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CAS No. : | 33216-52-3 | MDL No. : | MFCD00051685 |
Formula : | C5H2Cl3N | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | KKWRVUBDCJQHBZ-UHFFFAOYSA-N |
M.W : | 182.44 | Pubchem ID : | 3786531 |
Synonyms : |
3,4,5-threechlorine pyridine
|
Num. heavy atoms : | 9 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 39.27 |
TPSA : | 12.89 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) : | -5.47 cm/s |
Log Po/w (iLOGP) : | 2.04 |
Log Po/w (XLOGP3) : | 2.74 |
Log Po/w (WLOGP) : | 3.04 |
Log Po/w (MLOGP) : | 2.28 |
Log Po/w (SILICOS-IT) : | 3.35 |
Consensus Log Po/w : | 2.69 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.19 |
Solubility : | 0.118 mg/ml ; 0.000645 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.67 |
Solubility : | 0.394 mg/ml ; 0.00216 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.87 |
Solubility : | 0.0245 mg/ml ; 0.000134 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.46 |
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 |
---|---|---|
90% | With dihydrogen peroxide; methyltrioxorhenium(VII); In dichloromethane; water; at 24℃; for 48h; | lntermediate-3 (prepared by Step 2.1)Formation of N-oxide3,4,5-Trichloropyridine 1 -oxide. A mixture of <strong>[33216-52-3]3,4,5-trichloropyridine</strong> (1.82 g, 10 mmol) and methylrhenium(VII) trioxide (12.5mg, 0.05 mmol ) in DCM (4 ml.) was treated with 30% H2O2 (2 ml_), The mixture was stirred for 48 h at 24 0C (water bath), Heptane was added to the reaction mixture and it was cooled to 0 0C. A precipitate was formed, which was filtered off and washed with cold heptane and a small amount of DCM. Finally the solid was dried to give the product (1.8 g, 90%). LC-MS (an20p5): Rt 0.8 min, m/z 198 [M + H]+. |
74% | With dihydrogen peroxide; In dichloromethane; at 0℃; | To a stirred solution of 3,4,5- trichloropyridine (1 g, 5.45 mmol) in dichloromethane (20 mL) at 0 0C, was added dropwise a 30% hydrogenperoxide solution (1.2 mL, 10.9 mmol). Following the addition, the temperature was allowed to rise to room temperature and was stirred for 15 hours. The reaction mixture was diluted with dichloromethane (50 mL) and was washed with water (10 mL) and then by brine (25 mL x 2). The organic phase was dried (Na2SO4), concentrated under vacuum to afford the title product as a white solid (0.8 g, 74% yield). 1H NMR (400 MHz, d6-OMSO) delta: 8.78 (2H, s). MS m/z: 197.90 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
265 mg (28%) | With NaH; In N,N-dimethyl-formamide; mineral oil; | A. 4-(3,5-Dichloro-pyridin-4-yloxy)-piperidine-1-carboxylic acid tert-butyl ester. To a stirred solution of 828 mg (4.12 mmol) of tert-butyl-4-hydroxy-1-piperidinecarboxylate in 10 mL of dry DMF was added 165 mg of 60% NaH in mineral oil (4.12 mmol). After stirring at room temperature for 10 min, 500 mg (2.74 mmol) of <strong>[33216-52-3]3,4,5-trichloropyridine</strong> was added. The mixture was stirred at 80 C. overnight and then partitioned between EtOAc (50 mL) and water (20 mL) and separated. The aqueous layer was further extracted with EtOAc (2*30 mL). The combined organic layers were washed with water (25 mL), brine, dried over Na2SO4, and the solvent was removed under reduced pressure. Column chromatography (silica, 60-100% CH2Cl2/hexanes) gave 265 mg (28%) of desired product. MS (electrospray): exact mass calculated for C15H20Cl2N2O3, 346.09; m/z found, 369.1 [M+Na]+. 1H NMR (CDCl3, 400 MHz): 8.45 (s, 2H), 4.66 (m, 1H), 3.90-3.80 (br m, 2H), 3.26 (m, 2H), 1.96-1.83 (br m, 4H),1.47 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | at 90℃; for 2.5h;Neat (no solvent); | l-(3,5-dichloropyridin-4-yl)-l,4-diazepane; 1,4-Diazepane (5.49g, 54.8 mmol) and <strong>[33216-52-3]3,4,5-trichloropyridine</strong> (2g, 3.0 mmol) were combined without solvent, and the mixture heated with stirring at 90 0C for 2.5 hours. The reaction mixture was cooled to room temperature and the product purified by flash column chromatography (CombiFlash Companion , 4Og silica column, eluting with a 10:1 mixture of DCM and methanol) to give the title compound as a yellow oil (2.06 g, 76% ); 1H NMR (400 MHz, CDCl3) delta 1.88 - 1.94 (2H, m), 3.02 - 3.04 (2H, m), 3.09 (2H, t), 3.34 - 3.37 (4H, m), 8.39 (2H, s), m/z 246 (M+H)+ [I]. |
