* 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.
With triethylamine In dichloromethane at 20℃; Cooling with ice
Compound (X) 40.12g (0.08mol) dissolved in 280 ml methylene chloride, then adding 16.2g (0.16mol) triethylamine, acryloyl chloride dropwise under ice bath 9.05g (0.10mol), and then room temperature reaction 4-5h. Remove the solvent under reduced pressure, to residue 200 ml water, stirring after-filtration, to obtain a kind of white solid, dichloromethane/methanol is recrystallized to get kind of white powder 41.0g, purity 99.6percent, yield 92percent.
Reference：
[1] Patent: CN105461640, 2016, A, . Location in patent: Paragraph 0006; 0028; 0029
2
[ 625-36-5 ]
[ 1374640-70-6 ]
Yield
Reaction Conditions
Operation in experiment
4.7 g
With sodium hydrogencarbonate In tetrahydrofuran; water at 0℃;
5g of intermediate V with 150mlTHF dissolved, then 75ml of water was dissolved 2.3g of sodium bicarbonate and water was added to the reaction mixture a solvent, 0 placed in the reaction, the reaction liquid at this time as a red supernatant, the chloropropionyl chloride with 1.3g 75mlTHF dilution, was slowly added dropwise to the reaction mixture.TLC analysis after the addition was complete the reaction was complete feed.The reaction solution was spin to most of the tetrahydrofuran, was added 100ml of saturated aqueous sodium bicarbonate, 3 × 100ml extracted three times with ethyl acetate, the organic phases combined, dried over anhydrous sodium sulfate, filtered, and ethyl acetate was removed by rotary evaporation 2/3.Was added to the rotovap 7gDBU, 60 stirred for 12h, TLC detection starting material the reaction was complete, the aqueous solution was washed with 100ml × 3 was added, the organic phase is retained, dried over anhydrous sodium sulfate, filtered, spin-dries off-white solid, ethyl acetate was added heavy crystallized 4.7g, HPLC purity 99.6percent detection products
Reference：
[1] Patent: CN105481779, 2016, A, . Location in patent: Paragraph 0013; 0047; 0048; 0049; 0050
3
[ 7530-31-6 ]
[ 1374640-70-6 ]
Yield
Reaction Conditions
Operation in experiment
2.15 g
With caesium carbonate In N,N-dimethyl-formamide at 90 - 100℃; for 12 h;
Adding 2-[[4-(4-acetyl-1 -piperazinyl)-2-methoxy- phenyl]amino]-5-(trifluoromethyl)-pyrimidin-4-one (IV) (2.06 g, 5 mmol) and phosphorus oxychloride (7.5 mL) into a reaction flask, starting stirring, cooling to 0° C. or below, and dropwisely adding 3.5 mL of 2,6-dimethylpyridine. Slowly heating to 50-70° C., and stirring to react for 9 hours while maintaining the temperature. Reducing the pressure to recover the phosphorus oxychloride, cooling the residue to room temperature, and quenching the reaction with ice watet Extracting with dichloromethane for 3 times, combining organic phases, washing with water, drying with anhydrous sodium sulfate, reducing the pressure to recover the solvent, dissolving an obtained oily matter 2-[[4-(4- acetyl- 1 -piperazinyl)-2-methoxyphenyl]amino] -5-(trifluo- romethyl)-4-chloro-pyrimidine (V) with 25 mL of N,Ndimethylformamide, transferring into the reaction flask, and adding N-(3-aminophenyl)-2-acrylamide (1.0 g, 6 mmol) and a catalyst cesium carbonate (0.3 g). Stirring to react for 12 hours while maintaining the temperature at 90-110° C., and performing TLC detection until the reaction is finished. Filtering, concentrating under reduced pressure, adding ethyl acetate and water into the residue, and regulating pH to 5-6 with dilute acid. Separating out the organic phases, and extracting a water phase with ethyl acetate for 3 times. Combining the organic phases, washing the organic phases sequentially with pure water and brine, drying, performing reduced pressure distillation to recover the solvent, and washing with ethanol to obtain 2.15 g of an off-white solid rociletinib, wherein the yield is 77.5percent. Mass spec (El):El-MS mlz: 556 [M+H], ‘H NMR (DMSO-d5): ö 2.05 (s, 3H), 3.01 (m, 4H), 3.55 (m, 4H), 3.77 (m, 3H), 5.78 (d, 1H),6.25 (d, 2H), 6.44 (m, 1H), 6.61 (s, 1H), 7.17 (s, 1H), 7.28 (m, 1H), 7.52 (m, 2H), 7.76 (s, 1H), 8.08 (s, 1H), 8.28 (s, 1H), 8.63 (s, 1H), 10.21 (s, 1H).
(N-(3-(2-(4-(4-acetylpiperazin-1-yl)-2-methoxyphenylamino)-5-(trifluoromethyl)pyrimidin-4-ylamino)phenyl)acrylamide) trifluoroacetate salt[ No CAS ]
[ 1374640-70-6 ]
Yield
Reaction Conditions
Operation in experiment
With sodium carbonate; In dichloromethane; at 0 - 20℃; for 0.583333h;
Step 5: [00185] To obtain the free base form of Compound 1 from the TFA salt, the salt was added to DCM and cooled to 0 C. Na2C03 solution (9.6% w/w) was added at 0 C. The mixture was warmed to 20 C and stirred for 35 min. The pH of the aqueous layer was > 8. The layers were separated. Extraction of the aqueous layer was performed using DCM. The organic layers were combined and washed with brine. The organic layer was collected and evaporated to yield a solid of Compound 1.
With water; sodium carbonate; In dichloromethane; at 0 - 20℃; for 0.583333h;pH > 8;
Step 5: [00239] To obtain the free base form of Compound 1 from the TFA salt, the salt was added to DCM and cooled to 0C. Na2C03 solution (9.6% w/w) was added at 0C. The mixture was warmed to 20C and stirred for 35 min. The pH of the aqueous layer was > 8. The layers were separated. Extraction of the aqueous layer was performed using DCM. The organic layers were combined and washed with brine. The organic layer was collected and evaporated to yield a solid of Compound 1.
With sodium carbonate; In dichloromethane; water; at 0 - 20℃; for 0.583333h;pH > 8;
To obtain the free base form of Compound 1 from the TFA salt, the salt was added to DCM and cooled to 0C. Na2CO3 solution (9.6% w/w) was added at 0C. The mixture was warmed to 20C and stirred for 35 min. The pH of the aqueous layer was > 8. The layers were separated. Extraction of the aqueous layer was performed using DCM. The organic layers were combined and washed with brine. The organic layer was collected and evaporated to yield a solid of Compound 1.
