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CAS No. : | 1413945-87-5 | MDL No. : | MFCD28139076 |
Formula : | C4H11NO4S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | XALXJVVARIGVBA-UHFFFAOYSA-N |
M.W : | 169.20 | Pubchem ID : | 73554240 |
Synonyms : |
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Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H332-H335 | 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 |
---|---|---|
91% | 10 g of diethyl [4-(3-chloro-4-fluoro-phenylamino)-7-((S)-tetrahydrofuran-3-yloxy)- quinazolin-6-ylcarbamoyl]-methyl}-phosphonate and 0.8 g lithium chloride are suspended in 60 ml of ethanol and cooled to -5C. 11 g of 45percent potassium hydroxidesolutio? is added dropwise first of all and then 4.8 g dimethylaminoacetaldehyde- hydrogen sulphite adduct in 48 ml of water is added. The reaction solution is stirred for 1 h and then 60 ml of water are added. The suspension is suction filtered, washed with 40 ml of water and dried in vacuo at 45C. Yield: 8 g (91 percent of theoretical) m.p.: 100 -1020C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.6% | 40 g of dimethylaminoacetaldehyde diethylacetal are heated to 400C in a mixture of 48 g cone, hydrochloric acid and 20 ml of water for 3 h. Then a solution of 42.4 g sodium pyrosulphite in 72 ml of water (sodium hydrogen sulphite solution) is added dropwise and the mixture is stirred for 1 h. 200 ml of ethanol are added and then the mixture is stirred for 2 h at 00C. The suspension is suction filtered, washed with 160 ml of ethanol and dried at 45C in vacuo. Yield: 42.5 g (89.6 percent of theoretical) decomp.: from 180C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | Step 6: Synthesis of 2-((5-chloro-2-((3-(4-(dimethylamino)but-2-enamido)phenyl) amino)pyrimidin-4-yl)amino)-N-methylbenzamide (Compound XIII-8); A solution of diethyl (2-((3-((5-chloro-4-((2-(methylcarbamoyl) phenyl)amino) pyrimidin-2- yl)amino)phenyl)amino)-2-oxoethyl) phosphonate (6, 50 mg, 0.09 mmol) in ethanol (2 mL) was obtained, LiCl (7 mg, 0.09 mmol) and 37 percent KOH solution (0.5 mL) were added to the solution to form a mixture, and the mixture was stirred at room temperature for 30 min and further heated to 50 °C for 5 min.Dimethyl amino acetaldehyde hydrogen sulphite (24 mg) in 0.5 mL of water was then added to the mixture and the mixture was stirred at room temperature for 3 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was concentrated to dryness and diluted with water, and the product extracted with ethyl acetate. The organic extract was then dried over anhydrous sodium sulfate and evaporated to dryness to obtain a crude product. The crude product was purified by preparative TLC using 5 percent MeOH-DCM (2 runs) to afford Compound XIII-8 as an off white solid ( 10 mg, 23 percent). NMR (400 MHz, CD3OD): delta 8.74-8.71 (d, 1H), 8.08 (s, 1 H), 7.92 (s, 1 H), 7.65-7.63 (dd, 1 H), 7.42-7.38 (t, 1 H), 7.33-7.30 (m, 2H), 7.26-7.22 (m, 2H), 7.10-7.06 (t, 1 H), 6.92-6.85 (m, 1H), 6.28-6.24 (d, 1 H), 3.19-3.17 (d, 2H), 2.92 (s, 2H), 2.30 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68.9% | With lithium chloride monohydrate; potassium hydroxide; In ethanol; water; at 20℃; for 0.25h; | Lithium chloride monohydrate (105 mg, 1.28 mmol) was added to a solution of Id (400 mg, 0.64 mmol) in EtOH (10 mL), followed by KOH (45percent (wt), 1 mL) at room temperature. After 5 min, a solution of <strong>[1413945-87-5]dimethylaminoacetaldehyde-hydrogen sulphite adduct</strong> (214 mg, 1.28 mmol, prepared according to method in WO2007/85638) in H20 (4 mL) was added, stirred for 15 min, concentrated, diluted in DCM (200 mL), washed with H20 (2 x 100 mL), brine (100 mL), dried over MgS04, and concentrated. Column chromatography (0-20 percent MeOH/DCM, gradient), followed by lyophilization afforded 1 as white solids (246 mg, 68.9percent). 