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Product Details of [ 133627-46-0 ]

CAS No. :133627-46-0
Formula : C12H9Cl2N3O
M.W : 282.13
SMILES Code : O=C(NC1=C(C)C=CN=C1Cl)C2=C(Cl)N=CC=C2
MDL No. :MFCD09031256
InChI Key :UVCHGYJPZGYMSW-UHFFFAOYSA-N
Pubchem ID :10423868

Safety of [ 133627-46-0 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P261-P280-P301+P312-P302+P352-P305+P351+P338

Application In Synthesis of [ 133627-46-0 ]

* 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.

  • Downstream synthetic route of [ 133627-46-0 ]

[ 133627-46-0 ] Synthesis Path-Downstream   1~3

  • 1
  • [ 49609-84-9 ]
  • [ 133627-45-9 ]
  • [ 133627-46-0 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In ethyl acetate; at 75 - 80℃; for 14h;Product distribution / selectivity; Example-3: Preparation of 2-Chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3 -pyridine carboxamide (V) [utilizing ethyl acetate as solvent during acylation]2-Chloro nicotinic acid (1.33kg; 8.44moles) was added to toluene (S.Olitres) and thionyl chloride (0.75 litres; 10.42 moles) and dimethyl formamide (100ml; 0.18moles) were added and the mixture refluxed at 80C-90C till completion of reaction. The reaction mixture was concentrated under reduced pressure and cooled between 25C and 300C. Ethyl acetate (8.0 litres) was added to the mixture followed by potassium carbonate (2.0kg; 15.15 moles). 3-Amino-2-chloro-4-methyl pyridine of formula (IIotaI).was dissolved in ethyl acetate and added to the acid chloride (IV). The mixture was refluxed at 75C to 8O0C for 14 hours. The reaction mixture was concentrated after completion of the reaction and water (5.0 litres) was added. The reaction mass was cooled between 10-150C, filtered and dried between 600C and 700C under reduced pressure..Yield: 1.73 kg. % Yield: 87.80%. HPLC Purity: 99.9%.
With potassium carbonate; In toluene; at 75 - 80℃; for 14h;Product distribution / selectivity; Example-4: Preparation of 2-Chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3 -pyridine carboxamide (V) [utilizing toluene as solvent and potassium carbonate as inorganic base during acylation]2-Chloro nicotinic acid (1.33kg; 8.44moles) was added to toluene (5.01itres) and thionyl chloride (0.75 litres; 10.42 moles) and dimethyl formamide (100ml; 0.18moles) were added and the mixture refluxed at 800C -9O0C till completion of reaction. The reaction EPO <DP n="20"/>mixture was concentrated under reduced pressure and cooled between 25C and 300C. Toluene (8.0 litres) was added to the residue containing compound (IV), followed by addition of potassium carbonate (2.0kg; 15.15 moles). 3-Amino-2-chloro-4-methyl pyridine of formula (III) dissolved in toluene was added to the acid chloride (IV). The mixture was refluxed at 750C to 800C for 14 hours. The reaction mixture was concentrated after completion of the reaction and quenched with water (5.0 litres). The reaction mass was cooled between 10-150C and filtered.Yield: 1.73 kg. % Yield: 87.80%. HPLC Purity: 99.9%.
With triethylamine; In toluene; at 25 - 32℃;Product distribution / selectivity; Example-5: Preparation of 2-Chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3 -pyridine carboxamide (V) [utilizing toluene as solvent during acylation and triethyl amine as organic base]2-Chloro nicotinic acid (1.33kg; 8.44moles) was added to toluene (5.01itres) and thionyl chloride (0.75 litres; 10.42 moles) and dimethyl formamide (100ml; 0.18moles) were added and the mixture refluxed at 800C -9O0C till completion of reaction. The reaction mixture was concentrated under reduced pressure. Toluene (8.0 litres) was added to the mixture. 3-Amino-2-chloro-4-methyl pyridine of formula (III) dissolved in toluene was added to the acid chloride (IV) and triethyl amine was added to the reaction mixture to adjust pH. The mixture was stirred at 250C to 32C. Impurity formation up to 30-40% was formed in the reaction mixture, therefore, the reaction was not worked up for isolation of compound (V).
