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CAS No. : | 3984-34-7 | MDL No. : | MFCD00002794 |
Formula : | C10H9ClO3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | AHVASTJJVAYFPY-UHFFFAOYSA-N |
M.W : | 212.63 | Pubchem ID : | 77604 |
Synonyms : |
|
Num. heavy atoms : | 14 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.2 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 53.03 |
TPSA : | 54.37 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.15 cm/s |
Log Po/w (iLOGP) : | 1.55 |
Log Po/w (XLOGP3) : | 2.04 |
Log Po/w (WLOGP) : | 2.39 |
Log Po/w (MLOGP) : | 1.88 |
Log Po/w (SILICOS-IT) : | 2.44 |
Consensus Log Po/w : | 2.06 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.85 |
Log S (ESOL) : | -2.5 |
Solubility : | 0.678 mg/ml ; 0.00319 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.81 |
Solubility : | 0.329 mg/ml ; 0.00155 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.15 |
Solubility : | 0.15 mg/ml ; 0.000705 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.34 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With potassium hydroxide; hydrazine hydrate In dichloromethane; water; diethylene glycol | 4-(p-chlorophenyl)butanoic acid (34a) A mixture of 3-(4-chlorobenzoyl) propionic acid (33) (2.50 g, 12.0 mmol), KOH (s) (1.75 g, 31.2 mmol), and hydrazine monohydrate (1.25 mL, 25.8 mmol) in 12.5 mL of diethylene glycol was refluxed azeotropically at 120-130° C. for 90 min to remove water. The reaction mixture was then refluxed at 170° C. for 3 h, cooled to RT, diluted with 12.5 mL of water, and poured into 15 mL 2.5 N HCl(aq). The precipate was filtered off, dissolved in CH2Cl2, and the solvent removed to give 34a (2.23 g, 96percent) as a white solid. UV λmax 223 (8980, 95percent ETHANOL); 1H NMR (400 MHz, CDCl3) δ 7.26 (d, J=7 Hz, 2H), 7.12 (d, J=8 Hz, 2H), 2.66 (t, J=4 Hz, 2H), 2.38 (t, J=4 Hz, 2H), 1.96 (m, 2H); 13C NMR (CDCl3) δ 179.3, 140.0, 132.2, 130.2, 128.9, 34.7, 33.4, 26.4; IR (drift) 3063 (s), 3051 (s), 2955 (s), 2923 (s,b), 2905 (s), 2814, 2797, 2493 (b), 2466, 2413, 2367 (b), 2321, 1706 (s), 1492 (s), 1212 (s), cm-1; MS (El) m/z (rel. intensity) 198 (M+, 22), 200 (7), 198 (22), 140 (32), 139 (17), 138 (99), 127 (15), 125 (48), 103 (10), 89 (13), 60 (9); HRMS (EI) calcd for 198.0448, found 198.0441. |
89% | With potassium hydroxide; hydrazine In ethylene glycol at 120 - 190℃; for 8 h; Heating / reflux | A mixture of 4-(4-chlorophenyl)4-oxobutanoic acid (1 eq.), KOH (3 eq.) and hydrazine hydrate (2.2 eq.) in ethylene glycol was refluxed azeotropically at 120-130° C. for 5 hours, the temperature was increased gradually to 180° C. Heating under reflux was then continued at 190° C. for 3 hours. The reaction mixture was cooled to 25° C., diluted with water and poured into a solution 2.5N HCl to give white crystals of 4-(4-chlorophenyl)butanoic acid (89percent). |
89% | With hydrazine hydrate; potassium hydroxide In diethylene glycol at 120 - 200℃; for 5 h; Dean-Stark | 4-(4-Chlorophenyl)butanoic acid: 4-(4-Chlorophenyl)-4-oxobutanoic acid (1.06 g, 5 mmol) and KOH (85percent by wt, 0.79 g, 12 mmol) were placed in a round-bottomed flask fitted with a Dean-Stark apparatus and a reflux condenser and suspended in diethylene glycol (10 mL) at RT. Then, hydrazine monohydrate (50percent by wt., 1.20 g, 12 mmol) was added slowly to the reaction at RT after which it was heated to 120- 130 °C for 2 h. The reaction became homogenous after heating for approximately 45 min. After 2 h, the temperature was increased to 180-200 °C and the reaction stirred for an additional 3 h to remove residual hydrazine and water via the Dean-Stark trap. The reaction was then cooled to RT, diluted with H20 (10 mL), and poured into a 2.5 N aqueous solution of HQ (20 mL). The suspension was cooled in an ice bath and the resulting precipitate was isolated by filtration. To remove residual diethylene glycol, the solid was dissolved in a saturated aqueous solution of K2CO3 (20 mL), diluted with H20 (20 niL), and poured into a 2.5 N aqueous solution of HC1 (20 mL). The suspension was again cooled in an ice bath and the precipitate isolated by filtration, washed with cold H20 (2x 15 mL), and dried under vacuum. The title compound was isolated as a white solid (0.89 g, 89percent). NMR (500 MHz, DMSO- d6): δ 12.06 (br, 1H), 7.32 (d, J= 8.5 Hz, 2H), 7.21 (d, J= 8.5 Hz, 2H), 2.57 (t, J= (0563) 7.4 Hz, 2H), 2.20 (t, J= 7.3 Hz, 2H), 1.77 (q, J= 7.5 Hz, 2H). 13C NMR (125 MHz, DMSO-i/6): δ 174.16, 140.57, 130.41, 130.17, 128.20, 33.63, 32.95, 26.1 1. ESI- LRMS: [M-H]- = m/z 284.3. ESI-HRMS: calcd. for C10H1 1C102: [M-H]- = m/z 197.0375, found: [M-H]- = m/z 197.0379. |
79% | With hydrazine hydrate; potassium hydroxide In diethylene glycol at 120 - 180℃; for 4.5 h; Dean-Stark | A heterogeneous mixture of 3-(4-chlorobenzoyl)-propionic acid (20 g, 188.1 mmol), potassium hydroxide (11.7 g, 208.7 mmol), hydrazine monohydrate (10 mL, 205.1 mmol), and diethylene glycol (84 mL) were heated in a flask equipped with a Dean-Stark trap and condenser. The mixture became homogeneous on heating. The mixture maintained at 120-130oC for 1.5 h and raised to 180oC for 3 h. The reaction mixture was cooled to room temperature, diluted with water and added 2.5M HCl. The mixture was allowed to stand for 16 h and the white solid collected by filtration. To remove the residual diethylene glycol, the solid dissolved in sat. K2CO3and water. The clear solution was poured into stirred 2.5M HCl. White solid was collected by filtration, washed with water (30.0 g, 79 percent).1H NMR (400 MHz, CDCl3) δ 2.12 -2.14 (m, 2H), 2.37 (t,J= 9.0, 2H), 2.56 (t,J= 6.0, 2H), 7.12 (s, 2H), 7.26 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With potassium hydroxide; hydrazine hydrate In dichloromethane; water; diethylene glycol | 4-(p-chlorophenyl)butanoic acid (35a). A mixture of 3-(4-chlorobenzoyl) propionic acid (34) (2.50 g, 12.0 mmol), KOH (s) (1.75 g, 31.2 mmol), and hydrazine monohydrate (1.25 mL, 25.8 mmol) in 12.5 mL of diethylene glycol was refluxed azeotropically at 120-130° C. for 90 min to remove water. The reaction mixture was then refluxed at 170° C. for 3 h, cooled to RT, diluted with 12.5 mL of water, and poured into 15 mL 2.5 N HCl(aq). The precipate was filtered off, dissolved in CH2Cl2, and the solvent removed to give 35a (2.23 g, 96percent) as a white solid. UV λmax 223 (8980, 95percent ETHANOL); 1H NMR (400 MHz, CDCl3) δ 7.26 (d, J=7 Hz, 2H), 7.12 (d, J=8 Hz, 2H), 2.66 (t, J=4 Hz, 2H), 2.38 (t, J=4 Hz, 2H), 1.96 (m, 2H); 13C NMR (CDCl3) δ 179.3, 140.0, 132.2, 130.2, 128.9, 34.7, 33.4, 26.4; IR (drift) 3063 (s), 3051 (s), 2955 (s), 2923 (s,b), 2905 (s), 2814, 2797, 2493 (b), 2466, 2413, 2367 (b), 2321, 1706 (s), 1492 (s), 1212 (s), cm-1; MS (EI) m/z (rel. intensity) 198 (M+, 22), 200 (7), 198 (22), 140 (32), 139 (17), 138 (99), 127 (15), 125 (48), 103 (10), 89 (13), 60 (9); HRMS (EI) calcd for 198.0448, found 198.0441. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With Aluminum Chloride In dichloromethane at 20℃; for 16h; | 5 Example 5: preparation of 4-(1-(6'-chloro-4,,4,-dimethyl-3,,4'-dihydro-2,H- spiro[cyclopropane-1,1'-naphthalen]-7'-yl)vinyl)benzoic acid (DSP-108; 108) A mixture of chlorobenzene (50 g, 444 mmol, 1.2 eq.), oxolane-2,5-dione (44.4 g, 444 mmol, 1.0 eq.) and aluminum trichloride (74.01 g, 555 mmol, 1.5 eq.) in CH2CI2 (500 ml_) was stirred at room temperature for 16 h, then quenched by the addition of 1 M HCI/ice (600 ml_). The resulting mixture was extracted with diethyl ether (3 c 300 ml_), then the combined extracts were dried (Na2S04) and concentrated under reduced pressure to give 73 g (93%) of 4-(4-chlorophenyl)-4-oxobutanoic acid as a white solid. |
90% | Stage #1: succinic acid anhydride With Aluminum Chloride In dichloromethane at 20℃; for 0.0833333h; Schlenk technique; Sealed tube; Stage #2: chlorobenzene In dichloromethane at 20℃; Schlenk technique; Sealed tube; | |
90% | With Aluminum Chloride In dichloromethane at 20℃; | 3.2.2. Chemistry General procedure: The general procedure (Scheme 1) for the preparation of compounds (2a, 2b and 2c): succinicanhydride (1 equiv, 10 mmol) was reacted with an appropriate aromatic compound (substitutedbenzene, 1 equiv, 10 mmol) in DCM (20 mL) in the presence of anhydrous aluminium chloride(1.5 equiv, 15 mmol). The reaction mixture was stirred under anhydrous conditions overnight at roomtemperature and then ice-cold diluted hydrochloric acid solution was added dropwise. A solid massseparated out which was filtered and purified by recrystallization to give 2a, 2b and 2c [44]. |
90% | With Aluminum Chloride In dichloromethane at 20℃; for 2h; | |
84% | Stage #1: succinic acid anhydride With Aluminum Chloride In dichloromethane at 0℃; for 0.166667h; Stage #2: chlorobenzene In dichloromethane at 20℃; for 16h; | |
83% | With Aluminum Chloride at 60℃; Ionic liquid; Irradiation; | |
76% | With Aluminum Chloride at 0 - 25℃; for 20h; Inert atmosphere; | |
75% | With aluminium chloride anhydrous at 20℃; for 0.416667h; | |
72% | With Aluminum Chloride for 2h; Reflux; | |
70% | With Aluminum Chloride at 80℃; for 4h; Reflux; | |
64% | With Aluminum Chloride In dichloromethane at 20℃; Inert atmosphere; | General synthesis of 3-benzoylpropionic acids (Method A): General procedure: AlCl3 (1.0 g, 7.5 mmol)was added portion-wise to a solution of succinic anhydride (0.5 g, 5 mmol) and anaromatic compound (6 mmol) in CH2Cl2 (5 mL) at room temperature. The mixture wasstirred at room temperature for overnight, and the mixture was poured into 1N HClsolution (10 mL), extracted with ethyl acetate (15 mL x 3). The organic layer was driedover MgSO4. The solvent was removed under reduced pressure, and the crude productwas purified by recrystallized from ethyl acetate and hexane. |
62% | With aluminium chloride anhydrous at 120℃; for 4h; | |
62% | Stage #1: succinic acid anhydride; chlorobenzene With Aluminum Chloride for 2h; Heating; Stage #2: With sodium hydroxide In water monomer | |
62% | With Aluminum Chloride In dichloromethane at 0 - 20℃; for 3h; | |
61% | With Aluminum Chloride Reflux; | |
54% | With [bmim]Cl*AlCl3 at 50℃; for 5h; | |
53% | ||
42% | Stage #1: succinic acid anhydride; chlorobenzene With Aluminum Chloride at 65℃; for 3h; Stage #2: With hydrogenchloride In water monomer at 80℃; for 0.333333h; | |
38% | With Aluminum Chloride for 6h; | |
With aluminium chloride anhydrous at 40 - 50℃; | ||
With aluminium chloride anhydrous for 2h; Heating; | ||
With aluminium chloride anhydrous | ||
With Aluminum Chloride Reflux; | ||
With Aluminum Chloride In nitrobenzene Heating; | ||
Stage #1: chlorobenzene With Aluminum Chloride In nitrobenzene Reflux; Stage #2: succinic acid anhydride In nitrobenzene Heating; | ||
With Aluminum Chloride at -10 - 20℃; | ||
With Aluminum Chloride | ||
With Aluminum Chloride | ||
With Aluminum Chloride Reflux; | ||
With HY-Zeolite In 1,2-dichloro-ethane Reflux; | ||
With Aluminum Chloride | ||
Stage #1: chlorobenzene With Aluminum Chloride at 20℃; for 0.5h; Stage #2: succinic acid anhydride at 20℃; for 6h; | 4.1.1 General procedure for the synthesis of aroylpropionic acids (1a-p) General procedure: To liquid aromatic hydrocarbon (30 ml), anhydrous aluminum chloride (16.6 g, 0.125 mol) was added. Nitrobenzene (30 ml) was used as solvent in case of solid aromatic hydrocarbons. The mixture was stirred using a magnetic stirrer at room temperature for 30 min. To this, succinic anhydride (5 g, 0.05 mol) was added in five portions with continuous stirring. Vigorous reaction started with the evolution of HCl gas. Stirring was continued for another 6 h at room temperature. The mixture was left at room temperature for 48 h and then decomposed by adding ice-cold hydrochloric acid (50%, 100 ml). The excess solvent was removed by steam distillation. The solid precipitated out was treated with aqueous saturated sodium bicarbonate solution and filtered. Filtrate was acidified with dilute HCl (4% v/v) to give a precipitate. It was filtered and residue was washed with cold water, dried and crystallized from the appropriate solvent to give 1a-p. | |
