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Chemical Structure| 98-98-6
Chemical Structure| 98-98-6
Structure of 98-98-6 * Storage: {[proInfo.prStorage]}
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Product Details of [ 98-98-6 ]

CAS No. :98-98-6 MDL No. :MFCD00006293
Formula : C6H5NO2 Boiling Point : -
Linear Structure Formula :- InChI Key :SIOXPEMLGUPBBT-UHFFFAOYSA-N
M.W : 123.11 Pubchem ID :1018
Synonyms :
PCL 016

Calculated chemistry of [ 98-98-6 ]

Physicochemical Properties

Num. heavy atoms : 9
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 : 31.2
TPSA : 50.19 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.54 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.74
Log Po/w (XLOGP3) : 0.72
Log Po/w (WLOGP) : 0.78
Log Po/w (MLOGP) : -1.13
Log Po/w (SILICOS-IT) : 0.75
Consensus Log Po/w : 0.37

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.56

Water Solubility

Log S (ESOL) : -1.48
Solubility : 4.04 mg/ml ; 0.0328 mol/l
Class : Very soluble
Log S (Ali) : -1.35
Solubility : 5.47 mg/ml ; 0.0444 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -1.35
Solubility : 5.46 mg/ml ; 0.0444 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.04

Safety of [ 98-98-6 ]

Signal Word:Danger Class:N/A
Precautionary Statements:P264-P270-P280-P305+P351+P338-P310-P330-P403-P501 UN#:N/A
Hazard Statements:H302-H318 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 98-98-6 ]

* 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.

  • Upstream synthesis route of [ 98-98-6 ]
  • Downstream synthetic route of [ 98-98-6 ]

[ 98-98-6 ] Synthesis Path-Upstream   1~52

  • 1
  • [ 98-98-6 ]
  • [ 63071-10-3 ]
Reference: [1] Inorganic Chemistry, 2013, vol. 52, # 11, p. 6481 - 6501
[2] Bulletin of the Chemical Society of Japan, 2015, vol. 88, # 6, p. 784 - 791
  • 2
  • [ 98-98-6 ]
  • [ 15862-72-3 ]
Reference: [1] Journal of the Chemical Society, 1931, p. 437,441
  • 3
  • [ 98-98-6 ]
  • [ 19798-80-2 ]
Reference: [1] Archiv der Pharmazie, 2013, vol. 346, # 11, p. 840 - 850
[2] European Journal of Medicinal Chemistry, 2014, vol. 76, p. 531 - 538
[3] Patent: CN108440402, 2018, A,
[4] Patent: WO2008/77188, 2008, A1,
  • 4
  • [ 98-98-6 ]
  • [ 63071-13-6 ]
Reference: [1] Inorganic Chemistry, 2013, vol. 52, # 11, p. 6481 - 6501
[2] Bulletin of the Chemical Society of Japan, 2015, vol. 88, # 6, p. 784 - 791
  • 5
  • [ 98-98-6 ]
  • [ 5346-38-3 ]
Reference: [1] Helvetica Chimica Acta, 1996, vol. 79, # 1, p. 295 - 306
  • 6
  • [ 98-98-6 ]
  • [ 16744-81-3 ]
Reference: [1] Bulletin of the Chemical Society of Japan, 2015, vol. 88, # 6, p. 784 - 791
  • 7
  • [ 98-98-6 ]
  • [ 19621-92-2 ]
Reference: [1] Tetrahedron Letters, 1988, vol. 29, # 35, p. 4389 - 4392
[2] Organic and Biomolecular Chemistry, 2004, vol. 2, # 15, p. 2253 - 2261
  • 8
  • [ 98-98-6 ]
  • [ 99586-65-9 ]
YieldReaction ConditionsOperation in experiment
95%
Stage #1: With sodium bromide In thionyl chlorideReflux
Stage #2: With ammonia In water at 20℃;
580 g of 2-pyridinecarboxylic acid was slowly added to 1.68 kg of thionyl chloride, and after completion, 48 g of sodium bromide was added thereto, and the reaction liquid was refluxed for 2 to 16 hours until the reaction of the raw materials was completed, and the thionyl chloride was recovered. 680 g of 4-chloropyridine-2-acid chloride were obtained; 4-Chloropyridine-2-acid chloride is added in batches to 4 kg of 30percent ammonia water and stirred at room temperature for 5-16 hours until the reactionAfter completion, most of the water is removed, the temperature is lowered to 0-5 ° C, and the white solid is precipitated to give 4-chloropyridine-2-amide, 550 g, yield.95percent.
