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CAS No. : | 7152-15-0 | MDL No. : | MFCD00009198 |
Formula : | C8H14O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | XCLDSQRVMMXWMS-UHFFFAOYSA-N |
M.W : | 158.20 | Pubchem ID : | 81583 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.75 |
Num. rotatable bonds : | 5 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 42.05 |
TPSA : | 43.37 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.35 cm/s |
Log Po/w (iLOGP) : | 1.92 |
Log Po/w (XLOGP3) : | 1.29 |
Log Po/w (WLOGP) : | 1.16 |
Log Po/w (MLOGP) : | 0.97 |
Log Po/w (SILICOS-IT) : | 1.38 |
Consensus Log Po/w : | 1.35 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.3 |
Solubility : | 7.86 mg/ml ; 0.0497 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.8 |
Solubility : | 2.5 mg/ml ; 0.0158 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.52 |
Solubility : | 4.72 mg/ml ; 0.0299 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.71 |
Signal Word: | Danger | Class: | 3 |
Precautionary Statements: | P210-P403+P235 | UN#: | 3272 |
Hazard Statements: | H225 | Packing Group: | Ⅲ |
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 |
---|---|---|
81% | for 3 h; Reflux | 10 g of ethylisobutyrylacetate (63.2 mmol) was dissolved in 30 ml of toluene, and6.5 g of aniline (70 mmol) was added to the resulting mixture and refluxed for 3 hours. When the reaction was completed, 50 ml of IN HCl was added to the resulting reaction mixture, and stirred to separate an organic phase. The organic phase was diluted with 50 ml of ethylacetate, washed with distilled water and saturated saline, and then concentrated under a reduced pressure to obtain brown oil. The resultant brown oil was washed with nucleic acid to obtain 10.5 g of brown oil (Yield: 81percent).[92] IH-NMR (CDC13)δ: 1.14 (d, 6H), 2.71 (m, IH), 3.58 (s, 2H), 7.09 (m, IH),7.24-7.31 (m, 2H), 7.53 (d, 2H), 9.20 (b, IH)[93] Mass (M+l): 206 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With aniline In acetic acid; ethyl acetate; toluene | EXAMPLE 19.1 3-Oxo-4-methylpentananilide A solution of 47.4 g (0.3 mol) of ethyl 3-oxo-4-methylpentanoate, 27.93 g (0.3 mol) of aniline and 0.6 ml of glacial acetic acid in 360 ml of toluene is boiled under reflux with a water trap for 4 hours. The reaction mixture is cooled and then washed twice with 0.5 N hydrochloric acid, then twice with saturated sodium bicarbonate solution and then with saturated brine, and is dried and concentrated in vacuo. The residue is chromatographed on 1 kg of silica gel using toluene/ethyl acetate 10:1. 40.5 g (66percent yield) of pale pink-colored oil. 1 H NMR (CDCl3): δ=1.2 (d, 6H), 2.8 (s, 2H), 3.65 (s, 2H), 7.0-7.75 (m, 5H, 9.1-9.4 (s, br., 1H). MS: C12 H15 NO2 (205) m/e=205 (M+), 93. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With N-chloro-succinimide In various solvent(s) at 20℃; for 1h; | |
70% | With sulfuryl dichloride In toluene at 20℃; for 18h; | N.1 Step 1. Preparation of2-chloro-4-methyl-3-oxopentanoic acid ethyl ester A solution of sulfuryl chloride (1.63 mL, 19.7 mmol) in toluene (5 mL) was added dropwise to a solution of 4-methyl-3-oxopentanoic acid ethyl ester (3.28 g, 19.7 mmol) in toluene (25 mL) over 10 min. The resulting mixture was stirred at rt for 18 h and then slowly quenched with water and NaHCO3 (saturated, aqueous). The mixture was extracted with ethyl acetate, and the combined organics were dried over IvIgSO4 and concentrated in vacuo to give 3.4 g (70%) of the desired product which was used without further purification. |
70% | Stage #1: ethyl 4-methyl-3-oxo-pentanoate With sulfuryl dichloride In toluene at 20℃; for 18h; Stage #2: With water In toluene | N.1 A solution of sulfuryl chloride (1.63 ml_, 19.7 mmol) in toluene (5 rriL) was added dropwise to a solution of 4-methyl-3-oxopentanoic acid ethyl ester (3.28 g, 19.7 mmol) in toluene (25 ml.) over 10 min. The resulting mixture was stirred at rt for 18 h and then slowly quenched with water and NaHCO3 (saturated, aqueous). The mixture was extracted with ethyl acetate, and the combined organics were dried over MgSO4 and concentrated in vacuo to give 3.4 g (70%) of the desired product which was used without further purification. LC-MS m/z 194.1 (M+H+); RT 2.69 min. |
70% | With sulfuryl dichloride In toluene at 20℃; for 18h; | 1N.1 Step 1. Preparation of2-chloro-4-methyl-3-oxopentanoic acid ethyl ester A solution of sulfuryl chloride (1.63 mL, 19.7 mmol) in toluene (5 mL) was added dropwise to a solution of 4-methyl-3-oxopentanoic acid ethyl ester (3.28 g, 19.7 mmol) in toluene (25 mL) over 10 min. The resulting mixture was stirred at rt for 18 h and then slowly quenched with water and NaHCO3 (saturated, aqueous). The mixture was extracted with ethyl acetate, and the combined organics were dried over IvIgSO4 and concentrated in vacuo to give 3.4 g (70%) of the desired product which was used without further purification. |
70% | With sulfuryl dichloride In toluene at 20℃; for 18h; | 1N.1 Step 1. Preparation of2-chloro-4-methyl-3-oxopentanoic acid ethyl ester A solution of sulfuryl chloride (1.63 mL, 19.7 mmol) in toluene (5 mL) was added dropwise to a solution of 4-methyl-3-oxopentanoic acid ethyl ester (3.28 g, 19.7 mmol) in toluene (25 mL) over 10 min. The resulting mixture was stirred at rt for 18 h and then slowly quenched with water and NaHCO3 (saturated, aqueous). The mixture was extracted with ethyl acetate, and the combined organics were dried over IvIgSO4 and concentrated in vacuo to give 3.4 g (70%) of the desired product which was used without further purification. |
67% | With sulfuryl dichloride In toluene at 20℃; | 14 EXAMPLE 14 Preparation of Ethyl 2-chloro-3-oxo-3-phenylpropanoate; [0107] EMI311.0[0108] A solution of sulfuryl chloride (12.4 mmol) in toluene (5 mL) was added dropwise via an additional funnel to a solution of ethyl isobutyrylacetate (12.4 mmol) in toluene (20 mL) over 5 minutes at rt. The resulting mixture was stirred at rt overnight. Water was added slowly. The resulting two-phase mixture was basified with saturated NaHCO3 and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhyd. sodium sulfate, and removed in vacuo to afford 2.2 g (84%) of product as a pale yellow oil. MH=227.0, retention time (LC-MS)=2.77 min. |
51% | With sulfuryl dichloride at 20℃; for 3h; | |
With sulfuryl dichloride | ||
With sulfuryl dichloride In diethyl ether for 1h; Ambient temperature; | ||
With sulfuryl dichloride In chloroform for 2h; Heating; | ||
With sulfuryl dichloride In chloroform at 20℃; for 18h; | P Intermediate Example P; EMI70.1Ethyl 4- (1-methylethyl)-2- [4- (trifluoromethyl) phenyl]-1, 3-thiazole-5-carboxylate(XI-5a) Ethyl isobutyrylacetate(XI-3a) (3.006 g, 19.0mmol) was dissolved in chloroform (20 mL). Sulfuryl chloride (1.70 mL, 21.2mmol) was added and the solution was stirred at RT for 18 hours, then was concentrated. The residue was dissolved in ethanol (50 mL).4- (Trifluoromethyl) benzenethioamide (4.234 g, 20.6mmol) was added and the solution was heated to reflux for 24 hours. The mixture was cooled to RT and filtered. The solid was washed with cold ethanol and dried to provide the title product (2.68 g, 32%) as a pale yellowsolid.'H NMR (400 MHz,CDCI3)6 8.09 (d, J= 8.1 Hz, 2H), 7.69 (d, J= 8.1 Hz, 2H), 4.35 (q, J= 7.1 Hz, 2H), 3.99 (qu, J= 6.8 Hz,1H), 1.39 (t, J= 7.1 Hz,3H), 1.35 (d, J= 6.8 Hz, 6H). | |
104% | With sulfuryl dichloride In dichloromethane | 8.A A. A. 2-Chloro-4-methyl-3-oxopentanoic Acid Ethyl Ester A 1M solution of sulfuryl chloride in dichloromethane (25 mL, 25 mmol) was added to a solution of 4-methyl-3-oxopentanoic acid ethyl ester (3.95 g, 25 mmol) in dichloromethane (15 mL) cooled in a water bath. The solution was stirred at room temperature for 2 h and then the reaction mixture was washed with water (2*20 mL). Each of the aqueous layers was extracted with dichloromethane and the combined organic layers were dried (MgSO4), filtered and evaporated to give 2-chloro-4-methyl-3-oxopentanoic acid ethyl ester (5.0 g, 104% of the theoretical amount). This was used directly in the next step without purification. |
With thionyl chloride In dichloromethane | ||
6 g | With sulfuryl dichloride In toluene at 0 - 20℃; for 24h; Inert atmosphere; | 26 [000262] Synthesis of ethyl 2-chloro-4-methyl-3-oxopentanoate (321) [000262] Synthesis of ethyl 2-chloro-4-methyl-3-oxopentanoate (321): To a stirred solution of ethyl 4-methyl-3-oxopentanoate 320 (5 g, 31.64 mmol) in Toluene (50 mL) under argon atmosphere was added sulfuryl chloride (4.26 g, 31.64 mmol) at 0 °C; warmed to RT and stirred for 24 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to afford compound crude 321 (6 g) as brown syrup. TLC: 10% EtOAc/ hexanes (R 0.8). |
With sulfuryl dichloride In tetrachloromethane at 20℃; | ||
With sulfuryl dichloride In dichloromethane at -5 - 0℃; for 10h; | ||
With sulfuryl dichloride In dichloromethane at 0℃; | 1.S1-3.S1 Example 1 S1. Prepare 4 grams of 4-methyl-3-oxopentanoic acid ethyl ester, 40ml of dichloromethane, 4 grams of sulfonyl chloride, and select a 2L four-necked flask with a water separator. Ethyl 4-methyl-3-oxopentanoate was dissolved in 40ml of dichloromethane, and the mixture was put into a four-necked flask, stirred and cooled to below 0, and 4g of sulfur was added dropwise at a very slow speed. Acid chloride, use less than 30min, then adjust pH=7.5 with saturated sodium bicarbonate aqueous solution, then use 400ml dichloromethane for liquid separation extraction, wash with saturated brine, dry, and remove the solvent to obtain the product of step S1 2-chloro-4- Ethyl methyl-3-oxopentanoate. | |
With sulfuryl dichloride |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | With bis(acetylacetonate)nickel(II) at 100℃; Overnight; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With piperidine; acetic acid In isopropyl alcohol at 20℃; for 22h; | |
86.7% | With piperidine; acetic acid In benzene Heating; | |
83.9% | With piperidine; acetic acid In isopropyl alcohol at 20℃; for 22h; Inert atmosphere; | 2 Example 2: synthesis of ethyl 4-methyl-2-(4-fluorobenzylidene)-3-oxopentanoate To a 250 mL round bottom flask, a suitable magnetic stirrer was added and isobutylacetic acid ethyl ester was added(21.10 g, 133.4 mmol), p-fluorobenzaldehyde (20.97 g, 172.9 mmol), isopropanol 76.0 mL, piperidinePyridine 720 μL, acetic acid 420 μL, the reaction mixture was then reacted under a nitrogen atmosphere at room temperature for 22h, the reaction junctionAfter the solvent was dried under reduced pressure, the remaining crude was dissolved in 50 mL of dichloromethane, washed with saturated bicarbonateSodium 100mL wash three times, dried over anhydrous magnesium sulfate, after drying to remove anhydrous magnesium sulfate and solvent to obtainCompound Ethyl 2- (4-fluorobenzylidene) -3-oxo-4-methylpentanoate I as a 1: 1 mixture of Z and E,As a light yellow liquid in a yield of 83.9% |
75% | With piperidine; acetic acid In toluene for 8h; Heating; | |
With piperidine; acetic acid In isopropyl alcohol at 20℃; for 22h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | In toluene; for 3h;Reflux; | 10 g of ethylisobutyrylacetate (63.2 mmol) was dissolved in 30 ml of toluene, and6.5 g of aniline (70 mmol) was added to the resulting mixture and refluxed for 3 hours. When the reaction was completed, 50 ml of IN HCl was added to the resulting reaction mixture, and stirred to separate an organic phase. The organic phase was diluted with 50 ml of ethylacetate, washed with distilled water and saturated saline, and then concentrated under a reduced pressure to obtain brown oil. The resultant brown oil was washed with nucleic acid to obtain 10.5 g of brown oil (Yield: 81%).[92] IH-NMR (CDC13)delta: 1.14 (d, 6H), 2.71 (m, IH), 3.58 (s, 2H), 7.09 (m, IH),7.24-7.31 (m, 2H), 7.53 (d, 2H), 9.20 (b, IH)[93] Mass (M+l): 206 |