With Aluminum Chloride In dichloromethane at 20℃; Inert atmosphere; | ||
With Aluminum Chloride | ||
With Aluminum Chloride at 20℃; Reflux; | Synthesis of 4-(4-Chloro Phenyl)-4-oxo-butyric Acid and4-(4-methy Phenyl)-4-oxo-butyric Acid (1a and 1b) General procedure: A mixture of 4-chloro-benzene or 4-methylbenzene (30ml) and anhydrous aluminium chloride (0.15 mol) was takenin a three-neck flask. The flask was refluxed on a water bathunder anhydrous condition, followed by the addition of succinicanhydride (0.10 mol) in small quantity with continuousstirring for 4 hrs. The reaction started immediately with theevolution of HCl gas. After the reflux, the reaction mixturewas kept overnight at room temperature. Then, the contentswere poured into ice cold hydrochloric acid (2.5% v/v) followedby steam distillation. The aqueous solution was concentratedto small volume by evaporating on a water bath toobtain crude product. It was purified by dissolving the 5%w/v of sodium bicarbonate solution followed by the extractionwith ether [12-14]. The aqueous layer, on acidificationwith dilute HCl acid, gave 4-(4-Chloro phenyl)-4-oxobutyricacid (1a) or 4-(4-methy-phenyl)-4-oxo-butyric acid(1b) and was re-crystallized with aqueous ethanol. | |
With Aluminum Chloride for 6h; | Preparation of 3-(4-substituted-benzoyl) propionic acid General procedure: Succinic anhydride (10 g, 10 mmol) was treated with differentaryl derivatives (17 g, 10 mmol) in the presence of anhydrous aluminum chloride (15 g, 11.25 mmol). The reaction mixture was stirred for 6 h. The desired product was purified by dissolving in 5 % sodium hydroxide solution and filtered. Dilute hydrochloric acid was added to mother liquor to precipitate the product. The solid mass so obtained was filtered, washed with cold water, dried and crystallized from acetone to give 8.6 g of the desired compound as a colorless solid. | |
With Aluminum Chloride In dichloromethane Inert atmosphere; | Synthesis of compounds S1a-h General procedure: To an oven dried 250 mL round bottom flask containing succinic anhydride (3.00 g, 30.0 mmol) and the aromatic compound (1.1 equiv) in DCM (100 mL) was added aluminum chloride (2.2 equiv) portion-wise at room temperature in an atmosphere of argon over 5 minutes and allowed to stir until completion of reaction. The reaction was cooled at 0 °C and quenched by carefully addition of aqueous solution of 1N HCl, extracted with THF and ethyl acetate (1:1) (2 x 200 mL), the organic layer dried under Na2SO4 and concentrated to give the product as a solid that was subsequently washed with hexanes and vacuum filtered to afford the crude product S1 used in the next step without further purification. | |
With Aluminum Chloride In dichloromethane at 20℃; for 6.5h; Cooling with ice; | 4.1 25 mmol of chlorobenzene was dissolved in 30 mL of dichloromethane,25 mmol succinic anhydride was added,Ice water bath stirring conditions,37.5 mmol of anhydrous AlCl3 was added in portions over 30 min,Followed by reaction at room temperature for 6 hours.After the reaction,Add ice hydrochloric acid quenching,Stir for ten minutes,Filter,Recrystallization from an appropriate 70% ethanol solution,dry,To give 4-(4-chlorophenyl)-4-oxobutyric acid. | |
With Aluminum Chloride | ||
With Aluminum Chloride In dichloromethane at 0 - 5℃; for 2h; Schlenk technique; Inert atmosphere; | ||
With Aluminum Chloride In dichloromethane at 20℃; for 16h; Inert atmosphere; | ||
With Aluminum Chloride In neat (no solvent) at 60℃; | ||
Stage #1: chlorobenzene With Aluminum Chloride at 20℃; for 0.5h; Schlenk technique; Stage #2: succinic acid anhydride With hydrogenchloride at 80℃; Schlenk technique; | ||
Stage #1: succinic acid anhydride; chlorobenzene In dichloromethane at 0℃; for 0.5h; Stage #2: With Aluminum Chloride In dichloromethane at 0 - 20℃; for 6h; | 3.1.1. Preparation of 4- oxo-4-(substituted phenyl) Butanoic Acids (2) and Their Esters (3) General procedure: Preparation of 4- oxo-4-(substituted phenyl) butanoic acids (2). These Compounds were synthesizedaccording to reports [26,27]. Succinic anhydride (1 equiv, 25 mmol) in 30 mL CH2Cl2 reactedwith substituted benzenes (1, 25 mmol) under stirring for 0.5 h in ice-water bath, then anhydrousaluminum chloride (37.5 mmol) was added to the CH2Cl2 solution (Scheme 1). The reaction was thenkept on room temperature for 6 h. After the reaction was stopped, icy aqueous hydrochloric acidsolution (0.1 mol/L, 10 mL) was drop to resultant solution under stirring for 10 min. Organic phasesolution was evaporated to give crude product. The crude product was further purified by crystallizationrepeatedly with 70% ethanol solution to afford 4-oxo-4-phenylbutanoic acid (2A) and4-oxo-4-(p-tolyl)butanoic acid (2B) [26], 4-(4-Methoxyphenyl)-4-oxobutanoic acid (2C) and 4-(4-Chlorophenyl)-4-oxobutanoic acid (2D). | |
With Aluminum Chloride In dichloromethane at 20℃; | ||
With Aluminum Chloride at 0 - 100℃; for 4h; Inert atmosphere; Sealed tube; | ||
With carbon disulfide; Aluminum Chloride at 40 - 50℃; for 4h; | Synthesis of 4-oxo-4-phenylbutanoic acid derivatives (I1-3) General procedure: A mixture of 0.275 mol aluminum chloride, 20 ml carbondisulfide, and 0.25 mol succinicanhydride was added portion wisein standard conditions to a mixture of 0.25 mol 2-fluoroanisole and50 ml carbon disulfide. Then the mixture was refluxed for 4 h at40-50 C. After cooling, the mixture was poured onto ice water andthe precipitate was collected, dried and recrystallized from water[37]. | |
With Aluminum Chloride | ||
With Aluminum Chloride for 6h; Reflux; | 4.2.1. General synthesis of 3-(4-substituted-benzoyl) propionic acid (1a-h) General procedure: Succinic anhydride (1.0 mmol) was reacted with substituted benzene(1.0 mmol) in the presence of anhydrous aluminum chloride (1.1 mmol)and stirred for 6 h. The resultant reaction mixture was purified by dissolvingin sodium hydroxide solution. The solution was filtered followed by addition of hydrochloric acid. The solid mass so obtained was againfiltered and washed with cold water. Washed solid was dried and crystallizedfrom acetone to give the 3-(4-substituted-benzoyl) propionicacid or alternately named as substituted 4-oxybutyric acid as a colorlesssolid. | |
Stage #1: succinic acid anhydride; chlorobenzene With Aluminum Chloride at 65℃; for 3h; Stage #2: With hydrogenchloride In water monomer at 80℃; for 0.333333h; | ||
With Aluminum Chloride In dichloromethane Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With acetyl chloride for 0.5h; Heating; | |
With acetyl chloride | ||
With acetic anhydride; acetic acid for 2h; Heating; |
With sulfuric acid In acetic anhydride at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With hydrogen; potassium hydroxide In isopropyl alcohol at 100℃; for 24h; Schlenk technique; Green chemistry; | |
93% | With C12H14N4*Ir(1+)*2CO*BF4(1-)*C3H7NO; hydrogen; potassium hydroxide In isopropyl alcohol at 100℃; for 4h; Autoclave; | |
70% | Stage #1: 4-(4-chlorophenyl)-4-oxobutanoic acid With sodium tetrahydroborate; sodium hydroxide In water at 0 - 20℃; Inert atmosphere; Stage #2: With trifluoroacetic acid In dichloromethane at 20℃; Inert atmosphere; | Lactone Derivatives 1 and 3; General Procedure General procedure: Method B:22 NaBH4 (227 mg, 6.00 mmol) was added at 0 °C to a solution of NaOH (500 mg, 12.5 mmol) and the corresponding keto acid (5mmol) in H2O (10 mL). The reaction mixture was stirred at r.t. for more than 2 h. After completion of the reaction, concd HCl was carefully added until the pH of the resultant solution reached 2. The solution was then extracted with CH2Cl2 (3 × 15 mL), and the organic phases were combined, dried (anhyd Na2SO4), and evaporated under reduced pressure. The resultant oil or solid was directly dissolved in CH2Cl2 (18 mL) with trifluoroacetic acid (0.75 mL) and the solution was stirred at r.t. for more than 24 h. Afterwards, the solution was cooled and washed with sat. aq Na2CO3 (15 mL). Then, the solution was extracted with CH2Cl2 (3 × 15mL), and the organic phases were combined, dried (anhyd Na2SO4) and evaporated under reduced pressure. The crude product was purified by a bulb-to-bulb distillation to give the corresponding lactone. |
63% | With gallium(III) trichloride; phenylsilane In benzene at 60℃; for 168h; | |
With sodium amalgam | ||
With potassium m-borate | ||
Multi-step reaction with 2 steps 1: hydrazine hydrate; potassium hydroxide / ethylene glycol / 10 h / 180 °C 2: iodine; 2,4,6-triphenylpyrylium tetrafluoroborate / 1,2-dichloro-ethane / 18 h / 20 °C / Irradiation | ||
Multi-step reaction with 2 steps 1.1: sodium hydroxide / water / 80 °C / pH 11 1.2: 4 h 2.1: hydrogenchloride / water / 3 h / pH 1 - 2 | ||
Multi-step reaction with 2 steps 1: sodium tetrahydroborate; sodium hydroxide; water / 2 h / 0 - 20 °C / Sealed tube; Inert atmosphere 2: trifluoroacetic acid / dichloromethane / 4 h / 20 °C / Sealed tube; Inert atmosphere | ||
Multi-step reaction with 2 steps 1: sodium tetrahydroborate; sodium hydroxide / water / 3 h / 0 - 20 °C 2: trifluoroacetic acid / dichloromethane / 4 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With hydrazine hydrate In ethanol for 17h; Heating; | |
70% | With sodium acetate; hydrazine hydrate In methanol for 6h; Reflux; | |
With hydrazine hydrate |
With hydrazine In ethanol at 80℃; | ||
Multi-step reaction with 2 steps 1: 66 percent / K2CO3 / acetone / Heating 2: 60 percent / hydrazine hydrate; CH3COONa / methanol / Heating | ||
16 g (80%) | With hydrazine hydrate In ethanol | 12.d c. d. 6-(4-chloropheny)-4,5-dihydropyridazinone To a solution of 3-(4-chlorobenzoyl)propionic acid (20 g) in absolute ethanol (200 ml) was added 5 g of hydrazine monohydrate. A thick solid was formed which dissolved after heating. The resulting solution was refluxed for 3 h, cooled and the solid formed filtered and dried to yield 16 g (80%) of 6-(4-chlorophenyl)-4,5-dihydropyridazinone. |
With hydrazine hydrate In ethanol Reflux; | ||
With hydrazine hydrate In methanol Reflux; | ||
With hydrazine hydrate | ||
With sodium acetate; hydrazine hydrate In methanol for 6h; Reflux; | ||
With hydrazine hydrate In ethanol at 60℃; | 1 6.1.2. General procedures for 2a-k General procedure: To a stirred solution of the suitable γ-keto acid 1a-k (1.00 mmol) in EtOH (2 mL), hydrazine hydrate (1.00 mmol) was added dropwise. The mixture was heated at 60 °C for 1-3h. After cooling, the precipitate was collected by suction and purified by recrystallization from either toluene or ethanol. | |
With hydrazine hydrate | ||
With sodium acetate; hydrazine hydrate In methanol for 6h; Reflux; | Synthesis of 6-(4-chlorophenyl)-4,5-dihydropyridazin-3(2H)-one and 6-(4-methylphenyl)-4,5-dihydro Pyridazin-3(2H)-one (2a and 2b) General procedure: 4-oxo-butyric acid (4-(4-Chloro phenyl)-4-oxo-butyricacid (1a) and 4-(4-methy Phenyl)-4-oxo-butyric acid (1b)(0.01 mol) were refluxed for 6 hrs with hydrazine hydrate(0.01 mol) in methanol (10 ml) containing sodium acetate(50 mg). The contents were concentrated and then pouredinto ice cold water to obtain products 6-(4-chlorophenyl)-4,5-dihydropyridazin-3(2H)-one (2a) or 6-(4-methylphenyl)-4,5-dihydro pyridazin-3(2H)-one (2b) and re-crystallizedwith ethanol [13, 14]. | |