Reference: [1] Patent: CN108440402, 2018, A, . Location in patent: Paragraph 0008; 0020-0021; 0024-0025; 0028-0029
[2] Archiv der Pharmazie, 2013, vol. 346, # 11, p. 840 - 850
[3] European Journal of Medicinal Chemistry, 2014, vol. 76, p. 531 - 538
  • 9
  • [ 98-98-6 ]
  • [ 5470-22-4 ]
YieldReaction ConditionsOperation in experiment
28%
Stage #1: for 20 h; Heating / reflux
Stage #2: at -2 - 2℃;
A suspension of picolinic acid (0.79 g, 6.35 mmol) and sodium bromide (1.30 g, 12.7 mmol) in 10 mL of thionyl chloride was heated under mild reflux for 20 h. The initially dark green mixture had changed to a dark red colour. Excess SOCl2 was removed by rotary evaporation and <n="50"/>the orange residue was taken up in about 15 mL of CH2CI2 and was filtered through celite to get rid of any insoluble residues. The orange filtrate was cooled to - 2°C and 20 mL of H2O (doubly distilled) was added dropwise while stirring vigorously, keeping the temperature between -2 and 2°C. The solution changed to a lighter orange colour and a white precipitate formed. The mixture was further stirred at r.t. for 20 h. The CH2Cl2 and H2O were removed by rotary evaporation. The solid was recrystallised from a minimum amount of EtOH to give a yield of 0.28 g (28percent) .1H NMR (DMS0-dff) : δ = 8.72 (I H, d, J = 4.9 Hz), 8.09 (1 H, d, J = 1.6 Hz), 7.84 (1 H, dd, J = 4.9, 1.6 Hz)
28%
Stage #1: for 20 h; Heating / reflux
Stage #2: at -2 - 2℃;
A suspension of picolinic acid (0.79 g, 6.35 mmol) and sodium bromide (1.30 g, 12.7 mmol) in 10 mL of thionyl chloride was heated under mild reflux for 20 h. The initially dark green mixture had changed to a dark red colour. Excess SOCl2 was removed by rotary evaporation and <n="50"/>the orange residue was taken up in about 15 mL of CH2CI2 and was filtered through celite to get rid of any insoluble residues. The orange filtrate was cooled to - 2°C and 20 mL of H2O (doubly distilled) was added dropwise while stirring vigorously, keeping the temperature between -2 and 2°C. The solution changed to a lighter orange colour and a white precipitate formed. The mixture was further stirred at r.t. for 20 h. The CH2Cl2 and H2O were removed by rotary evaporation. The solid was recrystallised from a minimum amount of EtOH to give a yield of 0.28 g (28percent) .1H NMR (DMS0-dff) : δ = 8.72 (I H, d, J = 4.9 Hz), 8.09 (1 H, d, J = 1.6 Hz), 7.84 (1 H, dd, J = 4.9, 1.6 Hz)
Reference: [1] Patent: WO2008/17855, 2008, A1, . Location in patent: Page/Page column 48-49
[2] Patent: WO2008/17855, 2008, A1, . Location in patent: Page/Page column 48-49
[3] Synthetic Communications, 1996, vol. 26, # 10, p. 2017 - 2025
[4] Patent: US2006/160803, 2006, A1, . Location in patent: Page/Page column 136
[5] Patent: EP1650194, 2006, A1, . Location in patent: Page/Page column 37
[6] Organic and Biomolecular Chemistry, 2013, vol. 11, # 5, p. 732 - 745
[7] Arkivoc, 2012, vol. 2012, # 3, p. 90 - 103
[8] Patent: WO2013/86266, 2013, A2, . Location in patent: Paragraph 00091
[9] Archiv der Pharmazie, 2013, vol. 346, # 11, p. 840 - 850
[10] European Journal of Medicinal Chemistry, 2014, vol. 81, p. 47 - 58
  • 10
  • [ 98-98-6 ]
  • [ 7719-09-7 ]
  • [ 5470-22-4 ]
  • [ 88912-25-8 ]
  • [ 496849-77-5 ]
Reference: [1] Journal fuer Praktische Chemie (Leipzig), 1932, vol. &lt;2&gt; 133, p. 36,49
  • 11
  • [ 98-98-6 ]
  • [ 405939-79-9 ]
Reference: [1] Patent: WO2013/86266, 2013, A2,
[2] Patent: US9533973, 2017, B2,
  • 12
  • [ 98-98-6 ]
  • [ 1452-63-7 ]
YieldReaction ConditionsOperation in experiment
14.6%
Stage #1: With sulfuric acid In methanol for 12 h; Reflux
Stage #2: With hydrazine hydrate In methanol for 12 h; Reflux
Add to the reaction flask2-picolinic acid (12.31 g, 100 mmol) and methanol (100 ml) were added dropwise 2 mL of concentrated sulfuric acid,Heated to reflux for 12 h. After cooling to room temperature, 20 mL of deionized water was added, and most of the methanol was removed under reduced pressure by a rotary evaporator, followed by extraction with ethyl acetate (100 mL x 5).The resulting organic liquid was dried in anhydrous, filtered, and the solvent was distilled off under reduced pressure. The resulting colorless transparent liquid was dried in a vacuum oven at 50C for 24 hours.To the above-mentioned intermediate was added 100 mL of methanol and 30 mL of 85percent hydrazine hydrate, stirred and refluxed for 12 h.After cooling, the mixture was poured into 200 mL of deionized water and extracted with dichloromethane (100 mL x 5).The resulting organic phase was dried over anhydrous MgSO4 and dried to remove the solid. The resulting filtrate was concentrated, added dropwise to 200 mL of vigorously stirred n-hexane, and stirring was continued for 30 min.The resulting white solid was washed with n-hexane and dried in a vacuum oven at 50 ° C for 24 h to give the product as a white solid, 2-pyridinecarboxylic acid hydrazide (2.0 g, 14.6 mmol) in 14.6percent yield.
