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CAS No. : | 152460-09-8 | MDL No. : | MFCD02179269 |
Formula : | C16H13N5O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | OJITWRFPRCHSMX-UHFFFAOYSA-N |
M.W : | 307.31 | Pubchem ID : | 10686149 |
Synonyms : |
|
Num. heavy atoms : | 23 |
Num. arom. heavy atoms : | 18 |
Fraction Csp3 : | 0.06 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 5.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 88.59 |
TPSA : | 96.52 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -6.14 cm/s |
Log Po/w (iLOGP) : | 2.18 |
Log Po/w (XLOGP3) : | 2.86 |
Log Po/w (WLOGP) : | 3.5 |
Log Po/w (MLOGP) : | 1.76 |
Log Po/w (SILICOS-IT) : | 0.93 |
Consensus Log Po/w : | 2.25 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.86 |
Solubility : | 0.0422 mg/ml ; 0.000137 mol/l |
Class : | Soluble |
Log S (Ali) : | -4.55 |
Solubility : | 0.00874 mg/ml ; 0.0000284 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -6.12 |
Solubility : | 0.000234 mg/ml ; 0.00000076 mol/l |
Class : | Poorly soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 2.84 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | 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 |
---|---|---|
84 - 88% | With sodium hydroxide; In butan-1-ol; for 10h;Heating / reflux; | A suspension of 20 Kg of 2-methyl-5-nitrophenyl guanidine nitrate in 132 L n-butanolis charged 13.6 Kg of 2-dimethylamino-l-(3-pyridyl)-2-propen-l-one is charged. 3.2Kgs of sodium hydroxide flakes are charged. The suspension is heated to reflux andmaintained reflux for 10 hours till product separated quantitatively from the reactionmass as heavy mass. As soon as the product separates out the reaction mass cooled to50-60C. and charged 117 L of isopropyl alcohol and 57 L of methanol. The reactionmass is cooled to 10C. Maintained half an hour at 10C. the mixture centrifuged andwashed with a mixture of 58 L Isopropyl ether and 28 L methanol. The product N-(2-methyl-5-nitro phenyl)-4-(3-pyridyl)-2-pyrimidineamine of the formula [VI] is dried at60-70CYield: 21 Kg(88%)MR: 193 - 198C.Purity by TLC : Single spot.Step-2 The preparation of N-(2-methyl-5-nitro phenyl)-4-(3-pyridyl)-2-pyrimidineamineA suspension of 2 Kg of 2-methyl-5-nitrophenyl guanidine nitrate in 16 L n-butanol ischarged 1.3 Kg of 2-dimethylamino-l-(3-pyridyl)-2-propen-l-one is charged. 0.3 Kgsof sodium hydroxide flakes are charged. The suspension is heated to reflux andmaintained reflux for 10 hours till product separated quantitatively from the reactionmass as heavy mass. As soon as the product separates out the reaction mass cooled to50-60C. and charged 15 L of isopropyl alcohol and 7 L of methanol. The reaction massis cooled to 10C. Maintained half an hour at 10C. the mixture centrifuged and washedwith a mixture of 5 L Isopropyl ether and 3 L methanol. The product N-(2-methyl-5-nitro phenyl)-4-(3-pyridyl)-2-pyrimidineamine (VI) is dried at 60-70 CYield: 2.0Kg(84%)MR : 192 - 197C.Purity by TLC : Single spot.Step-2 The preparation of N-(2-methyl-5-nitro phenyl)-4-(3-pyridyl)-2-pyrimidineamineof the formula [VI]. suspension of 2 Kg of 2-methyl-5-nitrophenyl guanidine nitrate in 16 L n-butanol ischarged 1.3 Kg of 2-dimethylamino-l-(3-pyridyl)-2-propen-l-one is charged. 0.3 Kgs}f sodium hydroxide flakes are charged. The suspension is heated to reflux andMaintained reflux for 8 hours till product separated quantitatively from the reaction massis heavy mass. As soon as the product separates out the reaction mass cooled to 50-50C. and charged 15 L of isopropyl alcohol and 7 L of methanol. The reaction mass is;ooled to 10C. Maintained half an hour at 10C. the mixture centrifuged and washedivith a mixture of 5 L Isopropyl ether and 3 L methanol. The product N-(2-methyl-5-litro phenyl)-4-(3-pyridyl)-2-pyrimidineamine of the formula [VI] is dried at 60-70CField: 2.0 Kg (85%)MR : 194 - 199C.Purity by TLC : Single spot. Step-2 The preparation of N-(2-methyl-5-nitro phenyl)-4-(3-pyridyl)-2-pyrimidineamineof the formula [VI]A suspension of 2 Kg of 2-methyl-5-nitrophenyl guanidine nitrate in 13 L n-butanol ischarged 1.3 Kg of 2-dimethylamino-l-(3-pyridyl)-2-propen-l-one is charged. 0.3 Kgsof sodium hydroxide flakes are charged. The suspension is heated to reflux andmaintained reflux for 10 hours till product separated quantitatively from the reactionmass as heavy mass. As soon as the product separates out the reaction mass cooled to50-60C. and charged 15 L of isopropyl alcohol and 7 L of methanol. The reaction massis cooled to 10C. Maintained half an hour at 10C. the mixture centrifuged and washedwith a mixture of 5 L Isopropyl ether and 3 L methanol. The product N-(2-methyl-5-nitro phenyl)-4-(3-pyridyl)-2-pyrimidineamine of the formula [VTJ is dried at 60-70CYield: 2.0Kg(85%)MR : 193 - 197C.Purity by TLC : Single spot. |
With sodium hydroxide; In methanol; isopropyl alcohol; | Step 20.2 248.2 g (0.96 mol) of 2-methyl-5-nitrophenylguanidine nitrate are added to a solution of 170 g (0.96 mol) of 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one in 2.0 liters of isopropanol. After the addition of 42.5 g of sodium hydroxide, the reddish suspension is boiled at reflux for 12 hours. After cooling to 0, filtration, washing with 2.0 liters of isopropanol and 3*400 ml of methanol and drying, there is obtained N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine-amine, m.p. 195-198, Rf =0.68 (methylene chloride:methanol=9.1). | |
With sodium hydroxide; In isopropyl alcohol; | To a mixture of 2-methyl-5-nitrophenylguanidine nitrate (25 g, 96 mmol) and 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one (17 g, 96 mmol) in isopropanol (200 ml) was added sodium hydroxide (4.5 g). The reaction was refluxed for 12 hours and cooled to 0 C. The precipitate was filtered and washed with isopropanol to give N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine-amine. |
With sodium hydroxide; In butan-1-ol; for 12h;Heating / reflux; | To 2-methyl-5-nitrophenyl guanidine 2 (0.0074 mol) in n-butanol (15 mL) is added 3 (0.0074 mol) and sodium hydroxide flakes (0.008 mol). The resulting mixture is heated at reflux for 12 h. After cooling to 0 C, the precipitate is collected by filtration and washed with isopropanol (6 mL) and methanol (3 mL) to afford 4. 1HNMR (400MHz, d6- DMSO) delta 9.31 (s, IH), 9.24 (s, IH), 8.78 (m, IH), 8.70 (m, IH), 8.61 (m, IH), 8.47 (m, IH), 7.88 (m, IH), 7.55 (m, 3H), 2.39 (s, 3H). | |
40 mmol of the appropriate dimethylamino-propenon derivative and 40 mmol of the nitrophenyl-guanidine salt were suspended with 60 cm3 of 2-propanol and the contents were stirred for 5-10 minutes. Then 44.1 mmol of sodium hydroxide were added to them and the reaction mixture was stirred and refluxed for 8-12 hours. The reaction mixture was cooled to 0 C. The product was filtered and washed with 2-propanol and then the crude material was stirred with 300 cm3 of water for 30 minutes. The product was filtered again, washed with water and then with ethanol and with diethyl ether and dried at room temperature in the end. | ||
With sodium hydroxide; In isopropyl alcohol; for 18h;Heating / reflux; | 3-DIMETHYLAMINO-1- (3-PYRIDYL)-2-PROPEN-1-ONE (25g, 0. 14MOL), 2-methyl-5- nitrophenyl-guanidine nitrate (36g, 0. 14MOL), and sodium hydroxide (6. 5g, 0. 163MOL) were dissolved in isopropanol and reacted under reflux for 18 hours. The reaction solution was cooled to 0C, filtered, washed with isopropanol and methanol, and dried to give N- (2-metllyl-5-nitrophenyl)-4- (3-pyridyl)-2-pyrimidine-amine (20g). Rf= 0.6 (Methylene chloride: Methanol = 9 : 1) LH-NMR (DMSO-D6) = 2.43 (s, 3H), 7.50-7. 60 (m, 2H), 7.89-7. 93 (m, LH), 8.47-8. 50 (M, LH), 8. 62-8.64 (m, LH), 8.71-8. 74 (m, LH), 8. 78-8. 81 (m, LH), 9.27-9. 33 (m, 2H) | |