For each counterion and solvent system, ca. 25 or 50 mg of the free base of Compound 1 was slurried in 200-300 mu of the allocated solvent. The solvents included acetone, dichloromethane, cyclohexane, ethyl acetate, methanol (methyl ethyl ketone for sulfonic acid-containing counterions), methyl isobutyl ketone, 2-propanol (isopropyl acetate for sulfonic acid-containing counterions), tetrahydrofuran and acetonitrile:water (90: 10). The respective counterion was also dissolved / slurried in 200-300 mu of the allocated solvent. The counterions included benzenesulfonic acid, camphor sulfonic acid, 1,2-ethane disulfonic acid, hydrobromic acid, hydrochloric acid, maleic acid, methanesulfonic acid, naphthalene-2- sulfonic acid, 1,5 -naphthalene disulfonic acid, oxalic acid, 4-toluenesulfonic acid and 2,4,6- trihydroxybenzoic acid. One equivalent of each counterion was used and additional experiments with two equivalents of benzenesulfonic acid, hydrochloric acid, sulphuric acid and p-toluenesulfonic acid were performed. The acid solution / slurry was then added to the slurry of Compound 1 in small aliquots in order to minimize the risk of degradation. The pH of the reaction was then checked using universal indicator paper. The mixtures of Compound 1/counterion/solvent created using the procedure above were temperature cycled between ca. 0C and ambient (ca. 22C) whilst stirring in 1 hour cycles for a period of 1-2 days. Overnight, samples were kept at ca. 2-5C. The mixtures were visually checked for any obvious signs of degradation (i.e. color changes) and then, if not visually degraded, any solids present were isolated and allowed to dry at ambient conditions prior to analysis. The solids represent isolated Compound 2.
For each counterion and solvent system, ca. 25 or 50 mg of the free base of Compound 1 was slurried in 200-300 mu of the allocated solvent. The solvents included acetone, dichloromethane, cyclohexane, ethyl acetate, methanol (methyl ethyl ketone for sulfonic acid-containing counterions), methyl isobutyl ketone, 2-propanol (isopropyl acetate for sulfonic acid-containing counterions), tetrahydrofuran and acetonitrile:water (90: 10). The respective counterion was also dissolved / slurried in 200-300 mu of the allocated solvent. The counterions included benzenesulfonic acid, camphor sulfonic acid, 1,2-ethane disulfonic acid, hydrobromic acid, hydrochloric acid, maleic acid, methanesulfonic acid, naphthalene-2- sulfonic acid, 1,5 -naphthalene disulfonic acid, oxalic acid, 4-toluenesulfonic acid and 2,4,6- trihydroxybenzoic acid. One equivalent of each counterion was used and additional experiments with two equivalents of benzenesulfonic acid, hydrochloric acid, sulphuric acid and p-toluenesulfonic acid were performed. The acid solution / slurry was then added to the slurry of Compound 1 in small aliquots in order to minimize the risk of degradation. The pH of the reaction was then checked using universal indicator paper. The mixtures of Compound 1/counterion/solvent created using the procedure above were temperature cycled between ca. 0C and ambient (ca. 22C) whilst stirring in 1 hour cycles for a period of 1-2 days. Overnight, samples were kept at ca. 2-5C. The mixtures were visually checked for any obvious signs of degradation (i.e. color changes) and then, if not visually degraded, any solids present were isolated and allowed to dry at ambient conditions prior to analysis. The solids represent isolated Compound 2. Approximately 3 mL of dichloromethane was added to a. 200 mg of Compound 1 to form a slurry. In a separate vial, a. 1 mL of dichloromethane was added to 1 equivalent of maleic acid in order to dissolve the acid. The acid solution was then added in small aliquots to the freebase slurry while stirring. The slurry obtained was yellow in color. The reaction was stirred for a. 1.5 days between 0 C and ambient temperature (Ca. 22 C) and remained at a. 4 C for a further 2 days before being isolated and dried at ambient. The material was dried at ambient temperature under vacuum (Ca. 22 C) for a. 2 days.
With hydrogen bromide; In dichloromethane; at 0 - 5℃; for 4.0h;
For each counterion and solvent system, ca. 25 or 50 mg of the free base of Compound 1 was slurried in 200-300 mu of the allocated solvent. The solvents included acetone, dichloromethane, cyclohexane, ethyl acetate, methanol (methyl ethyl ketone for sulfonic acid-containing counterions), methyl isobutyl ketone, 2-propanol (isopropyl acetate for sulfonic acid-containing counterions), tetrahydrofuran and acetonitrile:water (90: 10). The respective counterion was also dissolved / slurried in 200-300 mu of the allocated solvent. The counterions included benzenesulfonic acid, camphor sulfonic acid, 1,2-ethane disulfonic acid, hydrobromic acid, hydrochloric acid, maleic acid, methanesulfonic acid, naphthalene-2- sulfonic acid, 1,5 -naphthalene disulfonic acid, oxalic acid, 4-toluenesulfonic acid and 2,4,6- trihydroxybenzoic acid. One equivalent of each counterion was used and additional experiments with two equivalents of benzenesulfonic acid, hydrochloric acid, sulphuric acid and p-toluenesulfonic acid were performed. The acid solution / slurry was then added to the slurry of Compound 1 in small aliquots in order to minimize the risk of degradation. The pH of the reaction was then checked using universal indicator paper. The mixtures of Compound 1/counterion/solvent created using the procedure above were temperature cycled between ca. 0C and ambient (ca. 22C) whilst stirring in 1 hour cycles for a period of 1-2 days. Overnight, samples were kept at ca. 2-5C. The mixtures were visually checked for any obvious signs of degradation (i.e. color changes) and then, if not visually degraded, any solids present were isolated and allowed to dry at ambient conditions prior to analysis. The solids represent isolated Compound 2. Approximately lml of methanol was added to Ca. 200 mg of Compound 1 to form a slurry. In a separate vial, Ca. 1 mL of methanol was added to 2 equivalents of hydrobromic acid (48%). The acid solution was then added dropwise over a 1 hour period to the free base slurry whilst stirring and maintaining a temperature between 0-5 C. After the complete addition of the acid, a further 1 mL of methanol was added. The reaction was stirred for Ca. 3 hours before being isolated and dried. A yield of approximately 68% was obtained.
For each counterion and solvent system, ca. 25 or 50 mg of the free base of Compound 1 was slurried in 200-300 mu of the allocated solvent. The solvents included acetone, dichloromethane, cyclohexane, ethyl acetate, methanol (methyl ethyl ketone for sulfonic acid-containing counterions), methyl isobutyl ketone, 2-propanol (isopropyl acetate for sulfonic acid-containing counterions), tetrahydrofuran and acetonitrile:water (90: 10). The respective counterion was also dissolved / slurried in 200-300 mu of the allocated solvent. The counterions included benzenesulfonic acid, camphor sulfonic acid, 1,2-ethane disulfonic acid, hydrobromic acid, hydrochloric acid, maleic acid, methanesulfonic acid, naphthalene-2- sulfonic acid, 1,5 -naphthalene disulfonic acid, oxalic acid, 4-toluenesulfonic acid and 2,4,6- trihydroxybenzoic acid. One equivalent of each counterion was used and additional experiments with two equivalents of benzenesulfonic acid, hydrochloric acid, sulphuric acid and p-toluenesulfonic acid were performed. The acid solution / slurry was then added to the slurry of Compound 1 in small aliquots in order to minimize the risk of degradation. The pH of the reaction was then checked using universal indicator paper. The mixtures of Compound 1/counterion/solvent created using the procedure above were temperature cycled between ca. 0C and ambient (ca. 22C) whilst stirring in 1 hour cycles for a period of 1-2 days. Overnight, samples were kept at ca. 2-5C. The mixtures were visually checked for any obvious signs of degradation (i.e. color changes) and then, if not visually degraded, any solids present were isolated and allowed to dry at ambient conditions prior to analysis. The solids represent isolated Compound 2.
