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CAS No. : | 598-79-8 | MDL No. : | MFCD00014336 |
Formula : | C3H3ClO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | SZTBMYHIYNGYIA-UHFFFAOYSA-N |
M.W : | 106.51 | Pubchem ID : | 11735 |
Synonyms : |
|
Num. heavy atoms : | 6 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 22.63 |
TPSA : | 37.3 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.08 cm/s |
Log Po/w (iLOGP) : | 1.0 |
Log Po/w (XLOGP3) : | 1.22 |
Log Po/w (WLOGP) : | 0.82 |
Log Po/w (MLOGP) : | 0.38 |
Log Po/w (SILICOS-IT) : | 0.32 |
Consensus Log Po/w : | 0.75 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.85 |
Log S (ESOL) : | -1.2 |
Solubility : | 6.67 mg/ml ; 0.0627 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.6 |
Solubility : | 2.67 mg/ml ; 0.0251 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.25 |
Solubility : | 60.2 mg/ml ; 0.565 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.66 |
Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P264-P271-P280-P301+P330+P331-P303+P361+P353-P304+P340-P305+P351+P338-P310-P363-P403+P233-P501 | UN#: | 3261 |
Hazard Statements: | H314 | Packing Group: | Ⅱ |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid at 100 - 115℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; acetic acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ethanol; sulfuric acid at 100 - 115℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid | ||
With sulfuric acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With barium dihydroxide | ||
With barium hydroxide octahydrate In water |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With triethylamine In acetonitrile Heating; | |
90% | In water; dimethyl sulfoxide at 120℃; for 6h; | |
With sulfuric acid |
With potassium carbonate | ||
With barytes | ||
beim Erhitzen mit einem protonierten Kationenaustauscher unter vermindertem Druck; | ||
In water | 1 EXAMPLE 1 EXAMPLE 1 1,000 ml of water and 200 g of unsubstituted α,β-dichloropropionic acid are introduced into a 4 liter enamelled autoclave. The mixture is heated and the temperature is kept at 120°-130°C for 3 hours. The pressure prevailing in the autoclave is the autogenic pressure. After cooling, it is found that the degree of conversion to α-chloroacrylic acid is 70% and that the selectivity of the dehydrochlorination reaction is 100%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With oxygen; acetic acid; acetone at 30 - 60℃; am besten in Gegenwart von Vanadinsaeure und Manganacetat; | ||
With selenium(IV) oxide; dihydrogen peroxide; <i>tert</i>-butyl alcohol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydroxide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid | ||
With sulfuric acid Destillation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydroxide; ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With diethyl ether |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium fluoride |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With copper(l) chloride | ||
With antimonypentachloride |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrachloromethane; toluene-4-sulfonic acid; hydroquinone |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid at 100 - 115℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N,N-dimethyl-formamide | ||
With 1-chloro-1-(dimethylamino)-2-methyl-1-propene | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 2.5h; Cooling with ice; | 20 2-fluoroacrylic acid (2.Oeq.) (54 mg) was dissolved in DCM (10 ml)3 drops of DMF were added,Under ice-cooling conditions,Oxalyl chloride (1.7 eq.) (44 [mu] v)In the ice bath conditions for 30min,Remove the ice bath,Natural recovery to room temperature,The reaction was carried out for 2 hours,(4-fluorophenylamino) -6-amino-7- (tetrahydrofuran-3-oxy) quinazoline(1 eq.) (112 mg) was dissolved in DCM (20 ml)Stir at 0 ° C for 5 min,Was added to the above acid chloride solution,Et3N (4 Oeq.) (169yL) was added,In the ice bath conditions for 30min,Remove the ice bath,After natural recovery to room temperature,The reaction was stirred overnight.After completion of the reaction,Concentrated to dry under reduced pressure crude,Purification by column chromatography (mobile phase 10: lDCM / MeOH) afforded N- (4- (3-chloro-4-fluorophenylamino) -7- (tetrahydrofuran-3-oxy) quinazoline- Yl) -2-fluorobut-2-enamide 80mg Examples 19 to 25In the same manner as in Example 18, using different starting materials, the following compound was prepared. |
With trichlorophosphate at 80℃; | 4.1.1. General procedure for the synthesis of 16a-h General procedure: We used indole 7 as starting material to synthesize interediates15a-c by the method reported in the literature [32]. Different substituted acrylic acids were chlorinated by POCl3 to obtain the corresponding acyl chloride at 80 °C. Under an ice bath, differently substituted acryl chloride was dissolved in dichloromethane and stirred at 0 °C for 10-30 min. Another intermediates 15a-c were added to the above acryl chloride solution, and then added NaHCO3 solid powder, stirred at 0 °C for 0.5-3 h. After the reaction was completed, the reaction mixture was filtered and solvent was distilled off under reduced pressure. The crude product was purified using flash chromatography with dichloromethane/methanol(v/v, from 50:1 to 20:1) as eluents | |