With pyridine; In 1,4-dioxane; cyclohexane; at 25 - 32℃; for 2.5h;Product distribution / selectivity; Example 6: Preparation of 2-Chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridine carboxamide (V) [utilizing toluene as solvent during acylation and pyridine as organic base]2-Chloro nicotinic acid (41.5gms; 0.263moles) was added to toluene (125ml) and thionyl chloride (19ml; 0.26moles) and dimethyl formamide (2.5ml; 0.005moles) were added and the mixture refluxed at 800C -900C till completion of reaction. The reaction mixture was concentrated under reduced pressure and the residue diluted with dioxane (55ml). Pyridine (62.5ml; 0.77moles) was added to a mixture of 3-Amino-2-chloro-4-methyl pyridine of formula (111) stirred in cyclohexane (62.5ml). The acid chloride (IV) mixture in dioxane, EPO <DP n="21"/>was added to the mixture containing (III) and stirred for 2.5 hours at 25C to 32C. TLC monitoring of the reaction mixture showed lot of impurities. The solid separating out was filtered washed with cyclohexane. Compound (V) was dissolved in acetone (300ml), refiuxed, and concentrated to 50ml. The mixture was cooled between 5 and 100C, filtered and dried.Yield: 32gms % Yield: 64.9%.
With N,N-dimethyl-aniline; In toluene; at 25 - 40℃; for 2.5h;Product distribution / selectivity; Example 11: Preparation of 2-Chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridine carboxamide (V) [utilizing toluene as solvent and N,N-dimethyl aniline as organic base during acylation]2-Chloro nicotinic acid (165.75gms; 1.057moles) was added to toluene (542gms) and thionyl chloride (56.40gms; 0.477moles) and dimethyl formamide (5.9gms; 0.080moles) were added and the mixture refluxed at 80C-90C till completion of reaction. The reaction mixture was concentrated under reduced pressure and the residue diluted with toluene (542gms). 3-Amino-2-chloro-4-methyl pyridine (125gms; 0.877moles) of formula (III) was added to the mixture containing compound of formula (IV) at ambient temperature followed by addition of N,N-dimethyl aniline (127.12gms; 1.05moles). The reaction mixture was stirred for 2.5 hours at 250C to 4O0C. After completion of reaction, the reaction mixture was cooled to ambient temperature and neutralized with 10% sodium carbonate solution to pH 7.0 to 7.5. The solid separating out was filtered, washed with toluene and dried. Yield: 220-230 gms % Yield: 89-93%. Purity: 99%
With pyridine; In 1,4-dioxane; cyclohexane; at 20℃; for 48h;Product distribution / selectivity; 2-Chloro-N-(2-chloro-4-methyl-pyridin-3-yl)-nicotinamide: The procedure is carried out as described in Hargrave J. Med. Chem. 1991, 34, 2231-2241, which is hereby incorporated by reference in its entirety. To a solution of <strong>[133627-45-9]3-amino-2-chloro-4-methylpyridine</strong> (18.2 mmol) in 6:1 cyclohexane-dioxane (6 mL), and pyridine (5.75 mL) is added a solution of 2-chloronicotinoyl chloride (12.8 mmol) in 1,4-dioxane (5 mL). The resulting mixture is stirred at ambient temperature for 48 hours and the precipitate is filtered and washed with water. The solid is taken up in ethanol (17.5 mL) and aqueous NaOH (0.1 N, 3.6 mL). The solution is then heated to reflux for 2 hours, cooled to ambient temperature and stirred overnight. The solvent is removed under vacuum and water (10 mL) is added to residue, with stirring. The mixture is cooled to 1OC and the crystalline product is filtered, washed with cold water and dried under vacuum to give the desired product, 2-chloro-N-(2-chloro-4-methyl-pyridin-3-yl)-nicotinamide.
With pyridine; In acetonitrile; at 20 - 45℃;Product distribution / selectivity; Step 3[00287] 2-Chloro-N-(2-chloro-4-methyl-pyridin-3-ylVnicotinamide: Pyridine (125 g, 1.58 mol, 1.10 equiv) was added to a solution of 2-chloro-4-methyl-pyridin-3-ylamine (204.6 g, 1.44 mol, 1.00 equiv) in acetonitrile (1500 ml) in a 2 liter 3 -necked round-bottom flask. 2- chloronicotinoyl chloride (270 g, 1.54 mol, 1.07 equiv) was added dropwise to the solution while maintaining the temperature at 20 C. The solution was allowed to react overnight while maintaining the temperature at 45 C in an oil bath. The solution was then diluted with water (2 L) and sodium carbonate was added till the pH of the solution reached 8. The solution was filtered, the filter cake was washed with water (100mLx3), and the filter cake was dissolved in tetrahydrofuran (3 L). The solution was decolorized by the addition of active carbon, and then filtered. The filtrate was then dried over sodium sulfate, concentrated in vacuo using a rotary evaporator. The product of 2-chloro-lambda/-(2-chloro-4-methyl-pyridin-3-yl) nicotinamide (32Og, purity: 94%, yield:79%) was obtained as a light red solid. The material was used in next step without further purification.

