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CAS No. : | 7305-71-7 | MDL No. : | MFCD00078317 |
Formula : | C4H6N2S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | GUABFMPMKJGSBQ-UHFFFAOYSA-N |
M.W : | 114.17 | Pubchem ID : | 351770 |
Synonyms : |
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Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-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 |
---|---|---|
93% | With t-butyl thionitrite; copper dichloride In acetonitrile at 25℃; for 2.66667 h; Inert atmosphere | 72 g (0.6 mol) of t-butyl sulfonitrile was dissolved in dry acetonitrile (1.5 L) to prepare a solution.The reactor was purged with nitrogen, then 65 g (0.48 mol) of dry anhydrous copper (II) chloride was added, and the prepared t-butyl sulfonitrile solution was added to the reaction vessel under vigorous stirring and nitrogen protection, and then kept. 2-Amino-5-methylthiazole (45.6 g, 0.40 mol) was added portionwise over a period of 40 min at 25 °C.The reaction mixture was reacted at 25 ° C for 2 h.Then 20percent hydrochloric acid solution was added.The solvent was distilled off under reduced pressure, and then 300 ml of chloroform was added thereto, and 100 mL × 3 was washed with brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 49.7 g of 2-chloro-5-methylthiazole, yield 93percent; |
93% | With t-butyl thionitrite; copper dichloride In acetonitrile at 25℃; for 2.66667 h; Inert atmosphere | (1) Preparation of 2-chloro-5-methylthiazole:72 g (0.6 mol) of t-butyl sulfonitrile was dissolved in dry acetonitrile (1.5 L) to prepare a solution.Nitrogen gas was introduced into the reaction vessel, followed by the addition of dry anhydrous copper (II) chloride (65 g (0.48 mol)).The formulated t-butyl sulfonitrile solution was added to the reaction vessel under vigorous stirring and nitrogen protection.Then, at 25 ° C, 2-amino-5-methylthiazole (45.6 g, 0.40 mol) was added portionwise over a period of about 40 min.The reaction mixture was reacted at 25 ° C for 2 h.Then 20percent hydrochloric acid solution was added. The solvent was distilled off under reduced pressure.300 ml of chloroform was added, and 100 mL × 3 was washed with saturated brine.Drying with anhydrous magnesium sulfate and distilling off the solvent under reduced pressure.49.7 g of 2-chloro-5-methylthiazole were obtained.Yield 93percent; |
81% | With 2-methylchlorobenzene; copper(l) chloride In hexane at 6 - 65℃; for 15 h; | In the reaction vessel was added 2-amino-5-methylthiazole (2) 0.23mol, mass fraction of 60percent o-chlorotoluene solution 0.29mol, cuprous chloride 0.31mol, mass fraction of 45percent hexane 310ml, stirred for control speed 170rpm, temperature of the solution is reduced to 6 , reaction 8h, the solution temperature rises to 65 , the reaction was continued 7h, reducing the solution temperature to 15 , mass fraction of 65percent acetonitrile extraction seven times the mass fraction of 75percent isopropyl washed with alcohol, isopropyl alcohol was distilled off under reduced pressure, the temperature of the solution is reduced to 7 , allowed to stand for 35h, the precipitated solid was filtered, washed with sodium sulfate solution, the mass fraction of 85percent ethyl acetate and washed, in the mass fraction of 95percent triacetate recrystallization amines crystals of 2-chloro-5-methylthiazole 24.96g, yield 81percent. |
71% | With hydrogenchloride; sodium nitrite In water | EXAMPLE 1 Synthesis of 2-chloro-5-methylthiazole In a 300 ml volume three necked flask equipped with a stirrer, a dropping funnel and a thermometer, 20 g of 2-amino5-methylthiazole (0.175 mol), 80 ml of 36percent hydrochloric acid (0.931 mol) and 30 ml of water were placed and cooled to -5° C. To the mixture, 14 g of sodium nitrite (0.203 mol) dissolved in 30 ml of water was gradually added dropwise at 0° C. or lower. The reaction mixture was further caused to react for three hours at 0° C. or lower to give the diazonium base. The reaction mixture was heated to 80° C. for three hours and extracted with three 40 ml portions of chloroform to give a chloroform solution containing 2-chloro-5-methylthiazole. The chloroform was removed by atmospheric distillation and remained fraction was distilled under reduced pressure to isolate 16.6 g of 2-chloro-5-methylthiazole (0.124 mol) with a yield of 71percent. |
44% | With hydrogenchloride; sodium nitrite In water | Comparative Example 1 Synthesis of 2-chloro-5-methylthiazole In a 300 ml volume three necked flask equipped with a stirrer, a dropping funnel and a thermometer, 20 g of 2-amino5-methylthiazole (0.175 mol), 35 ml of 36percent hydrochloric acid (0.407 mol) and 30 ml of water were placed and cooled to -5° C. To the mixture, 14 g of sodium nitrite (0.203 mol) dissolved in 30 ml of water was gradually added dropwise at 0° C. or lower. The reaction mixture was further caused to react for three hours at 0° C. or lower to give the diazonium base. The reaction mixture was heated to 80° C. for three hours and extracted with three 40 ml portions of chloroform to give a chloroform solution containing 2-chloro-5-methylthiazole. The chloroform was removed by atmospheric distillation and remained fraction was distilled under reduced pressure to isolate 10.3 g of 2-chloro-5-methylthiazole (0.077 mol) with a yield of 44percent. |
36% | With hydrogenchloride; sodium hydroxide; sodium nitrite In water | Comparative Example 3 Synthesis of 2-chloro-5-methylthiazole In a 300 ml volume three necked flask equipped with a stirrer, a dropping funnel and a thermometer, 20 g of 2-amino5-methylthiazole (0.175 mol), 80 ml of 36percent hydrochloric acid (0.931 mol) and 30 ml of water were placed and cooled to -5° C. To the mixture, 14 g of sodium nitrite (0.203 mol) dissolved in 30 ml of water was gradually added dropwise at 0° C. or lower. The reaction mixture was further caused to react for three hours at 0° C. or lower to give the diazonium base solution. In a 300 ml volume three necked flask equipped with a stirrer, a dropping funnel and a thermometer, 17.3 g of copper(I) chloride (0.175 mol) and 80 ml of 36percent hydrochloric acid were placed and cooled to -5° C. In the resultant aqueous solution, the diazonium base solution was gradually added dropwise at 0° C. or lower. The reaction mixture was further caused to react for three hours at 0° C. or lower and heated at 80° C. for further three hours. After the reaction, the reaction mixture was made alkaline by addition of 15percent sodium hydroxide aqueous solution and the precipitated copper salt was removed by filtration. The resulting filtrate was extracted with three 40 ml portions of chloroform to give a chloroform solution containing 2-chloro-5-methylthiazole. The chloroform was removed by atmospheric distillation and remained fraction was distilled under reduced pressure to isolate 8.4 g of 2-chloro-5-methylthiazole (0.063 mol) with a yield of 36percent |
22% | With hydrogenchloride; sodium nitrite In water | Comparative Example 2 Synthesis of 2-chloro-5-methylthiazole In a 300 ml volume three necked flask equipped with a stirrer, a dropping funnel and a thermometer, 20 g of 2-amino5-methylthiazole (0.175 mol), 23 ml of 36percent hydrochloric acid (0.267 mol) and 30 ml of water were placed and cooled to -5° C. To the mixture, 14 g of sodium nitrite (0.203 mol) dissolved in 30 ml of water was gradually added dropwise at 0° C. or lower. The reaction mixture was further caused to react for three hours at 0° C. or lower to give the diazonium base. The reaction mixture was heated to 80° C. for three hours and extracted with three 40 ml portions of chloroform to give a chloroform solution containing 2-chloro-5-methylthiazole. Chloroform was removed by atmospheric distillation and remained fraction was distilled under reduced pressure to isolate 5.1 g of 2-chloro5-methylthiazole (0.038 mol) with a yield of 22percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.8% | at 25 - 145℃; for 33.5 - 38 h; Industry scale | Ortho xylene (1800 L), 18 kg of methyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxalate1,1-dioxide (IV) and 8.6 kg of 2-amino-5-methyl-thiazole were added into a reactor. The reaction mass was heated to 142 to 145° C. and maintained under reflux maintained for 8 to 9 hours at the same temperature. During the reflux, 50-55 L of distillate was collected separately for every 1 hour. The reaction mass was cooled to 130 to 135° c., and 400 liters of ortho xylene was added to the reaction mass, which was then heated to 142 to 145° C. and maintained for 8 to 9 hours at the same temperature. During the reflux, 50-55 L of distillate was collected separately for every 1 hour. The reaction mass was cooled to 130 to 135° c., and 400 liters of ortho xylene was added to the reaction mass, which was then heated to 142 to 145° C. and maintained for 8 to 9 hours at the same temperature. Similarly, During the reflux, 50-55 L of distillate was collected separately for every 1 hour. The reaction mass was cooled to 130 to 135° c., and 400 liters of ortho xylene was added to the reaction mass, which was then heated to 142 to 145° C. and maintained for 8 to 9 hours at the same temperature. During the reflux, 50-55 L of distillate was collected separately for every 1 hour. The reaction mass was then cooled to 25 to 35° C., and stirred for about 11/2-2 hours at the same temperature. The reaction mass was filtered and the filtered wet solid was washed with acetone thoroughly. The wet solid was suck dried for 45 to 60 minutes to obtain a technical grade titled compound. (Yield: 16.0 kg, 88.8percent) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | for 24 h; Heating / reflux | EXAMPLE 1 20.4 g of 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide ethyl ester and 8.8 g of 2-amino-5-methylthiazole are refluxed in 300 ml of o-xylene for 24 hr and the reaction by-product, ethanol, is removed by means of a soxhlet extraction device fitted with 4A molecular sieves. The crude meloxicam (4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide) is isolated by cooling and filtration in a yield of 24.0 g (95percent of theory). |
92.48% | at 139 - 140℃; for 32 - 37 h; Heating / reflux; Molecular sieve | EXAMPLE 1- Process for preparing crude meloxicam In a 6 litre round-bottom flask, in a nitrogen flow, are placed respectively 226.64g (0.80 mol) of 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate of ethyl-1,1-dioxide and 91.36g (0.80 mol) of 2-amino-5-methyl-thiazole and 3.6 l of xylene. The suspension is heated under reflux (139-140°C), passing the condensate on a bed of molecular sieves 4Å. Initially a dark brown solution is obtained and then, as the reaction proceeds, the reaction product is crystallised in the form of a yellow-green solid. It is kept under reflux until completion of the reaction (32-37 hours). When the reaction is completed it is cooled to a temperature comprised between 20 and 25°C in at least 2 hours. The crude product is filtered and washed with xylol and acetone. 279.34g of wet yellow-greenish crude product are obtained, the equivalent of 260.0 g of dry product. Theoretical yield 281.12 g RDT =92.48percent. The crude meloxicam thus obtained has a content of the impurity composed of ethylamide amounting to 0.707percent assessed with HPLC using the "Related substances" method given in the monographic report of the British Pharmacopoeia 2002. Repeating example 1, products are obtained that contain the above-mentioned impurity in variable quantities between 0.230 and 0.782percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: With phosphoric acid; nitric acid; sodium nitrite In water at 0℃; for 0.333333 h; Stage #2: With hydrogen bromide; copper(I) bromide In water for 1.5 h; |
2-Amino-5-methylthiazole (2.0 g, 17.6 mmol) was dissolved in H3PO4 (20 mL) and HNO3 (10 mL). The mixture was cooled to 0 °C before NaNO2 (3.8 g, 55 mmol) in H2O (8 mL) was added. After 20 min, the solution was slowly added to a cooled solution CuBr (2.6 g, 18 mmol) in HBr (19 mL). This mixture was stirred for 1.5 h then neutralized with NaOH. Sat. aq NaHCO3 (50 mL) was added and the mixture was extracted with EtOAc (3 × 40 mL), dried with MgSO4, and evaporated. Heptane was added and the mixture was decanted and evaporated to give 17. |
73% | Stage #1: With phosphoric acid; nitric acid; sodium nitrite In water at 0℃; for 0.333333 h; Stage #2: With hydrogen bromide; copper(I) bromide In water at 20℃; for 2 h; |