76% | at 90℃; for 2.5h;Heating / reflux; Neat (no solvent); | Intermediate A: l-(3,5-dichlororhoyridin-4-yl)-l,4-diazepane <n="31"/>1,4-diazepane (5.49g, 54.8 mmol) and <strong>[33216-52-3]3,4,5-trichloropyridine</strong> (2g, 3.0 mmol) were combined without solvent and the mixture heated with stirring at 90 0C for 2.5 hours. The reaction mixture was cooled to room temperature and the product purified by flash column chromatography (CombiFlash Companion , 4Og silica column, eluting with a 10:1 mixture of DCM and methanol) to give the title compound as a yellow oil (2.06 g, 76% ); 1H NMR (400 MHz, CDCl3) deltal.88 - 1.94 (2H, m), 3.02 - 3.04 (2H, m), 3.09 (2H, t), 3.34 - 3.37 (4H, m), 8.39 (2H, s), m/z 246 (M+H)+ [I]. |
72% | at 90 - 100℃; for 2h; | General procedure: 3.1 Preparation of Compound 3 Compound 1 (5.00 g, 27.50 mmol) and compound 2 (13.75 g, 137.50 mmol) were combined without solvent and the mixture was stirring at 90-100 C. for 2 h. The mixture was diluted with DCM (250 mL) and washed with NH4Cl (100 mL×2). The combined organic layer was concentrated to give the crude product, which was purified by silica chromatography gel to give the desired product (5.80 g, 72%). 1H NMR (400 MHz, CDCl3): delta ppm: 8.43 (s, 2H), 3.40 (m, 4H), 3.16 (t, J=5.6 Hz, 2H), 3.09 (m, 2H), 1.99 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | at 100℃; for 64h;Heating / reflux; | (RS) tert-butyl 4-(3,5-dichloropyridin-4-yl)-2-methyl-piperazine-l-carboxylate(RS) tert-butyl 2-methylpiperazine-l-carboxylate (2.2Og, 10.98 mmol) and 3,4,5 trichloropyridine were combined and heated at 100 0C for 64 hours. The reaction mixture was cooled to ambient temperature and purified by flash column chromatography (4Og silica column, eluting with DCM containing 0 - 10% of methanol) to give the title compound as a brown oil, 5.87 g, 100 %, 1H NMR (400 MHz, DMSOd6) delta 1.22 (3H, d), 1.42 (9H, s), 2.74- 3.09 (5H, m), 3.76 - 3.77 (2H, m), 7.96 (2H, s), m/z 346 (M+H)+ [I]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4-Amino-8-(cyclopentyloxy)-7-methoxyquinolin-2(lH)-one (340 mg, 1.24 mmol) was added in 3 portions over 5 min to a mixture of sodium hydride (110 mg, 60%, 2.75 mmol) and DMSO (4 mL) at rt under N2. After 5 min, 3,4,5- trichloropyridine (271 mg, 1.49 mmol) was added. After 19 h, more sodium hydride (100 mg, 60%, 2.5 mmol) was added followed by more <strong>[33216-52-3]3,4,5-trichloropyridine</strong> (250 mg, 1.37 mmol). After an additional 4 h, the reaction was poured into IM KH2PO4 (75 mL) and stirred for 5 min. The solids were filtered, washed with water (25 mL), and then purified by reverse-phase HPLC (3:7 - >1 :0; acetonitrile: water). In some cases, additional purification by silica gel chromatography (l :0?9:l; dichlormethane methanol) was needed to give 8-(cyclopentyloxy)-4-(3,5- dichloropyridin-4-ylamino)-7-methoxyquinolin-2(lH)-one: 1H NMR (400 MHz, DMSO-d6): delta 9.39 (s, IH), 8.86 (s, IH), 8.76 (s, 2H), 7.87 (d, IH), 7.06 (d, IH), 4.97 (m, IH), 4.78 (s, IH), 3.90 (s, 3H), 1.83-1.48 (m, 8H); MS (ESI): 419.7. | ||
Step 7 4-Amino-8-(cyclopentyloxy)-7-methoxyquinolin-2(1H)-one (340 mg, 1.24 mmol) was added in 3 portions over 5 min to a mixture of sodium hydride (110 mg, 60%, 2.75 mmol) and DMSO (4 mL) at rt under N2. After 5 min, <strong>[33216-52-3]3,4,5-trichloropyridine</strong> (271 mg, 1.49 mmol) was added. After 19 h, more sodium hydride (100 mg, 60%, 2.5 mmol) was added followed by more <strong>[33216-52-3]3,4,5-trichloropyridine</strong> (250 mg, 1.37 mmol). After an additional 4 h, the reaction was poured into 1M KH2PO4 (75 mL) and stirred for 5 min. The solids were filtered, washed with water (25 mL), and then purified by reverse-phase HPLC (3:7?1:0; acetonitrile:water). In some cases, additional purification by silica gel chromatography (1:0?9:1; dichlormethane:methanol) was needed to give 8-(cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one: 1H NMR (400 MHz, DMSO-d6): delta 9.39 (s, 1H), 8.86 (s, 1H), 8.76 (s, 2H), 7.87 (d, 1H), 7.06 (d, 1H), 4.97 (m, 1H), 4.78 (s, 1H), 3.90 (s, 3H), 1.83-1.48 (m, 8H); MS (ESI): 419.7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With potassium tert-butylate; In N,N-dimethyl-formamide; at 80℃; | Example 22; l-(5-tert-Butyl-3-(thiomorrhoholine-l,l-dioxide-4-carbonyl)thiophen-2-yl)-3-(4-(3,5- dichloropyridin-4-yloxy)phenyl)urea [0256] 