With sodium hydroxide; In isopropyl alcohol; for 18h;Heating / reflux; | 3-DIMETHYLAMINO-L- (3-PYRIDYL)-2-PROPEN-LONE (25g, 0. 14MO1), 2-METHYL-5-NI- trophenyl-guanidine nitrate (36g, 0. 14MOL), and sodium hydroxide (6. 5g, 0. 163MOL) were dissolved in isopropanol and reacted under reflux for 18 hours. The reaction solution was cooled B 0 C, filtered, washed with isopropanol and methanol, and dried to give N- (2-METHYL-5-NITROPHENYL)-4- (3-PYRIDYL)-2-PYRIMIDINE-AMINE (20g). [149] [150] Rf = 0.6 (Methylene chloride : Methanol = 9 : 1) [151] 1H-NMR(DMSO-d)= 2.43(s,3H), 7.50-7.60(m,2H), 7.89-7.93 (m,1H), 8.47-8.50 6 (m, LH), 8.62-8. 64 (m, 1H), 8.71-8. 74 (m, 1H), 8.78-8. 81 (m, 1H), 9.27-9. 33 (m, 2H) | |
With sodium hydroxide; | 2-methyl-5-nitroanilinewith cyanamide, guanidine nitrate was the addition, and then (E) -3-dimethylamino-1- (pyridin-3-yl) -1-oxo-2-propenyl cyclization was pyrimidinaminecompound, and finally reducing the nitro group to give. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With hydrazine hydrate; In N,N-dimethyl-formamide; at 100℃; for 3h;Green chemistry; | General procedure: A mixture of the organic nitro compound (1.0 mmol), NH2NH2·H2O (2.5 equiv.) and H2O2-treated AC powder (50 wt%) in DMF (1.5 mL) was stirred vigorously magnetically at 100 C. The reaction was monitored by LC-MS or GC-MS. On completion the reaction mixture was filtered to remove the catalyst. The combined organic mixture material was dried using anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure to obtain the products. All the compounds were known and characterised by their 1H NMR and MS spectra and comparison with literature data. |
98% | With hydrazine hydrate;palladium 10% on activated carbon; In methanol; at 25℃; for 8h;Reflux; Inert atmosphere; | Example 4: Preparation of 4-methyl-N-3-(4-pyridin-3-ylpyriinidin-2-vI)benzene-l,3-dianiineTo a solution of (2-methyl-5-nitrophenyl)-(4-pyridin-3-ylpyrimidin-2-yl)amine ( lOOg, 0.32mol) in methanol (600 ml), 10% palladium on carbon (5g, 50% wet) and aqueous hydrazine hydrate (81.45g, 80 %) were added at 25-30 C and reaction mixture was refluxed for 8 hours under inert atmosphere. After completion of reaction, the catalyst was removed by filtration and the solvent was distilled out completely under vacuum. The resulting residue was diluted with demineralized water (400 ml). The precipitated solid was filtered, washed with demineralized water and dried to give 88g (98%) of the title compound having purity 99.8% by HPLC. |
96.1% | With palladium 10% on activated carbon; hydrogen; In tetrahydrofuran; methanol; at 130℃; under 7500.75 Torr; for 0.0116667h; | Weigh imatinib intermediate nitration 180.0g2.0 L of methanol and 2.5 L of tetrahydrofuran were added,10.0g of 10% Pd / C was added and mixed well to form material I;The flow rate of the slurry pump was adjusted so that the flow rate of the material I was 27.5 g / min,Adjust H2 gas flow meter flow rate of 300ml / min,Reaction temperature is 130 ,Imatinib intermediate nitrobenzene and H2 molar ratio of 1: 3.5,The residence time of the reaction was 42 s and the reaction pressure was 1.0 Mpa.The reaction liquid flowing out from the exit of the reactor was collected,Palladium-carbon was removed by filtration, the organic solvent was distilled off under reduced pressure,700 ml of 2-methyltetrahydrofuran and methylene chloride (1: 1) were added,After stirring and dissolving, 700 ml of n-hexane was slowly added dropwise thereto,A large amount of yellow solid precipitated after dripping,Incubated at 20 C under stirring for 2 hours, filtered,Washed and dried under vacuum at 50 C for 12 hours to give i6.genin intermediate 156.10g,Yield 96.1%,Liquid phase purity of 99.7%. |
95% | With palladium on activated charcoal; hydrogen; In methanol; N,N-dimethyl-formamide; at 20℃; for 6h; | Add <strong>[152460-09-8]N-(2-methyl-5-nitrophenyl)-4-(pyridin-3-yl)pyrimidin-2-amine</strong> (3.3 g, 0.01 mol) in a 50 mL dry single-mouth bottle, DMF (5 mL) , methanol (100mL) and palladium carbon (0.3g), and hydrogen, stirred at room temperature, reaction for 6 hours, TLC detection reaction has ended,Stop the reaction. After suction filtration, the filtrate was evaporated to dryness to give crude N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-aminopyrimidine.Recrystallization from dichloromethane gave 2.63 g of a yellow solid.Yield: 95.0%. |
94% | With hydrogen;palladium 10% on activated carbon; In ethyl acetate; at 25℃; under 3040.2 Torr; | 4. Preparation of N-(5-amino-2-methyl)-4-(3-pyridyl)-pyrimidine-amine A 1000 ml reactor, equipped with a mechanical stirrer and a reflux condenser, was charged with N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-pyrimidine-amine (36.5 g) and ethyl acetate (550 ml) was added into the reactor to obtain a suspension. 10% palladium on activated carbon (18 g) was then added. The hydrogen reduction was carried on at 25 and ~4 atm until no hydrogen was absorbed anymore. The reaction mixture was then filtered, and the thus obtained solution was evaporated under reduced pressure to dryness to give 31 g of crude product in an yield of 94%, having a purity of 96%. |
88.2% | With potassium borohydride; zirconium(IV) chloride; In methanol; for 6h;Reflux; | 620g of methanol was added to three 1000ml flask, stirred open, then successively added 48gN- (2- methyl-5-nitrophenyl) -4- (3-pyridyl) -2-pyrimidine, 8.4g KBH4 and 0.2g ZrCl4. Addition was completed, heating under reflux for 6h, evaporated under reduced pressure, 600g of purified water was added and evaporated to dryness, filtered, and the resulting solid at 60 ~ 65 , dried for 5 to 7 hours to give the product N- (5- amino-2-methyl-benzene yl) -4- (3-pyridyl) -2-amino-pyrimidine (imatinib amine) 38g. HPLC content of 99.6%, 88.2% yield of the crystallization. |
83.65% | With hydrated iron(III) oxide; hydrazine hydrate; In water; isopropyl alcohol; at 70℃; for 7h;Large scale; | In a 100 L three-necked flaskN- (5-nitro-2-methylphenyl) -4- (3-pyridyl) -2-pyrimidinamine (4.81 Kg, 15.65 mol)Hydrazine hydrate 80% aqueous solution (7.5 Kg)And FeO (OH) (360 g), 24 L of isopropanol,70 C stirring refluxing reaction 7 hours,TLC monitored reaction (DCM: MeOH = 15: 1),After the raw material reaction was completed,The filtrate was stirred at room temperature overnight,Isopropyl alcohol washing, filter cake vacuum drying,The product was 3.63 Kg, 15.09 mol.Yield 83.65%. |
82.7% | With hydrogen; In methanol; at 25℃; under 3102.97 Torr; for 45h; | In to a hydrogenation kettle a N-(5-nitro-2-methylphenyl)-4-(3-pyridinyl)-2- pyridineamine (20 g; 0.0.0651 mol) obtained from step-B and methanol (400ml) were added. Wet Raney's nickel (8g) was washed thoroughly with water and was charged into hydrogenation kettle. Hydrogenation was conducted at 60psi at 25C for 45hours. The reaction mixture was filtered and washed with methanol (200ml). The combined filtrates were concentrated in vacuum, treated with a mixture of water (100ml) and chloroform (200 ml). The organic layer was washed with water (3x50ml) and distilled under vacuum. Residual solid was brought to room temperature and ethyl acetate (150ml) was charged. The solution was heated to reflux temperature and cooled down with stirring to 0-5C. The crystalline solid was filtered off and washed with chilled ethyl acetate (10ml), dried to afford title compound (15.0g, yield: 82.7%) of the title product. Purity (by HPLC): 99.40%) Melting point: 143-147C |
80% | General procedure: <strong>[152460-09-8]N-(5-nitro-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine</strong> (8a) (3.08 g 10 mmol) was added to a stirred suspension of stannous chloride (50 mmol) and con HCl, the mixture was stirred at room temperature for 12 h. The reaction mixture was poured into crushed ice and was basified with potassium carbonate. The aqueous layer extracted with ethyl acetate and dried over anhydrous sodium sulfate, evaporated in vacuum to afford the compound as yellow solid (2.21 g, 80%). | |