With hydrazine hydrate for 6h; Reflux; | ||
With hydrazine hydrate In ethanol Reflux; | Synthesis of 6-substitutedphenyl-4,5-dihydropyridazin-3(2 H)-onederivatives (II1-3) General procedure: 0.01 Mol 4-(2-fluoro-4-methoxyphenyl)-4-oxobutanoic acidand 0.015 mol hydrazine hydrate (0.85 ml, 55%) in 30 ml ethanolwere refluxed for 4 h. The reaction mixture was cooled andprecipitate thus formed was collected byfiltration, dried, andcrystallized from ethanol [30]. | |
With hydrazine hydrate for 6h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With thionyl chloride In methanol | 16.a (a) (a) Methyl 3-(4-chlorobenzoyl)propionate Thionyl chloride (2.4 ml, 33 mmol) was added dropwise to a stirred solution of 3-(4-chlorobenzoyl)propionic acid (5.0 g, 24 mmol) in dry methanol (50 ml) at 0° C. The mixture was heated at reflux for 2 h, cooled and the solvent removed under reduced pressure to give methyl 3-(4-chlorobenzoyl)propionate (5.3 g, 97%) as a colourless oil. deltaH (250 MHz, CDCl3) 7.93 (2H, d, J 8.5 Hz), 7.45 (2H, d, J 8.6 Hz), 3.72 (3H, s), 3.29 (2H, t, J 6.6 Hz), 2.78 (2H, t, J 6.6 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With bromine In dichloromethane | 1C General procedure for preparation of bromoketoacids (compounds 4.4.01-10): The aryl ketoacid (either synthesized in-house or purchased from a commercial source) was dissolved in dichloromethane (0.2 M) and cooled to 0° C. The Br2 (1.1 equiv) was added dropwise, then the reaction was warmed to room temperature and stirred until reaction was complete as judged by TLC analysis. For some more slowly-reacting derivatives, the reaction mixture was heated to reflux at 40° C. The reaction mixture was concentrated in vacuo to yield the brominated ketoacid which could be further purified if necessary by recrystallization in dichloromethane. |
With chloroform; bromine | ||
With bromine In chloroform |
With perchloric acid; bromine; acetic acid; sodium bromide In water at 19.9 - 49.9℃; ΔH(excit.), ΔS(excit.); | ||
With bromine In diethyl ether | 4 EXAMPLE 4 EXAMPLE 4 Bromine (2.6 ml) was added dropwise to a solution of 3-(4-chlorobenzoyl)propionic acid (10.6 g) in ethyl ether (200 ml) under stirring. The ethyl ether was distilled off to give 3-bromo-3-(4-chlorobenzoyl)propionic acid. | |
With bromine In diethyl ether at 20℃; | 3-(4-Chlorobenzoyl)propionic acid(21.2 g, 0.1 mol) was dissolved in ether (200 ml.) and bromine (6.6 ml_, 0.13 mol) was added slowly. The mixture was stirred at room temperature over night. Reduced under vacuum and stirred with heptane/water to give a white precipitate that was filtered and dried. | |
With bromine In diethyl ether at 20℃; for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With potassium hydroxide; hydrazine hydrate; In dichloromethane; water; diethylene glycol; | 4-(p-chlorophenyl)butanoic acid (34a) A mixture of 3-(4-chlorobenzoyl) propionic acid (33) (2.50 g, 12.0 mmol), KOH (s) (1.75 g, 31.2 mmol), and hydrazine monohydrate (1.25 mL, 25.8 mmol) in 12.5 mL of diethylene glycol was refluxed azeotropically at 120-130 C. for 90 min to remove water. The reaction mixture was then refluxed at 170 C. for 3 h, cooled to RT, diluted with 12.5 mL of water, and poured into 15 mL 2.5 N HCl(aq). The precipate was filtered off, dissolved in CH2Cl2, and the solvent removed to give 34a (2.23 g, 96%) as a white solid. UV lambdamax 223 (8980, 95% ETHANOL); 1H NMR (400 MHz, CDCl3) delta 7.26 (d, J=7 Hz, 2H), 7.12 (d, J=8 Hz, 2H), 2.66 (t, J=4 Hz, 2H), 2.38 (t, J=4 Hz, 2H), 1.96 (m, 2H); 13C NMR (CDCl3) delta 179.3, 140.0, 132.2, 130.2, 128.9, 34.7, 33.4, 26.4; IR (drift) 3063 (s), 3051 (s), 2955 (s), 2923 (s,b), 2905 (s), 2814, 2797, 2493 (b), 2466, 2413, 2367 (b), 2321, 1706 (s), 1492 (s), 1212 (s), cm-1; MS (El) m/z (rel. intensity) 198 (M+, 22), 200 (7), 198 (22), 140 (32), 139 (17), 138 (99), 127 (15), 125 (48), 103 (10), 89 (13), 60 (9); HRMS (EI) calcd for 198.0448, found 198.0441. |
89% | With potassium hydroxide; hydrazine; In ethylene glycol; at 120 - 190℃; for 8h;Heating / reflux; | A mixture of 4-(4-chlorophenyl)4-oxobutanoic acid (1 eq.), KOH (3 eq.) and hydrazine hydrate (2.2 eq.) in ethylene glycol was refluxed azeotropically at 120-130 C. for 5 hours, the temperature was increased gradually to 180 C. Heating under reflux was then continued at 190 C. for 3 hours. The reaction mixture was cooled to 25 C., diluted with water and poured into a solution 2.5N HCl to give white crystals of 4-(4-chlorophenyl)butanoic acid (89%). |
89% | With hydrazine hydrate; potassium hydroxide; In diethylene glycol; at 120 - 200℃; for 5h;Dean-Stark; | 4-(4-Chlorophenyl)butanoic acid: 4-(4-Chlorophenyl)-4-oxobutanoic acid (1.06 g, 5 mmol) and KOH (85% by wt, 0.79 g, 12 mmol) were placed in a round-bottomed flask fitted with a Dean-Stark apparatus and a reflux condenser and suspended in diethylene glycol (10 mL) at RT. Then, hydrazine monohydrate (50% by wt., 1.20 g, 12 mmol) was added slowly to the reaction at RT after which it was heated to 120- 130 C for 2 h. The reaction became homogenous after heating for approximately 45 min. After 2 h, the temperature was increased to 180-200 C and the reaction stirred for an additional 3 h to remove residual hydrazine and water via the Dean-Stark trap. The reaction was then cooled to RT, diluted with H20 (10 mL), and poured into a 2.5 N aqueous solution of HQ (20 mL). The suspension was cooled in an ice bath and the resulting precipitate was isolated by filtration. To remove residual diethylene glycol, the solid was dissolved in a saturated aqueous solution of K2CO3 (20 mL), diluted with H20 (20 niL), and poured into a 2.5 N aqueous solution of HC1 (20 mL). The suspension was again cooled in an ice bath and the precipitate isolated by filtration, washed with cold H20 (2x 15 mL), and dried under vacuum. The title compound was isolated as a white solid (0.89 g, 89%). NMR (500 MHz, DMSO- d6): delta 12.06 (br, 1H), 7.32 (d, J= 8.5 Hz, 2H), 7.21 (d, J= 8.5 Hz, 2H), 2.57 (t, J= (0563) 7.4 Hz, 2H), 2.20 (t, J= 7.3 Hz, 2H), 1.77 (q, J= 7.5 Hz, 2H). 13C NMR (125 MHz, DMSO-i/6): delta 174.16, 140.57, 130.41, 130.17, 128.20, 33.63, 32.95, 26.1 1. ESI- LRMS: [M-H]- = m/z 284.3. ESI-HRMS: calcd. for C10H1 1C102: [M-H]- = m/z 197.0375, found: [M-H]- = m/z 197.0379. |
83% | With potassium hydroxide; hydrazine; In diethylene glycol; at 170℃; for 5h; | A solution of 4-(4-chlorophenyl)-4-oxobutanoic acid (50 g, 235 mmol, 1.0 eq.), hydrazine (9.78 g, 305 mmol, 1.3 eq.) and potassium hydroxide (34 g, 606 mmol, 2.6 eq.) in diethylene glycol (250 ml_) was heated at 170 C for 5 h, then cooled to room temperature and quenched by the addition of aqueous HCI (200 ml_). The resulting solution was diluted with H20 (100 ml_) and the pH of the solution was adjusted to 12 by the action of sodium hydroxide (2 M). The resulting mixture was extracted with CH2CI2 (3 c 200 ml_), then the combined organic layers were dried (Na2S04) and concentrated to give 39 g (83%) of 4-(4- chlorophenyl)butanoic acid as a yellow solid. |
79% | With hydrazine hydrate; potassium hydroxide; In diethylene glycol; at 120 - 180℃; for 4.5h;Dean-Stark; | A heterogeneous mixture of 3-(4-chlorobenzoyl)-propionic acid (20 g, 188.1 mmol), potassium hydroxide (11.7 g, 208.7 mmol), hydrazine monohydrate (10 mL, 205.1 mmol), and diethylene glycol (84 mL) were heated in a flask equipped with a Dean-Stark trap and condenser. The mixture became homogeneous on heating. The mixture maintained at 120-130oC for 1.5 h and raised to 180oC for 3 h. The reaction mixture was cooled to room temperature, diluted with water and added 2.5M HCl. The mixture was allowed to stand for 16 h and the white solid collected by filtration. To remove the residual diethylene glycol, the solid dissolved in sat. K2CO3and water. The clear solution was poured into stirred 2.5M HCl. White solid was collected by filtration, washed with water (30.0 g, 79 %).1H NMR (400 MHz, CDCl3) delta 2.12 -2.14 (m, 2H), 2.37 (t,J= 9.0, 2H), 2.56 (t,J= 6.0, 2H), 7.12 (s, 2H), 7.26 (s, 2H). |
With potassium hydroxide; hydrazine hydrate; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; 2,2'-[1,2-ethanediylbis(oxy)]bisethanol; | a. 4-(4-Chlorophenyl)butyric acid. 3-(4-Chlorobenzoyl)propionic acid (49.94 g) was dissolved in triethylene glycol (320 mL). To the stirred solution was added potassium hydroxide (44.5 g) followed by 98% hydrazine hydrate (29.0 g). The mixture was heated to reflux (142 C.) for 2 hours. Water and hydrazine hydrate were distilled at atmospheric pressure; the pot temperature rose to 195-200 C. After 0.5 hour at 195-200 C., the mixture was cooled to ambient temperature and diluted with water (320 mL). The aqueous solution was poured into 6N hydrochloric acid (200 mL) and further diluted with 200 mL of ice water. Upon standing, a solid formed which was filtered, washed (water) and dried under vacuum (25 C., 15 Pa) to afford the acid as a white solid (43.61 g). | |
With potassium hydroxide; hydrazine hydrate; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; 2,2'-[1,2-ethanediylbis(oxy)]bisethanol; | a. 4-(4-Chlorophenyl)butyric acid. 3-(4-Chlorobenzoyl)-propionic acid (49.94 g) was dissolved in triethylene glycol (320 mL). To the stirred solution was added potassium hydroxide (44.5 g) followed by 98% hydrazine hydrate (29.0 g). The mixture was heated to reflux (142 C.) for 2 hours. Water and hydrazine hydrate were distilled at atmospheric pressure; the pot temperature rose to 195-200 C. After 0.5 hour at 195-200 C., the mixture was cooled to ambient temperature and diluted with water (320 mL). The aqueous solution was poured into 6N hydrochloric acid (200 mL) and further diluted with 200 mL of ice water. Upon standing, a solid formed which was filtered, washed (water) and dried under vacuum (25 C. 15 Pa) to afford the acid as a white solid (43.61 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With aluminium trichloride; N-tert-butylaminoborane In dichloromethane for 216h; Heating; | |
62% | With aluminium trichloride; borane tert-butylamine In dichloromethane at 22℃; for 20h; | |
Stage #1: 4-(4-chlorophenyl)-4-oxobutanoic acid With hydrogenchloride; zinc In water Inert atmosphere; Reflux; Stage #2: With lithium aluminium tetrahydride In diethyl ether at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In tetrahydrofuran at -20℃; for 0.5h; | ||
With triethylamine In dichloromethane at 0℃; for 0.666667h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | In acetic acid Heating; | |
In ethanol; hexane | 201 Example 201 Example 201 6-(4-chlorophenyl)-2-methyl-4,5-dihydropyridazinone To a 250 ml flask equipped with magnetic stirrer and reflux condenser was charged 10 g of 3-(4-chlorobenzoyl)-propionic acid, 250 ml of absolute ethanol, and 2.5 ml of methyl hydrazine. The reaction was refluxed for 3 hours and cooled to yield a solid which was collected by vacuum filtration, washed with 50 ml of hexane, and air dried. Isolated 9.5 g of product as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | In toluene for 4h; Heating; | |
45% | With toluene-4-sulfonic acid In toluene for 16h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; triethylamine In tetrahydrofuran for 6h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | Stage #1: 4-(4-chlorophenyl)-4-oxobutanoic acid With <(chlorosulfinyloxy)methylene>dimethylammonium chloride In dichloromethane at 0℃; for 0.25h; Stage #2: 1,3-diphenyl-4-formylpyrazole With triethylamine In dichloromethane at 20℃; for 5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With diphenyl sulfide; hydrogen In methanol at 20℃; for 24h; | |