A solution of NaN02 (5.70 g, 61.0 mmol) in water (10 mL) was added at 0°C to a solution of 5- methylthiazol-2-amine (3.00 g, 26.4 mmol) in cone. H3P04 (30 mL) and cone. HN03 (15 mL) and the mixture was stirred at 0°C for 20 min. The RM was then added to mixture of Cu(l)Br (3.9 g, 26.4 mmol) in HBr (46percent, 30 mL) and the RM was stirred at RT for 2 h. The mixture was chilled in an ice bath and NaOH (5M) followed by NaHC03 were added. The mixture was extracted with EtOAc, the combined organic layers were washed with sodium thiosulfate and brine, were dried and the volatiles were removed under reduced pressure. The residue was recrystallized (Cy) to yield the desired compound (4.78 g, 73percent). LC-MS (Method 1): m/z: [M+H]+ = 256.0 (MW calc. = 254.84), R, = 3.3 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.8% | In o-xylene; at 25 - 145℃; for 33.5 - 38h;Industry scale; | Ortho xylene (1800 L), 18 kg of methyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxalate1,1-dioxide (IV) and 8.6 kg of 2-amino-5-methyl-thiazole were added into a reactor. The reaction mass was heated to 142 to 145 C. and maintained under reflux maintained for 8 to 9 hours at the same temperature. During the reflux, 50-55 L of distillate was collected separately for every 1 hour. The reaction mass was cooled to 130 to 135 c., and 400 liters of ortho xylene was added to the reaction mass, which was then heated to 142 to 145 C. and maintained for 8 to 9 hours at the same temperature. During the reflux, 50-55 L of distillate was collected separately for every 1 hour. The reaction mass was cooled to 130 to 135 c., and 400 liters of ortho xylene was added to the reaction mass, which was then heated to 142 to 145 C. and maintained for 8 to 9 hours at the same temperature. Similarly, During the reflux, 50-55 L of distillate was collected separately for every 1 hour. The reaction mass was cooled to 130 to 135 c., and 400 liters of ortho xylene was added to the reaction mass, which was then heated to 142 to 145 C. and maintained for 8 to 9 hours at the same temperature. During the reflux, 50-55 L of distillate was collected separately for every 1 hour. The reaction mass was then cooled to 25 to 35 C., and stirred for about 11/2-2 hours at the same temperature. The reaction mass was filtered and the filtered wet solid was washed with acetone thoroughly. The wet solid was suck dried for 45 to 60 minutes to obtain a technical grade titled compound. (Yield: 16.0 kg, 88.8%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With t-butyl thionitrite; copper dichloride; In acetonitrile; at 25℃; for 2.66667h;Inert atmosphere; | 72 g (0.6 mol) of t-butyl sulfonitrile was dissolved in dry acetonitrile (1.5 L) to prepare a solution.The reactor was purged with nitrogen, then 65 g (0.48 mol) of dry anhydrous copper (II) chloride was added, and the prepared t-butyl sulfonitrile solution was added to the reaction vessel under vigorous stirring and nitrogen protection, and then kept. 2-Amino-5-methylthiazole (45.6 g, 0.40 mol) was added portionwise over a period of 40 min at 25 C.The reaction mixture was reacted at 25 C for 2 h.Then 20% hydrochloric acid solution was added.The solvent was distilled off under reduced pressure, and then 300 ml of chloroform was added thereto, and 100 mL × 3 was washed with brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 49.7 g of 2-chloro-5-methylthiazole, yield 93%; |
93% | With t-butyl thionitrite; copper dichloride; In acetonitrile; at 25℃; for 2.66667h;Inert atmosphere; | (1) Preparation of 2-chloro-5-methylthiazole:72 g (0.6 mol) of t-butyl sulfonitrile was dissolved in dry acetonitrile (1.5 L) to prepare a solution.Nitrogen gas was introduced into the reaction vessel, followed by the addition of dry anhydrous copper (II) chloride (65 g (0.48 mol)).The formulated t-butyl sulfonitrile solution was added to the reaction vessel under vigorous stirring and nitrogen protection.Then, at 25 C, 2-amino-5-methylthiazole (45.6 g, 0.40 mol) was added portionwise over a period of about 40 min.The reaction mixture was reacted at 25 C for 2 h.Then 20% hydrochloric acid solution was added. The solvent was distilled off under reduced pressure.300 ml of chloroform was added, and 100 mL × 3 was washed with saturated brine.Drying with anhydrous magnesium sulfate and distilling off the solvent under reduced pressure.49.7 g of 2-chloro-5-methylthiazole were obtained.Yield 93%; |
81% | With 2-methylchlorobenzene; copper(l) chloride; In hexane; at 6 - 65℃; for 15.0h; | In the reaction vessel was added 2-amino-5-methylthiazole (2) 0.23mol, mass fraction of 60% o-chlorotoluene solution 0.29mol, cuprous chloride 0.31mol, mass fraction of 45% hexane 310ml, stirred for control speed 170rpm, temperature of the solution is reduced to 6 , reaction 8h, the solution temperature rises to 65 , the reaction was continued 7h, reducing the solution temperature to 15 , mass fraction of 65% acetonitrile extraction seven times the mass fraction of 75% isopropyl washed with alcohol, isopropyl alcohol was distilled off under reduced pressure, the temperature of the solution is reduced to 7 , allowed to stand for 35h, the precipitated solid was filtered, washed with sodium sulfate solution, the mass fraction of 85% ethyl acetate and washed, in the mass fraction of 95% triacetate recrystallization amines crystals of 2-chloro-5-methylthiazole 24.96g, yield 81%. |
71% | With hydrogenchloride; sodium nitrite; In water; | EXAMPLE 1 Synthesis of 2-chloro-5-methylthiazole In a 300 ml volume three necked flask equipped with a stirrer, a dropping funnel and a thermometer, 20 g of 2-amino5-methylthiazole (0.175 mol), 80 ml of 36% hydrochloric acid (0.931 mol) and 30 ml of water were placed and cooled to -5 C. To the mixture, 14 g of sodium nitrite (0.203 mol) dissolved in 30 ml of water was gradually added dropwise at 0 C. or lower. The reaction mixture was further caused to react for three hours at 0 C. or lower to give the diazonium base. The reaction mixture was heated to 80 C. for three hours and extracted with three 40 ml portions of chloroform to give a chloroform solution containing 2-chloro-5-methylthiazole. The chloroform was removed by atmospheric distillation and remained fraction was distilled under reduced pressure to isolate 16.6 g of 2-chloro-5-methylthiazole (0.124 mol) with a yield of 71%. |
44% | With hydrogenchloride; sodium nitrite; In water; | Comparative Example 1 Synthesis of 2-chloro-5-methylthiazole In a 300 ml volume three necked flask equipped with a stirrer, a dropping funnel and a thermometer, 20 g of 2-amino5-methylthiazole (0.175 mol), 35 ml of 36% hydrochloric acid (0.407 mol) and 30 ml of water were placed and cooled to -5 C. To the mixture, 14 g of sodium nitrite (0.203 mol) dissolved in 30 ml of water was gradually added dropwise at 0 C. or lower. The reaction mixture was further caused to react for three hours at 0 C. or lower to give the diazonium base. The reaction mixture was heated to 80 C. for three hours and extracted with three 40 ml portions of chloroform to give a chloroform solution containing 2-chloro-5-methylthiazole. The chloroform was removed by atmospheric distillation and remained fraction was distilled under reduced pressure to isolate 10.3 g of 2-chloro-5-methylthiazole (0.077 mol) with a yield of 44%. |
36% | With hydrogenchloride; sodium hydroxide; sodium nitrite;copper(I) chloride; In water; | Comparative Example 3 Synthesis of 2-chloro-5-methylthiazole In a 300 ml volume three necked flask equipped with a stirrer, a dropping funnel and a thermometer, 20 g of 2-amino5-methylthiazole (0.175 mol), 80 ml of 36% hydrochloric acid (0.931 mol) and 30 ml of water were placed and cooled to -5 C. To the mixture, 14 g of sodium nitrite (0.203 mol) dissolved in 30 ml of water was gradually added dropwise at 0 C. or lower. The reaction mixture was further caused to react for three hours at 0 C. or lower to give the diazonium base solution. In a 300 ml volume three necked flask equipped with a stirrer, a dropping funnel and a thermometer, 17.3 g of copper(I) chloride (0.175 mol) and 80 ml of 36% hydrochloric acid were placed and cooled to -5 C. In the resultant aqueous solution, the diazonium base solution was gradually added dropwise at 0 C. or lower. The reaction mixture was further caused to react for three hours at 0 C. or lower and heated at 80 C. for further three hours. After the reaction, the reaction mixture was made alkaline by addition of 15% sodium hydroxide aqueous solution and the precipitated copper salt was removed by filtration. The resulting filtrate was extracted with three 40 ml portions of chloroform to give a chloroform solution containing 2-chloro-5-methylthiazole. The chloroform was removed by atmospheric distillation and remained fraction was distilled under reduced pressure to isolate 8.4 g of 2-chloro-5-methylthiazole (0.063 mol) with a yield of 36% |
22% | With hydrogenchloride; sodium nitrite; In water; | Comparative Example 2 Synthesis of 2-chloro-5-methylthiazole In a 300 ml volume three necked flask equipped with a stirrer, a dropping funnel and a thermometer, 20 g of 2-amino5-methylthiazole (0.175 mol), 23 ml of 36% hydrochloric acid (0.267 mol) and 30 ml of water were placed and cooled to -5 C. To the mixture, 14 g of sodium nitrite (0.203 mol) dissolved in 30 ml of water was gradually added dropwise at 0 C. or lower. The reaction mixture was further caused to react for three hours at 0 C. or lower to give the diazonium base. The reaction mixture was heated to 80 C. for three hours and extracted with three 40 ml portions of chloroform to give a chloroform solution containing 2-chloro-5-methylthiazole. Chloroform was removed by atmospheric distillation and remained fraction was distilled under reduced pressure to isolate 5.1 g of 2-chloro5-methylthiazole (0.038 mol) with a yield of 22% |
With hydrogenchloride; sodium nitrite; In water; at -5 - 60℃; for 3.25h; | 5-methylthiazol-2-amine (2.0 g, 17.5 mmol, 1.0 equiv) was taken in con. HCI (35%) (9 ml) and cooled in ice-salt mixture (- 5C). A solution of NaN02 (1.33 g, 19.2 mmol, 1.1 equiv) in water (10 ml) was added drop wise over 15 min and stirred for 1 h at 0C and slowly warmed to room temperature. Reaction mixture was heated to 60C and stirred for about 2h. Reaction mixture was monitored by TLC and LCMS. After consumption of starting material reaction mixture was diluted with ice water and extracted with DCM (3 x 50 mL). Combined organic layers were washed with water and brine solution, dried over Na2S04, filtered and concentrated to get crude product as black oil, yield (1.3g, 75%). LC- MS (ES) m/z = 134.1 [M+H]+. H NMR (400 MHz, DMSOcfe) delta ppm 2.40 (s, 3 H), 7.38 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetra-(n-butyl)ammonium iodide; In N,N-dimethyl-formamide; at 85℃; for 24h; | Example 203B 5-methyl-3-((tetrahydro-2H-pyran-4-yl)methyl)thiazol-2(3H)-imine A mixture of Example 203A (1.9 g, 7.0 mmol), 2-amino-5-methylthiazole (0.80 g, 7.0 mmol) and tetrabutylammonium iodide (1.3 g, 3.5 mmol) in 3 mL of N,N-dimethylformamide was warmed to 85 C. and was allowed to stir for 24 hours. The mixture was diluted with 10 mL of CH2Cl2, washed with 10% aqueous NaHCO3, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification via column chromatography (SiO2, 10% methanol in ethyl acetate then 9:1:0.1 CH2Cl2:methanol:NH4OH) afforded the title compound. MS (DCI/NH3) m/z 213 (M+H)+. | |
With tetra-(n-butyl)ammonium iodide; In N,N-dimethyl-formamide; at 85℃; for 24h; | A mixture of Example 203A (1.9 g, 7.0 mmol), 2-amino-5-methylthiazole (0.80 g, 7.0 mmol) and tetrabutylammonium iodide (1.3 g, 3.5 mmol) in 3 mL of N,N- dimethylformamide was warmed to 85 0C and was allowed to stir for 24 hours. The mixture was diluted with 10 mL OfCH2Cl2, washed with 10% aqueous NaHCO3, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification via column chromatography (SiO2, 10% methanol in ethyl acetate then 9:1 :0.1 CH2Cl2 : methanol : NH4OH) afforded the title compound. MS (DCI/NH3) m/z 213 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With triethylamine; In chloroform; at 0 - 20℃; | General procedure: To a stirred solution of -corresponding hetero amines a?e (0.04 mol) and triethyl amine (0.04 mol) in chloroform (200 ml) was added drop wise chloroacetyl chloride (0.04 mol) at 0?5 °C. After addition, the resulting mixture was stirred overnight at room temperature. Reaction completion was monitored through thin layer chromatography using hexane:ethyl acetate (8:2) as mobile phase. The reaction mixture was concentrated to get solid and as such taken in the methanol solution. The precipitates thus separated out were allowed to stand 2 h. The resultant solid 1a?e was filtered, washed, dried and as such taken for the next step. |
65% | With potassium carbonate; at 20℃; | General procedure: A solution of Aryl-or heteroary-amine (1.0 mol) in chloroformor dichloromethane was stirred with potassium carbonate(1.5 mol). To this solution was then added 1.5 mol of chloroacetylchloride under cold. Reaction was stirred overnight at room temperature.After completion of reaction (monitored by TLC), solventwas removed under reduced pressure. To the solid mass, ice coldwater was added. The solid thus obtained was then filtered driedand recrystallized from ethanol. |