77% | With hydrazine hydrate; In ethanol; at 50℃;Reflux; Green chemistry; | General procedure: A suspension of 0.5 mmol of nitro compound 1 or 2 in 1 mL of ethanol was heated to 50C, 0.05 mmol of Ni/Co nanocatalyst in 1 mL of ethanol was added with stirring, the mixture was stirred for 5-7 min, and 0.18 mL (3.5 mmol, 5 equiv) of hydrazine hydrate was added dropwise. The mixture was refluxed for 20-45 min, the progress of the reaction being monitored by TLC. When the reaction was complete, the warm mixture was filtered through a layer of celite, the sorbent was washed with ethanol, and the filtrate was combined with the washings and evaporated. The residue was dissolved in 10 mL of ethyl acetate, the solution was washed with water and evaporated to 1/3 of the initial volume, and the product was precipitated with petroleum ether. |
76% | With m-phenylenediamine dihydrochloride; In methanol; at 20 - 60℃; for 1h;Green chemistry; | General procedure: To 0.177 g (0.5 mmol) of 1 or 6-10, the nanocatalyst (0.05 mmol, 0.1 equiv.) dispersed in 2 mL of methanol was added at room temperature, after which 0.3 mL of hydrazine hydrate (3.5 mmol, 5 or 8 equiv.) was poured dropwise into the resulting mass. The reaction mixture was refluxed for 1-4 h; after ~15 min of heating it started to foam. Warm reaction mixture was filtered through Celite, washed with methanol, and the combined filtrate was evaporated. The residue was dissolved in 10 mL of ethyl acetate, washed with water, dried, and evaporated to reduce by 2/3 its original volume, and the product was precipitated by the addition of petroleum ether. |
75.13% | With ammonium chloride; zinc; In tetrahydrofuran; at 80℃; for 0.166667h;Microwave irradiation; | The imatinib intermediate of N-(2-methyl-5-nitrophenyl) - 4-(pyridin-3-yl) pyrimidin-2-amine (1 mmol), was dissolved in THFfollowed by activated zinc (4 mmol) and ammonium chloride(10 mmol) were added. The reaction mixture was irradiated in themicrowave synthesizer at 80 C for 10 min. After completion of thereaction filtered and washed with THF. The filtrate was evaporatedand crude product was stirred with crushed ice. The resulting pale yellow precipitate was dried under vacuum (Yield, 0.208 g, 75.13%);m.p. 142-144 C. ES-MS (M1) found (m/z): 278.1. 1H NMR (DMSOd6):2.16 (S, 3H); 4.44 (S, 2H); 6.39-6.41 (m, 1H); 6.91-6.93 (m,1H); 7.15-7.18 (m, 1H); 7.22-7.23 (m, 1H); 7.92-7.94 (m, 1H); 8.128.13 (m, 1H); 8.46-8.48 (m, 1H); 8.68-8.69 (m, 1H); 9.26 (S, 1H). |
73.2 - 80.9% | With hydrazine;nickel; In methanol; water; at 35℃; for 1 - 5.5h;Heating / reflux;Conversion of starting material; | Example 3 To a stirred suspension of N-(5-nitro-2-methylphenyl)-4-(3- pyridinyl)-2-pyridineamine (65 g; 0.21 M) in methanol (1400 mL) was added wet Raney's nickel (6.25 g) followed by the first portion of an 80% solution of hydrazine hydrate (52.5 g; 0.84 M) in methanol (50 mL). After 1 hour, the reaction mixture was cooled down to 350C and stirring was continued for further 1.5 hour. Next, the second portion of an 80% solution of hydrazine hydrate (52.5 g; 0.84 M) in methanol EPO <DP n="25"/>(50 mL) was added dropwise and stirring was continued for 3 hours. The reaction mixture was cooled down to room temperature and filtered through a pad of Celite. The layer of Celite was washed with methanol (150 mL). The combined filtrates were concentrated in vacuo, treated with dichloromethane (500 mL), and the organic layer was washed with water (3 * 300 mL). The organic layer was dried with anhydrous MgStheta4 (12 g) and filtered through a pad of SiOQ (60 g). The layer of silica gel was washed subsequently with a mixture of dichloromethane-ethyl acetate (50:50; 300 mL) and ethyl acetate (600 mL). The combined filtrates were concentrated under normal pressure to approximately 100 mL and cooled down with stirring to room temperature. The crystalline solid was filtered off and washed with a small volume of dichloromethane to afford 47.5 g (80.9 %) of the product. Purity (by HPLC): 99.84%. Example 4 Wet Raney's nickel (2.5 g) was added to a stirred suspension of N-(5-nitro-2-methylphenyl)-4-(3-pyridinyl)-2-rhoyridineamine (24 g; 78.1 mM) in methanol (380 mL). The mixture was heated to reflux and the first portion of a 40% solution of hydrazine hydrate (10 mL; 79.9 mM) was added dropwise. After refluxing the mixture for 20 minutes, the second portion of a 40% solution of hydrazine hydrate (10 mL; 79.9 mM) was added dropwise. After 40 minutes of refluxing, the reaction mixture was cooled down to room temperature and filtered through a pad of Celite. The layer of Celite was washed with methanol (150 mL). The combined filtrates were concentrated in vacuo. The residue was treated with dichloromethane (300 mL) and active charcoal (2.5 g) and then refluxed for 30 minutes. After cooling EPO <DP n="26"/>the reaction mixture to room temperature, charcoal was filtered off and washed with dichloromethane (100 mL). Next, the procedure described in Example 3 was followed to afford 16.552 g (76.4%) of the product. Purity (by HPLC): 99.64%. Example 5 Wet Raney's nickel (2.5 g) was added to a stirred suspension of N-(5-nitro-2-methylphenyl)-4-(3-pyridinyl)-2-pyridineamine (24 g; 78.1 mM) in methanol (380 mL). The mixture was heated to reflux and the first portion of an 80% solution of hydrazine hydrate (7.5 mL; 119.9 mM) was added dropwise. After refluxing the mixture for 20 minutes, the second portion of an 80% solution of hydrazine hydrate (7.5 mL; 119.9 mM) was added dropwise. After 40 minutes of refluxing, the reaction mixture was cooled down to room temperature and filtered through a pad of Celite. The layer of Celite was washed with methanol (100 mL). The combined filtrates were concentrated in vacuo. The residue was treated with dichloromethane (200 mL) and active charcoal (2.5 g) and then refluxed for 30 minutes. After cooling the reaction mixture to room temperature, charcoal was filtered off and washed with dichloromethane (100 mL). Next, the procedure described in Example 3 was followed to afford 15.886 g (73.2%) of the product. Purity (by HPLC): 99.75%. |
60 - 64.5% | With hydrogenchloride; tin(ll) chloride; at 0 - 35℃; for 4.5 - 5.5h; | 170 L of Cone. Hydrochloric acid is charged into the reactor. 70 Kg of stannous chloride dihydrate is charged. Stirred for 10 minutes. Cooled the reaction mass to 0-5C. Added compound of the formula (VI) slowly during 3-4 hours at 0-5 C. reaction mass is brought to 25-35C. Maintained 1 V2 hour at 25-35C. Charged 500 Its of DM water to the reaction mass and charged slowly 400 L of 50% sodium hydroxide solution at 25-3 5C. Reaction mass is extracted with 2 x 250 L chloroform. The chloroform layer is water wash thoroughly and carbon treatment is given . Distilled off chloroform completely under vacuum and charged 20 L ethyl acetate. Cooled to 0-10C. Maintained 1 hour at 0-10C. Centrifuged and washed with 10 L ethyl acetate to provide N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-pyrimidineamine of the formula [VII]Yield: 10 Kg (61.5%)MR: 141-144C.PuritybyHPLC:99.8%.Step -3:The preparation of N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-pyrimidineamine (VII)20 L of Cone. Hydrochloric acid is charged into the reactor. 7 Kg of stannous chloridedihydrate is charged. Stirred for 10 minutes. Cooled the reaction mass to 0-5C. Addedcompound of the formula (VI) slowly during 2-3 hours at 0-5C. reaction mass is broughtto 25-35C. Maintained 3 hours at 25-35C. Charged 500 Its of DM water to thereaction mass and charged slowly 40 L of 50% sodium hydroxide solution at 25-35C.Reaction mass is extracted with 2 x 35 L chloroform. The chloroform layer is waterwash thoroughly and carbon treatment is given . Distilled off chloroform completelyunder vacuum and charged 2 L ethyl acetate. Cooled to 0-10C. Maintained 1 hour at 0-10C. Centrifuged and washed with 1 L ethyl acetate to provide N-(5-amino-2-methylphenyi)-4-(3-pyridyl)-2-pyrimidineamine of the formula [VII]Yield: 0.98Kg(60%)MR: 140-143C.Purity by HPLC: 99.8%.Step -3: The preparation of N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-pyrimidineamine of theformula [VH] 17 L of Cone. Hydrochloric acid is charged into the reactor. 