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Structure of 4-Chlorobutanoyl Chloride
CAS No.: 4635-59-0
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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Selective and Cell-Active PBRM1 Bromodomain Inhibitors Discovered through NMR Fragment Screening
Shifali Shishodia ; Raymundo Nuñez ; Brayden P. Strohmier ; Karina L. Bursch ; Christopher J. Goetz ; Michael D. Olp , et al.
Abstract: PBRM1 is a subunit of the PBAF chromatin remodeling complex that uniquely contains six bromodomains. PBRM1 can operate as a tumor suppressor or tumor promoter. PBRM1 is a tumor promoter in prostate cancer, contributing to migratory and immunosuppressive phenotypes. Selective chemical probes targeting PBRM1 bromodomains are desired to elucidate the association between aberrant PBRM1 chromatin binding and cancer pathogenesis and the contributions of PBRM1 to immunotherapy. Previous PBRM1 inhibitors unselectively bind SMARCA2 and SMARCA4 bromodomains with nanomolar potency. We used our protein-detected NMR screening pipeline to screen 1968 fragments against the second PBRM1 bromodomain, identifying 17 hits with Kd values from 45 μM to >2 mM. Structure–activity relationship studies on the tightest-binding hit resulted in nanomolar inhibitors with selectivity for PBRM1 over SMARCA2 and SMARCA4. These chemical probes inhibit the association of full-length PBRM1 to acetylated histone peptides and selectively inhibit growth of a PBRM1-dependent prostate cancer cell line.
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Purchased from AmBeed: 77326-36-4 ; 104-87-0 ; 2148-56-3 ; 63329-53-3 ; 1591-37-3 ; 387-45-1 ; 936-08-3 ; 1123-56-4 ; 2819989-75-6 ; 703-80-0 ; 1885-29-6 ; 115643-59-9 ; 15764-16-6 ; 487-68-3 ; 145737-61-7 ; 5779-95-3 ; 88-68-6 ; 6575-11-7 ; 77326-62-6 ; 88-65-3 ; 4635-59-0 ; 5779-94-2 ; 56043-01-7 ; 5779-93-1 ; 1591-38-4 ; 446-52-6 ; 62803-47-8 ; 1885-31-0 ; 620-23-5 ; 54166-95-9 ; 22179-72-2 ; 529-20-4 ; 100-52-7 ; 123-11-5 ; 1711-06-4 ; 454-89-7 ; 170875-01-1 ; 883032-29-9 ; 2819989-61-0 ; 1915012-21-3 ; 2819989-58-5 ; 2819989-60-9 ; 2819989-57-4 ; 2819989-68-7 ; 2819989-67-6 ; 111478-13-8 ; 73096-42-1 ; 2835-78-1 ; 118-92-3 ; 22458-07-7 ; 80258-99-7 ; 24782-64-7 ; 1108790-90-4 ; 175204-03-2 ; 97-96-1 ; 780802-33-7 ; 89-98-5
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CAS No. : | 4635-59-0 |
Formula : | C4H6Cl2O |
M.W : | 141.00 |
SMILES Code : | O=C(Cl)CCCCl |
MDL No. : | MFCD00000754 |
InChI Key : | CDIIZULDSLKBKV-UHFFFAOYSA-N |
Pubchem ID : | 78370 |
GHS Pictogram: |
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Signal Word: | Danger |
Hazard Statements: | H331-H314-H227 |
Precautionary Statements: | P501-P261-P210-P271-P264-P280-P370+P378-P303+P361+P353-P301+P330+P331-P363-P304+P340+P310-P305+P351+P338+P310-P403+P233-P403+P235-P405 |
Class: | 8(6.1) |
UN#: | 2922 |
Packing Group: | Ⅱ |
* 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 |
---|---|---|
(b) Reaction of Methyl-alpha,alpha-dimethylphenyl acetic acid with 4-Chlorobutyryl chlorideMethyl-alpha,alpha-dimethylphenylacetic acid on Fridel-Craft's acylation with 4-chlorobutyryl chloride in presence of anhydrous aluminum chloride in ethylene dichloride produced acylated Methyl-alpha,alpha-dimethylphenyl acetic acid, i.e., ketone intermediate as meta and para- isomers.More particularly, aluminum chloride was taken in dichloroethane and cooled in between about 0 to 2O0C. To the above pre cooled solution, Methyl-alpha,alpha-dimethylphenyl acetic acid was added at low temperature. To the reaction mixture, 4-chlorobutyryl chloride was added between about 0 to 20C. After addition of acid chloride the reaction mixture was stirred for about 8 