With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0℃; for 0.5h; | ||
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide In methanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With phosphorus pentachloride 1) Et2O, 0 deg C, 40 min, 2) toluene, 0 deg C, 2 h, then 25 deg C, 12 h; Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzoyl fluoride Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dimethylsulfide In chloroform-d1 at 0℃; for 2h; Yield given. Yields of byproduct given; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With hydrogenchloride In acetonitrile for 4h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | In ethyl acetate for 40h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With hydrogenchloride In benzonitrile for 14h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In ethyl acetate at 0℃; for 2.25h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 2,2'-azobis(isobutyronitrile) In dichloromethane Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
at 170℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
ist nach 2d weitgehend polymerisiert; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
ClCH2CH(OH)CN, wssr. H2SO4 (ohne Det.); | ||
2-Chlor-acrylnitril, wss. H2SO4; | ||
Acrylsaeure (III), Cl2 in Ggw. v. Perlit mit Ca-, Si-, Mg- u. Na-Oxides b. 170-180grad; |
Vinylchlorid, 1. BuLi-Lsg., (wfr. THF/Ae./PAe. 4:1:1, unter N2, -110grad) (-> H2C=CClLi), 2. CO2 (fest); | ||
(yield)99percent; | ||
2-Chlor-3-nitro-propionsaeure in CCl3F, KF; | ||
aus α,β-Dichlorpropionat; | ||
2,3-Dichlorpropionsaeuremethylester, NaOH, KOH; | ||
Dichlorpropionsaeure; | ||
Poly(β-hydroxy-α-chlorpropionsaeure) (I), /BRN= 43335/, Δ; | ||
Acrylsaeure, Chlor, 175-180grad; | ||
H2C=CHCl, BuLi, CO2; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
at 100℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; benzene Entfernen des entstehenden Wassers; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With dicyclohexyl-carbodiimide In tetrahydrofuran at 20℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate buffer; Burkholderia sp. WS expressing reductase at 30℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In benzene at 20℃; for 336h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With potassium hydroxide; tetrabutylammomium bromide In water; benzene at 60 - 65℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | In benzene for 5.5h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In <i>N</i>-methyl-acetamide | 1 EXAMPLE 1 EXAMPLE 1 To 48 parts of α-chloroacrylic acid, at room temperature, is added slowly 58 parts of oxalyl chloride. After the initial rapid reaction has subsided, 1 part of dimethylformamide is added to the stirred mixture and the mixture is heated to 40°, then allowed to cool to room temperature. Distillation of that mixture under reduced pressure affords α-chloroacrylyl chloride, boiling at approximately 45°-48° at 78-80 mm. of pressure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
C.1 COMPARATIVE EXAMPLE 1 (ACCORDING TO GERMAN PAT. NO. 1,167,819) COMPARATIVE EXAMPLE 1 (ACCORDING TO GERMAN PAT. NO. 1,167,819) 106.5 g of phosgene were introduced at 40° C into a mixture of 106.5 g of α-chloroacrylic acid and 11.7 g of dimethyl formamide for a period of 3 hours. Thereafter the reaction product was split off under a pressure of from 60 to 70 torrs (temperature of the bath 115° to 150° C), the chloroacrylic acid chloride formed was then distilled off, condensed in a brine condenser (-20° to -30° C) and collected in a receiver cooled with isopropanol/dry ice. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride In benzene | 2 EXAMPLE 2 EXAMPLE 2 Production of [2-(chloroformyl)-vinyl]-methyl-phosphinic acid chloride by reacting 2-chloroacrylic acid with methyldichlorophosphane in the presence of benzene as an inert solvent. A 2 l four necked flask provided with an agitator, thermometer, reflux condenser and heatable dropping funnel was supplied under nitrogen at room temperature with 234 g (2 mol) of methyldichlorophosphane in 200 ml of benzene. 240 g (2.25 mol) of a solution of 2-chloroacrylic acid in 200 ml of benzene was added with through agitation through the dropping funnel heated to 40° C. No appreciable visually recognizable reaction was observed. Heating to 35° C. was accompanied by a slight evolution of HCl. Upon the further dropwise addition of 2-chloroacrylic acid solution, the evolution of HCl was found to intensify and the reaction temperature increased to about 45° C. After all of the 2-chloroacrylic acid had been added, the batch was heated to 60° C. and stirring was continued for a further 30 minutes at that temperature. Altogether 70 g of gaseous HCl (1.9 mol) was found to escape. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With N,O-bis-(trimethylsilyl)-acetamide In dichloromethane at 0 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | In water NaOH in H2O was added to a soln. of 2-chloroacrylic acid in water, Fe-salt was added dropwise to the stirred soln.; filtered, washed with H2O, dissolved in acetone, the solvent was rotary removed to dryness, dissolved in min acetone and layered with cyclohexane; elem. anal.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | In water NaOH in H2O was added to a soln. of 2-chloroacrylic acid in water, Fe-salt was added dropwise to the stirred soln., filtered, dissolved in CH3CN/1,4-dioxane, refluxed for 1 h; the solvent was rotary removed to dryness; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With hydrogenchloride; tetrabutylammomium bromide In water at 100℃; for 10h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bis-(2-oxo-3-oxazolidinyl)phosphoryl chloride; N-ethyl-N,N-diisopropylamine In dichloromethane |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0℃; for 48h; | 5 4.2.5. 1-N-(2-chloroacryloyloxy-3-chloroprop-1-yl)amino-5-isocyanonaphthalene (CACAIN) Into a 50 ml round-bottom flask charged with 1-N-(3-chloro-2-hydroxyprop-1-yl)amino-5-isocyanonaphthalene (500 mg, 1.92 mmol), 4-N,N-dimethylaminopyridine (26.0 mg, 0.210 mmol) and 2-chloroacrylic acid (225 mg, 2.11 mmol) dissolved in dichloromethane (15 ml) N,N-dicyclohexyl carbodiimide (435 mg, 2.11 mmol) dissolved in dichloromethane (5 ml) was added dropwise at 0 °C, then stirred with a magnetic stirrer for 2 days. The solvent was removed on a rotary evaporator and the crude product was purified on a column filled with normal-phase silica gel, using dichloromethane as eluent. Yield: 0.33 g, 49% (pale yellow viscous oil). 1H NMR (360 MHz, CDCl3) δ = 7.84 (d, J = 8.6 Hz, 1H), 7.65-7.46 (m, 3H), 7.41 (dd, J = 8.6, 7.4 Hz, 1H), 6.83 (d, J = 7.5 Hz, 1H), 6.59 (d, J = 10.3 Hz, 1H), 6.09 (d, J = 10.2 Hz, 1H), 5.52-5.40 (m, 1H), 4.77 (s, 1H), 3.86 (d, J = 4.8 Hz, 2H), 3.73 (t, J = 5.8 Hz, 2H) ppm. 13C NMR (91 MHz, CDCl3) δ = 167.15 (CC=O), 161.75 (CNC), 142.91 (C9,10), 130.80 (C5), 129.19 (C1), 128.88 (CChloroacryl CH2), 127.29 (CChloroacryl CH), 126.61 (C3), 124.80 (C7), 123.92 (C6), 121.73 (C8), 113.01 (C2), 106.15 (C4), 73.56 (CCHO), 44.87 (CCH2), 43.38 (CCH2Cl) ppm. ESI-TOF MS (m/z): calculated m/z of [C17H14Cl2N2O2-H]- ion is 346.036; found; 346.036. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14% | Stage #1: 2-Chloroacrylic acid With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 20℃; for 2.5h; Cooling with ice; Stage #2: 6-amino-4-(3-bromo-phenylamino)-7-ethoxy-quinoline-3-carbonitrile In dichloromethane; N,N-dimethyl-formamide at 0℃; for 0.0833333h; Stage #3: With triethylamine In dichloromethane; N,N-dimethyl-formamide at 20℃; Cooling with ice; | 30.3 preparation of N-(4-(3-bromophenylamino)-3-cyano-7-ethoxyquinoline-6-yl)-2-chloroacrylamide 2-Chloroacrylic acid (2.Oeq.) (167 mg) was dissolved in DCM (10 ml)3 drops of DMF were added,Under ice-cooling conditions,Oxalyl chloride (1.7 eq.) (138 [mu]In the ice bath conditions for 30min,Remove the ice bath,Natural recovery to room temperature,The reaction was carried out for 2 hours,The 3-cyano-6-amino-4 - ((3-bromophenyl) amino) -7-ethoxyquinoline was obtained(Leq.) (300 mg) was dissolved in DCM (20 ml)Stir at 0 ° C for 5 min,Was added to the above acid chloride solution,Et3N (4.0 eq.) (474 yL) was added,In the ice bath conditions for 30min,Remove the ice bath,After natural recovery to room temperature,The reaction was stirred overnight.After completion of the reaction,Concentrated to dry under reduced pressure crude,Purification by column chromatography (mobile phase 10: lDCM / MeOH) gave a pale yellow colorN- (4- ((3-bromophenyl) amino) -3-cyano-7-ethoxyquinoline-Yl) -2- chloroacrylamide 80 mg,Yield 14%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 2h; Inert atmosphere; | 366 (R)-N-(1-(2-chloroacryloyl)piperidin-3-yl)-5-(*S)-(2-methyl-4-phenoxyphenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide To a solution of (R)-5-(*S)-(2-Methyl-4-phenoxyphenyl)-4-oxo-N-(piperidin-3-yl)-4,5-dihydro- 3H-1-thia-3,5,8-triazaacenaphthylene-2-carboxamide (Example 98, 50 mg, 0.09 mmol), 2- chloroprop-2-enoic acid (20 mg, 0.19 mmol), HATU (46 mg, 0.12 mmol), anddiisopropylethylamine (30 mg, 0.23 mmol) in DMF (5 mL) was stirred at rt for 2 h. The mixture was purified by flash column chromatography, and by preparative TLC to give the title compound as a white solid (10 mg, 18% yield). MS (ESI): mass calcd. for C30H26ClN5O4S, 588.1; m/z found, 588.2 [M+H]+.1H NMR (400 MHz, CD3OD): δ 8.36-8.30 (m, 1H), 7.44-7.37 (m, 2H), 7.33-7.27 (m, 1H), 7.21-7.14 (m, 1H), 7.12-7.03 (m, 3H), 7.01-6.95 (m, 1H), 6.11-6.05 (m, 1H), 5.72 (m, 2H), 4.45-3.88 (m, 3H), 3.25-2.90 (m, 2H), 2.17-2.02 (m, 4H), 1.95-1.84 (m, 1H), 1.81-1.69 (m, 1H), 1.66-1.57 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | Stage #1: 1-chlorovinyl phenyl sulfoxide With cyclohexylmagnesiumchloride In tetrahydrofuran; toluene at -78℃; for 0.166667h; Inert atmosphere; Stage #2: carbon dioxide In tetrahydrofuran; toluene at -78℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With phenylsilane; C12H23N2O2P In tetrahydrofuran at 23℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2-Chloroacrylic acid With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 45℃; for 2.41667h; Stage #2: 2-((2-methoxy-4-(4-acetylpiperazin-1-yl)phenyl)amino)-4(((3-amino)phenyl)amino)-5-chloropyrimidine With triethylamine In dichloromethane; N,N-dimethyl-formamide at 20℃; | 4.3 Synthesis of final compounds General procedure: To a solution of acrylic acid (4.0mmol, 4.0 equiv) in anhydrous DCM (8mL) was added 3 drops of DMF at 0°C and oxalyl chloride (3.47mmol, 3.47 equiv) in DCM (2mL) was added dropwise. Then the mixture was stirred at 0-10°C for 20min and at 25°C for 2h, then the temperature of reaction mixture is adjusted to 45°C for 5min. Next, the mixture was cooled to 0°C. A solution of the aniline 7, 12 or 16 (1.0mmol) and Et3N (5.0mmol, 5.0 equiv) in anhydrous DCM-DMF (6mL/1mL) was added dropwise to the above mixture. The mixture was stirred at room temperature for another 3-4h. The mixture was quenched with saturated Na2CO3 solution, extracted with EtOAc (3×20mL) and dried over anhydrous sodium sulfate. The combined organic layer was evaporated to dryness under reduced pressure. The residue was purified through silica gel to give pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2-Chloroacrylic acid With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 45℃; for 2.41667h; Stage #2: C21H21ClN6 With triethylamine In dichloromethane; N,N-dimethyl-formamide at 20℃; | 4.3 Synthesis of final compounds General procedure: To a solution of acrylic acid (4.0mmol, 4.0 equiv) in anhydrous DCM (8mL) was added 3 drops of DMF at 0°C and oxalyl chloride (3.47mmol, 3.47 equiv) in DCM (2mL) was added dropwise. Then the mixture was stirred at 0-10°C for 20min and at 25°C for 2h, then the temperature of reaction mixture is adjusted to 45°C for 5min. Next, the mixture was cooled to 0°C. A solution of the aniline 7, 12 or 16 (1.0mmol) and Et3N (5.0mmol, 5.0 equiv) in anhydrous DCM-DMF (6mL/1mL) was added dropwise to the above mixture. The mixture was stirred at room temperature for another 3-4h. The mixture was quenched with saturated Na2CO3 solution, extracted with EtOAc (3×20mL) and dried over anhydrous sodium sulfate. The combined organic layer was evaporated to dryness under reduced pressure. The residue was purified through silica gel to give pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2-Chloroacrylic acid With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 45℃; for 2.41667h; Stage #2: C23H26ClN7O With triethylamine In dichloromethane; N,N-dimethyl-formamide at 20℃; | 4.3 Synthesis of final compounds General procedure: To a solution of acrylic acid (4.0mmol, 4.0 equiv) in anhydrous DCM (8mL) was added 3 drops of DMF at 0°C and oxalyl chloride (3.47mmol, 3.47 equiv) in DCM (2mL) was added dropwise. Then the mixture was stirred at 0-10°C for 20min and at 25°C for 2h, then the temperature of reaction mixture is adjusted to 45°C for 5min. Next, the mixture was cooled to 0°C. A solution of the aniline 7, 12 or 16 (1.0mmol) and Et3N (5.0mmol, 5.0 equiv) in anhydrous DCM-DMF (6mL/1mL) was added dropwise to the above mixture. The mixture was stirred at room temperature for another 3-4h. The mixture was quenched with saturated Na2CO3 solution, extracted with EtOAc (3×20mL) and dried over anhydrous sodium sulfate. The combined organic layer was evaporated to dryness under reduced pressure. The residue was purified through silica gel to give pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2-Chloroacrylic acid With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 45℃; for 2.41667h; Stage #2: C22H23Cl2N7O With triethylamine In dichloromethane; N,N-dimethyl-formamide at 20℃; | 4.3 Synthesis of final compounds General procedure: To a solution of acrylic acid (4.0mmol, 4.0 equiv) in anhydrous DCM (8mL) was added 3 drops of DMF at 0°C and oxalyl chloride (3.47mmol, 3.47 equiv) in DCM (2mL) was added dropwise. Then the mixture was stirred at 0-10°C for 20min and at 25°C for 2h, then the temperature of reaction mixture is adjusted to 45°C for 5min. Next, the mixture was cooled to 0°C. A solution of the aniline 7, 12 or 16 (1.0mmol) and Et3N (5.0mmol, 5.0 equiv) in anhydrous DCM-DMF (6mL/1mL) was added dropwise to the above mixture. The mixture was stirred at room temperature for another 3-4h. The mixture was quenched with saturated Na2CO3 solution, extracted with EtOAc (3×20mL) and dried over anhydrous sodium sulfate. The combined organic layer was evaporated to dryness