Home Cart 0 Sign in  

[ CAS No. 5326-23-8 ]

{[proInfo.proName]} ,{[proInfo.pro_purity]}
Cat. No.: {[proInfo.prAm]}
Chemical Structure| 5326-23-8
Chemical Structure| 5326-23-8
Structure of 5326-23-8 * Storage: {[proInfo.prStorage]}

Quality Control of [ 5326-23-8 ]

Related Doc. of [ 5326-23-8 ]

SDS
Alternatived Products of [ 5326-23-8 ]
Alternatived Products of [ 5326-23-8 ]

Product Details of [ 5326-23-8 ]

CAS No. :5326-23-8 MDL No. :MFCD00006241
Formula : C6H4ClNO2 Boiling Point : 330.1°C at 760 mmHg
Linear Structure Formula :- InChI Key :-
M.W :157.55 g/mol Pubchem ID :79222
Synonyms :

Safety of [ 5326-23-8 ]

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:

Application In Synthesis of [ 5326-23-8 ]

  • Upstream synthesis route of [ 5326-23-8 ]
  • Downstream synthetic route of [ 5326-23-8 ]

[ 5326-23-8 ] Synthesis Path-Upstream   1~24

  • 1
  • [ 5326-23-8 ]
  • [ 133081-24-0 ]
YieldReaction ConditionsOperation in experiment
96% at 100℃; for 4 h; Inert atmosphere 6-Chloronicotinic acid (0.30 g; 1.9 mmol) was added to a64percent hydrazine monohydrate solution (2 mL, 26 mmol) andplaced at 100°C for 4h. Thereafter, the reaction mixtureturned brown and was concentrated to dryness. The residuewas dissolved in water and pH adjusted to 5.5 with concentratedHCl. A precipitate was formed, filtered and washedwith ethanol, then ether to give a yellow solid (0.346 g,96percent). Mp = 292-293°C. IR (ATR, cm-1) 3210; 3058; 3039;1696; 1636; 1613; 1536-1444; 1170; 757; 736. 1H NMR(DMSO-d6) 8.63 (s, 1H); 8.07 (d, 1H, J= 9 Hz); 6.94 (d,1H, J = 9 Hz). 13C NMR (DMSO-d6) 167.2; 159.61;140.9; 119.9; 110.6. HRMS (ESI+) [M]+: 153.0531 observed,153.0538 Calcd for C6H7N3O2.
91% With hydrazine hydrate In ethanolReflux Example 72: 3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carbonyl chloride; [0235] To a solution of 6-chloronicotinic acid (20 g, 127 mmol) in 200 mL of EtOH was added hydrazine hydrate (14.8 mL, 317 mmol). The mixture was refluxed overnight, then cooled to room temperature to give a solid, which was collected by filtration, washed with petroleum ether/EA (2: 1) to give 18 g of 6-hydrazinylnicotinic acid as a yellow solid (Yield: 91percent). 1HNMR (DMSO, 400MHz) δ: 8.52 (s, IH), 7.88 (dd, J = 2.0 Hz, 8.8 Hz, IH), 6.63 (d, J = 8.8Hz, IH).[0236] To a suspension of 6-hydrazinylnicotinic acid (18 g, 117 mmol) in 100 mL of dry THF was added dry pyridine (23 g, 293 mmol), then the mixture was stirred at room temperature for 15 min, then bis(trichloromethyl)carbonate (80 g, 270 mmol) was added slowly. The reaction mixture was stirred overnight at room temperature, then MeOH was added and continued stirring for 15 hours to give a solid. The solid was collected by filtration and washed with petroleum ether/EA (1: 1) to give 20 g of dimethyl 3-oxo-[l,2,4]triazolo[4,3- a]pyridine-2,6(3H)-dicarboxylate. 