Reference: [1] Zeitschrift fur Naturforschung - Section B Journal of Chemical Sciences, 2011, vol. 66, # 12, p. 1202 - 1208
[2] Patent: CN104262404, 2017, B, . Location in patent: Paragraph 0045; 0047
[3] Organic Preparations and Procedures International, 2003, vol. 35, # 4, p. 369 - 374
[4] Indian Journal of Chemistry - Section A Inorganic, Physical, Theoretical and Analytical Chemistry, 2002, vol. 41, # 12, p. 2544 - 2547
[5] Australian Journal of Chemistry, 1985, vol. 38, # 10, p. 1491 - 1497
[6] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 1, p. 184 - 187
[7] Asian Journal of Chemistry, 2010, vol. 22, # 7, p. 5535 - 5542
[8] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 16, p. 5185 - 5189
[9] Journal of Heterocyclic Chemistry, 2012, vol. 49, # 5, p. 1114 - 1119,6
[10] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 8, p. 2286 - 2297
[11] Photochemistry and Photobiology, 2013, vol. 89, # 5, p. 1020 - 1028
[12] Organic and Biomolecular Chemistry, 2014, vol. 12, # 27, p. 4975 - 4982
[13] Archiv der Pharmazie, 2014, vol. 347, # 8, p. 576 - 588
[14] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2014, vol. 54B, # 2, p. 228 - 239
[15] Dalton Transactions, 2015, vol. 44, # 9, p. 4123 - 4132
[16] Russian Journal of General Chemistry, 2015, vol. 85, # 3, p. 746 - 751
[17] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 13, p. 3397 - 3407
[18] New Journal of Chemistry, 2015, vol. 39, # 12, p. 9535 - 9542
[19] Research on Chemical Intermediates, 2016, vol. 42, # 12, p. 8201 - 8215
[20] Journal of Heterocyclic Chemistry, 2017, vol. 54, # 2, p. 1423 - 1429
[21] ChemMedChem, 2017, vol. 12, # 12, p. 972 - 985
[22] Patent: CN107011255, 2017, A,
[23] Journal of Heterocyclic Chemistry, 2017, vol. 54, # 5, p. 2773 - 2780
[24] Inorganica Chimica Acta, 2018, vol. 479, p. 148 - 153
  • 13
  • [ 1702-17-6 ]
  • [ 98-98-6 ]
  • [ 57266-69-0 ]
Reference: [1] Electrochimica Acta, 2016, vol. 210, p. 762 - 772
[2] Electrochimica Acta, 2016, vol. 210, p. 762 - 772
  • 14
  • [ 98-98-6 ]
  • [ 57266-69-0 ]
Reference: [1] Tetrahedron, 2002, vol. 58, # 33, p. 6723 - 6728
  • 15
  • [ 98-98-6 ]
  • [ 73841-32-4 ]
YieldReaction ConditionsOperation in experiment
66%
Stage #1: With 2,2,6,6-tetramethyl-piperidine; n-butyllithium In tetrahydrofuran at -78 - 30℃; for 0.5 h;
Stage #2: With iodine In tetrahydrofuran at 20℃; for 1 h;
A solution of 2,2,6,6-tetramethylpiperidine (8.48 g, 60 mmol) in tetrahydrofuran (100 mL)Cooling to -78 deg C, N-butyllithium (2.5 mol / L, 16 mL, 40 mmol) was added dropwise, Slowly warmed to room temperature for 30 minutes. Cooling to -78 deg C, This was added dropwise to a suspension of pyridine-2-carboxylic acid (2.46 g, 20 mmol) in tetrahydrofuran, After completion of the dropwise addition, the reaction was allowed to proceed at room temperature for 30 minutes, Cooling to -30 deg C, A solution of iodine (15.23 g, 60 mmol) in tetrahydrofuran was added dropwise to the reaction flask, The mixture was stirred at room temperature for 1 hour, add water, Standing overnight Precipitation of solids, The target compound was filtered (3.3 g, yield 66percent).