In water; acetonitrile; at 0 - 22℃;
General procedure: General Preparation of Compound 2 [00240] For each counterion and solvent system, ca. 25 or 50 mg of the free base of Compound 1 was slurried in 200-300 mu of the allocated solvent. The solvents included acetone, dichloromethane, cyclohexane, ethyl acetate, methanol (methyl ethyl ketone for sulfonic acid-containing counterions), methyl isobutyl ketone, 2-propanol (isopropyl acetate for sulfonic acid-containing counterions), tetrahydrofuran and acetonitrile: water (90: 10). The respective counterion was also dissolved / slurried in 200-300 mu of the allocated solvent. The counterions included benzenesulfonic acid, camphor sulfonic acid, 1,2-ethane disulfonic acid, hydrobromic acid, hydrochloric acid, maleic acid, methanesulfonic acid, naphthalene-2- sulfonic acid, 1,5 -naphthalene disulfonic acid, oxalic acid, 4-toluenesulfonic acid and 2,4,6- trihydroxybenzoic acid. One equivalent of each counterion was used and additional experiments with two equivalents of benzenesulfonic acid, hydrochloric acid, sulphuric acid and p-toluenesulfonic acid were performed. The acid solution / slurry was then added to the slurry of Compound 1 in small aliquots in order to minimize the risk of degradation. The pH of the reaction was then checked using universal indicator paper. [00241] The mixtures of Compound 1/counterion/solvent created using the procedure above were temperature cycled between ca. 0C and ambient {ca. 22C) whilst stirring in 1 hour cycles for a period of 1-2 days. Overnight, samples were kept at ca. 2-5 C. The mixtures were visually checked for any obvious signs of degradation {i.e. color changes) and then, if not visually degraded, any solids present were isolated and allowed to dry at ambient conditions prior to analysis. The solids represent isolated Compound 2.
For each counterion and solvent system, ca. 25 or 50 mg of the free base of Compound 1 was slurried in 200-300 mu of the allocated solvent. The solvents included acetone, dichloromethane, cyclohexane, ethyl acetate, methanol (methyl ethyl ketone for sulfonic acid-containing counterions), methyl isobutyl ketone, 2-propanol (isopropyl acetate for sulfonic acid-containing counterions), tetrahydrofuran and acetonitrile:water (90: 10). The respective counterion was also dissolved / slurried in 200-300 mu of the allocated solvent. The counterions included benzenesulfonic acid, camphor sulfonic acid, 1,2-ethane disulfonic acid, hydrobromic acid, hydrochloric acid, maleic acid, methanesulfonic acid, naphthalene-2- sulfonic acid, 1,5 -naphthalene disulfonic acid, oxalic acid, 4-toluenesulfonic acid and 2,4,6- trihydroxybenzoic acid. One equivalent of each counterion was used and additional experiments with two equivalents of benzenesulfonic acid, hydrochloric acid, sulphuric acid and p-toluenesulfonic acid were performed. The acid solution / slurry was then added to the slurry of Compound 1 in small aliquots in order to minimize the risk of degradation. The pH of the reaction was then checked using universal indicator paper. The mixtures of Compound 1/counterion/solvent created using the procedure above were temperature cycled between ca. 0C and ambient (ca. 22C) whilst stirring in 1 hour cycles for a period of 1-2 days. Overnight, samples were kept at ca. 2-5C. The mixtures were visually checked for any obvious signs of degradation (i.e. color changes) and then, if not visually degraded, any solids present were isolated and allowed to dry at ambient conditions prior to analysis. The solids represent isolated Compound 2.
In acetone; at 0 - 22℃;
General procedure: General Preparation of Compound 2 [00240] For each counterion and solvent system, ca. 25 or 50 mg of the free base of Compound 1 was slurried in 200-300 mu of the allocated solvent. The solvents included acetone, dichloromethane, cyclohexane, ethyl acetate, methanol (methyl ethyl ketone for sulfonic acid-containing counterions), methyl isobutyl ketone, 2-propanol (isopropyl acetate for sulfonic acid-containing counterions), tetrahydrofuran and acetonitrile: water (90: 10). The respective counterion was also dissolved / slurried in 200-300 mu of the allocated solvent. The counterions included benzenesulfonic acid, camphor sulfonic acid, 1,2-ethane disulfonic acid, hydrobromic acid, hydrochloric acid, maleic acid, methanesulfonic acid, naphthalene-2- sulfonic acid, 1,5 -naphthalene disulfonic acid, oxalic acid, 4-toluenesulfonic acid and 2,4,6- trihydroxybenzoic acid. One equivalent of each counterion was used and additional experiments with two equivalents of benzenesulfonic acid, hydrochloric acid, sulphuric acid and p-toluenesulfonic acid were performed. The acid solution / slurry was then added to the slurry of Compound 1 in small aliquots in order to minimize the risk of degradation. The pH of the reaction was then checked using universal indicator paper. [00241] The mixtures of Compound 1/counterion/solvent created using the procedure above were temperature cycled between ca. 0C and ambient {ca. 22C) whilst stirring in 1 hour cycles for a period of 1-2 days. Overnight, samples were kept at ca. 2-5 C. The mixtures were visually checked for any obvious signs of degradation {i.e. color changes) and then, if not visually degraded, any solids present were isolated and allowed to dry at ambient conditions prior to analysis. The solids represent isolated Compound 2.
For each counterion and solvent system, ca. 25 or 50 mg of the free base of Compound 1 was slurried in 200-300 mu of the allocated solvent. The solvents included acetone, dichloromethane, cyclohexane, ethyl acetate, methanol (methyl ethyl ketone for sulfonic acid-containing counterions), methyl isobutyl ketone, 2-propanol (isopropyl acetate for sulfonic acid-containing counterions), tetrahydrofuran and acetonitrile:water (90: 10). The respective counterion was also dissolved / slurried in 200-300 mu of the allocated solvent. The counterions included benzenesulfonic acid, camphor sulfonic acid, 1,2-ethane disulfonic acid, hydrobromic acid, hydrochloric acid, maleic acid, methanesulfonic acid, naphthalene-2- sulfonic acid, 1,5 -naphthalene disulfonic acid, oxalic acid, 4-toluenesulfonic acid and 2,4,6- trihydroxybenzoic acid. One equivalent of each counterion was used and additional experiments with two equivalents of benzenesulfonic acid, hydrochloric acid, sulphuric acid and p-toluenesulfonic acid were performed. The acid solution / slurry was then added to the slurry of Compound 1 in small aliquots in order to minimize the risk of degradation. The pH of the reaction was then checked using universal indicator paper. The mixtures of Compound 1/counterion/solvent created using the procedure above were temperature cycled between ca. 0C and ambient (ca. 22C) whilst stirring in 1 hour cycles for a period of 1-2 days. Overnight, samples were kept at ca. 2-5C. The mixtures were visually checked for any obvious signs of degradation (i.e. color changes) and then, if not visually degraded, any solids present were isolated and allowed to dry at ambient conditions prior to analysis. The solids represent isolated Compound 2. Approximately 5 mL of acetone was added to approximately 800 mg of Compound 1 to form a slurry. In a separate vial, approximately 3 mL acetone was added to 2 equivalents of benzenesulfonic acid to dissolve the acid. The acid solution was then added in small aliquots to the free base slurry while stirring. After the complete addition of the acid, a gumloil-like material initially formed, however, this converted to a solid after Ca. 30 minutes of stirring. The reaction was stirred for Ca. 1.5 days before being isolated and dried. The material was initially dried at ambient under vacuum (ca. 22C) for 3 days, however, approximately 6.7% acetone was still present at this stage. A portion was then dried for a further 2 days at 40C under vacuum after which Ca. 2.7% acetone remained. The material was then dried for a further 2 days at 60C under vacuum. The yield was 1.1 g of material (86%).
