Structure of 897732-75-1
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CAS No. : | 897732-75-1 |
Formula : | C7H10N2O2S |
M.W : | 186.23 |
SMILES Code : | NC1=CC=C(S(=O)(C)=O)N=C1C |
MDL No. : | MFCD15475086 |
InChI Key : | UFMCZYUTXQRFKR-UHFFFAOYSA-N |
Pubchem ID : | 51050527 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P261-P280-P305+P351+P338 |
Num. heavy atoms | 12 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.29 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 46.7 |
TPSA ? Topological Polar Surface Area: Calculated from |
81.43 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.6 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.14 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.46 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-0.34 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.38 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.45 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.39 |
Solubility | 7.64 mg/ml ; 0.041 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.41 |
Solubility | 7.3 mg/ml ; 0.0392 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.37 |
Solubility | 0.8 mg/ml ; 0.0043 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
No |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-7.34 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.99 |
* 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 |
---|---|---|
50% | at 150℃; for 4 h; | Intermediate 4: 6-Methanesulfonyl-2-methyl-pyridin-3-ylamine; A mixture of 3-amino-6-bromo-2-methylpyridine (ECA International Corporation, Palatine, Ill., USA; 2.0 g, 10.7 mmol), sodium methanesulfinate (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA 5.13 g, 42.8 mmol), copper trifluoromethanesulfonate benzene complex (598 mg, 1.07 mmol), and N,N'-dimethylethylenediamine (115 μL, 1.07 mmol) in dimethylsulfoxide (15 mL) was heated at 150° C. for 4 h. The mixture was cooled and water and ethyl acetate were added. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed twice with water, and then concentrated to approximately 5 mL. This gave a precipitate which was filtered off, washed with a small amount of ethyl acetate and air dried to give 6-Methanesulfonyl-2-methyl-pyridin-3-ylamine (1 g, 50percent) as a brown powder. 1H NMR (300 MHz, DMSO-d6) δ 2.30 (s, 3H), 3.05 (s, 3H), 6.04 (br s, 2H), 6.98 (d, 1H, J=8.4 Hz), 7.55 (d, 1H, J=8.2 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With sodium methansulfinate In dimethyl sulfoxide at 150℃; for 4 h; | Example 3.2: Preparation of 2-Methyl-6-(methylsulfonyl)pyridin-3-amine (Method 1); A mixture of 6-bromo-2-methylpyridin-3 -amine (40.0 g, 214 mmol), sodium methanesulfinate (87.3 g, 855 mmol), copper(I) trifluoromethanesulfonate-benzene complex (10.8 g, 21.4 mmol), and N1, N2-dimethylethane-l,2-diamine(10.8 g, 21.4 mmol) in DMSO (300 mL) was heated at 150 0C for four hours, cooled, and H2O (100 rnL) was added. The dark brown solution was extracted with ethyl acetate (6 x 30 mL). The organic layer was washed with H2O (100 mL) to remove DMSO. The aqueous layer was back extracted three times with ethyl acetate. The organic layers were combined, washed with brine, dried over Na2SO4, and filtered. After the volume of the filtrate was reduced to about 200 mL under reduced pressure, a solid product was precipitated and collected by filtration to give the title compound (24.0 g, 60percent) as a brown powder. Exact mass calculated for C7Hi0N2O2S: 186.1, Found: LCMS m/z - 187.1 (M+H4); 1H NMR (400 MHz, CDCl3) δ 2.44 (s, 3 H), 3.13 (s, 3 H)54.66 (bs, 2 H), 7.01 (d, /=8.34 Hz5 1 H), 7.71 (d, J= 8.34 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With ammonium chloride; zinc In water; ethyl acetate at 0 - 20℃; for 17 h; | Step 2: Preparation of 2-Methyl-6-(methylsulfonyl)pyridin-3-amine; To a suspension of zinc dust (146 g, 2.01 mol) and aqueous ammonium chloride solution (3 M, 800 ml) was added dropwise a solution of 2-methyl-6-(methylsulfonyl)-3-nitropyridine (87.0 g, 401 mmol) in ethyl acetate (500 mL) via an addition funnel at 0 0C. The mixture was stirred at room temperature for 17 h and filtered through Celite.