7 Kg of stannous chloride dihydrate is charged. Stirred for 10 minutes. Cooled the reaction mass to 0-5C. Added compound of the formula (VI) slowly during 2-3 hours at 0-5C. reaction mass is brought to 25-35C. Maintained 3 hours at 25-35C. Charged 500 Its of DM water to the reaction mass and charged slowly 40 L of 50% sodium hydroxide solution at 25-35C. Reaction mass is extracted with 2 x 50 L chloroform. The chloroform layer is waterwash thoroughly and carbon treatment is given . Distilled off chloroform completelyunder vacuum and charged 2 L ethyl acetate. Cooled to 0-10C. Maintainedl hour at 0-10C. Centrifuged and washed with 1 L ethyl acetate to provide N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidineamine of the formula [VII]Yield : 0.97 Kg (60%)MR: 140-143C.Purity by HPLC: 99.7%. Step -3 ;The preparation of N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-pyrimidineamine of theformula [VII]19 L of Cone. Hydrochloric acid is charged into the reactor. 7 Kg of stannous chloridedihydrate is charged. Stirred for 10 minutes. Cooled the reaction mass to 0-5C. Addedcompound of the formula (VI) slowly during 2-3 hours at 0-5C. reaction mass is broughtto 25-35C. Maintained 2 1A hour at 25-35C. Charged 500 Its of DM water to thereaction mass and charged slowly 40 L of 50% sodium hydroxide solution at 25-35C.Reaction mass is extracted with 2 x 50 L chloroform. The chloroform layer is waterwash thoroughly and carbon treatment is given . Distilled off chloroform completelyunder vacuum and charged 2 L ethyl acetate. Cooled to 0-10C. Maintained 1 hour at 0-10C. Centrifuged and washed with 1 L ethyl acetate to provide N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidineamine of the formula [VII]Yield: 1.05 Kg (64.5%)MR: 142-144C.Purity by HPLC: 99.85%. |
56.4% | With iron(III) chloride; pyrographite; hydrazine hydrate; In methanol; ethyl acetate; at 80℃; for 24h; | N-(2-methyl-5-nitrophenyl)-4-(pyridine-3-yl) pyridine-2-amine (3.07 g, 10.0 mmol), hydrazine monohydrate (1.54 g of 65% solution in water, 20.0 mmol), FeCl3 (21 mg, 0.13 mmol), and activated carbon (0.2 g) were dissolved in a mixture of methanol (200 mL) and ethyl acetate (100 mL). The reaction mixture was heated to 80 C. with stirring and maintained for 24 hours. The reaction mixture was cooled own to room temperature. The insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (150 mL) and washed with water (150*2). The organic phase was dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the resulting residue was purified by column chromatography (biotage: DMC/Methanol, 1-8%, 25 CV). The product was obtained (1.57 g, yield: 56.4%) as a yellow solid and 0.53 g starting material of N-(2-methyl-5-nitrophenyl)-4-(pyridine-3-yl) pyridine-2-amine was recovered; 1H NMR (500 MHz, CDCl3) delta 2.28 (s, 3H), 3.68 (s, 2H), 6.45 (d, 1H), 6.95 (s, 1H), 7.02 (d, 1H), 7.18 (d, 1H), 7.45 (m, 1H), 7.35 (d, 1H), 7.65 (s, 1H), 8.37 (d, 1H), 8.52 (d, 1H), 8.74 (d, 1H), 9.28 (s, 1H). LC-MS (m/z) calculated, 277.3, found, 278.2 [M+H]+. |
46% | Step 4: 4-Methyl-N-3-(4-pyridin-3-yl-pyrimidin-2-yl)-benzene-1,3-diamine (Intermediate A): A solution of SnCl2.2H2O (2.14 g, 9.48 mmol) in concentrated hydrochloric acid (8 mL) was added to 2-methyl-5-nitro-phenyl-(4-pyridin-3-yl-pyrimidin-2-yl)-amine (0.61 g, 1.98 mmol) with vigorous stirring. After 30 min of stirring the mixture was poured onto crushed ice, made alkaline with K2CO3, and extracted three times with of ethyl acetate (50 ml). Organic phases were combined, dried over MgSO4, and evaporated to dryness. Recrystallization from dichloromethane resulted in 252.6 mg (0.91 mmol) of 4-methyl-N-3-(4-pyridin-3-yl-pyrimidin-2-yl)-benzene-1,3-diamine (yield: 46%) as an off-white solid. | |
With stannous chloride; In ethanol; ethyl acetate; for 4h;Heating / reflux; | <strong>[152460-09-8]N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine-amine</strong> (35 g, 0.114 mol) and stannous chloride dihydrate (128.5 g, 0.569 mol) were dissolved in a solvent mixture of ethyl acetate and ethanol (250 ml, 10/1, v/v), and the reaction solution was refluxed for 4 hours. The solution was cooled to room temperature, washed with 10% aqueous sodium hydroxide solution, and concentrated to give N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine-amine (35 g). Rf=0.45 (Methylene chloride:Methanol=9:1). 1H-NMR(DMSO-d6)=2.04(s, 3H), 6.30-6.34(m, 1H), 6.76-6.77(m, 1H), 6.84-6.87 (d, 1H), 7.34-7.35(m, 1H), 7.50-7.56(m, 1H), 8.38-8.47(m, 1H), 8.53-8.57(m, 2H), 8.66-8.70(m, 1H), 9.23-9.24(d, 1H). | |
With sodium disulfide; In ethanol; for 1h;Heating / reflux; | To a solution of commercial sodium sulphide nonahydrate (Na2S.9H2O, 2Og) in ethanol (200ml) is charged sulphur (3g) and the mass refluxed for 2 hr. the resulting solution of sodium disulphide is treated with the nitro compound N-(2-Methyl-5- nitrophenyl)-4-(3-pyridyl)-2-rhoyrimidineamine (12.5g) in one lot. The reaction mixture is refluxed for lhr and the solvent ethanol is distilled off under reduced pressure. The reaction mixture is diluted with water (100ml) and extracted with chloroform (2x100ml). The chloroform layer is washed with water (2x50ml), dried over anhy. Na2SO4 (2g) and the solvent distilled off. The cooled mass is crystallized from ethylacetate (40ml) to yield the intermediate amine N-(5-Amino-2-methyl phenyl)-4-(3-rhoyridyl)-2-pyrimidineamine (II) (1Og). mp: 142 - 147C | |
A reactor is charged with concentrated hydrochloric acid (17 mL) followed by stannous chloride dehydrate (0.03 mol). The mixture is stirred for 10 min and then cooled to 0-5 C. A solution of compound 4 (5.6 mmol) in ethyl acetate (3 mL) is slowly added (during 3-4 minutes) while maintaining the temperature at 0-5 0C. The reaction mixture is brought to rt and stirred for 1.5 h. To this is added water (50 mL) followed by a slow addition of 50% sodium hydroxide solution (40 mL). The resulting mixture is extracted with chloroform (2 x 25 mL). The organic layer is washed with water thoroughly and evaporated. The residue is dissolved in ethyl acetate (2 mL), cooled to 0-10 0C and maintained at this temperature for 1 h. The resulting precipitate is collected by filtration and washed with ethyl acetate (1 mL) to provide 1.0 g of 5. 1H NMR (400MHz, J-chloroform) delta 9.26 (d, J = 2.0 Hz, IH), 8.71 (m, IH), 8.48 (d, J = 6.8 Hz, IH), 8.34 (m, IH), 7.59 (d, J = 4.0 Hz, IH), 7.41 (m, IH), 7.12 (m, IH), 7.04 (m, IH), 6.42 (m, IH), 3.50 (bs, 2H), 2.24 (s, 3H). | ||
10 mmol of the appropriate aromatic nitro compound were added to a solution of 40 mmol of tin(II) chloride dihydrate and 25 cm3 of concentrated hydrochloric acid at 50 C. while stirring thoroughly. The solution warmed to 90-100 C. and the product precipitated. The contents were stirred and warmed at 100 C. for another 30 minutes. After cooling, the contents were poured into a mixture of ice, water and about 35 g of potassium carbonate bit by bit while stirring (it must be alkaline in the end). The mixture was extracted three times with 150 cm3 of ethyl acetate, the combined organics were washed with water/brine and dried over magnesium sulfate. Evaporation of the solvent gave the crude product, which was purified by recristallization from 20-30 cm3 of dichloromethane to afford the product as an almost white solid. | ||
With hydrogen;palladium 10% on activated carbon; In ethyl acetate; under 760.051 Torr; for 6.5h; | A suspension of 143.0 g (0.46 mol) of <strong>[152460-09-8]N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine-amine</strong> in 7.15 liters of ethyl acetate is stirred with 14.3 g of palladium on active carbon (10% Pd) under a hydrogen atmosphere at normal pressure for 6.5 hours. The suspension is filtered and the filtrate is concentrated in a rotary evaporator. The crude product is recrystallised from methylene chloride, yielding N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine-amine; m.p. 138 C.-140 C., Rf=0.36 (methylene chloride:methanol=9:1). | |
