Structure of 13958-93-5
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CAS No. : | 13958-93-5 |
Formula : | C6H3Cl2NO2 |
M.W : | 192.00 |
SMILES Code : | OC(=O)C1=C(Cl)C=NC=C1Cl |
MDL No. : | MFCD01861975 |
InChI Key : | BUQPTOSHKHYHHB-UHFFFAOYSA-N |
Pubchem ID : | 605763 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 11 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 41.22 |
TPSA ? Topological Polar Surface Area: Calculated from |
50.19 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.09 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.63 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.09 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.09 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.04 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.39 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.39 |
Solubility | 0.773 mg/ml ; 0.00403 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.3 |
Solubility | 0.97 mg/ml ; 0.00505 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.63 |
Solubility | 0.446 mg/ml ; 0.00232 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.31 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.56 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.41 |
* 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 |
---|---|---|
41% | With lithium diisopropyl amide; In tetrahydrofuran; at -78 - 20℃; for 2h; | Intermediate 1 3.5-Dichloropyridine-4-carboxylic acid A solution of 3,5-dichloropyridine (5.00 g, 33.8 mmol) in THF (25 ml) was added to a solution of LDA [generated from NBuLi (2.5M solution hexanes, 14.9 ml, 37.2 mmol) and diisopropylamine (4.10 g, 5.7 ml, 40.6 mmol)] in THF (25 ml) at -78 then CO2 gas was bubbled through to give a clear brown solution that slowly gave a precipitate, warmed to room temperature over 2 h, then quenched with water (20 ml) and partitioned between diethylether (100 ml) and 1M NaOH (100 ml).. The aqueous layer was separated and acidified to PH1 with concentrated hydrochloric acid and then extracted with 10% MeOH in DCM (100 ml*3).. The combined organic layers were dried (MgSO4) and the solvent removed in vacuo to give a brown solid that was recrystallized from ethanol and dried under vacuum to give the title compound as pinkish crystals (2.63 g, 41%): deltaH (DMSO d6) 8.72 (2H, s). |
41% | A solution of 3, [5-DICHLOROPYRIDINE] (5. [00G,] 33. [8MMOL)] in THF [(25ML)] was added to a solution of LDA [generated from nBuLi (2.5M solution in hexanes, 14. [9MI,] 37. [2MMOL)] and diisopropylamine (4. 10g, 5. [7MOI,] 40. 6mmol)] in THF [(25MOI)] [AT-78 . ? UNDER] nitrogen, to give a yellow/brown slurry. The reaction was stirred for 30min [AT-78XB0;] then C02 gas was bubbled through to give a clear brown solution that slowly gave a precipitate, warmed to room temperature over 2h, then quenched with water [(20MI)] and partitioned between [ET2O] [(100MOI)] and [1 M NAOH] [(100ML).] The aqueous layer was separated and acidified to pH 1 with concentrated hydrochloric acid and then extracted with 10% [MEOH] in DCM [(100MIX3).] The combined organic layers were dried [(MGS04)] and the solvent removed under vacuum to give a brown solid that was [RECRYSTALLISED] from ethanol and dried under vacuum to give the title compound as pinkish crystals (2.63g, [41%). 8H] (DMSO-d6) 8.74 (2H, s). | |
41% | A solution of 3, [5-DICHLOROPYRIDINE (5. 00G,] 33. [8MMOL)] in THF [(25ML)] was added to a solution of LDA [generated from nBuLi (2.5M solution in hexanes, 14. [9MOI,] 37. [2MMOL)] and diisopropylamine (4. [1 OU,] 5. [7MI,] 40. 6mmol)] in THF [(25ML)] at- [78-UNDER] nitrogen, to give a [YELLOW/BROWN SLURRY.] The reaction was stirred for 30min [AT-78G] then COs gas was bubbled through to give a clear brown solution that slowly gave a precipitate, warmed to RT over 2h, then quenched with water [(20MI)] and partitioned between [ET20] [(100ML)] and [1 M NAOH] [(100MI).] The aqueous layer was separated and acidified to pH 1 with concentrated hydrochloric acid and then extracted with 10% [MEOH] in DCM [(1 00MIX3).] The combined organic layers were dried [(MGS04)] and the solvent removed under vacuum to give a brown solid that was recrystallised from ethanol and dried under vacuum to give the title compound as pinkish crystals (2.63g, [41%). 5H] (DMSO-d6) 8.74 (2H, s). 8C (DMSO-d6) 163.5, 147.7, 141.0, 126.7. |