With pyridine; In toluene; for 16h;Reflux; | Preparation of 4-methyl-3-oxo-N-phenyl-pentanamide (3) A solution of ethyl 4-methyl-3-oxo-pentanoate (1086 mg, 7.5 mmol) in toluene/pyridine (5 mL/1 mL) was heated to gentle reflux for 30 min. Aniline (465 mg, 5.0 mmol) was then added dropwise into the above reaction mixture and it was refluxed for 16h. The solution was allowed to cool to 25 C and was extracted with 2M NaOH. The aqueous layer was separated and made weakly acidic with cone. HCl. It was then extracted with EtOAc (2x30 mL). Organic layer was concentrated under reduced pressure to give 1.048 g of crude 4-methyl-3-oxo-N-phenyl-pentanamide. Product was used as such without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sodium ethanolate In ethanol | 1.B B. To a mixture of (E)-3-(4-fluorophenyl)-1-phenyl-2-propen-1-one (4.59 gm, 20.3 mmol) and ethyl isobutyrylacetate (3.86 gm, 24.4 mmol) in absolute EtOH (100 ml) was added a solution of EtONa in EtOH. The EtONa solution was prepared by dissolving Na metal (50 mg, 2.2 mmol) in EtOH (10 ml). After stirring at room temperature for 3 hours, additional ethyl isobutyrylacetate (1.0 gm, 6.3 mmol) was added. Stirring continued for an additional 2 hours. The mixture was poured into a separatory funnel containing Et2 O and saturated NH4 Cl. The phases were shaken and separated. The aqueous layer was extracted once with EtOAc and the combined organic layers were washed with brine and dried (Na2 SO4). Filtration and removal of the solvent gave a solid/liquid mixture. Crystallization of the residue from hot hexane/EtOAc gave β-(4-fluorophenyl)-α-(2-methyl-1-oxopropyl)-δ-oxobenzenepentanoic acid, ethyl ester (5.91 gm, ~95% one diastereomer) as colorless needles. The mother liquor was stripped and recrystallized from hot hexane to afford additional product, giving a total of 7.21 gm (92%) β-(4-fluorophenyl)-α-(2-methyl-1-oxopropyl)-δ-oxobenzenepentanoic acid, ethyl ester as a 7:3:1 mixture of diastereomers. |
With sodium ethanolate In ethanol for 4.5h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; acetic acid at 110℃; | ||
6.47 g (55%) | With sulfuric acid In acetic acid | 1.a Ethyl 4-(4'-fluorophenyl)-2-(1'-methylethyl)-quinolin-3-yl-carboxylate (compound VII-1) EXAMPLE 1-a Ethyl 4-(4'-fluorophenyl)-2-(1'-methylethyl)-quinolin-3-yl-carboxylate (compound VII-1) The synthesis was conducted in accordance with the method disclosed in J. Org. Chem., 2899 (1966). 6.45 g (0.03 mol) of 2-amino-4'-fluorobenzophenone, 5.53 g (0.035 mol) of ethyl isobutyrylacetate and 0.1 ml of conc. sulfuric acid were dissolved in 30 ml of glacial acetic acid, and the mixture was heated at 100° C. for about 10 hours. After confirming the substantial disappearance of 2-amino-4'-fluorobenzophenone by thin layer chromatography, the reaction solution was cooled to room temperature, and a mixture of 45 ml of conc. aqueous ammonia and 120 ml of water cooled with ice, was gradually added thereto. A separated oily substance was solidified when left to stand overnight in a refrigerator. This solid was recrystallized from a small amount of ethanol to obtain 6.47 g (55%) of white powder. Melting point: 68°-70.5° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With sodium methylate In methanol; ethanol at 100℃; Sealed tube; | 126.1 Step 1: 2-Amino-6-isopropylpyrimidin-4(5H)-one (180) To a suspension of ethyl isobutyrylacetate (5 g, 30 mmol) and guanidine hydrochloride (4.5 g, 45 mmol) in absolute ethanol 60 mL was added sodium methoxide (25% in methanol: 2.5 g, 45 mmol). The resuling mixture was sealed in a pressure seal vessel and heated to 100C overnight. The solvent was removed in vacuo and the resulting residue was purified by flash chromatography (gradient, 20-80% EtOAc in hexanes; 0-20% MeOH in dichloromethane) to obtain the desired compound as a pale yellow solid (3.7 g, 76%). This material was used directly in the next step. |
71.5% | With sodium methylate In ethanol for 2h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | Stage #1: ethyl 4-methyl-3-oxo-pentanoate; benzylamine In toluene at 110℃; for 3h; Dean-Stark; Inert atmosphere; Stage #2: With sodium cyanoborohydride; acetic acid at 20℃; for 2h; Dean-Stark; Inert atmosphere; | 2.1 Step 1 Compound 1 (1.02ml, 6.32mmol) and benzylamine (690ul, 6.32mmol) were dissolved in anhydrous toluene (8ml) and refluxed at 110°C (Dean-Stark trap) for 3h under nitrogen protection. The solvent was evaporated to dryness, the residue was dissolved in 10 ml of glacial acetic acid, NaCNBH3 (1.8 g, 28.45 mmol) was added in portions, and the reaction mixture was stirred at room temperature for 2 h. The residue was extracted with ether, the organic layer was washed with 1N NaOH and saturated brine, dried over anhydrous Na2SO4, filtered and concentrated to give compound 1 (1.2 g, 76%) |
With sodium cyanoborohydride 1.) benzene, reflux, 3 h, 2.) acetic acid, room temp., 2 h; Yield given. Multistep reaction; | ||
Stage #1: ethyl 4-methyl-3-oxo-pentanoate; benzylamine In benzene for 8h; Heating; Stage #2: With sodium cyanoborohydride; acetic acid at 20℃; for 2h; Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With ammonium acetate In cyclohexane; isopropyl alcohol | |
85% | With ammonium acetate In methanol at 20℃; for 72h; | 30 Ammonium acetate (2.44 g, 31.6 mol, 5 eq) was added to a solution of 4-methyl-3-oxo- pentanoic acid ethyl ester (1.0 g, 6.32 mol, 1 eq) in methanol (10 mL) and the mixture was stirred at room temperature for 3 days. Solvent was evaporated in vacuo and the solid residue was triturated with [DICHLOROMETHANE] (20 mL) and filtered off. The filtrate was then washed with water and brine, dried over [NA2SO4] and concentrated in vacuo to afford the title compound as a yellow oil (0.85 g, yield = 85%). |
With ammonia In ethanol at 25℃; for 42h; |
With ammonium acetate In cyclohexane |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With 4-toluenesulfonyl azide; caesium carbonate In tetrahydrofuran at 25℃; for 3h; Inert atmosphere; | |
85% | With sodium azide; 3-Carboxybenzenesulfonyl chloride; potassium carbonate In water; acetonitrile at 20℃; for 2h; | |
With 4-toluenesulfonyl azide; triethylamine |
With triethylamine In dichloromethane at 20℃; for 6h; Inert atmosphere; | ||
With 4-acetamidobenzenesulfonyl azide; triethylamine In acetonitrile at 0 - 20℃; | ||
With 4-acetamidobenzenesulfonyl azide; triethylamine In acetonitrile at 20℃; for 8h; | ||
With 4-toluenesulfonyl azide; 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 0 - 20℃; for 3h; | 3.2.2. Procedure for the Synthesis of Diazo Substrates General procedure: Diazo substrates were synthesized from the corresponding ketonic esters or 1,3 di-ketones asshown in Scheme S1. 2a-2o was synthesized according to the literatures [36].To a solution of ketonic ester or 1,3-di-ketone (5 mmol) in CH3CN, 6 mmol TsN3 was added.Then the reaction mixture was cooled to 0 °C and a solution of DBU (6 mmol) in 10 mL CH3CN wasadded dropwise. Next, the reaction temperature was raised to room temperature. After stirring for3 h, the residue was extracted with EA for 3 times. The combined organic layers were washed withwater and brine sequentially, dried over Na2SO4, filtered and concentrated. The crude product waspurified by flash chromatography on silica gel (PE: EA = 100:1) to afford the corresponding product in50-90% yields. | |
With 4-toluenesulfonyl azide; triethylamine In acetonitrile at 0 - 20℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With N-Bromosuccinimide In various solvent(s) at 20℃; for 0.916667h; | |
90% | With bromine In tetrachloromethane; water at 0℃; for 2h; | 9.a a) Synthesis of 2-bromo-4-methyl-3-oxo-pentanoicacid ethyl ester a) Synthesis of 2-bromo-4-methyl-3-oxo-pentanoic acid ethyl ester To a stirred mixture of 4-methyl-3-oxo-pentanoic acid ethyl ester (5.0 g, 31.5 mmol) in carbon tetrachloride/water (1:1) (30 ml) is added a solution of bromine (1.61 ml, 31.5 mmol) in carbon tetrachloride (15 ml) at 0° C. over a period of 1 h and the resulting reaction mixture is stirred at 0° C. for 1 h. After completion of the reaction, the organic layer is washed with water (100 ml), brine (50 ml), dried over sodium sulfate and evaporated in vacuo to yield 2-bromo-4-methyl-3-oxo-pentanoic acid ethyl ester (6.7 g, 28.37 mmol, 90%). |
90% | With bromine In tetrachloromethane; water at 0℃; for 2h; | 9.a Synthesis of 2-bromo-4-methyl-3-oxo-pentanoic acid ethyl ester To a stirred mixture of 4-methyl-3-oxo-pentanoic acid ethyl ester (5.0 g, 31.5 mmol) in carbontetrachloride/water (1:1) (30 ml) is added a solution of bromine (1.61 ml, 31.5 mmol) in carbon tetrachloride (15 ml) at 0 °C over a period of 1 h and the resulting reaction mixture is stirred at 0 °C for 1h. After completion of the reaction, the organic layer is washed with water (100 ml), brine (50 ml), dried over sodium sulfate and evaporated in vacuo to yield 2-bromo-4-methyl-3-oxo-pentanoic acid ethyl ester (6.7 g, 28.37 mmol, 90%). |
30.3 g | With bromine In tetrachloromethane; water at 0℃; for 0.75h; | |
With bromine; sodium acetate In acetic acid at 10 - 20℃; | S.2.2.1 To a suspension of sodium acetate (1.9 g) in glacial acetic acid (15 ml) was added 4-methyl-3-oxo-pentanoic acid ethyl ester (2 g) and the reaction mixture cooled to 10° C. Bromine (0.7 ml) was then added dropwise. The resulting solution was allowed to warm to room temperature and stirred for 1 h. The reaction was complete (by TLC) and was concentrated in vacuum affording 3.8 g crude ethyl product which was used directly in the next synthetic step. | |
With bromine In water at 0℃; for 0.5h; | 101 To a 0°C solution of ethyl 4-methyl-3-oxopentanoate (5.0 mL, 31 mmol) in water (20 mL) was added bromine (16 mL, 31.3 mmol) via syringe pump (0.5 hour). The mixture was stirred at 0°C for 0.5 hour. The solution was extracted with EtOAc (3 x 20 mL). The organic extracts were combined, extracted with brine (2 x 60 mL), dried over MgSO4, filtered, evaporated, and dried in vacuo, affording ethyl 2-bromo-4- methyl-3-oxopentanoate (6.0 g, 82% yield). The product was used without further purification | |
With bromine In chloroform at 0 - 20℃; for 0.333333h; Cooling with ice; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With recombinant E. coli cells coexpressing carbonyl reductase and glucose dehydrogenase on cell surface In aq. phosphate buffer; dibutyl ether at 20℃; | |
47.5% | With D-glucose In ethanol; water at 25℃; for 48h; Brewers' yeast; | |
29.2% | With D-glucose In ethanol; water at 25℃; for 48h; yeast Saccharomyces cerevisiae IFO 0565; yeast-mediated biochemical reduction of 3-oxoalkanoic esters, stereochemistry, enantiomeric excess; |
With ruthenium trichloride; hydrogen; (S)-(-)-(6,6’-dimethoxybiphenyl-2,2’-diyl)bis(diphenylphosphine) In methanol at 50℃; for 24h; | ||
With hydrogen In ethylene glycol at 20℃; for 24h; | ||
With hydrogen bromide; hydrogen; (R)-(6,6′-dimethoxy-[1,1′-biphenyl]-2,2′-diyl)bis(diphenylphosphine) In ethanol at 50℃; for 24h; | ||
With Candida magnoliae carbonyl reductase; D-glucose dehydrogenase; NADPH In water; dimethyl sulfoxide at 20℃; | ||
> 99 % ee | With hydrogen In ethanol at 50℃; for 24h; | 6.a The substrate to be hydrogenated (1 mmol) is then dissolved in 2 ml of hydrogenation solvent (of the alcohol or halogenated type, such as dichloromethane) and placed in an autoclave in the presence of the catalyst under the desired hydrogen pressure and at the desired temperature. |
> 99 % ee | With hydrogen | 8 EXAMPLE 8 TABLE 2 below shows a comparison of the results of the hydrogenation of different substrates obtained on the one hand with the ruthenium complexes according to the invention and on the other hand with complexes of the type Ru-Binap, under the same operating conditions (temperature, pressure and solvent). [0235] TABLE 2 shows a comparison of the results obtained in TABLE 1 with the complexes according to the invention and the results obtained with the corresponding complexes in which the ligand (1) according to the invention has been replaced by the ligand BINAP. |