4-(3,5-Dichloropyridin-4-yloxy)benzenamine. To a vial containing 4-aminophenol(2.185 g, 20.0 mmol, 1 equiv.) in 60 mL DMF was added t-BuOK (2.468 g, 22.0 mmol, 1.1 equiv.) followed by <strong>[33216-52-3]3,4,5-trichloropyridine</strong> (3.653 g, 20.0 mmol, 1 equiv.). The flask was fitted with a condenser and the mixture was stirred at 8O0C under nitrogen. After the reaction mixture was cooled, diluted with ethyl acetate (600 mL) and washed with water (3x150 mL) and brine. The organic layer was dried over Na2SO4, filtered and solvent was removed under vacuum. The crude material was absorbed onto silica gel and purified by flash column (7.5x12 cm silica) using 2500 mL 1:1 hexanes:ethyl acetate giving 4.6348 g (91%) of product as a light yellow crystaline solid.[0257] 5-tert-Butyl-2-(3-(4-(3,5-dichloropyridin-4-yloxy)phenyl)ureido)thiophene-3- carboxylic acid. [0259] A vial containing 6-fert-butyl-lH-thieno[2,3-J][l,3]oxazine-2,4-dione and 4-(3,5-Dichloropyridin-4-yloxy)benzenamine in THF was capped and stirred at 8O0C. After about 6h, the reaction was cooled and enough solvent was removed under vacuum to leave an oil residue. Dichloromethane was added (ca. 10 mL) to precipitate product and the mixture was allowed to sit at least Ih. The mixture was filtered (filter paper; vacuum suction) and the solids washed with dichloromethane. The solids on the filter and EPO <DP n="68"/>remaining in the flask were collected by dissolving in acetone. Solvent was removed under vacuum to give 89% of the product as a white fine crystaline solid.[0260] The reaction was performed as above (method 1) to give 91% of the desired product as a light yellow oil. 1H NMR (400 MHz, CD3ODZCDCl3): delta 8.50 (s, 2H), 7.39 (d, J=9.2 Hz, 2H), 6.76 (d, J-9.0 Hz, 2H), 6.47 (s, IH), 4.08 (t, J=4.9 Hz, 4H), 3.12 (t, J-5.1 Hz, 4H), 1.31 (s, 9H).[0261] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | In dimethyl sulfoxide; at 20℃; for 24h; | EXAMPLE 125 1-[4-(6-Methoxypyridin-3-yl)-5-methyl-4H-1,2,4-triazol-3-yl]azetidin-3-ol A mixture of the product of preparation 82 (135 mg, 0.52 mmol) and <strong>[33216-52-3]3,4,5-trichloropyridine</strong> (94 mg, 0.52 mmol) in dimethylsulfoxide (5 mL) was stirred at room temperature for 24 hours. The reaction mixture was then partitioned between dichloromethane and water and the organic layer was separated, washed with brine, dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluding with dichloromethane:methanol, 100:0 to 95:5, afforded the title compound as a crystalline solid in 43% yield, 90 mg. 1H NMR(400 MHz, CDCl3) delta: 2.21(s, 3H), 4.00(s, 3H), 4.07(m, 2H), 4.14(m, 2H), 4.96(m, 1H), 6.88(d, 1H), 7.50(dd, 1H), 8.10(d, 1H); LRMS ESI m/z 409 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In 5,5-dimethyl-1,3-cyclohexadiene; ethyl acetate; | Step 1 Synthesis of ethyl 1-(3,5-dichloropyridine-4-yl)-4-piperidinecarboxylate: 2.0 g (11 mmol) of <strong>[33216-52-3]3,4,5-trichloropyridine</strong>, 1.7 g (11 mmol) of ethyl piperidine-4-carboxylate and 4.6 ml (33 mmol) of triethylamine were stirred in 20 ml of xylene under heating under reflux for 10 hours. After the treatment with ethyl acetate as the extraction solvent in an ordinary manner, the obtained crude product was purified by the silica gel column chromatography to obtain the title compound. Yield: 800 mg (2.6 mmol) (24%) H-NMR (CDCl3) delta 1.28 (3H, t), 1.80-2.03 (4H, m), 2.44-2.58 (1H, m), 3.23-3.44 (4H, m), 4.17 (2H, q), 8.32 (2H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.23 g (74%) | With NaH; ammonium chloride; In dimethyl sulfoxide; | Example 16 3,5-Dichloro-4-(-cis-tert-butylcyclohexyloxy)pyridine A mixture of 1.82 g (10 mmol) of <strong>[33216-52-3]3,4,5-trichloropyridine</strong>, 2.03 g (13 mmol) of 4-cis-tert-butyl-cyclohexanol and 15 ml of DMSO is added dropwise at 25 C. to 0.36 g (12 mmol) of NaH (80% strength) in 25 ml of DMSO. The mixture is then stirred at 70 C. for 20 hours. For working up, saturated ammonium chloride solution is added at 20-25 C. and the mixture is extracted with ethyl acetate. The reaction product is purified by chromatography (SiO2; hexane/diisopropyl ether [1:3]). Yield: 2.23 g (74%); 1 H-NMR (CDCl3)=8.4 (s, 2H), 4.3 (m, 1H), 0.9-2.3 (m, 9H), 0.8 (s, 9H) ppm |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic acid; In toluene; | Alternatively, a suspension of 