With tin(ll) chloride; In ethanol; ethyl acetate; for 4h;Heating / reflux; | N- (2-METHYL-5-NITROPHENYL)-4- (3-PYRIDYL)-2-PYRIMIDINE-AMINE (35g, 0. 114mol) and stannous chloride DIHYDRATE (128. 5g, 0. 569MOL) were dissolved in a solvent mixture of ethyl acetate and ethanol (250INE, 10/1, v/v), and the reaction solution was refluxed for 4 hours. The solution was cooled to room temperature, washed with 10% aqueous sodium hydroxide solution, and concentrated to give N- (5-AMINO-2-METHYLPHENYL)-4- (3- PYRIDYL)-2-PYRIMIDINE-AMINE (35g). Rf= 0.45 (Methylene chloride: Methanol = 9 : 1) IH-NMR (DMSO-D6) = 2.04 (s, 3H), 6.30-6. 34 (m, LH), 6.76-6. 77 (m, LH), 6.84-6. 87 (d, lH), 7.34-7. 35 (M, LH), 7.50-7. 56 (m, LH), 8. 38-8. 47 (m, LH), 8. 53-8.57 (m, 2H), 8. 66- 8.70 (m, LH), 9.23-9. 24 (d, LH) The starting material was prepared as follows. | |
With tin(ll) chloride; In ethanol; ethyl acetate; for 4h;Heating / reflux; | N- (2-METHYL-5-NITROPHENYL)-4- (3-PYRIDYL)-2-PYRIMIDINE-AMINE (35g, 0. 114MOL) and stannous chloride dihydrate (128. 5g, 0. 569MOL) were dissolved in a solvent mixture of ethyl acetate and ethanol (250 M, 10/1, v/v), and the reaction solution was refluxed for 4 hours. The solution was COOLED) to room temperature, washed with 10% aqueous sodium hydroxide solution, and concentrated to give N- (5-AMINO-2-METHYLPHENYL)-4- (3- PYRIDYL)-2-PYRIMIDINE-AMINE (35g). [129] [130] Rf = 0.45 (Methylene chloride : Methanol = 9 : 1) [131] 1H-NMR(DMSO-d)- 2.04(s,3H), 6.30-6.34(m,1H), 6.76-6.77(m,1H), 6.84-6.87 6 (d, LH), 7.34-7. 35 (m, 1H), 7.50-7. 56 (m, 1H), 8.38-8. 47 (m, 1H), 8.53-8. 57 (m, 2H), 8.66- 8.70 (m, 1H), 9.23-9. 24 (d, LH) | |
With hydrogen;palladium 10% on activated carbon; In ethyl acetate; for 6.5h; | A suspension of 143.0 g (0.46 mol) of <strong>[152460-09-8]N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine-amine</strong> in 7.15 liters of ethyl acetate is stirred with 14.3 g of <n="60"/>palladium on active carbon (10% Pd) under a hydrogen atmosphere at normal pressure for 6.5 hours. The suspension is filtered and the filtrate is concentrated in a rotary evaporator. The crude product is recrystallised from methylene chloride, yielding N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine-amine; m.p. 138C- 1400C, Rf =0.36 (methylene chloride:methanol=9:l). | |
0.52 g | With hydrogenchloride; tin(ll) chloride; In methanol; at 50℃; for 10h; | 2-bromo-1-methyl-4-nitrobenzene(0.63 g, 2.9 mmol), 4-(pyridin-3-yl)pyrimidin-2-amine (1) (0.60 g, 3.5 mmol), and KOtBu(0.49 g, 4.40 mmol) was added flask containing PS-CuO (57.5 mg, 20 wt% of CuOin PS, 0.145 mmol based on Cu) in 15 mL DMSO. The resulting mixture was heatedto 120oC and stirred for 12 h. Aftercooling, the mixture was poured into EtOAc (20.0 mL) and washed with water (2 × 10.0 mL).The organic layer was separated and dried over MgSO4, and thenevaporated under reduced pressure. The resulting mixture was reacted with stannouschloride (1.64 g, 8.70 mmol) and 1.64 mL of Con. HCl in MeOH (10 mL) at at 50 oCfor 8 h. After completion the reaction mixture was poured into crushed ice followedby basification with sodium bicarbonate. The layer was separated and dried overanhydrous MgSO4, evaporated under reduced pressure to afford the crudeproduct which was purified by using column chromatography(hexane : EtOAc = 4:1) obtainedas yellow solid 67% (0.54 g, 1.95 mmol).1HNMR (300 MHz, CDCl3) delta 9.25 (dd, J= 1.5 Hz, 1H), 8.71 (dd, J1= 3.3 Hz, J2 = 1.5 Hz,1H), 8.48 (d, J = 5.1 Hz, 1H), 8.35-8.31(m, 1H), 7.59 (d, J = 2.1 Hz, 1H), 7.43 - 7.38 (m, 1H), 7.12 (d, J = 5.4Hz,1H) 7.03(bs, 1H), 6.98 (d, J = 8.1 Hz, 1H), 6.41 (dd, , J1 = 5.7 Hz, J2= 2.4 Hz, 1H), 3.59(bs, 2H), 2.24(s, 3H). 13C NMR (75 MHz, CDCl3): delta 162.5, 160.7, 159.0, 151.4, 148.5, 145.1,137.9, 134.4, 132.7, 131.0, 123.5, 118.1, 110.6, 108.4, 108.0 HRMS(ESI) calcd. for C16H16N5 [M+H]+ 278.1406, found 278.1400. |
35 g | With tin(II) chloride dihdyrate; In ethanol; ethyl acetate; for 4h;Reflux; | N-(2-Methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine-amine 5 (35g, 0.114mol) and stannous chloride dihydrate (128.5g, 0.569mol) were dissolved in a solvent mixture of ethyl acetate and ethanol (250mL, 10/1, v/v), and the reaction solution was refluxed for 4h. The solution was cooled to room temperature, washed with 10% aqueous sodium hydroxide solution, and concentrated to give N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine-amine 6 (35g). Rf=0.45 (DCM/MeOH, 9:1). NMR was in agreement with the reference. |
With hydrogenchloride; tin(ll) chloride; In water; | 2-methyl-5-nitroanilinewith cyanamide, guanidine nitrate was the addition, and then (E) -3-dimethylamino-1- (pyridin-3-yl) -1-oxo-2-propenyl cyclization was pyrimidinaminecompound, and finally reducing the nitro group to give. | |
A reactor is charged with concentrated hydrochloric acid (17 mL) followed by stannous chloride dehydrate (0.03 mol). The mixture is stirred for 10 min and then cooled to 0-5 0C. A solution of compound 4 (5.6 mmol) in ethyl acetate (3 mL) is then slowly added (during 3-4 minutes) while maintaining the temperature at 0-5 0C. The reaction mixture is brought to rt and stirred for 1.5 h. To this is added water (50 mL) followed by a slow addition of 50% sodium hydroxide solution (40 mL). The resulting mixture is extracted with chloroform (2 x 25 mL). The organic layer is washed with water thoroughly and evaporated. The residue is dissolved in ethyl acetate (2 mL), cooled to 0-10 0C and maintained at this temperature for 1 h. The resulting precipitate is collected by filtration and washed with ethyl acetate (1 mL) to provide 1.0 g of 5. 1H NMR (400MHz, J-chloroform) delta 9.26 (d, J = 2.0 Hz, IH), 8.71 (m, IH), 8.48 (d, J = 6.8 Hz, IH), 8.34 (m, IH), 7.59 (d, J = 4.0 Hz, IH), 7.41 (m, IH), 7.12 (m, IH), 7.04 (m, IH), 6.42 (m, IH), 3.50 (bs, 2H), 2.24 (s, 3H). | ||
267 g | With hydrazine hydrate; iron(III) chloride hexahydrate; pyrographite; In ethanol; at 78℃; for 6h; | N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidinamine 300gAnd 50g of ferric chloride hexahydrate was added to 2000mL of ethanol, and the oil bath was slowly heated to 78 C.Add 10g of activated carbon with stirring,600 g of hydrazine hydrate with a mass fraction of 85% was slowly added dropwise to the reaction.The reaction was continued for 6 hours, the reaction was stopped, suction filtered, and the filtrate was concentrated to give a yellow oil.Add 500 mL of ethanol to dissolve by heating.150 mL of distilled water was added dropwise with stirring at room temperature to obtain a bright yellow crystalline solid.N-(5-Amino-2-methylphenyl)-4-(3-pyridyl)-2-aminopyrimidine 267g,Purity is 99.9%. |
0.4 g | With hydrazine hydrate; In tetrahydrofuran; at 20℃; for 24h; | In a 100 ml flask, 0.5 g of <strong>[152460-09-8](2-methyl-5-nitrophenyl)-(4-pyridin-3-yl-pyrimidin-2-yl)amine</strong>, 2 ml of hydrazine hydrate, 60 ml of THF, a small amount of Raney Ni. The reaction was stirred at room temperature for 24 hours. After completion of the reaction, after careful filtration, the mother liquor was concentrated to give 0.4 g of a yellow product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With sodium hydroxide; In isopropyl alcohol; at 90℃; for 24h; | General procedure: To a solution of <strong>[55314-16-4]3-(N,N-dimethylamino)-1-(pyridin-3-yl)prop-2-en-1-one</strong> (7a) (1.76 g, 10 mmol) in 2-propanol was added phenyl guanidinium nitrate (5) (1.94 g, 10 mmol) and sodium hydroxide (12 mmol). The reaction mixture was refluxed at 90 C for 24 h and cooled at 0 C. The precipitate was collected by filtration and was washed with water and dried in air. The crude product was recrystallized from propanol to afford the compound 8a as light yellow solid (1.87 g, 62%). |