> 99 % ee | With [bis(2-methylallyl)cycloocta-1,5-diene]ruthenium(II); hydrogen bromide; hydrogen; (+)-(R)-[2,3,2',3'-tetrahydro-5,5'-bi(1,4-benzodioxin)-6,6'-diyl]bis(diphenylphosphane) In ethanol at 50℃; for 24h; Inert atmosphere; Autoclave; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With hydrogen at 50℃; for 48h; | |
99% | With C32H40F6O6P2Pd; hydrogen In acetone at 0℃; for 12h; Autoclave; enantioselective reaction; | |
99% | With (2R,2'R,3R,3'R)-3,3'-di-tert-butyl-2,2'-diisopropyl-2,2',3,3'-tetrahydro-4,4'-bibenzo[d][1,3]oxaphosphole; hydrogen; palladium diacetate In acetone at 0 - 20℃; for 20h; Glovebox; | 22 Example 22The optically active chiral β-hydroxycarboxylate (R)-5q was prepared using compound 4q as the hydrogenation substrate, the chiral diphosphine ligand L3 and palladium trifluoroacetate as catalysts. The reaction was as follows: In a nitrogen atmosphere, palladium trifluoroacetate (0.33 mg, 2 μmol) and L3 (1.1 mg, 2.4 μmol) were mixed in a glove box, 1 mL of degassed acetone was added, and the mixture was stirred at room temperature for 1 hour, and the solvent was drained to obtain The in-situ generated metal complex was dissolved in 0.5 mL of pentafluoropropanol, added to a hydrogenation bottle, and 4q (20 mg, 0.1 mmol) was added. The hydrogenated bottle was transferred to an autoclave. After the reaction vessel was closed, hydrogen was replaced three times, hydrogen gas was charged to 30 atm, and the reaction was carried out at 0° C. for 20 hours and then returned to room temperature. The hydrogen was vented and the reactor was opened. The crude reaction solution was filtered through a microporous membrane to remove metal ions. After diluting with isopropanol, the conversion rate and product were measured by chiral gas phase.(R)-3-Hydroxy-4-methylpentanoic acid ethyl esterThe ee value of [(R)-5q] is 92%. |
With 1,2-bis[(R,R)-2,5-diisopropylphospholano]ethane-RuBr2; hydrogen In methanol; water at 35℃; for 20h; | ||
With hydrogen In ethanol at 50℃; | ||
With hydrogen bromide; hydrogen; (S)-5',6'-benzo-6-methoxy-2,2'-bis(diphenylphosphanyl)biphenyl In methanol at 50℃; for 24h; | ||
With hydrogen In ethanol at 50℃; for 24h; | ||
99.9 % ee | With recombinant alcohol dehydrogenase from Stenotrophomonas maltophilia SmADH2; isopropyl alcohol; NADH In aq. phosphate buffer at 30℃; Green chemistry; Enzymatic reaction; stereoselective reaction; | |
94.7 % ee | With SmADH31 Enzymatic reaction; stereoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51.3% | With sodium acetate; acetic acid; In water; | (1) Ethyl 4-(4-fluorophenyl)-2-isopropylpyrrole-3-carboxylate 1 STR6 A mixture of 6.85 g (43.3 mmol) of ethyl isobutyrylacetate, 10.69 g (56.3 mmol) of 2-amino-4'-fluoracetophenone hydrochloride, 16.3 ml of acetic acid, 6.04 g of sodium acetate, and 10.8 ml of water is refluxed for 4 hours. After cooling, the reaction mixture is adjusted to pH 8 with saturated NaHCO3 and extracted with ether. The extract, 8.36 g, is subjected to column chromatography with silica gel, eluding with methylene chloride to give 6.12 g (Yield:51.3%) of the compound 1. NMR (CDCl3) delta: 1.14 (t, 3H, J=7 Hz); 1.31 (d, 6H, J=7 Hz); 3.81 (septet, 1H, J=7 Hz); 4.15 (q, 2H, J=7 Hz); 6.58 (d, 1H, J=2,4 Hz); 6.96-7.05 (m, 2H); 7.29-7.37 (m, 2H); 8.36 (brs, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.6% | With ammonium acetate; acetic acid In water; toluene Reflux; | 1.3 Step 3) Ethyl 3-amino-4-methyl-2-pentenoate Ethyl isobutyrylacetate(2.00g, 12.6mmol) ammonium acetate (1.95 g, 25.3 mmol) and acetic acid (0.65 mL, 11 mmol) were added to a solution of toluene (20 mL).The reaction was then refluxed with water and dried overnight.Cool to room temperature and dilute with ethyl acetate (50 mL).It was washed with a saturated aqueous solution of sodium bicarbonate (50 mL) and brine (50 mL) and evaporated.Filtering,The solvent was evaporated under reduced pressure and the residue was dried in vacuo to give a yellow oil.(1.76g, 88.6%). |
85% | With ammonium acetate In methanol at 20℃; for 72h; | 34 Ammonium acetate (2.44 g, 31.6 mol, 5 eq) was added to a solution of 4-methyl-3-oxo-pentanoic acid ethyl ester (1.0 g, 6. 32 mol, 1 eq) in methanol (10 mL) and the mixture was stirred at room temperature for 3 days. Solvent was evaporated in vacuo and the solid residue was triturated with dichloromethane (20 mL) and filtered off. The filtrate was then washed with water and brine, dried over Na2S04 and concentrated in vacuo to afford the title compound as a yellow oil (0.85 g, yield = 85%). |
With ammonium acetate In methanol at 20℃; for 72h; |
With ammonium acetate In methanol at 20℃; for 60h; | ||
With ammonium acetate In ethanol at 20℃; for 48h; | ||
Multi-step reaction with 2 steps 1: 40 percent / p-toluenesulfonic acid / toluene / 63 h / Heating 2: 83 percent / sodium ethoxide / ethanol / 18 h / Heating | ||
With ammonium acetate In methanol Reflux; | Synthesis of enamines 4 General procedure: The corresponding β-ketoester (1 eq.) and NH4OAc (5 eq.) were refluxed in methanol (for 4a-c, eh,j, l) or in mixture benzene-AcOH (5:1) with Dean-Stark trap (for 4d, i, k) for 5-6 hours. Afterremoving of solvents under reduced pressure the residue was extracted with ether, washed withwater, sat. NaHCO3 and brine, dried over CaCl2. Solvent was evaporated to give enamine, whichwas used without purification. | |
With ammonium formate In ethanol for 20h; Reflux; Schlenk technique; Inert atmosphere; | ||
With ammonium acetate In methanol Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | Stage #1: ethyl potassium malonate With triethylamine; magnesium chloride In ethyl acetate at 0 - 35℃; for 6.5h; Stage #2: isobutyryl chloride In ethyl acetate at 0 - 20℃; for 13h; | 1-5; 1.2.2 A preparation process of ethyl isobutyrylacetate, the specific steps are as follows: (1) Add 125mL to the three-necked flaskEthyl acetate and 13.6g (80mmol)Potassium monoethyl malonate,Stir and cool to 05, then add in order9.12g (96mol) anhydrous magnesium chloride and 27.8mL (0.2mol)Triethylamine, heat up to 35 within 0.5h and stir at this temperature for 6h:(2) Cool to 0°C, add 6mL (57mmol) isobutyryl chloride dropwise at 05°C for about 1h, and then react at room temperature for 12h:(3) Cool to 0, carefully add 70mL of 13% hydrochloric acid, keep the temperature not higher than 20 during this process:(4) Separate the organic phase, extract the aqueous layer with toluene (40mL×3), combine the organic phases, wash with saturated sodium bicarbonate solution until neutral, then wash with 25mL saturated brine, and evaporate the solvent under reduced pressure:(5) The crude product was distilled under reduced pressure to obtain 5.5 g of colorless liquid with a yield of 61%. |
With triethylamine; magnesium chloride In acetonitrile |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With sodium methylate In tetrahydrofuran; methanol at 20℃; for 16h; | 1a A stirred solution of isobutyryl acetate (16 g, 124.8 mmol) in 120 mL of dry THF was treated with a solution of sodium methoxide (252 mL, 0.5 M in MeOH) followed by a solution of compound A3a (28 g, 124.8 mmol) in 40 mL of dry THF. After stirring at room temperature for 16 h, the solvent was removed under reduced pressure. The residue was partitioned between 800 mL of Et2O and 800 mL of water. The organic layer was washed with brine, dried over Na2SO4, filtered, concentrated and purified by chromatography on silica gel (eluent: PBEtOAc = 10/1 ) to give 24.8 g of compoundA4a as a white solid (Yield: 62%). |
With sodium methylate In methanol at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With acetic acid; sodium nitrite In water at 0℃; | |
90% | With sodium nitrite In acetic acid at 0 - 20℃; | |
90% | With sodium nitrite In water; acetic acid at 0 - 20℃; |
With sodium nitrite In water; acetic acid at 5 - 20℃; for 2h; | A 42.4 g of ethyl 4-methyl-3-oxopentanoate are dissolved in 100 ml of glacial acetic acid, and 21 g of sodium nitrite, dissolved in 100 ml of water, are added at 5 C. Over a period of one hour, the mixture is allowed to warm to room temperature, 100 ml of water are added and the mixture is stirred at room temperature for another hour. The mixture is extracted three times with in each case 150 ml of methyl tert-butyl ether, 200 ml of water are added to the combined organic phases and the mixture is neutralized by addition of solid NaHCO3. The organic phase is removed, washed with saturated NaCI solution and dried over MgSO4, and the solvent is removed under reduced pressure. This gives 46 g of ethyl 2-hydroxy-imino-4-methyl-3-oxopentanoate as an oil. C8H13NO4 (187.20), MS (ESI) =188 (M+H+). | |
With acetic acid; sodium nitrite In water at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride; In tetrahydrofuran; at 0 - 70℃; for 72h; | To a solution of 4-bromo-2-methylbenzyl alcohol (9.0 g) in dichloromethane (50 mL) was added thionyl chloride (3.8 mL) under ice-cooling, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to give <strong>[24078-15-7]4-bromo-2-methylbenzyl chloride</strong> (9.8 g). To a suspension of sodium hydride (60%, 2.1 g) in tetrahydrofuran (90 mL) was added ethyl 4-methyl-3-oxopentanoate (7.5 g) under ice-cooling, and the reaction mixture was stirred at room temperature for 1 hour. 4-Bromo-2-methylbenzyl chloride (9.8 g) was added to the reaction mixture, and the resultingmixture was stirred at 70C for 3 days. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and the mixture was extracted with diethyl ether. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. To a solution of the residue in toluene (20 mL) was added hydrazine monohydrate (5.4 mL), and the mixture was stirred at 90C overnight. The reaction mixture was concentrated under reduced pressure, and the residue was treated with n-hexane-diethyl ether (10/1) to crystallize. The crystals were collected by filtration and washed with n-hexane, water andn-hexane successively, and dried under reduced pressure to give the title compound (12.4 g).1H-NMR (DMSO-d6) delta ppm: 1.05 (6H, d, J=6.8Hz), 2.28 (3H, s), 2.65-2.8 (1H, m), 3.45 (2H, s), 6.82 (1H, d, J=8.2Hz), 7.24 (1H, dd, J=8.2Hz, 1.8Hz), 7.33 (1H, d, J=1.8Hz), 8.5-12.0 (2H, br) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With aniline; In acetic acid; ethyl acetate; toluene; | EXAMPLE 19.1 3-Oxo-4-methylpentananilide A solution of 47.4 g (0.3 mol) of ethyl 3-oxo-4-methylpentanoate, 27.93 g (0.3 mol) of aniline and 0.6 ml of glacial acetic acid in 360 ml of toluene is boiled under reflux with a water trap for 4 hours. The reaction mixture is cooled and then washed twice with 0.5 N hydrochloric acid, then twice with saturated sodium bicarbonate solution and then with saturated brine, and is dried and concentrated in vacuo. The residue is chromatographed on 1 kg of silica gel using toluene/ethyl acetate 10:1. 40.5 g (66% yield) of pale pink-colored oil. 1 H NMR (CDCl3): delta=1.2 (d, 6H), 2.8 (s, 2H), 3.65 (s, 2H), 7.0-7.75 (m, 5H, 9.1-9.4 (s, br., 1H). MS: C12 H15 NO2 (205) m/e=205 (M+), 93. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 27 2,6-Diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-(3-methyl-1-butenyl)pyridine The title compound was prepared from ethyl isobutyrylacetate, 4-fluorobenzaldehyde and <strong>[22884-29-3]isobutyl triphenylphosphonium bromide</strong> according to the procedures described in Example 1, Steps A-G. 1H NMR (300 MHz, CDCl3): delta7.07 (m, 4 H), 5.92 (d, J=10.7 Hz, 1 H), 5.20 (dd, J=10.7, 11.4 Hz, 1 H), 4.42 (bs, 2 H), 3.45 (sept, J=6.6 Hz, 1 H), 3.30 (sept, J=6.6 Hz, 1 H), 2.06 (m, 1 H), 1.35 (d, J=6.6 Hz, 6 H), 1.31 (m, 1 H), 1.24 (m, 5 H), 0.69 (bs, 6 H). FAB-MS: calculated for (C23H30FNO) 355, found 356 (M+H). Anal. Calcd for C23H30FNO: C, 77.71; H, 8.51; N, 3.94. Found: C, 77.94; H, 8.59; N, 3.79. mp 112 C. Rf=0.3 (20% ethyl acetate/hexane). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Stage #1: ethyl 4-methyl-3-oxo-pentanoate With sodium hydroxide; water at 20℃; for 16h; Stage #2: With hydrogenchloride In water | 154 PREPARATION 154; 4-Methyl-3-oxo-pentanoic acid; Ethyl isobutyrylacetic acid (21 g, 132 mmol) was taken up in a 1.5M sodium hydroxide solution (15 g in 250 mL water) and stirred at room temperature over 16 h. The solution was cooled to 0° C. in an ice bath and was then acidified with 35 mL conc. Hydrochloric acid to pH 1-2. The resulting solution was saturated with sodium chloride and was then extracted with ethyl acetate (3×300 mL). The combined extracts were dried over sodium sulfate and then filtered and concentrated in vacuo to give the title compound as a clear oil (16.4 g, 95%).1HNMR (CDCl3, 400 MHz, approx. 4:1 mixture of keto and enol tautomers) (major keto form) 1.15-1.16 (d, 6H), 2.75-2.71 (m, 1H), 3.56 (s, 2H). |