41%
Stage #1: With 2,2,6,6-tetramethyl-piperidine; n-butyllithium In tetrahydrofuran; hexanes at -78 - 0℃; for 0.916667 h;
Stage #2: With iodine In tetrahydrofuran; hexanes at 0 - 25℃; for 1.25 h;
Stage #3: at 25℃; for 2 h;
Description 1; 3-Iodo-2-pyridinecarboxylic acid (D1); To a stirred solution of 2,2,6,6-tetramethylpiperidine (20 ml, 0.122 mol) in dry THF (100 ml) at -78° C., under argon was added n-butyllithium (52 ml, 0.163 mol, 2.5M solution in hexanes) dropwise, followed 15 min later by a solution of 2-pyridinecarboxylic acid (5.0 g, 0.0407 mol) in dry THF (30 ml). After 10 min at -78° C., the reaction mixture was warmed to 0° C. for 30 min. and then transferred to a solution of iodine (30.9 g, 0.243 mol) in dry THF (70 ml) at 0° C., under argon. After 15 min at 0° C. the reaction mixture was warmed to 25° C. and stirred for 1 h. After this period water (80 ml) was added and the reaction mixture concentrated in vacuo. The residue was re-dissolved in water (100 ml) and washed with EtOAc (100 ml). The aqueous layer was separated, concentrated in vacuo and the resulting residue triturated with diethyl ether. The solid material was filtered and dried in vacuo before being re-dissolved in MeOH (200 ml). To this solution was added Amberlyte IR-120 ion-exchange resin (100 g) and the reaction mixture stirred at 25° C. for 2 h. After this period the resin was filtered off and the solvents concentrated in vacuo to afford the title compound (4.15 g, 41percent). δH (DMSO-d6, 250 MHz) 6.79 (1H, bs) 7.28 (1H, dd), 8.37 (1H, dd), 8.58 (1H, dd). MS (ES): C6H41NO2 requires 249. found (M-H+) 248.
41%
Stage #1: With 2,2,6,6-tetramethyl-piperidine; n-butyllithium In tetrahydrofuran; hexane at -78 - 0℃; for 0.916667 h;
Stage #2: With iodine In tetrahydrofuran; hexane at 0 - 25℃; for 1.25 h;
Stage #3: With water In tetrahydrofuran; hexane
Description 1; 3-lodo-2-pyridinecarboxylic acid (D1);To a stirred solution of 2,2,6,6-tetramethylpiperidine (20ml, 0.122mol) in dry THF (100ml) at -78 °C, under argon was added /7-butyllithium (52ml, 0.163mol, 2.5M EPO <DP n="40"/>solution in hexanes) dropwise, followed 15min later by a solution of 2- pyridinecarboxylic acid (5.Og, 0.0407mol) in dry THF (30ml). After 10min at -78 0C, the reaction mixture was warmed to 00C for 30 min. and then transferred to a solution of iodine (30.9g, 0.243mol) in dry THF (70ml) at 00C, under argon. After 15min at O0C the reaction mixture was warmed to 25°C and stirred for 1h. After this period water (80ml) was added and the reaction mixture concentrated in vacuo. The residue was re-dissolved in water (100ml) and washed with EtOAc (100ml). The aqueous layer was separated, concentrated in vacuo and the resulting residue triturated with diethyl ether. The solid material was filtered and dried in vacuo before being re- dissolved in MeOH (200ml). To this solution was added Amberlyte IR-120 ion- exchange resin (100g) and the reaction mixture stirred at 25°C for 2h. After this period the resin was filtered off and the solvents concentrated in vacuo to afford the title compound (4.15g, 41percent). δH (DMSO-d6, 250MHz) 6.79 (1H, bs) 7.28 (1H, dd), 8.37 (1 H, dd), 8.58 (1H, dd). MS (ES): C6H4INO2 requires 249; found (M-H+) 248.