For each counterion and solvent system, ca. 25 or 50 mg of the free base of Compound 1 was slurried in 200-300 mu of the allocated solvent. The solvents included acetone, dichloromethane, cyclohexane, ethyl acetate, methanol (methyl ethyl ketone for sulfonic acid-containing counterions), methyl isobutyl ketone, 2-propanol (isopropyl acetate for sulfonic acid-containing counterions), tetrahydrofuran and acetonitrile:water (90: 10). The respective counterion was also dissolved / slurried in 200-300 mu of the allocated solvent. The counterions included benzenesulfonic acid, camphor sulfonic acid, 1,2-ethane disulfonic acid, hydrobromic acid, hydrochloric acid, maleic acid, methanesulfonic acid, naphthalene-2- sulfonic acid, 1,5 -naphthalene disulfonic acid, oxalic acid, 4-toluenesulfonic acid and 2,4,6- trihydroxybenzoic acid. One equivalent of each counterion was used and additional experiments with two equivalents of benzenesulfonic acid, hydrochloric acid, sulphuric acid and p-toluenesulfonic acid were performed. The acid solution / slurry was then added to the slurry of Compound 1 in small aliquots in order to minimize the risk of degradation. The pH of the reaction was then checked using universal indicator paper. The mixtures of Compound 1/counterion/solvent created using the procedure above were temperature cycled between ca. 0C and ambient (ca. 22C) whilst stirring in 1 hour cycles for a period of 1-2 days. Overnight, samples were kept at ca. 2-5C. The mixtures were visually checked for any obvious signs of degradation (i.e. color changes) and then, if not visually degraded, any solids present were isolated and allowed to dry at ambient conditions prior to analysis. The solids represent isolated Compound 2.
For each counterion and solvent system, ca. 25 or 50 mg of the free base of Compound 1 was slurried in 200-300 mu of the allocated solvent. The solvents included acetone, dichloromethane, cyclohexane, ethyl acetate, methanol (methyl ethyl ketone for sulfonic acid-containing counterions), methyl isobutyl ketone, 2-propanol (isopropyl acetate for sulfonic acid-containing counterions), tetrahydrofuran and acetonitrile:water (90: 10). The respective counterion was also dissolved / slurried in 200-300 mu of the allocated solvent. The counterions included benzenesulfonic acid, camphor sulfonic acid, 1,2-ethane disulfonic acid, hydrobromic acid, hydrochloric acid, maleic acid, methanesulfonic acid, naphthalene-2- sulfonic acid, 1,5 -naphthalene disulfonic acid, oxalic acid, 4-toluenesulfonic acid and 2,4,6- trihydroxybenzoic acid. One equivalent of each counterion was used and additional experiments with two equivalents of benzenesulfonic acid, hydrochloric acid, sulphuric acid and p-toluenesulfonic acid were performed. The acid solution / slurry was then added to the slurry of Compound 1 in small aliquots in order to minimize the risk of degradation. The pH of the reaction was then checked using universal indicator paper. The mixtures of Compound 1/counterion/solvent created using the procedure above were temperature cycled between ca. 0C and ambient (ca. 22C) whilst stirring in 1 hour cycles for a period of 1-2 days. Overnight, samples were kept at ca. 2-5C. The mixtures were visually checked for any obvious signs of degradation (i.e. color changes) and then, if not visually degraded, any solids present were isolated and allowed to dry at ambient conditions prior to analysis. The solids represent isolated Compound 2. Approximately 3 mL of dichloromethane was added to a. 200 mg of Compound 1 to form a slurry. In a separate vial, a. 1 mL of dichloromethane was added to 1 equivalent of maleic acid in order to dissolve the acid. The acid solution was then added in small aliquots to the freebase slurry while stirring. The slurry obtained was yellow in color. The reaction was stirred for a. 1.5 days between 0 C and ambient temperature (Ca. 22 C) and remained at a. 4 C for a further 2 days before being isolated and dried at ambient. The material was dried at ambient temperature under vacuum (Ca. 22 C) for a. 2 days.
For each counterion and solvent system, ca. 25 or 50 mg of the free base of Compound 1 was slurried in 200-300 mu of the allocated solvent. The solvents included acetone, dichloromethane, cyclohexane, ethyl acetate, methanol (methyl ethyl ketone for sulfonic acid-containing counterions), methyl isobutyl ketone, 2-propanol (isopropyl acetate for sulfonic acid-containing counterions), tetrahydrofuran and acetonitrile:water (90: 10). The respective counterion was also dissolved / slurried in 200-300 mu of the allocated solvent. The counterions included benzenesulfonic acid, camphor sulfonic acid, 1,2-ethane disulfonic acid, hydrobromic acid, hydrochloric acid, maleic acid, methanesulfonic acid, naphthalene-2- sulfonic acid, 1,5 -naphthalene disulfonic acid, oxalic acid, 4-toluenesulfonic acid and 2,4,6- trihydroxybenzoic acid. One equivalent of each counterion was used and additional experiments with two equivalents of benzenesulfonic acid, hydrochloric acid, sulphuric acid and p-toluenesulfonic acid were performed. The acid solution / slurry was then added to the slurry of Compound 1 in small aliquots in order to minimize the risk of degradation. The pH of the reaction was then checked using universal indicator paper. The mixtures of Compound 1/counterion/solvent created using the procedure above were temperature cycled between ca. 0C and ambient (ca. 22C) whilst stirring in 1 hour cycles for a period of 1-2 days. Overnight, samples were kept at ca. 2-5C. The mixtures were visually checked for any obvious signs of degradation (i.e. color changes) and then, if not visually degraded, any solids present were isolated and allowed to dry at ambient conditions prior to analysis. The solids represent isolated Compound 2.
For each counterion and solvent system, ca. 25 or 50 mg of the free base of Compound 1 was slurried in 200-300 mu of the allocated solvent. The solvents included acetone, dichloromethane, cyclohexane, ethyl acetate, methanol (methyl ethyl ketone for sulfonic acid-containing counterions), methyl isobutyl ketone, 2-propanol (isopropyl acetate for sulfonic acid-containing counterions), tetrahydrofuran and acetonitrile:water (90: 10). The respective counterion was also dissolved / slurried in 200-300 mu of the allocated solvent. The counterions included benzenesulfonic acid, camphor sulfonic acid, 1,2-ethane disulfonic acid, hydrobromic acid, hydrochloric acid, maleic acid, methanesulfonic acid, naphthalene-2- sulfonic acid, 1,5 -naphthalene disulfonic acid, oxalic acid, 4-toluenesulfonic acid and 2,4,6- trihydroxybenzoic acid. One equivalent of each counterion was used and additional experiments with two equivalents of benzenesulfonic acid, hydrochloric acid, sulphuric acid and p-toluenesulfonic acid were performed. The acid solution / slurry was then added to the slurry of Compound 1 in small aliquots in order to minimize the risk of degradation. The pH of the reaction was then checked using universal indicator paper. The mixtures of Compound 1/counterion/solvent created using the procedure above were temperature cycled between ca. 0C and ambient (ca. 22C) whilst stirring in 1 hour cycles for a period of 1-2 days. Overnight, samples were kept at ca. 2-5C. The mixtures were visually checked for any obvious signs of degradation (i.e. color changes) and then, if not visually degraded, any solids present were isolated and allowed to dry at ambient conditions prior to analysis. The solids represent isolated Compound 2.