1HNMR (CDCl3, 400MHz) δ: 3.95 (s, 3H), 4.13 (s, IH), 7.13 (dd, J = 1.6 Hz, 10 Hz, IH), 7.71 (dd, J = 1.6 Hz, 10 Hz, IH), 8.55 (t, J = 2 Hz, IH). [0237] To a solution of dimethyl 3-oxo-[l,2,4]triazolo[4,3-a]pyridine-2,6(3H)-dicarboxylate (10 g, 40 mmol ) in 60 mL of THF and 10 mL of H2O was added LiOH-H2O (4.8 g, 114 mmol), and then the reaction mixture was stirred at room temperature for 6 hours and then was concentrated in vacuo to remove THF, and then 1 mL of aq. HCl solution was added to adjust pH=2 to give a solid which was collected to give 1 Ig of compound 3-oxo-2,3-dihydro- [1 ,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid which was used without the further purification. 1HNMR (DMSO, 400MHz) δ: 7.23 (d, J = IO Hz, IH), 7.48 (dd, J = 1.6 Hz, 10Hz, IH), 8.25 (s, IH), 9.13 (s, IH), 12.89 (s, IH).[0238] To a solution of 3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid (3 g, 16.8 mmol) in 60 mL of dry DCM was added oxalyl chloride (8.8 g, 74 mmol) and 1 mL ofDMF. The reaction mixture was stirred for 6 hrs at room temperature and concentrated to give[0239] 3 g of the title compound as a gray solid which was used without the further purification.
87% With hydrazine In water at 95 - 100℃; for 4 h; A mixture of 6-chloronicotinic acid (10.0 g, 63.4 mmol), hydrazine (20 mL), and water (20 mL) was refluxed at 95-100 °C for 4 h. The mixture was concentrated under vacuum and the residue was dissolved in 40 mL water. The resulting solution was acidified with 1N HCl to reach a pH 5-5.5. The solution was kept in a refrigerator overnight. The precipitated solid was collected by filtration, washed with cold water (10 mL x 2) and ether (10 mL x 2). The solid was dried to give 8.5 g (87percent) of the title compound. ES-MS: Observed [MH]+ 154.1.
85%
Stage #1: With hydrazine hydrate In ethanol for 72 h; Reflux
Stage #2: With acetic acid In water for 0.25 h;
General procedure: A 0.5M solution of 2-chloropyridine-5-carboxylic acid (15 mmol) was treated with hydrazine hydrate (150 mmol, added at once) and heated at reflux for 72 h. The suspension was concentrated to dryness. The residue was dissolved in water and acidified (pH = 3) with acetic acid. The precipitate of 2-hydrazinopyridine-5-carboxylic acid that formed in 15 min was filtered off, washed with water and air-dried. It was dissolved in the respective aliphatic carboxylic acid and the solution (0.5M) was heated at reflux for 48 h. Upon cooling to room temperature, the volatiles were removed in vacuo and the residue was triturated with 1M aqueous sodium