61% | With potassium carbonate; In toluene; at 20℃; for 36h; | General procedure: A mixture of 2-aminothiazole (1) or 2-amino-5-methylthiazole (2, 0.01 mol), potassium carbonate (2.07 g, 0.015 mol) in dry toluene (50 ml) was stirred at room temperature, while 2-chloroacetyl chloride (3, 1.7 g, 1.2 ml, 0.015 mol) or 3-chloropropionyl chloride (4, 1.9 g, 1.4 ml. 0.015 mol), was added dropwise. Stirring continued for 36 h, solvent was then removed in vacuo and the residue obtained was triturated with water, filtered, dried and recrystallized (Table 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; | A mixture of 2-tert-butoxycarbonylamino-pentanoic acid (1.0 eq.), 2-amino-5-methyl thiazole (1.0 eq. ), HOBt (1.05 eq. ), EDC. HCI (1.2 eq. ) and a triethylamine (4 eq. ) in methylene chloride was stirred at room temperature overnight. The mixture was quenched with water and extracted with methylene chloride. The organic layer was washed with diluted HCI, separated, dried over sodium sulfate and filtered. The solvent was removed at reduced pressure to provide product. [M+1=314. 3, 1H] NMR (DMSO-d6) d 7.11 (s, 1H), 4.11 (m, 1H), 2.3 (s, 3H), 1.54 (m, 2H), 1.34 (t, 9H), 1.2-1. 4 (m, 2H), 0.83 (t, 3H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In xylene; at 139 - 140℃; for 32 - 37h; | In a 6 liter round-bottom flask, in a nitrogen flow, are placed respectively 226.64 g (0.80 mol) of 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate of ethyl-1,1-dioxide and 91.36 g (0.80 mol) of 2-amino-5-methyl-thiazole and 3.6 l of xylene The suspension is heated under reflux (139-140 C.), passing the condensate on a bed of molecular sieves 4 . Initially a dark brown solution is obtained and then, as the reaction proceeds, the reaction product is crystallised in the form of a yellow-green solid. It is kept under reflux until completion of the reaction (32-37 hours). When the reaction is completed it is cooled to a temperature comprised between 20 and 25 C. in at least 2 hours. The crude product is filtered and washed with xylol and acetone. 279.34 g of wet yellow-greenish crude product are obtained, the equivalent of 260.0 g of dry product. Theoretical yield 281.12 g RDT=92.48%. The crude meloxicam thus obtained has a content of the impurity composed of ethylamide amounting to 0.707% assessed with HPLC using the ?Related substances? method given in the monographic report of the British Pharmacopoeia 2002. Repeating example 1, products are obtained that contain the above-mentioned impurity in variable quantities between 0.230 and 0.782%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
pyrographite; In xylene; at 170 - 180℃; for 24h;Product distribution / selectivity; | 4-hydroxy-2-methyl-7V-(5 -methyl-2-thiazolyl)-2#- 1 ,2- benzothiazine-3-carboxamide- 1,1 -dioxide potassium salt monohydrate (compound of the Formula I)350 ml of xylene are transferred into an apparatus equipped with Marcusson head and provided with means for inert gas purging. Purging with argon is started and 35.0 g (130 mmol) 4-hydroxy-2- methyl-2H-l,2-benzothiazine-3-carboxylic acid methylester of the Formula (III) [wherein the meaning of R is methyl], 15.0 g (132 mmol) of 2-amino-5-methyl-thiazole of the Formula (IV) and 6.0 g of activated carbon are added during continous stirring and argon purge.The reaction mixture is heated for 24 hours using an oil bath at a temperature between 170 and 180 0C. The heating is adjusted in a way that only a minimal amount of distillate (2-5 ml/hour) is produced in the head. Distillation of methanol is ceased by the end of the reaction.The reaction mixture is cooled to 25 0C, crude meloxicam containing carbon and approximately 12% of the impurity of Formula (V) are filtered off and washed on the filter with xylene and ethanol. The crude product containing carbon is stirred in 1200 ml of 0.5 % aqueous potassium hydroxide solution at the temperature of 50 0C for one hour, carbon and the impurity of Formula (V) insoluble in the alkaline solution are filtered off and the clear yellow solution at 25 0C are added dropwise the solution of 3O g potassium hydroxide in 100 ml water. The potassium salt of meloxicar? is precipitated in the form of yellow crystals which are easily separable by filtration. The crystal suspension is stirred for two hours at 10 0C, filtered and washed with water. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | In o-xylene; for 24h;Heating / reflux;Product distribution / selectivity; | EXAMPLE 1 20.4 g of 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide ethyl ester and 8.8 g of 2-amino-5-methylthiazole are refluxed in 300 ml of o-xylene for 24 hr and the reaction by-product, ethanol, is removed by means of a soxhlet extraction device fitted with 4A molecular sieves. The crude meloxicam (4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide) is isolated by cooling and filtration in a yield of 24.0 g (95% of theory). |
92.48% | In xylene; at 139 - 140℃; for 32 - 37h;Heating / reflux; Molecular sieve;Product distribution / selectivity; | EXAMPLE 1- Process for preparing crude meloxicam In a 6 litre round-bottom flask, in a nitrogen flow, are placed respectively 226.64g (0.80 mol) of 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate of ethyl-1,1-dioxide and 91.36g (0.80 mol) of 2-amino-5-methyl-thiazole and 3.6 l of xylene. The suspension is heated under reflux (139-140C), passing the condensate on a bed of molecular sieves 4A. Initially a dark brown solution is obtained and then, as the reaction proceeds, the reaction product is crystallised in the form of a yellow-green solid. It is kept under reflux until completion of the reaction (32-37 hours). When the reaction is completed it is cooled to a temperature comprised between 20 and 25C in at least 2 hours. The crude product is filtered and washed with xylol and acetone. 279.34g of wet yellow-greenish crude product are obtained, the equivalent of 260.0 g of dry product. Theoretical yield 281.12 g RDT =92.48%. The crude meloxicam thus obtained has a content of the impurity composed of ethylamide amounting to 0.707% assessed with HPLC using the "Related substances" method given in the monographic report of the British Pharmacopoeia 2002. Repeating example 1, products are obtained that contain the above-mentioned impurity in variable quantities between 0.230 and 0.782%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
pyrographite; In xylene; at 170 - 180℃; for 24h;Product distribution / selectivity; | One proceeds according to Example 1 with the difference that instead of 4-hydroxy-2-methyl-2H-l ,2-benzothiazine-3-carboxylic acid methylester [compound of the Formula (III), wherein R is methyl)], 36.83 g (130 mmol) 4-hydroxy-2-methyl-2H-l,2- benzothiazine-3-carboxylic acid ethylester [compound of the Formula (III), wherein R is ethyl] are used. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74.2% | Sodium bromide (7.2 g, 69.98 mmol) and dichloroacetone (4.88 g, 38.43 mmol) were added to <strong>[7305-71-7]2-Amino-5-methylthiazole</strong> (4.0 g, 35.04 mmol) in ethyl acetate (140 ml_). The reaction mixture was stirred at room temperature for 14 hours. Significant amount of solid precipitated out and filtered off. The solid was dissolved in acetic acid (250 ml_) and heated to 110 0C for 1 hour. The reaction mixture was cooled to room temperature overnight. Significant amount of solid precipitated out again. The solid was filtered off, washed with acetic acid (75 mL), acetone (200 ml_), diethyl ether (200 ml_) and air dried overnight to afford 6-(chloromethyl)-2-methylimidazo[2,1 -jb][1 ,3]thiazole 1 (4.86 g, 74.2percent).LC/MS 151.2 [M+H-CIJ+ Rt, 0.72min. | |
74.2% | Sodium bromide (7.2 g, 69.98 mmol) and dichloroacetone (4.88 g, 38.43 mmol) were added to <strong>[7305-71-7]2-Amino-5-methylthiazole</strong> (4.0 g, 35.04 mmol) in ethyl acetate (140 mL). The reaction mixture was stirred at room temperature for 14 hours. Significant amount of solid precipitated out and filtered off. The solid was dissolved in acetic acid (250 mL) and heated to 110 0C for 1 hour. The reaction mixture was cooled to room temperature overnight. Significant amount of solid precipitated out again. The solid was filtered off, washed with acetic acid (75 mL), acetone (200 mL), diethyl ether (200 mL) and air dried overnight to afford 6-(chloromethyl)-2-methylimidazo[2,1-jb][1 ,3]thiazole 1 (4.86 g, 74.2percent).LC/MS 151.2 [M+H-CI]+ Rt, 0.72min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 0℃; for 3h; | (1) After t-butyl nitrite (1.99 g) was added dropwise to a suspension of 2-amino-5-methyltiazole (2.00 g) in acetonitrile (20 ml) while ice-cooling, copper(II) bromide (4.30 g) was gradually added thereto. This suspension was stirred for 3 hours at 0C. The reaction solution was charged with 1N hydrochloric acid (100 ml) and then extracted twice with ethyl acetate (200 ml). After the organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated. The residue was purified by silica gel column chromatography (neutral; hexane:ethyl acetate=80:20) to yield 2-bromo-5-methylthiazole (1.31 g) as a yellow oil. 1H NMR (300 MHz, CDCl3) delta ppm: 2.44 (3H, d, J = 1.2 Hz), 7.25 (1H, d, J = 1.1 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With 1,2-dichloro-ethane; | EXAMPLE 13 4-Hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide Prepared from ethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide and 2-amino-5-methylthiazole analogous to Example 1, but using o-dichlorobenzene as the solvent with a yield of 76% of theory. M.p.: 254 C. (decomp.) from ethylene chloride, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With toluene-4-sulfonic acid; 1,2-dichloro-ethane; | EXAMPLE 16 4-Hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide Prepared from 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide, 2-amino-5-methyl-thiazole and p-toluenesulfonic acid analogous to Example 15 with a yield of 48% of theory. M.p.: 254 C. (from ethylene chloride). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With triethylamine; In dichloromethane; at 0℃; for 1h; | To a solution of 2-amino-5-methylthiazole (1 g, 8.75 mmol) in dichloromethane (56 mL) cooled to 0 0C, was added bromoacetyl bromide (0.9 mL, 10.5 mmol) and TEA (1.83 mL, 13.1 mmol) dropwise, simultaneously and with stirring at same temperature for 1 hour. The reaction mixture was diluted with dichloromethane, washed with water and brine solution. The organic layer was dried over anhydrous Na2SO4 and concentrated to afford 1.6 g (78 percent yield) of crude compound as an off- white solid. |
78% | With triethylamine; In dichloromethane; at 0℃; for 1h; | Step 1: Preparation of 2-bromo-N-(5-methyl-1,3-thiazol-2-yl)acetamide To a solution of 2-amino-5-methylthiazole (1 g, 8.75 mmol) in dichloromethane (56 mL) cooled to 0° C., was added bromoacetyl bromide (0.9 mL, 10.5 mmol) and TEA (1.83 mL, 13.1 mmol) dropwise, simultaneously and with stirring at same temperature for 1 hour. The reaction mixture was diluted with dichloromethane, washed with water and brine solution. The organic layer was dried over anhydrous Na2SO4 and concentrated to afford 1.6 g (78percent yield) of crude compound as an off-white solid. |
With sodium carbonate; In water; for 2h;pH 9 - 10; | 2-Amino-5-methyl-1,3-thiazole (I) (0.038 mol) was dispersed in 25 mL distilled water in iodine flask(100 mL) and 20percent aq. Na2CO3 solution was poured to adjust pH to 9?10. 2-Bromoethanoyl bromide (II) (0.038 mol) was poured in small patches upon vigorous shaking and then set to stir for further 2 h. Reaction completion was monitored by TLC. Excess icecold distilled water (40 mL) was added and the formed precipitate was collected by filtration. The precipitateof compound (III) was washed with distilled water and dried. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14% | With sodium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 120℃; under 1292.9 Torr; for 3h;Microwave irradiation; | To a solution of N-(4-(6-chloropyrazin-2-ylthio)phenyl)cyclopropanecarboxamide (0.82 mmol) and 2-amino-5-methylthiazole (0.86 mmol) in 1,4-dioxan (3 mL), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.05 mmol), tris(dibenzylideneacetone)dipalladium (0.03 mmol) and sodium carbonate (1.15 mmol) were added. The resulting solution was heated at 120° C. in the microwave (175 W, 25 psi) for 3 h. Water (10 mL) and ethyl acetate (10 mL) were added and the layers separated. The aqueous layer was extracted further with ethyl acetate (2.x.10 mL), the combined organic layers dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography eluting with MeOH:CH2Cl2 (1:20) to give the title compound (42.5 mg, 14 percent) as a light brown solid; 1H NMR (400 MHz, DMSO-d6) delta 0.81 (4H, m), 1.82 (1H, m), 2.16 (3H, s), 3.32 masked signal, 6.99 (1H, m), 7.58 (2H, m), 7.76 (2H, m), 7.84 (1H, s), 8.04 (1H, s), 10.49 (1H, s), 11.50 (1H, br s); MS (ES+): m/e=384.48 (100percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tert.