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CAS No. : | 59786-31-1 | MDL No. : | MFCD03788226 |
Formula : | C7H6BrNO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | FASOJOLGUAUEPU-UHFFFAOYSA-N |
M.W : | 216.03 | Pubchem ID : | 2762700 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.14 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 43.22 |
TPSA : | 39.19 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.62 cm/s |
Log Po/w (iLOGP) : | 1.86 |
Log Po/w (XLOGP3) : | 1.4 |
Log Po/w (WLOGP) : | 1.63 |
Log Po/w (MLOGP) : | 1.09 |
Log Po/w (SILICOS-IT) : | 1.87 |
Consensus Log Po/w : | 1.57 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.33 |
Solubility : | 1.0 mg/ml ; 0.00464 mol/l |
Class : | Soluble |
Log S (Ali) : | -1.83 |
Solubility : | 3.22 mg/ml ; 0.0149 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.96 |
Solubility : | 0.237 mg/ml ; 0.0011 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.49 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | Heating / reflux | A mixture of 3.98 g of the acid obtained in the previous step (20 mmol, 1 eq.) in 50 ml of methanol is reflux heated in the presence of 4 ml of concentrated sulfuric acid. The mixture is allowed to return to ambient temperature and extracted 3 times with ethyl acetate. The organic phase is dried on Na2SO4 and the solvent is evaporated. 2.65 g (62percent) of esterified product is obtained. NMR (1H, CDCl3): 4.02 (s; 3H), 7.64 (d, J=4.9 Hz; 1H), 8.63 (d, J=4.9 Hz; 1H), 8.88 (s; 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | at 0 - 20℃; for 1 h; Inert atmosphere | To a stirred solution of 3-bromoisonicotinic acid 1 (2 g, 9.90 mmol) in MeOH: THF(2: 1, 30 mL) under argon atmosphere was added CH2N2 (2 g, 49.50 mmol) at 0 °C; warmed toRT and stirred for 1 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 20percent EtOAc/ hexanes to afford compound 2 (1.4 g, 66percent) as brown oil. TLC: 20percent EtOAc/ hexanes (R 0.7); ‘H-NMR (CDC13, 400 MHz): ö 8.87 (s, 1H),8.62 (d, J = 7.2 Hz, 1H), 7.63 (d, J = 5.6 Hz, 1H), 3.97 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | A mixture of 2.65 g of the product from the previous step (12 mmol, 1 eq.) with 1.1 ml of methyl thioglycolate (12 mmol, 1 eq.) in 100 ml of acetonitrile is reflux heated for 18 hrs in the presence of 2.54 g of potassium carbonate (18 mmol, 1.5 eq.). After that, the mixture is allowed to return to ambient temperature, the solvent is evaporated and the residue is dissolved in water. A few ml of acetic acid (pH 4) are added and the precipitate formed is filtered. It is vacuum dried. 1.51 g (59percent) of aromatized product is obtained. NMR (1H, CDCl3): 4.00 (s; 3H), 7.63 (d, J=4.9 Hz; 1H), 8.58 (d, J=4.9 Hz; 1H), 9.10 (s; 1H), 10.02 (s; 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With sulfuric acid;Heating / reflux; | A mixture of 3.98 g of the acid obtained in the previous step (20 mmol, 1 eq.) in 50 ml of methanol is reflux heated in the presence of 4 ml of concentrated sulfuric acid. The mixture is allowed to return to ambient temperature and extracted 3 times with ethyl acetate. The organic phase is dried on Na2SO4 and the solvent is evaporated. 2.65 g (62%) of esterified product is obtained. NMR (1H, CDCl3): 4.02 (s; 3H), 7.64 (d, J=4.9 Hz; 1H), 8.63 (d, J=4.9 Hz; 1H), 8.88 (s; 1H). |
Intermediate 33methyl 3-bromoisonicotinate H2SO4 (0.5 mL) was added to a solution of <strong>[13959-02-9]3-bromoisonicotinic acid</strong> (500 mg, 2.48 mmol) in MeOH (10 mL). The resulting solution was heated at reflux overnight. The mixture was cooled to 0 C. and a solution of 5% NaHCO3 (5 mL) was added. The aqueous layer was basified to pH=7-8 with 50% aqueous NaOH. It was then extracted with DCM (3×). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford title crude product (465 mg, 87%) as an oil. 1H NMR (300 MHz, CDCl3) delta ppm 3.96 (s, 3H) 7.61 (d, J=5.10 Hz, 1H) 8.61 (d, J=5.10 Hz, 1H) 8.85 (s, 1H). | ||
With sulfuric acid; for 14h;Reflux; | Preparation 4 4-Hydroxymethyl-3',4',5',6'-tetrahydro-2'H-[3,4]-bipyridinyl-1'-carboxylic Acid t-Butyl Ester H2SO4 (2.5 mL, 48.3 mmol, 1.0 eq.) was added to a solution of <strong>[13959-02-9]3-bromoisonicotinic acid</strong> (9.7 g, 48.3 mmol, 1.0 eq.) in MeOH (150 mL). The resulting solution was stirred for 14 hours while the temperature was maintained at reflux in an oil bath. The mixture was then cooled to room temperature and concentrated under vacuum. The residue was dissolved in EtOAc (200 mL). The pH of the solution was adjusted to 10 with Na2CO3. The resulting solution was extracted with EtOAc (100 mL). The organic layer was washed with water (1*200 mL) and saturated aqueous NaCl (2*100 mL). The mixture was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with EtOAc/PE (1:20) to yield <strong>[13959-02-9]3-bromoisonicotinic acid</strong> methyl ester (4.4 g) as a colorless liquid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