30% | With sodium hydroxide; In isopropyl alcohol; at 80℃; for 24h; | Step 3: 2-methyl-5-nitrophenyl-(4-pyridin-3-yl-pyrimidin-2-yl)-amine: To a suspension of 3-dimethylamino-1-pyridin-3-yl-propenone (1.70 g, 9.6 mmol) and N-(2-methyl-5-nitro-phenyl)-guanidinium nitrate (2.47 g, 9.6 mmol) in 2-propanol (20 mL) was added NaOH (430 mg, 10.75 mmol) and the resulting mixture was refluxed for 24 h. The reaction mixture was cooled to 0 C. and the resulting precipitate was filtered. The solid residue was suspended in water and filtered and then washed with 2-propanol and diethyl ether and dried. 0.87 g (2.83 mmol) of 2-methyl-5-nitrophenyl-(4-pyridin-3-yl-pyrimidin-2-yl)-amine was isolated. (Yield: 30%.) |
With sodium hydroxide; In isopropyl alcohol; for 18h;Heating / reflux; | 3-Dimethylamino-1-(3-pyridyl)-2-propen-1-one (25 g, 0.14 mol), 2-methyl-5-nitrophenyl-guanidine nitrate (36 g, 0.14 mol), and sodium hydroxide (6.5 g, 0.163 mol) were dissolved in isopropanol and reacted under reflux for 18 hours. The reaction solution was cooled to 0 C., filtered, washed with isopropanol and methanol, and dried to give N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine-amine (20 g). Rf=0.6 (Methylene chloride:Methanol=9:1). 1H-NMR(DMSO-d6)=2.43(s, 3H), 7.50-7.60(m, 2H), 7.89-7.93(m, 1H), 8.47-8.50 (m, 1H), 8.62-8.64(m, 1H), 8.71-8.74(m, 1H), 8.78-8.81(m, 1H), 9.27-9.33(m, 2H). |
20 g | With sodium hydroxide; In isopropyl alcohol; for 18h;Reflux; | Dimethylamino-1-(3-pyridyl)-2-propen-1-one 4 (25g, 0.14mol), 2-methyl-5-nitrophenyl-guanidine nitrate 2 (36g, 0.14mol), and sodium hydroxide powder (6.5g, 0.163mol) were dissolved in isopropanol and reacted under reflux for 18h. The reaction solution was cooled to 0C, filtered, washed with isopropanol and MeOH, and dried to give N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine-amine 5 (20g). Rf=0.6 (DCM/MeOH, 9:1). NMR was in agreement with the reference. |
With sodium hydroxide; In isopropyl alcohol; for 12h;Heating / reflux; | Experimental Preparation of intermediates; Synthesis of 6-methyl-Nl-(4-(pyridin-3-yl)pyrimidin-2-yl)benzene-l,3-diamine 5; To 2-amino-4-nitro toluene 1 (0.033 mol) in n-butanol (29 mL) is added nitric acid (2.1 g, <n="28"/>65% in water) followed by cyanamide solution in water (2 mL, 0.047 mmol). The resulting mixture is heated at reflux for 25 h. After cooling to 0 0C, filtration and washing with 1 : 1 = ethanol : diethyl ether (30 mL), 2-methyl-5-nitrophenyl guanidine nitrate 2 is obtained. To 2-methyl-5-nitrophenyl guanidine 2 (0.0074 mol) in isopropanol (15 mL) is added 3 (0.0074 mol) and sodium hydroxide flakes (0.008 mol). The resulting mixture is heated at reflux for 12 h. After cooling to 0 0C, the product is collected by filtration and washed with isopropanol (6 mL) and methanol (3 mL) to afford 4. 1H NMR (400MHz, Cl6-DMSO) delta 9.31 (s, IH), 9.24 (s, IH), 8.78 (m, IH), 8.70 (m, IH), 8.61 (m, IH), 8.47 (m, IH), 7.88 (m, IH), 7.55 (m, 3H), 2.39 (s, 3H). MS (m/z) (M+l)+: 278.2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In isopropyl alcohol; for 12h;Heating / reflux; | 248.2 g (0.96 mol) of 2-methyl-5-nitrophenylguanidine nitrate are added to a solution of 170 g (0.96 mol) of 3-dimethylamino-l-(3-pyridyl)-2-propen-l- one in 2.0 liters of isopropanol. After the addition of 42.5 g of sodium hydroxide, the reddish suspension is boiled at reflux for 12 hours. After cooling to 00C, filtration, washing with 2.0 liters of isopropanol and 3 400 ml of methanol and drying, there is obtained N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine-amine, m.p. 195C-198C, Rf =0.68 (methylene chloride:rnethanol==9.1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73.2% | Example 2: 26.60 g of 3-acetylpyridine (0.219 M; 1 eq.) and 44.0 mL of N,N-dimethylformamide dimethyl acetal (39.47 g; 0.331 M; 1.508 eq.) were placed in a reactor flask and the mixture was refluxed for 1.5 h.Methanol, produced in the reaction was removed by distillation and EPO <DP n="24"/>the mixture was refluxed for further 2 hours. The rest of methanol and excess of the acetal were removed by distillation under slightly reduced pressure. The hot residue was treated with 100 mL of DMF, and, after cooling down, with 56.3 g of l-(2-methyl-5- nitrophenyl)guanidine nitrate (0.219 M; 1 eq.). A solution of 8.8 g of sodium hydroxide in 17 mL of water was then added dropwise and the mixture was refluxed for 8 hours in an oil bath. Water (200 mL) was added with care to the hot solution, and the content of the flask was poured to 700 mL of warm water. The whole mixture was cooled with stirring to room temperature. The precipitated solid was isolated by filtration and dried in the air to afford 49.4 Ig of crude 2-(2-methyl-5-nitroanilino)-4-(3-pyridinyl)pyrimidine (yield 73.2% calculated on 3-acetylpyridine), m.p. 186-1880C; 1H NMR (DMSO-d6, 200 MHz): 2.43 (3H, s, CH3), 7.54 (3H, m, 3-H phenyl+ 5-H pyrimidine + 5-H pyridyl), 7.90 (IH, dd, J=8.2 i 2.2 Hz, 4-H phenyl), 8.48 (IH, dt, Ji=7.9 Hz, 4-H pyridyl), 8.62 (IH, d, J=5.4 Hz, 6-H pyrimidine), 8.71 (IH, dd, 6-H pyridyl), 8.79 (IH, d, J=2.2 Hz, 6-H phenyl), 9.27 (IH, s, NH), 9.32 (IH, d, J=1.6 Hz, 2-H pyridyl). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In butan-1-ol; for 38h;Heating / reflux; | A 250 ml reactor, equipped with a mechanical stirrer and a reflux condenser, was charged with 2-chloro-4-(3-pyridyl)-pyrimidine (0.5 g, 2.6 mmol), 2-amino-4-nitrotoluene (0.5 g, 3.2 mmol), n-butanol (15 ml) and concentrated HCl (5 drops) and the mixture was refluxed for 38 hours. Then, the mixture was cooled, and 6 N NaOH was added to pH 8. The solvent was evaporated under reduced pressure and water (20 ml) was added to the residue, followed by extraction with dichloromethane (2×20 ml). The combined organic phase was concentrated to dryness to give the crude N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-pyrimidine-amine, which was purified by column chromatography to yield a product having 80% purity. The residue was re-slurried twice in methanol (2×2 ml) and in water (3 ml) and dried under reduced pressure | |
290 g | With copper(l) iodide; 2-(dimethylamino)ethyl methacrylate; potassium carbonate; In 1,4-dioxane; at 100℃; for 20h;Inert atmosphere; | 190 g of 2-chloro-4-(pyridin-3-yl)pyridine under a nitrogen atmosphere,167 g of 2-methyl-5-nitroaniline, 47 g of cuprous iodide,Anhydrous potassium carbonate 276gAnd 22 g of dimethylaminoethyl methacrylate added to 1,4-dioxane solution 2000 mLMedium, heating at 100 C, reaction for 20 h, TLC detection,The raw material is completely reacted; first under reduced pressure,Evaporate most of the solvent dioxane, after cooling to room temperature,The reaction mixture was poured into ice water and a large amount of white solid precipitated.Filtration, a small amount of n-hexane rinse, vacuum dry to pureN-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidinamine 290 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethyl acetate; | Step 20.3 A suspension of 143.0 g (0.46 mol) of <strong>[152460-09-8]N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine-amine</strong> in 7.15 liters of ethyl acetate is stirred with 14.3 g of palladium on active carbon (10% Pd) under a hydrogen atmosphere at normal pressure for 6.5 hours. The suspension is filtered and the filtrate is concentrated in a rotary evaporator. The crude product is recrystallized from methylene chloride, yielding N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine-amine; m.p. 138-140, Rf =0.36 (methylene chloride:methanol=9:1). | |