under reduced pressure. The residue was purified through silica gel to give pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2-Chloroacrylic acid With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 45℃; for 2.41667h; Stage #2: C22H23ClFN7O With triethylamine In dichloromethane; N,N-dimethyl-formamide at 20℃; | 4.3 Synthesis of final compounds General procedure: To a solution of acrylic acid (4.0mmol, 4.0 equiv) in anhydrous DCM (8mL) was added 3 drops of DMF at 0°C and oxalyl chloride (3.47mmol, 3.47 equiv) in DCM (2mL) was added dropwise. Then the mixture was stirred at 0-10°C for 20min and at 25°C for 2h, then the temperature of reaction mixture is adjusted to 45°C for 5min. Next, the mixture was cooled to 0°C. A solution of the aniline 7, 12 or 16 (1.0mmol) and Et3N (5.0mmol, 5.0 equiv) in anhydrous DCM-DMF (6mL/1mL) was added dropwise to the above mixture. The mixture was stirred at room temperature for another 3-4h. The mixture was quenched with saturated Na2CO3 solution, extracted with EtOAc (3×20mL) and dried over anhydrous sodium sulfate. The combined organic layer was evaporated to dryness under reduced pressure. The residue was purified through silica gel to give pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2-Chloroacrylic acid With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 45℃; for 2.41667h; Stage #2: 3-[2-[[4-(4-acetyl-1-piperazinyl)phenyl]amino]-5-(chloro)-4-pyridinyl]aminobenzene With triethylamine In dichloromethane; N,N-dimethyl-formamide at 20℃; | 4.3 Synthesis of final compounds General procedure: To a solution of acrylic acid (4.0mmol, 4.0 equiv) in anhydrous DCM (8mL) was added 3 drops of DMF at 0°C and oxalyl chloride (3.47mmol, 3.47 equiv) in DCM (2mL) was added dropwise. Then the mixture was stirred at 0-10°C for 20min and at 25°C for 2h, then the temperature of reaction mixture is adjusted to 45°C for 5min. Next, the mixture was cooled to 0°C. A solution of the aniline 7, 12 or 16 (1.0mmol) and Et3N (5.0mmol, 5.0 equiv) in anhydrous DCM-DMF (6mL/1mL) was added dropwise to the above mixture. The mixture was stirred at room temperature for another 3-4h. The mixture was quenched with saturated Na2CO3 solution, extracted with EtOAc (3×20mL) and dried over anhydrous sodium sulfate. The combined organic layer was evaporated to dryness under reduced pressure. The residue was purified through silica gel to give pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2-Chloroacrylic acid With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 45℃; for 2.41667h; Stage #2: N-[3-[[2-[[4-(4-acetylpiperazin-1-yl)-2-methoxyphenyl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]amine With triethylamine In dichloromethane; N,N-dimethyl-formamide at 20℃; | 4.3 Synthesis of final compounds General procedure: To a solution of acrylic acid (4.0mmol, 4.0 equiv) in anhydrous DCM (8mL) was added 3 drops of DMF at 0°C and oxalyl chloride (3.47mmol, 3.47 equiv) in DCM (2mL) was added dropwise. Then the mixture was stirred at 0-10°C for 20min and at 25°C for 2h, then the temperature of reaction mixture is adjusted to 45°C for 5min. Next, the mixture was cooled to 0°C. A solution of the aniline 7, 12 or 16 (1.0mmol) and Et3N (5.0mmol, 5.0 equiv) in anhydrous DCM-DMF (6mL/1mL) was added dropwise to the above mixture. The mixture was stirred at room temperature for another 3-4h. The mixture was quenched with saturated Na2CO3 solution, extracted with EtOAc (3×20mL) and dried over anhydrous sodium sulfate. The combined organic layer was evaporated to dryness under reduced pressure. The residue was purified through silica gel to give pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2-Chloroacrylic acid With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 45℃; for 2.41667h; Stage #2: C22H23Cl2N7O With triethylamine In dichloromethane; N,N-dimethyl-formamide at 20℃; | 4.3 Synthesis of final compounds General procedure: To a solution of acrylic acid (4.0mmol, 4.0 equiv) in anhydrous DCM (8mL) was added 3 drops of DMF at 0°C and oxalyl chloride (3.47mmol, 3.47 equiv) in DCM (2mL) was added dropwise. Then the mixture was stirred at 0-10°C for 20min and at 25°C for 2h, then the temperature of reaction mixture is adjusted to 45°C for 5min. Next, the mixture was cooled to 0°C. A solution of the aniline 7, 12 or 16 (1.0mmol) and Et3N (5.0mmol, 5.0 equiv) in anhydrous DCM-DMF (6mL/1mL) was added dropwise to the above mixture. The mixture was stirred at room temperature for another 3-4h. The mixture was quenched with saturated Na2CO3 solution, extracted with EtOAc (3×20mL) and dried over anhydrous sodium sulfate. The combined organic layer was evaporated to dryness under reduced pressure. The residue was purified through silica gel to give pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2-Chloroacrylic acid With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 45℃; for 2.41667h; Stage #2: C21H23ClN8O With triethylamine In dichloromethane; N,N-dimethyl-formamide