99% | With diphenyl sulfide; hydrogen In methanol at 20℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | Stage #1: 4-(4-chlorophenyl)-4-oxobutanoic acid; (S)-2-Amino-3-(1H-indol-3-yl)-propionic acid propyl ester With dicyclohexyl-carbodiimide In dichloromethane at 20℃; Stage #2: With acetyl chloride In methanol Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: α-(4-Chlorophenyl)-4-morpholineacetonitrile With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5h; Stage #2: acrylic acid methyl ester In N,N-dimethyl-formamide at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | Stage #1: 4-(4-chlorophenyl)-4-oxobutanoic acid; L-tryptophan methyl ester With dicyclohexyl-carbodiimide In dichloromethane at 20℃; Stage #2: With acetyl chloride In methanol for 2h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | Stage #1: 4-(4-chlorophenyl)-4-oxobutanoic acid; L-tryptophan ethyl ester With dicyclohexyl-carbodiimide In dichloromethane at 20℃; Stage #2: With acetyl chloride In methanol Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | [(S)-N- [3-] (3-fluoro-4-morpholinylphenyl) -2-oxo-5-oxazolidinyl] methyl amine [(0.] [100GM,] 0.00034 moles) was taken up in 1: 1 THF-water mixture (20 ml). To this was added 4- (4-chlorophenyl)-4-oxobutanoic acid [(0.] 072g, 0.00034 moles and HOBt (0.046g, 0.00034 moles). The resulting mixture was cooled to [0] C, and then 1- (3-dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride (0.071gm, 0.00037 moles) was added. The resulting mixture was allowed to warm to room temperature and then stirred for 24hr. The reaction mixture was concentrated and 2 ml of saturated aqueous sodium bicarbonate solution was added, stirred for 15 min and then extracted with dichloromethane. The organic layer was separated and evaporated off. The residue was chromatographed over silica gel (100-200 mesh, 20g) and eluted with mixture of ethyl acetate: hexane, and finally with ethyl acetate. The combined fractions were concentrated to give (0.070gm, 42%) of the title compound as a white solid. MS (M+1) = 490 [M/Z] ['H] NMR [(CDC13,] [8)] : 7.72 (d, 2H), 7.37 (dd, [LH),] 7.31 (d, 2H), 6.98 (dd, lH), 6.79 (t, lH), 6.28 (t, lH), 4.69 (m, 1H), 3.83 (t, 1H), 3.81 (m, 4H), 3. [4- 3.] m (m, 3H), 3.21 (dd, 2H), 2.97 (m, 4H), 2.54 (t, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride;dmap; at 20℃; for 20h; | A stirred mixture of 3- (4-chlorobenzoyl) propionic acid (0.153 g, 0.72 mmol) in pyridine (6 ml), under nitrogen, was treated with EDC (0.14 g, 0.73 MMOL), DMAP (10 mg) and 17B 1Z (0. 24 g, 0.72 MMOL), kept at ambient temperature for 20 h and concentrated in vacuo. Chromatography of the residue on silica gel with 5% MeOH- CHC13 and crystallization of the product from CH3CN gave 0.256 g of 139: mp 208- 209C ; IR (drift) 3328,1741, 1672,1645, 1625 cm-1. Anal. calcd for C26H2SCIFN405 : C, 58.81 ; H, 5.32 ; N, 10.55. Found: C, 58.78 ; H, 5. 36 ; N, 10.54. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride at 20℃; for 20h; | 50 A stirred mixture of 3- (4-chlorobenzoyl) propionic acid (0.153 g, 0.720 mmol) in pyridine (6 ml), under nitrogen was treated with EDC (0.13 g, 0.68 mmol), DMAP (10 mg) and 17c6 (0.25 g, 0.71 MMOL), kept at ambient temperature for 20 h and concentrated in vacuo. Chromatography of the residue on silica gel with 2% MeOH- CH2CL2 AND crystallization of the product from CH3CN gave 0.226 g of 140: mp 215- 216°C (DEC) ; IR (drift) 3235,1755, 1679,1620 CM ANAL. calcd FOR C26H28C1FN404S : C, 57.08 ; H, 5.16 ; N, 10.24. Found: C, 57.09 ; H, 5.24 ; N, 10.43. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With nitric acid at -5 - 0℃; for 1h; | A35 4-(4-chloro-3-nitrophenyl)-4-oxobutanoic acid EXAMPLE A354-(4-chloro-3-nitrophenyl)-4-oxobutanoic acidWhile cooling externally with a mixture of ice and common salt, 21.3 g (0.1 mol) of 4-(4-chlorophenyl)-4-oxobutanoic acid were added batchwise to 100 ml of fuming nitric acid in such a way that the temperature of the mixture did not exceed 0° C. The mixture was stirred for another 1 hour at an internal temperature of between -5 and 0° C., then stirred into 1 l of ice water, after ½ hour the precipitate was collected on a filter, thoroughly washed with water until free from acid, and the crystalline product was dried in a circulating air dryer. 23.4 g (91% of theoretical) of pale yellow crystals were obtained. |
With nitric acid at -7 - -5℃; for 4h; | 1.a.A.1 Fuming nitric acid (1.5 L) is cooled to about -5°C in an ice/salt bath. Over a period of 30 minutes, 4-(4-chloro-phenyl)-4-oxo-butyric acid (150 g) is added in portions to the mechanically stirred solution, and the reaction mixture is stirred at the temperature between about -50C and about - 7°C for 3.5 hours. The reaction mixture is poured onto crushed ice/water (3 L) and stirred overnight at room temperature. The solid material is filtered, washed with water until the washes are neutral, air EPO 5Qdried, and finally dried in a vacuum oven at about 850C to afford 4-r4-chloro-3-nitro-phenylV4-oxo- butyric acid as a solid (159.1 g). | |
With nitric acid at -7 - -5℃; for 4h; | 1.a.1 EXAMPLESExample 1 :(a) {2-r4-Chloro-3-(2,4-dichloro-benzylsulfamoyl)-phenyll-lH-indol-3-vU -acetic acid;Step 1;. Fuming nitric acid (1.5 L) is cooled to about -50C in an ice/salt bath. Over a period of 30 minutes, 4-(4-chloro-phenyl)-4-oxo-butyric acid (150 g, 0.706 mol) is added in portions to the mechanically stirred solution, and the reaction mixture is stirred at the temperature between about -50C and about -7°C for 3.5 hours. The reaction mixture is poured onto crushed ice/water (3 L) and stirred overnight at room temperature. The solid material is filtered, washed with water until the washes are neutral, air dried, and finally dried in a vacuum oven at about 850C to afford 4-(4-chloro-3-nitro-phenvD-4-oxo-butyric acid as a solid (159.1 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With potassium hydroxide; hydrazine hydrate; In dichloromethane; water; diethylene glycol; | 4-(p-chlorophenyl)butanoic acid (35a). A mixture of 3-(4-chlorobenzoyl) propionic acid (34) (2.50 g, 12.0 mmol), KOH (s) (1.75 g, 31.2 mmol), and hydrazine monohydrate (1.25 mL, 25.8 mmol) in 12.5 mL of diethylene glycol was refluxed azeotropically at 120-130 C. for 90 min to remove water. The reaction mixture was then refluxed at 170 C. for 3 h, cooled to RT, diluted with 12.5 mL of water, and poured into 15 mL 2.5 N HCl(aq). The precipate was filtered off, dissolved in CH2Cl2, and the solvent removed to give 35a (2.23 g, 96%) as a white solid. UV lambdamax 223 (8980, 95% ETHANOL); 1H NMR (400 MHz, CDCl3) delta 7.26 (d, J=7 Hz, 2H), 7.12 (d, J=8 Hz, 2H), 2.66 (t, J=4 Hz, 2H), 2.38 (t, J=4 Hz, 2H), 1.96 (m, 2H); 13C NMR (CDCl3) delta 179.3, 140.0, 132.2, 130.2, 128.9, 34.7, 33.4, 26.4; IR (drift) 3063 (s), 3051 (s), 2955 (s), 2923 (s,b), 2905 (s), 2814, 2797, 2493 (b), 2466, 2413, 2367 (b), 2321, 1706 (s), 1492 (s), 1212 (s), cm-1; MS (EI) m/z (rel. intensity) 198 (M+, 22), 200 (7), 198 (22), 140 (32), 139 (17), 138 (99), 127 (15), 125 (48), 103 (10), 89 (13), 60 (9); HRMS (EI) calcd for 198.0448, found 198.0441. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydroxide; hydrazine hydrate In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; water; 2,2'-[1,2-ethanediylbis(oxy)]bisethanol | 1.e 4-Chlorophenylbutyric acid [Formula VI: R1 =R2 =R3 =H; R =Cl] EXAMPLE 1e 4-Chlorophenylbutyric acid [Formula VI: R1 =R2 =R3 =H; R =Cl] 4-Chlorobenzoyl propionic acid [Formula VII: R1 =R2 =R4 =H; R3 =Cl] (49.94 g, 234.9 mM) was dissolved under nitrogen in 320 mL of triethylene glycol. To the stirred room temperature solution was added potassium hydroxide (44.5 g, 794 mM) followed by 98% hydrazine hydrate (29.0 g, 580.0 mM). The mixture was heated to reflux temperature (142° C.) for 2 hours. Water and hydrazine hydrate were distilled off at atmospheric pressure; the pot temperature rose to 195°-200° C. After 0.5 hours at 195°-200° C., the mixture was cooled to ambient temperature and diluted with 320 mL of water. The aqueous solution was poured into hydrochloric acid (200 mL, 6N) and further diluted with 200 mL of ice water. Upon standing a solid formed which was filtered off, washed with water and vacuum dried (25° C., 15 Pa) to render 43.61 g (93%) of white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrazine; In ethanol; | 6-(4-Chlorophenyl)pyridazin-3-one Hydrazine (8.9 mL, 0.28 mol) was added to a suspension of 3-(4-chlorobenzoyl)propionic acid (30.0 g, 0.14 mol) in EtOH. The resulting mixture was heated to reflux for 1 hour, stirred at room temperature overnight and chilled with an ice bath. The title compound precipitated out of this mixture (23.85 g, 81%) as a yellow solid: mp 175-176 C. The following pyridazin-3-ones listed in Table 1 were prepared essentially by the above procedure, using the appropriate starting materials. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; sodium hydroxide In water; toluene | 1.1 Step 1: Step 1: 2-(2-hydroxy-3-methylbutyl)-6-(p-chlorophenyl)-4,5-dihydro-3(2H)-pyridazinone A mixture of 9.5 grams (0.085 mol) of 1-hydrazino-3-methyl-2-butanol, 14.4 grams (0.070 mol) of 3-(p-chlorobenzoyl)-propanoic acid and 100 milliliters of toluene are stirred in a flask equipped with a condenser and Dean-Stark water collecting apparatus at reflux for about 2.0 hours during which 2.8 milliliters of water is collected in the Dean-Stark tube. The toluene solution is washed with 50 milliliters of 2 N sodium hydroxide solution, 25 ml. of 2 N hydrochloric acid and then water. The toluene layer is then dried with anhydrous magnesium sulfate, filtered and concentrated in vacuo. The solid obtained is crystallized from methylene chloride-petroleum ether to yield 19.0 grams of 2-(2-hydroxy-3-methylbutyl)-6-(p-chlorophenyl)4,5-dihydropyridazine-3(2H)-one, (m.p. 90°-92° C.) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With N-Bromosuccinimide at 70℃; for 20h; | 3.2.1. General Procedure for the Esterification between Carboxylic Acids and Alcohols General procedure: The mixture of carboxylic acid, alcohol and N-bromosuccinimide was stirred in a 25 mL reactortube at 70 °C for 2-40 h. After the completion of the reaction, the mixture was cooled to roomtemperature and alcohol was evaporated under reduced pressure. The isolation procedure was as follows, except where noted differently in Section 3.2.6. The residue was dissolved in ethyl acetate andconsecutively washed with 10 mL of 10% Na2S2O3 (aq), 5 mL of saturated NaHCO3 (aq) and 10 mL ofdistilled water. The water phase was extracted with ethyl acetate (3Χ5 mL). The organic layers were combined, dried over Na2SO4 and the solvent was evaporated under reduced pressure. |
99% | With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione at 70℃; for 20h; | 3.2.1. General Procedure for the Esterification between Carboxylic Acids and Alcohols General procedure: The mixture of carboxylic acid, alcohol, and 1,3-dibromo-5,5-dimethylhydantoin was stirredin a 25 mL reactor tube at 70 °C for 2-40 h. After reaction completion, the mixture was cooled toroom temperature and the alcohol was evaporated under reduced pressure. The isolation procedurewas as follows, except where noted dierently in the Supporting Information. The residue wasdissolved in 10 mL ethyl acetate and washed with a mixture of 1 mL saturated NaHCO3(aq), 1 mLsaturated Na2S2O3(aq), and 10 mL distilled water, and the water phase was extracted with ethyl acetate(2 10 mL). The organic layers were combined, dried over Na2SO4, and the solvent was evaporatedunder reduced pressure |
96% | With sulfuric acid for 0.025h; microwave irradiation; |
94% | With sulfuric acid for 18h; Reflux; | |
94% | With acetyl chloride at 20℃; for 12h; | |
92% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; for 24h; | |
With acetyl chloride at 0 - 20℃; | ||
With sulfuric acid Reflux; | ||
With sulfuric acid for 2h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a mixture of 3-(4-chlorobenzoyl)propionic acid (31.9 g, 150 mmol), DMF (200 ml), and N-hydroxybenzotriazole (40.6 g, 301 mmol) was added a solution of N-ethyl-/V-(3-dimethylaminopropyl)carbodiimide hydrochloride (28.8 g, 150 mmol) in DMF (100 ml). The mixture was stirred at room temperature for 1.5 hour, and a solution of <strong>[21043-40-3]1-cyclopentylpiperazine</strong> (23.2 g, 150 mmol) in DCM (100 ml) was added. The mixture was stirred at room temperature for 4 hours, concentrated under reduced pressure, and the residue was distributed between ethyl acetate (1.0 I) and a saturated, aqueous NaHCO3 solution (1.0 I). Phases were separated, the organic layer was dried (MgSO4), and concentrated, and the residue was redissolved in 1 molar aqueous hydrochloric acid (150 ml). The solution was concentrated, and the residue was dried by coevaporation with ethanol. Recrystallization of the residue from ethanol yielded 31.1 g (54%) of the title compound. Concentration of the mother liquor gave additional 19.4 g (34%) of product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0℃; for 2h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With hydrogenchloride In xylene for 12h; Reflux; | To a solution of 3-(4-chlorobenzoyl)propionic acid (4Og, 190mnnol) in xylene (25OmL) were added ethylenediamine (22.6g, 376mol), and 12M hydrochloric acid (0.50OmL, 6mmol). The reaction mixture was stirred at reflux under Dean- Stark for 12h, and cooled to RT. The solid was collected by filtration and washed with xylene to give the crude residue. This was dissolved in DCM (400ml) and filtered. The filtrate was concentrated in vacuo to give 36.6g (62%) of the racemic title compound as a beige solid.1H NMR (400 MHz, CD3CI) 5 2.22 -2.35 (2H, m), 2.49-2.56 (1 H, m), 2.78-2.95 (3H, m), 3.27-3.34 (1 H, m), 3.68-3.77 (1 H, m), 7.32-7.35 (2H, m), 7.42-7.46 (7.42-7.46 (2H, m). LRMS: APCI+ m/z 237 [MH+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | Stage #1: 4-(4-chlorophenyl)-4-oxobutanoic acid; aniline With dmap; dicyclohexyl-carbodiimide In tetrahydrofuran at 0℃; for 0.5h; Stage #2: In tetrahydrofuran at 20℃; | General procedure: The generalprocedure for the preparation of compounds (4a-c-5a-c): an appropriate acid 2a-b (1 equiv, 10 mmol),and 4-dimethylamioprdine (0.02 equiv, 0.2 mmol) was added to a solution of the furfuryl alcoholor aniline (1 equiv, 10 mmol) in THF (20 mL). The mixture was stirred and cooled to 0 °C andthen N,N-dicyclohexylcarbodiimide (DCC) (1.1 equiv, 11 mmol) was added over a 5-min period andthe reaction was stirred under anhydrous conditions for 6-8 h at room temperature. The mixturewas filtered and the filtrate was evaporated to yield a crude product which was finally purified byrecrystallization to give 4a, 4b, 4c, 5a, 5b and 5c as crystals [38-43]. |
With N-ethyl-N,N-diisopropylamine; HATU In dichloromethane at 20℃; for 0.333333h; | ||
With dmap; dicyclohexyl-carbodiimide; calcium chloride In tetrahydrofuran at 20℃; for 1h; | 7.2 2) Weigh 1O of 4-oxo-4- (4-chlorophenyl) butanoic acid prepared in Example (1)5% 4-dimethylaminopyridine To a 100 mL single-necked round bottom flask, 20 mL of tetrahydrofuran was added, and a dry tube containing CaCl2 was charged, stirred for 10 min in an ice bath, 1 l mmol of dicyclohexylcarbodiimide was added in portions, End, continue to ice bath for 0.5h, room temperature, TLC detection, 6h after the reaction without raw materials, add lmL water to continue to stir (remove the excess dicyclohexyl carbodiimide), lmin after the reaction. The filtrate was distilled off under reduced pressure to remove the solvent. After adding 50 mL of water, the mixture was extracted with ethyl acetate (3X 50 mL). The organic layers were combined and washed successively with water (3 X 20 mL), saturated brine ( 3 X 20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure and concentrated under reduced pressure. The product was recrystallized from EtOH / H2. To give white crystals N-phenyl-4-oxo-4- (4-chlorophenyl) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With sodium carbonate In ethanol at 80℃; for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With sulfuric acid at 20℃; | |
97% | With sulfuric acid In water for 16h; Reflux; | 1 Step 1: Synthesis of Ethyl 4-(4-chlorophenyl)-4-oxobutyrate (31) Into a dry 250 mL round-bottom flask, compound 30 (3 g, 14.15 mmol), 98% concentrated sulfuric acid (4 g,42.45 mmol) and ethanol (20mL) were sequentially added at RT. The mixture was heated to reflux under stirring for 16hours. The mixture was cooled to RT, and concentrated under reduced pressure. 50 mL water was added to the residue,and the mixture was extracted with ethyl acetate (30mL33). The combined organic phase was dried over anhydrousNa2SO4 and filtered. The filtrate was concentrated under reduced pressure to yield ethyl 4-(4-chlorophenyl)-4-oxobutyrate(31) (3.3 g, white solid), yield: 97%. LCMS: m/z 240.06, 262.9 (M+Na). |
94% | With toluene-4-sulfonic acid Reflux; | General procedure: The general procedure for the preparation of compounds (3a, 3b and 3c): a mixture of theappropriate acid 2a-c (1 equiv, 10 mmol) and p-toluenesulfonic acid (0.4 equiv, 4 mmol) in EtOH(20 mL) was refluxed for 6-8 h and evaporated to remove EtOH. The residue was suspended in H2O(30 mL) and extracted with EtOAc (2 x 50 mL) which was further purified by column chromatographyon silica gel eluting with AcOEt-petroleum ether (1:4, v/v) to get 3a-c as crystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine at 20℃; for 5h; | 4.1.4 Typical procedure for the conjugation reaction. 2-(6-Methoxy-2,3-dihydro-1H-inden-1-yl)-N-(4-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl)butyl)acetamide (6) General procedure: Compound 4 (30mg, 0.13mmol) was mixed with diisopropyl ethylamine (22.6μL, 0.13mmol), HBTU (49mg, 0.13mmol), and carboxylic acid (26.8mg, 0.13mmol) and the reaction was stirred at rt for 5h. After the mixture was concentrated, the crude sample was directly purified by CC (5-10% NH4OH in propanol, silica gel) to give 6 as a colorless oil (18.2mg, 0.043mmol, 33%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | In ethanol Reflux; | 4.1.2 General procedure for the synthesis of pyridazinones (2a-p) General procedure: A mixture of the appropriate aroylpropionic acid (1a-p) (0.001 mol) and (p-(methanesulfonyl)phenylhydrazine) (0.001 mol) in absolute ethanol (20-30 ml) was refluxed for 10-12 h. The reaction mixture was concentrated to one-third of its volume and left at room temperature, when a solid separated out. The crude product was filtered off, washed with a small volume of alcohol, and stirred with 5% sodium bicarbonate solution (25 ml). It was filtered, and washed with 2% acetic acid and then with water. The product was dried and recrystallized from the appropriate solvent to give pure compounds 2a-p. The solvent system used for TLC was toluene:ethyl acetate:formic acid (5:4:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With water; formamide at 160℃; for 5h; Autoclave; Green chemistry; | |
Multi-step reaction with 2 steps 1.1: triethylamine; dmap / dichloromethane / 18 h / 0 - 25 °C 2.1: ammonium acetate / methanol / 1 h / 25 °C 2.2: 18 h / Reflux | ||
Multi-step reaction with 2 steps 1.1: triethylamine / dichloromethane / 0.25 h / 0 °C / Inert atmosphere 1.2: 18 h / 25 °C / Inert atmosphere 2.1: ammonium acetate / methanol / 1 h / 25 °C 2.2: 18 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With dmap; triethylamine In dichloromethane at 0 - 25℃; for 18h; | 2.1 Step 1: Intermediate L Step 1: Intermediate L [0064] To a suitably substituted phenyl-4-oxobutanoic acid K (84.71 mmol) in DCM (180 mL) was added triethylamine (10.3 g, 0.102 mol) and cooled to 0 °C. Ethyl chloroformate (12.9 g, 0.118 mol) was added dropwise, with stirring, over 15 minutes, followed by DMAP (2.1 g, 16.9 mmol), after 18 hours at 25 °C the reaction mixture was extracted with of water (3 × 50mL). The organic phase was washed with brine, dried (MgSO4) and concentrated down under reduced pressure to afford the phenyl 4-oxobutanoate ester L. For example, ethyl 4-(4-chlorophenyl)-4-oxobutanoate was isolated in 89% yield. 1H NMR δ (ppm)(CHCl3-d): 7.92 (2 H, d), 7.45 (2H, d), 4.18 (2H, q), 3.28 (2H, d), 2.76 (2H, d), 1.28 (3H, t). LC/MS (M+H)+ 241 |
89% | Stage #1: 4-(4-chlorophenyl)-4-oxobutanoic acid; chloroformic acid ethyl ester With triethylamine In dichloromethane at 0℃; for 0.25h; Inert atmosphere; Stage #2: With dmap In dichloromethane at 25℃; for 18h; Inert atmosphere; | 2.1 Step 1: Intermediate L General procedure: To a suitably substituted phenyl-4-oxobutanoic acid K (84.71 mmol) in DCM (180 mL) was added triethylamine (10.3 g, 0.102 mol) and cooled to 0 °C. Ethyl chloroformate (12.9 g, 0.1 18 mol) was added dropwise, with stirring, over 15 minutes, followed by DMAP (2.1 g, 16.9 mmol), after 18 hours at 25 °C the reaction mixture was extracted with of water (3 χ 50mL). The organic phase was washed with brine, dried (MgS04) and concentrated down under reduced pressure to afford the phenyl 4-oxobutanoate ester L. For example, ethyl 4-(4- chlorophenyl)-4-oxobutanoate was isolated in 89% yield. NMR δ (ppm)(CHCl3-d): 7.92 (2 H, d), 7.45 (2H, d), 4.18 (2H, q), 3.28 (2H, d), 2.76 (2H, d), 1.28 (3H, t). LC/MS (M+H)+ 241 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Stage #1: 4-(4-chlorophenyl)-4-oxobutanoic acid; thiosemicarbazide With montmorillonite KSF In ethanol for 0.7h; Reflux; Stage #2: 2-bromo-1-(4'-hydroxyphenyl)-1-ethanone In ethanol for 0.2h; Reflux; regioselective reaction; | General Procedure for the Synthesis of 2-(Thiazol-2-yl)-4,5-dihydropyridazin-3(2H)-one General procedure: Absolute EtOH (20 mL), ketoacid (10 mmol), 0.2 g activated KSF, and thiosemicarbazide(10 mmol) were added to a 100-ml round-bottom flask equipped withcondenser and magnetic stir bar. The reaction mixture was refluxed for the requiredreaction time (about 7 h). The progress of reaction was monitored by thin-layer chromatography(TLC) (EtOAc-petroleum ether 2:1). After completion of the reaction,phenacyl bromide (10 mmol) was added and refluxed for the required reaction time(about 2 h). The progress of the reaction was monitored by TLC (EtOAc-petroleumether 1:2). The catalyst was removed by filtration. The reaction solution was cooledto rt. The product was isolated by filtration and purified by washing with EtOH. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Stage #1: 4-(4-chlorophenyl)-4-oxobutanoic acid; thiosemicarbazide With montmorillonite KSF In ethanol for 0.7h; Reflux; Stage #2: 2-Bromo-4'-methoxyacetophenone In ethanol for 0.2h; Reflux; regioselective reaction; | General Procedure for the Synthesis of 2-(Thiazol-2-yl)-4,5-dihydropyridazin-3(2H)-one General procedure: Absolute EtOH (20 mL), ketoacid (10 mmol), 0.2 g activated KSF, and thiosemicarbazide(10 mmol) were added to a 100-ml round-bottom flask equipped withcondenser and magnetic stir bar. The reaction mixture was refluxed for the requiredreaction time (about 7 h). The progress of reaction was monitored by thin-layer chromatography(TLC) (EtOAc-petroleum ether 2:1). After completion of the reaction,phenacyl bromide (10 mmol) was added and refluxed for the required reaction time(about 2 h). The progress of the reaction was monitored by TLC (EtOAc-petroleumether 1:2). The catalyst was removed by filtration. The reaction solution was cooledto rt. The product was isolated by filtration and purified by washing with EtOH. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In dichloromethane at 0℃; for 0.166667h; Inert atmosphere; | 1 4.3. General procedure 2 for synthesis of thioesters General procedure: A flame-dried flask was charged with 4-cyanobenzoic acid (5.8 mmol, 1 equiv) and CH2Cl2 (12 mL). The reaction was cooled to 0 °C and isobutyl chloroformate (6.38 mmol, 1.1 equiv) and Et3N (5.8 mmol, 1 equiv) were added dropwise. The resulting mixture was stirred vigorously for 10 min under N2, after which time Et3N (5.8 mmol, 1 equiv) and thiophenol (12.76 mmol, 2.2 equiv) were added dropwise. The reaction was stirred at 0 °C under N2 for 1 h. The reaction was warmed to room temperature and washed with 1 M HCl, water, 1 M NaOH, water, and brine. The combined aqueous layers were extracted with CH2Cl2. The combined organic layers were dried (MgSO4), filtered, and concentrated. The crude residue was purified by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II); sodium carbonate In 1,4-dioxane; water at 150℃; for 0.166667h; Sealed tube; Microwave irradiation; | 1.37 Example 1.37: Preparation of (R)-4-(4’-(2-(2-Methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)-4- oxobutanoic Acid (Compound 36). To a 2 mL heavy-walled tube was added (R)-4-(2-(2-methylpyrrolidin- 1- yl)ethyl)phenylboronic acid hydrochloride (127 mg, 0.471 mmol), 4-(4-chlorophenyl)-4-oxobutanoic acid (91 mg, 0.428 mmol), Na2CO3 (136 mg, 1.284 mmol), dichlorobis(p-dimethylaminophenyldi-tertbutylphosphine)palladium (3.03 mg, 4.28 tmol), dioxane (1 mL), and water (0.15 mL). The tube was sealed and heated to 150 °C for 10 mm under microwave irradiation. The mixture was purified bypreparative HPLC to give the title compound as a white solid. LCMS m/z = 366.1 [M+H] ‘H NMR(400 MHz, DMSO-d6) ö ppm 1.20 (d, J= 6.3 Hz, 0.4 H), 1.37 (d, J= 6.3 Hz, 2.6 H), 1.54-1.65 (m. 1H),1.90-2.05 (m, 2H), 2.18-2.26 (m, 1H), 2.62 (t, J= 7.8 Hz, 2H), 2.95-3.10 (m, 2H), 3.16-3.30 (m, 3H),3.38-3.68 (m, 4H), 7.46 (d, J= 8.2 Hz, 2H), 7.74 (d, J= 8.2 Hz, 2H), 7.84 (d, J= 8.2 Hz, 2H), 8.06 (d,J= 8.2 Hz, 2H), 9.34 (bs, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With sulfuric acid for 6h; Reflux; | 15.1 Preparation of isopropyl 4-(4-chlorophenyl)-4-oxobutanoate Preparation of isopropyl 4-chlorophenyl-4-oxobutanoate 50 g (235 mmol) of 4-chlorophenyl-4-oxobutanoic acid were solubilized in 300 ml of isopropanol, 0.63 ml (11.76 mmol) of sulfuric acid were added to this solution. The mixture was refluxed with heating for 6 d with magnetic stirring. After returning to r.t., the mixture was concentrated in vacuo, the crude residue was directly purified by flash chromatography on a silica gel cartridge (eluent: 100% dichloromethane). 59.83 g (yield=>99%) of isopropyl 4-chlorophenyl-4-oxobutanoate were obtained as a colorless oil. LC-MS: m/z=255 (MH+) UV purity at 254 nm=95%. 1H NMR (300 MHz, DMSO) δ 8.13-7.85 (m, 2H), 7.70-7.47 (m, 2H), 4.86 (dt, J=12.5, 6.3 Hz, 1H), 3.29-3.22 (m, 2H), 2.65-2.54 (m, 2H), 1.16 (d, J=6.3 Hz, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With Dimethylphenylsilane; iodine; indium(III) acetate In chloroform at 60℃; for 24h; Inert atmosphere; Sealed tube; | General preparation of tetralin derivatives: General procedure: Freshly distilled chloroform (0.6 mL)was placed into a screw-capped vial under N2, and a magnetic stirrer bar, In(OAc)3(0.0060 mmol, 1.8 mg), I2 (0.600 mmol, 152 mg), a carboxylic acid (0.6 mmol), andMe2PhSiH (3.90 mmol, 600 μL) were successively added. The vial was sealed with acap that contained a PTFE septum. The reaction vial was heated in an oil bath, and thereaction was monitored by GC and TLC until the ester had been completely consumed.After the reaction was complete, the mixture was cooled to room temperature, and wasquenched with HCl aqueous solution (2 mL). The aqueous layer was extracted withhexane (5 mL x 3). The combined organic phases were dried with anhydrous Na2SO4,and the solvent was evaporated under reduced pressure. The crude product was purifiedby silica gel column chromatography (hexane) to give the corresponding tetralinderivatives. If necessary, further purification was performed by gel permeationchromatography (eluent: CHCl3). |
Multi-step reaction with 3 steps 1: hydrazine hydrate; potassium hydroxide / ethylene glycol / 5 h / 130 °C / Reflux 2: polyphosphoric acid / 3 h / 90 °C 3: trifluoroacetic acid; triethylsilane / 0 - 35 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | With Dimethylphenylsilane; iodine; indium(III) acetate In chloroform at 60℃; for 5h; Inert atmosphere; Sealed tube; | General preparation of tetralin derivatives: General procedure: Freshly distilled chloroform (0.6 mL)was placed into a screw-capped vial under N2, and a magnetic stirrer bar, In(OAc)3(0.0060 mmol, 1.8 mg), I2 (0.600 mmol, 152 mg), a carboxylic acid (0.6 mmol), andMe2PhSiH (3.90 mmol, 600 μL) were successively added. The vial was sealed with acap that contained a PTFE septum. The reaction vial was heated in an oil bath, and thereaction was monitored by GC and TLC until the ester had been completely consumed.After the reaction was complete, the mixture was cooled to room temperature, and wasquenched with HCl aqueous solution (2 mL). The aqueous layer was extracted withhexane (5 mL x 3). The combined organic phases were dried with anhydrous Na2SO4,and the solvent was evaporated under reduced pressure. The crude product was purifiedby silica gel column chromatography (hexane) to give the corresponding tetralinderivatives. If necessary, further purification was performed by gel permeationchromatography (eluent: CHCl3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: Methyltriphenylphosphonium bromide With potassium hexamethylsilazane In tetrahydrofuran; toluene at 0℃; for 1h; Stage #2: 4-(4-chlorophenyl)-4-oxobutanoic acid In tetrahydrofuran; toluene at -78 - 20℃; | |
61% | Stage #1: Methyltriphenylphosphonium bromide With potassium <i>tert</i>-butylate In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; Stage #2: 4-(4-chlorophenyl)-4-oxobutanoic acid In tetrahydrofuran at 0℃; Inert atmosphere; | |
Stage #1: Methyltriphenylphosphonium bromide With sodium t-butanolate In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; Stage #2: 4-(4-chlorophenyl)-4-oxobutanoic acid In tetrahydrofuran at 0 - 20℃; for 17h; Inert atmosphere; |
Stage #1: Methyltriphenylphosphonium bromide With potassium <i>tert</i>-butylate In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; Stage #2: 4-(4-chlorophenyl)-4-oxobutanoic acid In tetrahydrofuran at 0 - 20℃; for 16h; Inert atmosphere; | Synthesis of compounds S2a-h General procedure: In an oven dried 250 mL round bottom flask was added at 0 °C potassium tert-butoxide (3 equiv, 5.27 g, 47.0 mmol) in a suspension of methyltriphenylphosphonium bromide (2 equiv, 11.2 g, 31.3 mmol) in THF (70 mL) in an atmosphere of argon. The mixture was the stirred for 30 min. The acid S1 (1 equiv) was then added to the reaction mixture at 0 °C. The mixture was allowed to warm to room temperature, and was then stirred for 16 h. After evaporation of THF, the crude product was diluted with 1 N NaOH (50 mL). The aqueous layers was washed with dichloromethane. The aqueous layer was treated with 12N HCl until pH=2, extracted with dichloromethane and dried under Na2SO4. The product S2 was used in the next step without further purification. | |
Stage #1: Methyltriphenylphosphonium bromide With sodium t-butanolate In tetrahydrofuran at 0℃; for 0.5h; Stage #2: 4-(4-chlorophenyl)-4-oxobutanoic acid In tetrahydrofuran at 0 - 20℃; for 16h; | ||
Stage #1: Methyltriphenylphosphonium bromide With sodium t-butanolate In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; Schlenk technique; Stage #2: 4-(4-chlorophenyl)-4-oxobutanoic acid In tetrahydrofuran at 0 - 20℃; for 17h; Inert atmosphere; Schlenk technique; | ||
Stage #1: Methyltriphenylphosphonium bromide With potassium <i>tert</i>-butylate In tetrahydrofuran at 20℃; for 2h; Inert atmosphere; Stage #2: 4-(4-chlorophenyl)-4-oxobutanoic acid In tetrahydrofuran Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With triethylamine In ethanol for 6h; Reflux; | 1-1.1 Step 1: Preparation of ethyl 2-[3-(4-chlorophenyl)-6-oxo-4,5-dihydropyridazin-l- yl] acetate Step 1: Preparation of ethyl 2-[3-(4-chlorophenyl)-6-oxo-4,5-dihydropyridazin-l- yl] acetate To a mixture of 4-(4-dichlorophenyl)-4-oxo-butanoic acid (4.25 g, 20.0 mmol, Aldrich, catalog number: 439924- 100G) and ethyl hydrazinoacetate hydrochloride (3.1 g, 20.0 mmol, Aldrich, Catalog number: 128279) in ethanol (28 mL) was added triethylamine (2.8 mL, 20.0 mmol). The mixture was heated with stirring under reflux for 6 hours. The resulting mixture was concentrated under vacuum and to the residue was added water (50 mL). The resulting mixture was extracted with ethyl acetate (50 mL) three times and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum and the residue was purified by column chromatography to afford ethyl 2-[3-(4-chlorophenyl)-6- oxo-4,5-dihydropyridazin-l-yl] acetate (4.5 g, 76 %). MS obsd. (ESI+) [(M+H)+]: 295. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; dicyclohexyl-carbodiimide In tetrahydrofuran at 20℃; | 15.2 15 mmol of 4-(4-chlorophenyl)-4-oxobutyric acid prepared in step (1) was addedAnd (15 mmol) of 3,4-methylenedioxybenzyl alcohol were dissolved in 100 ml of tetrahydrofuran,N, N'-dicyclohexylcarbodiimide (DCC, 15 mmol) was added successively,4-dimethylaminopyridine (0.25 g),The reaction was stirred at room temperature overnight.After stopping the reaction,Adding 1 mL of distilled water to decompose unreacted DCC,Stirring for 0.5 hours,The insoluble matter was removed by filtration,After the filtrate was evaporated to dryness, methylene chloride was added,The organic phase was washed successively with saturated sodium bicarbonate solution (2 x 30 mL)Distilled water (30 mL),Saturated sodium chloride solution (30 mL)Dried over anhydrous sodium sulfate.The solvent was distilled off under reduced pressure,The crude product was subjected to column chromatography [V (petroleum ether) :V (ethyl acetate) = 4] to give 4-(4-chlorophenyl)-4-oxobutanoic acid-3,4-methylenedioxybenzyl ester. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: (2-furyl)methyl alcohol; 4-(4-chlorophenyl)-4-oxobutanoic acid With dmap; dicyclohexyl-carbodiimide In tetrahydrofuran at 0℃; for 0.5h; Stage #2: In tetrahydrofuran at 20℃; | General procedure: The generalprocedure for the preparation of compounds (4a-c-5a-c): an appropriate acid 2a-b (1 equiv, 10 mmol),and 4-dimethylamioprdine (0.02 equiv, 0.2 mmol) was added to a solution of the furfuryl alcoholor aniline (1 equiv, 10 mmol) in THF (20 mL). The mixture was stirred and cooled to 0 °C andthen N,N-dicyclohexylcarbodiimide (DCC) (1.1 equiv, 11 mmol) was added over a 5-min period andthe reaction was stirred under anhydrous conditions for 6-8 h at room temperature. The mixturewas filtered and the filtrate was evaporated to yield a crude product which was finally purified byrecrystallization to give 4a, 4b, 4c, 5a, 5b and 5c as crystals [38-43]. |
