and pyridine (0.2 mL) and stirred overnight while heating. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The extracted organic layer is washed with 1 M NaHCO3 aqueous solution and brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure and purified by column chromatography to yield the target compound (188 mg). 1H NMR (CDCl3, 300 MHz): delta 8.03 (s, 1H), 7.91 (d, J=6.3 Hz, 1H), 7.52 (m, 2H), 7.42 (m, 1H), 6.79(s, 1H), 6.49 (s, 1H), 2.51 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With potassium hydroxide; In methanol; for 1h;Cooling with ice; | General procedure: In a dry two neck flask equipped with a reflux condenser and rubber septum and a stir bar, NaH (60% wt in mineral oil, 4.0 g, 100 mmol) was suspended in toluene (8 mL) and dimethylcarbonate (9.1 g, 100 mmol, 2.5 eq) was added. The mixture was heated to reflux and acetophenone (4.8 g, 40 mmol, 1.0 eq) in toluene (20 mL) was added dropwise. The reaction mixture was stir for 0.5 h when hydrogen evolution had ceased.The suspension was cooled to 0 C, diluted with EtOAc (150 mL) and carefully quenched with MeOH (10 mL), followed by H2O, and then acidified to pH < 5 using 1N HCl. The organic layer is separated and then washed with H2O (200 mL) then brine (100 mL), and dried over MgSO4, and concentrated in vacuo. The resulting biphasic liquid was partitioned between MeCN (20 mL) and hexanes (10 mL) and then washed with hexanes (25 mL x 2) and concentrated in vacuo to give the beta-ketoesters. Dicarbonyl compound (6mmol) was dissolved in MeOH (6 mL) and then cooled in a brine-ice bath. Then, 30% KOH in MeOH (6 mL) solution was added dropwise an the mixture was allowed to stir for 2 minutes after which a solution of iodobenzene diacetate (6 mmol) was added dropwise and the resulting mixture was allowed to stir for 1 hr and then poured onto icewater (100 mL). The suspension is then extracted with CH2Cl2 (50 mL x 3). The combined extracts were dried over MgSO4, filtered through Buchner funnel, then concentrated in vacuo to approximately one third of the original volume. The ylide was slowly precipitated using Et2O and/or hexanes, and cooled to 0 C and isolated by filtration. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With copper(l) iodide; potassium carbonate; propionic acid; In isopropyl alcohol; at 100℃; for 24h;Sealed tube; Inert atmosphere; Molecular sieve; | General procedure: 4.3.1. General procedure II for the CuI-catalyzed synthesis of 2 a-n. An oven-dried 10 mL vial equipped with a magnetic stir barwas charged with CuI (0.05 mmol, 10 mg) and K2CO3 (1 mmol,138 mg). The sealed tube was evacuated and backfilled with argon (two times). Then, themethyl 3-(2-bromophenyl)-3-oxopropanoate 1 (1 mmol), propionic acid (22 mg, 0.3 mmol) and freshly distilled isopropanol (2 mL) were added and the reaction mixturewas stirredat 100 C for 24 h. After cooling to room temperature, the reaction mixture was diluted with water (15 mL) and extracted with EtOAc(320 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and the solvents were evaporated in vacuo. The crude product was purified by flash column chromatography on silica gel to afford the 1-naphthol 2 in analytically pure form. |
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