at 20℃; | 4.3 Synthesis of final compounds General procedure: To a solution of acrylic acid (4.0mmol, 4.0 equiv) in anhydrous DCM (8mL) was added 3 drops of DMF at 0°C and oxalyl chloride (3.47mmol, 3.47 equiv) in DCM (2mL) was added dropwise. Then the mixture was stirred at 0-10°C for 20min and at 25°C for 2h, then the temperature of reaction mixture is adjusted to 45°C for 5min. Next, the mixture was cooled to 0°C. A solution of the aniline 7, 12 or 16 (1.0mmol) and Et3N (5.0mmol, 5.0 equiv) in anhydrous DCM-DMF (6mL/1mL) was added dropwise to the above mixture. The mixture was stirred at room temperature for another 3-4h. The mixture was quenched with saturated Na2CO3 solution, extracted with EtOAc (3×20mL) and dried over anhydrous sodium sulfate. The combined organic layer was evaporated to dryness under reduced pressure. The residue was purified through silica gel to give pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2-Chloroacrylic acid With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 45℃; for 2.41667h; Stage #2: C23H25ClN6O3 With triethylamine In dichloromethane; N,N-dimethyl-formamide at 20℃; | 4.3 Synthesis of final compounds General procedure: To a solution of acrylic acid (4.0mmol, 4.0 equiv) in anhydrous DCM (8mL) was added 3 drops of DMF at 0°C and oxalyl chloride (3.47mmol, 3.47 equiv) in DCM (2mL) was added dropwise. Then the mixture was stirred at 0-10°C for 20min and at 25°C for 2h, then the temperature of reaction mixture is adjusted to 45°C for 5min. Next, the mixture was cooled to 0°C. A solution of the aniline 7, 12 or 16 (1.0mmol) and Et3N (5.0mmol, 5.0 equiv) in anhydrous DCM-DMF (6mL/1mL) was added dropwise to the above mixture. The mixture was stirred at room temperature for another 3-4h. The mixture was quenched with saturated Na2CO3 solution, extracted with EtOAc (3×20mL) and dried over anhydrous sodium sulfate. The combined organic layer was evaporated to dryness under reduced pressure. The residue was purified through silica gel to give pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2-Chloroacrylic acid With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 45℃; for 2.41667h; Stage #2: 4-(3-aminophenoxy)-5-chloro-N-(2-methoxy-4-(4-methylpiperazin-1-yl)phenyl) pyrimidin-2-amine With triethylamine In dichloromethane; N,N-dimethyl-formamide at 20℃; | 4.3 Synthesis of final compounds General procedure: To a solution of acrylic acid (4.0mmol, 4.0 equiv) in anhydrous DCM (8mL) was added 3 drops of DMF at 0°C and oxalyl chloride (3.47mmol, 3.47 equiv) in DCM (2mL) was added dropwise. Then the mixture was stirred at 0-10°C for 20min and at 25°C for 2h, then the temperature of reaction mixture is adjusted to 45°C for 5min. Next, the mixture was cooled to 0°C. A solution of the aniline 7, 12 or 16 (1.0mmol) and Et3N (5.0mmol, 5.0 equiv) in anhydrous DCM-DMF (6mL/1mL) was added dropwise to the above mixture. The mixture was stirred at room temperature for another 3-4h. The mixture was quenched with saturated Na2CO3 solution, extracted with EtOAc (3×20mL) and dried over anhydrous sodium sulfate. The combined organic layer was evaporated to dryness under reduced pressure. The residue was purified through silica gel to give pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2-Chloroacrylic acid With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 45℃; for 2.41667h; Stage #2: C22H23ClN6O2 With triethylamine In dichloromethane; N,N-dimethyl-formamide at 20℃; | 4.3 Synthesis of final compounds General procedure: To a solution of acrylic acid (4.0mmol, 4.0 equiv) in anhydrous DCM (8mL) was added 3 drops of DMF at 0°C and oxalyl chloride (3.47mmol, 3.47 equiv) in DCM (2mL) was added dropwise. Then the mixture was stirred at 0-10°C for 20min and at 25°C for 2h, then the temperature of reaction mixture is adjusted to 45°C for 5min. Next, the mixture was cooled to 0°C. A solution of the aniline 7, 12 or 16 (1.0mmol) and Et3N (5.0mmol, 5.0 equiv) in anhydrous DCM-DMF (6mL/1mL) was added dropwise to the above mixture. The mixture was stirred at room temperature for another 3-4h. The mixture was quenched with saturated Na2CO3 solution, extracted with EtOAc (3×20mL) and dried over anhydrous sodium sulfate. The combined organic layer was evaporated to dryness under reduced pressure. The residue was purified through silica gel to give pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2-Chloroacrylic acid With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 45℃; for 2.41667h; Stage #2: C23H22ClF3N6O2 With triethylamine In dichloromethane; N,N-dimethyl-formamide at 20℃; | 4.3 Synthesis of final compounds General procedure: To a solution of acrylic acid (4.0mmol, 4.0 equiv) in anhydrous DCM (8mL) was added 3 drops of DMF at 0°C and oxalyl chloride (3.47mmol, 3.47 equiv) in DCM (2mL) was added dropwise. Then the mixture was stirred at 0-10°C for 20min and at 25°C for 2h, then the temperature of reaction mixture is adjusted to 45°C for 5min. Next, the