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CAS No. : | 2434-56-2 | MDL No. : | MFCD00044572 |
Formula : | C4H6N4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | MISVBCMQSJUHMH-UHFFFAOYSA-N |
M.W : | 110.12 | Pubchem ID : | 79608 |
Synonyms : |
|
Num. heavy atoms : | 8 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 30.84 |
TPSA : | 77.82 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.32 cm/s |
Log Po/w (iLOGP) : | 0.59 |
Log Po/w (XLOGP3) : | -0.49 |
Log Po/w (WLOGP) : | -0.34 |
Log Po/w (MLOGP) : | -0.9 |
Log Po/w (SILICOS-IT) : | -0.37 |
Consensus Log Po/w : | -0.3 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.77 |
Solubility : | 18.7 mg/ml ; 0.17 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.68 |
Solubility : | 23.2 mg/ml ; 0.21 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.87 |
Solubility : | 14.8 mg/ml ; 0.134 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.5 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280-P305+P351+P338-P310 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H332-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With hydrogenchloride In water at -5℃; for 0.5 h; | A solution of 250 mL of 11.5 mol / L hydrochloric acid was added to step 24,6-diamino-2-sulfite pyrimidine filter cake, cooled to -5 ° C and stirred for 0.5 h.The yield is 100percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | To a stirred suspension of pyrimidine-4,6- diamine (500 mg, 4.55 mmol) in dioxane (20 mL) was added acetic anhydride (465 mg, 4.55 mmol) and the resulting mixture was heated under reflux for 15 hours. The reaction was cooled to room temperature and the resulting preceipitate was collected by filtration. The filtercake was dissolved in IN HC1 and the pH of the aqueous phase adjusted to 7 by the addition of IN NaOH. The resulting white precipitate was collected by filtration and dried to afford the desired product as a white solid (420 mg, 61% yield). LCMS (ESI) m/z: 152.0 [M+H+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With hydrogenchloride; In water; at -5℃; for 0.5h; | A solution of 250 mL of 11.5 mol / L hydrochloric acid was added to step 24,6-diamino-2-sulfite pyrimidine filter cake, cooled to -5 C and stirred for 0.5 h.The yield is 100%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Representative of the compounds of formula II are: 4,5-diaminopyrimidine; 4-amino-5-aminomethyl-2-methylpyrimidine; 6-(piperidino)-2,4-diaminopyrimidine 3-oxide; 4,6-diaminopyrimidine; 4,5,6-triaminopyrimidine; 4,5-diamino-6-hydroxy pyrimidine; 2,4,5-triamino-6-hydroxypyrimidine; 2,4,6-triaminopyrimidine; 4,5-diamino-2-methylpyrimidine; ... | ||
Condensation product of melamine and p-aminophenol ... 3. 2-Aminocarbazole 4. 2,7-Diaminocarbazole 5. 2-Aminobenzimidazole 6. 2,6-Diaminopyridine 7. 4,6-Diaminopyrimidine 8. 2,6-Diaminopyrazine 9. 2,8-Diaminophenazine 10. 5,6-Diaminobenzimidazole ... | ||
Preferred compounds of formula (II) or (III) are chosen from: 2,3-diaminopyridine 3,4-diaminopyridine 2-aminopyridine 5,6-diamino-2,4-dihydroxypyrimidine, 4,6-diaminopyrimidine, 2,6-dimethoxy-3,5-diaminopyridine, and 6-methoxy-2,3-diaminopyridine. |
Representative compounds of the present invention are: ... 4,5-diaminopyrimidine; 4-amino-5-aminomethyl-2-methylpyrimidine; 6-(piperidino)-2,4-diaminopyrimidine 3-oxide; 3-amino-6-methyl-1,2,4-triazin-5(2H)-one; 4,6-diaminopyrimidine; 4,5,6-triaminopyrimidine; 4,5-diamino-6-hydroxypyrimidine; 2,4,5-triamino-6-hydroxypyrimidine; ... |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With iodine; potassium carbonate; In water; N,N-dimethyl-formamide; at 45℃; for 18h; | <strong>[2434-56-2]4,6-diaminopyrimidine</strong> 32d (1.0 g, 9.10 mmol) and potassium carbonate (1.9 g, 13.70 mmol) were dissolved in water (20.0 mL)In a mixture with N,N-dimethylformamide (10.0 mL). Elemental iodine (2.6 g, 10.00 mmol) was added thereto at 45 CStir under 18 hours. The reaction was quenched with saturated aqueous sodium sulphate (10 mL) then filtered. The filter cake was washed with water (40 mL).4,6-Diamino-5-iodopyrimidine 32e (1.2 g, 5.08 mmol, white solid), yield: 56%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; dihydrogen peroxide; acetic acid; In methanol; sodium hydroxide; ethanol; water; acetone; | PREPARATION 6 Synthesis of 4,6-diaminopyrimidine 167.78 g of 2-mercapto-4,6-diaminopyrimidine was dissolved in 1007 ml of 1.5N-aqueous sodium hydroxide solution, and the reaction solution was cooled down to 0 to 4 C. To this reaction solution was slowly added dropwise 267.55 g of 30% aqueous hydrogen peroxide solution. After the addition is completed, 170 ml of acetic acid was slowly added dropwise to the reaction solution to precipitate the solid product which was then filtered, washed successively with 200 ml of distilled water, 200 ml of methanol and 400 ml of diethylether and dried to obtain 185.56 g of the solid product as a white powder. The solid product thus obtained was slowly added to 1 L concentrated hydrochloric acid which was cooled to 0 C. to 4 C. The reaction solution was stirred for one hour at the same temperature, warmed to room temperature and then stirred for further 8 hours. The solid product produced during the reaction was filtered, washed with 1 L of acetone and 1 L of diethylether and then dried to obtain 109.13 g of the title compound in the form of hydrochloride salt. 109.13 g of the solid thus obtained was suspended in 400 ml of distilled water, and 200 ml of 15% aqueous sodium hydroxide solution was then added thereto. The mixture was stirred at room temperature for one hour and filtered. The filtered solid product was washed with 400 ml of ethanol and then dried to obtain 100.7 g of the title compound as a white powder. NMR (delta, DMSO-d6): 5.34(s, 1H), 6.01(s, 4H), 7.78(s, 1H) | |