Reference: [1] Patent: CN106317027, 2017, A, . Location in patent: Paragraph 0246; 0247; 0248
[2] Patent: US2008/312209, 2008, A1, . Location in patent: Page/Page column 13
[3] Patent: WO2007/7018, 2007, A1, . Location in patent: Page/Page column 38-39
[4] Tetrahedron, 2002, vol. 58, # 33, p. 6723 - 6728
[5] Patent: WO2006/25783, 2006, A1, . Location in patent: Page/Page column 120-121
[6] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 17, p. 4236 - 4238
  • 16
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  • [ 874-24-8 ]
Reference: [1] Heterocyclic Communications, 2003, vol. 9, # 5, p. 489 - 492
[2] Polish Journal of Chemistry, 2005, vol. 79, # 11, p. 1813 - 1819
[3] Croatica Chemica Acta, 2010, vol. 83, # 3, p. 291 - 298
  • 17
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  • [ 107-15-3 ]
  • [ 7471-05-8 ]
Reference: [1] Analytical Chemistry, 1954, vol. 26, p. 217,218
  • 18
  • [ 98-98-6 ]
  • [ 7719-09-7 ]
  • [ 5470-22-4 ]
  • [ 88912-25-8 ]
  • [ 496849-77-5 ]
Reference: [1] Journal fuer Praktische Chemie (Leipzig), 1932, vol. &lt;2&gt; 133, p. 36,49
  • 19
  • [ 98-98-6 ]
  • [ 67-56-1 ]
  • [ 24484-93-3 ]
YieldReaction ConditionsOperation in experiment
85%
Stage #1: at 20 - 72℃; for 16.6667 h;
Stage #2: at 20 - 55℃; for 0.75 h;
Stage #3: With water; sodium hydrogencarbonate In methanol at 45℃;
Example 1Preparation of (R)-4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)-N-(1-(hydroxyamino)-1-oxopropan-2-yl)picolinamide (Compound 1)Step 1a. Methyl 4-chloropicolinate (Compound 102); Anhydrous DMF (10 mL) was slowly added to SOCl2 (300 mL) at 40-48° C. The solution was stirred at room temperature for 10 minutes, and then compound 101 (100.0 g, 813.0 mmol) was added over 30 minutes. The resulting solution was heated at 72° C. (Vigorous SO2 evolution) for 16 h to generate a yellow solid. The resting mixture was cooled to room temperature, diluted with toluene (500 mL) and concentrated to 200 mL. The toluene addition/concentration process was repeated twice. The resulting solution and solid was added into 200 mL methanol at ice bath to keep the internal temperature below 55° C. The content were stirred at r.t. for 45 min, cooled to 5° C. and treated with Et2O (200 mL) dropwise. The resulting solid were filtered, washed with Et2O (200 mL) and dried under 35° C. to provide a white yellow solid. After the solid were solvated to hot water (500 mL, about 45° C.), NaHCO3 was added to adjust pH to 8-9. The mixture was extracted with ethyl acetate and the organic phase was concentrated to give desired compound 102 as a off-white solid (118.2 g, 85percent). LCMS: 172 [M+1]+.
71%
Stage #1: With thionyl chloride; sodium bromide In water; chlorobenzene for 16 h; Reflux; Large scale
Stage #2: for 1 h; Reflux; Large scale
77 Kg of chlorobenzene, 50 Kg of 2-picolinic acid, 6.7 Kg of sodium bromide, 360 g of water,Stirring the temperature to 72 ° C and control the temperature at60 ~ 72 ° C between the sulfide sulfone 270Kg dripping, slowly warming to reflux, the reaction 16 hours, most of the distillation of thionyl chloride under reduced pressure, adding 160Kg toluene, evaporated under reduced pressure thionyl chloride. Cooled to 10 ° C, 70 Kg of methanol was added dropwise, and the mixture was refluxed for 1 hour. The methanol was evaporated under reduced pressure and filtered to give a yellow solid. Add 150Kg of water dissolved, stirring slowly into the sodium carbonate solid neutralization to ρΗ7, filtered to obtain a yellow solid. The solid was recrystallized from water and air dried at 40 ° C to give a white crystal of 49.5 kg, yield 71.0 ο Μ 40 ^ 42 ° C, HPLC 99.6percent 0