320 ml of a tetrahydrofuran solution containing 22.4 ml ofdiisopropyl amine was cooled to -70°C or lower in a dry ice-acetonebath, then, 100 ml of n-butyl lithium (1.6M hexane solution) wasadded dropwise to the solution, and the resulting mixture wasstirred at the same temperature for 30 minutes. To the solutionwas added dropwise 250 ml of a tetrahydrofuran solution containing25 g of 3-bromopyridine over 4 hours. After completion of thedropwise addition, the mixture was stirred at -70°C or lower forfurther 1 hour. To the solution was added 8.8 g of dry ice thesurface of which had been well polished and finely pulverized, andthe mixture was stirred for 1 hour, and the temperature of themixture was gradually elevated to room temperature. After thesolvent and excess carbon dioxide were completely removed underreduced pressure, the residue was dissolved in 300 ml of N,N-dimethylformamide, 27.6 g of potassium carbonate and 12.6 ml ofmethyl iodide were added to the solution, and the mixture wasstirred at room temperature for 16 hours. Ethyl acetate and anaqueous sodium bicarbonate solution were added to the mixture,liquids were separated, and the organic layer was washed with waterand brine. The organic layer was dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:l) to give 13.5 g of methyl 3-bromoisonicotinateshown in Table 53 below. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; triphenylphosphine;palladium diacetate; In N,N-dimethyl-formamide; at 70℃; for 1h; | To 120 ml of N,N-dimethylformamide solution containing 12 g ofthe compound obtained in the above-mentioned (1) were added 9.3 gof 4-fluoro-2-methylphenylboric acid, 19.6 g of cesium carbonate,1.12 g of palladium acetate and 2.63 g of triphenylphosphine, andthe resulting mixture was stirred at 70 °C for 1 hour'. After completion of the reaction, ethyl acetate and brine were added tothe reaction mixture, and insoluble materials were filtered off.The filtrate was washed with brine and water, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=4:l) to give 7.9 g of methyl 3-(4-fluoro-2-methylphenyl)isonicotinate shown in Table 53 below. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
dichlorobis(triphenylphosphine)nickel (II); In tetrahydrofuran; hexane; | Step A Preparation of 3-(4-cyanobenzyl)pyridin-4-carboxylic acid methyl ester A solution of 4-cyanobenzyl bromide (625 mg, 3.27 mmol) in dry THF (4 mL) was added slowly over ~3 min. to a suspension of activated Zn (dust; 250 mg) in dry THF (2 mL) at 0° under an argon atmosphere. The ice-bath was removed and the slurry was stirred at room temperature for a further 30 min. Then <strong>[59786-31-1]3-bromopyridin-4-carboxylic acid methyl ester</strong> (540 mg. 2.5 mmol) followed by dichlorobis(triphenylphosphine)nickel (II) (50 mg). The resultant reddish-brown mixture was stirred for 3 h at ~40°-45° C. The mixture was cooled and distributed between EtOAc (100 ml,) and 5percent aqueous citric acid (50 mL). The organic layer was washed with H2 O(2*50 mL), dried with Na2 SO4. After evaporation of the solvent the residue was purified on silica gel, eluding with 35percent EtOAc in hexane to give 420 mg as a clear gum. FAB ms (M+1)253. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
dichlorobis(triphenylphosphine)nickel (II); In tetrahydrofuran; hexane; | Step A 3-(4-Cyanobenzyl)pyridin-4-carboxylic acid methyl ester A solution of 4-cyanobenzyl bromide (625 mg, 3.27 mmol) in dry THF (4 mL) was added slowly over ~3 min. to a suspension of activated Zn (dust; 250 mg) in dry THF (2 mL) at 0° under an argon atmosphere. The ice-bath was removed and the slurry was stirred at room temperature for a further 30 min. Then <strong>[59786-31-1]3-bromopyridin-4-carboxylic acid methyl ester</strong> (540 mg. 2.5 mmol) followed by dichlorobis(triphenylphosphine)nickel (II) (50 mg). The resultant reddish-brown mixture was stirred for 3 h at ~40°-45° C. The mixture was cooled and distributed between EtOAc (100 ml) and 5percent aqueous citric acid (50 mL). The organic layer was washed with H2 O (2*50 mL), dried with Na2 SO4. After evaporation of the solvent the residue was purified on silica gel, eluding with 35percent EtOAc in hexane to give 420 mg as a clear gum. FAB ms (M+1) 253. | |
dichlorobis(triphenylphosphine)nickel (II); In tetrahydrofuran; hexane; | Step A Preparation of 3-(4-Cyanobenzyl)pyridin-4-carboxylic acid methyl ester A solution of 4-cyanobenzyl bromide (625 mg, 3.27 mmol) in dry THF (4mL) was added slowly over ~3 min. to a suspension of activated Zn (dust; 250 mg) in dry THF (2 mL) at 0° under an argon atmosphere. The ice-bath was removed and the slurry was stirred at room temperature for a further 30 min. Then <strong>[59786-31-1]3-bromopyridin-4-carboxylic acid methyl ester</strong> (540 mg. 2.5 mmol) followed by dichlorobis(triphenylphosphine)nickel (II) (50 mg). The resultant reddish-brown mixture was stirred for 3 h at ~40°-45° C. The mixture was cooled and distributed between EtOAc (100 ml) and 5percent aqueous citric acid (50 mL). The organic layer was washed with H2 O (2*50 mL), dried with Na2 SO4. After evaporation of the solvent the residue was purified on silica gel, eluding with 35percent EtOAc in hexane to give 420 mg as a clear gum. FAB ms (M+1) 253. | |