bicarbonate. The precipitate thus formed was filtered off, washed with water and air dried. The resulting 1,2,4-triazolo[4,3-a]pyridine 12 was dissolved in methanol (0.25M and was hydrogenated over Pd(OH)2 catalyst (0.1 equiv.) at 100 atm and 100 °C over 24 hours. The mixture was filtered while still hot and concentrated in vacuo. The residue was crystallized from isopropyl alcohol to provide analytically pure carboxylic acids 11a-d.
77% With hydrazine hydrate In water Synthesis of 6-hydrazinopyridine-3-carboxylic acid
6-Chloronicotinic acid (8.0 g) was added to 85percent hydrazine hydrate (35 ml).
The reaction mixture was placed in a 100° C. oil bath for 4 hours.
The homogeneous reaction mixture was concentrated to dryness to give a white solid.
The solid was dissolved in water and on acidification to pH 5.5 with concentrated hydrochloric acid a precipitate formed.
The precipitate was isolated by filtration and the solid was washed with 95percent ethanol and ether to give 6.0 g of a pale brown solid; yield 77percent m.p. 292°-293° C.;
Analysis:
Calculated for C6 H7 N3 O2; C 47.06; H 4.61; N 27.44; Found: C 46.83; H 4.38; N 27.27.
1 H NMR- δ: 6.69(d,J=8.8 Hz,1H),7.84(dd,J=2.4,8.8 Hz,1H), 8.51(d,J=2.4 Hz,1H)
57.7% With hydrazine hydrate In 1,4-dioxane at 90℃; Preparation 6 6-hydrazinylnicotinic acid [0147] A suspension of 6-chloronicotinic acid (30.0 g, 189 mmol) in 1,4-dioxane (29.0 mL) was treated with hydrazine hydrate (134 mL, 1.51 mol) and heated to 90°C overnight. The mixture was cooled to ambient temperature and then in ice for 30 min. Precipitate formation was induced by etching the side of the flask and the precipitate was filtered and re-suspended in EtOH (500 mL) with vigorous stirring. The resulting suspension was filtered. The precipitate was dissolved in water (300 mL) and HC1 (6N) was added until pH = 1. The pH was then adjusted to 5 with NaOH (50percent, aq.) and the resulting suspension was stirred for lh. The solids were collected by filtration and dried in vacuum to give the title compound (16.65 g, 57.7 percent yield) as an off-white solid. XH NMR (400 MHz, DMSO-i/6) δ ppm 6.70 (d, 1 H) 7.86 (dd, J=8.97, 2.15 Hz, 1 H) 8.32 (br. s., 1 H) 8.52 (d, J=1.77 Hz, 1 H). MS m/z [M+H]+ 154.
40% With hydrazine hydrate In ethanol for 48 h; Reflux Synthesis of 6-hydrazinylnicotinic acid To a solution of 6-chloronicotinic acid (5g, 32 mmol)) in EtOll (50 mL) was added hydrazine hydrate (3.7 mL, 80 mmol). The mixture was heated to reflux with stirring for 48 hrs. The mixture was allowed to cooled to r.t. to give a gray precipitatewhich was collected by filtration and then washed with EtCH and petroleum ether/EtOAc (2:1) to give 2 g solid (40percent)