With hydrogenchloride; dihydrogen peroxide; acetic acid; In methanol; sodium hydroxide; ethanol; water; acetone; | PREPARATION 6: Synthesis of 4,6-diaminopyrimidine 167.78g of 2-mercapto-4,6-diaminopyrimidine was dissolved in 1007ml of 1.5N-aqueous sodium hydroxide solution, and the reaction solution was cooled down to 0 to 4C. To this reaction solution was slowly added dropwise 267.55g of 30% aqueous hydrogen peroxide solution. After the addition is completed, 170ml of acetic acid was slowly added dropwise to the reaction solution to precipitate the solid product which was then filtered, washed successively with 200ml of distilled water, 200ml of methanol and 400ml of diethylether and dried to obtain 185.56g of the solid product as a white powder. The solid product thus obtained was slowly added to 1L concentrated hydrochloric acid which was cooled to 0C to 4C. The reaction solution was stirred for one hour at the same temperature, warmed to room temperature and then stirred for further 8 hours. The solid product produced during the reaction was filtered, washed with 1L of acetone and 1L of diethylether and then dried to obtain 109.13g of the title compound in the form of hydrochloride salt. 109.13g of the solid thus obtained was suspended in 400ml of distilled water, and 200ml of 15% aqueous sodium hydroxide solution was then added thereto. The mixture was stirred at room temperature for one hour and filtered. The filtered solid product was washed with 400ml of ethanol and then dried to obtain 100.7g of the title compound as a white powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
PREPARATION 7 Synthesis of 4-aminopyrimidine According to the same procedure as Preparation 6 except that 150.07 g of 2-mercapto-4-aminopyrimidine is used instead of 167.78 g of 2-mercapto-4,6-diaminopyrimidine used in Preparation 6, 91.24 g of the title compound was obtained as a white powder. NMR (delta, DMSO-d6): 6.42(d, 1H), 6.85(s, 2H), 8.04(d, 1H), 8.36(s, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; sodium hydroxide; In ethanol; water; | (a) To a mixture of <strong>[2434-56-2]4,6-diaminopyrimidine</strong> (4.7 g), ethanol (500 ml) and water (200 ml) was added 1N sodium hydroxide (13.25 ml) while cooling with ice water. After the dropwise addition of 1N hydrochloric acid (26.5 ml) thereto, benzyloxycarbonyl chloride (4.5 g) was dropwise added thereto. After being stirred at room temperature for 2 hours, the mixture was concentrated under reduced pressure to give crystals. The crystals were collected by filtration and recrystallized from chloroform:methanol=5:1 to give 2.4 g of N-benzyloxycarbonyl-<strong>[2434-56-2]4,6-diaminopyrimidine</strong>, melting point 194 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
PREPARATION 8 Synthesis of 5-methyl-4,6-diaminopyrimidine According to the same procedure as Preparation 6 except that 184.30 g of 2-mercapto-5-methyl-4,6-diaminopyrimidine is used instead of 2-mercapto-4,6-diaminopyrimidine used in Preparation 6, 109.47 g of the title compound was obtained as a white powder. NMR (delta, DMSO-d6): 1.83(s, 3H), 6.48(s, 4H), 7.84(s, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
PREPARATION 9 Synthesis of 4-amino-5,6-cyclopentapyrimidine According to the same procedure as Preparation 6 except that 210.25 g of 2-mercapto-4-amino-5,6-cyclopentapyrimidine is used instead of 2-mercapto-4,6-diaminopyrimidine used in Preparation 6, 124.32 g of the title compound was obtained as a white powder. NMR (delta, DMSO-d6): 1.96(m, 2H), 2.62(t, 2H), 2.68(t, 2H), 6.56(s, 2H), 8.13(s, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
PREPARATION 10 Synthesis of 4,5,6-triaminopyrimidine According to the same procedure as Preparation 6 except that 200 g of 2-mercapto-4,5,6-triaminopyrimidine is used instead of 2-mercapto-4,6-diaminopyrimidine used in Preparation 6, 89 g of the title compound was obtained as a white powder. NMR (delta, DMSO-d6): 3.82(s, 2H), 5.60(s, 4H), 7.42(s, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With sodium hydrogencarbonate; In methanol; for 3h;Reflux; | Example 80; 4-Chloro-2-methyl-2H-pyrazole-3-carboxylic acid (2-phenyl-imidazo[1,2-c]pyrimidin-7-yl)-amide Step 1: 2-Phenyl-imidazo[1,2-c]pyrimidin-7-ylamineomega-Bromoacetophenone (9.04 g, 45 mmol) and NaHCO3 (4.30 g, 50 mmol) were added to a solution of <strong>[2434-56-2]4,6-diaminopyrimidine</strong> (5.00 g, 0.45 mmol) in methanol (80 ml), and the mixture was heated to reflux (3 h). Upon cooling, water (40 ml) was added, and the suspension was stirred at r.t. (15 min). The precipitated title compound (5.62 g, 59%) was isolated by filtration, washed with small amounts of water and methanol, and dried under vacuum. MS (m/e)=211.1 [M+H+]. |