To a solution of the commercially available 3,5-dichloropyridine (10 g, 0.067mol) in THE (20 mL) was added LDA (60 mL, 0.074 mol), the reaction was stirred at 780C for 1 hour. Then dry ice (5.9 g, 0.134 mol) was added to the solution. After 0.5 h, the mixture was quenched by adding water and adjusted the pH to 3-4. The solution was partitioned with EA and water. The combined organic layers were washed with brine, dried over anhydrous Na2504 andconcentrated to give the crude product KR-i (7 g, 55% yield) as a pale white solid. ESI-MS (Mi-i): 192 calc. for C6H3C12N02: 190.95. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With thionyl chloride; N,N-dimethyl-formamide; In toluene; at 110℃; for 3h;Heating / reflux; | Intermediate 1 (150 g) was suspended in toluene (450 mL) containing dimethyl formamide (1.5 mL). As this mixture was boiled under reflux, thionyl chloride (132.8 g) was charged to it over 1 h. The reaction was complete after a further 2.0 h at [110C.] The solvent was removed at atmospheric pressure and then the residue was vacuum distilled, giving the title compound fraction as a water white oil that partially crystallised on standing (151. 3g, 92.0% yield, b. p [70-72C/1.] 0 mmHg). AH (CDCI3) : 8.64 (2H, s). [ESI+] [(MILZ+1)] 209.9 |
With thionyl chloride; N,N-dimethyl-formamide; In dichloromethane; for 3h;Heating / reflux; | The Compound 1 h (1.50 g, 7.81 mmol) was placed in a round-bottom flask equipped with a stirrer and reflux condenser. DCM (20 mL) containing 2 drops of DMF was added as one portion followed by thionyl chloride (0.85 mL, 11.7 mmol). The reaction mixture was refluxed for 3 h resulting in a clear solution. The solution was evaporated under vacuum to yield a yellow oil, Compound 1i, which was used in the next step without purification. | |
With thionyl chloride; In dichloromethane; N,N-dimethyl-formamide; | Step C 3,5-Dichloropyridine-4-carboxylic acid chloride 3,5-Dichloropyridine-4-carboxylic acid (0.5 g, 2.6 mmol; Reference Example 1) was dissolved in CH2Cl2 (1.75 mL) and DMF (50 muL). Thionyl chloride (0.21 mL, 2.86 mL) was added and the reaction mixture was heated at 50 C. for 20 h. The residue was concentrated in vacuo. The formation of the acid chloride was observed by TLC (50% EtOAc/hexane) and the crude <strong>[13958-93-5]3,5-dichloropyridine-4-carboxylic acid</strong> chloride was used in Step E without further purification. |
With thionyl chloride; In N-methyl-acetamide; 1,2-dichloro-ethane; | Thus obtained <strong>[13958-93-5]3,5-dichloropyridine-4-carboxylic acid</strong> (384 mg, 2 mmol) was dispersed in 1,2-dichloroethane(30 mL) to prepare a slurry, added with thionyl chloride (0.44 mL, 5 mmol), further added with dimethylformamide (0.3 mL), and the mixture was refluxed under heating for 1 hour. The solvent was evaporated under reduced pressure to thereby obtain a crude product of 3,5-dichloropyridine-4-carbonylchloride. | |
With thionyl chloride; In DMF (N,N-dimethyl-formamide); dichloromethane; for 4h;Heating / reflux; | Intermediate 2 (S)-Ethyl-3-[4-(3.5-dichloropyrid-4-ylcarboxamido)phenyl]-2-(t-butoxycarbonylamino)propionate A slurry of Intermediate 1 (51.2 g, 0.267 mol) in DCM (195 ml) and thionyl chloride (195 ml, 2.67 mol) was treated with DMF (5 drops) and heated to reflux for 4 h.. The reaction was concentrated in vacuo and azeotroped with toluene (2*50ml) to give the acid chloride derivative of intermediate 1 as a yellow solid which was used without further purification. | |