to 10 hours at the same temperature. After completion of the reaction, mixture was quenched over chilled mixture of potable water and cone, hydrochloric acid followed by stirring the reaction mixture for another 4 hours. The reaction mixture was washed with aqueous solution of sodium bicarbonate and finally with water. Removal of dichloromethane provided Methyl-4-(4-chloro-l-oxobutyryl)-alpha,alpha-dimethylphenyl acetate (Ketone) in about 95 % HPLC purity.EXAMPLE 2Methyl-4-(4-chloro-l-oxobutyryl)- a, a-dimethyl phenyl acetate (Ketone)95 Kg (0.7124 Kmole) of aluminium chloride was taken in 120 Ltr dichloroethane and reaction mixture was cooled to 0 to 2O0C. To it was added ester of example 1, 46 Kg (0.2584 Kmole) through addition flask, maintaining the temperature 0 to 200C. Finally, to the reaction mixture was added 80 Kg (0.5673 Kmoles) of 4-chlorobutyryl chloride through addition flask maintaining the temperature 0 to 200C. After addition of acid chloride stirred the reaction mixture at 0 to 200C for 8 to 10 hours. After completion it was quenched over chilled mixture of potable water and concentrated hydrochloric acid. Then stirred the reaction mixture at 0 to 200C for 4 hours and finally extracted in dichloroethane. It was washed with 10% w/v aqueous solution of sodium bicarbonate and finally with water. Removal of the solvent under vacuum provides thick oily mass of Methyl-4-(4-chloro-l-oxobutyryl)-alpha-alpha-dimethyl phenyl acetate (Ketone). HPLC purity = 95%. Yield = 65 to 70 Kg. | ||
aluminum (III) chloride; In dichloromethane; at 15 - 45℃; for 3h; | Mix AlCl3 (128 g) and methylene chloride (66 mL) and cool with a dry ice/acetone bath to -15 C. Add, by dropwise addition, 4-chlorobutyryl chloride (73.8 g), keeping the temperature below 15 C. Add, by dropwise addition, <strong>[57625-74-8]methyl 2-methyl-2-phenylpropionate</strong> (77.8 g), keeping the temperature below 15 C. After addition is complete, stire the reaction mixture at 22 C. for 10 minutes, then heat to 45 C. for 3 hours. Quench into ice/water (875 g), filter through filter aid, separate the layers and wash the aqueous phase with methylene chloride (50 mL). Combine the organics and evaporate the solvent in vacuo to give 131 g. Decant solids off and place the oil? in a 500 mL 3-neck flask along with methanol (150 mL). Purge with HCl and heat at reflux for 1 hour and allow to stand overnight. Evaporate the solvent in vacuo, dissolve in methylene chloride (250 mL), wash with water (200 mL) and NaHCO3 (300 mL). Evaporate the solvent in vacuo to give a mixture of 2-[4-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methyl ester and 2-[3-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methyl ester (approximately m:p 50:50) (121 g). Place the mixture of 2-[4-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methyl ester and 2-[3-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methyl ester (approximately m:p 50:50) (40.1 g) in a 250 mL, 3-necked flask with a mechanical agitator, N2 blanket and cooling bath. Add methanol (80 mL) at room temperature and cool to -5 C. with and ice/acetone/water bath. Seed with 2-[4-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methyl ester and allow to stand at -5 C. for 1 hour. Cool to -10 C. with ice/acetone and allow to stand for 1.5 hours. Cool to -16 C. and hold for 30 minutes. Vacuum filter through a 60 mL sintered glass jacketed filter funnel chilled to -10 C. Wash the filtercake with cold (-50 C.) methanol (30 mL) and cold (-50 C.) n-pentane (30 mL). Dry the filtercake briefly in a stream of nitrogen and vacuum dry (20 C. at 15 mm Hg) to give the mixture of 2-[4-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methyl ester and 