With dmap; dicyclohexyl-carbodiimide In tetrahydrofuran at 20℃; for 7h; Cooling with ice; | 28.2 10 mmol of 4- (4-chlorophenyl) -4-carbonylbutyric acid prepared in step (1)10 mmol of 2-furanylmethanol,5% 4-dimethylaminopyridine in a 100 mL single-necked round bottom flask,20 mL of tetrahydrofuran was added,Equipped with CaCl2 drying tube,Ice bath for 10min,11 mmol of dicyclohexylcarbodiimide was added in portions,20min plus finished,After stirring for 0.5 hours,Stir at room temperature,TLC detection,After 6 hours of reaction, 1 mL of water was added to continue stirring (removal of excess dicyclohexylcarbodiimide)10min after stopping the reaction.The white solid dicyclohexylurea formed during the reaction was removed by filtration,The filtrate was distilled under reduced pressure to remove the solvent and 50 mL of water was added,Ethyl acetate extraction (3 x 50 mL),Combined organic layer,And sequentially washed with water (3 x 20 mL)Saturated brine (3 x 20 mL)Dried over anhydrous sodium sulfate,Concentrated under reduced pressure,By silica gel column chromatography,The mobile phase consisted of a petroleum ether having a boiling point of 60-90 ° C: a solvent having a volume ratio of ethyl acetate of 4: 1,To elute,To give 4-(4-chlorophenyl)-4-oxobutyric acid-2-furylmethyl ester as white crystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.5% | With toluene-4-sulfonic acid In dichloromethane for 4h; Reflux; | General procedure: Preparation of Cyclohexyl 4-(4-substituted phenyl) -4-oxobutanoates (3) Compound 2 (2A, 2B, 2C,2D, 15 mmol) reacted with cyclohexanol (30 mmol) in CH2Cl2 (20 mL) with p-methylbenzenesulfonicacid (TsOH) (2g, 11.6 mmol) under refluxing for 4 h (Scheme 1). After stopping, the resultant solutionwas washed with icy aqueous sodium bicarbonate solution (3%, 15 mL) for three times, then the organicsolution was dried with anhydrous sodium sulfate evaporated to give crude product. This crudeproduct was puried by ash column chromatography eluting with an eluent of ethyl acetate /petroleumether (1:7 v/v) to aord 3A, 3B, 3C, and 3D, respectively. |
With toluene-4-sulfonic acid In dichloromethane at 60℃; for 4h; | 4.2 15 mmol of 4-(4-chlorophenyl)-4-oxobutyric acid prepared in Example (1) was addedAnd 2 g of p-toluenesulfonic acid were dissolved in 20 mL of dichloromethane,Heated to 60 ° C,Reflux,30 mmol of cyclohexanol was added.60 constant temperature magnetic stirring reflux 4 hours.Upon detection of the reaction,Drying methylene chloride under reduced pressure,After washing with deionized water,Ethyl acetate (20 mL x 3)The combined organic layers were dried over anhydrous sodium sulfate,The solvent was distilled off under reduced pressure,Get crude.The crude product was subjected to column chromatography [V (petroleum ether): V (ethyl acetate) = 6: 1]To give 4-(4-chlorophenyl)-4-oxobutyric acid cyclohexyl ester. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 20℃; for 24h; | Preparation of library1,2 General procedure: In each 200 μL well of a microtiter plate, a mixture of diisopropyl ethylamine (5.0 μL, 180.0 mM solution in DMSO), HBTU (5 μL, 90 mM solution in DMSO), a carboxylic acid (10.0 μL, 30.0 mM solution in DMSO) and a scaffold (compound 3) (10.0 μL, 30.0 mM solution in DMSO) was shaken at rt for 24 h and analyzed by ESI-MS (or TLC) to verify the presence of the desired product. Each reaction mixture was diluted with H2O and transferred to another 96-well microtiter plate to make a 20 mM solution per each desired molecule (based on 100% conversion of amine) for the enzymatic assay directly without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | Stage #1: 4-(4-chlorophenyl)-4-oxobutanoic acid With pivaloyl chloride; triethylamine In dichloromethane at 0℃; for 1h; Inert atmosphere; Stage #2: N,O-dimethylhydroxylamine*hydrochloride In dichloromethane at 25℃; for 6h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With sodium hydroxide at 80℃; for 36h; | 3 Example 3 Preparation of 2-(4-chlorophenyl)-3-carboxymethyl-quinoline-4-carboxylic acid A concentration of 30% of 0.6 mol of sodium hydroxide solution was added to the reaction flask, 0.12 mol of eosin and 0.1 mol of 3-(4-chlorobenzoyl)propionic acid were added thereto, and the mixture was heated to 80 ° C for reflux for 36 h. The end point of the reaction was monitored by thin layer chromatography. After the reaction was completed, the reaction product was poured into water 10 times the volume of the reactant, and the pH was adjusted to 2 with concentrated hydrochloric acid. A large amount of solid was precipitated and dried by suction filtration to obtain a brown solid powder 2- (4-Chlorophenyl)-3-carboxymethyl-quinoline-4-carboxylic acid having the formula: C18H12NO4Cl, molecular weight 342, yield 70-81%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.916 g | With lithium aluminium hydride In tetrahydrofuran at 0 - 20℃; for 1h; Inert atmosphere; | |
With lithium aluminium hydride In diethyl ether at 0 - 27℃; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86 %Chromat. | In water at 180℃; for 2.15h; Sealed tube; | 2 Example 2 Synthesis of 5-(4-chlorophenyl)-2-pyrrolidone 2 mmol of 3-(4-chlorobenzoyl)propionic acid, 20 mmol of formamide and 80 mmol of water were placed in a 15 mL polytetrafluoroethylene-lined stainless steel reaction vessel. The sealed reaction kettle was placed in an oil bath that had been heated to a predetermined temperature (180 ° C), and reacted at 500 r / min for 120 min. The reaction vessel was taken out and cooled to room temperature with tap water. Add 13 mL of methanol to the reaction kettle. The yield of 5-(4-chlorophenyl)-2-pyrrolidone was determined by GC, The conversion of 3-(4-chlorobenzoyl)propionic acid was measured by HPLC. Using naphthalene as an internal standard to make a standard curve, The yield of 5-(4-chlorophenyl)-2-pyrrolidone (m/z: 194.1) in the reaction mixture was determined by gas chromatography to be 86%. The conversion of 3-(4-chlorobenzoyl)propionic acid was determined by liquid chromatography to be 100%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | Stage #1: trimethylsulfoxonium iodide With sodium hydride In dimethyl sulfoxide; mineral oil at 0 - 10℃; for 1h; Stage #2: 4-(4-chlorophenyl)-4-oxobutanoic acid In dimethyl sulfoxide at 20℃; for 20h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
120 g | With acetic acid; zinc In water at 20℃; | 1 138 g of the compound of the formula 2, 50 g of zinc powder, 700 ml of acetic acid, and 150 ml of water were mixed, mechanically stirred, and allowed to react at room temperature overnight. After the reaction of the starting material by TLC, suction filtration was carried out, and the filter cake was washed with ethyl acetate. The filtrate was collected and concentrated to dryness under reduced pressure. The residue was crystallized from ethyl acetate: n-hexane = 1:12, filtered, filtered, and filtered to give 120 g of compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-(4-chlorophenyl)-4-oxobutanoic acid With sodium hydroxide In water at 80℃; Stage #2: With sodium tetrahydroborate; water for 4h; | 1 55 g of the compound of the formula 3 was dissolved in 120 ml of water, and the temperature was raised to 80 ° C, and the pH was adjusted to 11 by adding 1.5 N sodium hydroxide, and the mixture was stirred and dissolved. 80 ml of 12 g of an aqueous solution of sodium borohydride was added dropwise, which was slow when added dropwise, and the system released a large amount of bubbles. At the end of the addition, the reaction was carried out for 4 hours, and the raw materials were filtered.The white insoluble matter was filtered off to obtain an aqueous solution of the compound of the formula 4. | |
With sodium tetrahydroborate; water; sodium hydroxide at 0 - 20℃; for 2h; Sealed tube; Inert atmosphere; | ||
With sodium tetrahydroborate; sodium hydroxide In water at 0 - 20℃; for 3h; | Path D: Synthesis from γ-carbonyl acids (1k, 1l). General procedure: The first two steps are according to the literature procedure [57]. Under a nitrogen atmosphere, NaBH4 (1.2 equiv.) was added slowly to a solution of NaOH (1.0 equiv.) and the corresponding γ-keto acid (30 mmol, 1.0 equiv.) in H2O (60 mL) at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 3 h, following with carefully adding 2 M HCl until the pH of the resultant solution reached 2. The aqueous phase was extracted with DCM (3 times). The organic phase was dried with sodium sulfate (Na2SO4) and then concentrated in vacuum to afford the corresponding alcohol, which could be used directly without further purification. To the solution of alcohol in anhydrous DCM (60 mL), CF3COOH (0.2 equiv.) was added at room temperature. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was quenched with saturated aqueous NaHCO3 (10 mL), extracted with DCM (3 times), and then concentrated in vacuum. The crude mixture was purified by flash column chromatography. After that, the substrates were prepared according to Path C. For detail, see ESI. Path C: Synthesis via Mitsunobu reaction. The substrates were prepared according to the literature procedure [55,56]. To a solution of lactone (20 mmol, 1 equiv.) in CH2Cl2 (40 mL), a solution of DIBAL-H (1 M in hexane, 24 mL, 1.2 equiv.) was added at -78 °C and the mixture was stirred for 4 h. The reaction was quenched by addition of a solution of aqueous potassium sodium tartrate (20 g in 120 mL water, about 3 equiv.) and then extracted with CH2Cl2 3 times. The combined organic phase were then dried over Na2SO4 and concentrated in vacuo. The hemiacetal was purified by flash column chromatography on silica gel eluting with PE/EA. After that, to a solution of hemiacetal (1.0 equiv.), NHPI (1.2 equiv.) and PPh3 (1.2 equiv.) in THF (0.2 M), diisopropyl azodicarboxylate (1.2 equiv.) was added dropwise at 0 °C. Then the reaction was allowed to room temperature and stirred overnight. Upon done, the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel and then recrystallization if necessary. For detail, see ESI. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20 - 40℃; for 6h; | 1766.1766B 1766B: N-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2- methoxypyridin-3-yl)-4-(4-chlorophenyl)-4-oxobutanamide To a solution of 7-(5-amino- 6-methoxypyridin-3-yl)-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (64 mg, 0.197 mmol), 4-(4-chlorophenyl)-4-oxobutanoic acid (54.6 mg, 0.257 mmol) and DIPEA (0.069 mL, 0.395 mmol) in DMF (1 mL) was added HATU (105 mg, 0.276 mmol). The mixture was stirred at rt for 3 h, then at 40 C for 3 h. Saturated aqueous sodium bicarbonate (5 mL) was added. The solid was collected by filtration and air dried to give crude N-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2- methoxypyridin-3-yl)-4-(4-chlorophenyl)-4-oxobutanamide (56 mg, 0.108 mmol, 55 % yield). The material was used for the next step without any purification. (2225) MS ESI m/z 519.1 (M+H)+. 1H NMR (500 MHz, CDCl3) δ 9.11 (d, J=2.0 Hz, 1H), 8.52 (d, J=2.3 Hz, 1H), 8.12 - 8.09 (m, 1H), 8.04 - 8.00 (m, 1H), 7.99 - 7.96 (m, 2H), 7.49 - 7.46 (m, 2H), 7.18 - 7.15 (m, 1H), 4.13 - 4.12 (m, 3H), 3.47 - 3.43 (m, 2H), 2.94 - 2.91 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With (R,R)-(−)-2,3-bis(t-butylmethylphosphino)quinoxaline; hydrogen; palladium diacetate; zinc trifluoromethanesulfonate In 1,2-dichloro-ethane at 70℃; for 24h; enantioselective reaction; | |
97% | With (R,R)-(−)-2,3-bis(t-butylmethylphosphino)quinoxaline; hydrogen; nickel(II) acetate tetrahydrate; zinc trifluoromethanesulfonate In 1,4-dioxane at 70℃; Autoclave; enantioselective reaction; | 22 Example 22 In a glove box, add 0.01 mmol of nickel acetate tetrahydrate and 0.012 mmol of ligand to a Snack reaction tube with a stir bar, and dissolve it in 1 mL of 1,4-dioxane solvent. The upper rubber stopper was stirred at room temperature for 30 minutes, and then 0.2 mmol of 3-(4-chlorobenzoyl) propionic acid as the substrate was added, zinc triflate (0.02 mmol) and 1 mL of 1,4-dioxane solvent were added.Take out the reaction tube and put it into the autoclave, replace the hydrogen for 3 times, set the hydrogen pressure at 3Mpa to 70°C in the oil bath, and wait until the reaction is completed.After the reaction, the reaction tube was taken out, and the reaction solution was used under reduced pressure to remove volatile solvents using a rotary evaporator, and purified by column chromatography with ethyl acetate/petroleum ether as the eluent to obtain the product (97% yield, 94% ee). |