(TM).. The filtrate was then extracted with ethyl acetate. The organic phase was separated, dried over MgSO4, filtered, and concentrated. The residue was recrystallized from ethanol to give the title compound (34.7 g, 46percent) as a solid. Exact mass calculated for C7Hi0N2O2S: 186.1, Found: LCMS m/z = 187.2 (M+H4). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With sodium methansulfinate;copper(I) trifluoromethanesulfonate benzene; N,N`-dimethylethylenediamine; In dimethyl sulfoxide; at 150℃; for 4.0h;Product distribution / selectivity; | Example 3.2: Preparation of 2-Methyl-6-(methylsulfonyl)pyridin-3-amine (Method 1); A mixture of 6-bromo-2-methylpyridin-3 -amine (40.0 g, 214 mmol), sodium methanesulfinate (87.3 g, 855 mmol), copper(I) trifluoromethanesulfonate-benzene complex (10.8 g, 21.4 mmol), and N1, N2-dimethylethane-l,2-diamine(10.8 g, 21.4 mmol) in DMSO (300 mL) was heated at 150 0C for four hours, cooled, and H2O (100 rnL) was added. The dark brown solution was extracted with ethyl acetate (6 x 30 mL). The organic layer was washed with H2O (100 mL) to remove DMSO. The aqueous layer was back extracted three times with ethyl acetate. The organic layers were combined, washed with brine, dried over Na2SO4, and filtered. After the volume of the filtrate was reduced to about 200 mL under reduced pressure, a solid product was precipitated and collected by filtration to give the title compound (24.0 g, 60%) as a brown powder. Exact mass calculated for C7Hi0N2O2S: 186.1, Found: LCMS m/z - 187.1 (M+H4); 1H NMR (400 MHz, CDCl3) delta 2.44 (s, 3 H), 3.13 (s, 3 H)54.66 (bs, 2 H), 7.01 (d, /=8.34 Hz5 1 H), 7.71 (d, J= 8.34 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With ammonium chloride; zinc; In water; ethyl acetate; at 0 - 20℃; for 17.0h;Product distribution / selectivity; | Step 2: Preparation of 2-Methyl-6-(methylsulfonyl)pyridin-3-amine; To a suspension of zinc dust (146 g, 2.01 mol) and aqueous ammonium chloride solution (3 M, 800 ml) was added dropwise a solution of 2-methyl-6-(methylsulfonyl)-3-nitropyridine (87.0 g, 401 mmol) in ethyl acetate (500 mL) via an addition funnel at 0 0C. The mixture was stirred at room temperature for 17 h and filtered through Celite. The filtrate was then extracted with ethyl acetate. The organic phase was separated, dried over MgSO4, filtered, and concentrated. The residue was recrystallized from ethanol to give the title compound (34.7 g, 46%) as a solid. Exact mass calculated for C7Hi0N2O2S: 186.1, Found: LCMS m/z = 187.2 (M+H4). |
With iron; ammonium chloride; In water; at 90℃; for 0.5h; | A solution of Fe (11.7 g, 209 mmol), NH4Cl (600 mg, 11.3 mmol), and 2-methyl-6- (methylsulfonyl)-3-nitropyridine (15 g, 69.4 mmol) in H2O (150 mL) was stirred for 30 min at 9O0C. The reaction mixture was cooled to O0C with an ice/salt bath. The solids <n="192"/>were collected by filtration. The crude product was purified by recrystallization fromEtOHl. This resulted in 2-methyl-6-(methylsulfonyl)pyridin-3-amine as a light yellow solid. LCMS: 187 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | With sodium t-butanolate;palladium diacetate; 2,8,9-tris(2-methylpropyl)-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane; In 1,4-dioxane; at 90℃; for 2.0h; | Example 3.5: Preparation of 4-[6-(6-Methanesulfonyl-2-methyl-pyridin-3-ylamino)-5- methyl-pyrimidin-4-yloxy]-piperidine-l-carboxylic Acid Isopropyl Ester; A mixture of 4-(6-chloro-5-methyl-pyrimidin-4-yloxy)-piperidine-l-carboxylic acid isopropyl ester (13.7 g, 43.6 mmol), <strong>[897732-75-1]6-methanesulfonyl-2-methyl-pyridin-3-ylamine</strong> (8.10 g, 43.5 mmol), palladium acetate (97.7 mg, 0.435 mmol), 2,8,9-triisobutyl-2,5,8,9-tetraaza-l- phosphabicyclo[3.3.3]undecane (309 mul, 0.870 mmol) and sodium fer/-butoxide (10.0 g, 104 mmol) in dioxane (210 mL) was heated at 90 0C for 2 h. The reaction mixture was quenched with H2O and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over MgSO4, filtered, and concentrated. The residue obtained was