-butylnitrite; In acetonitrile; | Preparation 30 2-Bromo-5-methyl-1,3-thiazole To a solution of 2-amino-5-methyl-1,3-thiazole (11.7 g) in acetonitrile (200 ml) was added dropwise tert-butyl nitrite (8.33 ml) at 0 C. followed by addition of copper(II) bromide (5 g) over 0.5 minutes. After stirring at 0 C. for 3 hours, the mixture was concentrated and partitioned between 1N hydrochloric acid and ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered through a pad of Celite, and concentrated in vacuo to give the title compound (3.24 g) as an oil. ESI-MS: 177.8(M+H) 1H-NMR (300 MHz, CDCl3) delta 7.25(s, 1H), 2.44(s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | Example 21 (E)-2-(3-Chloro-4-methanesulfonyl-phenyl)-2-cyclopentyloxyimino-N-(5-methyl-thiazol-2-yl)-acetamide (E)-(3-Chloro-4-methanesulfonyl-phenyl)-cyclopentyloxyimino-acetic acid (prepared as in Example 1, 84 mg, 0.24 mmol), 5-methyl-thiazol-2-ylamine (28 mg, 0.24 mmol) and N,N-diisopropylethylamine (127 muL, 0.73 mmol) were combined in methylene chloride (2 mL) and cooled in an ice bath. O-(7-Azabenzotriazole-1-yl)-N,N,N'N'-tetramethyluronium hexafluorophosphate (92 mg, 0.24 mmol) was added and the ice bath was removed. After stirring 2 h, the reaction mixture was evaporated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2*3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 mum; 40percent ethyl acetate/hexanes) to afford (E)-2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclopentyloxyimino-N-(5-methyl-thiazol-2-yl)-acetamide (74 mg, 69percent) as a white solid after lyophilization from aqueous acetonitrile: LC-MS (ESI) m/e calcd for C18H20ClN3O4S2 [M+] 441.06, found 442 [M+H+]; H1-NMR (400 MHz, CDCl3) delta ppm 1.66 (m, 4 H, 2*CH2), 1.89 (m, 4 H, 2*CH2), 2.45 (d, J=1.2 Hz, 3 H, ArCH3), 3.31 (s, 3 H, SO2CH3), 4.93 (m, 1 H, OCH), 7.15 (brq, 1 H, Ar), 7.59 (dd, Jo=8.2, Jm=1.5 Hz, 1 H, Ar), 7.70 (d, Jm=1.5 Hz, 1 H, Ar), 8.21 (d, Jo=8.2 Hz, 1 H, Ar), 10.03 (s, 1 H, NH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With N-ethyl-N,N-diisopropylamine; HATU; In ISOPROPYLAMIDE; at 25 - 60℃; for 3h; | EXAMPLE 72 4-(Aminomethyl)-N-(5-methylthiazol-2-yl)-l-(9H-purin-6-yl)piperidine-4-carboxamide; HATU (222 mg, 0.58 mmol) was added in one portion to 4-((toet-butoxycarbonyl- amino)methyl)-l-(9H-purin-6-yl)piperidine-4-carboxylic acid* (200mg, 0.53mmol), 5- methylthiazol-2-amine (60.7 mg, 0.53 mmol) and DIPEA (278 mul, 1.59 mmol) in DMA (2657 mul) at 250C, under nitrogen. The resulting solution was stirred at 60 0C for 3 hours. The crude reaction mixture was then purified using ion exchange chromatography (5g SCX-2 column, 20percent 7M NH3 in MeOH/DCM eluent). The NH3 fraction was then evaporated to dryness. The BOC-group was then removed by reaction with trifluoroacetic acid (123 mul, 1.59 mmol) in DCM (5 ml), the reaction mixture being stirred at room temperature for 16 hrs. The crude product was purified by ion exchange chromatography, again using a 5g SCX-2 column and 20percent 7M NH3 in MeOH/DCM eluent. The NH3 fraction was evaporated to dryness, as before, to afford 4-(aminomethyl)-N-(5- <n="220"/>methylthiazol-2-yl)-l-(9H-purin-6-yl)piperidine-4-carboxamide (161 mg, 81 percent) as a fine white solid.IH NMR (400.13MHz, CDCB) 1.59-1.66 (2H, td), 2.29 (2H, d), 2.32-2.33 (IH, d), 2.40 (3H, s), 2.99 (2H, s), 3.49 (IH, s), 4.00 (2H, broad), 4.99 (2H, broad), 7.09 (IH, s), 7.27 (IH, s), 7.95 (IH, s), 8.37 (IH, s)MS m/e MH+ 373-37 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 95℃; for 6h; | Example 45-Fluoro-N--r(iy)- 1 -(5-fluoropyrimidin-2-yl)ethyl"|-A^-(5-methyl- 1 ,3-thiazol-2-yl)-6-morpholin- 4-ylpyrimidine-2,4-diamine; A microwave reaction vessel was charged with 4-chloro-5-fluoro-N-[(15)-l-(5-fluoropyrimidin- 2-yl)ethyl]-6-morpholin-4-ylpyrimidin-2-amine (Intermediate 17, 72 mg, 0.2 mmol), 5-methyl- l,3-thiazol-2-amine (28 mg, 0.22 mmol), Pd2(dba)3 (18 mg, 0.02 mmol), BINAP (25 mg, 0.04 mmol), Cs2CO3 (228 mg, 0.7 mmol) in dioxane. The reaction was degassed and was heated at 950C for 6 hours. Solvent was removed and the residue was partitioned between DCM and H2O. The dichloromethane layer was concentrated down and was purified by silica gel chromatography twice (by ISCO Combiflash with gradient MeOH and DCM) to afford the title compound as a light pale solid (47 mg, 52percent). LC-MS, 435 (M+l). 1H NMR (DMSO) delta 8.50 (s, 2H), 7.02 (s, IH), 5.21(m, IH), 3.63 (m, 4H), 3.52 (m, 4H), 2.32 (s, 3H), 1.54 (d, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | A solution of 6-chloro-1H-indole (1.0 g, 6.60 mmol) in tetrahydrofuran cooled to 0° C. was treated with trifluoroacetic anhydride. This solution was stirred at 0° C. for 30 min and then was allowed to warm to 25° C. where it was stirred for 1 h. At this time, the reaction was poured into water (75 mL). The resulting precipitate was collected by filtration, washed with water, and dried in vacuo to afford 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone (1.52 g, 93percent) as an off-white solid: mp 256-258° C.; EI-HRMS m/e calcd for C10H15ClF3NO (M+) 247.0012, found 247.0006. [0154] A solution of 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone in N,N-dimethylformamide (5 mL) was treated with potassium carbonate (698 mg, 5.05 mmol). The reaction was stirred at 25° C. for 15 min and then was treated with 2-iodopropane (0.30 mL, 3.03 mmol). This mixture was heated at 65° C. for 20 h. At this time, the reaction was cooled to 25° C., quenched with water (5 mL), and then partitioned between water (50 mL) and ethyl acetate (50 mL). This mixture was treated with a saturated aqueous sodium chloride solution (1.x.25 mL), shaken, and separated. The organic layer was then dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 3/1 hexanes/ethyl acetate) afforded 1-(6-chloro-1-isopropyl-1H-indol-3-yl)-2,2,2-trifluoro-ethanone (483 mg, 83percent) as a pale pink solid: mp 94-96° C.; EI-HRMS m/e calcd for C13H11ClF3NO (M+) 289.0481, found 289.0482. [0155] A mixture of 1-(6-chloro-1-isopropyl-1H-indol-3-yl)-2,2,2-trifluoro-ethanone (475 mg, 1.64 mmol) in a 20percent aqueous sodium hydroxide solution was heated at 110° C. for 18 h. At this time, the reaction was cooled to 25° C. and treated with a 1N aqueous hydrochloric acid solution. This solution was extracted with ethyl acetate (1.x.50 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (385 mg, 99percent) as a yellow solid: mp 206-208° C.; EI-HRMS m/e calcd for C12H12ClNO2 (M+) 237.0056, found 237.0554. [0156] A solution of triphenylphosphine (251 mg, 0.82 mmol) in methylene chloride (3 mL) cooled to 0° C. was treated with N-bromosuccinimide (146 mg, 0.82 mmol). This solution was stirred at 0° C. for 5 min. At this time, the reaction was treated with 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (150 mg, 0.63 mmol). This solution was stirred at 0° C. for 5 min and then was allowed to warm to 25° C. where it was stirred for 30 min. The reaction was then treated with 5-methyl-thiazol-2-ylamine (166 mg, 1.45 mmol) and was stirred at 25° C. for 2 d. At this time, the reaction was diluted with water (25 mL) and ethyl acetate (25 mL). This mixture was treated with a 1N aqueous hydrochloric acid solution (5 mL). The organic layer was separated and was washed with a saturated aqueous sodium bicarbonate solution (1.x.10 mL) and a saturated aqueous sodium chloride solution (1.x.10 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/1 hexanes/ethyl acetate) afforded 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (5-methyl-thiazol-2-yl)-amide (120 mg, 57percent) as a pink solid: mp 216-219° C.; (ES)+-HRMS m/e calcd for C16H16ClN3OS (M+) 333.0703, found 333.0708. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; at 150℃; for 0.0833333h;microwave irradiation; | Example 1 - Synthesis of Compounds of General Formula (I); The Compounds were synthesised using the following general reaction scheme:; 6-(3',4'-Dichlorophenyl)-2-methylimidazo[2,l-b]thiazole (Compound 15); A solution of 5-methylthiazol-2-amine (lOOmg, 0.88mmol) and 2-bromo-l-(3,4- dichlorophenyl)ethanone (235mg, 0.88mmol) in ethanol (5mL) was heated in the <n="21"/>microwave at 15O0C for 5min. After cooling, the mixture was concentrated in vacuo, and dissolved in ethyl acetate. The organic layer was washed with saturated aqueous NaHCC>3 and the combined organic layers were dried over anhydrous MgSO4. The resulting solid, obtained after evaporation, was purified by column chromatography eluting with ethyl acetate/hexanes 1:2 v/v to afford 64mg (26%) of the title compound (LCMS RT= 7.50min, MH+ 282.9) 1H NMR (DMSO): 8.30 (IH, s), 8.04 (IH, d, J 2.0 Hz), 7.79 (IH, dd, J 8.4 2.0 Hz), 7.75-7.73 (IH, m), 7.63 (IH, d, J 8.4 Hz), 2.41 (3H, d, J 1.5 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19% | With pyridine; at 0℃; for 5h;Inert atmosphere; | 5-Methyl-2-aminothiazole (1.5 g, 13.1 mmol) was dissolved in pyridine (8 ml) and cooled to 0C under N2. Phenyl chloroformate (3.62 ml, 28.9 mmol) was then added dropwise and reaction stirred for 5 h at this temperature. The reaction was then quenched with water (10 ml) and the resulting precipitate filtered. The crude precipitate was then purified by column chromatography (100% DCM) to obtain WIN-321 -194-01 as a white solid (590 mg, 19%). 1H NMR (CDCI3): delta 7.48 - 7.36 (m, 2H), 7.31-7.25 (m, 2H), 7.24 - 7.22 (m, 1 H), 7.10 (d, J 1.3 Hz, 1 H), 2.37 (d, J 1.1 Hz, 3H). MS, m/z = 235 [M+H]+. |
19% | With pyridine; at 0℃; for 5h;Inert atmosphere; | 5-Methyl-2-aminothiazole (1.5g, 13mmol) was dissolved in pyridine (8mL) and cooled to 0C under a N2 atmosphere. Phenyl chloroformate (3.6mL, 29mmol) was then added dropwise and reaction stirred for 5hat this temperature. The reaction was then quenched with water (10mL) and the resulting precipitate filtered off. The crude solid was then purified by column chromatography gradient eluting with 100% DCM to obtain 93 as a solid (590mg, 19%). 1H NMR (300MHz, CDCl3): delta 7.48-7.36 (m, 2H), 7.31-7.26 (m, 2H), 7.24-7.22 (m, 1H), 7.10 (d, J 1.3Hz, 1H), 2.37 (d, J 1.1Hz, 3H). MS, m/z=235 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
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Example 33AN-(3-fluorobenzyl)-N-methyl-N'-(5-methyl-1,3-thiazol-2-yl)urea; 5-Methylthiazol-2-amine (571 mg, 5.00 mmol) was dissolved into dichloromethane (30 mL) and cooled to near -45 C. Diphosgene (360 muL, 3.0 mmol) was added rapidly over a second or two, and the mixture was stirred for 5 minutes before diisopropylethylamine (1.74 mL, 10 mmol) was added. The solution was stirred for another 30 minutes, 3-fluorobenzyl-methylamine (1.03 mL, 7.5 mmol) was added, and after another couple of minutes, the cold bath was removed. When the reaction solution had warmed to near room temperature, it was quenched with 1 M aqueous potassium phosphate monobasic (15 mL). The aqueous phase was separated and back-extracted with dichloromethane, and the combined organic phases were washed with more 1 M aqueous KH2PO4 (5 mL). The aqueous phase was separated and back-extracted with dichloromethane. The combined organic phases were dried (sodium sulfate), concentrated, and chromatographed on acidic alumina (ethyl acetate/hexanes) to give the title compound.1H NMR (300 MHz, d6-DMSO) delta ppm 2.26 (3H), 2.93 (3H), 4.59 (2H), 6.9-7.2 (4H), 7.33-7.44 (1H); MS (ESI) m/z 280 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | Example 3C tert-butyl 3-((2-imino-5-methylthiazol-3(2H)-yl)methyl)azetidine-1-carboxylate A mixture of 2-amino-5-methylthiazole (0.32 g, 2.8 mmol), the product of Example 3B (0.95 g, 2.8 mmol) and tetrabutylammonium iodide (0.51 g, 1.4 mmol) in 1 mL N,N-dimethylformamide was warmed to 85 C. and was allowed to stir for 16 h. The mixture was allowed to cool to ambient temperature, was diluted with CH2Cl2 (10 mL) and washed with 5 mL saturated, aqueous NaHCO3. The layers were separated and the aqueous layer was extracted with 3*5 mL CH2Cl2. The combined organics were dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and purified by column chromatography (SiO2, 10% CH3OH in ethyl acetate then 9:1:0.1 CH2Cl2:CH3OH:NH4OH) to give the title compound (0.55 g, 1.9 mmol, 69% yield). MS (DCI/NH3) m/z 284 (M+NH4)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In tetrahydrofuran; ethyl acetate; at 22℃; for 14h; | Example 20A; 2,5-dichloro-N-(5-methylthiazol-2-yl)benzamide; To a solution of 5-methylthiazole-2-amine (Aldrich, 1.0 g, 8.76 mmol) in tetrahydrofuran (10 mL) was added <strong>[50-79-3]2,5-dichlorobenzoic acid</strong> (Aldrich) (2.01 g, 10.51 mmol), triethylamine (2.93 mL, 21.02 mmol), and 1-propanephosphonic acid cyclic anhydride (Aldrich, 50% solution in ethyl acetate, 6.19 mL, 10.51 mmol). The reaction mixture was stirred at 22 C. for 14 h., cooled, and quenched with saturated aqueous NaHCO3 (20 mL). The aqueous layer was extracted with ethyl acetate (2×40 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix Intelliflash280 (SiO2, 0-100% ethyl acetate in hexanes) to afford 1.99 g of the title compound. MS (ESI+) m/z 287 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
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90% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃;Inert atmosphere; | To a suspension of p-tolylacetic acid (1.00 g, 6.66 mmol) and 2-amino-5-methylthiazole (0.760 g, 6.66 mmol) in dichloromethane (10 mL) was added at 0° C. under a nitrogen atmosphere 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.40 g, 7.32 mmol), 1-hydroxybenzotriazole (90 mg, 0.67 mmol) and N,N-diisopropyl ethyl amine (1.8 mL, 10 mmol). The ice bath was removed and the resulting solution was stirred for 3 h at ambient temperature. The reaction mixture was diluted with dichloromethane (20 mL) and washed with aqueous sodium carbonate (half-concentrated, 20 mL) and water (20 mL). The aqueous layers were extracted with dichloromethane (20 mL) and the combined organic layers were dried over sodium sulfate. The filtrate was concentrated and the residue was suspended in TBME (20 mL) and filtered. Washing with TBME (10 mL) afforded the title compound (1.48 g, 90percent) as a white solid. MS m/e: 247.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