With thionyl chloride; N,N-dimethyl-formamide; In dichloromethane; for 4h;Heating / reflux; | A slurry of the compound of Intermediate 1 (51.2g, 0. 267mol) in DCM [(195MUT)] and thionyl chloride [(195MOI,] 2. [67MOL)] was treated with DMF (5 drops) and heated to reflux for 4h. The reaction was concentrated in vacuo and azeotroped with toluene [(2X50M1)] to give a yellow solid which was used without further purification. A solution of [ETHYL- (S)-3- (4-] aminophenyl)-2- (t-butoxycarbonylamino) propanoate (130.8g, 0. [425MOL)] in [DCM (800ML) WAS COOLED TO 0XB0; AND TREATED WITH NMM 0.51MOL),] stirred for 5 minutes and then a solution of the acid chloride (98.3g, 0. [468MOL)] in DCM [(200ML)] was added dropwise keeping the reaction temperature [BELOW 5XB0;.] The reaction was stirred for 1h, quenched with NaHCO3 solution [(500ML),] the organic layer separated, washed with NaHCO3 [SOLUTION (500ML),] 10% citric acid solution [(500MOI)] and [NAHCO3] [SOLUTION (500M1),] dried [(MGS04)] and concentrated in vacuo to give a yellow solid which was [RECRYSTALLISED] (EtOAc/hexane) to give the title compound, (140g, [69%).] [8H] (DMSO d6), 8.8 (2H, s), 7.55 (2H, d, J 8.5Hz), 7.23 (2H, d, J 8.5Hz), 4.0 (3H, m), 3.4 (2H, b s), 2.9 (1H, m), 2.8 [(1 H,] m), 1.3 (9H, s), 1.25 (3H, t); m/z (ES+, 70V) 504 (MNa+). | |
With thionyl chloride;N,N-dimethyl-formamide; In dichloromethane; for 3h;Heating / reflux; | Preparation of the 3,5-dichloro-isonicotinoyl chloride, The acid (1.50 g, 7.81 mmol) was placed in the round-bottom flask equipped with stirrer and reflux condenser, DCM (20 ml_) containg 2 drops of DMF was added as one portion followed by thionyl chloride (1.40 g, 0.85 ml, 1.5 eq.). The reaction mixture was refluxed for 3 hr resulting clear solution. The solution was evaporated in vacuum providing yellow oil, which was used in the next step without purification. | |
With thionyl chloride; for 7h;Reflux; | Reference Production Example 11 A mixture of 1 g of <strong>[13958-93-5]3,5-dichloroisonicotinic acid</strong> and 5 ml of thionyl chloride was heated to reflux for seven hours. Then, the mixture was cooled to room temperature, and then concentrated under reduced pressure. The residue was dissolved in 3 ml of DMF, which was added dropwise to a mixture of 2-amino-4-trifluoromethylphenol, 5 ml of DMF and 1.05 g of triethylamine at 0C. The reaction mixture was stirred at room temperature for two hours, and then water was added thereto, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with diethyl ether to give 0.75 g of 3,5-dichloro-N-(2-hydroxy-5-trifluoromethylphenyl)isonicotinamide. [Show Image] 1H-NMR (CDCl3+DMSO-d6) delta: 9.03 (br s, 1H), 8.59 (s, 2H), 8.45 (d, J=2.0 Hz, 1H), 7.30 (dd, J=8.5, 2.2 Hz, 1H), 7.04 (d, J=8.5 Hz, 1H) | |
With thionyl chloride; for 7h;Reflux; | Reference Production Example 11A mixture of 1 g of <strong>[13958-93-5]3,5-dichloroisonicotinic acid</strong> and 5 ml of thionyl chloride was heated to reflux for seven hours. Then, the mixture was cooled to room temperature, and then concentrated under reduced pressure. The residue was dissolved in 3 ml of DMF, which was added dropwise to a mixture of 2-amino-4-trifluoromethylphenol, 5 ml of DMF and 1.05 g of triethylamine at 0 C. The reaction mixture was stirred at room temperature for two hours, and then water was added thereto, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with diethyl ether to give 0.75 g of 3,5-dichloro-N-(2-hydroxy-5-trifluoromethylphenyl)isonicotinamide.1H-NMR (CDCl3+DMSO-d6) delta: 9.03 (br s, 1H), 8.59 (s, 2H), 8.45 (d, J=2.0 Hz, 1H), 7.30 (dd, J=8.5, 2.2 Hz, 1H), 7.04 (d, J=8.5 Hz, 1H) | |