In ethyl acetate; | A suspension of <strong>[152460-09-8]N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine-amine</strong> (1.5 g, 4.6 mmol) and palladium on active carbon (150 mg, 10%) in ethyl acetate (100 ml) was hydrogenated under a hydrogen atmosphere for 2 hours. The reaction was filtered and the filtrate was concentrated to give N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine-amine for future use without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With copper(l) iodide; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 120℃; for 0.5h;Microwave irradiation; | The mixture of 4-(Pyridin-3-yl) pyrimidin-2- amine (0.378 g,2.2 mmol), copper iodide (0.5 mmol) and anhydrous K2CO3(4 mmol), Dioxane (5 mL), 2-bromo-1-methyl-4- nitrobenzene(2 mmol), and DMEDA (0.5 mmol) was irradiated in the microwave synthesizer and heated at 120 C for 30 min. After completion of the reaction, ammonium hydroxide and brine solution was added andthen extracted with ethyl acetate. The organic layer was dried overanhydrous sodium sulphate, the solvent was evaporated in buchirotary evaporator and the resulting solid was dried under vacuum.The crude was purified by using silica gel column chromatographyusing ethyl acetate: chloroform (50:50) to yield 0.498 g (79.0percent) ofthe imatinib intermediate compound as yellowish powder. Melting point194-196 °C. ES-MS (M1) found (m/z): 308.1. 1H NMR (DMSOd6):2.49(S, 3H); 7.32-7.37 (m, 1H); 7.40-7.48 (m, 1H); 7.49e7.51(m, 1H); 7.85-7.88 (m, 1H); 8.02 (m, 1H); 8.48-8.51 (m, 1H);8.57-8.59 (m, 1H); 9.20(S, 1H); 9.29 (S, 1H). |
60% | With copper(l) iodide; potassium carbonate; potassium iodide; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 110℃; for 24h;Inert atmosphere; Schlenk technique; | 4-(Pyridine-3-yl) pyridine-2-amine (8.60 g, 0.05 mol), CuI (2.39 g, 0.0125 mmol), anhydrous K2CO3 (14.0 g, 0.1 mol), KI (2.08 g, 0.0125 mol) were added to a Schlenk-type three-neck flask fitted with a thermometer, magnetic stirbar, and septum. The flask was evacuated and back filled with N2 three times. Dioxane (250 mL) and 2-bromo-4-nitrotoluene (9.82 g, 0.045 mol) were added to the flask. Finally, N,N'-dimethylethylenediamine (1.10 g, 0.0125 mol) was added by syringe at room temperature with stirring. The reaction mixture was stirred at 110° C. under N2 for 24 hours and then cooled to room temperature. Ammonia (30percent, 100 mL) and saturated NaCl (400 mL), were added to the reaction mixture which was then extracted with ethyl acetate (500 mL*3). The organic phase was dried over Na2SO4 and a yellow solid was obtained after the solvent was removed under reduced pressure. The crude product was purified by column chromatography (biotage: DMC/Methanol, 1-8percent, 20 CV). The desired product was obtained as a yellow solid (8.3 g, yield: 60percent); 1H NMR (500 MHz, CDCl3) delta 2.49 (s, 3H), 7.36 (m, 1H), 7.15 (br., 1H), 7.35 (d, 1H), 7.38 (d, 1H), 7.52 (m, 1H), 7.88 (d, 1H), 8.55 (d, 1H), 8.60 (d, 1H), 8.76 (d, 1H), 9.28 (s, 1H), 9.50 (s, 1H). LC-MS (m/z) calculated, 307.3, found, 308.3 [M+H]+. |
With potassium tert-butylate; In dimethyl sulfoxide; at 120℃; for 12h; | 2-bromo-1-methyl-4-nitrobenzene(0.63 g, 2.9 mmol), <strong>[66521-66-2]4-(pyridin-3-yl)pyrimidin-2-amine</strong> (1) (0.60 g, 3.5 mmol), and KOtBu(0.49 g, 4.40 mmol) was added flask containing PS-CuO (57.5 mg, 20 wtpercent of CuOin PS, 0.145 mmol based on Cu) in 15 mL DMSO. The resulting mixture was heatedto 120oC and stirred for 12 h. Aftercooling, the mixture was poured into EtOAc (20.0 mL) and washed with water (2 × 10.0 mL).The organic layer was separated and dried over MgSO4, and thenevaporated under reduced pressure. The resulting mixture was reacted with stannouschloride (1.64 g, 8.70 mmol) and 1.64 mL of Con. HCl in MeOH (10 mL) at at 50 oCfor 8 h. After completion the reaction mixture was poured into crushed ice followedby basification with sodium bicarbonate. The layer was separated and dried overanhydrous MgSO4, evaporated under reduced pressure to afford the crudeproduct which was purified by using column chromatography(hexane : EtOAc = 4:1) obtainedas yellow solid 67percent (0.54 g, 1.95 mmol).1HNMR (300 MHz, CDCl3) delta 9.25 (dd, J= 1.5 Hz, 1H), 8.71 (dd, J1= 3.3 Hz, J2 = 1.5 Hz,1H), 8.48 (d, J = 5.1 Hz, 1H), 8.35-8.31(m, 1H), 7.59 (d, J = 2.1 Hz, 1H), 7.43 ? 7.38 (m, 1H), 7.12 (d, J = 5.4Hz,1H) 7.03(bs, 1H), 6.98 (d, J = 8.1 Hz, 1H), 6.41 (dd, , J1 = 5.7 Hz, J2= 2.4 Hz, 1H), 3.59(bs, 2H), 2.24(s, 3H). 13C NMR (75 MHz, CDCl3): delta 162.5, 160.7, 159.0, 151.4, 148.5, 145.1,137.9, 134.4, 132.7, 131.0, 123.5, 118.1, 110.6, 108.4, 108.0 HRMS(ESI) calcd. for C16H16N5 [M+H]+ 278.1406, found 278.1400. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In isopropyl alcohol; toluene; at 20℃; for 19h;Heating / reflux;Product distribution / selectivity; | Example 3; N- (2-methgammal-5-nitrophenyl) -4- (3-pyridinyl) -2- pyrimidine amine 1 (Ri = NO2); Under inert atmosphere, 5 g of sodium salt of the beta-oxo- 3 -pyridinepropanal , with HPLC purity of 99% (A%) and salt content of 25% (residue by calcination) , and 8 mL hydrochloric acid in isopropanol in 50 mL toluene is suspended. 3.7 g (2-methyl-5-nitrophenyl) guanidine is added, and the mixture is stirred at room temperature for an hour. The mixture is refluxed for 18 hours, removing the water with a Dean Stark apparatus. Once completed the conversion, the suspension is cooled to 10 C, and the precipitate is filtrated; this is crushed in warm water, yielding, upon filtration and drying, 2,5 g of product with HPLC purity of 96% (A%) , identified through GC-MS.MS m/e (int. rel . ) : 307 (M+) (100) ; 292 (76); 260 (63); 246 (38) . | |
With hydrogenchloride; In water; isopropyl alcohol; toluene; at 20℃; for 19h;Inert atmosphere; Reflux; | Example 3; N-(2-methyl-5-nitrophenyl)-4-(3-pyridinyl)-2-pyrimidine amine 1 (R1NO2); Under inert atmosphere, 5 g of sodium salt of the beta-oxo-3-pyridinepropanal, with HPLC purity of 99% (A %) and salt content of 25% (residue by calcination), and 8 mL hydrochloric acid in isopropanol in 50 mL toluene is suspended. 3.7 g (2-methyl-5-nitrophenyl)guanidine is added, and the mixture is stirred at room temperature for an hour. The mixture is refluxed for 18 hours, removing the water with a Dean Stark apparatus. Once completed the conversion, the suspension is cooled to 10 C., and the precipitate is filtrated; this is crushed in warm water, yielding, upon filtration and drying, 2.5 g of product with HPLC purity of 96% (A %), identified through GC-MS.MS m/e (int. rel.): 307 (M+) (100); 292 (76); 260 (63); 246 (38). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With copper(II) oxide; In 1-methyl-pyrrolidin-2-one; at 175 - 180℃; for 2h;Product distribution / selectivity; | Example 7; N- (2-methyl-5-nitrophenyl) -4- (3-pyridinyl) -2- pyrimidine amine 13; To 25 mli N-methylpyrrolidone, 5,0 g 2- [ (2-methyl-5- nitrophenyl) amino] -4- (3-pyridinyl) pyrimidine-5- carboxylic acid and 0,2 g cupric oxide is added. The mixture is heated to 180 C for 2 hours, then cooled to 60 C, and 30% aqueous ammonia 1 mL and 50 mL water is added. It is cooled to 25 C, and the precipitate is filtrated, yielding, upon drying, 4,3 g of product with HPLC purity of 97% (A%) , which is identified through GC- MS. MS m/e (int. rel . ) : 307 (M+) (100) ; 292 (76); 260 (63); 246 (38) .; Example 8; N- (2-methyl-5-nitrophenyl) -4- (3-pyridinyl) -2 pyrimidine amine 13; 140 g ethyl 2- [ (2-methyl-5-nitrophenyl) amino] -4- (3- pyridinyl) pyrimidine-5-carboxylate and 109 g potassium carbonate is suspended in a mixture composed by 1050 mL water and 560 mL ethanol. The mixture is refluxed for 1 hour, then 700 mL solvent are slowly distilled. Once completed the conversion, the mixture is cooled to 80 C and it is adjusted to pH a 7 with 95 mL acetic acid. 560 <n="40"/>mL N-methylpyrrolidone and 0.9 g CuO is added. The water present is distilled under reduced pressure, and the mixture is heated to 175-180 C for 2 hours. Once completed the conversion, the mixture is cooled to 80- 90 C, 1000 mL water and 5 g EDTA is slowly added, the mixture is stirred at room temperature, the product is filtrated and washed with water. Upon drying, 108 g of product with HPLC purity of 95% (A%) is achieved. This can be recrystallized from 10 volumes of 95:5 xylene/N- methylpyrrolidone to yield a product with 98% purity(A%) in a 80% yield. | |