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91% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at -5℃;Inert atmosphere; | A solution of 2-amino-5-methylthiazol (1.30 g, 13.56 mmol) and DIPEA (2.00 mL, 11.48 mmol) in THF (55 ml,) was added dropwise to a stirred solution of cyanuric chloride (2.50 g, 13.56 mmol) in THF (70 mL) at -5° C. After the addition was complete, the reaction mixture was stirred at -5° C for 15 more minute. During the stirring, large amount of yellow precipitate formed, which was collected by filtration, wahed with THF (3X20 mL), ethyl acetate (3X20 mL) and hexanes (1X10 mL). The compound 46 (2.72 g, 91percent) was used directly for further reaction without purification. |
91% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at -5℃; | Example 1 A solution of 2-amino-5-methylthiazol (1.30 g, 13.56 mmol) and DIPEA (2.00 mL, 11.48 mmol) in THF (55 ml,) was added dropwise to a stirred solution of cyanuric chloride (2.50 g, 13.56 mmol) in THF (70 mL) at -5 * C. After the addition was complete, the reaction mixture was stirred at -5 ° C for 15 more minute. During the stirring, large amount of yellow precipitate fopined, which was collected by filtration, wahed with THF (3X20 mL), ethyl acetate (3X20 mL) and hexanes (1X10 mL). The compound 1 (2.72 g, 91percent) was used directly for further reaction without purification. |
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at -5℃; | Example 5A solution of 2-amino-5-methylthiazol (1.30 g, 13.56 mmol) and DIPEA (2.00 mL, 11.48 mmol) in THF (55 ml,) was added dropwise to a stirred solution of cyanuric chloride (2.50 g, 13.56 mmol) in THF (70 mL) at -5 ° C. After the addition was complete, the reaction mixture was stirred at -5 ° C for 15 more minute. During the stirring, large amount of yellow precipitate formed, which was collected by filtration, wahed with THF (3X20 mL), ethyl acetate (3X20 mL) and hexanes (1X10 mL). The compound (2.72 g, 91percent) was used directly for further reaction without purification.Example 6 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 150℃; for 0.166667h;microwave initiator; Inert atmosphere; | To a solution of compound 7 (1.0Og, 2.93 mmol) in THF (20 mL) was added DIPEA (0.45 mL, 2.60 mmol) and 2-amino-5-methyl-thiazole (285 mg, 2.50 mmol). The mixture was heated at 150° C for 10 minutes using microwave initiator. After cooled to room temperature, 5 mL ethyl acetate was added and the orange solids on the wall of the tube were scratched off. The mixture was stirred at room temperature for 30 min and the solids were collected by filtration to give compound 17 (1.09 g, 88percent). The crude product was used directly for the next step reaction without further purification. |
Yield | Reaction Conditions | Operation in experiment |
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83% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at -20 - 20℃;Inert atmosphere; | A solution of compound 7 (2.0Og, 5.86 mmol) in THF (80 mL) was cooled by using ice-NaCl batch (bath temperature -20° C ). A solution of DIPEA (1.00 mL, 5.75 mmol) and 2-amino-5-methyl-thiazole (570 mg, 5.00 mmol) was added to the above solution at -20° C (batch temperature) dropwise. After the addition, the temperature was stirred 0° C for 2 additional hours and then let it warmed to room temperature. The solids formed during the reaction was filtered off, washed with THF followed by ethyl acetate and dried to give light yellow solids of compound 18 (1.75 g, 83percent) The crude product was used directly for the next step reaction without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In dichloromethane; at 0℃;Inert atmosphere; | General procedure: The compounds L1 and L2 were prepared by reacting 3-nitrobenzoylchloride with the corresponding isomer of 2-amino-methylthiazole. Similarly for the L3 and L4 2-nitrobenzoyl chloride andfor the L5 and L6 4-nitrobenzoyl chloride were used in place of3-nitrobenzoyl chloride. In a typical experiment 3-nitrobenzoylchloride (0.185 g, 1 mmol) was dissolved in dichloromethane(20 mL) under nitrogen atmosphere. Solution was cooled to 0 Cby placing on an ice-bath and 2-amino-5-methylthiazole (0.114 g,1 mmol) was added to the reaction mixture. It was stirredovernight. A white precipitate of N-(5-methylthiazol-2-yl)-3-nitrobenzamide (L1) was obtained, which was filtered, washed withwater and dried in vacuum |
Yield | Reaction Conditions | Operation in experiment |
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66% | With sodium carbonate;tris(dibenzylideneacetone)dipalladium(0) chloroform complex; 4a,9a-dihydro-9,9-dimethyl-4,5-bis(diphenylphosphino)-xanthene; water; In methanol; dichloromethane; toluene; at 100℃; for 1.5h;Microwave irradiation; | Preparation N-(3-(4-fluorophenylsulfinyl)isoquinolin-l-yl)-5-methylthiazol-2- amine[00257] To l-bromo-3-(4-fluorophenylsulfinyl)isoquinoline from Example 10Step D (200 mg, 0.57 mmol) in toluene (4 mL) were addedPd2(dibenzylideneacetone)3 (23 mg, 0.025 mmol), 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (45 mg, 0.075 mmol), 5-methylthiazol-2-amine (35 mg, 0.34 mmol), and Na2C03 (87 mg, 0.80 mmol), and then water (1 drop) was added with stirring. The mixture was heated in a microwave synthesizer at 100 °C for 1.5 h. The mixture was dissolved in 1 : 1 DCM/MeOH and filtered. The filtrate was concentrated and the residue was triturated with Et20 and EtOAc to afford N-(3-(4- fluorophenylsulfinyl)isoquinolin-l-yl)-5-methylthiazol-2-amine (145 mg, 66 percent) as a yellow solid. 1H NMR (300 MHz, DMSO-t/6) delta 2.3 (s, 3H) 7.14 (s, IH) 7.39 (t, 2H) 7.71 (t, IH) 7.83 (t, IH) 7.92-7.96 (m, 3H) 8.08 (d, IH) 8.70 (d, IH) 1 1.88 (br s, IH); LC-MS (ESI) m/z 384 (M + H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5% | With sodium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;tris-(dibenzylideneacetone)dipalladium(0); In toluene; at 110℃; for 2h;Inert atmosphere; | Example 30Preparation of N-(2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazolin-4-yl)-5-methylthiazol-2-amine Step A: To a mixture of 4-chloro-2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazoline from Example 4 Step A (100 mg, 0.32 mmol), Pd2(dibenzylideneacetone)3 (12 mg, 0.013 mmol), 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (23 mg, 0.04 mmol), 5-methylthiazol-2-amine (51 mg, 0.45 mmol), and Na2CO3 (48 mg, 0.45 mmol) was added toluene (3 mL). The mixture was evacuated and flushed with argon three times and then heated at 110° C. for 2 h. The mixture was diluted with MeOH, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Varian diphenyl reverse phase column, eluted with gradient of solvent B=0.05percent HOAC/ACN and solvent A=0.05percent HOAc/H2O) to afford N-(2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazolin-4-yl)-5-methylthiazol-2-amine (6 mg, 5percent). 1H NMR (300 MHz, DMSO-d6) delta 12.45 (br s, 1H), 8.64 (d, J=2.4 Hz, 2H), 7.88-8.15 (m, 4H), 7.66-7.76 (m, 1H), 7.19 (s, 1H), 2.28 (s, 3H). LCMS (ESI) m/z 388 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | <strong>[7305-71-7]2-Amino-5-methylthiazole</strong> (2.0 g, 17.6 mmol) was dissolved in H3PO4 (20 mL) and HNO3 (10 mL). The mixture was cooled to 0 °C before NaNO2 (3.8 g, 55 mmol) in H2O (8 mL) was added. After 20 min, the solution was slowly added to a cooled solution CuBr (2.6 g, 18 mmol) in HBr (19 mL). This mixture was stirred for 1.5 h then neutralized with NaOH. Sat. aq NaHCO3 (50 mL) was added and the mixture was extracted with EtOAc (3 × 40 mL), dried with MgSO4, and evaporated. Heptane was added and the mixture was decanted and evaporated to give 17. | |
73% | A solution of NaN02 (5.70 g, 61.0 mmol) in water (10 mL) was added at 0°C to a solution of 5- methylthiazol-2-amine (3.00 g, 26.4 mmol) in cone. H3P04 (30 mL) and cone. HN03 (15 mL) and the mixture was stirred at 0°C for 20 min. The RM was then added to mixture of Cu(l)Br (3.9 g, 26.4 mmol) in HBr (46percent, 30 mL) and the RM was stirred at RT for 2 h. The mixture was chilled in an ice bath and NaOH (5M) followed by NaHC03 were added. The mixture was extracted with EtOAc, the combined organic layers were washed with sodium thiosulfate and brine, were dried and the volatiles were removed under reduced pressure. The residue was recrystallized (Cy) to yield the desired compound (4.78 g, 73percent). LC-MS (Method 1): m/z: [M+H]+ = 256.0 (MW calc. = 254.84), R, = 3.3 min. | |
With nitric acid; sodium nitrite; In phosphoric acid; water; hydrogen bromide; acetic acid;liquid HBr; | Example 22 2,4-Dibromo-5-methyl-1,3-thiazole <strong>[7305-71-7]2-Amino-5-methylthiazole</strong> (10 g) was dissolved in phosphoric acid (100 mL) and nitric acid (50 mL), and an aqueous solution (40 mL) of sodium nitrite (19 g) was slowly added dropwise under ice-cooling over about 30 minutes. After stirring for 20 minutes on an ice bath, the solution was added to a suspension solution of copper bromide (13 g) suspended in a hydrobromic acid/acetic acid solution (60 mL) and water (30 mL) over 30 minutes, and the mixture was stirred at room temperature for 3 hours. A 2N aqueous sodium hydroxide solution was added to the reaction liquid for neutralization, followed by extraction twice with ethyl acetate (200 mL). The organic layer was washed with saturated saline (200 mL), then dried using anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was washed with hexane to give the title compound (13 g) having the following physical properties. TLC: Rf 0.75 (hexane:ethyl acetate=3:1); 1H-NMR (CDCl3):delta 2.36 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With potassium carbonate; In toluene; at 20℃; for 36h; | General procedure: A mixture of 2-aminothiazole (1) or 2-amino-5-methylthiazole (2, 0.01 mol), potassium carbonate (2.07 g, 0.015 mol) in dry toluene (50 ml) was stirred at room temperature, while 2-chloroacetyl chloride (3, 1.7 g, 1.2 ml, 0.015 mol) or 3-chloropropionyl chloride (4, 1.9 g, 1.4 ml. 0.015 mol), was added dropwise. Stirring continued for 36 h, solvent was then removed in vacuo and the residue obtained was triturated with water, filtered, dried and recrystallized (Table 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With N-ethyl-N,N-diisopropylamine; sodium iodide; In N,N-dimethyl-formamide; at 70℃; | The solution of 5-((4,6-dichloropyrimidin-2-yl)oxy)-4-fluoro-2-methyl-lH-indole (0.5g, 1.60 mmol), 5-methylthiazol-2-amine (0.22 g, 1.92 mmol), sodium iodide (0.29 g, 1.92 mmol) and DIPEA (0.39 mL, 1.92 mmol) in DMF (16.0 mL) was stirred at 70 °C overnight. The mixture was slowly added to the ice-water (10.0 mL). The mixture was cooled by ice bath and the solids were collected by filtration, washed with water and hexanes to provide compound 77 as pale white solid (0.59 g, 95percent). NMR (400 MHz, DMSO-d6) delta 1 1.34 (bs, 1H), 9.81 (bs, H), 8.70 (bs, 1H), 7.22 (m, 1H), 7.14 (m, 1H), 6.97 (m, 1H), 6.25 (m, 1H), 2.40 (s, 3H), 2.02 (s, 3H); ESI-MS: calcd for (C17H13C1FN50S) 389, found 390 [M-H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | General procedure: The heterocyclic amines (1a?h, 10 mmol) were dissolved in 10 mL water followed by addition of 40 mL of 6M HCl and the systems were cooled in the ice-salt bath down to ?10°C. Afterwards, an aqueous solution of NaNO2 (10 mmol, 0.7g/5 mL H2O) was added slowly drop by drop and stirred vigorously on a magnetic stirrer. After 15min, fresh solution of 4-hydroxycoumarin (3, 10 mmol, 1.62 g) in 10 mL NaOH (10 wt.) was added. Intensively colored and voluminous precipitates (4a?h) were obtained immediately which were stirred 15 min. in the bath and 30 min. on room temperature. Finally, they were filtrated by vacuum, washed 3 times with distilled water and dried on air. The purification was carried out by the technique of recrystallization using ethanol as solvent. |
Yield | Reaction Conditions | Operation in experiment |
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91% | 1003791 Step A: Preparation of 2-methyl-6-phenyl-N-(2,4,4-trimethylpentan-2- yl)imida.zo[2. 1 -blthiazol-5-amine: To a solution of 5-methylthiazol-2-amine (1.16 g, 10.0 mmol) and benzaldehyde (1.11 mE, 11.0 mmol) in 2:1 DCM-MeOH (30 mL) was added Sc(OTf)3 (0.246 g, 0.500 mmol) and the mixture was stirred at ambient temperature for 30 minutes. 1,1,3,3-tetramethylbutyl isocyanide (2.32 mE, 12.0 mmol) was added and the mixture was stirred at ambient temperature for 24 hours. The mixture was concentrated and the residue was purified by silica column chromatography eluting with a step gradient of DCM, 10percent then 20percent EtOAc/hexanes. The title compound was obtained as a cream colored solid (3.10 g, 91percent yield). ?H NMR (CDC13) 7.80 (d, J= 7.5 Hz, 211), 7.37 (t, J 7.6 Hz., 211), 7.25 (d, J= 8.5 Hz, 111), 7.08 (s, 1H), 3.10 (br s, 1H), 2.41 (s, 311), 1.53 (s, 211), 1.02 (s, 9H), 1.00 (s, 6H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