65% Heating / reflux Example 2.4: Preparation of 3-Hydroxy-8-morpholin-4-yl-4-oxo-4//-pyrido[l,2- α]pyrimidine-2-carboxylic acid methyl ester; rt t-Butanol 2-Picolinic acid was reacted with thionyl chloride and methanol to provide methyl 4- chloro-2-picolinate which was hydrolysed and the hydrochloride salt and subjected to a Curtius rearrangement. Cleavage of the Boc protecting group afforded 2-amino-4- chloropyridine. The procedure described in W02006040520 was adapted to introduce the morpholine at position 4. This was cyclised to the intermediate ester using an adaptation of the procedure described in Example 2 where the reaction was performed at 60° C.1H NMR (300 MHz, DMSO-/) δ 3.43 (t, J=4.7 Hz, 4H), 3.73 (t, J=4.7 Hz, 4H), 3.85 (s, 3H), 6.67 (d, J=2.4 Hz, 1H),7.27 (dd, J=8.2 Hz, 2.5 Hz, IH), 8.59 (d, J=8.2 Hz, IH), 9.29-9.63 (brs, IH) MS (ESI+) m/z 328 (M+23)
64%
Stage #1: at 80℃; for 5 h;
Stage #2: at 20℃; for 0.5 h;
A mixture of picolinic acid (10.0 g, 81.0 mmol, 1 equiv.) and sodium bromide (16.7 g, 162.0 mmol, 2 equiv.) in thionyl chloride (41 mL) was refluxed for 5 h at 80° C. After that, the solvent was removed under the vacuum at 85° C. to afford the brown residue. 80 mL of anhydrous methanol was slowly added into the residue and the mixture was stirred at room temperature for half an hour. The solvent was evaporated, and the residue was taken up in the saturated sodium bicarbonate and extracted with ethyl acetate (three times). The organic layers were combined, washed with saturated brine, dried over anhydrous Na2SO4 and evaporated. The residue was purified by silica gel column; eluting with 33percent EtOAc in hexane afforded 4-chloropicolinic acid methyl ester (CYD-1-1) (8.0 g, 64percent) as a brown solid; silica gel TLC Rf=0.15 (1:3 EtOAc/hexane); mp 55-56° C.; 1H NMR (600 MHz, CDCl3) δ 8.67 (d, 1H, J=4.8 Hz), 8.16 (d, 1H, J=1.8 Hz), 7.51 (m, 1H), 4.04 (s, 3H).
58%
Stage #1: With thionyl chloride In water at 0℃; for 120.5 h; Reflux
Stage #2: at 20℃; for 1 h;
To a cooled (0 °C) solution of picolinic acid (5.0 g, 40.6 mmol) in SOCl2 (15 mL) was carefully added H2O (950 μL). After refluxing for 30 min, SOCl2 (5 mL) was added at rt and the mixture was reflux for 3 days. SOCl2 (10 mL) and H2O (950 μL) was added at rt and the mixture was refluxed for further 2 days. After concentration under reduced pressure, the residue was dissolved in dry toluene (30 mL). MeOH (2.5 mL) was added, and the mixture was stirred at rt for 1 hr. After filtration, the solid was dissolved in CHCl3 and washed with sat. NaHCO3.The extracts were dried over MgSO4 and concentrated by evaporation. The residue was purified by flash column chromatography on SiO2 (hexane : AcOEt = 3 : 1) to give 24 (4.1 g, 58 percent) as a pale yellow solid.
44%
Stage #1: With thionyl chloride In DMF (N,N-dimethyl-formamide) at 45 - 80℃; for 24.75 h;
Stage #2: at 0℃; for 1 h;
60 mi Thionylchloride are heated to a temperature of 45 °C under a nitrogen atmosphere and 1.83 mi DIMETHYLFORMAMIDE is added slowly. 20 g Pyridin-2-carboxylic acid is added to the solution in portions, the reaction mixture is stirred another 15 min at 45 °C and then heated to 80 °C for 24 hrs. The reaction mixture is evaporated and the resulting residue treated with dry toluene as a carrier and then evaporated. This procedure is repeated several times. The resulting oil is dissolved in toluene, cooled to 0 °C, slowly treated with methanol and stirred for one hour. The resulting precipitate is filtered by suction, washed with toluene and recrystallised from acetone. Yield : 15 g (44 percent) 1, colourless crystals
44%
Stage #1: With thionyl chloride In DMF (N,N-dimethyl-formamide) at 45 - 80℃; for 24 h;
Stage #2: at 0℃; for 1 h;
1) Synthesis of (4-Chloropvridine-2-carboxylic acid)-methvlamide (2) ci I 1. SOC12 CH NH DMF MgClz _ O \\ THF O 2. MeOH N N Toluene 1 60 ml of thionylchloride are heated to 45 °C under a N2 atmosphere, and slowly mixed with 1.83 ml dimethyl formamide. To this solution, 20 g of pyridine-2-carboxylic acid are added portion wise. The reaction mixture is stirred for another 15 min at 45 °C and subsequently kept at 80 °C for 24 hours. The reaction mixture is evaporated to dryness, the residue is stripped several times with water free toluene. The oil obtained by this procedure is dissolved in toluene, chilled to 0 °C, slowly mixed with methanol and stirred for 1 hour. The precipitated solid is separated by suction filtration, washed with toluene and recrystallized from acetone. Yield : 15 g (44 percent) of 1, colorless crystals