first purified by column chromatography on silica gel using hexane/ethyl acetate (1:1, v/v) and then recrystallized from methanol to give the title compound (5.76 g, 29%) as a white solid. Exact mass calculated for C21H29N5O5S: 463.2, Found: LCMS m/z = 464.3 (M+lT); 1H NMR (400 MHz, CDCl3) delta 1.27 (d, J = 6.32 Hz5 6 H), 1.76-1.79 (m, 2 H), 1.98-2.02 (m, 2 H), 2.15 (s, 3 H), 2.65 (s, 3 H), 3.19 (s, 3 H), 3.37-3.44 (m, 2 H), 3.77-3.79 (m, 2 H), 4.94 (sept, J= 6.32 Hz, 1 H), 5.34-5.36 (m, IH), 6.39(s, 1 H), 7.96 (d, J= 8.34 Hz, 1 H), 8.36 (s, 1 H), 8.82 (d, J= 8.34 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium t-butanolate; 2,8,9-tris(2-methylpropyl)-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane;palladium diacetate; In 1,4-dioxane; at 120℃; for 2.0h;Irradiation; | A mixture of 4-(6-chloro-5-methoxy-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester (611 mg, 1.85 mmol), <strong>[897732-75-1]2-methyl-6-(methylsulfonyl)pyridin-3-amine</strong> (345 mg, 1.85 mmol), palladium acetate (37.2 mg, 0.166 mmol), 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phospha-bicyclo[3.3.3]undecane (118 mul, 0.332 mmol), and sodium 2-methylpropan-2-olate (267 mg, 2.78 mmol) in 15 mL dioxane was heated under microwave irradiation at 120 C. After 2 h, mixture was purified by HPLC; fractions containing product were collected and concentrated. Residue was extracted with 1M NaOH and CH2Cl2. Organic phases were dried over MgSO4, filtered, and concentrated. Residue was re-purified by column chromatography (AcOEt/hexane 5:1). Fractions containing product were concentrated, treated with 4M HCl and concentrated to give 4-[6-(6-methanesulfonyl-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester as a white solid (HCl salt, 326 mg, 34%). 1HNMR (MeOH-d4, 400 MHz) delta 1.23-1.24 (d, J=6.2 Hz, 6H), 1.77-1.85 (m, 2H), 2.01-2.07 (m, 2H), 2.59 (s, 3H), 3.20 (s, 3H), 3.40-3.46 (m, 2H), 3.71-3.77 (m, 2H), 3.98 (s, 3H), 4.83-4.89 (m, 1H), 5.41-5.46 (m, 1H), 7.97-7.99 (d, J=8.3 Hz, 1H), 8.11 (s, 1H), 8.29-8.31 (d, J=8.3 Hz, 1H). Exact mass calculated for C21H29N5O6S 479.18, found 480.2 (MH+). | |
With sodium t-butanolate;1,1'-bis(di-tertbutylphosphino)ferrocene; palladium diacetate; In 1,4-dioxane; at 20 - 50℃; for 18.0h;Inert atmosphere;Product distribution / selectivity; | A 5-L 3-neck flask equipped with an overhead mechanical stirrer, N2 inlet/outlet adapter, reflux condenser, and thermocouple was charged with 1 ,4- dioxane (715 mL) and degassed for 10 min. 1 ,1 '-Bis(di-tert-butylphosphino) ferrocene (22.9 g, 0.046 mol), and Pd(OAc)2 (5.1 g, 0.023 mol) was added at room temperature and the resulting mixture was degassed and purged with N2 three times. The resulting heterogeneous solution was heated to 75C and stirred for 30 min. The resulting mixture was then cooled to room temperature and sodium t-butoxide (62.5 g, 0.65 mol) was added all at once. The catalyst solution was degassed and purged with N2 three times. 4-(6-chloro-5-methoxy- pyrimidin-4-yloxy)-pipehdine-1-carboxylic acid isopropyl ester (143.0 g, 0.43 mol) and 2-methyl-6-(methylsulfonyl)-3-pyhdinamine (80.8 g, 0.43 mol) were then added together with 1 ,4-dioxane (715 mL) to the catalyst solution via addition funnel over 10 min. The resulting mixture was heated to 500C for 18 h. The resulting mixture was cooled to room temperature, poured into ethyl acetate (2L), and washed with 1 N HCI (2 x 500 ml_). The organic layer was then washed with brine (500 ml_), dried over MgSO4, filtered, and concentrated to dryness to yield the compound of formula (A) as a residue.The residue was purified using the lsco LC prep to yield the compound of formula (A) as a yellow solid (81 % isolated yield, 99% HPLC purity).The chromatographed yellow solid was re-crystallized from ethyl acetate (350 mL) and heptane (450 mL) as follows. The slurry was heated to 75C for 30 min. The resulting slurry was cooled to room temperature over 30 min and then aged 30 min. The resulting thick slurry was filtered, rinsed with heptane (3 x 25 mL), and placed into a vacuum oven at 400C for 36 h to yield crystalline form (A-I) of the compound of formula (A) as a solid. | |