omega-Bromoacetophenone (9.04 g, 45 mmol) and NaHC03 (4.30 g, 50 mmol) were added to a solution of <strong>[2434-56-2]4,6-diaminopyrimidine</strong> (5.00 g, 0.45 mmol) in methanol (80 ml), and the mixture was heated to reflux (3 h). Upon cooling, water (40 ml) was added, and the suspension was stirred at r.t. (15 min). The precipitated title compound (5.62 g, 59%) was isolated by filtration, washed with small amounts of water and methanol, and dried under vacuum. MS (m/e) = 211.1 [M+H+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a soluntion of <strong>[2434-56-2]4,6-diaminopyrimidine</strong> (33 mg, 0.3 mmol) in DMF (2 niL) at 0 C was added NaH (60% in mineral oil, 16 mg, 0.4 mmol) in one portion. The reaction mixture was warmed up to room temperature and stirred for 1 hr. The mixture was then cooled to 0 C. A solution of 8-(2,6-dichlorophenyl)-6-(methylsulfonyl)-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purine (47 mg, 0.1 mmol) in DMF (0.5 niL) was added. The reaction mixture was warmed up to room temperature and stirred for 0.5 h. The reaction was quenched with ice water (30 niL), extracted with EtOAc (3 x 20 niL). The combined organics were dried (Na2S04), filtered and concentrated to give crude N-4-(8-(2,6- dichlorophenyl)-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purin-6-yl)<strong>[2434-56-2]pyrimidine-4,6-diamine</strong> (44 mg, 88% yield) which was used in the next step without purification. LCMS(ESI) m/z: 503.2 [M+H+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 120℃; for 1h;Inert atmosphere; Microwave irradiation; | Step 4: To a 10 mL microwave tube was added 2-(4-bromo-3H-imidazo[4,5-c]pyridin-2-yl)-3- fluorobenzonitrile (50 mg, 0.16 mmol), <strong>[2434-56-2]pyrimidine-4,6-diamine</strong> (17 mg., 0.16 mmol), Pd2(dba)3 (15 mg, 0.016 mmol), XantPhos (18 mg, 0.032 mmol), CS2CO3 (57 mg, 0.18 mmol), and dioxane (2.0 mL). The mixture was degassed with N2 for 10 min. The resulting mixture was irradiated in a microwave reactor at 120 C for 1 hour and then cooled to room temperature. The mixture was filtered through Celite and the filtrate was concentrated. The residue was purified by Prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm x 20 mm x 2, gradient: CH3CN / 10 mm/LNH4HCO3, 17 min) to give the desired product (50 mg, 45% yield) as a solid. lU NMR (DMSO-i/6 , 500 MHz): delta 13.41 (s, 1H), 8.12 - 7.79 (m, 6H), 7.58 (s, 1H), 7.29 (s, 1H), 6.76 (s, 2H). LCMS (ESI) Method C: RT = 3.48 min, m/z: 347.7 [M+H+]. |
45% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 120℃; for 1h;Inert atmosphere; Microwave irradiation; | Step 4: To a 10 mL microwave tube was added 2-(4-bromo-3H-imidazo[4,5-c]pyridin-2-yl)-3-fluorobenzonitrile (50 mg, 0.16 mmol), <strong>[2434-56-2]pyrimidine-4,6-diamine</strong> (17 mg., 0.16 mmol), Pd2(dba)3 (15 mg, 0.016 mmol), XantPhos (18 mg, 0.032 mmol), Cs2CO3 (57 mg, 0.18 mmol), and dioxane (2.0 mL). The mixture was degassed with N2 for 10 min. The resulting mixture was irradiated in a microwave reactor at 120 C. for 1 hour and then cooled to room temperature. The mixture was filtered through Celite and the filtrate was concentrated. The residue was purified by Prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm*20 mm*2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min) to give the desired product (50 mg, 45% yield) as a solid. 1H NMR (DMSO-d6, 500 MHz): delta 13.41 (s, 1H), 8.12-7.79 (m, 6H), 7.58 (s, 1H), 7.29 (s, 1H), 6.76 (s, 2H). LCMS (ESI) Method C: RT=3.48 min, m/z: 347.7 [M+H+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With tris-(dibenzylideneacetone)dipalladium(0); potassium carbonate; caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; N,N-dimethyl-formamide; at 150℃; for 0.166667h;Microwave irradiation; | Alternatively, (+)-l-(4-chlorothiazolo[5,4-c]pyridin-2-yl)piperidine-3-carbonitrile could also be prepared by a one-pot procedure: A mixture of 4-chloro-2-methylsulfonyl-thiazolo[5,4- c]pyridine (100 mg, 0.4 mmol), piperidine-3-carbonitrile (49 mg, 0.4 mmol), potassium carbonate (117 mg, 0.8 mmol), Xantphos (6 mg, 0.01 mmol), Cs2C03 (397 mg, 1.2 mmol), 4,6- diaminopyrimidine (133 mg, 1.2 mmol) and Pd2(dba)3 (12 mg, 0.01 mmol) in DMF (1 mL) and 1,4-dioxane (1 mL) was heated in a microwave reactor at 150 C for 10 minutes. The resulting mixture was filtered and the filter cake washed with ethyl acetate. Combined filtrate was washed with saturated NaHC03 solution and brine. The aqueous layer was further extracted with DCM (x2) and the combined organic extracts were dried (MgS04), concentrated and purified by flash column chromatography (0-10% methanol in DCM) to yield a crude title compound. The crude material was further purified by prep-HPLC to yield the title compound (racemic mixture) as a pale yellow powder (58 mg, 41% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bromine; acetic acid; at -5 - 0℃; | <strong>[2434-56-2]4,6-Diaminopyrimidine</strong> 9 (15.00 g, 14mmol) was poured into a litre of three-necked flask equipped with a reflux condenser, mechanical glass stirrer and dropping funnel. Glacial acetic acid cooled to 18 oC was added and the mixture wasfurther cooled in an ice-salt bath. Sodiumthiocyanate (22.00 g) was added with stirring while maintaining the temperature at -5 oC and 0 