mixture was cooled to 0°C. A solution of the aniline 7, 12 or 16 (1.0mmol) and Et3N (5.0mmol, 5.0 equiv) in anhydrous DCM-DMF (6mL/1mL) was added dropwise to the above mixture. The mixture was stirred at room temperature for another 3-4h. The mixture was quenched with saturated Na2CO3 solution, extracted with EtOAc (3×20mL) and dried over anhydrous sodium sulfate. The combined organic layer was evaporated to dryness under reduced pressure. The residue was purified through silica gel to give pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2-Chloroacrylic acid With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In tetrahydrofuran for 0.25h; Cooling with ice; Inert atmosphere; Stage #2: aniline In tetrahydrofuran at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14.9 mg | Stage #1: 2-Chloroacrylic acid With oxalyl dichloride In dichloromethane at 0℃; for 2h; Stage #2: 3-(4-(1-(2-((4-((2-(2-(6-chloro-8- fluoro-4-(piperazin-1-yl)quinazolin-7-yl)-3-fluorophenoxy)ethoxy)methyl)benzyl)oxy)ethyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidin-2,6-dione trifluoroacetate With triethylamine In dichloromethane at 0℃; for 0.5h; | 16 To a solution of 2-chloroacrylic acid (16 mg, 0.148 mmol) in DCM (2 mL) was added (COCl)2 (16 mg, 0.126 mmol) and the mixture was stirred at 0°C for 2 h. To a solution of 3-(4-(1-(2-((4-((2-(2-(6-chloro-8-fluoro-4-(piperazin-1-yl)quinazolin-7-yl)-3-fluorophenoxy)ethoxy)methyl)benzyl)oxy)ethyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (crude, 0.O74lmmol) in DCM (3 ml) 0 °C were added TEA (30 mg, 0.294 mmol) and the 2-chloroacryloyl chloride solution dropwise (11 mg, 0.083 mmol). After 30 mm at 0 °C, the mixture was concentrated and the residue was purified using prep-HPLC to give 3-(4-(1-(2-((4-((2-(2-(6-chloro-4-(4-(2-chloroacryloyl)piperazin-1-yl)-8 -fluoroquinazolin-7-yl)-3-fluorophenoxy)ethoxy)methyl)benzyl)oxy)ethyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione 101 (14.9 mg) in 20% yield. 1H NMR (400 MHz, DMSO-d6) 5 11.00 (s, 1H), 8.73 (d, J= 4.8 Hz, 1H), 8.07-7.85 (m, 1H), 7.59-7.50 (m, 1H), 7.41-7.35 (m, 2H), 7.12-6.92 (m, 6H), 5.83 (s, 1H), 5.80-5.78 (m, 1H), 5.13 (dd, J= 4.8, 13.2 Hz, 1H), 4.54-4.33 (m, 5H), 4.29-4.17 (m, 4H), 3.86-3.80 (m, 4H), 3.68-3.51 (m, 9H), 3.11-3.09 (m, 2H), 2.95-2.89 (m, 1H), 2.69-2.67 (m, 2H), 2.62-2.58 (m, 1H), 2.43-2.40 (m, 1H), 2.29-2.23 (m, 1H), 2.02-1.99 (m, 1H), 1.78 (s, 4H); MS (ESI) m/z: 1000.3 [M+H] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | Stage #1: 2-Chloroacrylic acid With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 2h; Stage #2: 3-(6-fluoro-4-(1-(7-(3-fluoro-2-(6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-4-((S)-2-methylpiperazin- 1-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-7-yl)phenoxy)heptyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidin-2,6-dione With triethylamine In dichloromethane at 0℃; for 0.333333h; | 20 To a solution of 2-chloroacrylic acid (30 mg, 0.28 mmol) in DCM (1 mL) at 0 °C were added oxalyl chloride (30 mg, 0.24 mmol) and DMF (1 drop). The solution was stirred for 2 h at room temperature. To a solution of (3 -(6-fluoro-4-(1-(7-(3-fluoro-2-(6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-4-((S)-2-methylpiperazin-1-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-7- yl)phenoxy)heptyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (80 mg, 0.084 mmol) in DCM (1 mL) at 0 °C were added the 2-chloroacryloyl chloride solution and TEA (25 mg, 0.25 mmol). After 20 min at 0 °C, the mixture was quenched with saturated aqueous NaHCO3 (5 mL) and extracted with DCM. The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified using prep-HPLC to give 3-(4-(1-(7-(2-(4-((S)-4-(2-chloroacryloyl)-2-methylpiperazin-1-yl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-7-yl)-3-fluorophenoxy)heptyl)piperidin-4-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione 122 (37.1 mg) in 43% yield. 1H NMR (400 MHz, DMSOd6) (5 11.00 (s, 1H), 8.40-8.37 (m, 2H), 8.15 (d, J= 3.2 Hz, 1H), 7.46-7.34 (m, 3H), 7.19 (dd, J= 4.0, 12.8 Hz, 1H), 6.96 (d, J= 8.8 Hz, 1H), 6.86 (t, J= 8.8 Hz, 1H), 5.87-5.84 (m, 2H), 5.13 (dd, J=5.6, 13.2 Hz, 1H), 5.01-4.85 (m, 1H), 4.54-4.26 (m, 4H), 3.95-3.91 (m, 2H), 3.80-3.66 (m, 2H),2.96-2.92 (m, 3H), 2.69-2.62 (m, 1H), 2.44-2.38 (m, 2H), 2.27-2.21 (m, 3H), 2.01-1.88 (m, 7H),1.75-1.72 (m, 4H), 1.51-1.46 (m, 2H), 1.37-1.34 (m, 5H), 1.17-1.13 (m, 5H), 1.07 (d, J= 6.4Hz, 3H), 0.94 (d, J = 6.4 Hz, 2H), 0.85 (d, J = 5.2 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | Stage #1: 3-pyridinecarboxaldehyde; 4-phenylalanine In methanol at 20℃; for 0.5h; Inert atmosphere; Stage #2: 2-Chloroacrylic acid; (S)-1-isocyano-1-phenylethane In methanol at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; | General Synthesis of (II), (III) and (IX) General procedure: The mixture of (VII) or (XI) (100 mg, 0.21 mmol)and substituted acrylic acids (0.25 mmol), HOBT(43mg, 0.23 mmol), EDCI (31 mg, 0.23mmol), Et3N(62 