With sodium t-butanolate;palladium diacetate; bis[2-(diphenylphosphino)phenyl] ether; In toluene; at 60℃;Inert atmosphere;Product distribution / selectivity; | Example 3 4-[6-(6-Methanesulfonyl-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin- 4-yloxy]-piperidine-1-carboxylic acid isopropyl esterSTEP A: Catalyst PreparationA 250 ml, 4-necked flask equipped with thermometer, mechanical stirrer and condenser with gas inlet is purged with argon and charged with toluene (120 ml; 1 L/mol). The toluene was degassed by bubbling with argon for 15 min. Bis(2-diphenylphosphinophenyl) ether (2.59 g; 4 mol%) was dissolved under a stream of argon. Palladium(ll) acetate (0.54 g; 2 mol%) was added in one portion; with the orange powder observed to go into solution. After a few minutes a solid appeared and a yellow suspension was observed. STEP B: CouplingA 250 ml, 4-necked flask equipped with thermometer, mechanical stirrer and condenser with gas inlet was purged with Argon and then charged with toluene (360 ml, 3 L/mol). The toluene was degassed by bubbling with argon for 15 minutes. 4-(6-Chloro-5-methoxy-pyrimidin-4-yloxy)-piperidine-1- carboxylic acid isopropyl ester (39.6 g; 0.12 mol), 6-methanesulfonyl-2-methyl- pyridin-3-ylamine (22.3 g; 0.12 mol) and NaO-t-Bu (17.3 g; 1.5 eq.) were added at room temperature. The resulting suspension was heated to 600C while being degassed by bubbling with Argon. The catalyst suspension prepared as in STEP A above was added in one portion to the reaction mixture (the catalyst suspension is fluid enough to be added via an addition funnel). After 30 minutes, the Ar-stream was stopped and switched to a N2 stream. The resulting mixture was stirred over 16-18h at 600C.Water (120 ml; 1 L/mol) was then added to the hot reaction mixture while maintaining the temperature at 600C. The solid was observed to dissolve. A brown organic layer was obtained after discarding the aqueous one together with the black interface. Aqueous 1 M HCI (120 ml; 1 .2 eq.) was added and the color of the mixture was observed to go from brown to light brown. The resulting mixture was then heated to 600C. The same extraction procedure was carried out a second time (aqueous layer discarded, organic layer heated to 60C).To the resulting mixture was added water (120 ml, 1.2L/mol) and the aqueous layer was discarded. To the organic layer was then added sodium sulfate (9.0 g; 75 g/mol), Silica Gel Thiol 3 (1 1.4 g; 95 g/mol) and NORIT A SUPRA (2.4 g; 20 g/mol) and the resulting mixture stirred for 30 min at 600C; then filtered over dicalite. The filter cake was rinsed with toluene (12 ml; 0.1 L/mol) to yield the title compound as a solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.11% | 4-(6-Chloro-5-methoxy-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid 1-ethyl-propyl ester, (0.50 g, 1.40 mmol) and <strong>[897732-75-1]6-methanesulfonyl-2-methyl-pyridin-3-ylamine</strong> (0.26 g, 1.40 mmol) and palladium acetate (0.062 g, 0.28 mmol) and 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phospha-bicyclo[3.3.3]undecane (0.191 g, 0.559 mmol) were combined in 50 mL dioxane, purged with nitrogen and a 1M solution of potassium t-butoxide in THF (2.79 mL, 2.79 mmol) added dropwise. The reaction was heated to 100 C. and stirred for 2 hours, then was filtered, concentrated, acidified and purified by prep HPLC, the desired fractions partitioned between saturated sodium hydrogen carbonate and ethyl acetate, the organic phase washed with brine and dried with magnesium sulfate to yield (15 mg, 0.029 mmol, 2.11% yield) desired product, as a white solid. 