  • 2
  • [ 133627-46-0 ]
  • [ 765-30-0 ]
  • [ 133627-47-1 ]
YieldReaction ConditionsOperation in experiment
79% With calcium oxide; In xylene; at 140℃; lambda/-(2-Chloro-4-methyl-pyridin-3-yl)-2-cyclopropylamino-nicotinamide:; Cyclopropanamine (120 g, 2.11 mol, 10.00 equiv) and calcium oxide (24 g, 428.57 mmol, 2.00 <n="75"/>equiv) were added to a solution of 2-chloro-N-(2-chloro-4-methyl-pyridin-3-yl)nicotinamide (60 g, 213.52 mmol, 1.00 equiv) in xylene (300 ml) in a 1 L high pressure reactor. The solution was allowed to react overnight while maintaining the temperature at 140 C. The solution was filtered, the filter cake was washed with tetrahydrofuran (50mL><2), and the filtrate was concentrated in vacuo using a rotary evaporator. The residue was purified by flash chromatography on silica gel (10% ethyl acetate in petroleum ether) The product of JV-(2-chloro- 4-methyl-pyridin-3-yl)-2-cyclopropylamino-nicotinamide (51. Ig, purity: 95%, yield:79%) was obtained as a light yellow solid.
With potassium fluoride; In o-xylene; at 25 - 140℃; for 5 - 9h;In autoclave;Product distribution / selectivity; 2-Chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridine carboxamide (10 g), potassium fluoride (6.17 g), cyclopropylamine (8.08 g) were suspended in o-xylene (30 ml) and heated to 130-1400C in autoclave for 5-6 h. Then the reaction mass was cooled to 25-30C, diluted with o-xylene (50 ml) and further heated the reaction mass to 70-75C. Thereafter, DM water (30iota ml), added and stirred for 10 min at 70-75C. The aqueous layer was separated at hot condition and organic layer was washed with DM water (30 ml) at 70-750C and organic layer was concentrated at 60-630C under reduced pressure. The concentrated mass was cooled to 25-300C and stirred for 15 min and further cooled to 5-100C and stirred for 30 min. Filtered the solid obtained and washed with chilled o-xylene (10 ml, 5-100C). Dried the obtained solid at 45- 500C under reduced pressure. Yield - 9.85 g HPLC purity - 99.28 %; 2-Chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridine carboxamide (100 g), potassium fluoride (22.62 g), cyclopropylamine (80.85 g) were suspended in o-xylene (300 ml) and heated to 130-1400C in autoclave for 5-9 h. Then the reaction mass was cooled to 25-30C, diluted with o-xylene (500 ml) and further heated the reaction mass to 70-750C. Thereafter, DM water (300 ml) added and stirred for 10 min at 70- 75C. The aqueous layer was separated at hot condition and organic layer was washed with DM water (300 ml) at 70-750C and organic layer was concentrated at 60-630C under reduced pressure up to residue weight attained is approximately 400 g. The concentrated mass was cooled to 25-300C and stirred for 15 min and further cooled to 5-100C and stirred for 30 min. Filtered the solid obtained and washed with chilled o-xylene (100 ml, 5-100C). Dried the obtained solid at 50-600C under reduced pressure. Yield - 97 g HPLC purity - 99.85 %; 2-Chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridine carboxamide (100 g), potassium fluoride (41.13 g), cyclopropylamine (80.85 g) were suspended in o-xylene (300 ml) and heated to 130-1400C in autoclave for 5-9 h. Then the reaction mass was cooled to 25-300C, diluted with o-xylene (500 ml) and further heated the reaction mass to 70-750C. Thereafter, DM water (300 ml) added and stirred for 10 min at 70- 75C. The aqueous layer was separated at hot condition and organic layer was washed with DM water (300 ml) at 70-750C and organic layer was concentrated at <n="8"/>60-63C under reduced pressure up to residue weight attained is approximately 400 gThe concentrated mass was cooled to 25-300C and stirred for 15 min and furthei cooled to 5-100C and stirred for 30 min. Filtered the solid obtained and washed wit. chilled o-xylene (100 ml, 5-1O0C). Dried the obtained solid at 50-600C under reducec pressure.Yield - 95 gHPLC purity - 99.76 %; 2-Chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridine carboxamide (50 g), potassium fluoride (30.85.g), cyclopropylamine (40.43 g) were suspended in o-xylene (150 ml) and heated to 130-140C in autoclave for 5-8 h. Then the reaction mass was cooled to 25-300C, diluted with o-xylene (250 ml) and further heated the reaction mass to 70-75C. Thereafter, DM water (150 ml) added and stirred for 10 min at 70- 75C. The aqueous layer was separated at hot condition and organic layer was washed with DM water (150 ml) at 70-750C and organic layer was concentrated at 60-630C under reduced pressure up to residual weight attained is approximately 200 g. The concentrated mass was cooled to 25-300C and stirred for 15 min and further cooled to 5-100C and stirred for 30 min. Filtered the solid obtained and washed with chilled o-xylene (50 ml, 5-100C). Dried the obtained solid at 45-500C under reduced pressure. Yield - 46.5 g Assay (By HPLC) - 99.9 %.