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60% | General procedure: 2 mmol heterocyclic amines were dissolved in hot glacial aceticacid?propionic acid mixture (2:1, 6.0 mL) and was rapidly cooled inan ice-salt bath to?5 °C. The liquor was then added in portions during30 min to a cold solution of nitrosyl sulfuric acid (prepared fromsodiumnitrite (0.15 g) and concentrated sulfuric acid, 98percent (3mL at 50 °C)). Themixturewas stirred for an additional 2 h at 0 °C. Excess nitrous acidwasdestroyed by the addition of urea. The resulting diazonium salt wascooled in ice?salt bath. After diazotization was complete the azo liquorwas slowly added to vigorously stirred solution of 8-hydroxyquinoline(2 mmol, 0.29 g) in potassium hydroxide (2.0 × 10?3 mol, 0.112 g)and water (2 mL). The solution was stirred at 0?5 °C for 2 h. After thatthe pH of the reaction mixture was maintained at 4?6 by the simultaneousaddition of saturated sodium carbonate solution. The mixturewas stirred for 1 day at room temperature. The resulting solid was filtered,washed with cold water and dried. The obtained compoundswere purified by crystallization using ethanol and then analyzed. Theyields of the dyes are in range of 54?78percent. Characterization data areshown below. This dye was obtained from 2-amino-5-methylthiazole and 8-hydroxyquinoline as dark violet crystals (yield: 0.32 g, 60percent; m.p: 232-233 °C). IR (KBr): numax: 3416-3268 (quinoline OH), 3070 (aromatic CH), 2928, 2870 (aliphatic CH), 1573, 1510 (C=C), 1208 (C-O) cm- 1; 1H NMR (DMSO-d6): delta 9.10 (d,1H), 9.00 (d,1H), 8.10 (d,1H), 7.80 (m,2H), 7.30 (d,1H), 2,55 (s,3H). Anal. calcd. for C13H10N4OS (270.31): C, 57.76; H, 3.73; N, 20.73; S, 11.86. Found C, 57.68; H, 3.68; N, 20.71; S, 11.48. MS: (m/z, 70 eV): 270 (M+), 144. |
Yield | Reaction Conditions | Operation in experiment |
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52% | With tris-(dibenzylideneacetone)dipalladium(0); sodium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 1h;Inert atmosphere; Sealed tube; | A mixture of 4-Benzenesulfonyl-2,6-dichloro-pyridine (100 mg, 0.35 mmol), 5- Methyl-thiazol-2-ylamine (48 mg, 0.42 mmol), 4,5-Bis(diphenylphosphino)-9,9- dimethylxanthene (20 mg, 0.03 mmol) and Na2C03 (52 mg, 0.49 mmol) in anhydrous 1,4- Dioxane (3 mL) was sonicated under a flow of nitrogen for 5 min before tris(dibenzylideneacetone)dipalladium (0) (16 mg, 0.02 mmol) was added and the reaction heated to 100 °C in a sealed tube for lh. The reaction was cooled, filtered through a pad of Celite, washed with EtOAc and concentrated. The crude material was purified by flash chromatography, eluting with EtOAc (0 - 75 percent) in heptane to give the title compound as a yellow/ brown solid (80 mg, 52 ). MS: m/z = 365.9 (M + H)+. |
Yield | Reaction Conditions | Operation in experiment |
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73% | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃; | The compound 1 (2.0 g, 100 mol-percent) was dissolved in dry DCM (80 ml). 2-Amino-5-methylthiazol (200 mol-percent), /V-methylmorpholine (NMM) (300 mol-percent) ja 1 -hydroxy-1 H-benzotriazole (HOBT) (170 mol-percent) were added. The reaction mixture was stirred for five minutes, cooled to 0-5 °C and 1 -ethyl-3- (3'dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (220 mol-percent) was added. The reaction mixture was stirred at rt overnight and then diluted with DCM, washed with 1 N HCI-solution and 5percent KOH-solution. The organic phase was finally washed with water and brine. The crude product was purified by chromatography affording 1 .85 of the product; the yield was 73percent. 1H-NMR (CDCIs): 1 .06 (s, 3H), 1 .37-2.60 (m, 22H), 2.90 (m, 2H), 3.79 (s, 3H), 6.70 (m, 2H), 7.05 (s, 1 H), 7.19 (d, 1 H), 12.1 1 (s, 1 H). |
73% | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃; | Compound 5 3-((13S,15R)-3-Methoxy-13-methyl-17-oxo- 7,8,9,1 1 ,12, 13,14, 15,16, 17-decahydro-6H-cyclopenta[a]phenanthren-15-yl)-/V- (5-methylthiazol-2-yl)propanamide The compound 4 (2.0 g, 100 mol-percent) was dissolved in dry DCM (80 ml). 2-Amino-5-methylthiazol (200 mol-percent), N-methylmorpholine (NMM) (300 mol-percent) ja 1 -hydroxy-1 H-benzotriazole (HOBT) (170 mol-percent) were added. The reaction mixture was stirred for five minutes, cooled to 0 to 5 °C and 1 -ethyl-3- (3'dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (220 mol-percent) was added. The reaction mixture was stirred at rt overnight and then diluted with DCM, washed with 1 N HCI-solution and 5percent KOH-solution. The organic phase was finally washed with water and brine. The crude product was purified by chromatography affording 1 .85 (73percent) of the product 5. 1H-NMR (CDCIs): 1 .06 (s, 3H), 1 .37-2.60 (m, 22H), 2.90 (m, 2H), 3.79 (s, 3H), 6.70 (m, 2H), 7.05 (s, 1 H), 7.19 (d, 1 H), 12.1 1 (s, 1 H). |
73% | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃; | Compound X 3-((13S,15R)-3-Methoxy-13-methyl-17-oxo- 7,8,9,1 1 ,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-15-yl)-/V- (5-methylthiazol-2-yl)propanamide The amide coupling: The compound IX (2.0 g, 100 mol-percent) was dissolved in dry DCM (80 ml). 2-Amino-5-methylthiazol (200 mol-percent), N- methylmorpholine (NMM) (300 mol-percent) ja 1 -hydroxy-1 H-benzotriazole (HOBT) (170 mol-percent) were added. The reaction mixture was stirred for five minutes, cooled to 0-5 °C and 1 -ethyl-3-(3'dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (220 mol-percent) was added. The reaction mixture was stirred at room temperature (rt) overnight and then diluted with DCM, washed with 1 N HCI- solution and 5percent KOH-solution. The organic phase was finally washed with water and brine. The crude product was purified by chromatography affording 1 .85 of the product X; the yield was 73percent. 1H-NMR (CDCI3): 1 .06 (s, 3H), 1 .37-2.60 (m, 22H), 2.90 (m, 2H), 3.79 (s, 3H), 6.70 (m, 2H), 7.05 (s, 1 H), 7.19 (d, 1 H), 12.1 1 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | Synthesis of N-(5-methylthiazol-2-yl)-4-oxo-4H-chromene-2-carboxamide (2) To a solution of the chromone-2-carboxylic acid (1 g, 5.26 mm) in DMF (12 mL) at 4 °C was added a solution of PyBOP (2.73 mg, 5.26 mmol) in CH2Cl2 (12 mL). The mixture was kept in an ice bath and stirred for half hour. After this period 5-methylthiazol-2-amine (599 mg, 5.26 mmol) was added and the mixture was allowed to warm up to room temperature. The reaction was kept with stirring by 4 h. The solution was diluted with water and the formed precipitate formed was filtered and washed with water and MeOH. N-(5-methylthiazol-2-yl)-4-oxo-4H-chromene-2-carboxamide was obtained as a white powder (Yield: 48percent). 1H NMR (CDCl3): delta = 2.39 (3H, d, J = 1.1 Hz, CH3), 7.04 (1H, s, H(3)), 7.32 (1H, q, J = 1.1 Hz, H(4')), 7.56 (1H, ddd, J = 8.1, 7.2, 1.1 Hz, H(6)), 7.83 (1H, d, J = 7.9 Hz, H(8)), 7.91 (1H, ddd, J = 8.6, 7.1, 1.7 Hz, H(7)), 8.07 (1H, dd, J = 8.0, 1.4 Hz, H(5)), 13.18 (1H, bs, NH). 13C NMR (CDCl3): delta = 11.4 (CH3), 111.7 (C3), 119.1 (C8, C3'), 123.8 (C4a), 124.9 (C5), 126.1 (C6), 135.1 (C7, C4'), 155.4 (C1', C2, C8a, CONH), 177.4 (C4). MS/EI m/z: 288 (M+?, 53), 286 (86), 258 (72), 230 (62), 230 (62), 173 (95), 145 (82), 68 (100). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); XPhos; In 1,4-dioxane; at 100℃; for 12h;Inert atmosphere; | Step 2. A vial containing a mixture of the obtained intermediate (206.5 mg, 0.694 mmol), 2-amino-5-methylthiazole (159.9 mg, 1.401 mmol), tris(dibenzylideneacetone)dipalladium(0) (34.6 mg, 0.038 mmol), 2-dicyclohexylphosphino- 2',4',6'-triisopropylbiphenyl (37.1 mg, 0.078 mmol) and a solution of tripotassium phosphate (314.3 mg, 1.481 mmol) in dioxane (5 mL) was degassed by two successive cycles of vacuum pumping and N2 purging. The reaction mixture was heated at 100 °C for 12 hours, cooled and poured into water, then filtered through Celite and extracted with dichloromethane. The organic extract was dried over MgS04, then filtered and evaporated. The residue was separated by column chromatography (silica gel, 50:50 ethyl acetate:hexane) to afford the title compound (161 mg, 0.429 mmol, 62percent) as a powder, m.p. 270-271 °C. TLC RF 0.11 (50:50 ethyl acetate:hexane); ]H NMR (500 MHz, CDC13): delta 8.54 (1H, dt, J = 7.0, 1.0 Hz), 7.89 (1H, dd, J = 8.2, 7.6 Hz), 7.81 (1H, dt, J = 9.1, 1.1 Hz), 7.42 (1H, ddd, J = 9.1, 6.7, 1.3 Hz), 7.37 (1H, d, J = 7.5 Hz), 7.21 (1H, d, J = 8.2 Hz), 7.05 (1H, d, J = 1.2 Hz), 7.94 (1H, td, J = 6.7, 1.1 Hz), 2.30 (3H, d, J = 1.2 Hz); MS (ES+): m/e 377.2 (30), 376.2 (100); MS (ES-): m/e 375.2 (20), 374.2 (100). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | In dichloromethane; at 0℃;Inert atmosphere; | Synthesis and characterization The compounds L1 and L2 were prepared by reacting 3-nitrobenzoyl chloride with the corresponding isomer of 2-amino-methyl thiazole. Similarly for the L3 and L4 2-nitrobenzoyl chloride and for the L5 and L6 4-nitrobenzoyl chloride were used in place of 3-nitrobenzoyl chloride. In a typical experiment 3-nitrobenzoyl chloride (0.185 g, 1 mmol) was dissolved in dichloromethane (20 mL) under nitrogen atmosphere. Solution was cooled to 0 °C by placing on an ice-bath and 2-amino-5-methylthiazole (0.114 g, 1 mmol) was added to the reaction mixture. It was stirred overnight. A white precipitate of N-(5-methylthiazol-2-yl)-3-nitrobenzamide (L1) was obtained, which was filtered, washed with water and dried in vacuum. Yield, 0.240 g (92percent). 1H NMR (400 MHz, DMSO-d6): 8.65 (s, 1H), 8.48 (d, 9.2 Hz, 1H), 8.36 (d, 7.6 Hz, 1H), 7.91 (t, 8.0 Hz, 1H), 7.20 (s, 1H), 6.60 (s, 1H), 2.09 (s, 3H). Mass (ESI): Calc. m/z for C11H9N3O3S, 263.0365; found (m + 1), 264.0445. IR (KBr, cm-1): 3458 (w), 3092 (m), 1669 (m), 1614 (m), 1533 (s), 1436 (m), 1343 (s), 1152 (m), 1070 (m), 917 (s), 714 (s), 514 (m). Crystallographic parameters: Crystal system, Monoclinic; Space group, P21/n; a (A), 3.9164(5); b (A), 13.1518(12); c (A), 22.183(3); alpha = beta (°), 90.00; gamma (°), 94.628(11); V (A3), 1138.9(2); Z, 4; Density (g cm-3), 1.535; Absorption coefficient (mm-1), 0.288; Absorption correction, multi-scan; F(0 0 0), 544; Total reflections, 2008; Reflections, I > 2sigma(I), 1164; Max. theta (°), 25.00; Ranges (h, k, l), -4 ? h ? 4, -9 ? k ? 15, -26 ? l ? 11; Completeness to 2theta (percent), 99.9; Data/restrain/parameter; 2008/0/164; Goof, 1.005; R indices [I > 2sigma(I)], 0.0594; R indices (all data), 0.1144. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50.1% | General procedure: A solution of compound 3 (0.5 g, 2.0mmol), EDCI (0.45 g, 2.34 mmol), HOBT (0.28 g, 2.05 mmol) in anhydrous CH2Cl2 (20 mL) was stirred for 1 h at room temperature under nitrogen atmosphere, followed adding various amines or alcohols (1.95 mmol) and Et3N(0.24 g, 2.34 mmol). The reaction mixture was then stirred overnight at room temperature. After completion of the reaction, the mixture was washed with H2O (20mL), saturated NaHCO3 (20 mL) and brine (20 mL), the organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatograph on silica gel (200-300 mesh) by ethyl acetate and petroleum ether (v/v = 1:41:1) as eluent to afford target compounds (yield 50.1percent-86.4percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | 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 70℃; for 0.75h;Microwave irradiation; | General procedure: To a solution of carbazolyl-2-oxoacetic acid 6 (0.275 mmol) in DMF (2 mL), HATU (0.12 g, 0.317 mmol), N,N-diisopropylethylamine (0.09 g, 0.687 mmol) and an appropriate aryl/heteroarylamine (0.303 mmol) was taken in a 10 mL microwave tube. The reaction mixture was irradiated in microwave oven for 45 min at 70 °C. Upon completion of the reaction, as confirmed by TLC, reaction contents were poured into ice-cold water (30 mL) and stirred for 20 min at 25 °C. Suspension so obtained was filtered, dried and purified through column chromatography on silica gel using ethyl acetate:hexane (3:7) as eluent to afford pure yellow coloured solids (7a?x) in 70?91percent yields. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 5.5h; | To a solution of 4-[(3- { l -[(tert-butoxy)carbonyl]piperidin-3-yl} - l -[(4- methoxyphenyl)methyl]-lH-pyrazolo[3,4-b]pyridin-4-yl)oxy]benzoic acid (452 mg, 0.65 mmol) in DMF (9 mL) was added 5-methyl-l,3-thiazol-2-amine (105.0 mg, 0.91 mmol), HATU (351, 0.92 mmol) and DIPEA (180 1.04 mmol). The solution was stirred at room temperature for 5.5 hours, water was added and the mixture extracted three times with AcOEt. The collected organic phases were dried over Na2S04, filtered and evaporated to dryness. The crude product was purified by flash chromatography (silica gel, 50 g, EtOAc in cyclohexane from 10percent to 50percent) to give tert-butyl 3- { l-[(4- methoxyphenyl)methyl]-4- {4-[(5-methyl- 1 ,3-thiazol-2-yl)carbamoyl]phenoxy} - lH-pyrazolo[3,4- b]pyridin-3-yl}piperidine-l-carboxylate as white solid (438.0 mg, Yield: 78percent). LC-MS (ESI): mlz (M+l)+, 655.5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With tris-(dibenzylideneacetone)dipalladium(0); dicyclohexyl-(2?,4?,6?-triisopropyl-3,6-dimethoxy-[1,1?-biphenyl]-2-yl)phosphine; potassium carbonate; acetic acid; In tert-butyl alcohol; at 115℃; for 3h;Molecular sieve; Sealed tube; Inert atmosphere; | General procedure: An oven-dried pressure tube equipped with a magnetic stirringbar was charged with Pd2dba3 (4.7 mg, 0.51 mol %), BrettPhos (11.3 mg, 2.1 mol %), K2CO3 (192 mg, 1.4. mmol, 1.4 equiv.), arylamine (1 mmol, 1 equiv.), aryl bromide (1 mmol, 1 equiv.), and activated molecular sieves of 4 A (100 mg). The vessel was flushed well with argon. Dry tert-butanol (4 mL) and acetic acid (1.7 mL,3 mol %) were added, and the pressure tube was sealed with aTeflon screw cap and placed into an oil bath at 115 C for 3 h. The reaction mixture was then cooled to room temperature and filtered.The solvent was removed under reduced pressure, and the crude product was purified by flash chromatography. In the case where the aryl bromide (ethyl 4-bromobenzoate) was a liquid, it was added after tert-butanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