For each counterion and solvent system, ca. 25 or 50 mg of the free base of Compound 1 was slurried in 200-300 mu of the allocated solvent. The solvents included acetone, dichloromethane, cyclohexane, ethyl acetate, methanol (methyl ethyl ketone for sulfonic acid-containing counterions), methyl isobutyl ketone, 2-propanol (isopropyl acetate for sulfonic acid-containing counterions), tetrahydrofuran and acetonitrile:water (90: 10). The respective counterion was also dissolved / slurried in 200-300 mu of the allocated solvent. The counterions included benzenesulfonic acid, camphor sulfonic acid, 1,2-ethane disulfonic acid, hydrobromic acid, hydrochloric acid, maleic acid, methanesulfonic acid, naphthalene-2- sulfonic acid, 1,5 -naphthalene disulfonic acid, oxalic acid, 4-toluenesulfonic acid and 2,4,6- trihydroxybenzoic acid. One equivalent of each counterion was used and additional experiments with two equivalents of benzenesulfonic acid, hydrochloric acid, sulphuric acid and p-toluenesulfonic acid were performed. The acid solution / slurry was then added to the slurry of Compound 1 in small aliquots in order to minimize the risk of degradation. The pH of the reaction was then checked using universal indicator paper. The mixtures of Compound 1/counterion/solvent created using the procedure above were temperature cycled between ca. 0C and ambient (ca. 22C) whilst stirring in 1 hour cycles for a period of 1-2 days. Overnight, samples were kept at ca. 2-5C. The mixtures were visually checked for any obvious signs of degradation (i.e. color changes) and then, if not visually degraded, any solids present were isolated and allowed to dry at ambient conditions prior to analysis. The solids represent isolated Compound 2.
For each counterion and solvent system, ca. 25 or 50 mg of the free base of Compound 1 was slurried in 200-300 mu of the allocated solvent. The solvents included acetone, dichloromethane, cyclohexane, ethyl acetate, methanol (methyl ethyl ketone for sulfonic acid-containing counterions), methyl isobutyl ketone, 2-propanol (isopropyl acetate for sulfonic acid-containing counterions), tetrahydrofuran and acetonitrile:water (90: 10). The respective counterion was also dissolved / slurried in 200-300 mu of the allocated solvent. The counterions included benzenesulfonic acid, camphor sulfonic acid, 1,2-ethane disulfonic acid, hydrobromic acid, hydrochloric acid, maleic acid, methanesulfonic acid, naphthalene-2- sulfonic acid, 1,5 -naphthalene disulfonic acid, oxalic acid, 4-toluenesulfonic acid and 2,4,6- trihydroxybenzoic acid. One equivalent of each counterion was used and additional experiments with two equivalents of benzenesulfonic acid, hydrochloric acid, sulphuric acid and p-toluenesulfonic acid were performed. The acid solution / slurry was then added to the slurry of Compound 1 in small aliquots in order to minimize the risk of degradation. The pH of the reaction was then checked using universal indicator paper. The mixtures of Compound 1/counterion/solvent created using the procedure above were temperature cycled between ca. 0C and ambient (ca. 22C) whilst stirring in 1 hour cycles for a period of 1-2 days. Overnight, samples were kept at ca. 2-5C. The mixtures were visually checked for any obvious signs of degradation (i.e. color changes) and then, if not visually degraded, any solids present were isolated and allowed to dry at ambient conditions prior to analysis. The solids represent isolated Compound 2.
For each counterion and solvent system, ca. 25 or 50 mg of the free base of Compound 1 was slurried in 200-300 mu of the allocated solvent. The solvents included acetone, dichloromethane, cyclohexane, ethyl acetate, methanol (methyl ethyl ketone for sulfonic acid-containing counterions), methyl isobutyl ketone, 2-propanol (isopropyl acetate for sulfonic acid-containing counterions), tetrahydrofuran and acetonitrile:water (90: 10). The respective counterion was also dissolved / slurried in 200-300 mu of the allocated solvent. The counterions included benzenesulfonic acid, camphor sulfonic acid, 1,2-ethane disulfonic acid, hydrobromic acid, hydrochloric acid, maleic acid, methanesulfonic acid, naphthalene-2- sulfonic acid, 1,5 -naphthalene disulfonic acid, oxalic acid, 4-toluenesulfonic acid and 2,4,6- trihydroxybenzoic acid. One equivalent of each counterion was used and additional experiments with two equivalents of benzenesulfonic acid, hydrochloric acid, sulphuric acid and p-toluenesulfonic acid were performed. The acid solution / slurry was then added to the slurry of Compound 1 in small aliquots in order to minimize the risk of degradation. The pH of the reaction was then checked using universal indicator paper. The mixtures of Compound 1/counterion/solvent created using the procedure above were temperature cycled between ca. 0C and ambient (ca. 22C) whilst stirring in 1 hour cycles for a period of 1-2 days. Overnight, samples were kept at ca. 2-5C. The mixtures were visually checked for any obvious signs of degradation (i.e. color changes) and then, if not visually degraded, any solids present were isolated and allowed to dry at ambient conditions prior to analysis. The solids represent isolated Compound 2.
For each counterion and solvent system, ca. 25 or 50 mg of the free base of Compound 1 was slurried in 200-300 mu of the allocated solvent. The solvents included acetone, dichloromethane, cyclohexane, ethyl acetate, methanol (methyl ethyl ketone for sulfonic acid-containing counterions), methyl isobutyl ketone, 2-propanol (isopropyl acetate for sulfonic acid-containing counterions), tetrahydrofuran and acetonitrile:water (90: 10). The respective counterion was also dissolved / slurried in 200-300 mu of the allocated solvent. The counterions included benzenesulfonic acid, camphor sulfonic acid, 1,2-ethane disulfonic acid, hydrobromic acid, hydrochloric acid, maleic acid, methanesulfonic acid, naphthalene-2- sulfonic acid, 1,5 -naphthalene disulfonic acid, oxalic acid, 4-toluenesulfonic acid and 2,4,6- trihydroxybenzoic acid. One equivalent of each counterion was used and additional experiments with two equivalents of benzenesulfonic acid, hydrochloric acid, sulphuric acid and p-toluenesulfonic acid were performed. The acid solution / slurry was then added to the slurry of Compound 1 in small aliquots in order to minimize the risk of degradation. The pH of the reaction was then checked using universal indicator paper. The mixtures of Compound 1/counterion/solvent created using the procedure above were temperature cycled between ca. 0C and ambient (ca. 22C) whilst stirring in 1 hour cycles for a period of 1-2 days. Overnight, samples were kept at ca. 2-5C. The mixtures were visually checked for any obvious signs of degradation (i.e. color changes) and then, if not visually degraded, any solids present were isolated and allowed to dry at ambient conditions prior to analysis. The solids represent isolated Compound 2.