mg, 0.62 mmol) in DMF (5 mL) was stirred atroom temperature for 4-8 h until the completion ofthe reaction on TLC. Then the reaction mixture wasdiluted with water (5 mL) and extracted with ethyl acetate(10 mL × 3). The organic layer was dried over Na2SO4and evaporated to afford the crude product that waspurified on TLC to give the desired product (II), (III)and (IX) in 56-75% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; | General Synthesis of (II), (III) and (IX) General procedure: The mixture of (VII) or (XI) (100 mg, 0.21 mmol)and substituted acrylic acids (0.25 mmol), HOBT(43mg, 0.23 mmol), EDCI (31 mg, 0.23mmol), Et3N(62 mg, 0.62 mmol) in DMF (5 mL) was stirred atroom temperature for 4-8 h until the completion ofthe reaction on TLC. Then the reaction mixture wasdiluted with water (5 mL) and extracted with ethyl acetate(10 mL × 3). The organic layer was dried over Na2SO4and evaporated to afford the crude product that waspurified on TLC to give the desired product (II), (III)and (IX) in 56-75% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | With triethylamine In dichloromethane for 1h; Cooling with ice; | 18.6 Step 6: Synthesis of 4-(1-(2-Chloroacrylamido)piperidin-4-yl)-2-(5-phenoxypyridin-2-yl)benzamide Compound j (250 mg, 641.92 μmol), Compound h (115.61 mg, 1.28 mmol) was dissolved in dichloromethane (5 mL), triethylamine (267.68 mmL, 1.93 mmol) was added dropwise, ice bath for 1 h, the reaction was quenched with water, ethyl acetate was added, washed with water and saturated brine successively, the organic phase was dried over anhydrous sodium sulfate, filtered, concentration under reduced pressure and purification by column chromatography gave Exp 18 (Example Compound 18) (100 mg, 34%), |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
203.5 kg | Stage #1: 2-Chloroacrylic acid; para-nitrobenzenethiol With sodium hydroxide In N,N-dimethyl-formamide at -5 - 20℃; for 3h; Large scale; Stage #2: With phosphoric acid at 90℃; for 4h; Large scale; | 5 Synthesis of 6-nitro-3-dimethylaminothiochroman-4-one p-nitrothiophenol (155Kg, 1mol) was added to 300L of DMF and sodium hydroxide (44Kg, 1.1mol), and 2-chloroacrylic acid (114Kg, 1.15mol) was added dropwise at a temperature of -5°C to 5°C. The reaction mixture was stirred at -5°C to 5°C for 1 hour, then at room temperature for 2 hours, adjusted to pH 2-5 by adding 2N hydrochloric acid, and extracted twice with 400 L of dichloroethane. The solvent was removed from the organic phase under reduced pressure to obtain 237.5Kg of the intermediate with a yield of 91%. 237.5Kg of the above intermediate was added to 500L of 96% concentrated phosphoric acid, and stirred at 90°C for 4h. After cooling to room temperature, the reaction solution was poured into 1300 L of ice water, extracted twice by adding 700 L of ethyl acetate each time, the organic phases were combined, the organic layer was washed with 500 L of saturated NaHCO solution and 500 L of water to neutrality, and the organic layer was reduced The solvent was removed under pressure to obtain 203.5Kg of 3-chloro-6-nitrothiochroman-4-one with a yield of 92%. Add 203.5Kg of the above-mentioned intermediate to 600L of ethanol, add a small amount of tetrabutylammonium bromide catalyst, slowly circulate dimethylamine gas, maintain the reaction temperature at 50-55 ° C and react for 8 hours, remove the solvent under reduced pressure and re-weight with toluene. Crystallized 3-dimethylamino-6-nitrothiochroman-4-one 181Kg, yield 86% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
150 kg | Stage #1: 2-Chloroacrylic acid; p-Chlorothiophenol With sodium hydroxide In N,N-dimethyl-formamide at -5 - 20℃; for 3h; Large scale; Stage #2: With sulfuric acid at 90℃; for 4h; Large scale; | 4 Synthesis of 3,6-dichlorothiochroman-4-one p-chlorothiophenol (117Kg, 810mmol) was added to 200L of DMF and sodium hydroxide (34Kg, 850mmol), and 69.6Kg of 2-chloroacrylic acid (84L, 972mmol) was added dropwise at a temperature of -5°C to 5°C. The reaction mixture was stirred at -5°C to 5°C for 1 hour, then at room temperature for 2 hours, adjusted to pH 2-5 by adding 2N hydrochloric acid, and extracted twice with 300 L of dichloroethane. The solvent was removed from the organic phase under reduced pressure to obtain 190.4Kg of the intermediate with a yield of 94%. 165.7Kg of the above intermediate was added to 400L of 98% concentrated sulfuric acid and stirred at 90°C for 4h. After cooling to room temperature, the reaction solution was poured into 1000 L of ice water, extracted three times by adding 500 L of ethyl acetate each time, and the organic phases were combined. The solvent was removed to obtain 150Kg of 3,6-dichlorothiochroman-4-one with a yield of 85%. |
Tags: 598-79-8 synthesis path| 598-79-8 SDS| 598-79-8 COA| 598-79-8 purity| 598-79-8 application| 598-79-8 NMR| 598-79-8 COA| 598-79-8 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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