39.6%
Stage #1: With thionyl chloride In N,N-dimethyl-formamide at 20 - 72℃; for 16 h;
Stage #2: at 20 - 55℃; for 0.75 h;
Anhydrous DMF (1 mL) was slowly added to sulfurous di chloride (30 mL) at 45 °C. The solution was stirred at room temperature for 10 min, and then picolinic acid (10 g, 81 mmol) was added over 30 min. The resulting solution was heated at 72 °C for 16 hours to generate a yellow solid. The mixture was cooled to room temperature, diluted with toluene (50 mL) and concentrated to 20 mL. The toluene addition/ concentration process was repeated twice. The resulted solid was added into 20 mL methanol at ice bath to keep the internal temperature below 55 °C. The mixture was stirred at room temperature for 45 min, cooled to 5 °C and treated with ethyl ether (20 mL) dropwise. The resulted solid was filtered, washed with ethyl ether (20 mL) and dried under 35 °C to provide a white yellow solid. After the solid was solvated with hot water (50 mL, 45 °C), sodium bicarbonate aqueous solution was added to adjust pH to 8-9. The mixture was extracted with ethyl acetate (2 x 30 mL) and the organic phase was concentrated to give desired compound (5.5 g, yield: 39.6percent) as a off-white solid.
25 g
Stage #1: at 0 - 20℃; for 7 h; Reflux
Stage #2: for 16 h; Reflux
Stage #3: for 2 h; Reflux
To 150 g of thionyl chloride, 38 g of a mixture of 2-pyridinecarboxylic acid hydrochloride and methyl 2-pyridinecarboxylate hydrochloride and 3 g of sodium bromide were added,Slowly warmed to reflux and then maintained at reflux for 16 h. After cooling down to 40 ° C, 200 g of toluene was added, the thionyl chloride was distilled off under reduced pressure, the temperature was lowered to 10 ° C, and 50 g of methanol was added dropwise and refluxed for 2 h. And then cooled to 0 ° C. The filtrate was washed with toluene and suspended in 10 ° C water. Sodium carbonate was added to precipitate a pale yellow solid. The solid was filtered off, recrystallized from water and dried at room temperature for 18 hours to obtain 25 g of white needle crystals.

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[2] Patent: CN105175325, 2017, B, . Location in patent: Paragraph 0024; 0025
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[4] Patent: US9533973, 2017, B2, . Location in patent: Page/Page column 34
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[8] Patent: WO2005/58832, 2005, A1, . Location in patent: Page/Page column 157
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[10] Patent: WO2014/206344, 2014, A1, . Location in patent: Page/Page column 141
[11] Patent: WO2008/60568, 2008, A2, . Location in patent: Page/Page column 57
[12] Patent: WO2008/70014, 2008, A2, . Location in patent: Page/Page column 53
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[15] Patent: CN105218436, 2016, A, . Location in patent: Paragraph 0014
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YieldReaction ConditionsOperation in experiment
72% With sodium bromide In methanol; thionyl chloride; sodium hydrogencarbonate Method P
4-Chloropicolinic acid methyl ester
A mixture of picolinic acid (20 g, 162 mmol, 1 equiv) and sodium bromide (33.43 g, 325 mmol, 2 equiv) in thionyl chloride (81 mL) was refluxed for 5 h.
The solvent was removed under vacuum.
Absolute methanol (160 mL) was added and the mixture was stirred at rt for 30 minutes.
The solvent was evaporated, and the residue was taken up in 5percent sodium bicarbonate and extracted with ethyl acetate (3*).
The organic layers were combined and dried over MgSO4 and evaporated.
The residue was purified by chromatography to afford 4-chloropicolinic acid methyl ester (19.9 g, 72percent) as a white solid: 1H NMR (300 MHz, CDCl3) δ 8.63 (d, J=5.4, 1), 8.13 (d, J=2.1, 1), 7.48 (dd, J=2.0, 5.3, 1), 4.00 (s,3).