With water; sodium hydroxide at 0 - 20℃; for 16h; | 74.1 Step 1 : Synthesis of 4-methyl-3-oxopentanoic acid To a stirring solution of ethyl 4-methyl-3-oxopentanoate (1 g, 6.32 mmol) in water (12 niL) was added NaOH (758 rng, 18.9 mmol) at 0°C and the reaction mixture was stirred at room temperature for 16 h. After consumption of the starting material (by TL.C), the reaction mixture was acidified with aqueous 2/V HC1 solution (pH = 4-5) and extracted with EtOAc (2 x 50 ml.). The organic layer was dried over anhydrous Na2S(>4 and concentrated under reduced pressure to afford the desired product (700 mg, crude) as a thick liquid. This material was used as is without any further purification. LCMS (ESI): m/z 131.0 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | Stage #1: ethyl 4-methyl-3-oxo-pentanoate With potassium carbonate In tetrahydrofuran at 20℃; for 3h; Inert atmosphere; Stage #2: methyl iodide In tetrahydrofuran at 0 - 20℃; | 5.1 A solution of ethyl 4-methyl-3-oxopentanoate (3.0 g, 19.0 mmol) and potassium carbonate (7.86 g, 56.9 mmol) in THF (40 mL) was stirred at room temperature for 3 h under N2 (g). The mixture was cooled to 0 °C and methyl iodide (3.23 g, 22.8 mmol) was added dropwise over 5 min. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. Subsequent filtration and concentration provided ethyl 2,4-dimethyl-3- oxopentanoate (2.89 g, 89% yield) as a clear yellow oil that was used without further purification. MS (EI) for C9H16O3: 172 (MH+). |
Stage #1: ethyl 4-methyl-3-oxo-pentanoate With potassium carbonate In tetrahydrofuran at 20℃; for 3h; Inert atmosphere; Stage #2: methyl iodide In tetrahydrofuran at 0℃; Inert atmosphere; | 5.1 Rengent Preparation 5 [00505] STEP I : A solution of ethyl 4-mcthyl-3-oxopcntanoate (3.0 g, 1 .0 minol) and potassium carbonate (7.86 g, 56.9 mmol) in THF (40 mL) was stirred at room temperature l or 3 It under N2 (g). The mixture was cooled to 0 "C and methyl iodide (3.23 g, 22.8 nimol) as added dropwise over 5 min. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. Subsequent filtration and concentration provided ethyl 2.4-dimethyl-3- :pxopentanoaie-(2.8 g, 89% yield) as a clear, yel low oil that was used without further purification. MS (El) for (¼-¼(¾: 172 (MB*). | |
With potassium carbonate In N,N-dimethyl-formamide Inert atmosphere; |
With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 4h; Inert atmosphere; | ||
With potassium carbonate In tetrahydrofuran Inert atmosphere; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | Stage #1: 3-Guanyl-4-n-propoxybenzoic acid; ethyl 4-methyl-3-oxo-pentanoate With potassium carbonate In N,N-dimethyl-formamide at 100℃; Inert atmosphere; Stage #2: With acetic acid In water; N,N-dimethyl-formamide Cooling with ice; | 62 Example 62 4-n-Propoxy-3-(1,6-dihydro-4-isopropyl-6-oxopyrimidin-2-yl)benzoic acid [Show Image] The compound(4.0g, 14mmol) of preparation example 12 and K2CO3(7.7g, 56mmol) were mixed and suspended in DMF(30ml), and then added with ethyl isobutyrylacetate(2.7g, 17mmol) in one batch. The reaction mixture was stirred overnight at 100°C under nitrogen protection, cooled, poured into ice water, and adjusted to a pH of 4∼5 by addition of glacial acetic acid to give a yellowish solid crude. After filtered, the solid was washed with water (250mL) and dried at 60°C. The crude was recrystallized from ethyl acetate to give the white title compound(3.4g, yield: 77%). 1H NMR (CD3OD) δ: 8.57 (1H, d), 8.19 (1H, dd), 7.26 (1H, d), 6.25 (1H, s), 4.20 (2H, t), 2.86 (1H, m), 1.89 (2H, m), 1.29 (6H, d), 1.06 (3H, t). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With tert-butyl hydroxyperoxide; tetra-(n-butyl)ammonium iodide In water; ethyl acetate at 40℃; for 10h; | |
75% | With [Cu(1,10-phenanthroline)2Cl]Cl; iodine; oxygen In acetonitrile at 60℃; for 24h; Molecular sieve; | Typical procedure General procedure: Iodine (1.2 mmol), 1,3-dicarbonyl compounds (1 mmol), [Cu(o-phen)2Cl]Cl (0.2 mmol), 4 Å M.S.(0.1 g) were successively added to a solution of benzylamine (1.5 mmol) derivatives in CH3CN (5 mL). The resulting solution was stirred at 60 °C for 24 h (the progress of the reaction was monitored by TLC). Then H2O (5 mL) and EtOAc (15 mL) were added. The aqueous phase was extracted with EtOAc (3 × 15 mL). The combined organic phases were washed with brine, dried (anhyd. Na2SO4), filtered, and concentrated. The residue was purified by column chromatography to give ethyl 5-methyl-2-phenyloxazole-4-carboxylate (1ab); yield 182 mg (79%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: ethyl 4-methyl-3-oxo-pentanoate With sodium hydride In tetrahydrofuran; mineral oil at 20℃; for 0.5h; Stage #2: ethyl iodide In tetrahydrofuran; mineral oil Reflux; | Method A: General procedure: Appropriate 3-oxoester (1.0 equiv.) was added to a suspension of NaH (60% in mineral oil, 1.0 mol. equiv.) in THF (1 ml/1 mmol of 3-oxoester) at room temperature and resulting mixture was stirred for 30 min at room temperature. Then alkyl halide (1 mol. equiv.) was added and mixture was refluxed for defined period of time (TLC control). After cooling to room temperature reaction was quenched with saturated aqueous NH4Cl (1.2 ml/1 mmol of NaH). The aqueous layer was separated and extracted with AcOEt (3×). Organic layers were combined, dried over MgSO4, filtered and concentrated in vacuo (at 30° C.). The crude product was purified by flash column chromatography on silica gel giving colorless liquid which was pure enough to be used in the next step without additional purification and fraction contaminated with starting material which was not further purified. |
With potassium carbonate In N,N-dimethyl-formamide Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78.2% | With potassium <i>tert</i>-butylate In methanol at 0℃; for 4.5h; Reflux; | |
54% | With potassium carbonate In water at 20℃; for 0.25h; Microwave irradiation; | Ultrasound-Promoted Synthesis of 4-Pyrimidinols 3; General Procedure 1 General procedure: The corresponding amidine hydrochloride (2.54 mmol) and powdered K2CO3 (5.76 mmol) were dissolved in water (5.0 mL) in a 20-mL vessel. The β-keto ester (2.31 mmol) was added and the resulting mixture was irradiated for 5-15 min (see Table 2). Upon the end of the reaction (TLC, hexanes/EtOAc, 5:1), the mixture was diluted with sat. aq NH4Cl (5.0 mL) and extracted with CH2Cl2 (3 × 15 mL). The combined organic phases were dried (anhyd Na2SO4) and filtered. The filtrate was rotary evaporated and the obtained crude product was purified by column chromatography [silica gel, hexane/EtOAc mixtures or recrystallized (EtOH)]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With potassium phosphate; copper(I) bromide In acetonitrile at 90℃; for 24h; Inert atmosphere; | General procedure II for the Cu(I)-catalyzed synthesis of 4H-chromenes 3a-m General procedure: An oven-dried 10 mL vial was equipped with a magnetic stir barand charged with CuBr (7 mg, 0.05 mmol), K3PO4 (424 mg, 2 mmol), the 2-bromo-1-(4-methylbenzenesulfonatemethyl)benzene derivative 1 (0.5 mmol) and the b-ketoester 2 (1 mmol) under air. The vial was sealed, evacuated and backfilled with argon three times,then dry CH3CN (2 mL)was added. The reaction mixture was stirred at 90 C for 24 h. After cooling to room temperature, the reaction mixture was partitioned between CH2Cl2 (30 mL) and brine (20 mL). The aqueous phase was extracted with CH2Cl2 (220 mL).The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue thus obtained was purified by flash column chromatography over silica gel to afford the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 10h; Inert atmosphere; | |
86% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 10h; Molecular sieve; | 28 Example 28 ethyl 3-(4-bromophenyl)-2-(trifluoromethyl)prop-2-enoate(0.6 mmol), ethyl 4-methyl-3-oxopentanoate0.2mmol) as a starting material, and other operations were carried out in the samemanner as in Reference Example 1. The mixture was stirred at room temperaturefor 10 hours and purified by silica gel column chromatography (petroleum ether:Ethylacetate = 20: 1) to give the mono-fluoro-substituted 4H-pyran derivative pureproduct III-28 (76 mg, 86%).ethyl 3-phenyl-2-(trifluoromethyl)propenoate(0.6 mmol) and acetylacetone (0.2 mmol) were dissolved in1.0 mL of N, N-dimethylformamide was injected through a syringe into a reactor equipped with a molecular sieve and potassium carbonate 1.2 times the amount of 1,3-dicarbonyl compound of the formula (II) in the dry reaction tube, at 50 ° C to room temperature for a full reaction, reaction for 6 hours, by TLC detection reaction, to acetylacetone completely disappeared. After completion of the reaction, the reaction was quenched with 5.0 ml of distilled water and extracted with ether or ethyl acetate (3 * 5.0 ml). The combined organic phases were dried and evaporated to remove the solvent. The crude product was purified by flash column chromatography on silica gel : Ethyl acetate = 20: 1) to obtain the pure ethyl 5-acetyl-2-fluoro-6-methyl-4-phenyl-4H-pyran-3-carboxylate III-1 (44 mg, 73%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With sulfuric acid In ethanol at 80℃; for 48h; | 2 Example 2 Isobutyrylacetic acid ethyl ester (158 g), p-fluorobenzaldehyde (130 g), and urea (120 g) were dissolved in 800 mL of ethanol. Added mass fraction of 98.3% concentrated sulfuric acid (98 g). 80°C reflux reaction for 24h. TLC plate detection reaction is complete and cooled to room temperature. Filter. The filter cake was washed with a small amount of ethanol. Dried to obtain 278 g of a white solid. The yield was 91%. The filtered mother liquor was used as the solvent system for the reaction. Isobutyrylacetic acid ethyl ester (142 g), p-fluorobenzaldehyde (117 g), and urea (108 g) were added. 2g concentrated sulfuric acid was added. 80°C reflux reaction for 24h. TLC plate detection reaction is complete and cooled to room temperature. Filter. The filter cake was washed with a small amount of ethanol. Dried to obtain 274 g of a white solid. The yield was 99%. |