1HNMR (CDC13, 300 MHz) delta 9.16 (s, IH), 8.66 (s, IH), 8.04 (s, IH), 7.90 (d, IH), 7.75 (s, IH), 7.56 (m, IH), 7.40 (s, IH), 7.17 (m, IH), 7.06 (m, IH), 6.25 (d, IH), 5.05 (s, IH), 4.85 (t, IH), 4.74 (d, IH), 4.32 (m, 2H), 4.01 (m, 2H), 3.78 (t, IH), 3.54 (s, 2H), 3.20 (d, 2H), 2.35 (s, 6H). LCMS (ESI) m/z = 559 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68.9% | Lithium chloride monohydrate (105 mg, 1.28 mmol) was added to a solution of 1d (400 mg, 0.64 mmol) in EtOH (10 mL), followed by KOH (45percent (wt), 1 mL) at room temperature. After 5 min, a solution of <strong>[1413945-87-5]dimethylaminoacetaldehyde-hydrogen sulphite adduct</strong> (214 mg, 1.28 mmol, prepared according to method in WO2007/85638) in H2O (4 mL) was added, stirred for 15 min, concentrated, diluted in DCM (200 mL), washed with H2O (2×100 mL), brine (100 mL), dried over MgSO4, and concentrated. Column chromatography (0-20percent MeOH/DCM, gradient), followed by lyophilization afforded 1 as white solids (246 mg, 68.9percent). 1HNMR (CDCl3, 300 MHz) delta 9.16 (s, 1H), 8.66 (s, 1H), 8.04 (s, 1H), 7.90 (d, 1H), 7.75 (s, 1H), 7.56 (m, 1H), 7.40 (s, 1H), 7.17 (m, 1H), 7.06 (m, 1H), 6.25 (d, 1H), 5.05 (s, 1H), 4.85 (t, 1H), 4.74 (d, 1H), 4.32 (m, 2H), 4.01 (m, 2H), 3.78 (t, 1H), 3.54 (s, 2H), 3.20 (d, 2H), 2.35 (s, 6H). LCMS (ESI) m/z=559 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Starting material: 2-(dimethylamino)-acetaldehyde sulfite was prepared according to the method in WO2007/85638. [0193] Diethyl (2-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)amino)-1-fluoro-2-oxoethyl)phosphonate (1 eq.) and NaH (1.5 eq.) were dissolved in DMF (10 ml), and stirred at 0° C. for 30 min, then 2-(dimethylamino)-acetaldehyde sulfite (2.0 eq.) was added, ice bath was removed, and then the mixture warmed to room temperature naturally, and the reaction was stirred for another 3-5 h. After the reaction finished, the mixture was quenched with saturated NaHCO3, extracted with EtOAc, and the organic phase was dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, the crude product was purified by column chromatography (mobile phase 30:1 DCM/MeOH) and pale yellow of N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(dimethylamino)-2-fluorobut-2-enamide was given. MS (ESI+): m/z=448, 449, 450 [M+H]+. [0194] Rf values: 0.30 (Silica gel, ethyl acetate/methanol=5:1; two isomers were not separated); [0195] 0.53, 0.56 (Silica gel, dichloromethane/methanol=10:1; two isomers were separated). Example 2 [0196] The preparation of (Z)?N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(dimethylamino)-2-fluorobut-2-enamide and (E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(dimethylamino)-2-fluorobut-2-enamide [0197] Use Gilson 215 semi-preparative chromatography (322 pump, 156 UV detector) to separate the mixture of cis and trans-isomers obtained in example 1. [0198] Column: Phenomenex Gimini 30×250 mm, 10 mum; [0199] Detection wavelength: 254 nm; [0200] Column temperature: room temperature; [0201] Sample treatment method: sample (a mixture of cis and trans isomers) was dissolved in methanol, filtered. Concentration: 22 mg/ml, the volume of each needle injection was 800 muL. [0202] Mobile phase: water:acetonitrile (with 0.05percent aqueous ammonia)=49:51 [TABLE-US-00001] Time (min) Water (percent) Acetonitrile(percent) Gradient: 0 49 51 15.0 29 71 15.5 0 100 18.0 0 100 18.5 49 51 20.0 49 51 [0203] Collected the component at retention time of 14.5 min to obtain (Z)-isomer (Compound 2-1); and retention time of 16.0 min to obtain (E)-isomer (Compound 2-2). [0204] (Z)-Isomer Hydrochloride [0205] The obtained (Z)-isomer was dissolved in ethyl acetate, and concentrated hydrochloric acid was added dropwise until pH=1.0 to precipitate solid, a little diethyl ether was added dropwise, and the mixture was stirred overnight at room temperature, filtered and the residue was dried under reduced pressure to obtain hydrochloride. [0206] 1H NMR [(CD3)2SO]: delta 11.41 (s, 1H), 10.30 (s, 1H), 8.99 (s, 1H), 8.88 (s, 1H), 8.04 (dd, 1H), 7.77-7.70 (m, 1H), 7.58 (s, 1H), 7.56 (dd, 1H), 6.47 (td, 1H), 4.03 (s, 3H), 3.99 (br, 2H), 2.79 (s, 6H). [0207] (E)-Isomer [0208] 1H NMR (300 MHz, DMSO) delta 10.26 (s, 1H), 10.02 (s, 1H), 8.92 (d, J=2.7 Hz, 1H), 8.88 (d, J=1.5 Hz, 1H), 8.01 (dd, J1=6.6 Hz, J2=2.1 Hz, 1H), 7.70-7.67 (m, 1H), 7.56 (t, J=9.0 Hz, 1H), 7.42 (d, J=2.7 Hz, 1H), 6.34 (dt, J1=33.6 Hz, J2=7.5 Hz, 1H), 4.06 (s, 3H), 4.04 (brs, 2H), 2.33 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | (E)-N-(4-(3-chloro-4-fluorophenylamino)-7-(2-(tetrahydrofuran-3-yl)ethynyl)quinazolin-6-yl)-4-(dimethylamino)but-2-enamide (Example 1) Lithium chloride monohydrate (105 mg, 1.28 mmol) was added to a solution of 1.3 (358 mg, 0.64 mmol) in EtOH (3 mL), followed by KOH (45percent wt, 0.5 mL) at room temperature. After 5 min, a solution of <strong>[1413945-87-5]dimethylaminoacetaldehyde-hydrogen sulphite adduct</strong> (214 mg, 1.28 mmol) in H2O (2 mL) was added, stirred for 2 h. Water (5 mL) was added to the reaction. After 15 min, solid was collected by filtration, and rinsed with water, and dried to afford Example 1 as a white solid (246 mg, 78percent). 1HNMR (CDCl3, 300 MHz) delta 9.16 (s, 1H), 8.66 (s, 1H), 8.25 (s, 1H), 7.98 (dd, 1H), 7.94 (s, 1H), 7.72 (s, 1H), 7.56 (m, 1H), 7.17 (t, 1H), 7.08 (dt, 1H), 6.24 (d, 1H), 4.10 (m, 2H), 3.97 (m, 2H), 3.41 (m, 1H), 3.21 (d, 2H), 2.44 (m, 1H), 2.35 (s, 6H), 2.23 (m, 1H). MS (ESI) m/z=494 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In a 100 mL single-necked flask, 1 g (1.8 mmol)[2 - [[4 - [(3-chloro-4-fluorophenyl) -amino] -7-[(S) -tetrahydrofuran-3-yl) oxy] quinazolin-6-yl] amino]2-oxoethyl] phosphoric acid diethyl ester (2) and 0.077 g (1.8 mmol)Lithium chloride was added to 10 mL of ethanol and stirred to -5 ° C with stirring.First, 1 g of a KOH (45percent) aqueous solution was slowly added dropwise.Followed by the dropwise addition of 0.49 g (2.9 mmol)Dimethylaminoacetaldehyde bisulfiteOf aqueous solution 5mL, reaction 1h. The reaction was completed by adding 100 mL of water to precipitate a white solid,Filtration drying to get 0.8g, the yield of 90percent, purity 98.0percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.09 g | With lithium chloride; sodium hydroxide; In tetrahydrofuran; water; at 0 - 30℃;Inert atmosphere; | Under nitrogen protection,Methyl [bis(2,2,2-trifluoroethoxy)phosphinyl]acetate (3.18 g, 1 eq) was dissolved in tetrahydrofuran and lithium chloride (0.42 g, 1 eq) was added.Add sodium hydroxide in water (2.0 g, 5 eq, 1 mol/L) solution,Control temperature is 0 ° C to 30 ° C,Join again2-(Dimethylamino)acetaldehyde sulfite (3.4 g, 2 eq),Stir the reaction for 3 hours,After the reaction is completed, it is acidified,Extraction and column purification gave (2Z)-4-(dimethylamino)-2-butenoic acid hydrochloride (1.09 g). |
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