dichlorobis(triphenylphosphine)nickel (II); In tetrahydrofuran; hexane; | Step A Preparation of 3-(4-cyanobenzyl)pyridin-4-carboxylic acid methyl ester A solution of 4-cyanobenzyl bromide (625 mg, 3.27 mmol) in dry THF (4 mL) was added slowly over 3 min. to a suspension of activated Zn (dust; 250 mg) in dry THF (2 mL) at 0° under an argon atmosphere. The ice-bath was removed and the slurry was stirred at room temperature for a further 30 min. Then <strong>[59786-31-1]3-bromopyridin-4-carboxylic acid methyl ester</strong> (540 mg. 2.5 mmol) followed by dichlorobis(triphenylphosphine)nickel (II) (50 mg). The resultant reddish-brown mixture was stirred for 3 h at ~40-45° C. The mixture was cooled and distributed between EtOAc (100 ml) and 5percent aqueous citric acid (50 mL). The organic layer was washed with H2 O (2*50 mL), dried with Na2 SO4. After evaporation of the solvent the residue was purified on silica gel, eluding with 35percent EtOAc in hexane to give 420 mg as a clear gum. FAB ms (M+1) 253. |
dichlorobis(triphenylphosphine)nickel (II); In tetrahydrofuran; hexane; | Step A Preparation of 3-(4-cyanobenzyl)pyridin-4-carboxylic acid methyl ester A solution of 4-cyanobenzyl bromide (625 mg, 3.27 mmol) in dry THF (4mL) was added slowly over ~3 min. to a suspension of activated Zn (dust; 250 mg) in dry THF (2 mL) at 0° under an argon atmosphere. The ice-bath was removed and the slurry was stirred at room temperature for a further 30 min. Then <strong>[59786-31-1]3-bromopyridin-4-carboxylic acid methyl ester</strong> (540 mg. 2.5 mmol) followed by dichlorobis(triphenylphosphine)nickel (II) (50 mg). The resultant reddish-brown mixture was stirred for 3 h at ~40°-45° C. The mixture was cooled and distributed between EtOAc (100 ml) and 5percent aqueous citric acid (50 mL). The organic layer was washed with H2 O (2*50 mL), dried with Na2 SO4. After evaporation of the solvent the residue was purified on silica gel, eluding with 35percent EtOAc in hexane to give 420 mg as a clear gum. FAB ms (M+1) 253. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
dichlorobis(triphenylphosphine)nickel (II); In tetrahydrofuran; hexane; | Example 4 2(S)-n-Butyl-1-[3-(4-cyanobenzyl)pyridin-4-yl]-4-(2,2,2-trifluoroethyl)piperazin-5-one dihydrochloride STR31 Step A: 3-(4-Cyanobenzyl)pyridin-4-carboxylic acid methyl ester A solution of 4-cyanobenzyl bromide (0.625 g, 3.27 mmol) in dry THF (4 mL) was added slowly over ~3 min to a suspension of activated zinc (dust; 0.250 g) in dry THF (2 mL) at 0° C. under an argon atmosphere. The ice-bath was removed and the slurry was stirred at room temperature for a further 30 min. Then <strong>[59786-31-1]3-bromopyridin-4-carboxylic acid methyl ester</strong> (0.540 g. 2.5 mmol) followed by dichlorobis(triphenylphosphine)nickel (II) (50 mg). The resultant reddish-brown mixture was stirred for 3 h at ~40-45° C. The mixture was cooled and distributed between ethyl acetate (100 ml) and 5percent aqueous citric acid (50 mL). The organic layer was washed with water (2*50 mL), dried with Na2 SO4. After evaporation of the solvent the residue was purified on silica gel, eluding with 35percent ethyl acetate in hexane to give 0.420 g as a clear gum. FAB ms (M+1) 253. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 7 Methyl 3-bromoisonicotinate Using the procedure described in Example 6 but employing <strong>[13959-02-9]3-bromoisonicotinic acid</strong> (prepared as desribed in Example 5) in place of 2-chloronicotinic acid provided the title compound. 1 H NMR (CDCl3, 400 MHz): delta3.95 (s; CH3); 8.85 (s; H2); 8.61 (d; J=5H; H6); 7.61 (d; J=5 Hz; H5). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;palladium diacetate; triphenylphosphine; In N,N-dimethyl-formamide; at 70℃; for 1h; | (2) To 120 ml of an N,N-dimethylformamide solution containing 12 g of the compound obtained in the above-mentioned (1) were added 9.3 g of 4-fluoro-2-methylphenylboric acid, 19.6 g of cesium carbonate, 1.12 g of palladium acetate and 2.63 g of triphenylphosphine, and the mixture was stirred at 700C for 1 hour. After completion of the reaction, ethyl acetate and brine were added to the mixture, and insoluble materials were filtered off. The filtrate was washed successively with brine and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n- hexane:ethyl acetate=4:l) to give 7.9 g of methyl 3- (4-fluoro-2- methylphenyl) isonicotinate shown in the following Table 66. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h; | Reference example 3; (1) 320 ml of a tetrahydrofuran solution containing 22.4 ml of diisopropylamine was cooled to -700C or lower with a dry ice- acetone bath, 100 ml of n-butyl lithium (1.6M hexane solution) was added dropwise, and the mixture was stirred at the same temperature for 30 minutes. To the solution was added dropwise 250 ml of a tetrahydrofuran solution containing 25 g of 3-bromopyridine over 4 hours, and the mixture was further stirred at -7O0C or lower for 1 hour. To the solution was added 8.8 g of dry ice which had been finely pulverized after wiping the surface well, the resulting mixture was stirred for 1 hour, and the temperature of the mixture was gradually raised to room temperature. The solvent and the excess carbon dioxide were completely removed under reduced pressure, the residue was dissolved in 300 ml of N,N-dimethylform- amide, 27.6 g of potassium carbonate and 12.6 ml of methyl iodide were added to the solution, and the mixture was stirred at room temperature for 16 hours. Ethyl acetate and an aqueous sodium bicarbonate solution were added to the mixture, the mixture was separated, and the organic layer was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:l) to give 13.5 g of methyl 3-bromoisonicotinate shown in the following Table 66. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 120℃; for 3h;Microwave irradiation; | Intermediate U; (2,4-Dioxo-l,4-dihydro-2H-pyrido[3,4-d]pyrimidin-3-yl)-acetic acid tert-butyl ester; A 2-5ml microwave vial is charged with Pd(OAc)2 (2.5 mol%, 6.6mg, 0.0231 mmol), Xantphos (5 mol%, 27.1mg, 0.0463mmol), ureido-acetic acid tert-butyl ester (259mg, 1.482mmol), and CS2CO3 (770.2mg, 2.315mmol). 3-Bromo-isonicotinic acid methyl ester (216.3mg, 0.926mmol) is added, followed by 1,4-dioxane (4 ml). The vessel is sealed and treated in the microwave at 1200C for 3 x 3600 seconds. EtOAc is added to the reaction mixture which is then washed with brine (3 x 20 ml) and water (2 x 10 ml). The organic phase is passed through Celite(filter material), dried (MgSO4), filtered and concentrated. The material is purified via flash column chromatography, eluting with iso-hexane:EtOAc to afford the title compound; [M+H]+ 278. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | Methyl 3-bromoisonicotinate (1.0 eq, 1.76 g, 7.65 mmol), 2-aminophenylboronic acid hydrochloride (1.0 eq, 1.33 g, 7.67 mmol) and cesium carbonate (2.0 eq, 4.99 g, 15.31 mmol) were suspended in dioxane (15 ml). The mixture was degassed by bubbling nitrogen for 10 minutes. PdCl2(dppf) (0.05 eq, 280 mg, 0.383 mmol) was added and the mixture was stirred at reflux for 2 hours. The resulting solid was filtered, washed with methanol, water and methanol and dried. Benzo[c][2,6]naphthyridin-5(6H)-one was isolated as an off-white solid (823 mg, 55percent yield). LCMS (ES): 95percent pure, m/z 197 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44.4% | With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; In water; toluene; at 90℃;Inert atmosphere; | Compound 105a. To a solution of ethyl 3-bromoisonicotinate (0.2 g, 0.925 mmol, 1.0 equiv) in Toluene (8 mL) and water (2 mL) was added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.429 g, 1.39 mmol, 1.5 equiv), K2CO3 (0.255 g, 1.85 mmol, 2.0 equiv) and resulting reaction mixture purged with N2 gas for 10 minute, followed by the addition of Pd(PPh2)Cl2 (0.033 g, 0.046 mmol. 0.05 equiv). The resulting reaction mixture was heated at 90 C. for overnight. Product formation was confirmed by LCMS. After the completion of reaction, the mixture was filtered through celite bed, washed with ethyl acetate (100 mL). Filtrate was concentrated under reduced pressure. The crude product obtained was purified by flash chromatography (0-20% ethyl acetate in hexane as an eluent) to obtain 1?-(tert-butyl) 4-methyl 3?,6?-dihydro-[3,4?-bipyridine]-1?,4(2?H)-dicarboxylate (0.130 g, 44.4% Yield) as an yellow oil. (0848) LCMS 319.2 [M+H]+ (0849) 1H NMR (400 MHz, DMSO-d6) delta 8.65 (d, J=4.8 Hz, 1H), 8.59-8.52 (m, 1H), 7.63 (d, J=4.8 Hz, 1H), 5.68 (br. s., 1H), 3.96 (br. s., 2H), 3.87-3.69 (m, 3H), 3.52 (br. s., 2H), 2.27 (br. s., 2H), 1.53-1.25 (m, 9H), 1.07 (s, 3H). |
With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In tetrahydrofuran; water; for 14h;Inert atmosphere; Reflux; | PdCl2(PPh3)2 (0.7 g, 1.03 mmol, 0.05 eq.) was added to a solution of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (6.3 g, 20.5 mmol, 1.0 eq.) in THF (120 mL) under nitrogen. To this was added <strong>[59786-31-1]3-bromoisonicotinic acid methyl ester</strong> (4.4 g, 20.5 mmol, 1.0 eq.). This was followed by the addition of a solution of Na2CO3 (8.7 g, 82.1 mmol, 4.0 eq.) in water (41 mL). The resulting solution was stirred for 14 hours while the temperature was maintained at reflux in an oil bath. The resulting solution was diluted with EtOAc (100 mL), and washed with saturated aqueous NaCl (2*100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with EtOAc/PE (1:10) to yield 3',6'-dihydro-2'H-[3,4']bipyridinyl-4,1'-dicarboxylic acid 1'-t-butyl ester 4-methyl ester (5.6 g) as a yellow oil. H-NMR: (300 MHz, CDCl3, ppm): 8.65 (1H, d, J=4.8 Hz), 8.54 (1H, s), 7.65 (1H, d, J=4.8 Hz), 5.65 (1H, m), 4.08 (2H, m), 3.90 (3H, s), 3.65 (2H, m), 2.34 (2H, m), 1.51 (9H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tetrakis(triphenylphosphine) palladium(0); In ISOPROPYLAMIDE; at 180℃; for 0.05h;Inert atmosphere; Sealed tube; Microwave irradiation; | Intermediate 34methyl 3-cyanoisonicotinate In a flame dried microwave tube, Zn(CN)2 (54 mg, 0.463 mmol) and Pd(PPh3)4 (16 mg, 0.014 mmol) were added to a solution of Intermediate 33 (100 mg, 0.463 mmol) in DMAc (4 mL). Nitrogen was bubbled through the solution for 5 min and then the tube was sealed. The reaction mixture was heated in a microwave apparatus to 180° C. for 3 min. The resulting mixture was purified on a reverse phase silica gel cartridge (25 g) with H2O and acetonitrile from 90:10 to 80:20. The product obtained was then purified by flash chromatography on silica gel, eluting with mixtures of hexanes and EtOAc (92:8 to 30:70) to afford title product (74 mg, 99percent) as a solid. 