38% | With cerium(III) chloride heptahydrate In ethanol at 80℃; for 24h; | 12 4.1.1. General procedure for the Biginelli reactions (9a-e) General procedure: Procedure A: A mixture of β-ketoester (1 mmol), aldehyde(1 mmol) and urea (1.5 mmol) was heated at 80 °C during 15 min inthe presence of Ce(NO3)3*6H2O (5 mol%). The obtained solid wasfiltered and washed with ice-cold water and recrystallized from hot ethanol to afford the desired 1,3-dihydropyrimidinone derivative. Procedure B: A solution of β-ketoester (1 mmol), aldehyde(1 mmol) and urea (1.5 mmol) in EtOH (20 mL) was heated at reflux (80 °C) during 24 h in the presence of CeCl3*7H2O (25 mol%). The mixture was cooled down to room temperature, poured intocrushed ice and stirred/triturated until precipitation was observed.The solid was filtered and washed with ice-cold water and recrystallized from hot ethanol to afford the desired 1,3-dihydropyrimidinone derivative. 4.1.12 Ethyl 4-(4-fluorophenyl)-6-isopropyl-2-oxo-3,4-dihydro-1H-pyrimidine-5-carboxylate (9h) Yield: 38%, white solid. 1H NMR (400 MHz, CDCl3) δ 7.38 (s, 1H), 7.34-7.20 (m, 2H), 6.99 (t, J = 8.7 Hz, 2H), 6.12 (s, 1H), 5.37 (d, J = 2.9 Hz, 1H), 4.28-4.13 (m, 1H), 4.06 (q, J = 7.1 Hz, 2H), 1.21 (d, J = 7.0 Hz, 2H), 1.18 (d, J = 7.0 Hz, 2H), 1.15 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 165.3, 163.5, 161.1, 154.4, 153.1, 139.7, 139.7, 128.3, 128.2, 115.7, 115.4, 60.1, 55.0, 27.5, 19.7, 19.5, 14.0. HRMS (ESI): m/z [M+H]+ calcd for C16H20N2O3: 307.1452, found: 307.1452. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With sulfuric acid; at 0 - 20℃; | To the mixture of compound 1 (3.0 g, 21.0 mmol) and compound 2 (4.0 g, 25.0 mmol), H2SO4(9 mL) was added slowly at 0 C. The mixture was stirred at RT overnight. The reaction mixture was poured into H2O (10 mL) and stirred for 30 mins, the formed precipitate was filtered and washed with water, dried to give compound 3 (2.0 g, 41% yield) as light yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With triethylamine; In ethanol; N,N-dimethyl acetamide; at 20 - 100℃; for 2h; | Taking 25 ml round-bottom flask, the intermediate isobutyryl ethyl acetate (1.33g, 8 . 39mmol) dissolved in 11mLN, dipropylene N-dimethyl formamide methanol 100 C stirring overnight. After the reaction is distilled under reduced pressure to obtain crude products. The intermediate is dissolved in 11 ml of ethanol, add 1.1 ml triethylamine, <strong>[658-27-5]3-fluorophenylhydrazine</strong> hydrochloride compound (1.36g, 8 . 39mmol), the reaction room temperature for 2 hours. After the reaction, by adding 150 ml water, ethyl acetate extraction three times (50mLx3), combined with the phase, saturated salt water washing three times (50mLx3), anhydrous sodium sulfate for drying; concentrated, dry sample, rapid preparation of chromatographic silica gel column (ethyl acetate: petroleum ether = 30:1) separated to obtain oily liquid 832 mg, yield 36%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | General procedure: The precatalysts trans-4,5-methano-L-proline 5 (3.18 mg,0.025 mmol, and 5 mol%), quinidine thiourea 6 (14.86 mg,0.025 mmol, and 5 mol%) and DCM (2.0 mL) were addedto a capped sample vial at room temperature. After themixture had been stirred for 10 min, a solution of aldehyde1 (0.5 mmol and 1.0 equiv.) and thiourea 2 (57 mg, 0.75mmol, and 1.5 equiv.) in DCM mL) were added and thestirring was continued for 3 h at room temperature. Then beta-dicarbonyl compound 3 (0.55 mmol and 1.1 equiv.) wasadded, the reaction mixture was stirred at 50 C for 15 h asmonitored by TLC. After the reaction was completed, themixture was purified through flash CC on a silica gel using(PE/EA = 4/1) as eluent to afford pure products. | |
92% | General procedure: The precatalysts trans-4,5-methano-L-proline 5a (3.18 mg,0.025 mmol, 5 mol %), quinidine thiourea 6a (14.86 mg,0.025 mmol, 5 mol %) and DCM (2.0 mL) were added to a capped sample vial at room temperature. After the mixture had been stirred for 10 min, a solution of aldehyde 1 (0.5 mmol, 1.0 equiv) and thiourea 2 (57 mg, 0.75 mmol, 1.5 equiv) in DCM (1.0 mL) wasadded and stirring was continued for 3 h at room temperature. Next, beta-dicarbonyl compound 3 (0.55 mmol, 1.1 equiv) was added, and the reaction mixture was stirred at 50 C for 15 h monitored byTLC. After the reaction was completed, the mixture was purified through flash column chromatography on a silica gel using (PE/EA = 4/1) as eluent to afford pure products. | |
92% | General procedure: The precatalysts trans-4,5-methano-l-proline 5a (3.18 mg, 0.025 mmol, 5 mol %), quinidine thiourea 6a (14.86 mg, 0.025 mmol, 5 mol %) and DCM (2.0 mL) were added to a capped sample vial at room temperature. After the mixture had been stirred for 10 min, a solution of aldehyde 1a (0.5 mmol, 1.0 equiv) and thiourea 2 (57 mg, 0.75 mmol, 1.5 equiv) in 111DCM (1.0 mL) was added and stirring was continued for 3 h at room temperature. Next, beta-dicarbonyl compound 3 (0.55 mmol, 1.1 equiv) was added, and the reaction mixture was stirred at 50 C for 15 h monitored by TLC. After the reaction was completed, the mixture was purified through flash column chromatography on a silica gel using (PE/EA = 4/1) as eluent to afford pure products 4a. Compounds 4b~4v were synthesized by similar methods (the purity of all compounds > 90%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | Stage #1: 4-chlorocinnamaldehyde; thiourea With quinidine thiourea A; (1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3 -carboxylic acid In dichloromethane at 20℃; for 3h; Sealed tube; Stage #2: ethyl 4-methyl-3-oxo-pentanoate In dichloromethane at 50℃; for 15h; Sealed tube; enantioselective reaction; | General synthetic procedure General procedure: The precatalysts trans-4,5-methano-L-proline 5 (3.18 mg,0.025 mmol, and 5 mol%), quinidine thiourea 6 (14.86 mg,0.025 mmol, and 5 mol%) and DCM (2.0 mL) were addedto a capped sample vial at room temperature. After themixture had been stirred for 10 min, a solution of aldehyde1 (0.5 mmol and 1.0 equiv.) and thiourea 2 (57 mg, 0.75mmol, and 1.5 equiv.) in DCM mL) were added and thestirring was continued for 3 h at room temperature. Then β-dicarbonyl compound 3 (0.55 mmol and 1.1 equiv.) wasadded, the reaction mixture was stirred at 50 °C for 15 h asmonitored by TLC. After the reaction was completed, themixture was purified through flash CC on a silica gel using(PE/EA = 4/1) as eluent to afford pure products. |
93% | Stage #1: 4-chlorocinnamaldehyde; thiourea With 1-(3,5-bis(trifluoromethyl)phenyl)-3-((S)-(6-methoxyquinolin-4-yl)((1S,2S,4S,5R)-5-vinylquinuclidin-2-yl)methyl)thiourea; (1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3 -carboxylic acid In dichloromethane at 20℃; for 3h; Stage #2: ethyl 4-methyl-3-oxo-pentanoate In dichloromethane at 50℃; for 15h; enantioselective reaction; | 4.2. General procedure for the asymmetric Biginelli reaction General procedure: The precatalysts trans-4,5-methano-L-proline 5a (3.18 mg,0.025 mmol, 5 mol %), quinidine thiourea 6a (14.86 mg,0.025 mmol, 5 mol %) and DCM (2.0 mL) were added to a capped sample vial at room temperature. After the mixture had been stirred for 10 min, a solution of aldehyde 1 (0.5 mmol, 1.0 equiv) and thiourea 2 (57 mg, 0.75 mmol, 1.5 equiv) in DCM (1.0 mL) wasadded and stirring was continued for 3 h at room temperature. Next, β-dicarbonyl compound 3 (0.55 mmol, 1.1 equiv) was added, and the reaction mixture was stirred at 50 °C for 15 h monitored byTLC. After the reaction was completed, the mixture was purified through flash column chromatography on a silica gel using (PE/EA = 4/1) as eluent to afford pure products. |
93% | Stage #1: 4-chlorocinnamaldehyde; thiourea With C30H29F6N3OS; (1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3 -carboxylic acid In dichloromethane at 20℃; for 3h; Sealed tube; Stage #2: ethyl 4-methyl-3-oxo-pentanoate at 50℃; for 15h; enantioselective reaction; | 1.2 General procedure for the 4a~4v General procedure: The precatalysts trans-4,5-methano-l-proline 5a (3.18 mg, 0.025 mmol, 5 mol %), quinidine thiourea 6a (14.86 mg, 0.025 mmol, 5 mol %) and DCM (2.0 mL) were added to a capped sample vial at room temperature. After the mixture had been stirred for 10 min, a solution of aldehyde 1a (0.5 mmol, 1.0 equiv) and thiourea 2 (57 mg, 0.75 mmol, 1.5 equiv) in 111DCM (1.0 mL) was added and stirring was continued for 3 h at room temperature. Next, β-dicarbonyl compound 3 (0.55 mmol, 1.1 equiv) was added, and the reaction mixture was stirred at 50 °C for 15 h monitored by TLC. After the reaction was completed, the mixture was purified through flash column chromatography on a silica gel using (PE/EA = 4/1) as eluent to afford pure products 4a. Compounds 4b~4v were synthesized by similar methods (the purity of all compounds > 90%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | General procedure: The precatalysts trans-4,5-methano-L-proline 5 (3.18 mg,0.025 mmol, and 5 mol%), quinidine thiourea 6 (14.86 mg,0.025 mmol, and 5 mol%) and DCM (2.0 mL) were addedto a capped sample vial at room temperature. After themixture had been stirred for 10 min, a solution of aldehyde1 (0.5 mmol and 1.0 equiv.) and thiourea 2 (57 mg, 0.75mmol, and 1.5 equiv.) in DCM mL) were added and thestirring was continued for 3 h at room temperature. Then beta-dicarbonyl compound 3 (0.55 mmol and 1.1 equiv.) wasadded, the reaction mixture was stirred at 50 C for 15 h asmonitored by TLC. After the reaction was completed, themixture was purified through flash CC on a silica gel using(PE/EA = 4/1) as eluent to afford pure products. | |
93% | General procedure: The precatalysts trans-4,5-methano-L-proline 5a (3.18 mg,0.025 mmol, 5 mol %), quinidine thiourea 6a (14.86 mg,0.025 mmol, 5 mol %) and DCM (2.0 mL) were added to a capped sample vial at room temperature. After the mixture had been stirred for 10 min, a solution of aldehyde 1 (0.5 mmol, 1.0 equiv) and thiourea 2 (57 mg, 0.75 mmol, 1.5 equiv) in DCM (1.0 mL) wasadded and stirring was continued for 3 h at room temperature. Next, beta-dicarbonyl compound 3 (0.55 mmol, 1.1 equiv) was added, and the reaction mixture was stirred at 50 C for 15 h monitored byTLC. After the reaction was completed, the mixture was purified through flash column chromatography on a silica gel using (PE/EA = 4/1) as eluent to afford pure products. | |
93% | General procedure: The precatalysts trans-4,5-methano-l-proline 5a (3.18 mg, 0.025 mmol, 5 mol %), quinidine thiourea 6a (14.86 mg, 0.025 mmol, 5 mol %) and DCM (2.0 mL) were added to a capped sample vial at room temperature. After the mixture had been stirred for 10 min, a solution of aldehyde 1a (0.5 mmol, 1.0 equiv) and thiourea 2 (57 mg, 0.75 mmol, 1.5 equiv) in 111DCM (1.0 mL) was added and stirring was continued for 3 h at room temperature. Next, beta-dicarbonyl compound 3 (0.55 mmol, 1.1 equiv) was added, and the reaction mixture was stirred at 50 C for 15 h monitored by TLC. After the reaction was completed, the mixture was purified through flash column chromatography on a silica gel using (PE/EA = 4/1) as eluent to afford pure products 4a. Compounds 4b~4v were synthesized by similar methods (the purity of all compounds > 90%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: 4-(trifluoromethyl)cinnamaldehyde; thiourea With quinidine thiourea A; (1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3 -carboxylic acid In dichloromethane at 20℃; for 3h; Sealed tube; Stage #2: ethyl 4-methyl-3-oxo-pentanoate In dichloromethane at 50℃; for 15h; Sealed tube; enantioselective reaction; | General synthetic procedure General procedure: The precatalysts trans-4,5-methano-L-proline 5 (3.18 mg,0.025 mmol, and 5 mol%), quinidine thiourea 6 (14.86 mg,0.025 mmol, and 5 mol%) and DCM (2.0 mL) were addedto a capped sample vial at room temperature. After themixture had been stirred for 10 min, a solution of aldehyde1 (0.5 mmol and 1.0 equiv.) and thiourea 2 (57 mg, 0.75mmol, and 1.5 equiv.) in DCM mL) were added and thestirring was continued for 3 h at room temperature. Then β-dicarbonyl compound 3 (0.55 mmol and 1.1 equiv.) wasadded, the reaction mixture was stirred at 50 °C for 15 h asmonitored by TLC. After the reaction was completed, themixture was purified through flash CC on a silica gel using(PE/EA = 4/1) as eluent to afford pure products. |
90% | Stage #1: 4-(trifluoromethyl)cinnamaldehyde; thiourea With 1-(3,5-bis(trifluoromethyl)phenyl)-3-((S)-(6-methoxyquinolin-4-yl)((1S,2S,4S,5R)-5-vinylquinuclidin-2-yl)methyl)thiourea; (1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3 -carboxylic acid In dichloromethane at 20℃; for 3h; Stage #2: ethyl 4-methyl-3-oxo-pentanoate In dichloromethane at 50℃; for 15h; enantioselective reaction; | 4.2. General procedure for the asymmetric Biginelli reaction General procedure: The precatalysts trans-4,5-methano-L-proline 5a (3.18 mg,0.025 mmol, 5 mol %), quinidine thiourea 6a (14.86 mg,0.025 mmol, 5 mol %) and DCM (2.0 mL) were added to a capped sample vial at room temperature. After the mixture had been stirred for 10 min, a solution of aldehyde 1 (0.5 mmol, 1.0 equiv) and thiourea 2 (57 mg, 0.75 mmol, 1.5 equiv) in DCM (1.0 mL) wasadded and stirring was continued for 3 h at room temperature. Next, β-dicarbonyl compound 3 (0.55 mmol, 1.1 equiv) was added, and the reaction mixture was stirred at 50 °C for 15 h monitored byTLC. After the reaction was completed, the mixture was purified through flash column chromatography on a silica gel using (PE/EA = 4/1) as eluent to afford pure products. |