oC.Bromine (8.00 mL) was added in droplets from thedropping funnel to the ice cooled mixture for over 1h and stirring was continued for a period of 5 hwhile maintaining the temperature near 0 oC. Theslurry was left overnight, water was added andmixture warmed to 80 oC and filtered hot. The filtratewas preserved and the orange residue extracted withacetic acid. The acetic acid extract was combined with the preserved filtrate and neutralized with concentrated ammonia while cooling and maintaining the temperature below 30 oC. It was thenfiltered and the residue recrystallized from methanol to give 4,6-diamino-5-thiocyanatopyrimidine asbright yellow solid, m.p.181-182 oC (lit. 183-184oC)[15]; FT-IR (KBr): max 3475, 3415 (NH2), 1579(C=C, C=N), 1160, 790 and 730 cm-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With hydrogenchloride; sodium nitrite; In water; at -10℃; for 1.5h; | The hydrochloric acid reaction solution was diluted to 1.5 mol / L,Cooled to -10 C,Add 82g in batchesSodium nitrite,After stirring for 1.5 h, sodium carbonate was added and the reaction solution was neutralized to pH neutral,Filtered to give a damp 4,6-diamino-5-nitrosylpyrimidine cake.The yield was 85%. |
78% | With hydrogenchloride; sodium nitrite; In water; at 0 - 20℃; for 2.5h; | A solution of <strong>[2434-56-2]4,6-pyrimidinediamine</strong> (16.0 g, 110 mmol) in 3 N HCl (367 mL) was cooled in an ice bath, and then NaNO2 (8.73 g, 126 mmol) in H2O (30 mL) was added dropwise. The mixture was stirred for 30 min at 0 C, and then 2 h at rt. The violet solution was neutralized with NaHCO3 to pH 8, the resulting precipitate collected, suspended in H2O and head to 70 C, filtered, washed with MeOH, and dried to give a blue solid product 5 (14.5 g, 78%). Rf = 0.81 (1:5 MeOH/CH2Cl2), mp >350 C. 1H NMR (DMSO-d6): delta 7.93 (s, 1H, Ar-H), 8.04 (s, 1H, NHH), 8.44 (s, 1H, NHH), 9.11 (s, NHH), 10.05 (s, 1H, NHH). MS (ESI): 140 ([M+H]+, 100%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | In acetone; at 75℃; for 16h; | Compound 2~(5-chloro-2,4-dimethoxypheny])imidazo[l ,2-c]pyrimidin-7-amme 195 was prepared in the same manner as 2-(5-chloro-2,4-dimethox phenyl)-7-(pyrrolidin-l - yl)-imidazo[l ,2-o]pyridine 5a. Solid was basified with aqueous ammonia, washed with water, collected by filtration and dried. The product was obtained as a white solid (52 mg, 18% yield). 1H NMR (300 MHz, DMSO-d6): delta 8.96 (s, III), 8.14 (s, 1H), 7,99 (s, 1 H), 6.87 (s, 1H), 6.15 (tn, 2H), 4.01 (s, 3H), 3.94 (s, 3H); HPLC (Method 3) 95.12% (AUC), = 16.24 niin; ESI MS m/z 305 [M+H|+. A solution of 2-bromo-1-(5-chloro-2,4-dimethoxyphenyl)ethanone 3 (70 mg, 0.24 mmol) and 4-(pyrrolidin-1-yl)pyridin-2-amine 4a (39 mg, 0.24 mmol) in acetone (3 mL) was heated at 75 C for 16 h. The reaction mixture was cooled to room temperature; the white precipitate was collected by filtration, washed with acetone, and dried under reduced pressure to afford 2-(5-chloro-2,4-dimethoxyphenyl)-7-(pyrrolidin-1-yl)imidazo[1 ,2-a]pyridine hydrobromide 5a (45 mg, 43%) as a pink solid. 1H NMR (300 MHz, DMSO-d6) . delta 13.03 (s, 1H), 8.50 (d, J = 7.6 Hz, 1H). 8.20 (s, 1H), 7.89 (s, 1H), 6.97 (s, 1H), 6.95 (dd, J=2.2, 7.6 Hz, 1H), 6.30 (d, J= 2.0 Hz, 1H), 4.05 (s, 3H), 3.99 (s, 3H). 3.48-3.38 (m, 4H), 2.08- 1.98 (m, 4H); HPLC ( Method 4) 98.7% (AUG), tR = 19.02 min. APCI MS m/z 358 [M + H]+ . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; 1,2-dimethoxyethane; at 150℃; for 0.166667h;Microwave irradiation; | General procedure: A mixture of 4-bromo-2-(2,6-dichlorophenyl)-3H-imidazo[4,5-c]pyridine (400 mg, 1.166mmol)andcyclopropanecarboxamide(198 mg, 2.33mmol), Pd2dba3(53 mg, 0.0583mmol),XantPhos(67 mg, 0.117mmol) and Cs2CO3(1.14 g, 3.5mmol) in 1,4-dioxanes (5 mL)and 1,2-dimethoxyethane (5 mL) was heated in a microwave at 150C for 10 min. The reaction mixture was cooled and filtered, and the filter cake was washed withdichloromethane. The combined organics were washed with brine, dried over MgSO4and concentrated. The crude product was purified by reverse phase HPLC to give the title compound (321 mg, 79% yield) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; 1,2-dimethoxyethane; at 150℃; for 0.166667h;Microwave irradiation; | General procedure: A mixture of 4-bromo-2-(2,6-dichlorophenyl)-3H-imidazo[4,5-c]pyridine (400 mg, 1.166mmol)andcyclopropanecarboxamide(198 mg, 2.33mmol), Pd2dba3(53 mg, 0.0583mmol),XantPhos(67 mg, 0.117mmol) and Cs2CO3(1.14 g, 3.5mmol) in 1,4-dioxanes (5 mL)and 1,2-dimethoxyethane (5 mL) was heated in a microwave at 150C for 10 min. The reaction mixture was cooled and filtered, and the filter cake was washed withdichloromethane. The combined organics were washed with brine, dried over MgSO4and concentrated. The crude product was purified by reverse phase HPLC to give the title compound (321 mg, 79% yield) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With palladium diacetate; sodium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 3h;Inert atmosphere; | Intermediate 5 (237 mg, 0.538 mmol) , pyrimidine-4, 6-diamine (118.2 mg, 1.07 mmol, 2 eq. ) , Pd (OAc) 2 (60 mg, 0.269 mmol, 0.5 eq. ) , Xantphos (186.5 mg, 0.322 mmol, 0.6 eq. ) and Na2CO3 (125 mg, 1.184 mmol, 2.2 eq. ) in 1.4-dioxane (5 mL) under heating at 100 for 3 hour under N2 atmosphere. LC-MS: m/z 516.5 (M+H) +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 120℃; for 16h;Inert atmosphere; | Compound <strong>[2434-56-2]4,6-diaminopyrimidine</strong> 20a (11.0 mg, 0.1 mmol),5-bromo-6-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (36.0 mg, 0.05 mmol)Mixed with 1,4-dioxane (2.0 mL),Tris(dibenzylideneacetone)dipalladium (9.0 mg, 0.01 mmol) and cesium carbonate (65.0 mg, 0.2 mmol) were added under argon atmosphere.4,5-Di-diphenylphosphino-9,9-dimethylxanthene (12.0 mg, 0.02 mmol) was stirred at 120 C for 16 hours and cooled to room temperature.The mixture was quenched with 10 mL of water and the organic phase was separated.The aqueous phase was extracted with dichloromethane (15 mL×2).Combined organic phase with saturated brine(50 mL x 2) wash. The organic phase was dried over anhydrous sodium sulfate.The desiccant is removed by filtration and decomposed under reduced pressure to obtain a crude product.Purification by preparative plate (dichloromethane/methanol = 20:1) gave 1-((2-(trimethylsilyl)ethoxy)methyl)-5-(6-Aminopyrimidin-4-ylamino)-6-methoxyindazole 20b (22.0 mg, 0.057 mmol, yellow solid). Yield: 57%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9% | With potassium carbonate; In tetrahydrofuran; at 15 - 30℃;Inert atmosphere; | 4,6-Aminopyrimidine 19a(550 mg, 5.0 mmol) was dissolved in tetrahydrofuran (5 mL).Add isobutyryl chloride (1.07 g, 10.0 mmol) at room temperature,Potassium carbonate (2.07 g, 15.0 mmol) was reacted overnight at room temperature.Reduce the pressure to obtain a crude product.The desired product N-(6-aminopyrimidin-4-yl)isobutyramide was obtained by flash column chromatography (dichloromethane/methanol = 1:0 to 10:1).19b (80.6 mg, 0.4 mmol, white solid). Yield: 9%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16% | With caesium carbonate; In N,N-dimethyl acetamide; at 110℃; for 3h;Inert atmosphere; | Compound 4,6-diaminopyrimidine 21a (70.0 mg, 0.6 mmol), <strong>[34941-92-9]4-chloro-2-fluoropyridine</strong> (65.0 mg, 0.5 mmol) andN,N-Dimethylacetamide (5.0 mL) was added, and cesium carbonate (327.0 mg, 1 mmol) was added at room temperature, and stirred at 110 C for 3 hours.The mixture was quenched with 20 mL of water and the organic phase was separated. The aqueous phase was extracted with dichloromethane (15 mL×2)Wash with saline (50 mL × 2). The organic phase is dried over anhydrous sodium sulfate, and the desiccant is removed by filtration, and the residue is evaporated to dryness.Purification by preparative silica gel plate (dichloromethane/methanol = 10:1) gave the desired product 4-(4-chloropyridin-2-yl)amino-6-aminoPyrimidine 21b (18.0 mg, 0.08 mmol, yellow solid). Yield: 16%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | With sodium hydride; In N,N-dimethyl acetamide; mineral oil; at 70℃; for 2h;Inert atmosphere; | Compound <strong>[2434-56-2]4,6-diaminopyrimidine</strong> 24a (110.0 mg, 1.0 mmol),Sodium hydrogen (mineral oil dispersion 60%, 120.0mg,5.0 mmol) mixed with N,N-dimethylacetamide (10 mL),2,5-Dichloropyridine (150.0 mg, 1.0 mmol) was added at room temperature.The reaction was carried out at 70 C for 2 hours. Cool to room temperature,The mixture was quenched with 10 mL of aq.(30 mL × 3) was extracted, and the combined organic layers were washed with brine (30 mL). The organic phase is dried over anhydrous sodium sulfate, and the desiccant is removed by filtration.The concentrate was purified by flash column chromatography (dichloromethane / methanol = 10:1).The title product N-(5-chloropyridin-2-yl)<strong>[2434-56-2]pyrimidine-4,6-diamine</strong> 24b (45.0 mg, 0.20 mmol, white solid)Yield: 20%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | With sodium hydride; In N,N-dimethyl acetamide; mineral oil; at 70℃; for 2h;Inert atmosphere; | To the compound <strong>[2434-56-2]4,6-diaminopyrimidine</strong> 69a (110.0 mg, 1.0 mmol) at room temperature, sodium hydrogen (mineral oil dispersion 60%,120.0 mg, 5.0 mmol) was mixed with N,N-dimethylacetamide (10 mL), and 2-chloropyrimidine (114.0 mg,1.0 mmol), reacted at 70 C for 2 hours. After cooling to room temperature, the mixture was quenched with 10 mL of aq.The organic layer was washed with brine (30 mL). Dry the organic phase with anhydrous sodium sulfateDrying, filtering to remove the desiccant, and purifying the concentrate by flash column chromatography (dichloromethane / methanol = 10:1) to obtain the desired product N-(Pyrimidin-2-yl)<strong>[2434-56-2]pyrimidine-4,6-diamine</strong> 69b (47.0 mg, 0.20 mmol, white solid), yield: 25%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 125℃; for 1h;Inert atmosphere; Microwave irradiation; | Compound 1-tert-butoxycarbonyl-5-bromo-6-methoxyindazole 9a (50.0 mg, 0.15 mmol), <strong>[2434-56-2]4,6-diaminopyrimidine</strong>(22.0 mg, 0.2 mmol) mixed with 1,4-dioxane (2.0 mL),Tris(dibenzylideneacetone)dipalladium (14.0 mg, 0.015 mmol) and 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (17.0 mg, 0.03 mmol) were added under argon atmosphere. And cesium carbonate (98.0 mg, 0.3 mmol),The reaction was carried out in a microwave at 125 C for 1 hour, and the temperature was cooled. The mixture was diluted with dichloromethane (10 mL) and filtered.Preparation of silica gel plate purification (dichloromethane / methanol = 10:1) to obtain the desired product5-(6-Aminopyrimidin-4-ylamino)-6-methoxy-1H-indazole 9 (2.0 mg, 0.01 mmol, white solid). Yield: 7%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-[2-(di(1-adamantyl)phosphino)phenyl]morpholine; MorDalphos-G3-palladacycle; caesium carbonate; In 1,4-dioxane; at 110℃;Inert atmosphere; | 7-Chloro-3-methyl-5-(4-methyl-6-trifluoromethyl-pyridin-3-yloxy)-3H-imidazo[4,5-b]pyridine j0316j (40mg, 0.117 mmol, 1.0 eq), Pyrimidine-4,6-diamine (CAS [79364-63-9], 26mg, 0.234 mmol, 2.0 eq), MorDALPhos Pd G3 (2 mg, 0.002 mmol, 0.02 eq), MorDALPhos (1 mg, 0.002 mmol, 0.02 eq), Cs2CO3 (46 mg, 0.140 mmol, 1.2 eq) were mixed together under N2 after which 1 ,4-dioxane (1 mL) was added. The resulting mixture was stirred at 110C. After one night, it was cooled down to room temperature. The mixture was diluted with 2 mL of DMSO and purified preparative-HPLC to afford the desired product. LCMS: mlz = 417 [M+H]b. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-[2-(di(1-adamantyl)phosphino)phenyl]morpholine; MorDalphos-G3-palladacycle; caesium carbonate; In 1,4-dioxane; at 110℃;Inert atmosphere; | 7-Chloro-5-(2-fluoro-4-methanesulfonyl-6-methyl-phenoxy)-3 -methyl-3H-imidazo [4,5-b]pyridine (50mg, 0.136 mmol, 1.0 eq), Pyrimidine-4,6-diamine (CAS [79364-63-9], 30 mg, 0.271 mmol, 2.0 eq), MorDALPhos Pd G3 (2 mg, 0.002 mmol, 0.02 eq), MorDALPhos (1 mg, 0.002 mmol, 0.02 eq) and Cs2CO3 (53 mg, 0.163 mmol, 1.2 eq) were mixed together under N2, 1,4-dioxane (1 mL) was added. The resulting mixture was stirred at 110C. After one night, it was cooled down to room temperature. The mixture was diluted with 2 mL of DMSO and purified preparative-HPLC to afford the desired product. LCMS: mlz = 444 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tris-(dibenzylideneacetone)dipalladium(0); N-[2-(di(1-adamantyl)phosphino)phenyl]morpholine; caesium carbonate; In 1,4-dioxane; at 110℃;Inert atmosphere; | 6-(7-Chloro-3-methyl-3H-imidazo[4,5-b]pyridin-5-yloxy)-5-methyl-pyridazine-3-carbonitrile (50 mg, 0.167 mmol, 1.0 eq), Pyrimidine-4,6-diamine [79364-63-9] (37 mg, 0.333 mmol, 2.0 eq), Pd2(dba)3 (3 mg, 0.003 mmol, 0.02 eq), MorDALPhos (3 mg, 0.006 mmol, 0.04 eq) and Cs2CO3 (65 mg, 0.200 mmol, 1.2 eq) were mixed together under N2, dioxane (1 mL) was added and the mixture was stirred at 110C. After one night, it was cooled down to room temperature. The mixture was diluted with 2 mL of DMSO and purified preparative-HPLC to afford the desired product. LCMS: mlz = 375 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tris-(dibenzylideneacetone)dipalladium(0); N-[2-(di(1-adamantyl)phosphino)phenyl]morpholine; caesium carbonate; In 1,4-dioxane; at 110℃;Inert atmosphere; | 5-[(7-Chloro-3 -methyl-3H-imidazo[4,5-b]pyridin-5-yl)-(3-methoxy-propyl)-amino] -4-methyl-pyridine-2-carbonitrile (113 mg, 0.30 mmol, 1.0 eq), Pyrimidine-4,6-diamine (CAS [79364-63-9], 66mg,0.60 mmol, 2.0 eq), Pd2(dba)3 (5 mg, 0.006 mmol, 0.02 eq), MorDALPhos (5 mg, 0.012 mmol, 0.04 eq) and Cs2CO3 (117 mg, 0.36 mmol, 1.2 eq) were mixed together under N2 after which 1.4-dioxane (2 mL) was added and the mixture was stirred at 110C. After one night, it was cooled down to room temperature and DMSO (1 mL) was added. Mixture was filtered and purified by preparative HPLC to afford the desired product. LCMS: mlz = 445 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tris-(dibenzylideneacetone)dipalladium(0); N-[2-(di(1-adamantyl)phosphino)phenyl]morpholine; caesium carbonate; In 1,4-dioxane; at 110℃;Inert atmosphere; | 5-[[3-(tert-Butyl-dimethyl-silanyloxy)-propyl]-(7-chloro-3-methyl-3H-imidazo[4,5-b]pyridin-5- yl)-amino]-4-methyl-pyridine-2-carbonitrile (102 mg, 0.217 mmol, 1.0 eq), Pyrimidine-4,6-diamine (CAS [79364-63-9], 48 mg, 0.434 mmol, 2.0 eq), Pd2(dba)3 (4 mg, 0.046 mmol, 0.02 eq), MorDALPhos (4 mg, 0.08 mmol, 0.04 eq) and Cs2CO3 (85 mg, 0.26 mmol, 1.2 eq) were mixed together under N2 after which1 ,4-dioxane (2 mL) was added. Next, the mixture was stirred at 110C during ovemight.Afier letting the mixture cool down till room temperature, DMSO (1 mL) and TBAF (1M in THF, 0.6 mL, 0.6 mmol, 2.8 eq) were added. The mixture was stirred for 10 mm at room temperature. Reaction mixture was then filtered and purified by preparative HPLC to afford the desired product. LCMS: mlz = 431 [M+H]b. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-[2-(di(1-adamantyl)phosphino)phenyl]morpholine; MorDalphos-G3-palladacycle; caesium carbonate; In 1,4-dioxane; at 110℃; for 2h;Inert atmosphere; | In a 5 ml. vial, 5- [2- [tert-butyl(dimethyl)silyl] oxypropyl-(7-chloro-3 -methyl-imidazo [4,5- b]pyridin-5-yl)amino]-4-methyl-pyridine-2-carbonitrile (50 mg, 0.22 mmol, 1 eq), <strong>[2434-56-2]4,6-diaminopyrimidine</strong> (49 mg, 0.44 mmol, 2 eq), MorDalPhos Pd G3 (18 mg, 0.022 mmol, 0.1 eq), MorDalPhos (10 mg, 0.022 mmol, 0.1 eq) and Cs2CO3 (143 mg, 0.44 mmol, 2 eq) were added. Anhydrous 1,4-dioxane was added, the mixture was brought under N2 and degassed. It was subsequently stirred at 110C for 2h. The mixture was cooled to room temperature, water and ethyl acetate were added, the layers were separated and the water layer was washed with EtOAc. The combined organic layers were dried over sodium sulphate, filtered and evaporated to give the