2-[3-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methyl ester (approximately m:p 10:90) (10.5 g). Dissolve the mixture of 2-[4-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methyl ester and 2-[3-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methyl ester (approximately m:p 10:90) in methanol (30 mL), cool to 10 C. in an ice/water bath and seed with 2-[4-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methyl ester. Cool to 0 C. and hold for 20 minutes. Vacuum filter, wash and dry as above to give the title compound (5.6 g) as an off-white solid; mp 29.5-30.5 C. | |
aluminum (III) chloride; In dichloromethane; at 15 - 45℃; for 3h; | Mix AlCl3 (128 g) and methylene chloride (66 mL) and cool with a dry ice/acetone bath to -15 C. Add, by dropwise addition, 4-chlorobutyryl chloride (73.8 g), keeping the temperature below 15 C. Add, by dropwise addition, <strong>[57625-74-8]methyl 2-methyl-2-phenylpropionate</strong> (77.8 g), keeping the temperature below 15 C. After addition is complete, stire the reaction mixture at 22 C. for 10 minutes, then heat to 45 C. for 3 hours. Quench into ice/water 875 g), filter through filter aid, separate the layers and wash the aqueous phase with methylene chloride (50 mL). Combine the organics and evaporate the solvent in vacuo to give 131 g. Decant solids off and place the oil in a 500 mL 3-neck flask along with methanol (150 mL). Purge with HCl and heat at reflux for 1 hour and allow to stand overnight. Evaporate the solvent in vacuo, dissolve in methylene chloride (250 mL), wash with water (200 mL) and NaHCO3 (300 mL). Evaporate the solvent in vacuo to give a mixture of 2-[4-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methyl ester and 2-[3-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methyl ester (121 g) (approximately 50:50 m:p). Place the mixture of 2-[4-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methyl ester and 2-[3-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methyl ester (approximately 50:50 m:p) (40.1 g) in a 250 mL, 3-necked flask with a mechanical agitator, N2 blanket and cooling bath. Add methanol (80 mL) at room temperature and cool to -5 C. with and ice/acetone/water bath. Seed with 2-[4-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methyl ester and allow to stand at -5 C. for 1 hour. Cool to -10 C. with ice/acetone and allow to stand for 1.5 hours. Cool to -16 C. and hold for 30 minutes. Vacuum filter through a 60 mL sintered glass jacketed filter funnel chilled to -10 C. Wash the filtercake with cold (-50 C.) methanol (30 mL) and cold (-50 C.) n-pentane (30 mL). Dry the filtercake briefly in a stream of nitrogen and vacuum dry (20 C. at 15 mm Hg) to give the mixture of 2-[4-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methyl ester and 2-[3-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methyl ester (approximately 10:90 m:p) (10.5 g). To the methanol solution of the mixture of 2-[4-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methyl ester and 2-[3-(4-chloro-butyrl)-phenyl]-2-methyl-proprionic acid, methyl ester (approximately 50:50 m:p) (approximately 70:30 m:p) from crystallization (i.e. mother liquor), slowly add 1 to 1.2 euivalents of 25% NaOMe/MeOH solution. Agitate for approximately 30 minutes at 25 C. Neutralize the excess NaOMe with excess carbon dioxide. Add water (300 mL) per mole of subtrate, evaporate the methanol by vacuum distiallation and decant the aqueous layer to give a mixture of 2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, methyl ester and 2-(3-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, methyl ester (approximately 70:30 m:p). Distill the mixture of 2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, methyl