90% | Stage #1: 4-(trifluoromethyl)cinnamaldehyde; thiourea With C30H29F6N3OS; (1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3 -carboxylic acid In dichloromethane at 20℃; for 3h; Sealed tube; Stage #2: ethyl 4-methyl-3-oxo-pentanoate at 50℃; for 15h; enantioselective reaction; | 1.2 General procedure for the 4a~4v General procedure: The precatalysts trans-4,5-methano-l-proline 5a (3.18 mg, 0.025 mmol, 5 mol %), quinidine thiourea 6a (14.86 mg, 0.025 mmol, 5 mol %) and DCM (2.0 mL) were added to a capped sample vial at room temperature. After the mixture had been stirred for 10 min, a solution of aldehyde 1a (0.5 mmol, 1.0 equiv) and thiourea 2 (57 mg, 0.75 mmol, 1.5 equiv) in 111DCM (1.0 mL) was added and stirring was continued for 3 h at room temperature. Next, β-dicarbonyl compound 3 (0.55 mmol, 1.1 equiv) was added, and the reaction mixture was stirred at 50 °C for 15 h monitored by TLC. After the reaction was completed, the mixture was purified through flash column chromatography on a silica gel using (PE/EA = 4/1) as eluent to afford pure products 4a. Compounds 4b~4v were synthesized by similar methods (the purity of all compounds > 90%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: 3-(4-nitrophenyl)-2-propenal; thiourea With quinidine thiourea A; (1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3 -carboxylic acid In dichloromethane at 20℃; for 3h; Sealed tube; Stage #2: ethyl 4-methyl-3-oxo-pentanoate In dichloromethane at 50℃; for 15h; Sealed tube; enantioselective reaction; | General synthetic procedure General procedure: The precatalysts trans-4,5-methano-L-proline 5 (3.18 mg,0.025 mmol, and 5 mol%), quinidine thiourea 6 (14.86 mg,0.025 mmol, and 5 mol%) and DCM (2.0 mL) were addedto a capped sample vial at room temperature. After themixture had been stirred for 10 min, a solution of aldehyde1 (0.5 mmol and 1.0 equiv.) and thiourea 2 (57 mg, 0.75mmol, and 1.5 equiv.) in DCM mL) were added and thestirring was continued for 3 h at room temperature. Then β-dicarbonyl compound 3 (0.55 mmol and 1.1 equiv.) wasadded, the reaction mixture was stirred at 50 °C for 15 h asmonitored by TLC. After the reaction was completed, themixture was purified through flash CC on a silica gel using(PE/EA = 4/1) as eluent to afford pure products. |
91% | Stage #1: 3-(4-nitrophenyl)-2-propenal; thiourea With 1-(3,5-bis(trifluoromethyl)phenyl)-3-((S)-(6-methoxyquinolin-4-yl)((1S,2S,4S,5R)-5-vinylquinuclidin-2-yl)methyl)thiourea; (1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3 -carboxylic acid In dichloromethane at 20℃; for 3h; Stage #2: ethyl 4-methyl-3-oxo-pentanoate In dichloromethane at 50℃; for 15h; enantioselective reaction; | 4.2. General procedure for the asymmetric Biginelli reaction General procedure: The precatalysts trans-4,5-methano-L-proline 5a (3.18 mg,0.025 mmol, 5 mol %), quinidine thiourea 6a (14.86 mg,0.025 mmol, 5 mol %) and DCM (2.0 mL) were added to a capped sample vial at room temperature. After the mixture had been stirred for 10 min, a solution of aldehyde 1 (0.5 mmol, 1.0 equiv) and thiourea 2 (57 mg, 0.75 mmol, 1.5 equiv) in DCM (1.0 mL) wasadded and stirring was continued for 3 h at room temperature. Next, β-dicarbonyl compound 3 (0.55 mmol, 1.1 equiv) was added, and the reaction mixture was stirred at 50 °C for 15 h monitored byTLC. After the reaction was completed, the mixture was purified through flash column chromatography on a silica gel using (PE/EA = 4/1) as eluent to afford pure products. |
91% | Stage #1: 3-(4-nitrophenyl)-2-propenal; thiourea With C30H29F6N3OS; (1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3 -carboxylic acid In dichloromethane at 20℃; for 3h; Sealed tube; Stage #2: ethyl 4-methyl-3-oxo-pentanoate at 50℃; for 15h; enantioselective reaction; | 1.2 General procedure for the 4a~4v General procedure: The precatalysts trans-4,5-methano-l-proline 5a (3.18 mg, 0.025 mmol, 5 mol %), quinidine thiourea 6a (14.86 mg, 0.025 mmol, 5 mol %) and DCM (2.0 mL) were added to a capped sample vial at room temperature. After the mixture had been stirred for 10 min, a solution of aldehyde 1a (0.5 mmol, 1.0 equiv) and thiourea 2 (57 mg, 0.75 mmol, 1.5 equiv) in 111DCM (1.0 mL) was added and stirring was continued for 3 h at room temperature. Next, β-dicarbonyl compound 3 (0.55 mmol, 1.1 equiv) was added, and the reaction mixture was stirred at 50 °C for 15 h monitored by TLC. After the reaction was completed, the mixture was purified through flash column chromatography on a silica gel using (PE/EA = 4/1) as eluent to afford pure products 4a. Compounds 4b~4v were synthesized by similar methods (the purity of all compounds > 90%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | Stage #1: thiourea; 3-(4-methylphenyl)acrylaldehyde With quinidine thiourea A; (1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3 -carboxylic acid In dichloromethane at 20℃; for 3h; Sealed tube; Stage #2: ethyl 4-methyl-3-oxo-pentanoate In dichloromethane at 50℃; for 15h; Sealed tube; enantioselective reaction; | General synthetic procedure General procedure: The precatalysts trans-4,5-methano-L-proline 5 (3.18 mg,0.025 mmol, and 5 mol%), quinidine thiourea 6 (14.86 mg,0.025 mmol, and 5 mol%) and DCM (2.0 mL) were addedto a capped sample vial at room temperature. After themixture had been stirred for 10 min, a solution of aldehyde1 (0.5 mmol and 1.0 equiv.) and thiourea 2 (57 mg, 0.75mmol, and 1.5 equiv.) in DCM mL) were added and thestirring was continued for 3 h at room temperature. Then β-dicarbonyl compound 3 (0.55 mmol and 1.1 equiv.) wasadded, the reaction mixture was stirred at 50 °C for 15 h asmonitored by TLC. After the reaction was completed, themixture was purified through flash CC on a silica gel using(PE/EA = 4/1) as eluent to afford pure products. |
96% | Stage #1: thiourea; 3-(4-methylphenyl)acrylaldehyde With 1-(3,5-bis(trifluoromethyl)phenyl)-3-((S)-(6-methoxyquinolin-4-yl)((1S,2S,4S,5R)-5-vinylquinuclidin-2-yl)methyl)thiourea; (1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3 -carboxylic acid In dichloromethane at 20℃; for 3h; Stage #2: ethyl 4-methyl-3-oxo-pentanoate In dichloromethane at 50℃; for 15h; enantioselective reaction; | 4.2. General procedure for the asymmetric Biginelli reaction General procedure: The precatalysts trans-4,5-methano-L-proline 5a (3.18 mg,0.025 mmol, 5 mol %), quinidine thiourea 6a (14.86 mg,0.025 mmol, 5 mol %) and DCM (2.0 mL) were added to a capped sample vial at room temperature. After the mixture had been stirred for 10 min, a solution of aldehyde 1 (0.5 mmol, 1.0 equiv) and thiourea 2 (57 mg, 0.75 mmol, 1.5 equiv) in DCM (1.0 mL) wasadded and stirring was continued for 3 h at room temperature. Next, β-dicarbonyl compound 3 (0.55 mmol, 1.1 equiv) was added, and the reaction mixture was stirred at 50 °C for 15 h monitored byTLC. After the reaction was completed, the mixture was purified through flash column chromatography on a silica gel using (PE/EA = 4/1) as eluent to afford pure products. |
96% | Stage #1: thiourea; 3-(4-methylphenyl)acrylaldehyde With C30H29F6N3OS; (1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3 -carboxylic acid In dichloromethane at 20℃; for 3h; Sealed tube; Stage #2: ethyl 4-methyl-3-oxo-pentanoate at 50℃; for 15h; enantioselective reaction; | 1.2 General procedure for the 4a~4v General procedure: The precatalysts trans-4,5-methano-l-proline 5a (3.18 mg, 0.025 mmol, 5 mol %), quinidine thiourea 6a (14.86 mg, 0.025 mmol, 5 mol %) and DCM (2.0 mL) were added to a capped sample vial at room temperature. After the mixture had been stirred for 10 min, a solution of aldehyde 1a (0.5 mmol, 1.0 equiv) and thiourea 2 (57 mg, 0.75 mmol, 1.5 equiv) in 111DCM (1.0 mL) was added and stirring was continued for 3 h at room temperature. Next, β-dicarbonyl compound 3 (0.55 mmol, 1.1 equiv) was added, and the reaction mixture was stirred at 50 °C for 15 h monitored by TLC. After the reaction was completed, the mixture was purified through flash column chromatography on a silica gel using (PE/EA = 4/1) as eluent to afford pure products 4a. Compounds 4b~4v were synthesized by similar methods (the purity of all compounds > 90%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Stage #1: 4-methoxycinnamaldehyde; thiourea With quinidine thiourea A; (1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3 -carboxylic acid In dichloromethane at 20℃; for 3h; Sealed tube; Stage #2: ethyl 4-methyl-3-oxo-pentanoate In dichloromethane at 50℃; for 15h; Sealed tube; enantioselective reaction; | General synthetic procedure General procedure: The precatalysts trans-4,5-methano-L-proline 5 (3.18 mg,0.025 mmol, and 5 mol%), quinidine thiourea 6 (14.86 mg,0.025 mmol, and 5 mol%) and DCM (2.0 mL) were addedto a capped sample vial at room temperature. After themixture had been stirred for 10 min, a solution of aldehyde1 (0.5 mmol and 1.0 equiv.) and thiourea 2 (57 mg, 0.75mmol, and 1.5 equiv.) in DCM mL) were added and thestirring was continued for 3 h at room temperature. Then β-dicarbonyl compound 3 (0.55 mmol and 1.1 equiv.) wasadded, the reaction mixture was stirred at 50 °C for 15 h asmonitored by TLC. After the reaction was completed, themixture was purified through flash CC on a silica gel using(PE/EA = 4/1) as eluent to afford pure products. |
95% | Stage #1: 4-methoxycinnamaldehyde; thiourea With 1-(3,5-bis(trifluoromethyl)phenyl)-3-((S)-(6-methoxyquinolin-4-yl)((1S,2S,4S,5R)-5-vinylquinuclidin-2-yl)methyl)thiourea; (1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3 -carboxylic acid In dichloromethane at 20℃; for 3h; Stage #2: ethyl 4-methyl-3-oxo-pentanoate In dichloromethane at 50℃; for 15h; enantioselective reaction; | 4.2. General procedure for the asymmetric Biginelli reaction General procedure: The precatalysts trans-4,5-methano-L-proline 5a (3.18 mg,0.025 mmol, 5 mol %), quinidine thiourea 6a (14.86 mg,0.025 mmol, 5 mol %) and DCM (2.0 mL) were added to a capped sample vial at room temperature. After the mixture had been stirred for 10 min, a solution of aldehyde 1 (0.5 mmol, 1.0 equiv) and thiourea 2 (57 mg, 0.75 mmol, 1.5 equiv) in DCM (1.0 mL) wasadded and stirring was continued for 3 h at room temperature. Next, β-dicarbonyl compound 3 (0.55 mmol, 1.1 equiv) was added, and the reaction mixture was stirred at 50 °C for 15 h monitored byTLC. After the reaction was completed, the mixture was purified through flash column chromatography on a silica gel using (PE/EA = 4/1) as eluent to afford pure products. |
95% | Stage #1: 4-methoxycinnamaldehyde; thiourea With C30H29F6N3OS; (1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3 -carboxylic acid In dichloromethane at 20℃; for 3h; Sealed tube; Stage #2: ethyl 4-methyl-3-oxo-pentanoate at 50℃; for 15h; enantioselective reaction; | 1.2 General procedure for the 4a~4v General procedure: The precatalysts trans-4,5-methano-l-proline 5a (3.18 mg, 0.025 mmol, 5 mol %), quinidine thiourea 6a (14.86 mg, 0.025 mmol, 5 mol %) and DCM (2.0 mL) were added to a capped sample vial at room temperature. After the mixture had been stirred for 10 min, a solution of aldehyde 1a (0.5 mmol, 1.0 equiv) and thiourea 2 (57 mg, 0.75 mmol, 1.5 equiv) in 111DCM (1.0 mL) was added and stirring was continued for 3 h at room temperature. Next, β-dicarbonyl compound 3 (0.55 mmol, 1.1 equiv) was added, and the reaction mixture was stirred at 50 °C for 15 h monitored by TLC. After the reaction was completed, the mixture was purified through flash column chromatography on a silica gel using (PE/EA = 4/1) as eluent to afford pure products 4a. Compounds 4b~4v were synthesized by similar methods (the purity of all compounds > 90%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | Stage #1: thiourea; 3-phenyl-propenal With quinidine thiourea A; (1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3 -carboxylic acid In dichloromethane at 20℃; for 3h; Sealed tube; Stage #2: ethyl 4-methyl-3-oxo-pentanoate In dichloromethane at 50℃; for 15h; Sealed tube; enantioselective reaction; | General synthetic procedure General procedure: The precatalysts trans-4,5-methano-L-proline 5 (3.18 mg,0.025 mmol, and 5 mol%), quinidine thiourea 6 (14.86 mg,0.025 mmol, and 5 mol%) and DCM (2.0 mL) were addedto a capped sample vial at room temperature. After themixture had been stirred for 10 min, a solution of aldehyde1 (0.5 mmol and 1.0 equiv.) and thiourea 2 (57 mg, 0.75mmol, and 1.5 equiv.) in DCM mL) were added and thestirring was continued for 3 h at room temperature. Then β-dicarbonyl compound 3 (0.55 mmol and 1.1 equiv.) wasadded, the reaction mixture was stirred at 50 °C for 15 h asmonitored by TLC. After the reaction was completed, themixture was purified through flash CC on a silica gel using(PE/EA = 4/1) as eluent to afford pure products. |