desired product which was used as such. LCMS (M+1): 545.3 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-[2-(di(1-adamantyl)phosphino)phenyl]morpholine; MorDalphos-G3-palladacycle; caesium carbonate; In 1,4-dioxane; at 110℃;Inert atmosphere; | General procedure: Aryl chloride (1.0 eq), aniline (2.0 eq), MorDALPhos Pd G3 (0.03 eq), MorDALPhos (0.03 eq) and Cs2CO3 (1.3 eq) are mixed under N2 at room temperature after which 1 ,4-dioxane is added and the mixture was stirred at 110C. Upon completion, the mixture is cooled down to room temperature and diluted in DMSO. After filtration, the filtrate is purified by preparative HPLC to give the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In 1,4-dioxane; at 105℃; | To a suspension of 6-bromo-2,3-dimethylimidazo[l,2-a]pyridine (1.40 g, 6.22 mmol) in anhydrous l,4-dioxane (40 mL) were added diphenylmethanimine (2.25 g, 12.4 mmol), Pd2(dba)3 (0.58 g, 0.63 mmol), BINAP (0.78 g, 1.25 mmol) and t-BuONa (1.21 g, 12.59 mmol). The mixture was degassed and refilled with N2 for several times and heated to 105 C and stirred overnight. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v) = 1/10 to DCM/(a solution of NH3 in MeOH (3M)) (v/v) = 2/1) to afford the title compound as a brown liquid (2.03 g, yield 100%).MS (ESI, pos. ion) m/z: 326.3 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17.4% | With sodium hydrogencarbonate; In ethanol; hexane; chloroform; at 85℃;Sealed tube; | To a suspension of pyrimidine-4, 6-diamine (342.0 mg, 3.10 mmol) and NaHCCb (286.0 mg, 3.40 mmol) in EtOH (20 mL) was added a solution of 2-chloropropanal (0.57 M, 57 mmol) in a mixed solvent of chloroform and hexane (1/2 (v/v), 100 mL). The reaction mixture was stirred in a sealed tube at 85 C overnight, then cooled down to rt and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v) = 1/20) to give the title compound as brown oil (80.0 mg, yield 17.4%).MS (ESI, pos. ion) m/z: 149.2 [M+H]+;1H NMR (400MHz, DMSO-^) d (ppm): 8.84 (s, 1H), 7.09 (s, 1H), 6.46 (s, 2H), 6.26 (s, 1H), 2.40 (s, 3H). |
17.4% | With sodium hydrogencarbonate; In ethanol; hexane; chloroform; at 85℃;Sealed tube; | Pyrimidine-4,6-diamine (342.0 mg, 3.10 mmol)And NaHCO3 (286.0 mg, 3.40 mmol)2-Chloropropanal (0.57M, 57mmol) was added to a suspension of EtOH (20 mL)A solution of chloroform and n-hexane (1/2 (v/v), 100 mL).The reaction mixture is placed in a sealed tube,And stirred at 85 C overnight,After the reaction,Cool to room temperature,It was concentrated under reduced pressure.The residue obtained is purified by silica gel column chromatography (MeOH/DCM (v/v) = 1 / 20).The title compound was obtained as a brown oil (80.0 mg, yield 17.4%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With ammonia; at 125℃;Sealed tube; | A mixture of 6-bromopyrimidin-4-amine (1.01 g, 5.80 mmol) and ammonia solution (25 mL) was stirred in a sealed tube at 125 C overnight, then cooled down to rt and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v) = 1/15) to give the title compound as a yellow solid (0.46 g, yield 72%).MS (ESI, pos. ion) m/z: 111.2 [M+H]+; (ppm): 7.82 (s, 1H), 6.10 (s, 4H), 5.39 (s, 1H). |
72% | With ammonium hydroxide; at 125℃;Sealed tube; | 6-bromopyrimidine-4-amine (1.01 g, 5.80 mmol)And an aqueous ammonia solution (25 mL) was placed in a sealed tube.The mixture was stirred at 125 C overnight.Then cool to room temperature,It was concentrated under reduced pressure.The residue obtained was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/15).The title compound was obtained as a yellow solid (0.46 g, yield 72%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.8% | With sodium methylate at 70℃; for 4h; | 1-5 In a 1000 ml four-neck reaction flask, 80.5 g (1.0 mol) of formazan hydrochloride and 486.0 g (2.7 eq) of 30% sodium methoxide were added, and a reflux condenser, mechanical stirring, a constant-pressure dropping funnel, and a thermometer were installed. 72.7 g (1.1 eq) of malononitrile was added to the constant pressure funnel. After the dropping, the temperature was raised to 70 ° C and the reaction was started for 4 hours. The methanol was distilled to dryness, 261 g of methanol was distilled off, and 300 g of water was added to dissolve. The temperature was lowered to 5 ° C., and suction-dried to obtain 105.5 g of a solid. The purity by HPLC was 99.2% and the yield was 95.8% (based on formazan hydrochloride). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.4% | Stage #1: 4,6-diaminopyrimidine With hydrogenchloride; sodium nitrite In water at -5℃; for 2h; Stage #2: With hydrogenchloride; copper(l) chloride In water at 45℃; for 2h; | 1-5 Dissolve 105.5g of 4,6-diaminopyrimidine in 660.0g of 31% hydrochloric acid and pour into a 2000ml bottle to cool to -5 ° C and dropwise add 500.3g of 33% sodium nitrite. After 2 hours of reaction, HPLC detects 4,6-diamino Pyrimidine is less than 0.5%. 