With sodium phosphate; In o-xylene; at 130 - 140℃; for 6 - 8h;In S.S. bomb;Product distribution / selectivity; 2-Chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridine carboxamide (15 g), tri sodium phosphate dodecahydrate (20.21 g), cyclopropylamine (12.12 g) wen suspended in o-xylene (45 ml) and heated to 130-1400C for 6-8 h in S. S. Bomb wit. occational shaking. Then the reaction mass was cooled to 70-750C, diluted with o xylene (75 ml) and DM water (45 ml) and stirred for 10 min at 70-800C. The aqueou: layer was separated and washed the organic layer with DM water (45 ml) at 70-800C The organic layer was concentrated at 60-650C under reduced pressure. Th< concentrated mass was cooled to 5-100C and stirred for 30 min. Filtered the solk obtained and washed with chilled o-xylene (15 ml, 5-100C). Dried the obtained solic at 55-6O0C under reduced pressure. Yield - 14 g HPLC purity - 99 %;
With sodium phosphate; In o-xylene; at 70 - 140℃; for 6 - 8h;In autoclave;Product distribution / selectivity; 2-Chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridine carboxamide (50 g), tri- sodium phosphate dodecahydrate (67.37 g), cyclopropylamine (40.43 g) were suspended in o-xylene (150 ml) and heated to 130-1400C for 6-8 h in autoclave. Then the reaction mass was cooled to 70-750C, diluted with o-xylene (250 ml) and DM water (150 ml) and stirred for 10 min at 70-800C. The aqueous layer was separated and washed the organic layer with DM water (150 ml) at 70-800C. The organic layer was concentrated at 60-650C under reduced pressure up to residual weight attained is <n="10"/>approximately 200 g. The concentrated mass was cooled to 5-1O0C and stirred for 30 min. Filtered the solid obtained and washed with chilled o-xylene (50 ml, 5-100C).Dried the obtained solid at 55-6O0C under reduced pressure.Yield - 46.5 gHPLC purity - 99.70 %
With potassium fluoride; In o-xylene; at 70 - 140℃;In autoclave;Product distribution / selectivity; EXAMPLE 1Preparation of N-(2-chloro-4-methyl-3-pyridyl)-2-(cyclopropylamino)-3-pyridine carboxamide2-Chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridine carboxamide (10 g), potassium fluoride (6.17 g), cyclopropylamine (8.08 g) were suspended in o-xylene (30 ml) and heated to 130-140 C. in autoclave for 5-6 h. Then the reaction mass was cooled to 25-30 C., diluted with o-xylene (50 ml) and further heated the reaction mass to 70-75 C. Thereafter, DM water (30 ml), added and stirred for 10 min at 70-75 C. The aqueous layer was separated at hot condition and organic layer was washed with DM water (30 ml) at 70-75 C. and organic layer was concentrated at 60-63 C. under reduced pressure. The concentrated mass was cooled to 25-30 C. and stirred for 15 min and further cooled to 5-10 C. and stirred for 30 min. Filtered the solid obtained and washed with chilled o-xylene (10 ml, 5-10 C.). Dried the obtained solid at 45-50 C. under reduced pressure. Yield-9.85 g HPLC purity-99.28%

  • 3
  • 2-chloronicotinoyl chloride [ No CAS ]
  • [ 133627-45-9 ]
  • [ 133627-46-0 ]
YieldReaction ConditionsOperation in experiment
With pyridine; In 1,4-dioxane; dichloromethane; cyclohexane; c 2-Chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridinecarboxamide Using a procedure analogous to that described in Example 1a, the carboxamide was prepared from 12.8 g of 3-amino-2-chloro-4-methyl pyridine, 15.8 g of 2-chloronicotinoyl chloride, 7.1 g of pyridine, 30 ml of cyclohexane and 60 ml of dioxane. After removal of the solvent, the product was dissolved in methylene chloride, washed with water and dried (sodium sulfate). After removal of the solvent, the residue was washed with ethyl acetate to give 1.2 g of the title compound, m.p. 193-194 C.
 

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