96% | Stage #1: thiourea; 3-phenyl-propenal With C30H29F6N3OS; (1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3 -carboxylic acid In dichloromethane at 20℃; for 3h; Sealed tube; Stage #2: ethyl 4-methyl-3-oxo-pentanoate at 50℃; for 15h; enantioselective reaction; | 1.2 General procedure for the 4a~4v General procedure: The precatalysts trans-4,5-methano-l-proline 5a (3.18 mg, 0.025 mmol, 5 mol %), quinidine thiourea 6a (14.86 mg, 0.025 mmol, 5 mol %) and DCM (2.0 mL) were added to a capped sample vial at room temperature. After the mixture had been stirred for 10 min, a solution of aldehyde 1a (0.5 mmol, 1.0 equiv) and thiourea 2 (57 mg, 0.75 mmol, 1.5 equiv) in 111DCM (1.0 mL) was added and stirring was continued for 3 h at room temperature. Next, β-dicarbonyl compound 3 (0.55 mmol, 1.1 equiv) was added, and the reaction mixture was stirred at 50 °C for 15 h monitored by TLC. After the reaction was completed, the mixture was purified through flash column chromatography on a silica gel using (PE/EA = 4/1) as eluent to afford pure products 4a. Compounds 4b~4v were synthesized by similar methods (the purity of all compounds > 90%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With copper(I) oxide; tert.-butylhydroperoxide; ammonium acetate In water at 120℃; for 24h; | 11 Embodiment XI: The reaction bottle by adding 1 k (4 mmol, 632 mg), cuprous oxide (0.4 mmol, 57 mg), tert-butyl hydrogen peroxide (8 mmol, 70% aqueous solution, 1.2 ml), ammonium acetate (8 mmol, 616 mg) and DMA (10 ml), then in 120 °C heating reaction 24 hours. After the reaction is finished first saturated sodium sulfite solution for quenching, and then the extraction of ethyl acetate, the combined organic phase after drying with anhydrous sodium sulfate, concentrated using petroleum ether and ethyl acetate mixed solvent of column chromatography to obtain the product 2 k, yield is 68%. |
58% | With copper(I) oxide; tert.-butylhydroperoxide; ammonium acetate at 120℃; for 24h; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | Stage #1: ethyl 4-methyl-3-oxo-pentanoate With sodium hydride In tetrahydrofuran; mineral oil for 1h; Cooling; Stage #2: [5-bromo-3-methylpent-2-en-1-yl]benzene In tetrahydrofuran; mineral oil at 0 - 20℃; for 18h; | Ethyl (E,Z)-5-methyl-2-(2-methylpropanoyl)-7-phenylhept-4-enoate (31). Ethyl (E,Z)-5-methyl-2-(2-methylpropanoyl)-7-phenylhept-4-enoate (31). Yield 98%, colorless oilysubstance. IR spectrum, ν, cm-1: 1728, 1710 (=),1598 (=). 1 NMR spectrum, δ, ppm: 1.06-1.15 m(6, 23), 1.23-1.28 m (3, 3=), 1.68 s(0.8·3, 3=), 1.73 s (0.2·3, 3=), 2.26 t(2, 2=, J 7.2 Hz), 2.55 t (2, 2=, J 6.8 Hz),2.66-2.77 m (3, , 2Ph), 3.59 t (1, , J 6.8 Hz),4.12-4.21 m (2, 2), 5.06 t (1, =, J 6.8 Hz),7.12-7.28 m (5Ar). Mass spectrum, m/z (Irel., %):317.29 (100) [M + ]+. Found, %: 75.78; 9.07.20283. Calculated, %: 75.93; 8.96. M 316.4 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With sulfuric acid at 20℃; for 1h; | 4.1.2.1 General procedure General procedure: To a solution of 1 or 2 (10.0mmol) in the appropriate acetoacetic ester (10.0mmol), 32 H2SO4 (7mL) was added dropwise and the mixture was stirred at room temperature for 1h. The solution was poured into an ice/water mixture (100g) and the obtained precipitate was filtered and washed with water to give the corresponding alkyl-7-hydroxycoumarin. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | Stage #1: ethyl 4-methyl-3-oxo-pentanoate With lithium hydroxide In water; toluene at 5 - 10℃; Stage #2: trifluoromethylsulfonic anhydride In water; toluene at 5 - 15℃; | 3A ethyl 4-methyl-2-[(trifluoromethane)sulfonyloxy]pent-2-enoate Ethyl isobutyrylacetate (5 g, 31 mmol) was added to a round-bottom flask and dissolved in toluene (150 ml). The solution was cooled with an ice bath to 5-10°C (internal temperature) followed by addition of a saturated aqueous solution of LiOH (50 ml_, 240 mmol) in one portion. The resulting biphasic mixture was vigorously stirred at 5-10°C for ~5 minutes followed by the addition of triflic anhydride (13 ml, 79 mmol) dropwise at a rate to maintain the internal temperature between 5-15°C. Upon completion of the reaction (as judged by TLC, typically 1H NMR (400 MHz, DMSO-de) 6.09 (1H, s), 4.19-4.13 (2H, m), 2.57-2.53 (1H, m), 1.24-1.14(9H, m) |
Stage #1: ethyl 4-methyl-3-oxo-pentanoate With water; lithium hydroxide In toluene at 10℃; for 0.0833333h; Stage #2: trifluoromethylsulfonic anhydride In toluene at 10 - 25℃; for 2h; | Intermediate 15A ethyl 4-methyl-3-[(trifluoromethyl)sulfonyl]oxy}pent-2-enoate To a solution of ethyl 4-methyl-3-oxopentanoate 10.0 g (63.2 mmol) in toluene (400 ml) was added a solution of lithium hydroxide (11.4 g, 474.1 mmol) in water (120 ml) at 10°C. After stir- ring for 5 minutes at 10°C, trifluoromethanesulfonic anhydride (21.5 ml, 126.4 mmol) was added slowly to the reaction mixture maintaining the temperature below 25°C. After stirring for 2 h, the reaction mixture was poured into 400 ml of water and extracted with ethyl acetate. The combined organic layers were washed with water and brine and dried over anhydrous sodium sulfate. Fil- tration and evaporation gave 16.5 g (73% of theory, 81 % purity) of the title compound. LC/MS [Method 8]: Rt = 1.43 min; MS (ESIpos): m/z = 291 [M+H]+. 1H-NMR (400 MHz, DMSO-d6): d [ppm] = 6.12 (d, 1H), 4.17 (q, 2H), 2.57 (sept, 1H), 1.23 (t, 3H), 1.15 (d, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With piperidine; acetic acid; In isopropyl alcohol; at 20℃; for 12h;Inert atmosphere; | Placed in a 150 mL round bottom flask equipped with a magnetic stirrer<strong>[105191-12-6]6-bromo-1H-indole-2-carbaldehyde</strong> (Compound 1) (8.07 g, 36.00 mmol),Ethyl 4-methyl-3-oxopentanoate (Compound 2) (5.70 g, 36.03 mmol),Isopropanol (21.1 mL), piperidine (2.2 mL) and glacial acetic acid (1.2 mL).The reaction mixture was stirred at room temperature under nitrogen for 12 hours.The solvent was removed under reduced pressure. The residue was taken up in dichloromethane (1. After drying over anhydrous MgSO 4 , MgSO 4 was removed by filtration.After concentrating the solvent under reduced pressure, the column was separated by flash column chromatography.Obtained an off-white solid (Z)-2-((6-bromo-1H-indol-2-yl)methylene)-4-methyl-3-oxopentanoate (Compound 3), 12.46 g The yield is 95%. |
95% | With piperidine; acetic acid; In isopropyl alcohol; at 20℃; for 12h;Inert atmosphere; | In the equipped with a magnetic stirrer of the 150 ml round-bottom flask put in 6 - bromo - 1H - indole -2 - formaldehyde (compound 1) (8.07 g, 36 . 00 mmol), 4 - methyl -3 - oxo-pentanoic acid ethyl ester (compound 2) (5.70 g, 36 . 03 mmol), isopropyl alcohol (21.1 ml), piperidine (2.2 ml) and acetic acid (1.2 ml). The reaction mixture at room temperature under stirring in nitrogen environment 12 hours. The solvent is removed under reduced pressure. The residue dichloromethane is used for (13.88 ml) dissolved and saturated NaHCO3(3 * 30 Ml) the solution, anhydrous MgSO4After drying, filtering to remove the MgSO4, After the solvent is concentrated under reduced pressure, rapid column chromatographic separation, resulting in a white solid (Z)-2 - ((6 - bromo - 1H - indole -2 - yl) methylene) -4 - methyl -3 - oxo-pentanoic acid ethyl ester (compound 3), 12.46 g, yield 95%. |
95% | With piperidine; acetic acid; In isopropyl alcohol; at 20℃; for 12h;Inert atmosphere; | In a 150mL equipped with a magnetic stirrerIn a round bottom flask, <strong>[105191-12-6]6-bromo-1H-indole-2-carbaldehyde</strong> (Compound 1) (8.07 g, 36.00 mmol), 4-methyl-3-oxopentanoate (Compound 2) (5.70 g) , 36.03 mmol), isopropanol (21.1 mL), piperidine (2.2 mL) and glacial acetic acid (1.2 mL). The reaction mixture was stirred at room temperature under nitrogen for 12 h.The solvent was removed under reduced pressure. The residue was taken in dichloromethane (13.88 mL)Dissolve and wash with saturated NaHCO3 (3*30 mL) solution. After drying over anhydrous MgSO4, MgSO4 was removed by filtration. After concentrating the solvent under reduced pressure, the column was separated by flash column chromatography. Obtained an off-white solid (Z)-2-((6-bromo-1H-indol-2-yl)methylene)-4-methyl-3-oxopentanoate (Compound 3), 12.46 g The yield is 95%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With toluene-4-sulfonic acid In cyclohexane at 80℃; | 4.1 1) Ethyl 3-benzoylamino-4-methyl-2-pentenoate In a 1000ml clean three-necked flask,Add ethyl 4-methyl-3-oxopentanoate160g, benzamide127g, p-toluenesulfonic acid 24g, cyclohexane 480ml, heated to 80 ° C,The reaction process separates the water produced,The reaction reflux is about 10h or more.At the end of the reaction, cyclohexane was recovered by distillation under reduced pressure, and the mixture was evaporated to dryness, and then methyl t-butyl ether was added to be beaten.Filtration of benzamide,The organic layer is washed with water until it is free of benzamide.The organic layer was concentrated under reduced pressure.Crystallized to a white solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With piperidine; acetic acid In isopropyl alcohol at 20℃; for 12h; Inert atmosphere; | 1.1 In a 150 mL round bottom flask equipped with a magnetic stirrer, put 8-bromo-quinoline-4-carbaldehyde (Compound 1)(8.50g, 36.00mmol),Ethyl 4-methyl-3-oxopentanoate (Compound 2) (5.70 g, 36.03 mmol),Isopropanol (21.1 mL), piperidine (2.2 mL) and glacial acetic acid (1.2 mL).The reaction mixture was stirred at room temperature under nitrogen for 12 hours.The solvent was removed under reduced pressure.The residue was taken up in dichloromethane (1. After drying over anhydrous MgSO 4, MgSO4 was filtered and evaporated.Obtained a white solid(Z)-2-((8-Bromo-quinolin-2-yl)methylene)-4-methyl-3-oxopentanoate (Compound 3), 12.05 g,The yield was 89%. |
89% | With pyridine; acetic acid In isopropyl alcohol at 20℃; for 12h; Inert atmosphere; | 1.1 1. (Z)-2 - ((8 - bromo - quinoline -2 - yl) methylene) -4 - methyl -3 - oxo-valeric acid ethyl ester synthesis In the equipped with a magnetic stirrer of the 150 ml round-bottom flask put in 8 - bromo - quinoline -4 - formaldehyde (compound 1) (8.50 g, 36 . 00 mmol), 4 - methyl -3 - oxo-pentanoic acid ethyl ester (compound 2) (5.70 g, 36 . 03 mmol), isopropyl alcohol (21.1 ml), piperidine (2.2 ml) and acetic acid (1.2 ml). The reaction mixture at room temperature under stirring in nitrogen environment 12 hours. The solvent is removed under reduced pressure. The residue dichloromethane is used for (13.88 ml) dissolved and saturated NaHCO3(3 * 30 Ml) the solution, anhydrous MgSO4After drying, filtering to remove the MgSO4.After concentrating the solvent under reduced pressure, rapid column chromatographic separation, resulting in a white solid (Z)-2 - ((8 - bromo - quinoline -2 - yl) methylene) -4 - methyl -3 - oxo-pentanoic acid ethyl ester (compound 3), 12.05 g, yield 89%. |