42.8 g of cuprous chloride and 214.0 g of 31% hydrochloric acid are prepared in a 2000 ml bottle. The diazonium salt mother liquor is added dropwise to the bottle. After the dropwise reaction, the reaction is performed at 45 ° C for 2 hours. .Extract with 400g of recovered trichloroethane (200x2 times less than new ones), combine the organic layers for distillation, control the water flush pump 5KPa, temperature 40-140 , collect 404.2g of solvent in the early 40-90 , 90-140 in the later The product was collected at a temperature of 14 ° C to obtain 146.9 g of 4,6-dichloropyrimidine. The yield was 86.4% (based on formazan hydrochloride) and the purity was 99.4%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; at 70℃; | To a mixture of pyrimidine-4, 6-diamine (Int 2a) (3.3 g, 30 mmol) and 2-bromo-1 -(2- (trifluoromethyl)phenyl)ethan-1 -one (Int 2b) (8.0 g, 30 mmol) in DMF (60 ml_), NaHC03 (3.0 g, 36 mmol) was added at rt. The mixture was stirred at 70 C overnight. Water was added and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2S04, filtered and concentrated to dryness. The residue was purified by silca gel chromatography (gradient PE/EtOAc 2:1 to 1 :1 ) to give the title compound as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With N-ethyl-N,N-diisopropylamine at 140℃; for 72h; | N4-(2-chloro-5-methylpyrimidin-4-yl)pyrimidine-4,6-diamine (MA10-155): This compound was prepared by the reaction of pyrimidine-4,6-diamine (2.0 g, 18.16 mmol) and 2,4- dichloro-5-methylpyrimidine (2.96 g, 18.16 mmol) in the presence of DIPEA (7.0 g, 54.49 mmol) usinng the general procedure B. After 3 days heating at 140 oC in oil bath, the crude was evaporated and stirred with MeOH (50 mL) for ~30 minutes and filtered. The pricpitates were rinsed with hexane (~50 mL) to get semi-pure product (~HPLCMS purity ~90%) which was used for the next step wtihout further purification. Yield (1.81 g, 42%). 1H NMR (500 MHz, DMSO-d6): d 9.98 (s, 1H), 8.49 (d, J = 0.8 Hz, 1H), 8.10 (d, J = 1.0 Hz, 1H), 7.21 (d, J = 1.1 Hz, 1H), 6.80-6.61 (m, 2H), 2.22 (s, 3H); HPLC-MS (ESI+): m/z 237.2 [100%, (M+H)+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16.3% | With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 150℃; for 0.25h; Microwave irradiation; | 11 Synthesis of target compound: Add intermediate 11-b (0.10g, 0.0.30mmol) to the microwave tube,4,6-Diaminopyrimidine (0.10g, 0.90mmol),Cesium carbonate (0.20g, 0.65mmol), palladium acetate (0.010g, 0.03mmol), Xantphos ligand (0.035g, 0.06mmol) and 1,4-dioxane (18mL).After the addition, the reactants were stirred at 150°C for 15 minutes under microwave conditions.Cool to room temperature, concentrate to remove the solvent, and purify the residue by silica gel column chromatography.The target product (0.020 g, 16.3%) was obtained as a brown solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51.1% | With triethylamine In tetrahydrofuran at 0℃; for 5h; | 31 Synthesis of Intermediate 31-a: Under the protection of nitrogen, dissolve triethylamine (606.0mg, 0.6mmol) and 4,6-diaminopyrimidine (440.0mg, 4.0mmol) in 5ml of anhydrous tetrahydrofuran, then lower the reaction solution to 0, and slowly add tetrahydrofuran. Hydropyran-4-carbonyl chloride (300.0 mg, 2.0 mmol).After dripping, react at 0°C for 5 hours; after the completion of the reaction, quench the reaction with a small amount of saturated sodium bicarbonate solution;Ethyl acetate was added for extraction, and the ethyl acetate was dried over anhydrous sodium sulfate, spin-dried and separated by silica gel column chromatography to obtain intermediate 31-a224.6 mg, 51.1%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 150℃; for 0.5h; Microwave irradiation; | 7 The synthesis steps are as follows: Add the product of Example 1 (0.10g, 0.24mmol) into the microwave tube,4,6-Diaminopyrimidine (0.053g, 0.48mmol),Cesium carbonate (0.20g, 0.60mmol),Palladium acetate (0.007g, 0.03mmol),Xantphos ligand (0.035g, 0.06mmol) and1,4-Dioxane (18mL).Gaby,The reactants are under microwave conditions,Stir at 150°C for 30 minutes.Cool to room temperature,Concentrate to remove the solvent,The residue was purified by silica gel column chromatography,The product (0.045g, 42%) was obtained,White solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With sodium hydrogencarbonate In methanol for 12h; Inert atmosphere; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With MorDalphos-G3-palladacycle; caesium carbonate In 1,4-dioxane at 110℃; for 24h; Inert atmosphere; Sealed tube; | 1.1.1.4.1a 1.1.1.4. Illustrative example of method la with in situ deprotection: Synthesis of N4-(1H- pyrazolo[4, 3-c]pyridin-6-yl)pyrimidine-4, 6-diamine To a solution of tert-butyl 6-chloro-lH-pyrazolo[4,3-c]pyridine-l-carboxylate (5g, 19.76 mmol, leq) in dry dioxane (100 mL) were added 4,6-pyrimidinediamine (CAS2434-56-2; 6.52g, 59.29 mmol, 3 eq), Cs2C03 (7.73 g, 23.71 mmol, 1.2 eq) and MorDalPhos Pd G3 (823 mg, 0.988 mmol, 0.05 eq) under N2 atmosphere. The reaction mixture was stirred in sealed tube at 110°C for 24h, cooled to room temperature, diluted in a mixture of MeOH/DCM (1:4) and fdtered through pall-seitz thick paper fdter. Solids were washed with MeOH/DCM (1:4), the fdtrate was coated on S1O2 and purified by flash chromatography on S1O2 (eluting with 2 to 10% 7N NH3 MeOH solution in DCM) to afford the title compound |
Tags: 2434-56-2 synthesis path| 2434-56-2 SDS| 2434-56-2 COA| 2434-56-2 purity| 2434-56-2 application| 2434-56-2 NMR| 2434-56-2 COA| 2434-56-2 structure
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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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