3-cyclopentyloxy-4-methoxybenzamide (2.58 g; that is prepared as described in Reference Example 73) in dry toluene (40 mL) is heated at reflux and treated with potassium t-butoxide (1.4 g), followed by <strong>[33216-52-3]3,4,5-trichloro-pyridine</strong> (1.82 g). The mixture is then heated at reflux for 3 hours and 45 minutes, and is then treated with a further quantity of potassium t-butoxide (1.4 g) and heated at reflux for a further period of 7 hours. The mixture is allowed to cool and is then filtered. The filtrate is evaporated and the resulting residue is extracted with aqueous sodium hydroxide solution (2M). The alkaline solution is then acidified by treatment with acetic acid, and the solid which separates is collected by filtration, washed with water and dried, to give N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxy-benzamide (2.09 g) in the form of a buff solid, m.p. 153-155 C. | |
With acetic acid; In toluene; | Alternatively, a suspension of 3-cyclopentyloxy-4-methoxybenzamide (2.58 g; that is prepared as described in Reference Example 73) in dry toluene (40 mL) is heated at reflux and treated with potassium t-butoxide (1.4 g), followed by <strong>[33216-52-3]3,4,5-trichloro-pyridine</strong> (1.82 g). The mixture is then heated at reflux for 3 hours and 45 minutes, and is then treated with a further quantity of potassium t-butoxide (1.4 g) and heated at reflux for a further period of 7 hours. The mixture is allowed to cool and is then filtered. The filtrate is evaporated and the resulting residue is extracted with aqueous sodium hydroxide solution (2M). The alkaline solution is then acidified by treatment with acetic acid, and the solid which separates is collected by filtration, washed with water and dried, to give N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide (2.09 g) in the form of a buff solid, m.p. 153-155 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Example 2 4-O-Benzylhydroxylamino-3,5-dichloropyridine hydrochloride Prepared analogously to Example 1 from <strong>[33216-52-3]3,4,5-trichloropyridine</strong> and O-benzylhydroxylamine. Yield: 78%; 1 H-NMR (100 MHz, CDCl3)=8.4 (s, 2H), 7.6 (s, 1H), 7.4 (s, 5H), 5.0 (s, 2H) ppm |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.85 g (79.5%) | With NaH; ammonium chloride; In dimethyl sulfoxide; | Example 49 3,5-Dichloro-4-[4-cis-(1,1,3,3-tetramethylbut-1-yl)cyclohexyloxy]pyridine A mixture of 1.82 g (10 mmol) of <strong>[33216-52-3]3,4,5-trichloropyridine</strong>, 2.76 g (13 mmol) of 4-cis-(1,1,3,3-tetramethylbut-1-yl)cyclohexanol and 15 ml of DMSO is added dropwise at 25 C. to 0.36 g (12 mmol) of NaH (80% strength) in 25 ml of DMSO. The mixture is then stirred at 60 C. for 6 hours. For working up, saturated ammonium chloride solution is added at 20 to 25 C. and the mixture is extracted with ethyl acetate. The reaction product is purified by chromatography (SiO2; diisopropyl ether). Yield: 2.85 g (79.5%) 1 H-NMR (CDCl3)=8.4 (s, 2H), 4.9 (m, 1H), 1.0 to 2.2 (m, 9H), 1.3 (s, 2H), 0.9 and 0.95 (2s, 15H) ppm |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Example 3 4-O-Benzylhydroxylamino-3,5-dichloropyridine Prepared analogously to Example 1 from <strong>[33216-52-3]3,4,5-trichloropyridine</strong> and O-benzylhydroxylamine. Yield: 78% 1 H-NMR (100 MHz, CDCl3)=8.4 (s, 2H), 7.6 (s, 1H), 7.4 (s, 5H), 5.0 (s, 2H) ppm |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1) Preparation of 3,5-Dichloro-4-hydrazinopyridine The procedure of Example 12-(1) was repeated, except for replacing 2-chloro-3-methoxypyridine with 5.0 g of <strong>[33216-52-3]3,4,5-trichloropyridine</strong>, to give 2.85 g of the title compound. 1H-NMR (CDCl3) delta: 4.16 (brs, 2H), 6.09 (brs, 1H), 8.23 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | A solution of 3- (5-HYDROXY-1 H-INDOL-2-YL)-1H-QUINOXALIN-2-ONE (100 mg, 0.36 MMOL) and potassium TERT-BUTOXIDE (44.5 mg, 0.40 MMOL) in DMF (2 mL) was stirred at rt for 2 h. To the solution, was added 3,4, 5-TRICHLOROPYRIDINE (65.8 mg, 0.36 MMOL) and K2CO3 (29.9 mg, 0.22 MMOL). The mixture was heated to 100 C overnight. The reaction was allowed to cool to rt and poured into water (20 mL). The crude product was precipitated as a yellow solid. The solid was filtered, washed with water and dried to give 120 mg (79%) of product. 1H NMR (400 MHz, DMSO) 8 12. 