89% | With piperidine; acetic acid In isopropyl alcohol at 20℃; for 12h; Inert atmosphere; | 1.1 1. Synthesis of ethyl (Z)-2-((8-bromo-quinolin-4-yl)methylene)-4-methyl-3-oxopentanoate In a 150 mL round bottom flask equipped with a magnetic stirrer was placed 8-bromo-quinoline-4-carbaldehyde (Compound 1) (8.50 g, 36.00 mmol), 4-methyl-3-oxopentanoate ( Compound 2) (5.70 g, 36.03 mmol), isopropanol (21.1 mL), piperidine (2.2 mL) and glacial acetic acid (1.2 mL). The reaction mixture was stirred at room temperature under nitrogen for 12 h. The solvent was removed under reduced pressure.The residue was dissolved in dichloromethane (13.88 mL) and sat. NaHCO3 (3*30mL)The solution was washed, dried over anhydrous MgSO 4 and filtered and evaporated.After concentrating the solvent under reduced pressure, it was separated by flash column chromatography to give white solid.(Z)-2-((8-bromo-quinolin-4-yl)methylene)-4-methyl-3-oxopentanoic acidEthyl ester (Compound 3), 12.05 g, yield 89%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With fluorescein free acid In acetonitrile at 20℃; UV-irradiation; | |
80% | With fluorescein In acetonitrile at 20℃; for 6h; Irradiation; | 17 Embodiment 17:4 - methyl -3 - amino -2 sulfur cyano pentenoic acid ethyl ester synthesis Under the room temperature condition, isobutyryl ethyl acetate (79.1 mg, 0.5 mmol), thiocyanate amine (114, 2 mg, 1.5 mmol), fluorescein (3.3 mg, 2 μM %) is added to 10 ml reaction tube, then adding solvent acetonitrile 2 ml, in 3.0 W under the irradiation of blue LED, in the air reaction 6 hours, detected by TLC. After the completion of the reaction, the reaction mixture is concentrated in vacuo, the remaining crude by column chromatography to obtain 4 - methyl -3 - amino -2 sulfur cyano pentenoic acid ethyl ester colorless liquid 85.6 mg, yield 80%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Stage #1: ethyl 4-methyl-3-oxo-pentanoate With sulfur tetrafluoride; hydrogen fluoride at 20℃; Cooling with liquid nitrogen; Autoclave; Stage #2: With potassium permanganate In dichloromethane; water for 1h; | Deoxofluorination Protocol A1 General procedure: The keto ester 1 (1 mol) was placed in a Hastelloy autoclave (1200 mL) and cooled with liquid nitrogen. Anhydrous hydrogenfluoride (1 mL per 0.01 mol of the keto ester) was added.The autoclave was evacuated and SF4 (about 1.7 equiv) was condensed into it. The autoclave was warmed up to room temperature and was stirred on a magnetic stirrer overnight. Gaseous products were released, the solution was removed from the autoclave and poured onto ice, the oil obtained was extracted with MTBE, the extracts were combined and washed with aqueous solution of Na2CO3, dried, evaporated and distilled. Inthe case of obtaining an admixture of monofluoroalkene duringthe fluorination (substrates 1a-c,h,i,u), the crude product was dissolved in dichloromethane/water mixture before purification (100 g of product per 1 L of dichloromethane and water), and KMnO4 was added in portions under stirring until the boiling was ceased and the raspberry color was stabilized for 1 h (usually0.3-0.7 g of potassium permanganate per 1 g of the mixture). Excess of potassium permanganate was quenched with Na2S2O3, the precipitate was filtered and washed with dichloromethane. The organic phase was separated, dried, and distilled. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12% | In N,N-dimethyl-formamide Reflux; | Method F: General procedure: To an appropriate 2-aminoimidazole derivative (1 mol. equiv.) in DMF (1-1.5 ml/1 mmol of starting material) was added 3-oxoester (1-1.64 mol. equiv.) and the mixture was refluxed for several hours (TLC control). Upon disappearance of starting materials or no further progress of the reaction mixture was cooled to room temperature. If precipitation occurred MeOH or EtOH was added, solid was filtered off, washed with solvent indicated and dried under vacuum. In other case volatiles were removed and residue was purified on silica gel column chromatography. (0301) Purity of all products was determined by HPLC analysis and was at least 95%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | Stage #1: ethyl 4-methyl-3-oxo-pentanoate With acetic acid; sodium nitrite In water at 0 - 20℃; for 3h; Stage #2: acetylacetone With zinc In water at 0 - 85℃; for 4h; | General procedure A for the synthesis of compounds 6a - 6g General procedure: To a stirred ice-cooled solution of compound 1a - 1e (20mmol) in HOAc (40mL), the sodium nitrite (30mmol) in H2O (5mL) was added dropwise. The reaction mixture was stirred at r.t. for about 3h, then Zn (40mmol) and pentane-2,4-dione (20mmol) was added at 0°C. And the reaction mixture was heated to 85°C for about 4h. Upon completion, the reaction mixture was poured into water and was extracted with ethyl acetate (100mL×3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was chromatographed, eluting with a gradient of 2-10% EtOAc/petroleum ether to afford compound 2a - 2e (yield, 58-89%) as a clear oil. (0047) To a suspension of compound 2a - 2e (10mmol), KOH (50mmol) in ethylene glycol (20mL). The resulting mixture was stirred at 140°C for about 3h. After completion of reaction, the mixture was poured into water and was extracted with ethyl acetate (100mL×3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum to give 3a - 3e (yield, 72-91%) without further purification. (0048) To a solution of 3a (2.0g, 14.6mmol) in THF (20mL) at - 78°C was added NBS (2.6g, 14.6mmol) in four batches. The reaction mixture was stirred at - 78°C for 1h. Then the reaction was partitioned between water and ethyl acetate, the aqueous layer was extracted with additional ethyl acetate twice. The combined organic layers was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was chromatographed, eluting with a gradient of 10-20% EtOAc/petroleum ether to afford compound 4 (1.8g, yield, 57%) as a yellow solid. (0049) A mixture of 3a - 3e (10mmol) in anhydrous DMF (20mL) was stirred at 0°C, the solution was added dropwise POCl3 (20mmol). The mixture was stirred at ambient temperature for about 3h. Then the mixture was added dropwise 5M KOAc (50mmol) solution at 0°C, and the solution was stirred at 105°C under nitrogen for about 3h. After cooling, the mixture was poured into water and was extracted with ethyl acetate (100mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting crude product was purified by silica gel column chromatography (10-30% EtOAc/petroleum ether) to yield 5a - 5e (yield, 51-74%) as a brown solid. (0050) A flask was charged with compound 4 (0.22g, 1mmol), corresponding boric ester (1.2mmol), PdCl2(dppf) (0.1mmol), K2CO3 (5mmol) and sparged with nitrogen. Degassed dioxane (7mL) and water (2mL) was added and the mixture was heated at 100°C for 4h. The reaction mixture was partitioned between water and ethyl acetate, the aqueous layer was extracted with additional ethyl acetate twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography (30-80% EtOAc/petroleum ether) to yield 6a - 6e (yield, 49-68%) as a white solid. (0051) A mixture of 5a (0.2g, 1.2mmol), Na2S2O5 (0.023g, 0.12mmol), benzene-1,2-diamine (0.13g, 1.2mmol) or 2-aminobenzenethiol (0.15g, 1.2mmol) in DMF (10mL) was degassed under a stream of nitrogen. The resulting brown solution was heated at 140°C overnight. The cooled reaction was purified by silica gel column chromatography (gradient elution, 1-2% MeOH/dichloromethane) to afford 6f - 6g (yield, 59, 62%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | With polyphosphoric acid; at 120℃; for 2.0h; | To a solution of 6-chioro-3-amino-4,5-dimethylpyridazine (550 mg) in polyphosphoric acid (5 mL) was added ethyl 4-methyl-3-oxo-pentanoate (1.13 mL}. The mixture was heated to 85 C for 1 hour, then 120 C for 1 hour. While still hot, the mixture was slowly added to a stirred solution of saturated aqueous NaHCOg (150 mL) and chloroform/IPA (4:1) (50 mL). Upon complete addition, the mixture was stirred for 10 minutes and the organic layer was isolated. The aqueous layer was further extracted with chloroform/IPA (4:1) (3 x 50 L) and the organic layers were pooled, dried over MgSC , filtered, and concentrated. The crude product was purified using a Teledyne I5CO Combi-Flash system (liquid loading with DCM, 80G column, 0 - 65% EtOAc/Hex, 20 min run). The column was then flushed with hexanes followed by 0 - 2% MeOH/DCM, 10 min to give the title compound (204 mg; 23% yield) as a solid. : NMR (400 MHz, CDCI3) d 6.47 (s, 1H), 3.63 (hept, J = 6.8 Hz, 1H), 2.56 (d, 1 = 1.0 Hz, 3H), 2.44 (d, J = 1.0 Hz, 3H), 1.32 (s, 3H), 1.30 (s, 3H). ES-MS [M+l]+: 252. |
23% | With polyphosphoric acid; at 120℃; for 2.0h; | To a solution of 6-chioro-3-amino-4,5-dimethylpyridazine (550 mg) in polyphosphoric acid (5 mL) was added ethyl 4-methyl-3-oxo-pentanoate (1.13 mL}. The mixture was heated to 85 C for 1 hour, then 120 C for 1 hour. While still hot, the mixture was slowly added to a stirred solution of saturated aqueous NaHCOg (150 mL) and chloroform/IPA (4:1) (50 mL). Upon complete addition, the mixture was stirred for 10 minutes and the organic layer was isolated. The aqueous layer was further extracted with chloroform/IPA (4:1) (3 x 50 L) and the organic layers were pooled, dried over MgSC , filtered, and concentrated. The crude product was purified using a Teledyne I5CO Combi-Flash system (liquid loading with DCM, 80G column, 0 - 65% EtOAc/Hex, 20 min run). The column was then flushed with hexanes followed by 0 - 2% MeOH/DCM, 10 min to give the title compound (204 mg; 23% yield) as a solid. : NMR (400 MHz, CDCI3) d 6.47 (s, 1H), 3.63 (hept, J = 6.8 Hz, 1H), 2.56 (d, 1 = 1.0 Hz, 3H), 2.44 (d, J = 1.0 Hz, 3H), 1.32 (s, 3H), 1.30 (s, 3H). ES-MS [M+l]+: 252. |
23% | With polyphosphoric acid; at 120℃; for 2.0h; | To a solution of 6-chioro-3-amino-4,5-dimethylpyridazine (550 mg) in polyphosphoric acid (5 mL) was added ethyl 4-methyl-3-oxo-pentanoate (1.13 mL}. The mixture was heated to 85 C for 1 hour, then 120 C for 1 hour. While still hot, the mixture was slowly added to a stirred solution of saturated aqueous NaHCOg (150 mL) and chloroform/IPA (4:1) (50 mL). Upon complete addition, the mixture was stirred for 10 minutes and the organic layer was isolated. The aqueous layer was further extracted with chloroform/IPA (4:1) (3 x 50 L) and the organic layers were pooled, dried over MgSC , filtered, and concentrated. The crude product was purified using a Teledyne I5CO Combi-Flash system (liquid loading with DCM, 80G column, 0 - 65% EtOAc/Hex, 20 min run). The column was then flushed with hexanes followed by 0 - 2% MeOH/DCM, 10 min to give the title compound (204 mg; 23% yield) as a solid. : NMR (400 MHz, CDCI3) d 6.47 (s, 1H), 3.63 (hept, J = 6.8 Hz, 1H), 2.56 (d, 1 = 1.0 Hz, 3H), 2.44 (d, J = 1.0 Hz, 3H), 1.32 (s, 3H), 1.30 (s, 3H). ES-MS [M+l]+: 252. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With glacial acetic acid at 130℃; Microwave irradiation; | 4.10 General procedure for preparation of alkylated pyrazolones (22-27) General procedure: The corresponding β-keto ester (1 eq.) and hydrazine (1.5 eq.) were dissolved in glacial acetic acid (6M). The mixture was subjected to microwave irradiations for 2.5-5min at 130°C and 150W. The reaction of followed by TLC. The acetic acid was then evaporated under reduced pressure. |
95% | With glacial acetic acid at 130℃; Microwave irradiation; | 4.10 General procedure for preparation of alkylated pyrazolones (22-27) General procedure: The corresponding β-keto ester (1 eq.) and hydrazine (1.5 eq.) were dissolved in glacial acetic acid (6M). The mixture was subjected to microwave irradiations for 2.5-5min at 130°C and 150W. The reaction of followed by TLC. The acetic acid was then evaporated under reduced pressure. |
Tags: 7152-15-0 synthesis path| 7152-15-0 SDS| 7152-15-0 COA| 7152-15-0 purity| 7152-15-0 application| 7152-15-0 NMR| 7152-15-0 COA| 7152-15-0 structure
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P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
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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