1H NMR (300 MHz, CDCl3) delta ppm 4.06 (s, 3H) 7.98 (d, J=5.10 Hz, 1H) 8.96 (d, J=5.10 Hz, 1H) 9.06 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19% | palladium bis[bis(diphenylphosphino)ferrocene] dichloride; In 1,4-dioxane; toluene; at 70℃; for 3.5h; | Methyl 3-bromopyridine-4-carboxylate (5 g, 23.1 mmol) was dissolved in anhydrous dioxane (150 mL). A solution of diethyl zinc (18.9 mL, 20.8 mmol, 1.1 M in toluene) was added dropwise and then was added catalyst ((1,1'- bis(diphenylphosphino)ferrocene) dichloropalladium (254 mg, 347 mumol). The mixture was heated at 70°C for 3.5 hours and then water followed with 1 N HCl was added. The mixture was extracted 3 times with ethyl acetate. The combined organic phase was washed with brine and dried over sodium sulfate. After evaporation, the residue was dissolved in DCM and purified on silica gel using 0-20percent hexane/ethyl acetate to afford methyl 3-ethylpyridine-4-carboxylate (730 mg, 19percent yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | To a stirred solution of <strong>[59786-31-1]methyl 3-bromoisonicotinate</strong> (2.5 g, 1 1.57 mmol) in THF (46 mL) at -78 C was added methylmagnesium bromide (7.91 mL, 23.72 mmol, 3M in Et20). The reaction mixture was then stirred at room temperature overnight, quenched with saturated aqueous NH4C1 and extracted with (¾(¾ (2x20 mL). The combined organics were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (80 g BIOTAGE column, eluting with CH2Cl2:EtOAc /85: 15) to provide Intermediate 42A (1.62 g, 65% yield). MS (ES): m/z=216.09 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13% | With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; In tetrahydrofuran; at 60 - 80℃; for 0.833333h;Sealed tube; Microwave irradiation; | Intermediate 40: methyl 3-(3-phenylpropyl)-4-pyridi necarboxylate To a mixture of <strong>[59786-31-1]methyl 3-bromo-4-pyridinecarboxylate</strong> (70mg, 0.32 mmol), palladium (II) acetate (5.5mg, 0.024 mmol) and S-Phos (13 mg, 0.032 mmol) in a microwave vial was added 0.5M bromo(3-phenylpropyl)zinc in THF (10.5m1, 5.25 mmol). The vial was sealed then the mixture heated at 80°C for 20 mins, then at 60°C for a further 10 mins and then at 80°C for a further 10 mins. Further 0.5M bromo(3-phenylpropyl)zinc in THF (1 0.5m1, 5.25 mmol) was added to the reaction mixture which was then heated at 80°C for a further 10 mins.Separately, to a mixture of <strong>[59786-31-1]methyl 3-bromo-4-pyridinecarboxylate</strong> (758mg, 3.51 mmol), palladium (II)acetate (59mg, 0.26 mmol) and 5-Phos (1 44mg, 0.35 mmol) in a microwave vial was added 0.5M bromo(3-phenylpropyl)zinc in THF (10.5m1, 5.25 mmol). The vial was sealed then the mixture heated at 80°C for 20 mins.The two reaction mixtures were combined then filtered using a phase separator, then partitioned between EtOAc (50m1) and ammonium chloride (25m1). The organic layer was isolated, washed withbrine then dried over magnesium sulfate then filtered and concentrated under reduced pressure to give the crude product as an oil. The crude product was purified with column chromatography (eluted with 0-20percent EtOAc in cyclohexane) then MDAP (Method E) to give the title compound as a yellow oil (118mg, 13percent).LCMS (Method B): Rt = 1 .l6mins, MH+ = 256.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 135℃; for 1.33333h;Microwave irradiation; Inert atmosphere; | 2-teri-butyltetrahydro-2H-pyran-4-ol (3.09 g, 19.5 mmol, Eq: 1.00), Silica gel (15 g, 19.5 mmol, Eq: 1.00) and PCC (6.31 g, 29.3 mmol, Eq: 1.5) stirred in dichloromethane (100 mL) at RT overnight. The reaction mixture was filtered through Celite and the filtrate was concentrated. A biphasic oily mixture was obtained; the lighter, liquid top layer was pipetted to give 2-tert- butyldihydro-2H-pyran-4(3H)-one as brown liquid (2.9g, 95percent yield). H NMR (CDCl3) : 4.29 - 4.39 (m, 1H), 3.57 - 3.68 (m, 1H), 3.21 (dd, J = 11.5, 2.8 Hz, 1H), 2.53 - 2.66 (m, 1H), 2.28 - 2.45 (m, 3H), 0.96 (s, 9H). Methyl 3-bromoisonicotinate (0.4 g, 1.85 mmol, Eq: 1.00), 2-tert-butyldihydro-2H-pyran- 4(3H)-one (347 mg, 2.22 mmol, Eq: 1.2), Pd2(dba)3 (0) (33.9 mg, 37.0 muetaiotaomicron, Eq: 0.02), xantphos (42.9 mg, 74.1 muiotaetaomicron, Eq: 0.04) and Cs2C03 (800 mg, 2.46 mmol, Eq: 1.33) were placed in a microwave vial. Under N2, toluene (10.0 mL) was added. The resulting mixture stirred in the microwave (Biotage Initiator) at 135°C for 80 minutes. The solvent was pipetted off onto a column for purification by flash chromatography (40g Si02, hexanes/EtOAc 0-40percent EtOAc). The combined fractions were concentrated and the remaining yellow solid was triturated in hexanes to give 7-teri-butyl-4a,7,8,10a-tetrahydro-5H-6,9-dioxa-3-aza-phenanthren-10-one as light yellow solid (125mg, 26percent yield). 1H NMR (CDC13) delta: 8.80 (d, J = 5.0 Hz, 1H), 8.74 (s, 1H), 8.16 (d, J = 5.3 Hz, 1H), 5.01 (dd, J = 14.1, 1.5 Hz, 1H), 4.72 (dt, J = 14.1, 2.9 Hz, 1H), 3.43 (dd, J = 11.0, 3.3 Hz, 1H), 2.67 - 2.80 (m, 1H), 2.49 (dt, J = 17.4, 2.7 Hz, 1H), 1.04 (s, 9H). MS calcd. for Ci5Hi7N03 [(M+H)+] 260.3, obsd. 260. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 130℃; for 1.83333h;Microwave irradiation; Inert atmosphere; | Methyl 3-bromoisonicotinate (0.4 g, 1.85 mmol, Eq: 1.00), 2-cyclopentyldihydro-2H- pyran-4(3H)-one (374 mg, 2.22 mmol, Eq: 1.2), Pd2(dba)3 (0) (33.9 mg, 37.0 muiotaetaomicron, Eq: 0.02), xantphos (42.9 mg, 74.1 muetaiotaomicron, Eq: 0.04) and Cs2C03 (800 mg, 2.46 mmol, Eq: 1.33) were placed in a microwave vial. Under N2, toluene (10 mL) was added. The resulting mixture stirred in the microwave (Discover CEM) at 130°C for 50 minutes. Fresh Pd2(dpa)3 (33.9 mg, 37.0 muetaiotaomicron, Eq: 0.02) and xantphos (42.9 mg, 74.1 muetaiotaomicron, Eq: 0.04) were added and the mixture stirred in the microwave (discover CEM) at 130°C for 60 minutes. The solvent was pipetted off onto a column for purification by flash chromatography (40g Si02, hexanes/EtOAc 0-40percent EtOAc) to give 7-cyclopentyl-7,8-dihydro-5H-6,9-dioxa-3-aza-phenanthren-10-one as light yellow solid (103mg, 20percent yield). H NMR (CDC13) delta: 8.81 (d, J = 5.3 Hz, 1H), 8.73 (s, 1H), 8.08 - 8.16 (m, 1H), 4.99 (d, J = 14.1 Hz, 1H), 4.75 (dt, J = 14.2, 2.8 Hz, 1H), 3.53 - 3.61 (m, 1H), 2.56 - 2.73 (m, 2H), 2.06 - 2.18 (m, 1H), 1.89 - 2.00 (m, 1H), 1.76 - 1.87 (m, 1H), 1.57 - 1.75 (m, 5H), 1.46 - 1.56 (m, 1H), 1.26 - 1.38 (m, 1H). MS calcd. for Ci6Hi7N03 [(M+H)+] 272.3, obsd. 272. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 80℃; for 3h;Inert atmosphere; | To a solution of 3-bromo-isonicotinic acid methyl ester (648 mg, 3.00 mmol) in DMF (6 ml) are added bis(triphenylphosphine)-palladium(ll)-chloride (2 0 mg, 0.30 mmol), copper(l) iodide (17.1 mg, 0.090 mmol), triethylamine (1.25 ml, 9.00 mmol) and 1-tert-butyl-4-ethynyl-benzene (570 mg, 3.60 mmol). The resulting dark brown solution is flushed with nitrogen, heated to 80°C and stirred in a closed reaction vial at this temperature for 3 hours. The reaction mixture is allowed to cool to room temperature and reduced in volume under vacuum. The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to give 3-(4-tert-butyl-phenylethynyl)- isonicotinic acid methyl ester as brown oil; HPLC/MS 2.28 min (A), [M+H] 294. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | 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 100℃;Inert atmosphere; | Preparation 52C 3-[(1-methyl-1H-pyrrolo[2,3-b]pyridine-3-yl)amino]pyridine-4-carboxylate To a suspension of Preparation 52B (208 mg, 1.4 mmol), methyl 3-bromo-isonicotinate (350 mg, 1.6 mmol), Cs2CO3 (887 mg, 2.7 mmol), and Xantphos (118 mg, 0.20 mmol) in dioxane (20 mL) was added Pd2(dba)3 (62 mg, 0.068 mmol) under N2 at rt. The suspension was heated at 100° C. overnight. Solids were removed by filtration, and the solution was concentrated and purified by prep-HPLC to give 80 mg (15percent) of the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): delta 3.97 (3H, s), 4.09 (3H, s), 7.22 (1H, dd, J=4.8, 7.6 Hz), 7.60 (1H, s), 7.91 (1H, d, J=8.0 Hz), 8.03 (1H, d, J=9.2 Hz), 8.14 (1H, s), 8.22 (1H, d, J=5.6 Hz), 8.39 (1H, d, J=5.2 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | 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 20℃;Inert atmosphere; | General procedure: 3-iodo-2-methyl-2H-indazole (300 mg, 14percent) was isolated as the minor isomer eluting secondTo a suspension of compound Preparation 1A (100 mg, 0.39 mmol), methyl-3-aminoisonicotinate (83 mg, 0.54 mmol), Cs2CO3 (176 mg, 0.54 mmol), and Xantphos (68 mg, 0.12 mmol) in dioxane (10 mL) was added Pd2(dba)3 (36 mg, 0.039 mmol) under N2 at rt. The suspension was heated at 110° C. overnight. The reaction was filtered and concentrated. Purification by silica gel chromatography (20percent-60percent EtOAc/hexanes) gave 75 mg (69percent) of the title compound as a yellow solid. The title compound was prepared in 23percent yield from <strong>[59786-31-1]methyl 3-bromoisonicotinate</strong> and Preparation 57B according to the general procedure for Preparation 1A. 1H NMR (400 MHz, CD3OD): delta 0.98 (3H, t, J=7.2 Hz), 1.90-1.96 (2H, m), 4.08 (3H, s), 4.23 (2H, t, J=6.8 Hz), 7.03-7.06 (2H, m), 7.50-7.56 (2H, m), 7.99-8.02 (2H, m), 8.20 (1H, d, J=5.2 Hz). [M+H] calc'd for C18H18FN3O2, 328. found, 328 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | 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 116℃; for 1.5h;Inert atmosphere; Microwave irradiation; | To a suspension of <strong>[59786-31-1]methyl 3-bromoisonicotinate</strong> (220 mg, 1.02 mmol), 3-amino-6-fluoro-1-methyl-indazole (220 mg, 1.33 mmol), Cs2CO3 (500 mg, 1.53 mmol), and Xantphos (89 mg, 0.15 mmol) in dioxane (5 mL) was added Pd2(dba)3 (47 mg, 0.051 mmol) under N2 at rt. The suspension was heated at 116° C. in a microwave for 90 min. The reaction was filtered and concentrated. Purification by silica gel chromatography (10percent-40percent EtOAc/DCM) gave 228 mg (75percent) of the intermediate ester as a yellow solid. The ester was hydrolyzed in 1N NaOH (1 mL) in MeOH (5 mL) at 35° C. for 1 h. The solution was neutralized with HOAc and concentrated. The residue was taken up in water, sonicated, and the solid was collected by filtration. The solid was taken up in MeOH and collected by filtration to give 148 mg (71percent) of the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): delta 3.96 (3H, s), 7.02 (1H, td, J=8.9, 1.6 Hz), 7.50 (1H, d, J=8.2 Hz), 7.63 (1H, dd, J=8.7, 5.0 Hz), 7.79 (1H, d, J=5.0 Hz), 8.18 (1H, d, J=5.0 Hz), 9.67 (1H, s), 10.59 (1H, br s), 14.20 (1H, br s). [M+H] calc'd for C14H11FN4O2, 287. found 287. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | 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 128℃; for 1h;Inert atmosphere; Microwave irradiation; | Methyl 3-bromoisonicotinate (930 mg, 4.3 mmol), Preparation 60A (980 mg, 4.3 mmol), and cesium carbonate (3.5 g, 10.8 mmol) were combined in dioxane (12 mL) under N2 in a microwave vial. Pd2dba3 (197 mg, 0.22 mmol) and Xantphos (373 mg, 0.65 mmol) were added, and the reaction stirred at 128 oc in the microwave for 1 h. As there was very little conversion by HPLC at this point, the reaction was heated an additional 2 hat 148 °C. The reaction was filtered, washing with acetone, and concentrated in vacuo. Purification by silica gel chromatography (20-80percent EtOAc/hexanes) gave 256 (18percent) of the title compound light yellow oil. 1H NMR (400 MHz, CDCh): 8 8.32 (s, 1H), 7.91 (d,1H, J = 5.2 Hz), 7.62 (dd, 1H, J = 5.2, 0.5 Hz), 7.56 (br s, 1H), 7.16 (d, 1H, J = 8.5 Hz),6.74 (dd, 1H, J = 8.4, 2.7 Hz), 6.65 (d, 1H, J = 2.7 Hz), 3.89 (s, 3H), 3.78 (s, 3H), 3.52-3.58 (m, 1H), 3.37-3.43 (m, 1H), 3.11-3.15 (s, 1H), 2.77-2.82 (m, 2H), 1.76-1.95 (m, 4H). [M+H] calc'd for C19HzzNz03, 327; found 327. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | 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 116℃; for 1h;Inert atmosphere; Microwave irradiation; Sealed tube; | Methyl 3-bromoisonicotinate (220 mg, 1.02 mmol), 4-fluorobenzylamine (132).lL, 1.22 mmol), tris(dibenzylideneacetone)dipalladium(O) (47 mg, 0.051 mmol), Xantphos (89 mg, 0.153 mmol), and cesium carbonate (500 mg, 1.53 mmol) werecombined in dioxane (4 mL) under N2 in a sealed microwave tube. The reaction mixturewas heated at 116 oc in a microwave for 1 h. The mixture was then filtered, washing with DCM, to remove solids. The solution was concentrated in vacuo and purified bysilica gel chromatography (20-50percent EtOAc/hexanes) to give 228 mg (88percent) of the title compound as a white solid. 1H NMR (400 MHz, CDCh): delta 8.18 (s, 1H), 7.93 (d, 1H, J =5.0 Hz), 7.79 (br s, 1H), 7.63 (d, 1H, J = 5.0 Hz), 7.27-7.34 (m, 2H), 7.03 (t, 2H, J = 8.6Hz), 4.47 (d, 2H, J = 5.6 Hz), 3.89 (s, 3H). [M+H] calc'd for C14H13FN2O2, 261; found 261. |
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 128℃; for 1.5h;Inert atmosphere; Microwave irradiation; | Methyl 3-bromoisonicotinate (1.34 g, 6.2 mmol) 1,2,3,4-tetrahydro-1- naphthalenemethanamine (1.0 g, 6.62 mmol), and cesium carbonate (3.0 g, 9.43 mmol) were combined in dioxane (12 mL) under N2 in a microwave vial. Pd2dba3 (284 mg,0.31 mmol) and Xantphos (538 mg, 0.93 mmol) were added, and the reaction stirred at 128 oc in the microwave for 90 min. The reaction was filtered, washing with acetone,and concentrated in vacuo. Purification by silica gel chromatography (20-80percent EtOAc/hexanes) gave 826 (45percent) ofthe title compound as a light orange solid. 1H NMR(400 MHz, CDCh): 8 8.32 (s, IH), 7.91 (d, IH, J = 5.1 Hz), 7.64 (d, IH, J = 5.0 Hz),7.59 (s, IH), 7.24 (d, IH, J = 4.9 Hz), 7.11-7.19 (m, 3H), 3.89 (s, 3H), 3.56-3.63 (m, IH),3.39-3.47 (m, IH), 3.18-3.21 (s, IH), 2.78-2.84 (m, 2H), 1.77-1.97 (m, 4H). [M+H]calc'd for C1sHzoNzOz, 297; found 297. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Compounds 19 and 20 were synthesized by a method similar to that illustrated in paragraph [0313] above except that the starting compound was 2-(2-oxopropyl)isoindoline- 1,3-dione. [0340] Synthesis of 3-((l,3-Diphenyl-lH-pyrazol-5-yl)amino)isonicotinic acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4%; 4% | To a stirred solution of mixture of 4-(4-fluorophenyl)- 1 - methyl- 1H- pyrazol-3 -amine and 4-(4-fluorophenyl)-l -methyl- lH-pyrazol-5-amine (1.5 g, 7.85 mmol) in 1,4-dioxane (20 mL), methyl 3-aminoisonicotinate (3.39 g, 15.70 mmol) and cesium carbonate (3.57 g, 10.99 mmol) was added and purged with argon for 10 min, followed by the addition of xantphos (1.36 g, 2.35 mmol) and purged with argon for an additional 5 min. Pd2(dba)3 (0.719 g, 0.785 mmol) was added and stirred at 100 °C for 12 h. Progress of the reaction was monitored by TLC. Upon completion the reaction mixture was filtered through a bed of celite and evaporated to dryness. The residue was taken in ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The crude product was purified by preparative HPLC to afford methyl 3-((4-(4- fluorophenyl)- 1 -methyl- lH-pyrazol-3-yl)amino)isonicotinate (O. lg, 4percent) and 3 methyl 3-((4- (4-fluorophenyl)- 1 -methyl- lH-pyrazol-5-yl)amino) isonicotinate (0.1 g, 4percent) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a mixture of methyl 3-((3-(3-chlorophenyl)-l-(l,4- dioxaspiro[4.5]decan-8-yl)lH-pyrazol-5-yl)amino) isonicotinate and methyl 3-((5-(3- chlorophenyl)-l-(l,4-dioxaspiro[4.5]decan-8-yl) -lH-pyrazol-3-yl)amino)isonicotinate (2.5 g, 5.34 mmol) in dioxane:HCl (25 mL) and reaction