For each counterion and solvent system, ca. 25 or 50 mg of the free base of Compound 1 was slurried in 200-300 mu of the allocated solvent. The solvents included acetone, dichloromethane, cyclohexane, ethyl acetate, methanol (methyl ethyl ketone for sulfonic acid-containing counterions), methyl isobutyl ketone, 2-propanol (isopropyl acetate for sulfonic acid-containing counterions), tetrahydrofuran and acetonitrile:water (90: 10). The respective counterion was also dissolved / slurried in 200-300 mu of the allocated solvent. The counterions included benzenesulfonic acid, camphor sulfonic acid, 1,2-ethane disulfonic acid, hydrobromic acid, hydrochloric acid, maleic acid, methanesulfonic acid, naphthalene-2- sulfonic acid, 1,5 -naphthalene disulfonic acid, oxalic acid, 4-toluenesulfonic acid and 2,4,6- trihydroxybenzoic acid. One equivalent of each counterion was used and additional experiments with two equivalents of benzenesulfonic acid, hydrochloric acid, sulphuric acid and p-toluenesulfonic acid were performed. The acid solution / slurry was then added to the slurry of Compound 1 in small aliquots in order to minimize the risk of degradation. The pH of the reaction was then checked using universal indicator paper. The mixtures of Compound 1/counterion/solvent created using the procedure above were temperature cycled between ca. 0C and ambient (ca. 22C) whilst stirring in 1 hour cycles for a period of 1-2 days. Overnight, samples were kept at ca. 2-5C. The mixtures were visually checked for any obvious signs of degradation (i.e. color changes) and then, if not visually degraded, any solids present were isolated and allowed to dry at ambient conditions prior to analysis. The solids represent isolated Compound 2.
For each counterion and solvent system, ca. 25 or 50 mg of the free base of Compound 1 was slurried in 200-300 mu of the allocated solvent. The solvents included acetone, dichloromethane, cyclohexane, ethyl acetate, methanol (methyl ethyl ketone for sulfonic acid-containing counterions), methyl isobutyl ketone, 2-propanol (isopropyl acetate for sulfonic acid-containing counterions), tetrahydrofuran and acetonitrile:water (90: 10). The respective counterion was also dissolved / slurried in 200-300 mu of the allocated solvent. The counterions included benzenesulfonic acid, camphor sulfonic acid, 1,2-ethane disulfonic acid, hydrobromic acid, hydrochloric acid, maleic acid, methanesulfonic acid, naphthalene-2- sulfonic acid, 1,5 -naphthalene disulfonic acid, oxalic acid, 4-toluenesulfonic acid and 2,4,6- trihydroxybenzoic acid. One equivalent of each counterion was used and additional experiments with two equivalents of benzenesulfonic acid, hydrochloric acid, sulphuric acid and p-toluenesulfonic acid were performed. The acid solution / slurry was then added to the slurry of Compound 1 in small aliquots in order to minimize the risk of degradation. The pH of the reaction was then checked using universal indicator paper. The mixtures of Compound 1/counterion/solvent created using the procedure above were temperature cycled between ca. 0C and ambient (ca. 22C) whilst stirring in 1 hour cycles for a period of 1-2 days. Overnight, samples were kept at ca. 2-5C. The mixtures were visually checked for any obvious signs of degradation (i.e. color changes) and then, if not visually degraded, any solids present were isolated and allowed to dry at ambient conditions prior to analysis. The solids represent isolated Compound 2.
For each counterion and solvent system, ca. 25 or 50 mg of the free base of Compound 1 was slurried in 200-300 mu of the allocated solvent. The solvents included acetone, dichloromethane, cyclohexane, ethyl acetate, methanol (methyl ethyl ketone for sulfonic acid-containing counterions), methyl isobutyl ketone, 2-propanol (isopropyl acetate for sulfonic acid-containing counterions), tetrahydrofuran and acetonitrile:water (90: 10). The respective counterion was also dissolved / slurried in 200-300 mu of the allocated solvent. The counterions included benzenesulfonic acid, camphor sulfonic acid, 1,2-ethane disulfonic acid, hydrobromic acid, hydrochloric acid, maleic acid, methanesulfonic acid, naphthalene-2- sulfonic acid, 1,5 -naphthalene disulfonic acid, oxalic acid, 4-toluenesulfonic acid and 2,4,6- trihydroxybenzoic acid. One equivalent of each counterion was used and additional experiments with two equivalents of benzenesulfonic acid, hydrochloric acid, sulphuric acid and p-toluenesulfonic acid were performed. The acid solution / slurry was then added to the slurry of Compound 1 in small aliquots in order to minimize the risk of degradation. The pH of the reaction was then checked using universal indicator paper. The mixtures of Compound 1/counterion/solvent created using the procedure above were temperature cycled between ca. 0C and ambient (ca. 22C) whilst stirring in 1 hour cycles for a period of 1-2 days. Overnight, samples were kept at ca. 2-5C. The mixtures were visually checked for any obvious signs of degradation (i.e. color changes) and then, if not visually degraded, any solids present were isolated and allowed to dry at ambient conditions prior to analysis. The solids represent isolated Compound 2.
For each counterion and solvent system, ca. 25 or 50 mg of the free base of Compound 1 was slurried in 200-300 mu of the allocated solvent. The solvents included acetone, dichloromethane, cyclohexane, ethyl acetate, methanol (methyl ethyl ketone for sulfonic acid-containing counterions), methyl isobutyl ketone, 2-propanol (isopropyl acetate for sulfonic acid-containing counterions), tetrahydrofuran and acetonitrile:water (90: 10). The respective counterion was also dissolved / slurried in 200-300 mu of the allocated solvent. The counterions included benzenesulfonic acid, camphor sulfonic acid, 1,2-ethane disulfonic acid, hydrobromic acid, hydrochloric acid, maleic acid, methanesulfonic acid, naphthalene-2- sulfonic acid, 1,5 -naphthalene disulfonic acid, oxalic acid, 4-toluenesulfonic acid and 2,4,6- trihydroxybenzoic acid. One equivalent of each counterion was used and additional experiments with two equivalents of benzenesulfonic acid, hydrochloric acid, sulphuric acid and p-toluenesulfonic acid were performed. The acid solution / slurry was then added to the slurry of Compound 1 in small aliquots in order to minimize the risk of degradation. The pH of the reaction was then checked using universal indicator paper. The mixtures of Compound 1/counterion/solvent created using the procedure above were temperature cycled between ca. 0C and ambient (ca. 22C) whilst stirring in 1 hour cycles for a period of 1-2 days. Overnight, samples were kept at ca. 2-5C. The mixtures were visually checked for any obvious signs of degradation (i.e. color changes) and then, if not visually degraded, any solids present were isolated and allowed to dry at ambient conditions prior to analysis. The solids represent isolated Compound 2.