<strong>[1129634-44-1](S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid</strong> (0.61g, 2.5 mmol) and NMI (0.45 g, 5.6 mmol) in DMF (10 mL), cooled to 0 oC,was added by MsCl (1.15 g,2.5 mmol) dropwise, and keptstirring for 15 min. Then 5-methylthiazol-2-amine (0.29 g, 2.5 mmol) was added.The reaction was monitored by TLC. After completion, the mixture was diluted byEA, washed by 10% citric acid, and extracted by EA (2x50 mL). The combinedorganic layers were washed by saturated Na2CO3 solutionand brine. Concentration under reduced pressure gave the crude |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With 2,6-di-t-butyl catechol; acetic acid; In ethanol; for 3h;Reflux; | General procedure: A mixture of equal volumes of heterocyclic amine (0.02 mol), and vinylbenzaldehyde (1p and 1m) (0.02 mol) in the presence of some traces of 2,6-di-t-butyl catechol as the polymerization inhibitor, and 4-5 drops of glacial acetic acid used as reaction catalyst in 30 mL of absolute ethanol was refluxed for 3 h in water bath as shown in the Scheme 1. The resulting solution was concentrated in vacuum and cooled down in a freezer for 24 h. The precipitated product was filtered, washed with cold absolute ethanol and then dried.N-(4-vinylbenzylidene)-5-methyl-thiazol-2-amine (2p)yellow crystals, [Yield: 73%]; M.p. 88-90 C; IR (KBr) cm-1: 3078.80 (C-H arom), 1609.31 (CH=N imin), 1525.42 (CH=N thiaz), 997.01, 923.73 (C=C vinyl). 1H NMR (CDCl3) dppm 2.49 (d, 3H, J= 1.15 Hz, CH3 thiaz), 7.35 (d, 1H, J= 1.17 Hz CH thiaz), 5.40 (d, 1H, J= 11.10 Hz, CH2=CH), 5.90 (d, 1H, J= 17.59 Hz, CH2=CH), 6.79 (dd, 1H, J= 10.91 Hz, J = 17.60 Hz, CH2=CH), 7.52 (d, 2H, J = 8.29 Hz, H-arom), 7.93 (d, 2H, J = 8.29 Hz, H-arom), 8.92 (s, 1H, CH=N imin). 13C-RMN (CDCl3) dppm 12.67 (-CH3 thiaz), 116.31, 126.63, 129.98, 133.14, 134.51, 136.13, 138.95 141.51 (C Vinyl, Arom, thiaz), 161.54 (C=N thiaz), 171.14 (CH=N imin). UV (Ethanol C = 10-4 mol L-1) lmax(epsilon, L·mol-1·cm-1) 361 (14580), 239 (9260) nm, 213 (9680). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With 2,6-di-t-butyl catechol; acetic acid; In ethanol; for 3h;Reflux; | General procedure: A mixture of equal volumes of heterocyclic amine (0.02 mol), and vinylbenzaldehyde (1p and 1m) (0.02 mol) in the presence of some traces of 2,6-di-t-butyl catechol as the polymerization inhibitor, and 4-5 drops of glacial acetic acid used as reaction catalyst in 30 mL of absolute ethanol was refluxed for 3 h in water bath as shown in the Scheme 1. The resulting solution was concentrated in vacuum and cooled down in a freezer for 24 h. The precipitated product was filtered, washed with cold absolute ethanol and then dried. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 45℃; for 1h; | A solution of 2-(3-(3-(4-chloro-2-fluorophenyl)ureido)-4-(cyclohexyl(isobutyl)amino)phenoxy)acetic acid (Example 1) (0.02 g, 0.041 mmol) in DMF (0.3 mL) was treated with 5-methylthiazol-2-amine (9.28 mg, 0.081 mmol) followed by triethylamine (0.014 mL, 0.102 mmol) then BOP (0.023 g, 0.053 mmol). The reaction was stirred at 45°C for lh then purified by prep. HPLC. Concentration of the appropriate fractions afforded 2-(3-(3-(4-chloro-2-fluorophenyl)ureido)-4-(cyclohexyl(isobutyl)amino)phenoxy)-N-(5-methylthiazol-2-yl)acetamide-TFA (0.023 g, 80percent yield). MS (ES): m/z = 588 [M+H]+, Tr = 2.61 min (Method C). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.61% | A mixture of 97 (0.30 g, 0.88 mmol), HBTU (0.50 g, 1.32 mmol), DIPEA (0.23 ml, 1.32 mmol) and DMF (2.5 ml) was stirred for a while, to which was then added 2-amino-5- methylthiazole (0.15 g, 1.32 mmol) at room temperature and the mixture was stirred overnight. The residue was filtered by suction filtration to yield a red product. The residue was filtered without further purification to afford 23 (0.38 g, 98.61 percent) as a red solid. 1H- NMR (300 MHz, DMSO-d6): delta 2.36 (s, 3H), 5.03 (d, J= 7.2 Hz, 2H), 7.20 (s, 1H), 7.45 (d, J= 8.1 Hz, 2H), 7.72-7.78 (m, 1H), 7.80-7.85 (m, 1H), 7.50-7.99 (m, 2H), 8.03 (d, J= 8.1 Hz, 2H), 8.10 (t, J= 8.1 Hz, 1H), 12.21 (br, 1H). | |
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | [00158]A mixture of 97 (0.30 g, 0.88 mmol), HBTU (0.50 g, 1.32 mmol), DIPEA (0.23 ml, 1.32 mmol) and DMF (2.5 ml) was stirred for a while, to which was then added 2-amino-5- methylthiazole (0.15 g, 1.32 mmol) at room temperature and the mixture was stirred overnight. The residue was filtered by suction filtration to yield a red product. The residue was filtered without further purification to afford 23 (0.38 g, 98.61 percent) as a red solid. 1H-NMR (300 MHz, DMSO-d6): ^2.36 (s, 3H), 5.03 (d, J= 7.2 Hz, 2H), 7.20 (s, 1H), 7.45 (d, J= 8.1 Hz, 2H), 7.72- 7.78 (m, 1H), 7.80-7.85 (m, 1H), 7.50-7.99 (m, 2H), 8.03 (d, J= 8.1 Hz, 2H), 8.10 (t, J= 8.1 Hz, 1H), 12.21 (br, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | In methanol; for 6h;Reflux; | A solution of <strong>[199177-26-9]3-bromo-5-hydroxybenzaldehyde</strong> (1.31 g,6.55 mM) in methanol (10 mL) was added dropwise with continuousstirring to a solution of the primary amine, 5-methylthiazol-2-ylamine (0.75 g, 6.57 mM) in methanol (15 mL), over a period of5 min. The reaction mixture was refluxed at 60 C for about 6 h.The completion of the reaction was monitored by TLC. The productwas isolated by pouring the reaction mixture into ice cold water.The precipitate formed was filtered off and dried to obtain a paleyellow solid. The compound was then purified by column chromatographyusing silica gel (230-400 mesh size) with ethyl acetateand petroleum ether as eluents.Yield: 0.81 g (67%). 1H NMR (400 MHz, CDCl3, ppm), d: 9.88(s, 1H, OH), 8.69 (s, 1H, AHCN), 6.93-7.38 (m, 4H, Ar-H), 2.19(s, 3H, Ar-CH3). 13C NMR (100 MHz, CDCl3, ppm) d: 169.9, 161.1,160.3, 136.3, 135.7, 130.1, 125.1, 124.5, 125.1, 121.4, 112.8, 12.1.ESI-MS calc. for C11H9N2OSBr [M+]: 295.96; found 296.11 [M+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 12h;Inert atmosphere; | General procedure: To a solution of 7 or 8 (0.61 mmol) in DCM (10 mL) was added EDCI(234 mg, 1.2 mmol), HOBt (162 mg, 1.2 mmol), DMAP (293 mg,2.4 mmol) and amine (120 mg, 1.2 mmol) under N2 at room temperature.The reaction mixture was stirred for 12 h and then poured intowater (30 mL) and extracted with DCM (20 mL× 3). The organic layerwas washed with brine, dried over anhydrous Na2SO4 and concentrated.The residue was purified through column chromatography(petroleum ether/AcOEt, 5/1 v/v) to give the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 12h;Inert atmosphere; | General procedure: To a solution of 7 or 8 (0.61 mmol) in DCM (10 mL) was added EDCI(234 mg, 1.2 mmol), HOBt (162 mg, 1.2 mmol), DMAP (293 mg,2.4 mmol) and amine (120 mg, 1.2 mmol) under N2 at room temperature.The reaction mixture was stirred for 12 h and then poured intowater (30 mL) and extracted with DCM (20 mL× 3). The organic layerwas washed with brine, dried over anhydrous Na2SO4 and concentrated.The residue was purified through column chromatography(petroleum ether/AcOEt, 5/1 v/v) to give the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.6% | In a 100 ml single-mouth round bottom flask,Will 9.98mmol 1.14g2-amino-5-methylthiazole and other compound solutions of substituted aromatic amines or aliphatic amines R1NH2 dissolved in 30 ml of anhydrous methylene chloride,Then add 9.98 mmol ie 1.01 g of triethylamine.Stir for 10 minutes under ice bath conditionsA solution of 1.80 g of 8.32 mmol of 3,4-dichloroisothiazole-5-carbonyl chloride II in dichloromethane was gradually added dropwise, and the mixture was stirred at room temperature for 3 h.There is a yellow precipitate, filtered,The cake was washed twice with ethyl acetate.2.2 g of a yellow solid was obtained, and the yield was calculated using the resulting pure product.Yield 91.6percent; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | General procedure: To a solution of mycophenolic acid (2 mmol) in absolute DMF (1.5 mL) carbonyldiimidazole(2.2 mmol) was added and stirred for 2 h at room temperature. Then appropriate amine (2.2 mmol) wasadded and the reaction mixture is stirred at 70 C for 10 h. The mixture was cooled to room temperatureand distilled water (10 mL) was added. The precipitate formed was filtered and crystallized fromaqueous methanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | General procedure: To a solution of mycophenolic acid (2 mmol) in absolute DMF (1.5 mL) carbonyldiimidazole(2.2 mmol) was added and stirred for 2 h at room temperature. Then appropriate amine (2.2 mmol) wasadded and the reaction mixture is stirred at 70 C for 10 h. The mixture was cooled to room temperatureand distilled water (10 mL) was added. The precipitate formed was filtered and crystallized fromaqueous methanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Ca. 83% | The new thiazolylazodye ligand has been synthesized by the diazotization coupling reaction (Scheme-I) by Al-Adilee [20] and Fan et al.[21] method with some modification. <strong>[7305-71-7]2-Amino-5-methylthiazole</strong> (1.14 g, 0.01 mol) was dissolved in mixture 5 mL offormic acid and 7 mL of concentrated sulfuric acid, then 16 mLdistilled water were added. To this solution was added dropwisea solution of 0.80 g (0.012 mol) of sodium nitrite (NaNO2)in 35 mL distilled water at (0-5) °C and the mixture was stirredfor 30 min at (0-5) °C. The resulting diazonium solution wasadded drop-wise with cooling and stirring continuously at (0-5) °C in to beaker (500 mL) containing 1.65 g (0.01 mol) of3-dimethyl amino benzoic acid was dissolved in 10 mL ofpyridine and 30 mL of methanol and cooled to (0-5) °C. Themixture was stirred for 2 h in an ice-bath and allowed to standovernight. The precipitate formed was filtered off and firstpurified by the base-acid recrystallized method and furtherpurified by recrystallization from DMF-water (1:1). A darkpurplish crystals, which decomposes at 198 °C, was obtainedin a yield of about 83 percent. The purity was confirmed by theelement analysis and TLC techniques. Its structure was verifiedby 1H NMR, mass spectrum, IR and UV-visible spectrometry. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With montmorillonite MK10 impregnated with ZnCl2; In o-xylene; for 24h;Reflux; Green chemistry; | 2-Amino-5-methylthiazole (85 mg, 0.7 mmol) and Zn-MK10 (30 mg, 0.037 mmol) were added to a solution of methyl 2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide 4a (200 mg, 0.7 mmol) in o-xylene (3 mL) and the mixture was stirred at reflux during 24 h. After cooling to room temperature, the mixture was filtered to recover the supported catalyst, the xylene was evaporated and CH2Cl2 (10 mL) was added to the crude. The mixture was then purified on flash chromatography (EtOAc:n-heptane, 00:100 to 50:50) to provide the 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxyde (3) in 90% yield. White solid; mp 245-246 C (CH2Cl2); Rf 0.62 (EtOAc:n-Heptane, 60:40), IR nu cm- 1: 3288, 1549, 1344, 1264, 1183 (Fig. 2). 1H NMR (400 MHz, CDCl3) delta (ppm): 2.46 (s, 3H, CH3), 2.89 (s, 3H, CH3), 7.23 (s, 1H, thiazolylH), 7.75 (dquint, J = 7.2, 1.6 Hz, 2H, ArH), 7.91 (dd, J = 7.4, 2.0 Hz, 1H, ArH), 8.06 (dd, J = 8.2, 1.6 Hz, 1H, ArH) (Fig. 3). 13C NMR (100 MHz, DMSO-d6) delta (ppm): 11.8 (CH3), 38.0 (CH3), 114.3 (C), 123.3 (CH; C), 126.1 (CH), 129.3 (CH), 132.1 (CH), 132.9 (CH; C), 134.4 (2C), 155.7 (C), 168.4 (C) (Fig. 4). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | General procedure: A mixture of 4-Hydroxycoumarin (1 mmol, 0.162 g) and 4-chlorobenzaldehyde (1 mmol, 0.140 g), with 5 ml LTTM was takenin a 50 ml round bottomed flask at room temperature to form theKnoevenagel product, monitored by TLC and then 2-mino 5-methylthiazole (1 mmol, 0.106 g) were added and continued at reflux conditionfor 20 min. The progress of the reaction was monitored by TLCusing petroleum ether- ethyl acetate (8:2 v/v). After completion, thereaction mixture was cooled to room temperature. Water was addedto the reaction mixture and the product was collected by simple filtration,washed with hot ethanol and diethyl ether. Finally, thecrude product was recrystallized from ethanol to obtain the pureproduct (Scheme 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | General procedure: A mixture of 4-Hydroxycoumarin (1 mmol, 0.162 g) and 4-chlorobenzaldehyde (1 mmol, 0.140 g), with 5 ml LTTM was takenin a 50 ml round bottomed flask at room temperature to form theKnoevenagel product, monitored by TLC and then 2-mino 5-methylthiazole (1 mmol, 0.106 g) were added and continued at reflux conditionfor 20 min. The progress of the reaction was monitored by TLCusing petroleum ether- ethyl acetate (8:2 v/v). After completion, thereaction mixture was cooled to room temperature. Water was addedto the reaction mixture and the product was collected by simple filtration,washed with hot ethanol and diethyl ether. Finally, thecrude product was recrystallized from ethanol to obtain the pureproduct (Scheme 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | General procedure: A mixture of 4-Hydroxycoumarin (1 mmol, 0.162 g) and 4-chlorobenzaldehyde (1 mmol, 0.140 g), with 5 ml LTTM was takenin a 50 ml round bottomed flask at room temperature to form theKnoevenagel product, monitored by TLC and then 2-mino 5-methylthiazole (1 mmol, 0.106 g) were added and continued at reflux conditionfor 20 min. The progress of the reaction was monitored by TLCusing petroleum ether- ethyl acetate (8:2 v/v). After completion, thereaction mixture was cooled to room temperature. Water was addedto the reaction mixture and the product was collected by simple filtration,washed with hot ethanol and diethyl ether. Finally, thecrude product was recrystallized from ethanol to obtain the pureproduct (Scheme 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | General procedure: A mixture of 4-Hydroxycoumarin (1 mmol, 0.162 g) and 4-chlorobenzaldehyde (1 mmol, 0.140 g), with 5 ml LTTM was takenin a 50 ml round bottomed flask at room temperature to form theKnoevenagel product, monitored by TLC and then 2-mino 5-methylthiazole (1 mmol, 0.106 g) were added and continued at reflux conditionfor 20 min. The progress of the reaction was monitored by TLCusing petroleum ether- ethyl acetate (8:2 v/v). After completion, thereaction mixture was cooled to room temperature. Water was addedto the reaction mixture and the product was collected by simple filtration,washed with hot ethanol and diethyl ether. Finally, thecrude product was recrystallized from ethanol to obtain the pureproduct (Scheme 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | General procedure: A mixture of 4-Hydroxycoumarin (1 mmol, 0.162 g) and 4-chlorobenzaldehyde (1 mmol, 0.140 g), with 5 ml LTTM was takenin a 50 ml round bottomed flask at room temperature to form theKnoevenagel product, monitored by TLC and then 2-mino 5-methylthiazole (1 mmol, 0.106 g) were added and continued at reflux conditionfor 20 min. The progress of the reaction was monitored by TLCusing petroleum ether- ethyl acetate (8:2 v/v). After completion, thereaction mixture was cooled to room temperature. Water was addedto the reaction mixture and the product was collected by simple filtration,washed with hot ethanol and diethyl ether. Finally, thecrude product was recrystallized from ethanol to obtain the pureproduct (Scheme 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | General procedure: A mixture of 4-Hydroxycoumarin (1 mmol, 0.162 g) and 4-chlorobenzaldehyde (1 mmol, 0.140 g), with 5 ml LTTM was takenin a 50 ml round bottomed flask at room temperature to form theKnoevenagel product, monitored by TLC and then 2-mino 5-methylthiazole (1 mmol, 0.106 g) were added and continued at reflux conditionfor 20 min. The progress of the reaction was monitored by TLCusing petroleum ether- ethyl acetate (8:2 v/v). After completion, thereaction mixture was cooled to room temperature. Water was addedto the reaction mixture and the product was collected by simple filtration,washed with hot ethanol and diethyl ether. Finally, thecrude product was recrystallized from ethanol to obtain the pureproduct (Scheme 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | General procedure: A mixture of 4-Hydroxycoumarin (1 mmol, 0.162 g) and 4-chlorobenzaldehyde (1 mmol, 0.140 g), with 5 ml LTTM was takenin a 50 ml round bottomed flask at room temperature to form theKnoevenagel product, monitored by TLC and then 2-mino 5-methylthiazole (1 mmol, 0.106 g) were added and continued at reflux conditionfor 20 min. The progress of the reaction was monitored by TLCusing petroleum ether- ethyl acetate (8:2 v/v). After completion, thereaction mixture was cooled to room temperature. Water was addedto the reaction mixture and the product was collected by simple filtration,washed with hot ethanol and diethyl ether. Finally, thecrude product was recrystallized from ethanol to obtain the pureproduct (Scheme 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | General procedure: A mixture of 4-Hydroxycoumarin (1 mmol, 0.162 g) and 4-chlorobenzaldehyde (1 mmol, 0.140 g), with 5 ml LTTM was takenin a 50 ml round bottomed flask at room temperature to form theKnoevenagel product, monitored by TLC and then 2-mino 5-methylthiazole (1 mmol, 0.106 g) were added and continued at reflux conditionfor 20 min. The progress of the reaction was monitored by TLCusing petroleum ether- ethyl acetate (8:2 v/v). After completion, thereaction mixture was cooled to room temperature. Water was addedto the reaction mixture and the product was collected by simple filtration,washed with hot ethanol and diethyl ether. Finally, thecrude product was recrystallized from ethanol to obtain the pureproduct (Scheme 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | General procedure: A mixture of 4-Hydroxycoumarin (1 mmol, 0.162 g) and 4-chlorobenzaldehyde (1 mmol, 0.140 g), with 5 ml LTTM was takenin a 50 ml round bottomed flask at room temperature to form theKnoevenagel product, monitored by TLC and then 2-mino 5-methylthiazole (1 mmol, 0.106 g) were added and continued at reflux conditionfor 20 min. The progress of the reaction was monitored by TLCusing petroleum ether- ethyl acetate (8:2 v/v). After completion, thereaction mixture was cooled to room temperature. Water was addedto the reaction mixture and the product was collected by simple filtration,washed with hot ethanol and diethyl ether. Finally, thecrude product was recrystallized from ethanol to obtain the pureproduct (Scheme 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | General procedure: A mixture of 4-Hydroxycoumarin (1 mmol, 0.162 g) and 4-chlorobenzaldehyde (1 mmol, 0.140 g), with 5 ml LTTM was takenin a 50 ml round bottomed flask at room temperature to form theKnoevenagel product, monitored by TLC and then 2-mino 5-methylthiazole (1 mmol, 0.106 g) were added and continued at reflux conditionfor 20 min. The progress of the reaction was monitored by TLCusing petroleum ether- ethyl acetate (8:2 v/v). After completion, thereaction mixture was cooled to room temperature. Water was addedto the reaction mixture and the product was collected by simple filtration,washed with hot ethanol and diethyl ether. Finally, thecrude product was recrystallized from ethanol to obtain the pureproduct (Scheme 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | General procedure: A mixture of 4-Hydroxycoumarin (1 mmol, 0.162 g) and 4-chlorobenzaldehyde (1 mmol, 0.140 g), with 5 ml LTTM was takenin a 50 ml round bottomed flask at room temperature to form theKnoevenagel product, monitored by TLC and then 2-mino 5-methylthiazole (1 mmol, 0.106 g) were added and continued at reflux conditionfor 20 min. The progress of the reaction was monitored by TLCusing petroleum ether- ethyl acetate (8:2 v/v). After completion, thereaction mixture was cooled to room temperature. Water was addedto the reaction mixture and the product was collected by simple filtration,washed with hot ethanol and diethyl ether. Finally, thecrude product was recrystallized from ethanol to obtain the pureproduct (Scheme 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | General procedure: A mixture of 4-Hydroxycoumarin (1 mmol, 0.162 g) and 4-chlorobenzaldehyde (1 mmol, 0.140 g), with 5 ml LTTM was takenin a 50 ml round bottomed flask at room temperature to form theKnoevenagel product, monitored by TLC and then 2-mino 5-methylthiazole (1 mmol, 0.106 g) were added and continued at reflux conditionfor 20 min. The progress of the reaction was monitored by TLCusing petroleum ether- ethyl acetate (8:2 v/v). After completion, thereaction mixture was cooled to room temperature. Water was addedto the reaction mixture and the product was collected by simple filtration,washed with hot ethanol and diethyl ether. Finally, thecrude product was recrystallized from ethanol to obtain the pureproduct (Scheme 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | General procedure: A mixture of 4-Hydroxycoumarin (1 mmol, 0.162 g) and 4-chlorobenzaldehyde (1 mmol, 0.140 g), with 5 ml LTTM was takenin a 50 ml round bottomed flask at room temperature to form theKnoevenagel product, monitored by TLC and then 2-mino 5-methylthiazole (1 mmol, 0.106 g) were added and continued at reflux conditionfor 20 min. The progress of the reaction was monitored by TLCusing petroleum ether- ethyl acetate (8:2 v/v). After completion, thereaction mixture was cooled to room temperature. Water was addedto the reaction mixture and the product was collected by simple filtration,washed with hot ethanol and diethyl ether. Finally, thecrude product was recrystallized from ethanol to obtain the pureproduct (Scheme 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Mix 2-chloroacetophenone (0.5 mmol, 77 mg) and p-toluenesulfonyl hydrazide (0.5 mmol, 93 mg) in 1,4-dioxane (4 mL) and react at 50 oC 2 Hours, then add 2-amino-5-methylthiazole (0.4 mmol, 46mg), CuSO4 5H2O (15 mg), lithium t-butoxide (85 mg) to the above reaction system and continue the reaction at 100 oC 3 hour. After the TLC detection reaction was completed, dichloromethane was added to the system, which was successively washed with brine and water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain the final pure compound 3u (80%, 80.9 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With acetic acid; at 110℃; for 4h; | General procedure: The starting materials 1 and 2 were commercially available (Energy Chemical, Shanghai, China).Compound 2 (3.72 mmol) was added to a stirred solution of compound 1 (3.38 mmol) in glacial aceticacid (10 mL). The reaction mixture was then stirred at 110 C for 4 h. After completion of the reaction,the solvent was evaporated, and the residue was purified on a silica gel column chromatography andeluted with ethyl acetate/petroleum ether (bp 60-90 C) (1:3, v/v) to give compounds 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In 1,2-dichloro-ethane; at 45℃; for 16h; | 108 (33mg, 0.13mmol), 5-methyl-2-aminothiazole (18mg, 0.16mmol), EDCI (30mg, 0.16mmol), and DMAP (1.9mg, 0.013mmol) in DCE (5mL) were stirred at 45C for 16h. To the reaction was added 10% citric acid solution (10mL) and the mixture extracted with DCM (2×10mL). The organic layer was then washed with 10% NaHCO3 solution (1×15mL), dried with MgSO4 and concentrated in vacuo. The crude residue was then purified by column chromatography gradient eluting with 100% CyHex to 60% EtOAc/CyHex to obtain 36 as a solid (24mg, 53%). 1H NMR (300MHz; CDCl3): delta 7.04-7.17 (m, 2H), 6.96 (d, J 2.6Hz, 1H), 6.80 (dd, J 2.6, 8.4Hz, 1H), 3.73 (td, J 3.1, 12.4Hz, 2H), 2.90-2.72 (m, 2H), 2.68-2.51 (m, 1H), 2.42 (ad, J 2.0Hz, 3H), 2.31 (s, 3H), 2.10-2.00 (m, 4H). 13C NMR (75MHz, DMSO-d6) delta 172.8, 156.2, 150.1, 134.6, 133.7, 131.3, 126.0, 124.9, 115.8, 114.9, 48.2, 41.0, 27.4, 18.5, 11.0. MS, m/z=350 (100) [M+H]+, 352 (30). HRMS found: (M+H) 350.1090; C17H20ClN3OS requires (M+H), 350.1089. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With cesium fluoride; In neat (no solvent); at 80℃; under 30.0 Torr; | General procedure: The target compounds were synthesized according to a clean solvent-free protocol recently reported by the lab (Scheme 2) [25]. Pterolactam A (17.4 mmol, 1eq) and CsF (0.086 mmol, 5 mol%) were added to the nucleophile (17.4 mmol, 1eq), without any solvent, and the mixture was stirred under moderate vacuum (30 mmHg) at 80C, until the 1H NMR conversion showed no more progression, or after caking of the medium. After cooling at room temperature, diethyl ether (20 mL) was added to the crude mixture. The precipitate was filtered off and the solid obtained was recrystallized from EtOH or purified by flash chromatography (silica gel, gradient of ethyl acetate in n-heptane), to afford the target compounds. In these conditions, N,O and N,S-acetals 1a-j, and N,N?-aminals 2a-g, 3a-t and 4a-f were obtained in moderate to excellent yields (Table 1). |
Tags: 7305-71-7 synthesis path| 7305-71-7 SDS| 7305-71-7 COA| 7305-71-7 purity| 7305-71-7 application| 7305-71-7 NMR| 7305-71-7 COA| 7305-71-7 structure
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H412 | Harmful to aquatic life with long-lasting effects |
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H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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