ester and 2-(3-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, methyl ester (approximately 70:30 m:p) at 0.5 mm Hg and discard a light fraction boiling at 25-130 C. (pot temp-105-165 C.). Continue distilling the oil at 0.5 mm Hg and collect a second fraction boiling at 130-150 C. (pot temperature 165-190) to give the mixture of 2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, methyl ester and 2-(3-cyclopropanecarbonyl-phenyl)-2-methyl-propionic acid, methyl ester (approximately 70:30 m:p) Pack a {fraction (31/32)} in. I.D. vacuum jacked and silvered column with 53 inches of 1 in. diameter, 316 stainless steel packing. For high temperature distillation, the column is fitted with an adiabatic jacket composed of an inner layer of 1 in. fiber glass wrapped with heat tape in an upper and lower zone and finally covered with 2 in. fiber glass insulation. The upper zone is heated at 135 C. and the lower z |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With triethylamine; In dichloromethane; at 20℃; for 0.833333h; | To a solution of <strong>[23218-93-1]3-amino-5-nitro-benzoic acid methyl ester</strong> (D1) (38 g, 194 mmol, 1 equiv) in CH2CI2 (350 ML) was added NEt3 (32 ml, 230 mmol, 1.2 equiv) followed by 4-chlorobutyryl chloride (24.7 MI, 220 mmol, 1.13 equiv) dropwise over 20 mn. The resulting mixture was allowed to warm to room temperature and stirred for 30 min. The organic phase was then washed with 2N aqueous HCI solution, dried over MGS04 and concentrated in vacuo. The residue was triturated with iso-hexane and ET20 to give 3- (4-CHLORO-BUTANOYLAMINO)-5-NITRO- benzoic acid methyl ester D2 (56 g, 96%) as a brown solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With potassium carbonate; In toluene; at 20.0℃; for 24.0h; | A mixture of <strong>[3034-57-9]5-bromo-4-methylthiazol-2-amine</strong> (7.72 g, 0.04 mol), 4-chlorobutyryl chloride (11.3 g, 0.08 mol), and potassium carbonate (5.5 g, 0.04 mol) in toluene (100 ml) was stirred at room temperature for 24 h. The toluene was then evaporated under reduced pressure. The residue was then quenched with water, stirred, and filtered. The solid obtained was washed, dried and recrystallized from chloroform to give the required product (7.5 g, 63percent yield), mp 112-4°C, m/e 297.6, 25percent (consistent with molecular formula C8H10BrClN2OS, calcd. 297.6). 1H NMR (DMSO-d6): delta 2.02-2.08 (m, 2H, J = 7.0 Hz, -CH2-CH 2-CH2-), 2.61-2.65 (m, 5H, CH 3- & -CH 2-CH2-CH2-), 3.69 (t, 2H, J= 7.0 Hz, -CH2-CH2-CH 2-), 12.42 (brs, 1H, NH).13C NMR: delta 14.7, 27.3, 32.0, 44.7, 62.9, 158.3, 159.1, 170.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With potassium carbonate; In toluene; at 20℃; for 24h; | A mixture of ethyl 2-amino-4-methylthiazole-5-carboxylate(7.44 g, 0.04 mol), 4-chlorobutyryl chlorine (11.3 g, 0.08 mol), and potassium carbonate (5.5 g, 0.04 mol) in toluene (100 ml) was stirred at room temperature for 24 h. The toluene was then evaporated under reduced pressure. The residue was then quenched with water, stirred, and filtered. The solid obtained was washed, dried and recrystallized from chloroform to give the required product (8.7 g, 75% yield), mp 140-2C, m/e 290.6, 100% (consistent with molecular formula C11H15ClN2O3S, calcd. 290.77).1H NMR (CDCl3): δ 1.29 (t, 3H, J= 7.0 Hz, CH 3-CH2-), 2.14 (t, 2H, J = 6.0 Hz, -CH2-CH 2-CH2-), 2.59-2.61 (m, 5H, CH 3- & -CH 2-CH2-CH2-), 3.57 (t, 2H, J = 6.0 Hz, -CH2-CH2-CH 2-), 4.24-4.28 (q, 2H, J - 7.0 Hz, CH3-CH 2-), 9.92 (brs, 1H, NH). 13C NMR: δ 14.3, 17.3, 27.2, 32.8, 43.6, 61.1, 116.1, 155.6, 160.1, 162.6, 170.