60 (b, 1H), 11.69 (s, 1H), 8.75 (s, 2H), 7.81 (d, J = 8.8 Hz, 1 H), 7.73 (s, 1 H), 7.51 (m, 2H), 7.34-7. 32 (m, 2H), 7.05 (s, 1 H), 6.95 (d J =8.8 Hz, 1 H) ; LCMS (ESI-MS) RT = 3.77 ; 423.2 (M+H) +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With triethylamine; In 1-methyl-pyrrolidin-2-one; at 220℃; for 1h;Microwave irradiation; | To a solution of (RS)-3-cyanopyrrolidine (0.12 g, 1.3 mmol) and <strong>[33216-52-3]3,4,5-trichloropyridine</strong> (0.23 g, 1.3 mmol), in NMP (8 ml.) was added triethylamine (0.36 ml_, 2.6 mmol). The mixture was heated at 220 0C for 60 min in a microwave reactor, poured into a saturated solution of sodium hydrogen carbonate (50 ml.) and extracted with EtOAc (2 x 100 ml_). The combined organic extracts were washed with water (50 ml_), brine (50 ml_), dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (CH2CI2, MeOH, 99:1 ) to furnish the title compound as a colourless oil (155 mg, 50%), umax (CHCI3)/ cm"1 3053, 2245, 1558, 1468, 1402; m/z (ESI) Ci0H10CI2N3 requires 242.0246 found [M+H]+ 242.0249. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | To a solution of Lambda/-methylpiperidine-4-carboxamide 5 (26 mg, 0.18 mmol) and 3,4,5- trichloropyridine (33 mg, 0.18 mmol) in NMP (1.5 mL) was added triethylamine (76 muL, 0.54 mmol). The mixture was heated in a microwave reactor at 220 0C for 60 min, cooled to r.t. and then poured into a saturated solution of sodium hydrogen carbonate (50 mL). The solution was extracted with EtOAc (2 x 25 mL), the combined organic extracts were washed with water (50 mL), brine (50 mL), dried (MgSO4) and the solvent was removed under reduced pressure. The crude product was purified by flash column chromatography on silica gel (hexane/ EtOAc, 1 :1 ) to furnish the title compound as a white solid (46 mg, 88%), m.p. 175-177 0C; umax (CHCI3)/ cm"1 3462, 3006, 2853, 1665, 1558, 1385, 1146, 1096; mlz (ESI) Ci2H16CI2N3O requires 288.0665, found [M+H]+ 288.0664. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In 1-methyl-pyrrolidin-2-one; at 220℃; for 1h;Microwave irradiation; | To a solution of ethyl Lambda/-Boc-4-methylpiperidine-4-carboxylate (130 mg, 0.47 mmol) in CH2CI2 (8 ml.) was added trifluoroacetic acid (0.86 ml_, 1 1 mmol) and the reaction stirred at r.t. for 2 hr before evaporation and aziotrope with toluene (2 x 25 ml). The crude was dissolved in NMP (4.3 ml) and <strong>[33216-52-3]3,4,5-trichloropyridine</strong> (135 mg, 0.74 mmol) was added followed by triethylamine (0.42 ml_, 3.0 mmol) and the mixture was heated in a microwave reactor at 220 0C for 60 min. The mixture was poured into a saturated solution of sodium hydrogen carbonate (50 ml.) and extracted with EtOAc (2 x 100 ml_). The combined organic extracts were washed with water (2 x 50 ml_), brine (50 ml_), dried (MgSO4) and concentrated under reduced pressure to give a crude pale brown/orange oil (175 mg). The crude product was purified by flash column chromatography on silica gel (cyclohexane, EtOAc, 99:1-88:12, biotage 25+S) to furnish the title compound as a clear colourless oil (85 mg, 56%), LC-MS (ESI, 4 min) R, 3.36 min, m/z 317 (100%, [M+H]+); m/z (ESI) C14H18N2O2CI2 requires 316.0745, found [M+H]+ 316.0745. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With sodium monohydrogen sulfide x-hydrate; In methanol; at 35℃; for 17h; | Sodium hydrosulfide hydrate (0.248 g, 3.14 mmol) was suspended in anhydrous methanol (10 mL), 3, 4, 5- trichloropyridine (0.475 g, 2.62 mmol) was added and the mixture was stirred at 35 0C for 17 hours. The reaction mixture was filtered to remove solid residues and the filtrate was concentrated to give a solid. The solid was triturated with dichloromethane to afford the title product as a white solid (0.4 g, 76% yield). 1H NMR (400 MHz, J6-DMSO) delta: 7.88 (2H, s). MS m/z: 179.9 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With triethylamine; In dimethyl sulfoxide; at 120℃; for 1.5h;Microwave irradiation; | STEP 3. 2-[l-(3, 5 -DICHLORO-PYRIDTN-4-YL)-AZETIDrN-3 -YL] -5 -METHYL- 1 H- BENZOIMIDAZOLE; [00196] The mixture of 2-azetidin-3-yl-5-methyl-lH-benzoimidazole (450 mg, 2.4 mmol), 3, 4, 5-trichloro-pyridine (438 mg, 2.4 mmol) and Et3N (969 mg, 9.6 mmol) in DMSO (20 ml) was heated at 120 C under microwave for 1.5 h. Then it was diluted with DCM and I¾0. The organic layers were concentrated to give the title compound which was purified by column chromatography and followed by preparative HPLC to afford the pure product 2-[l-(3, 5- dichloro-pyridin-4-yl)-azetidin-3-yl]-5-methyl-lH-benzoimidazole (800 mg, yield 55%). [M+1] 333. IC50 (uM) 0.21. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.03 g | With potassium carbonate; In N,N-dimethyl-formamide; at 25℃; for 18h; | A mixture of <strong>[33216-52-3]3,4,5-trichloropyridine</strong> (566 mg, 3.1 mmol), 4-trifluoromethoxy benzenethiol (662 mg, 3.4 mmol), anhydrous potassium carbonate (643 mg, 4.7 mmol) and anhydrous DMF (6 mL) was stirred at 25 C for 18 h. The resulting mixture was partitioned between ethyl acetate and water, the organic phase was washed with water and saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous magnesium sulfate and concentrated to give the title compound, a compound of the present invention, as a yellow oil (1.03 g). H NMR (CDCI3) delta 8.55 (s, 2H), 7.28 (d, 2H), 7.14 (d, 2H). 19F NMR (CDC13) 5 -58.01. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
180 mg | With triethylamine; In 1-methyl-pyrrolidin-2-one; at 250℃; for 1h;Microwave irradiation; | A solution of <strong>[33216-52-3]3,4,5-trichloropyridine</strong> (400 mg, 2.2 mmol), 4-fert-butylaniline (0.71 mL, 4.5 mmol), triethylamine (0.61 mL, 4.4 mmol), and anhydrous l-methyl-2- pyrrolidinone (12 mL) was heated at 250 C in a microwave reactor (C.E.M. Discover) for 1 h. The resulting mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution, the organic phase was washed with water, saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated onto silica gel. Purification by medium pressure liquid chromatography on a silica column eluting with a gradient of 0% to 50% ethyl acetate in hexanes gave the title compound, a compound of the current invention, as an orange solid (180 mg). H NMR (CDCI3) delta 8.34 (s, 2H), 7.33 (d, 2H), 6.89 (d, 2H), 6.37 (br s, 1H), 1.32 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With sodium t-butanolate; In N,N-dimethyl-formamide; at 0 - 5℃;Large scale; | The reaction is carried out by dissolving 1.08 kg (11.2 mol) of sodium tert-butoxide in 3.08 kg (3.26 L) of DMF (Nu,Nu-dimethylformamide) in a Schott bottle. The reactor is charged with 1.07 kg of 1-(2,3,4-trimethoxyphenyl)ethanone (6) and 1.12 kg of <strong>[33216-52-3]3,4,5-trichloropyridine</strong> (5) followed by 1.03 kg (1.08 L) of DMF. The slurry is cooled towards 0 to 5 C (jacket temperature = -10 C) and the DMF solution of sodium tert-butoxide is added over a period of 6 hours. The reaction mixture is stirred at 0 to 5 C overnight (approx. 12 to 18 hours) . In- Process Control (HPLC) is carried out in order to verify conversion (Area% of (6) NMT 5%) . The reaction is quenched by addition of 1.32 kg (1.70 L) of EtOH followed by the addition of 6.42 kg (6.42 L) of water, during which the temperature increases to 20 to 25 C. The resulting slurry is heated to 50 C and stirred for 5 to 17 hours before cooling to 0 C and isolation by filtration on paper filter is taking place. The crude product is washed on the filter with 2 x 1.50 L of ethanol/water (1 : 5 v/v) and dried in vacuo at 40 to 50 C. The off-white to beige 2-(3,5-dichloro-4-pyrididyl)-1-(2,3,4-trimethoxyphenyl)ethanone (4), 1.52 kg is obtained in 84 % chemical yield in high purity (> 99 % by HPLC) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium t-butanolate; In N,N-dimethyl-formamide; at 5℃; for 4h; | A mixture of 1.0 g 2-(6-acetyl -2,3-dimethoxy-phenoxy)-N-propyl -acetamide ( 10) (3.4 mmol), 1.0 g <strong>[33216-52-3]3,4,5-trichloropyridine</strong> (5) (5.5 mmol) and 1.0 g tert-BuONa ( 10.2 mmol) was stirred at 5 C in 20 ml DM F for 4 hours. After 4 hours no further reaction was detected by H PLC and addition of 50 ml water caused a precipitate to form which was isolated by filtration and washed with 10 ml water before drying at 40 C in vacuum . By this method was isolated 120 mg of ( 1) (0.2 mmol ; 6 %) as yellow material having 75 % purity judged from H PLC analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 180℃; for 0.5h;Microwave irradiation; | General procedure: 3.23 Preparation of Compound 7 A mixture of compound 5 (650 mg, 3.8 mmol), compound 6 (650 mg, 3.6 mol) and DIPEA (981 mg, 7.6 mol) in NMP (10 mL) was radiated at 180 