copper(II) oxide; In 1-methyl-pyrrolidin-2-one; at 175 - 180℃; for 2h;Product distribution / selectivity; | Example 8; N-(2-methyl-5-nitrophenyl)-4-(3-pyridinyl)-2 pyrimidine amine 13; 140 g ethyl 2-[(2-methyl-5-nitrophenyl)amino]-4-(3-pyridinyl)pyrimidine-5-carboxylate and 109 g potassium carbonate is suspended in a mixture composed by 1050 mL water and 560 mL ethanol. The mixture is refluxed for 1 hour, then 700 mL solvent are slowly distilled. Once completed the conversion, the mixture is cooled to 80 C. and it is adjusted to pH a 7 with 95 mL acetic acid. 560 mL N-methylpyrrolidone and 0.9 g CuO is added. The water present is distilled under reduced pressure, and the mixture is heated to 175-180 C. for 2 hours. Once completed the conversion, the mixture is cooled to 80-90 C., 1000 mL water and 5 g EDTA is slowly added, the mixture is stirred at room temperature, the product is filtrated and washed with water. Upon drying, 108 g of product with HPLC purity of 95% (A %) is achieved. This can be recrystallized from 10 volumes of 95:5 xylene/N-methylpyrrolidone to yield a product with 98% purity (A %) in a 80% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | In hydrogenchloride; | Step 4: 4-Methyl-N-3-(4-pyridin-3-yl-pyrimidin-2-yl)-benzene-1,3-diamine (Intermediate A): A solution of SnCl2.2H2O (2.14 g, 9.48 mmol) in concentrated hydrochloric acid (8 mL) was added to 2-methyl-5-nitro-phenyl-(4-pyridin-3-yl-pyrimidin-2-yl)-amine (0.61 g, 1.98 mmol) with vigorous stirring. After 30 min of stirring the mixture was poured onto crushed ice, made alkaline with K2CO3, and extracted three times with ethyl acetate (50 ml). Organic phases were combined, dried over MgSO4, and evaporated to dryness. Recrystallization from dichloromethane resulted in 252.6 mg (0.91 mmol) of 4-methyl-N-3-(4-pyridin-3-yl-pyrimidin-2-yl)-benzene-1,3-diamine (yield: 46%) as an off-white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With sodium hydroxide; In water; isopropyl alcohol; | Step 3: 2-methyl-5-nitrophenyl-(4-pyridin-3-yl-pyrimidin-2-yl)-amine To a suspension of 3-dimethylamino-1-pyridin-3-yl-propenone (1.70 g, 9.6 mmol) and N-(2-methyl-5-nitro-phenyl)-guanidinium nitrate (2.47 g, 9.6 mmol) in 2-propanol (20 mL) was added NaOH (430 mg, 10.75 mmol) and the resulting mixture was refluxed for 24 h. The reaction mixture was cooled to 0 C. and the resulting precipitate was filtered. The solid residue was suspended in water and filtered and then washed with 2-propanol and diethyl ether and dried. 0.87 g (2.83 mmol) of 2-methyl-5-nitrophenyl-(4-pyridin-3-yl-pyrimidin-2-yl)-amine was isolated. (Yield: 30%.) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In isopropyl alcohol; for 12h;Reflux; | 248.2 g (0.96 mol) of 2-methyl-5-nitrophenylguanidine nitrate are added to a solution of 170 g (0.96 mol) of 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one in 2.0 liters of isopropanol. After the addition of 42.5 g of sodium hydroxide, the reddish suspension is boiled at reflux for 12 hours. After cooling to 0 C., filtration, washing with 2.0 liters of isopropanol and 3 400 ml of methanol and drying, there is obtained N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine-amine, m.p. 195 C.-1 98 C., Rf=0.68 (methylene chloride:methanol=9.1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With water-d2; potassium carbonate; In tetrahydrofuran; deuteromethanol; for 36h;Reflux; | A round-bottomed flask was charged with commercially available N-(2-methyl-5-nitrophenyl)-4- (pyridin-3-yl)pyrimidin-2-amine (13-d0) (2.0 g, 6.51 mmol), THF (21.7 mL), MeOD (21.7 mL, Sigma- Aldrich, 99.9% D), D2O (21.7 mL) and K2CO3 (9.04 g). The mixture was heated at reflux for approximately 18 hours. The mixture was concentrated in vacuo nearly to dryness, charged with THF (21.7 mL), MeOD (21.7 mL, Sigma-Aldrich, 99.9% D), D2O (21.7 mL) and K2CO3 (9.04 g), and heated at reflux for another 18 hours. The reaction was then cooled to room temperature and partitioned between CH2Cl2 and D2O. The aqueous layer was washed with CH2Cl2 (3X) and then the combined organic solutions were washed with D2O (IX). The combined organic solutions were dried (Na2SO4), filtered and concentrated in vacuo. Purification via automated flash column chromatography (40 g SiO2, 30 to 100% EtOAc in heptanes) afforded 13-d3 (895 mg, 44%). MS (M+H): 311.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | Method B: A solution of 3-acetylpyridine (25g, 0.20mol) and N,N-dimethylformamide dimethylacetal (37g, 0.3 1 mol) in acetic acid (2.5 ml) was heated at 90-95 C for 2 hours with continuous removal of methanol. After completion of reaction, the reaction mixture was concentrated under vacuum. The resulting residue was diluted with methylisobutylketone (250 ml). N-(2-Methyl-5-nitrophenyl)guanidine (46g) was added to the reaction mixture and refluxed for 12 hours. After completion of reaction, the reaction mass was cooled, filtered and purified with methyl isobutylketone to give 50g (79%) of the title compound having purity 98.1% by HPLC. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.9% | In butan-1-ol; at 120℃; for 9h; | l-(2-methyl-5-nitrophenyl)guanidine (63g, 0.324moles) obtained from step-A, 3- dimethylamino-l-(3-pyridyl)-2-propen-l-one(62.5g, 0.357) and n-butanol (560ml) were placed in reaction flask. The reaction mixture was heated to 120C for nine hours. Reaction mass was brought to room temperature, water (450ml) was added and stirred at room temperature for 3-4 hours. The precipitated solid was isolated by filtration and dried to afford 2-(2-methyl-5-nitroanilino)-4-(3-pyridinyl)pyrimidine. (73.7g, yield 81.9%%, purity by HPLC: 99.9%), Melting point: 195.6-195.9G; |
70% | In 4-methyl-2-pentanone; for 12h;Reflux; | Example-3: Preparation of (2-methyl-5-nitrophenyl)-(4-pyridin-3-ylpyrimidin-2-yl)amineMethod A: A solution of N-(2-methyl-5-nitrophenyl) guanidine (88g, 0.45mol) and 3-dimethyl pyridin-3- yl-propenone (68.6g, 0.39mol as prepared above) in methyl isobutylketone (880 ml) was refluxed for 12 hours. After completion of reaction, the reaction mass was cooled and filtered. The resulting solid was washed and purified with methyl isobutylketone to give 96.8g (70%) of the title compound as yellow solid having purity 98.3% by HPLC. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.2 g | With sodium hydroxide; In isopropyl alcohol; for 24h;Reflux; | 2.75 g of 2-methyl-5-nitrophenylguanidine nitrate, 1.76 g of 3-dimethylamino-1-(pyridin-3-yl)propen-1-one, 0.24 g of sodium hydroxide were added to a 100 ml flask. 40 ml of isopropanol was stirred under reflux for 24 hours. After the reaction was completed, it was cooled to room temperature. After filtration, the filter cake was added to 20 ml of water, stirred for 1 hour, filtered, and washed with 30 ml of ethanol. The filter cake was filtered and dried to give 1.2 g of a white product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With sodium hydroxide; In ethanol; for 12h;Reflux; | In a dry reaction flask, 2-methyl-5-nitrophenylhydrazine 45 g (0.18 moL) was added in that order.3-dimethylamino-1-(3-pyridyl)-2-propen-1-one 30.7 (0.18 mol) and solvent ethanol,7.7 g (0.2 moL) of sodium hydroxide was added in portions under stirring.The temperature was raised to reflux reaction for 12 hours, and the reaction was terminated by TLC, and the reaction was stopped.Cool to room temperature, filter with suction, recrystallize from methanol,Dry N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)pyrimidin-2-amine 34.6 g. 87%. |
Tags: 152460-09-8 synthesis path| 152460-09-8 SDS| 152460-09-8 COA| 152460-09-8 purity| 152460-09-8 application| 152460-09-8 NMR| 152460-09-8 COA| 152460-09-8 structure
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Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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