was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC and LCMS. Upon completion the reaction was quenched with sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were washed with sodium bicarbonate solution, dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain a crude residue. The residue (1 g, 2.358 mmol) and 2-methylpropane-2-sulfinamide(0.428 g, 3.53mmol) in DCE (10 mL), TiOipr3( 4.02g, 14.1mmol) was added and stirred at room temperature for 30 min. Sodium borohydride(0.178 g, 4.71mmol) was added and stirred at room temperature for 12 h. Upon completion the reaction was diluted with ice water and extracted with ethyl acetate. The combined organic layers were washed with sodium bicarbonate solution, dried over anhydrous Na2S04 and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to afford the mixture of two isomers compound (0.5 g, 38.16percent) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of methyl 3-((l-(l-(tert-butoxycarbonyl)piperidin-4-yl) -3- methyl-lH-pyrazol-4-yl)amino)isonicotinate (1.0 g, 2.40 mmol) in DCM (10 mL) was added trifluoroacetic acid (3.07 g, 2.0 mL). The reaction mixture was stirred at 15 °C for lh. Then concentrated to give the methyl 3-(3-methyl-l-(piperidin-4- yl)-lH-pyrazol-4-yl (0729) amino)isonicotinate (1.2 g , Yield: 92percent) as 2 TFA salt which was used directly in next reaction without further purification. ESI-LCMS (m/z): 316.1 [M+1]. Same protocol used for methyl 3-((5-methyl-l-(piperidin-4-yl)- lH-pyrazol-4-yl)amino) isonicotinate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40.3% | To a solution of methyl-3-bromoisonicotinate (2.337 g, 10.82 mmol) in anhydrous acetonitrile (100 ml, degassed by nitrogen gas) was added bis(triphenylphosphine) palladium (II) chloride (0.633 g, 0.901 mmol) at 25°C. The reaction mixture was heated and stirred at 80 °C for 10 min and to this warmed reaction mixture was added diisopropylethyl amine (9.45 ml, 54.10 mmol) followed by the addition of a solution of (R)-4-(4-(3-ethynylcyclopent-2-en- l-yl)piperazin- l- yl)benzonitrile (Compound lj -Prepared according to the procedure given in Example 1; step 10, 2.5 g, 9.01 mmol) in acetonitrile (25 ml). The reaction mixture was heated at same temperature for 18 hrs. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (200 ml), washed with water (100 ml). The aqueous layer was again extracted with ethyl acetate (100 ml) and the combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give crude intermediate, which was purified by flash column chromatography over silica gel (100 - 200 mesh) using 70- 100percent ethyl acetate in hexane as eluent to obtain title compound (1.5 g, 40.3percent yield). NMR (400 MHz, CDC13) delta 8.89 - 8.81 (m, 1H), 8.70 - 8.60 (m, 1H), 7.81 - 7.76 (m, 1H), 7.53 (d, J = 8.6 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H), 6.31 (s, 1H), 3.99 (s, 3H), 3.54 - 3.38 (m, 4H), 2.85 - 2.63 (m, 6H), 2.24 - 2.02 (m, 3H). MS: m/z 413 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51.4% | With tris-(dibenzylideneacetone)dipalladium(0); | Step E: 6-Bromo-1-[(4-methoxycarbonyl-pyridin-3-ylamino)-methyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester To a solution of 1-aminomethyl-6-bromo-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (2.5 g, 7.35 mmol) in toluene under N2 atmosphere was added <strong>[59786-31-1]3-bromoisonicotinic acid methyl ester</strong> (1.98 g, 8.82 mmol), Pd2(dba)3 (340 mg, 0.37 mmol), Xant-phos (260 mg, 0.45 mmol) and Cs2CO3 (3.36 g, 10.3 mmol). The reaction mixture refluxed overnight. Upon completion, the reaction mixture was filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by flash column chromatography (EA:PE=1:4) to afford the title compound (1.8 g, 51.4percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19% | With tris-(dibenzylideneacetone)dipalladium(0); | Step F: 5-Bromo-1-[(2-methoxycarbonyl-phenylamino)-methyl]-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester To a solution of 1-aminomethyl-5-bromo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (1.2 g, 3.68 mmol) in toluene under N2 atmosphere was added <strong>[59786-31-1]3-bromoisonicotinic acid methyl ester</strong> (0.87 g, 4.02 mmol), Pd2(dba)3 (169 mg, 0.18 mmol), Xant-phos (319 mg, 0.55 mmol), and Cs2CO3 (1.68 g, 5.15 mmol). The reaction mixture was stirred at reflux overnight. Upon completion, the reaction was concentrated in vacuo, and residue was purified by flash chromatography (EA:PE=1:2) to afford the title compound (0.4 g, 19percent). |
Tags: 59786-31-1 synthesis path| 59786-31-1 SDS| 59786-31-1 COA| 59786-31-1 purity| 59786-31-1 application| 59786-31-1 NMR| 59786-31-1 COA| 59786-31-1 structure
[ 882499-87-8 ]
Methyl 2-amino-5-bromo-4-pyridinecarboxylate
Similarity: 0.92
[ 1000339-23-0 ]
2-Amino-5-bromoisonicotinic acid
Similarity: 0.85
[ 882499-87-8 ]
Methyl 2-amino-5-bromo-4-pyridinecarboxylate
Similarity: 0.92
[ 882499-87-8 ]
Methyl 2-amino-5-bromo-4-pyridinecarboxylate
Similarity: 0.92
[ 1000339-23-0 ]
2-Amino-5-bromoisonicotinic acid
Similarity: 0.85
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P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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