Reference: [1] Letters in Organic Chemistry, 2014, vol. 11, # 3, p. 208 - 214
[2] Patent: WO2010/96722, 2010, A1, . Location in patent: Page/Page column 54-55
[3] Polish Journal of Chemistry, 2004, vol. 78, # 7, p. 951 - 959
[4] Patent: WO2017/177144, 2017, A1, . Location in patent: Page/Page column 33; 39
[5] Pharmazie, 2006, vol. 61, # 4, p. 269 - 273
[6] Tetrahedron Letters, 2016, vol. 57, # 9, p. 1056 - 1059
[7] Patent: US5206370, 1993, A,
[8] Journal of Labelled Compounds and Radiopharmaceuticals, 2001, vol. 44, p. S66 - S68
[9] Journal of the American Chemical Society, 2012, vol. 134, # 28, p. 11392 - 11395
[10] Patent: WO2014/160810, 2014, A1, . Location in patent: Paragraph 0146; 0147
[11] Patent: WO2013/67597, 2013, A1, . Location in patent: Page/Page column 90; 91
[12] Journal of Labelled Compounds and Radiopharmaceuticals, 1997, vol. 40, p. 455 - 457
[13] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 12, p. 3440 - 3444
[14] Chemische Berichte, 1903, vol. 36, p. 1114
[15] Patent: US5659041, 1997, A,
[16] Patent: WO2010/19899, 2010, A1, . Location in patent: Page/Page column 156
[17] Patent: US2010/305085, 2010, A1, . Location in patent: Page/Page column 16
[18] Bioorganic Chemistry, 2011, vol. 39, # 4, p. 138 - 142
[19] Chemical Communications, 2013, vol. 49, # 47, p. 5366 - 5368
[20] RSC Advances, 2015, vol. 5, # 113, p. 93374 - 93385
[21] Molecules, 2016, vol. 21, # 6,
[22] Chemical Biology and Drug Design, 2017, vol. 89, # 5, p. 755 - 761
[23] Journal of Labelled Compounds and Radiopharmaceuticals, 2017, vol. 60, # 9, p. 431 - 438
[24] Journal of Labelled Compounds and Radiopharmaceuticals, 2018, vol. 61, # 2, p. 68 - 76
[25] Inorganic Chemistry, 2017, vol. 56, # 16, p. 9725 - 9741
  • 2
  • [ 5326-23-8 ]
  • [ 133081-24-0 ]
  • [ 731005-24-6 ]
Reference: [1] Chemische Berichte, 1903, vol. 36, p. 1114
  • 3
  • [ 5326-23-8 ]
  • [ 1802-30-8 ]
YieldReaction ConditionsOperation in experiment
84% With hydrogenchloride; sodium hydroxide In methanol; water Example 2
25 g of 6-chloronicotinic acid and 14 g of sodium hydroxide are dissolved in a mixture of 100 ml of water and 80 ml of methanol.
Following the addition of 5 g of palladium (10percent by weight on activated carbon) as catalyst, the mixture is stirred for 24 h at 80-85° C. at 0.1 MPa.
The catalyst is then filtered off.
Following acidification to pH 1 using hydrochloric acid, the product, 2,2'-bipyridyl-5,5'-dicarboxylic acid, precipitates out as a white solid.
This gives 16.3 g (84percent yield).
81% With hydrogenchloride; sodium hydroxide In water; ethylene glycol Example 1
25 g of 6-chloronicotinic acid and 14 g of sodium hydroxide are dissolved in a mixture of 100 ml of water and 80 ml of ethylene glycol.
Following the addition of 0.56 g of palladium (30percent by weight on activated carbon; corresponds to an addition of 168 mg of pure palladium) as catalyst, the mixture is stirred for 5 h at 80-85° C. at 0.1 MPa.
The catalyst is then filtered off.
Following acidification to pH 1 using hydrochloric acid, the product, 2,2'-bipyridyl-5,5'-dicarboxylic acid, precipitates out as a white solid.
This gives 15.7 g (81percent yield).
79% With hydrogenchloride; sodium hydroxide In methanol; water Example 3
25 g of 6-chloronicotinic acid and 14 g of sodium hydroxide are dissolved in a mixture of 100 ml of water and 80 ml of methanol.