72% With sodium bromide In methanol; thionyl chloride; sodium hydrogencarbonate Method P
4-Chloropicolinic Acid Methyl Ester
A mixture of picolinic acid (20 g, 162 mmol, 1 equiv) and sodium bromide (33.43 g, 325 mmol, 2 equiv) in thionyl chloride (81 mL) was refluxed for 5 h.
The solvent was removed under vacuum.
Absolute methanol (160 mL) was added and the mixture was stirred at rt for 30 minutes.
The solvent was evaporated, and the residue was taken up in 5percent sodium bicarbonate and extracted with ethyl acetate (3*).
The organic layers were combined and dried over MgSO4 and evaporated.
The residue was purified by chromatography to afford 4-chloropicolinic acid methyl ester (19.9 g, 72percent) as a white solid: 1H NMR (300 MHz, CDCl3) δ 8.63 (d, J=5.4, 1), 8.13 (d, J=2.1, 1), 7.48 (dd, J=2.0, 5.3, 1), 4.00 (s,3).
50% With thionyl chloride In ethyl acetate; N,N-dimethyl-formamide EXAMPLE 21
Preparation of methyl 4-chloro-2-pyridinecarboxylate
To 50° C. thionyl chloride (14.8 mL, 203.1 mmol, 5.0 eq.) was added dry N,N-dimethylformamide (0.62 mL, 8.12 mmol, 0.20 eq.).
The solution was stirred for 15 minutes before picolinic acid (5.0 g, 40.6 mmol) was added as a solid.
The reaction was immediately warmed to reflux.
After 16 hours at reflux, the mixture was cooled to room temperature and concentrated by rotary evaporation.
The residue was diluted with toluene and concentrated again.
The resulting oil was poured into a molar excess of methanol and stirred for 1 hour at room temperature.
The methanol was removed by rotary evaporation, and the resulting crude was partitioned between ethyl acetate and water.
The aqueous layer was adjusted to pH 7 with 1N aqueous sodium hydroxide, and the layers were separated.
The organic layer was washed with brine, dried (MgSO4), and concentrated in vacuo to a dark oil.
Purification by flash chromatography on silica gel eluted on a gradient from 100:0 to 70:30 hexanes/ethyl acetate provided the title compound as a pale orange solid (3.5 g, 50percent): 1H NMR (300 MHz, CDCl3) δ 8.61 (d, 1H), 8.10 (s, 1H), 7.46 (d, 1H), 3.98 (s, 3H); MS m/z 172.1 (MH+).
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YieldReaction ConditionsOperation in experiment
26%
Stage #1: With thionyl chloride In water at 0℃; for 97 h; Reflux
Stage #2: Reflux
Stage #3: for 48 h; Reflux
To a cooled (0 °C) solution of picolinic acid (5.0 g, 40.6 mmol) in SOCl2 (15 mL) was carefully added H2O (950 μL), and the mixture was refluxed for 1 hr. SOCl2 (15 mL) was added at rt and the mixture was refluxed for 2 days. SOCl2 (15 mL) was added at rt and the mixture was refluxed for further 2 days. After removal of the solution under reduced pressure, the residue was dissolved in MeOH (30 mL) and the mixture was refluxed overnight. A solution of NaOMe (4.4 g, 81.2 mmol) in MeOH (50 mL) was added and the mixture was refluxed for further 2 days. After removal the solvent under reduced pressure, the residue was dissolved in water and extracted with CHCl3. The extracts were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on SiO2 (hexane :AcOEt = 1 : 1 → 1: 4 → 1 : 10) to give a solid. This material was washed with hexane-Et2O (1 : 1) to give 16 (1.8 g, 26 percent) as a pale yellow solid.
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YieldReaction ConditionsOperation in experiment
2.48 g
Stage #1: With 1,1'-carbonyldiimidazole In tetrahydrofuran at 10 - 35℃; for 2 h; Inert atmosphere
Stage #2: With magnesium chloride In tetrahydrofuran at 10 - 35℃; Inert atmosphere
A)
methyl 3-oxo-3-(pyridin-2-yl)propanoate
To a solution of picolinic acid (3.08 g) in tetrahydrofuran (62.5 mL) was added 1,1'-carbonyldiimidazole (4.86 g) at room temperature.
The reaction mixture was stirred under an argon atmosphere at room temperature for 2 hr.
To the reaction mixture were added monomethylmonopotassium malonate (3.90 g) and magnesium chloride (2.38 g) at room temperature, and the mixture was stirred under an argon atmosphere at room temperature overnight.
The reaction mixture was neutralized with 2M hydrochloric acid, and extracted with ethyl acetate.
The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate.
The solvent was evaporated under reduced pressure.
The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.48 g).
MS (API+): [M+H]+180.1.
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