C. for 0.5 h by microwave. The mixture was diluted with EA (100 mL) and washed with water. The organic layer was dried and concentrated to give the crude product, which was purified by flash column chromatography to give the desired product (370 mg, 31%). LCMS: 317/319 [M+1]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium t-butanolate; In 1-methyl-pyrrolidin-2-one; at -5 - 15℃;Large scale; | In a suitable reactor was placed l-(7-methoxyspiro[l,3-benzodioxole-2,4'-tetrahydro- thiopyran]-4-yl)ethanone (1.00 kg, 3.57 mol) and <strong>[33216-52-3]3,4,5-trichloropyridine</strong> (1.04 kg, 5.70 mol) followed by addition of NMP (2.5 kg). The solution was stirred and cooled to -5 C. In a separate vessel was prepared a solution of tert-BuONa (1.03 kg, 10.7 mol) in NMP (2.5 kg) which was slowly pumped into the reactor while keeping the temperature below 15 C during the addition. After complete addition the reaction temperature was kept at 15 C and the progression monitored by in-process control using HPLC. The reaction was considered complete when >98 % of the l-(7-methoxyspiro[l,3-benzodioxole-2,4'-tetrahydrothiopyran]-4-yl)ethanone was converted into 2-(3,5-dichloropyridine-4-yl)- l-(7-methoxy-2',3',5',6'-tetrahydro- spiro[l,3-benzodioxole-2,4'-(4H)-thiopyran]-4-yl)ethanone (not isolated intermediate), based on the ratio of HPLC %-area of l-(7-methoxyspiro[l,3-benzodioxole-2,4'- tetrahydrothiopyran]-4-yl)ethanone and 2-(3,5-dichloropyridine-4-yl)-l-(7-methoxy- 2' 3',5',6'-tetrahydro-spiro[l,3-benzodioxole'2,4'-(4H)-thiopyran]-4-yl)ethanone. At this point the reaction mixture can be kept for up to 2 days at 5 C if necessary. To the reaction mixture was added 5-tert-butyl-2-methyl thiophenol (1.03 kg, 5.70 mol) and 2C03 (0.54 kg, 3.92 mol) and the mixture was heated to 80 C. The reaction was considered complete when >85 % of the 2-(3,5-Dichloropyridine-4-yl)-l-(7-methoxy-2',3',5',6'- tetrahydro-spiro[l,3-benzodioxole-2,4'-(4H)-thiopyran]-4-yl)ethanone was converted into the title compound, based on the ratio of HPLC %-area of 2-(3,5-Dichloropyridine-4-yl)-l-(7- methoxy-2',3',5',6'-tetrahydro-spiro[l,3-benzodioxole-2(4'-(4H)-thiopyran]-4-yl)ethanone and the title compound. The reaction mixture was cooled to 20 C, added hexane (5 L), 27.7 %-w/w NaOH (0.35 L) and water (5 L) followed by rapid stirring for 15 min to 30 min. After stopping the agitation and the phases had separated, the aqueous phase was kept while the organic phase was discarded. To the aqueous phase was added toluene (0.8 L) and hexane (4.2 L) followed by- rapid stirring for 15 min to 30 min after which the agitation was stopped and the phases allowed to separate. The aqueous phase was kept and treated once more with toluene (2 L) and hexane (3 L) by rapid stirring for 15 min to 30 min, followed by stopping the agitation and allowing the phases to separate. The aqueous phase was kept and treated a third time with toluene (2.5 L) and hexane (2.5 L) by rapid stirring for 15 min to 30 min, followed by stopping the agitation and allowing the phases to separate. The aqueous phase was returned to the reactor, added EtOAc (6 L), water (2 L) and slowly added AcOH ( 1.03 kg) . Once the addition of AcOH was completed, stirring was continued for another 20 min to 30 min before agitation was stopped and the phases allowed to separate. The organic phase was transferred to a storage tank and kept, while the aqueous phase was returned to the reactor, added EtOAc (6 L), heated to 40C and stirred for 20 min to 30 min before agitation was stopped and the phases allowed to separate again. The aqueous phase was removed to waste and the organic phase on the storage tank was transferred to the reactor and combined . The combined organic phases was added water (4 L) and stirred at 40 C for 20 min to 30 min before agitation was stopped and the phases allowed to separate. The aqueous phase was removed and the organic phase once more added water (4 L) and NaC (sat. ) (4 L) followed by stirring at 40 C for 20 min to 30 min before agitation was stopped and the phases allowed to separate. The aqueous phase was removed and the organic phase concentrated as much as possible by vacuum and heating at 50 C to 60 C. When the distillation became slow addition of EtOAc (2 L) was followed by another concentration in vacuum to remove any water