Following the addition of 10 g of palladium (5percent by weight on activated carbon) as catalyst, the mixture is stirred for 30 h at 80-85° C. at 0.1 MPa.
The catalyst is then filtered off.
Following acidification to pH 1 using hydrochloric acid, the product, 2,2'-bipyridyl-5,5'-dicarboxylic acid, precipitates out as a white solid.
This gives 15.3 g (79percent yield).
Reference: [1] Patent: US6500956, 2002, B1,
[2] Patent: US6500956, 2002, B1,
[3] Patent: US6500956, 2002, B1,
  • 4
  • [ 5326-23-8 ]
  • [ 21543-49-7 ]
YieldReaction ConditionsOperation in experiment
75% With BH3 In tetrahydrofuran; ethyl acetate 9-Chloro-5-{3-[2-(6-chloropyridin-3-yl)-2-hydroxyethylamino]cyclohexyl}-3-methyl-5H-isoxazolo[4,3-c]quinolin4one
To a stirred solution of 6-chloronicotinic acid (900 mg, 5.7 mmol) in THF (7 mL) was added BH3 (16 mL, 17.1 mmol, 1M in THF) under N2 atmosphere.
The reaction mixture was stirred for 5 h.
It was quenched with methanol (5 mL) and then concentrated.
The crude was dissolved in EtOAc (30 mL), washed with 1N NaOH (15 mL*3), brine, dried and concentrated. Yield: 615 mg (75percent) of 6-chloro-pyridin-3-yl-methanol.
0.55 g With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 30℃; for 3 h; Inert atmosphere To a solution of methyl 6-chloronicotinate (1.08 g, 0.009 mole) in THF (30 mL) at 0 °C under N2, was added lithium aluminum hydride (1 M in THF, 7.5 mL, 0.0075 mole) drop wise. Reaction mixture was warmed to RT and stirred for 3 hours. The reaction mixture was cooled to 0 °C, diluted with ethyl acetate and treated with water (2 mL). The mixture was filtered through celite bed and concentrated under vacuum to obtain the crude compound which was further purified by flash chromatography using ethyl acetate: n-hexane (40: 60) to afford 2-chloro-5-hydroxymethylpyridine. Yield: 0.55 g; lH - NMR (CDC13, 400 MHz) δ ppm: 2.09 (bs, 1H), 4.72 (s, 2H), 7.31 - 7.34 (d, J = 8.1 Hz, 1H), 7.68 - 7.71 (dd, J = 2.2, 8.4 Hz, 1H), 8.36 (s, 1H); Mass (m/z): 144.1, 146.0 (M+H)+.
Reference: [1] Journal of Labelled Compounds and Radiopharmaceuticals, 1999, vol. 42, # SUPPL. 1, p. S99-S101
[2] Journal of Organic Chemistry, 1999, vol. 64, # 23, p. 8576 - 8581
[3] Synthesis, 1998, # 9, p. 1335 - 1338
[4] Journal of Organic Chemistry, 1993, vol. 58, # 21, p. 5600 - 5602
[5] Journal of Organic Chemistry, 1998, vol. 63, # 3, p. 760 - 768
[6] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 7, p. 2013 - 2016
[7] Organic Letters, 2001, vol. 3, # 19, p. 3009 - 3012
[8] Chemical and Pharmaceutical Bulletin, 2000, vol. 48, # 5, p. 694 - 707
[9] Journal of medicinal chemistry, 1998, vol. 41, # 26, p. 5265 - 5271
[10] Synlett, 1999, # 3, p. 342 - 344
[11] Patent: US2003/100576, 2003, A1,
[12] Patent: US4332944, 1982, A,
[13] Patent: WO2013/82661, 2013, A1, . Location in patent: Page/Page column 28
[14] Journal of the American Chemical Society, 2013, vol. 135, # 43, p. 16120 - 16132
[15] Patent: WO2014/167084, 2014, A1, . Location in patent: Page/Page column 79; 80
[16] Patent: WO2018/42362, 2018, A1, . Location in patent: Page/Page column 40
  • 5
  • [ 5326-23-8 ]
  • [ 182924-36-3 ]
Reference: [1] Patent: WO2018/42362, 2018, A1,
  • 6
  • [ 5326-23-8 ]
  • [ 101990-45-8 ]
Reference: [1] Synlett, 1999, # 3, p. 342 - 344
  • 7
  • [ 5326-23-8 ]
  • [ 79-37-8 ]
  • [ 136592-00-2 ]
YieldReaction ConditionsOperation in experiment
97%
Stage #1: for 2.5 h;