With thionyl chloride; N,N-dimethyl-formamide; In dichloromethane; at 40℃; for 2.5h; | To a suspension of <strong>[13958-93-5]3,5-dichloroisonicotinic acid</strong> (52 mmol) in 250 mL DCM and 5 mL DMF were added 1 1.4 mL thionylchloride. The mixture was heated to 40C for 2.5 h, cooled to RT before 100 mL EtOH were added. The solution was stirred at RT for 10 min and then concentrated in vacuo. The crude mixture was taken up in EtOAc and quenched with sat. aq. NaHC03 solution under ice cooling. The aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over MgS04 and concentrated in vacuo. Purification by CC using Hept/EtOAc (95/5 to 85/15) gives the desired product as colorless oil; | |
With thionyl chloride; In dichloromethane; N,N-dimethyl-formamide; for 3h;Reflux; | To a solution of KR-i (1.50 g, 7.85 mmol) in DCM (20 mL), containing two drops of DMF, was added thionyl chloride (1 .40 g, 0.85 mL, 1 .5 eq). The reaction was refluxed for 3 hours resulting a clear solution. The solution was evaporated in vaccum providing the crude product KR-4 (1 .35 g, 82.3% yield) as a yellow oil. ESI-MS (Mi-i): 210 calc. for C6H2CI3NO: 208.9. | |
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 3h; | i) To a suspension of <strong>[13958-93-5]3,5-dichloroisonicotinic acid</strong> (MANCHESTER, 50 g, 260.42 mmol) inDCM (500 ml) was added oxalyl chloride (ALDRICH, 24.24 ml, 286.462 mmol) and 30 dropsof N,N-Dimethylformamide (DMF).The reaction mixture was stirred at rt for 3h. UPLC with NHMe2 in CH3CN showed reaction was completed.The solvent was evaporated in vacuo to yield the desired product as a greenish solid (3,5-dichloropyridine-4-carbonyl chloride) and was used for the next step without any further purification. | |
With thionyl chloride;N,N-dimethyl-formamide; In dichloromethane; for 5.75h;Heating / reflux; | To a nitrogen flushed 500 mL round bottom flask was charged with 3,5-dichloro- isonicotinic acid (46.5 g, 0.24 mol), CH2CI2 (150 mL), DMF (0.5 mL), and thionyl chloride (20 mL,33.9 g 0.28 mol). After the slurry was refluxed for 5 h, additional thionyl chloride (5 mL, 0.70 mol) and CH2CI2 (100 mL) were added, and the reaction was refluxed for additional 45 min. The reaction mixture was concentrated, and the residue was azeotroped with toluene to give the crude acyl chloride, which was used immediately. Thus, the crude acyl chloride was dissolved in CH2CI2 (150 mL) and was added to N-BOC-4-amino-L-phenylalanine ethyl ester (60 g, 0.20 mol) and 4-methylmorpholine (44 mL, EPO <DP n="20"/>0.40 mol) in CH2CI2 (400 mL) at O0C over 5 min. After stirring at 00C for 1 h, the reaction was quenched with dilute aqueous NaHCtheta3. The organic layer was separated and the aqueous layer was extracted with CH2CI2 (500 mL). The organic layers were combined, dried over anhydrous MgSO4 and concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel eluting with 4:1 to 3:2 EtOAc/hexanes to afford the title compound (95 g, 100% yield). lH NMR (400 MHz, CD3OD) delta 8.60 (s, 2H), 7.54 (d, 2H), 7.20 (d, 2H), 4.20-4.36 (m, IH), 4.10 (q, 2H), 3.02-3.12 (m, IH)5 ),2.82-2.92 (in, IH), 1.34/1.30 (s, 9H).1.20 (t, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3,5-Dichloroisonicotinic acid (5 g) was suspended in 12 mL of thionyl chloride and stirred under reflux for 18 hours. The reaction mixture was concentrated. The resulting acid chloride (1.30 g, 6.2 mmol) was dissolved in 5 mL of 1,4-dioxane at 0C. The reaction mixture was stirred at 0C for 15 minutes and allowed to warm to room temperature and stirred for an additional 30 minutes. It was then cooled to 0C and carefully quenched with 15 mL of water. The reaction mixture was extracted with CH2Cl2 and the combined organic layers were dried with Na2SO4 and concentrated under reduced pressure. The resulting crude product was purified by chromatography (3: 1 hexanes/EtOAc) to afford 650 mg of the alcohol intermediate. This alcohol intermediate was dissolved in 1 mL of thionyl chloride and stirred under