still present. To the residue was added acetone (5.5 L) and the mixture was heated to reflux and complete dissolution was ensured. While the solution was refluxing, slow addition of hexane ( 12.5 L) took place such as reflux was maintained throughout the addition . Once the addition was completed the reaction mixture was cooled slowly to room temperature over a period of 5 hrs to 8 hrs and then further cooling to 0 C over a period of another 5 hrs to 8 hrs. The crude product was isolated by filtration, washed using a mixture of acetone (1 L) and hexane (2 L), dried in vacuum at 40 C. This produced the title compound (0.83 kg, 2.01 mol) as an off-white to yellowish solid in 56 % yield . H N (600 MHz, DMSO-d6) delta 10.76 (s, 1H), 8.65 (s, 2H), 7.26 (d, J = 9.0 Hz, 1H), 6.56 (d, J = 9.0 Hz, 1H), 4.59 (s, 2H), 2.97 - 2.89 (m, 2H), 2.86 - 2.79 (m, 2H), 2.39 - 2.31 (m, 2H), 2.23 - 2.15 (nr., 2H) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With potassium tert-butylate; In N,N-dimethyl-formamide; at 5 - 25℃;Large scale; | Dimethyl formamide (96 L) was charged to a suitable reactor followed by addition of potassium tert-butoxide (17.60 kg, 156.8 mol). Transfer of potassium tert-butoxide was ensured with a rinse of dimethyl formamide (3 L), and the mixture was stirred until potassium tert-butoxide had dissolved. The solution was transferred from the reactor to a container, the reactor was rinsed with dimethyl formamide (6 L), whichwas transferred to the container as well.The reactor was charged with 1-[7-(difluoromethoxy)spiro[1,3-benzodioxole-2,41- tetrahydrothiopyran]-4-yl]ethanone (19.08 kg, 60.32 mol), <strong>[33216-52-3]3,4,5-trichloropyridine</strong> (14.30 kg, 78.38 mol), and dimethylformamide (96 L). The mixture was stirred andcooled to 10-15C, and then the solution of potassium tert-butoxide in dimethylformamide was added slowly, keeping the temperature of the reaction mixture at 5- 25C. The transfer of the potassium tert-butoxide solution was ensured with a rinse of dimethyl formamide (6 L).The mixture was heated to 20-25C and stirred until the conversion was 98% as indicated by HPLC.Water (96 L) was added slowly with cooling to the reaction mixture keeping the temperature between 20-30C. This was followed by the addition of saturated sodium chloride in water (115.2 kg) and ethyl acetate (134 L). The mixture was stirred for 20- 60 minutes and then the agitation was stopped, allowing the phases to settle. Thephases were separated, and the aqueous phase was returned to the reactor. Ethyl acetate (96 L) was added, and the mixture was stirred for 20-60 minutes. The agitation was stopped, allowing the phases to settle. The phases were separated. The organic phases were combined in the reactor and stirred with water (48 L) and saturated sodium chloride in water (57.8 kg) for 20 minutes. The agitation was stopped allowing the phases to settle. The lower aqueous phase was discarded, and water (48 L) and saturated sodium chloride (57.6 kg) were added. The mixture was agitated for 20-60 minutes, and then the agitation was stopped, allowing the phasesto settle. The lower aqueous phase was discarded, and water (84 L) and sodium hydroxide (28% in water, 14.0 kg) were added. The mixture was stirred for 20- 60 minutes and then the agitation was stopped, allowing the phases to settle. The lower aqueous phase was discarded.The organic phase in the reactor was concentrated by use of vacuum and heating witha jacket temperature of 50-65C to a residual volume of approximately 40 L. Ethanol(57 L) was charged to the reactor, and the mixture was heated to reflux until a clearsolution was obtained. The mixture was cooled to 5C over 5 hours and stirred atthat temperature for 3 hours. The product was isolated by filtration, transfer wasensured with a rinse of ethanol (10 L). The product was washed with cold (5)ethanol (48 L) and dried in vacuo at 45-55C. Yield 15.57 kg (56 %). 1H NMR (600 MHz, Chloroform-d) O 8.52 (s, 2H), 7.46 (d, J = 8.9 Hz, 1H), 6.80 (d, J = 8.9 Hz, 1H), 6.73 (t, J = 73.3 Hz, 1H), 4.59 (s, 2H), 3.01 - 2.85 (m, 4H), 2.47 - 2.30 (m, 4H).HPLC: Purity: 97.8%. |
Tags: 33216-52-3 synthesis path| 33216-52-3 SDS| 33216-52-3 COA| 33216-52-3 purity| 33216-52-3 application| 33216-52-3 NMR| 33216-52-3 COA| 33216-52-3 structure
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