Multi-step reaction with 3 steps 1.1: zinc; mercury dichloride; hydrogenchloride / toluene / 4 h / 100 °C / Inert atmosphere; Sealed tube 2.1: sulfuric acid / toluene / 2 h / 80 °C / Inert atmosphere; Sealed tube 3.1: NADPH; 9‑mesityl-10-methylacridinium perchlorate; oxygen; ketoreductase-P2-C02 / acetonitrile; water / 24 h / 23 °C / Irradiation; Enzymatic reaction 3.2: Enzymatic reaction |
Multi-step reaction with 3 steps 1: acetyl chloride / 12 h / 20 °C 2: NADH; isopropyl alcohol / aq. buffer / 20 h / 30 °C / pH 5.5 / Microbiological reaction; Enzymatic reaction 3: trifluoroacetic acid / dichloromethane / 1 h / 30 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: 4-(4-chlorophenyl)-4-oxobutanoic acid With chloroformic acid ethyl ester; triethylamine In dichloromethane at 0℃; Stage #2: (carbethoxymethyl)triphenylphosphonium bromide In dichloromethane at 45℃; for 10h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; for 24h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | In toluene for 23h; Reflux; Dean-Stark; | 4.1.2. General procedure for cyclocondensation reactions General procedure: To a suspension of cis-1-aminoindan-2-ol (1.0 eq.) in toluene (0.13 M) was added the appropriate oxocarboxylic acid (1.0-1.2eq.). The mixture was heated at reflux for 10-24 h under Dean-Stark apparatus, until total consumption of the starting aminoalcohol. The reaction mixture was concentrated in vacuo and the residue obtained was dissolved in EtOAc. The organic phase was washed with saturated aqueous solution of NaHCO3 and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (elution with AcOEtand n-hexane). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | In toluene for 21h; Reflux; Dean-Stark; | 4.1.2. General procedure for cyclocondensation reactions General procedure: To a suspension of cis-1-aminoindan-2-ol (1.0 eq.) in toluene (0.13 M) was added the appropriate oxocarboxylic acid (1.0-1.2eq.). The mixture was heated at reflux for 10-24 h under Dean-Stark apparatus, until total consumption of the starting aminoalcohol. The reaction mixture was concentrated in vacuo and the residue obtained was dissolved in EtOAc. The organic phase was washed with saturated aqueous solution of NaHCO3 and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (elution with AcOEtand n-hexane). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: acetyl chloride / 12 h / 20 °C 2: galactose / dimethyl sulfoxide / 30 °C / pH 8.2 / Microbiological reaction; Enzymatic reaction | ||
With (R,R)-2,3-bis(tert-butylmethylphosphino)quinoxaline; hydrogen; nickel(II) acetate tetrahydrate In 2,2,2-trifluoroethanol at 60℃; for 24h; Glovebox; Autoclave; Overall yield = 97 percent; Overall yield = 23.7 mg; Optical yield = 86 percent ee; enantioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With Ni(ClO4)2·6H2O; (S,S)-2,3-bis(tert-butylmethylphosphino)quinoxaline; hydrogen In <i>tert</i>-butyl alcohol at 45℃; for 24h; Autoclave; enantioselective reaction; | |
Multi-step reaction with 3 steps 1: acetyl chloride / 12 h / 20 °C 2: NADH; isopropanol; (R)-1-(4-hydroxyphenyl)ethanol dehydrogenase from Aromatoleum aromaticum / aq. buffer / 40 h / 30 °C / pH 5.5 / Microbiological reaction; Enzymatic reaction 3: trifluoroacetic acid / dichloromethane / 1 h / 30 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With potassium phosphate; tetrabutylammomium bromide In water at 95℃; for 40h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56.5% | Stage #1: 4-(4-chlorophenyl)-4-oxobutanoic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 20℃; for 1h; Inert atmosphere; Stage #2: 2-amino-benzthiazole In tetrahydrofuran at 20℃; Inert atmosphere; | 4.2.2. General synthesis of final compound (2a-x) General procedure: Different substituted benzothiazolamines were synthesized usingknown method [16]. The weighed amounts of reactants (1a-h) (1 mol)were dissolved in dry tetrahydrofuran and a pinch of HOBt (10 mg) wasadded to the reaction mixture. 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide(EDC) (1.2 mol) was weighed and quickly added to reactionmass under nitrogen atmosphere after half an hour. The reaction masswas kept on stirring for another half hour and one equivalent of otherreactant (substituted benzothiazolamine) was added to it. Reactionprogress was monitored using TLC. The reaction mass was diluted withwater when the reactants were consumed and extraction was carried outusing ethyl acetate. Corresponding desired products (2a-x) were obtainedfrom organic layer. The organic layer was dried on anhydroussodium sulfate and concentrated to give the final product as solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57.8% | Stage #1: 4-(4-chlorophenyl)-4-oxobutanoic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 20℃; for 1h; Inert atmosphere; Stage #2: 6-chloro-2-aminobenzothiazole In tetrahydrofuran at 20℃; Inert atmosphere; | 4.2.2. General synthesis of final compound (2a-x) General procedure: Different substituted benzothiazolamines were synthesized usingknown method [16]. The weighed amounts of reactants (1a-h) (1 mol)were dissolved in dry tetrahydrofuran and a pinch of HOBt (10 mg) wasadded to the reaction mixture. 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide(EDC) (1.2 mol) was weighed and quickly added to reactionmass under nitrogen atmosphere after half an hour. The reaction masswas kept on stirring for another half hour and one equivalent of otherreactant (substituted benzothiazolamine) was added to it. Reactionprogress was monitored using TLC. The reaction mass was diluted withwater when the reactants were consumed and extraction was carried outusing ethyl acetate. Corresponding desired products (2a-x) were obtainedfrom organic layer. The organic layer was dried on anhydroussodium sulfate and concentrated to give the final product as solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60.5% | Stage #1: 4-(4-chlorophenyl)-4-oxobutanoic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 20℃; for 1h; Inert atmosphere; Stage #2: 2-Amino-6-ethoxybenzothiazole In tetrahydrofuran at 20℃; Inert atmosphere; | 4.2.2. General synthesis of final compound (2a-x) General procedure: Different substituted benzothiazolamines were synthesized usingknown method [16]. The weighed amounts of reactants (1a-h) (1 mol)were dissolved in dry tetrahydrofuran and a pinch of HOBt (10 mg) wasadded to the reaction mixture. 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide(EDC) (1.2 mol) was weighed and quickly added to reactionmass under nitrogen atmosphere after half an hour. The reaction masswas kept on stirring for another half hour and one equivalent of otherreactant (substituted benzothiazolamine) was added to it. Reactionprogress was monitored using TLC. The reaction mass was diluted withwater when the reactants were consumed and extraction was carried outusing ethyl acetate. Corresponding desired products (2a-x) were obtainedfrom organic layer. The organic layer was dried on anhydroussodium sulfate and concentrated to give the final product as solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58.3% | Stage #1: 4-(4-chlorophenyl)-4-oxobutanoic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 20℃; for 1h; Inert atmosphere; Stage #2: 1,3-benzothiazol-2-ylhydrazine In tetrahydrofuran at 20℃; Inert atmosphere; | 4.2.3. General synthesis of final compounds 3a-x General procedure: Different substituted benzothiazolylhydrazines were synthesizedusing known method [17]. One mole of reactant 1a-h (3-(4-substitutedbenzoyl)propionic acid or substituted 4-oxubutyric acid derivatives)was dissolved in minimum amount of dry tetrahydrofuran. After half anhour, a pinch of HOBt (10 mg) and 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) (1.2 mol) were quickly added to reaction massunder nitrogen atmosphere. The reaction mass was stirred for anotherhalf hour and then added one equivalent of substituted benzothiazolylhydrazine.The progress of reaction was monitored by using TLC.Once the reaction was complete, the reaction mass was diluted withwater and extracted from ethyl acetate. Corresponding desired products(3a-x) were obtained from organic layer. The organic layer was dried onanhydrous sodium sulfate and concentrated to give the final product assolid. Further purification of final product was done by recrystallizationin ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61.2% | Stage #1: 4-(4-chlorophenyl)-4-oxobutanoic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 20℃; for 1h; Inert atmosphere; Stage #2: 6-chloro-2-hydrazinobenzothiazole In tetrahydrofuran at 20℃; Inert atmosphere; | 4.2.3. General synthesis of final compounds 3a-x General procedure: Different substituted benzothiazolylhydrazines were synthesizedusing known method [17]. One mole of reactant 1a-h (3-(4-substitutedbenzoyl)propionic acid or substituted 4-oxubutyric acid derivatives)was dissolved in minimum amount of dry tetrahydrofuran. After half anhour, a pinch of HOBt (10 mg) and 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) (1.2 mol) were quickly added to reaction massunder nitrogen atmosphere. The reaction mass was stirred for anotherhalf hour and then added one equivalent of substituted benzothiazolylhydrazine.The progress of reaction was monitored by using TLC.Once the reaction was complete, the reaction mass was diluted withwater and extracted from ethyl acetate. Corresponding desired products(3a-x) were obtained from organic layer. The organic layer was dried onanhydrous sodium sulfate and concentrated to give the final product assolid. Further purification of final product was done by recrystallizationin ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58.7% | Stage #1: 4-(4-chlorophenyl)-4-oxobutanoic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 20℃; for 1h; Inert atmosphere; Stage #2: 6-ethoxy-2-hydrazinylbenzo[d]thiazole In tetrahydrofuran at 20℃; Inert atmosphere; | 4.2.3. General synthesis of final compounds 3a-x General procedure: Different substituted benzothiazolylhydrazines were synthesizedusing known method [17]. One mole of reactant 1a-h (3-(4-substitutedbenzoyl)propionic acid or substituted 4-oxubutyric acid derivatives)was dissolved in minimum amount of dry tetrahydrofuran. After half anhour, a pinch of HOBt (10 mg) and 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) (1.2 mol) were quickly added to reaction massunder nitrogen atmosphere. The reaction mass was stirred for anotherhalf hour and then added one equivalent of substituted benzothiazolylhydrazine.The progress of reaction was monitored by using TLC.Once the reaction was complete, the reaction mass was diluted withwater and extracted from ethyl acetate. Corresponding desired products(3a-x) were obtained from organic layer. The organic layer was dried onanhydrous sodium sulfate and concentrated to give the final product assolid. Further purification of final product was done by recrystallizationin ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With Aluminum Chloride In tetrahydrofuran at -40 - 20℃; for 13h; Inert atmosphere; |
Tags: 3984-34-7 synthesis path| 3984-34-7 SDS| 3984-34-7 COA| 3984-34-7 purity| 3984-34-7 application| 3984-34-7 NMR| 3984-34-7 COA| 3984-34-7 structure
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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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