reflux for an hour. The resulting reaction mixture was cooled to room temperature and concentrated under reduced pressure to afford the chloromethyl pyridine derivative as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 1A 3,5-Dichloroisonicotinamide A solution of <strong>[13958-93-5]3,5-dichloro-isonicotinic acid</strong> (9.54 g, 49.6 mmol, commercially available form TCI) in benzene (100 mL) was treated with oxalyl chloride (8.7 mL), a catalytic amount of DMF (5 drops), stirred overnight at room temperature, and concentrated under reduced pressure. The residue was dissolved in diglyme (10 mL) and added dropwise to 35% NH2OH in water (150 mL). The mixture was filtered to provide 8.2 g of the title compound as a white powder. MS ((DCI (+)) m/e 190.9 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; 3-[(diethoxyphosphinyl)oxy]-1,2,3-benzotriazin-4(3H)-one; In dichloromethane; at 20℃; for 24h; | Example 8 difluorocyclobutanecarboxamide.2HCI; 3,5-Dichloroiso?icotinic acid (84mg, 0.4mmol), the compound of Preparation 42 (150mg, 0.3mmol), 3- (diethoxyphosphoryloxy)-1 ,2,3-benzotriazin-4(3H)-one (132mg, 0.4mmol) and triethylamine (0.16mL, 1.2mmol) were dissolved in dichloromethane and stirred at room temperature for 24hours. The reaction was quenched by the addition of saturated sodium hydrogen carbonate solution and extracted using dichloromethane. The combined organic extracts were concentrated in vacuo to give the crude product. The crude mixture was purified by column chromatography on silica gel using dichloromethane-.methanol EPO <DP n="35"/>(100:0 to 90:10) as eluent. The resulting product was then dissolved in dichloromethane (5mL) and treated with 2M hydrochloric acid in diethyl ether (5mL), the solvents were removed in vacuo to give 43mg of title compound as a white solid.1H NMR (400MHz CDCI3) delta 0.95 (3H, s), 1.20-1.85 (9H, m), 1.85-2.00 (1 H, m), 2.05-2.30 (2H, m), 2.45(1 H, bs), 2.70-3.10 (6H, m), 3.25-3.50 (2H, m), 4.05-4.20 (1H, m), 4.40-4.65 (2H, m), 7.10-7.40 (5H1 m),8.50 (2H, bs).LRMS: m/z APCI+579[MH+] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-methyl-morpholine; thionyl chloride; In dichloromethane; N,N-dimethyl-formamide; | Step A N-(BOC)-4-((3',5'-dichloroisonicotinoyl)amino)-(L)-phenylalanine, methyl ester A slurry of <strong>[13958-93-5]3,5-dichloroisonicotinic acid</strong> (3.1 g, 16.11 mmol) in 10 mL of CH2Cl2 was treated with DMF (50 muL) and thionyl chloride (1.23 mL, 16.91 mmol) and heated to reflux for 5 h. The reaction was concentrated to give a yellow oil. This oil was dissolved in 5 mL of CH2Cl2 and added to N-(BOC)-4-amino-(L)-phenylalanine, methyl ester (4.00 g, 14.39 mmol) and 4-methylmorpholine (2.7 mL, 24.21 mmol) in 25 mL of CH2Cl2 at 0 C. After stirring for 2 h at this temperature, the reaction was quenched with water (50 mL) and extracted into CH2Cl2 (3*100 mL). The combined organics were combined, dried over anhydrous MgSO4 and concentrated in vacuo to give a yellow solid. Trituration with CH2Cl2 gave 5.5 g of a while solid 1H NMR (500 MHz, CDCl3): delta 8.63 (s, 2H); 7.58 (d, J=8.2 Hz, 2H); 7.23 (d, J=8.2 Hz, 2H); 6.91 (d, J=8.4 Hz, 1H); 4.39 (m, 1H); 3.70 (s, 3H); 3.11 (m, 1H); 2.91 (m, 1H); 2.00 (s, 9H); MS m/e 468.20 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With CO2; diisopropylamine; In tetrahydrofuran; | REFERENCE EXAMPLE 1 3,5-Dichloroisonicotinic acid To a solution of 3,5-dichloropyridine (10.00 g, 67.57 mmol) in 70 mL of THF was added 35.4 mL of a 2.0 M solution of LDA in THF at -78 C. The reaction was stirred for 1 h, then CO2 gas was bubbled through the solution for 20 mins. The reaction was allowed to warm to rt over 1 h then quenched with 1N NaOH (100 mL) and washed with Et2O (50 mL). The aqueous layer was acidified with conc HCl which caused a precipitate to form. The precipitate was collected by filtration and recrystallized from EtOH to give the title compound as a pale yellow solid (7.1 g, 36.97 mmol, 55%). 1H NMR (500 MHz, DMSO-d6): delta 8.73 (s, 2H). | |