1HNMR (CDCl3, 400 MHz) delta 0.91(t, J=7.33 Hz, 6H), 1.54-1.64 (m, 4H), 1.77-1.87 (m, 2H), 1.99-2.08 (m, 2H), 2.65 (s, 3H), 3.19 (s, 3H), 3.39-3.46 (m, 2H), 3.78-3.85 (m, 2H), 4.00 (s, 3H), 4.67 (pent, J=6.32 Hz, 1H), 5.36-5.43 (hept, J=3.79 Hz, 1H), 7.31 (bs, 1H), 7.96 (d, J=8.34 Hz, 1H), 8.20 (s, 1H), 9.02 (d, J=8.59 Hz, 1H). Exact mass calculated for C23H33N5O6S: 507.22, found: 508.5 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium t-butanolate; 2,8,9-tris(2-methylpropyl)-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane;palladium diacetate; In 1,4-dioxane; at 130 - 150℃; for 66.0h;Irradiation; Heating / reflux; | A mixture of 4-chloro-6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-5-methoxy-pyrimidine (1.78 g, 5.03 mmol), 6-Methanesulfonyl-2-methyl-pyridin-3-ylamine (1.12 g, 6.04 mmol), palladium acetate (102 mg, 0.45 mmol), 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phospha-bicyclo[3.3.3]undecane (322 mul, 0.91 mmol) and sodium tert-butoxide (725 mg, 7.54 mmol) in 30 mL of dioxane was heated under microwave irradiation at 150 C. for 1 hr. Additional 40 mL of dioxane were added and the mixture was refluxed under 130 C. After 65 hr, mixture was purified by HPLC. Fractions with product were collected, concentrated, and recrystalized with hot ethanol. 4N HCl in dioxane (ca 1 mL) and acetonitrile (ca 3 mL) were added and concentrated to give {6-[1-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-5-methoxy-pyrimidin-4-yl}-(6-methanesulfonyl-2-methyl-pyridin-3-yl)-amine as white solid (HCl salt, 360 mg, 13.3%). 1HNMR (DMSO-d6, 400 MHz) delta 1.19-1.21 (d, J=6.82 Hz, 6H), 1.83-1.85 (m, 2H), 2.06-2.08 (m, 2H), 2.51 (s, 3H), 2.81-2.84 (sept, J=6.82 Hz, 1H), 3.57-3.59 (m, 2H), 3.75-3.77 (m, 2H), 3.87 (s, 1H), 5.31-3.39 (m, 1H), 7.89-7.91 (d, J=8.34 Hz, 1H), 8.07 (s, 1H), 8.23-8.25 (d, J=8.34 Hz, 1H) 8.69 (s, 1H). Exact mass calculated for C22H29N7O5S 503.2, found 504.2 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | With 4a,9a-dihydro-9,9-dimethyl-4,5-bis(diphenylphosphino)-xanthene; caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); In toluene; at 110℃; for 18.0333h; | Example 125. Isopropyl 4-(4-(2-methyl-6-(methylsulfonyl)pyridin-3-ylamino)-7- oxo-6H-pyrimido[5,4-b][l,4]oxazin-8(7H)-yl)piperidine-l-carboxylate[00283] To a solution of isopropyl 4-(4-chloro-7-oxo-6H-pyrimido[5,4- b][l,4]oxazin-8(7H)-yl)piperidine-l-carboxylate from Example 125A (33 mg, 0.093 mmol) in degassed toluene (2 mL) was added 2-methyl-6-(methylsulfonyl)pyridin-3- amine (17.32 mg, 0.093 mmol), Cs2CO3 (42.4 mg, 0.130 mmol), Xantphos (8.07 mg, 0.014 mmol) and Pd2(dba)3 (8.52 mg, 9.30 mumol). Purged for 2 min with stream of argon, stirred in sealed vial at 110 0C for 18 h. The reaction was cooled, diluted with ethyl acetate, washed with brine, dried (MgSO4), filtered through a pad of silica gel and concentrated in vacuo to afford an oil. The residue was purified by silica gel chromatography (12 g ISCO cartridge, 0-80% ethyl acetate/hexane) to afford 8 mg (17%) of Example 125 as a pale yellow solid. 1H NMR (400 MHz, CHLOROFORM- <n="141"/>d) delta ppm 9.00 (1 H, d, J=8.35 Hz), 8.29 (1 H, s), 7.96 (1 H, d, J=8.35 Hz), 6.97 (1 H, s), 4.96 - 5.06 (1 H, m), 4.93 (1 H, quin, J=6.15 Hz), 4.76 (2 H, s), 4.19 - 4.41 (2 H, m), 3.18 (3 H, s), 2.75 - 2.89 (2 H, m), 2.65 - 2.75 (2 H, m), 2.64 (3 H, s), 1.61 - 1.69 (2 H, m), 1.25 (6 H, d, J=5.71 Hz). LRMS (ESI): 505.1 [M + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24% | With 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate;palladium diacetate; In 1,4-dioxane; at 100℃; for 16.0h; | Compound 34C (65 mg, 0.18 mmol), 2-inethyl-6-(methylsulfonyl)pyridine-3-amine (51 mg, 0.27 mmol), sodium-terr-butoxide (23 mg, 0.24 mmol), Pd(OAc)2 (6.5 mg), and X-Phos (13 mg) were combined in dioxane (2 mL). The reaction mixture was purged with nitrogen and heated to 100 C for 16 hours. The reaction was cooled to room temperature, washed with water and extracted with DCM. The organic phase was dried (Na2SO..) and concentrated in vacuo. The crude reaction mixture was purified using a silica gel cartridge withDCM/methanol (95 '5) to provide compound 131 as an off-white solid (22 mg, 24%). LCMS: 508.3 (MH"). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | Step 1: Acetic acid 6-methanesulfonyl-2-methyl-pyridin-3-yl ester; A solution of boron trifluoride etherate (670 muL, 5.3 mmol) in dimethylformamide (2 mL) was cooled to -15 C. using an ice-acetonitrile bath, and then stirred for 15 min at this temperature. A solution of <strong>[897732-75-1]6-methanesulfonyl-2-methyl-pyridin-3-ylamine</strong> (Intermediate 4; 653 mg, 3.5 mmol) in 1,2-dimethoxyethane (16 mL) was added dropwise to the solution at -15 C. and the stirring was continued for a further 15 min. tert-Butyl nitrite (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA 90%; 483 mg, 4.2 mmol) was added dropwise, and the reaction mixture was stirred at -15 C. for 15 min and then at 0 C. for 1 h. Hexane (20 mL) was added and the solid was filtered off and washed with hexane. The solid was added to acetic anhydride (5 g, 49 mmol) and the mixture was heated at 100 C. for 1 h. The acetic anhydride was evaporated under high vacuum and then 1 M aqueous sodium carbonate solution was added. The mixture was extracted three times with dichloromethane. The dichloromethane was evaporated and the residue was purified by silica gel column chromatography, eluting with 0-40% ethyl acetate/hexane to give acetic acid 6-methanesulfonyl-2-methyl-pyridin-3-yl ester (331 mg, 41%) as a solid. 1H NMR (CDCl3) delta 2.39 (s, 3H), 2.52 (s, 3H), 3.22 (s, 3H), 7.62 (d, 1H, J=8.2 Hz), 7.98 (d, 1H, J=8.4 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | copper(I) trifluoromethanesulfonate benzene; N,N`-dimethylethylenediamine; In dimethyl sulfoxide; at 150℃; for 4.0h; | Intermediate 4: 6-Methanesulfonyl-2-methyl-pyridin-3-ylamine; A mixture of 3-amino-6-bromo-2-methylpyridine (ECA International Corporation, Palatine, Ill., USA; 2.0 g, 10.7 mmol), sodium methanesulfinate (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA 5.13 g, 42.8 mmol), copper trifluoromethanesulfonate benzene complex (598 mg, 1.07 mmol), and N,N'-dimethylethylenediamine (115 muL, 1.07 mmol) in dimethylsulfoxide (15 mL) was heated at 150 C. for 4 h. The mixture was cooled and water and ethyl acetate were added. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed twice with water, and then concentrated to approximately 5 mL. This gave a precipitate which was filtered off, washed with a small amount of ethyl acetate and air dried to give 6-Methanesulfonyl-2-methyl-pyridin-3-ylamine (1 g, 50%) as a brown powder. 1H NMR (300 MHz, DMSO-d6) delta 2.30 (s, 3H), 3.05 (s, 3H), 6.04 (br s, 2H), 6.98 (d, 1H, J=8.4 Hz), 7.55 (d, 1H, J=8.2 Hz). |
copper(I) trifluoromethanesulfonate benzene; N,N`-dimethylethylenediamine; In dimethyl sulfoxide; at 150℃; for 1.0h; | Example 7 6-Methanesulfonyl-2-methyl-pyridin-3-ylamine A 5-L 4-neck flask equipped with a thermocouple controller, an overhead mechanical stirrer, a condenser, and a nitrogen inlet/outlet was charged with sodium methanesulfinate (568 g, 4.73 mol), copper(1 ) thfluoromethanesulfonate benzene complex (70 g, 0.139 mol), N, N'- dimethylethylenediamine (12.3 g, 0.139 mol), and bromo-amine (260 g, 1.39 mol) in DMSO (800 ml_). The resulting mixture was heated to 1500C for 1 hour. The resulting mixture was then diluted with H2O (1.5 L) and extracted with EtOAc (6 x 2 L). The combined organic layers were evaporated to dryness to yield a residue. The residue was purified via ISCO Prep chromatography system. The product containing fractions were combined and evaporated to dryness. The resulting product (residue) was placed in vacuum oven at 400C for 18 hours to yield 6-methanesulfonyl-2-methyl-pyhdin-3-ylamine as a as a brownish solid. MS: 187.1 MW+H+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With sodium t-butanolate;palladium diacetate; 2,8,9-tris(2-methylpropyl)-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane; In N,N-dimethyl-formamide; at 160℃; for 0.166667h;Microwave irradiation; | Example 84-[4-(6-Methanesulfonyl-2-methyl-pyridin-3-ylamino)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester; A mixture of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 50 mg, 0.15 mmol), <strong>[897732-75-1]6-methanesulfonyl-2-methyl-pyridin-3-ylamine</strong> (Intermediate 4; 28 mg, 0.15 mmol), palladium acetate (0.33 mg, 0.01 equivalent), sodium tert-butoxide (34 mg, 0.36 mmol), and 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane (Aldrich, 1 mg, 0.02 equivalents) in dimethylformamide (2 mL) was heated in the microwave oven at 160 C. for 10 min. Ethyl acetate and water were added, and the aqueous layer was extracted three times with ethyl acetate. The ethyl acetate layers were combined, evaporated, and purified by preparative C18 HPLC, eluting with 10-100% acetonitrile/water. Samples containing the product were extracted twice with dichloromethane and the solvent was evaporated under high vacuum to give 4-[4-(6-methanesulfonyl-2-methyl-pyridin-3-ylamino)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (34 mg, 46%) as a white powder. 1H NMR (300 MHz, DMSO-d6) delta 1.41 (s, 9H), 1.92-2.00 (m, 4H), 2.55 (s, 3H), 2.90-3.04 (m, 2H), 3.30 (water peak and SO2CH3 peak), 4.00-4.12 (m, 2H), 4.84-4.96 (m, 1H), 7.92 (d, 1H, J=8.5 Hz), 8.22-8.36 (m, 3H), 10.06 (br s, 1H). HRMS Calcd. for C22H30N7O4S (MH+): 488.2075. Found: 488.2073. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In dimethyl sulfoxide; at 60℃;Product distribution / selectivity; | Example 1(6-Chloro-5-methoxy-pyrimidin-4-yl)-(6-methanesulfonyl-2-methyl-pyridin-3-yl)-amine A 100-mL Schlenk flask with a magnetic stir bar was charged with 4,6-dichloro-5-methoxypyrimidine (4.66 g, 0.026 mol), <strong>[897732-75-1]6-methanesulfonyl-2-methyl-3-pyridinamine</strong> (3.72 g, 0.020 mol), and DMSO (20 mL). After the mixture was stirred to dissolve the components, Cs2CO3 (8.48 g, 0.026 mol) was added, and the resulting mixture heated to 60 C. After 4.5 h and additional portion of Cs2CO3 (2.00 g, 0.0061 mol) was added and heating continued overnight. The reaction was quenched by addition of the reaction mixture to well stirred, saturated NH4Cl (200 mL); resulting in the formation of a tan precipitate. The precipitate was filtered, air dried and stirred with MTBE, and the resulting mixture filtered again. The resulting solid was purified by column chromatography on silica gel (200 g) using CH2Cl2 followed by 1% IPA-CH2Cl2 after 2-L of CH2Cl2 had eluted to yield the title compound as a white to light yellow solid.1H NMR (300 MHz, CDCl3) delta: 8.99 (d, 1H, J=8.6 Hz), 8.37 (s, 1H), 8.00 (d, 1H, J=8.6 Hz), 7.49 (br s, 1H), 4.08 (s, 3H), 3.21 (s, 3H), 2.69 (s, 3H).HRMS: [MH]+ m/z=329.0465.NOTE: (6-Chloro-5-methoxy-pyrimidin-4-yl)-(6-methanesulfonyl-2-methyl-pyridin-3-yl)-methyl-amine was also isolated as a by-product from the above reaction mixture. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With sodium hydride; In tetrahydrofuran; at 20℃; for 16.0h; | EXAMPLE 55; 3-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)-N-(2-methyl-6-(methylsulfonyl) pyridin-3-yl)-[l,2,4]triazolo[4,3-b]pyridazin-8-amineStep 1: 3,6-Dichloro-N-(2-methyl-6-(methylsulfonyl)pyridin-3-yl)pyridazin-4- amine [0394] A 100-mL round-bottom flask was charged with a solution of 2-methyl- 6-(methylsulfonyl)pyridin-3-amine (500 mg, 2.69 mmol) in tetrahydrofuran (50 mL), sodium hydride (269 mg, 11.2 mmol), and 3,4,6-trichloropyridazine (1 g, 5.49 mmol). The resulting solution was stirred for 16 hrs at room temperature. The reaction was then quenched with brine (50 mL), extracted with ethyl acetate (4x50 mL). Combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. This residue was purified by a silica gel column chromatography eluted with dichloromethane/ethyl acetate (2/1) affording 3,6-dichloro-N-(2-methyl-6-(methylsulfonyl)pyridin-3-yl)pyridazin-4-amine as pale yellow solid (0.75 g, 84%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium tert-butylate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 70℃; | Step 3: 3-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)-N-(2-methyl-6- (methylsulfonyl) pyridin-3-yl)imidazo[l,2-a]pyridin-8-amine[0387] A 50-mL round-bottom flask was placed with a solution of 8-bromo-3- (l-(5-ethylpyrimidin-2-yl)piperidin-4-yl)H-imidazo[l,2-a]pyridine (300 mg, 0.78 mmol, 1.00 equiv), <strong>[897732-75-1]2-methyl-6-(methylsulfonyl)pyridin-3-amine</strong> (160 mg, 0.86 mmol, 1.10 equiv), Pd2(dba)3 (136 mg), BINAP (150 mg), potassium 2- methylpropan-2-olate (400 mg) in toluene (25 mL). The resulting solution was stirred at 700C overnight. Upon completion, the mixture was cooled down to room temperature and quenched with water. The mixture was rinsed into a seperatory funnel and extracted with ethyl acetate (3x50 mL). Combined organics were washed with water, brine and dried over Na2SO4, filtered and concentrated in vacuo to give the crude product that was purified by a silica gel column chromatography eluted with ethyl acetate in hexanes (1:1) to give 3-(l-(5-ethylpyrimidin-2- yl)piperidin-4-yl)-N-(2-methyl-6-(methylsulfonyl)pyridin-3-yl)H-imidazo[l,2- a]pyridin-8-amine as a white solid (350 mg, 90%). 1H NMR (300 MHz, DMSOd6) delta 8.29 (m, 4H), 7.76 (d, IH), 7.47 (t, 2H), 6.99 (d, 2H), 4.80 (d, 2H), 3.36 (t, 2H), 3.21 (s, 3H), 3.09 (t, 2H), 2.60 (s, 3H), 2.45 (m, 2H), 2.08 (d, 2H), 1.60 (m, 2H), 1.14 (t, 3H). LCMS 492 [M+l]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With potassium tert-butylate; In tetrahydrofuran; at 50℃; for 2.0h; | Step 4: Tert-butyl 4-(6-chloro-8-(2-methyl-6-(methylsulfonyl)pyridin-3- ylamino)imidazo[l,2-b]pyridazin-3-yl)piperidine-l-carboxylate[0391] A 100-mL round-bottom flask was charged with a solution of tert-butyl 4-(8-bromo-6-chloroimidazo[l,2-b]pyridazin-3-yl)piperidine-l-carboxylate (1 g, 2.40 mmol, 1.00 equiv), <strong>[897732-75-1]2-methyl-6-(methylsulfonyl)pyridin-3-amine</strong> (700 mg, 3.76 mmol, 1.57 equiv), potassium 2-methylpropan-2-olate (450 mg) in tetrahydrofuran (50 mL). The resulting mixture was stirred at 500C for 2 h. Upon completion, the reaction was quenched with brine (IL). The resulting mixture was extracted with ethyl acetate (3x300 mL). Combine organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give the crude that was purified by a silica gel column chromatography eluted with ethyl acetate/petroleum ether (1:1) affording tert-butyl 4-(6-chloro-8-(2-methyl-6- (methylsulfonyl)pyridin-3-ylamino)imidazo[l,2-b]pyridazin-3-yl)piperidine-l- carboxylate as yellow solid (1.5 g, 84%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4.54 g | With 1,1'-bis(di-tertbutylphosphino)ferrocene; palladium diacetate; caesium carbonate; In 1,4-dioxane; for 2.0h;Reflux; | 4-Chioro-5-methoxy-6-(i -(4-(trifluoromethyl)pyrimidin-2-yi)piperidin-4-ylox3)pvrunidlnc 6 0 g b 6 mmoi) 2 neth1 6 (nwthnlultonyhndrn 3 ?inn L (2 90 z 15.6 mmoi), cesium carbonate (17.8 g, 5.4.5 mmoi), diacetoxypalladium (0.70 g, 3.112 mmol). and i ,i ?-bis( i-t-butylphosphino)ferrocene (2.95 g, 6.22 mmol) were suspended in dioxane (52.0 mL) and stirred at reflux for 2 h. The solids were removed by filtration and the filtrate was concentrated and purified by column chromatography (silica gel, 50-70% EtOAc in hexanes). The purified material was recrystallized from MTBE/DCM/hexanes to afford 4.54 gof the title compound. Exact mass calculated for C22H24F3N704S?. 539.16, found: LCMS rn/a =540.4 [MH] ?H NMR (400 MHz, CDCi3) d ppm 186-1.96 (m, 21-1). 2.09-2.1 8 (m. 2H). 2.65(s, 3H), 3.19 (s, 3F1). 3.77-3.85 (m. 21-1), 4.01 (s, 3H), 4.21 -4.31 (m. 2F1). 5.48-5.55 (m. il-i),6.77 (ci, .J= 4.8 Hz. 1FI). 7.33 (s, ID;, 7.97 (d, ,J 8.6 Fiz, 111), 8.22 (s, 1F1). 8.51 d, J 5.01-li, il-I), 9.01 (d,J= .6Fiz, 1H). |
Tags: 897732-75-1 synthesis path| 897732-75-1 SDS| 897732-75-1 COA| 897732-75-1 purity| 897732-75-1 application| 897732-75-1 NMR| 897732-75-1 COA| 897732-75-1 structure
A126807 [187143-22-2]
6-(Methylsulfonyl)pyridin-3-amine
Similarity: 0.88
A131593 [1018949-67-1]
2-(3-Aminopyridin-2-yl)acetonitrile
Similarity: 0.55
A126807 [187143-22-2]
6-(Methylsulfonyl)pyridin-3-amine
Similarity: 0.88
A492786 [848141-14-0]
(5-(Methylsulfonyl)pyridin-2-yl)methanamine hydrochloride
Similarity: 0.54
A692431 [35144-22-0]
4,6-Dimethyl-2-methylsulfonylpyrimidine
Similarity: 0.51
A126807 [187143-22-2]
6-(Methylsulfonyl)pyridin-3-amine
Similarity: 0.88
A131593 [1018949-67-1]
2-(3-Aminopyridin-2-yl)acetonitrile
Similarity: 0.55
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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 |
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