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dichloromethane; chloroform; at 0 - 60℃; | To 100 mg of (R)-6-(4-aminophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)- one (0.49 mmol) dissolved in 2 mL of CHC13 and cooled to 0 C was added DIPEA (0.43 mL, 2.5 mmol) followed by 4-chlorobutanoyl chloride (60 L, 0.54 mmol). The reaction was stirred at 0 C for 1.5 h before heating to 60 C and stirring overnight. After cooling, aHC03(aq) was added and was extracted with CH2CI2. LC analysis indicated a 1 : 1 ratio of starting material to intermediate chloride. The crude material was then dissolved in 7 mL of CH2CI2 and to this was added 0.2 mL DIPEA (1.2 mmol) and 4-chlorobutanoyl chloride (60 mu, 0.54 mmol). After 30 min, the reaction was worked up as before, the crude product chromatographed with 0-25% EtOAc in hexane to produce 92 mg of impure compound. This material was dissolved in 6 mL of DMF and 124 mg of K2CO3 (0.90 mmol) was added and the mixture was heated at 60 C for 5 h. After cooling, water was added and was rinsed several times with EtOAc, the combined EtOAc layers were rinsed with brine, dried, concentrated, and chromatographed with 0-25% EtOAc in hexane to produce 38 mg of product as an off-white solid (47%). XH NMR (300 MHz, CDC13) delta 8.47 (s, 1H), 7.77 (d, J = 9.0, 2H), 7.71 (d, J= 9.1, 2H), 3.90 (t, J= 7.0, 2H), 3.45 - 3.29 (m, 1H), 2.73 (dd, J = 6.8, 16.9, 1H), 2.65 (t, J= 8.1, 2H), 2.48 (d, J= 16.8, 1H), 2.27 - 2.13 (m, 2H), 1.25 (d, J= 7.4, 3H). 13C MR (75 MHz, CDC13) delta 174.35, 166.75, 153.25, 140.58, 130.04, 126.36, 1 19.31, 48.39, 33.70 MS: 272 (M + 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
[000814j To a stirred solution of compound 1 (0.1 g, 1 eq) in DMF (5 mL),TEA ( 0.101 g, 2 eq) and 4-chlorobutanoyl chloride (0.06 1 g, 1 eq) was added at 0 C and stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under reduced pressure and the residue was basified using saturated sodium bicarbonate solution and extracted with ethyl acetate (2 X 20 mL). Combined organic extracts were washed with brine and dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was dissolved in acetic acid (5 mL) and was heated to 70 C for 18 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under vacuum and residue was basified with saturated sodium bicarbonate solution and extracted with ethyl acetate (2 X 25 mL). Combined organic extracts were washed with brine and dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel 100-200 mesh using 80% EtOAc-hexane to afford the title compound 2. LCMS (mlz): 289.00 (M + 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With triethylamine; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere; | General procedure: Asolutionoftheappropriatesubstituted2-aminobenzamide(1.0eq)inTHF(2.5mLpermmolsubstrate)wascooledto0Candtriethylamine(2.0eq)thentheappropriateacidchloride(1.2eq)inTHF(2mLpermmolsubstrate)wereaddedtothestirredsolution.ThereactionwasstirredatroomtemperatureuntilcompletionasindicatedbyTLC,whenthemixturewasdilutedwithEtOAcandquenchedwithNaHSO4(20mL).TheaqueousphasewasextractedwithEtOAc(320mL),combinedorganicphasesdriedoverMgSO4,excesssolventremovedinvacuoandtheresiduepurifiedbyFCC. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.2% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 10 - 25℃;Inert atmosphere; | in the 1e (1g, 3.66mmol) was dissolved in tetrahydrofuran (20ml) , was added N, N-diisopropylethylamine (0.6g, 4.58mmol), under ice-cooling, a solution of 4-chlorobutyryl chloride (0.62g, 4.40 mmol) to obtain a reaction mixture, said reaction mixture at room temperature overnight. Tracking progress of the reaction by TLC, the reaction was completed, water was added to the reaction solution, separated, washed with water three times, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed by distillation under reduced pressure 