For each counterion and solvent system, ca. 25 or 50 mg of the free base of Compound 1 was slurried in 200-300 mu of the allocated solvent. The solvents included acetone, dichloromethane, cyclohexane, ethyl acetate, methanol (methyl ethyl ketone for sulfonic acid-containing counterions), methyl isobutyl ketone, 2-propanol (isopropyl acetate for sulfonic acid-containing counterions), tetrahydrofuran and acetonitrile:water (90: 10). The respective counterion was also dissolved / slurried in 200-300 mu of the allocated solvent. The counterions included benzenesulfonic acid, camphor sulfonic acid, 1,2-ethane disulfonic acid, hydrobromic acid, hydrochloric acid, maleic acid, methanesulfonic acid, naphthalene-2- sulfonic acid, 1,5 -naphthalene disulfonic acid, oxalic acid, 4-toluenesulfonic acid and 2,4,6- trihydroxybenzoic acid. One equivalent of each counterion was used and additional experiments with two equivalents of benzenesulfonic acid, hydrochloric acid, sulphuric acid and p-toluenesulfonic acid were performed. The acid solution / slurry was then added to the slurry of Compound 1 in small aliquots in order to minimize the risk of degradation. The pH of the reaction was then checked using universal indicator paper. The mixtures of Compound 1/counterion/solvent created using the procedure above were temperature cycled between ca. 0C and ambient (ca. 22C) whilst stirring in 1 hour cycles for a period of 1-2 days. Overnight, samples were kept at ca. 2-5C. The mixtures were visually checked for any obvious signs of degradation (i.e. color changes) and then, if not visually degraded, any solids present were isolated and allowed to dry at ambient conditions prior to analysis. The solids represent isolated Compound 2.
For each counterion and solvent system, ca. 25 or 50 mg of the free base of Compound 1 was slurried in 200-300 mu of the allocated solvent. The solvents included acetone, dichloromethane, cyclohexane, ethyl acetate, methanol (methyl ethyl ketone for sulfonic acid-containing counterions), methyl isobutyl ketone, 2-propanol (isopropyl acetate for sulfonic acid-containing counterions), tetrahydrofuran and acetonitrile:water (90: 10). The respective counterion was also dissolved / slurried in 200-300 mu of the allocated solvent. The counterions included benzenesulfonic acid, camphor sulfonic acid, 1,2-ethane disulfonic acid, hydrobromic acid, hydrochloric acid, maleic acid, methanesulfonic acid, naphthalene-2- sulfonic acid, 1,5 -naphthalene disulfonic acid, oxalic acid, 4-toluenesulfonic acid and 2,4,6- trihydroxybenzoic acid. One equivalent of each counterion was used and additional experiments with two equivalents of benzenesulfonic acid, hydrochloric acid, sulphuric acid and p-toluenesulfonic acid were performed. The acid solution / slurry was then added to the slurry of Compound 1 in small aliquots in order to minimize the risk of degradation. The pH of the reaction was then checked using universal indicator paper. The mixtures of Compound 1/counterion/solvent created using the procedure above were temperature cycled between ca. 0C and ambient (ca. 22C) whilst stirring in 1 hour cycles for a period of 1-2 days. Overnight, samples were kept at ca. 2-5C. The mixtures were visually checked for any obvious signs of degradation (i.e. color changes) and then, if not visually degraded, any solids present were isolated and allowed to dry at ambient conditions prior to analysis. The solids represent isolated Compound 2.
For each counterion and solvent system, ca. 25 or 50 mg of the free base of Compound 1 was slurried in 200-300 mu of the allocated solvent. The solvents included acetone, dichloromethane, cyclohexane, ethyl acetate, methanol (methyl ethyl ketone for sulfonic acid-containing counterions), methyl isobutyl ketone, 2-propanol (isopropyl acetate for sulfonic acid-containing counterions), tetrahydrofuran and acetonitrile:water (90: 10). The respective counterion was also dissolved / slurried in 200-300 mu of the allocated solvent. The counterions included benzenesulfonic acid, camphor sulfonic acid, 1,2-ethane disulfonic acid, hydrobromic acid, hydrochloric acid, maleic acid, methanesulfonic acid, naphthalene-2- sulfonic acid, 1,5 -naphthalene disulfonic acid, oxalic acid, 4-toluenesulfonic acid and 2,4,6- trihydroxybenzoic acid. One equivalent of each counterion was used and additional experiments with two equivalents of benzenesulfonic acid, hydrochloric acid, sulphuric acid and p-toluenesulfonic acid were performed. The acid solution / slurry was then added to the slurry of Compound 1 in small aliquots in order to minimize the risk of degradation. The pH of the reaction was then checked using universal indicator paper. The mixtures of Compound 1/counterion/solvent created using the procedure above were temperature cycled between ca. 0C and ambient (ca. 22C) whilst stirring in 1 hour cycles for a period of 1-2 days. Overnight, samples were kept at ca. 2-5C. The mixtures were visually checked for any obvious signs of degradation (i.e. color changes) and then, if not visually degraded, any solids present were isolated and allowed to dry at ambient conditions prior to analysis. The solids represent isolated Compound 2.
With hydrogenchloride; In ethanol; water; for 6.0h;Reflux;
[00113] <strong>[1374640-70-6]CO-1686</strong> (18 g, 32 mmol) were dissolved in a solution of EtOH (200 proof, 250 mL) and concentrated HC1 solution (250 mL). The reaction mixture was heated to reflux for 6 hrs. After cooling down, half of the solvent was removed. The precipitate was collected by filtration and rinsed with cold ethanol (50 mL). After drying in vacuum oven, M460 (15 g) was obtained in 84% yield. The product may be further slurried in EtOH (50 mL) for 1 hr, and then filtered. The precipitate is collected and dried.
1-(4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)ethan-1-one[ No CAS ]
Ν-(3-aminophenyl)prop-2-enamide[ No CAS ]
[ 1374640-70-6 ]
Yield
Reaction Conditions
Operation in experiment
90%
With hydrogenchloride; In methanol; water; at 60℃;
Compound (VII) 51.58g (0.12mol) with compound (VIII) N-(3-aminophenyl) acrylamide 29.20g (0.18mol) into 200 ml methanol, at room temperature and then adding 1mol/LHCl (250 ml), slowly raising the temperature to 60 C, reaction 5-7h. Drop to room temperature, add 200 ml water, dichloromethane is used for 300 ml extraction 3 times, there will be phase water washing, washing with saturated sodium chloride, sodium sulfate for final drying. Remove the solvent under reduced pressure, to obtain solid kind of white, dichloromethane/methanol is recrystallized to get kind of white powder 60.0g, purity 99.8%, yield 90%.
N-[3-[[2-[[4-(4-acetylpiperazin-1-yl)-2-methoxyphenyl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]amine[ No CAS ]
[ 814-68-6 ]
[ 1374640-70-6 ]
Yield
Reaction Conditions
Operation in experiment
92%
With triethylamine; In dichloromethane; at 20℃;Cooling with ice;
Compound (X) 40.12g (0.08mol) dissolved in 280 ml methylene chloride, then adding 16.2g (0.16mol) triethylamine, acryloyl chloride dropwise under ice bath 9.05g (0.10mol), and then room temperature reaction 4-5h. Remove the solvent under reduced pressure, to residue 200 ml water, stirring after-filtration, to obtain a kind of white solid, dichloromethane/methanol is recrystallized to get kind of white powder 41.0g, purity 99.6%, yield 92%.