Stage #2: With diazomethyl-trimethyl-silane In dichloromethane; N,N-dimethyl-formamide for 2 h;
Example 34
((2S,5S)-2-{5-[4-(5-{2-[(S)-1-((8)-2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-pyridin-2-yl)-phenyl]-1H-imidazol-2-yl}-4-oxo-1,2,4,5,6,7-hexahydro-azepino[3,2,1-hi]indol-5-yl)-carbamic acid methyl ester
A suspension of 6-chloronicotinic acid (1.58 g, 10.0 mmol) in methylene chloride (50 ml) and DMF (4 drops) was treated with oxalyl chloride (1.53 g, 12.0 mmol).
Stir the reaction mixture for 2.5 h and add trimethylsilyldiazomethane (25 ml, 2.0M solution, 50.1 mmol).
Stir the reaction for 2 h and pass HCl gas through the mixture for 10 min.
The reaction mixture was washed with a saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate, filtered and concentrated to afford, 2-chloro-1-(6-chloropyridin-3-yl)ethanone as a light brown solid, (1.85 g, 97percent): ESI-LRMS m/e calcd for C7H5Cl2NO [M+] 190, found 191 [M+H']
Reference: [1] Patent: US2012/230951, 2012, A1, . Location in patent: Page/Page column 96
  • 8
  • [ 186581-53-3 ]
  • [ 5326-23-8 ]
  • [ 136592-00-2 ]
Reference: [1] Journal of Antibiotics, 1995, vol. 48, # 11, p. 1336 - 1344
  • 9
  • [ 5326-23-8 ]
  • [ 171178-47-5 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 11, p. 1401 - 1405
  • 10
  • [ 5326-23-8 ]
  • [ 75-65-0 ]
  • [ 171178-45-3 ]
YieldReaction ConditionsOperation in experiment
62 g for 2.5 h; Inert atmosphere; Reflux N-5[N-tert-Butoxycarbonyl)amino]-2-chloropyridine (0581) A stirred solution of 6-chloronicotinic acid (47.3 g), diphenylphosphoryl azide (89.6 g) and triethylamine (46 ml) in t-butanol (240 ml) were heated under reflux under nitrogen for 2.5 hours. The solution was cooled and concentrated in vacuo. The syrupy residue was poured into 3 liters of a rapidly stirred solution of 0.33N aqueous sodium carbonate. The precipitate was stirred for one hour and filtered. The solid was washed with water and dried in vacuo at 70° C. to give the title compound (62 g) as a pale brown solid; m.p. 144-146° C.; δH [2H6]-DMSO 8.25 (1H, d), 7.95 (1H, bd), 7.25 (1H, d), 6.65 (1H, bs), 1.51 (9H, s); m/z (M+1)+ 229.
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 11, p. 1401 - 1405
[2] Patent: US6933299, 2005, B1, . Location in patent: Page/Page column 73
[3] Patent: US2005/143401, 2005, A1, . Location in patent: Page/Page column 45
[4] Patent: US9199973, 2015, B2, . Location in patent: Page/Page column 37
  • 11
  • [ 5326-23-8 ]
  • [ 171178-46-4 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 11, p. 1401 - 1405
  • 12
  • [ 5326-23-8 ]
  • [ 133081-26-2 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 12, p. 3440 - 3444
[2] Journal of Labelled Compounds and Radiopharmaceuticals, 1997, vol. 40, p. 455 - 457
[3] Letters in Organic Chemistry, 2014, vol. 11, # 3, p. 208 - 214
[4] RSC Advances, 2015, vol. 5, # 113, p. 93374 - 93385
[5] Journal of Labelled Compounds and Radiopharmaceuticals, 2017, vol. 60, # 9, p. 431 - 438
  • 13
  • [ 5326-23-8 ]
  • [ 133081-25-1 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 12, p. 3440 - 3444
[2] Journal of Labelled Compounds and Radiopharmaceuticals, 1997, vol. 40, p. 455 - 457
[3] Bioorganic Chemistry, 2011, vol. 39, # 4, p. 138 - 142
[4] Patent: WO2013/67597, 2013, A1,
[5] Letters in Organic Chemistry, 2014, vol. 11, # 3, p. 208 - 214
[6] RSC Advances, 2015, vol. 5, # 113, p. 93374 - 93385