5f (1.12g, yellow solid), yield rate: 81.2%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With triethylamine; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere; | General procedure: Asolutionoftheappropriatesubstituted2-aminobenzamide(1.0eq)inTHF(2.5mLpermmolsubstrate)wascooledto0Candtriethylamine(2.0eq)thentheappropriateacidchloride(1.2eq)inTHF(2mLpermmolsubstrate)wereaddedtothestirredsolution.ThereactionwasstirredatroomtemperatureuntilcompletionasindicatedbyTLC,whenthemixturewasdilutedwithEtOAcandquenchedwithNaHSO4(20mL).TheaqueousphasewasextractedwithEtOAc(320mL),combinedorganicphasesdriedoverMgSO4,excesssolventremovedinvacuoandtheresiduepurifiedbyFCC. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With triethylamine; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere; | General procedure: Asolutionoftheappropriatesubstituted2-aminobenzamide(1.0eq)inTHF(2.5mLpermmolsubstrate)wascooledto0°Candtriethylamine(2.0eq)thentheappropriateacidchloride(1.2eq)inTHF(2mLpermmolsubstrate)wereaddedtothestirredsolution.ThereactionwasstirredatroomtemperatureuntilcompletionasindicatedbyTLC,whenthemixturewasdilutedwithEtOAcandquenchedwithNaHSO4(20mL).TheaqueousphasewasextractedwithEtOAc(320mL),combinedorganicphasesdriedoverMgSO4,excesssolventremovedinvacuoandtheresiduepurifiedbyFCC. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | A 1000 ml three-necked flask was charged with <strong>[1180-71-8]limonin</strong> (40.0 g, 85.01 mmol) andDichloromethane (500 mL),Cooled to 0 C with stirring,Aluminum trichloride (51.0 g, 382.5 mmol) was added in portions,After addition, keep stirring 20min,Add 4-chlorobutyryl chloride (14.4 g, 102.0 mmol) dropwiseA mixed solution of dichloromethane (15 mL)Dropwise, maintaining 0 ~ -5 1 hour,The reaction was further stirred at room temperature for 2 hours,Stop the reaction, the reaction solution was slowly poured into 500mL ice water,The methylene chloride layer was separated, the aqueous layer was extracted twice with dichloromethane (300 mL × 2)The combined organic layers were washed three times (300 mL x 3) with 1 mol / L aqueous sodium hydroxide solution,Washed with saturated brine twice (300 mL × 2), dried over anhydrous sodium sulfate, filtered,The solvent was evaporated under reduced pressure.The crude product was purified by column chromatography (methylene chloride: methanol = 160: 1) to give 20.5 g of pale green solid (IV-2) in a yield of 42% | |
42% | General procedure: To a solution of <strong>[1180-71-8]limonin</strong> (1) or deoxy<strong>[1180-71-8]limonin</strong> (6) (17.0 mmol) in CH2Cl2 (125 mL) at 0C was added anhydrous AlCl3 slowly (10.2 g, 76.5 mmol). After stirring the reaction mixture at 0C for 20 min, the acyl chlorides (2.2 g, 19.5 mmol) dissolved in CH2Cl2 (5.0 mL) was added slowly and stirred for another 1 h. The reaction mixture was then warmed to room temperature and stirred for 3 h. After that, the mixture was poured into ice water (100 mL), and extracted with CH2Cl2 (100 mL × 3). The combined organic extracts were then washed with 1N NaOH aqueous solution (100 mL × 3), brine (100 mL × 2), dried over anhydrous Na2SO4 and concentrated under vacuum. The resulting residue was then purified through flash chromatography on silica gel (CH2Cl2/MeOH = 0-1%) to give desired products in 31-53% yields. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(1) 10 mmol of <strong>[120068-37-3]fipronil</strong> was added to a 100 mL flask, and 30 mL of tetrahydrofuran was added as a solvent to add a magnetic stirrer.mix. Slowly add 20 mmol of NaH to the batch under stirring, continue stirring for 20 min after the addition, and then add to it.10mmol 4-chlorobutyryl chloride, then heated at 80 C for 12h under reflux, after the reaction is completed, the excess solvent is removed by rotary evaporation, using 50mL BExtraction with ethyl acetate and 120 mL of saturated Na2CO3 solution, collecting the organic phase, adding 5 g of silica gel powder to it, and spinning it to dryness.The sample was separated and purified by silica gel column chromatography using petroleum ether and ethyl acetate in a volume ratio of 4:1 to obtain 1-(2,6-dichloro-4-Trifluoromethyl-phenyl)-5-(pentacyclic imide-1-yl)-4-trifluoromethyl-1H-pyrazole-3-carbonitrile. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 20℃; for 3h;Cooling with ice; | First, 12.7 g (0.045 mol) of <strong>[1791-13-5]aspartic acid di-tert-butyl ester hydrochloride</strong> and 5.0 g (0.049 mol) of triethylamine were dissolved in 50 ml of dichloromethane and placed in an ice bath. 5.6 g (0.04 mol) of 4-chlorobutyrene chloride was slowly added dropwise.After the completion of the dropwise addition, the mixture was stirred at room temperature for 3 hours.Then, using a vacuum concentrator to remove the solvent,The first intermediate product represented by the following formula (II-11-1) can be obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With dmap; In dichloromethane; at 0 - 20℃;Inert atmosphere; | General procedure: Acyl chloride (0.18 mmol, 1.1 eq) was added at 0 C to a solution of <strong>[436-77-1]fangchinoline</strong> (100 mg, 0.16 mmol) and DMAP (0.032 mmol, 0.2eq) in 2 mL dry CH2Cl2 under argon and stirred for 2-4 h. The reaction mixture was quenched with a saturated aqueous solution of sodium bicarbonate and extracted three times with CH2Cl2. The combined organic phase was dried over anhydrous magnesium sulfate before vacuum suction filtration. The removal of the solventin vacuo afforded the crude product, which was chromatographied on silica gel (CH2Cl2/MeOH, 50/1 v/v, 0.1% TEA) to provide the pureproduct 1a-1e, 2a-2g, 3a-3e and 4a-4h. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With boron trifluoride; In dichloromethane; at 20℃;Cooling with ice; | General procedure: A solution of chloroacyl chlorides (4a-c, n= 1, 2, 3, 0.5mL) in DCM (10 mL) was added dropwise to an ice-coldsolution of triethylamine (6 mmol or 1.8 mL) and cycloalkano-quinoline amines 3a-c (5.0 mmol) in DCM (30mL). Upon completion of the addition, the reaction mixture was stirred for two hours at room temperature, diluted with DCM (20ml) and washed with water (10ml) followed by brine solution (10ml). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude intermediates 5a-c, 6a-c, and 7a-c, which were purified over silica. |
Tags: 4635-59-0 synthesis path| 4635-59-0 SDS| 4635-59-0 COA| 4635-59-0 purity| 4635-59-0 application| 4635-59-0 NMR| 4635-59-0 COA| 4635-59-0 structure
A907931 [63480-13-7]
4-Chloro-3-methylbutanoyl chloride
Similarity: 0.85
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P378 | |
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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 |
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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 |
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H272 | May intensify fire; oxidizer |
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Health hazards | |
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H305 | May be harmful if swallowed and enters airways |
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H311 | Toxic in contact with skin |
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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 |
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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 |
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