N-[3-[[2-[[4-(4-acetylpiperazin-1-yl)-2-methoxyphenyl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]amine[ No CAS ]
[ 625-36-5 ]
[ 1374640-70-6 ]
Yield
Reaction Conditions
Operation in experiment
4.7 g
With sodium hydrogencarbonate; In tetrahydrofuran; water; at 0℃;
5g of intermediate V with 150mlTHF dissolved, then 75ml of water was dissolved 2.3g of sodium bicarbonate and water was added to the reaction mixture a solvent, 0 placed in the reaction, the reaction liquid at this time as a red supernatant, the chloropropionyl chloride with 1.3g 75mlTHF dilution, was slowly added dropwise to the reaction mixture.TLC analysis after the addition was complete the reaction was complete feed.The reaction solution was spin to most of the tetrahydrofuran, was added 100ml of saturated aqueous sodium bicarbonate, 3 × 100ml extracted three times with ethyl acetate, the organic phases combined, dried over anhydrous sodium sulfate, filtered, and ethyl acetate was removed by rotary evaporation 2/3.Was added to the rotovap 7gDBU, 60 stirred for 12h, TLC detection starting material the reaction was complete, the aqueous solution was washed with 100ml × 3 was added, the organic phase is retained, dried over anhydrous sodium sulfate, filtered, spin-dries off-white solid, ethyl acetate was added heavy crystallized 4.7g, HPLC purity 99.6% detection products
1-(4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)ethan-1-one[ No CAS ]
[ 7530-31-6 ]
[ 1374640-70-6 ]
Yield
Reaction Conditions
Operation in experiment
2.15 g
With caesium carbonate; In N,N-dimethyl-formamide; at 90 - 100℃; for 12.0h;
Adding 2-[[4-(4-acetyl-1 -piperazinyl)-2-methoxy- phenyl]amino]-5-(trifluoromethyl)-pyrimidin-4-one (IV) (2.06 g, 5 mmol) and phosphorus oxychloride (7.5 mL) into a reaction flask, starting stirring, cooling to 0 C. or below, and dropwisely adding 3.5 mL of 2,6-dimethylpyridine. Slowly heating to 50-70 C., and stirring to react for 9 hours while maintaining the temperature. Reducing the pressure to recover the phosphorus oxychloride, cooling the residue to room temperature, and quenching the reaction with ice watet Extracting with dichloromethane for 3 times, combining organic phases, washing with water, drying with anhydrous sodium sulfate, reducing the pressure to recover the solvent, dissolving an obtained oily matter 2-[[4-(4- acetyl- 1 -piperazinyl)-2-methoxyphenyl]amino] -5-(trifluo- romethyl)-4-chloro-pyrimidine (V) with 25 mL of N,Ndimethylformamide, transferring into the reaction flask, and adding N-(3-aminophenyl)-2-acrylamide (1.0 g, 6 mmol) and a catalyst cesium carbonate (0.3 g). Stirring to react for 12 hours while maintaining the temperature at 90-110 C., and performing TLC detection until the reaction is finished. Filtering, concentrating under reduced pressure, adding ethyl acetate and water into the residue, and regulating pH to 5-6 with dilute acid. Separating out the organic phases, and extracting a water phase with ethyl acetate for 3 times. Combining the organic phases, washing the organic phases sequentially with pure water and brine, drying, performing reduced pressure distillation to recover the solvent, and washing with ethanol to obtain 2.15 g of an off-white solid rociletinib, wherein the yield is 77.5%. Mass spec (El):El-MS mlz: 556 [M+H], ?H NMR (DMSO-d5): oe 2.05 (s, 3H), 3.01 (m, 4H), 3.55 (m, 4H), 3.77 (m, 3H), 5.78 (d, 1H),6.25 (d, 2H), 6.44 (m, 1H), 6.61 (s, 1H), 7.17 (s, 1H), 7.28 (m, 1H), 7.52 (m, 2H), 7.76 (s, 1H), 8.08 (s, 1H), 8.28 (s, 1H), 8.63 (s, 1H), 10.21 (s, 1H).
2-[[4-(4-acetyl-1-piperazinyl)-2-methoxyphenyl]amino]-5-(trifluoromethyl)pyrimidin-4-one[ No CAS ]
[ 7530-31-6 ]
[ 1374640-70-6 ]
Yield
Reaction Conditions
Operation in experiment
With potassium tert-butylate; In dimethyl sulfoxide; at 90 - 110℃; for 12.0h;
Adding 2-[[4-(4-acetyl-1 -piperazinyl)-2-methoxy- phenyl]amino]-5-(trifluoromethyl)-pyrimidin-4-one (IV) (2.06 g, 5 mmol), phosphorus tribromide (2.7 g, 10 mmol) and dichloromethane (50 mE) into a reaction flask, starting stirring, cooling to 00 C. or below, and dropwisely adding 3.0 mE of diisopropylethylamine. Slowly heating for reflux, and stirring to react for 8 hours while maintaining the temperature. Afier cooling to room temperature, quenching the reaction with ice watet Extracting with dichloromethane for 2 times, combining organic phases, washing with water, drying with anhydrous sodium sulfate, reducing the pressure to recover the solvent, dissolving an obtained oily matter 2-[[4-(4-acetyl- 1 -piperazinyl)-2-methoxyphenyl]amino] -5- (trifluoromethyl)-4-bromo-pyrimidine (V) with 25 mE of dimethyl sulfoxide, transferring into the reaction flask, and adding N-(3-aminophenyl)-2-acrylamide (1.0 g, 6 mmol) and a catalyst potassium tert-butoxide (0.5 g). Stirring to react for 12 hours while maintaining the temperature at 90-110 C., and performing TEC detection until the reaction is finished. Filtering, concentrating under reduced pressure, adding ethyl acetate and water into the residue, and regulating pH to 5-6 with dilute acid. Separating out the organic phases, and extracting a water phase with ethyl acetate for 3 times. Combining the organic phases, washing the organic phases sequentially with pure water and brine, drying, performing reduced pressure distillation to recover the solvent, and washing with ethanol to obtain 1.98 g of an off-white solid rociletinib, wherein the yield is 7 1.4%. Mass spec (El): El-MS mlz: 556 [M+H], ?H NMR (DMSO-d5):o 2.05 (s, 3H), 3.01 (m, 4H), 3.55 (m, 4H), 3.77 (m, 3H), 5.78 (d, 1H), 6.25 (d, 2H), 6.44 (m, 1H), 6.61 (s, 1H), 7.17 (s, 1H), 7.28 (m, 1H), 7.52 (m, 2H), 7.76 (s, 1H), 8.08 (s, 1H), 8.28 (s, 1H), 8.63 (s, 1H), 10.21 (s, 1H).
Multi-step reaction with 3 steps
1.1: potassium-t-butoxide / tetrahydrofuran / 2 h / -10 °C
2.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 h / 80 °C
3.1: sulfuric acid / methanol / 2 h / 20 °C
3.2: 2 h / 0 °C
Stage #1: C32H36F3N7O5 With sulfuric acid In methanol at 20℃; for 2h;
Stage #2: With triethylamine In methanol at 0℃; for 2h;
1.d; 2.d (d) Preparation of Rociletinib from compound 7:
At room temperature, 10g of compound 7, methanol 150ml as a solvent, slowly add concentrated sulfuric acid to the system dropwise 10g, add 2h dropwise, cool down to 0 ° C, add triethylamine 15g, stir for 2h to precipitate white solid, filtration, methanol 100ml washing, vacuum drying, to obtain 7g of product, yield 83%.
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