With CO2; diisopropylamine; In tetrahydrofuran; TiF; | REFERENCE EXAMPLE 1 3,5-Dichloroisonicotinic acid To a solution of 3,5-dichloropyridine (10.00 g, 67.57 mmol) in 70 mL of THF was added 35.4 mL of a 2.0 M solution of LDA in TiF at -78 C. The reaction was stirred for 1 h, then CO2 gas was bubbled through the solution for 20 mins. The reaction was allowed to warm to rt over 1 h then quenched with 1N NaOH (100 mL) and washed with Et2O (50 mL). The aqueous layer was acidified with conc HCl which caused a precipitate to form. The precipitate was collected by filtration and recrystallized from EtOH to give the title compound as a pale yellow solid (7.1 g, 36.97 mmol, 55%). 1H NMR (500 MHz, DMSO-d6): delta8.73 (s, 2H). | |
With hydrogenchloride; n-butyllithium; diisopropylamine; In tetrahydrofuran; water; | [Example 39] Preparation of 3-[4-(3,5-dichloropyridine-4-carbonylamino)phenyl]-2-{3-[(2,2-dimethylpropionyl)iso butylamino]-4-methoxyphenyl}propionic acid Diisopropylamine (31 mL, 221 mmol) was dissolved in tetrahydrofuran (200 mL), and the solution was added drop-wisely with a 1.6 mol/L hexane solution of n-butyllithium (128 mL, 205 mmol) at -78ØC. The mixture was stirred for 15 minutes, and was added drop-wisely with a tetrahydrofuran solution (200 mL) of 3,5-dichloropyridine (25.1 g, 170 mmol) while keeping the temperature at -78ØC, and then stirred for additional 1 hour. The reaction solution was added with dry ice to thereby gradually heat to room temperature, and further stirred for 15 hours. The mixture was treated with water (1 L), added with a 1 mol/L aqueous sodium hydroxide solution (100 mL), and washed with ether. The separated aqueous phase was adjusted to be acidic using a 6 mol/L hydrochloric acid, and the resultant precipitate was collected by filtration. The filtrate was extracted with ethyl acetate, the extract was dried over anhydrous sodium sulfate, evaporated under reduced pressure so as to remove the solvent, and the mixture of the resultant residue and the precipitate previously colleted were re-crystallized from ethanol, which yielded 3,5-dichloropyridine-4-carboxylic acid (yield: 23 g, yield ratio: 70%) as a yellow crystal. |
Yield | Reaction Conditions | Operation in experiment |
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44% | With benzotriazol-1-ol; In N,N-dimethyl-formamide; | Preparation of 3,5-Dichloro-N-[4-(2-hydroxy-ethyl)-benzyl]-isonicotinamide: Using the EDCI coupling general procedure F: Reaction of 2-(4-Aminomethyl-phenyl)-ethanol (306 mg, 2.03 mmol), <strong>[13958-93-5]3,5-dichloroisonicotinic acid</strong> (385 mg, 2.03 mmol), 1-hydroxybenzotriazole (301 mg, 2.22 mmol), 4-methyl morpholine (0.50 mL, 4.45 mmol), and EDCI (426 mg, 2.22 mmol) in anhydrous DMF (5 mL) overnight at room temperature and overnight at 40 C. followed by column chromatography on silica gel (2:2:96 MeOH-NH4OH-CH2Cl2) gave the title compound (291 mg, 44%) as a white foam. |
Yield | Reaction Conditions | Operation in experiment |
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63% | In tetrahydrofuran; thionyl chloride; | Preparation of 3,5-dichloro-N-(4-hydroxymethyl-phenyl)-isonicotinamide: A suspension of <strong>[13958-93-5]3,5-dichloroisonicotinic acid</strong> (128 mg, 0.667 mmol) in thionyl chloride (2 mL) was heated at reflux for 2 h, then concentrated. To the residue was added 4-aminobenzyl alcohol (123 mg, 0.999 mmol) and THF (2.2 mL), and the mixture was stirred at room temperature for 19 h. The mixture was filtered, and the filtrate was concentrated to give a yellow foam (125 mg, 63%). 1H NMR (CD3OD) delta 4.60 (s, 2H), 7.38 (d, 2H, J=8.7 Hz), 7.63 (d, 2H, J=8.4 Hz), 8.66 (s, 2H). |
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