[7] Journal of Labelled Compounds and Radiopharmaceuticals, 2017, vol. 60, # 9, p. 431 - 438
[8] Patent: WO2017/177144, 2017, A1,
  • 14
  • [ 5326-23-8 ]
  • [ 24424-99-5 ]
  • [ 115309-57-4 ]
YieldReaction ConditionsOperation in experiment
94%
Stage #1: With dmap In tetrahydrofuran for 3 h; Reflux
Stage #2: for 3 h; Reflux
A solution of 6-chloronicotinic acid (31.6 g, 200 mmol) and 4-dimethylaminopyridine (2.4 g, 20 mmol) in THF (250 mE) was refluxed for 3 hours. Then di-tert-butyl dicarbonate (65.0 g, 300 mmol) was added dropwise. After addition, the reaction mixture was refluxed for 3 hours. Upon reaction completion, the reaction mixture was cooled to room temperature. The solvent was removed and the residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether=0.-1/10) to give tert-butyl 6-chloronicotinate (40 g, 94percent yield) as a white solid. EC-MS (Agilent ECMS 1200-6120, Column:Waters X-l3ridge C18 (50 mmx4.6 mmx3.5 pm); Column Temperature: 40° C.; Flow Rate: 2.0 mE/mm; Mobile Phase:from 95percent [water+10 mM NH4HCO3] and 5percent [CH3CN] to 0percent [water+10 mM NH4HCO3] and 100percent [CH3CN] in 1.6 mm, then under this condition for 1.4 mm, finally changed to 95percent [water+10 mM NH4HCO3] and 5percent [CH3CN] in 0.1mm and under this condition for 0.7 mm). Purity is 100percent,Rt=1.984 mm; MS Calcd.: 213.06; MS Found: 214.2[M+H]. ‘H NMR (400 MHz, DMSO-d5) ö 1.56 (9H, s),7.67 (1H, d, J=8.4 Hz), 8.26 (1H, dd, J=8.0, 2.4 Hz), 8.86(1H, d, J=2.4 Hz). Chemical Formula: C,QH,2C1N02, MolecularWeight: 213.66. Total H count from HNMR data: 12.
Reference: [1] Journal of Heterocyclic Chemistry, 2012, vol. 49, # 2, p. 442 - 445
[2] Patent: US2018/215731, 2018, A1, . Location in patent: Paragraph 0897; 0909; 0910; 0911; 0912; 0913; 0914
[3] Patent: WO2006/65908, 2006, A1, . Location in patent: Page/Page column 67; 68
[4] Organic Process Research and Development, 2011, vol. 15, # 1, p. 64 - 72
  • 15
  • [ 5326-23-8 ]
  • [ 115309-57-4 ]
Reference: [1] Patent: US6239152, 2001, B1,
[2] Organic Process Research and Development, 2010, vol. 14, # 4, p. 936 - 938
  • 16
  • [ 5326-23-8 ]
  • [ 36805-97-7 ]
  • [ 115309-57-4 ]
Reference: [1] Journal of Organic Chemistry, 2006, vol. 71, # 5, p. 2000 - 2008
[2] Patent: US2011/301148, 2011, A1, . Location in patent: Page/Page column 12
  • 17
  • [ 5326-23-8 ]
  • [ 75-65-0 ]
  • [ 115309-57-4 ]
  • [ 313350-11-7 ]
YieldReaction ConditionsOperation in experiment
70.3%
Stage #1: for 3 h; Heating / reflux
Stage #2: With triethylamine In dichloromethaneHeating / reflux
Stage #3: With sodium hydrogencarbonate In dichloromethane; water
A mixture of 6-chloronicotinic acid (12.0 g, 76 mmol) and thionyl chloride (65 mL) was heated at reflux for 3.0 h. The excess thionyl chloride was removed under reduced pressure, and the residual liquid was diluted with dichloromethane (20 mL) and then added to a solution of tert-butyl alcohol (71 mL, 760 mmol) in dichloromethane (40 mL). To the mixture was added triethylamine (31.7 mL, 760 EPO <DP n="68"/>mmol) and N,N-dimethylpyridine (0.5 g, 4.0 mmol), and the reaction mixture was stirred overnight (14 h) at reflux under nitrogen. The solution was diluted with dichloromethane (200 mL), washed with a saturated aqueous solution of sodium bicarbonate (3 x 100 mL), washed with water (3 x 100 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure provided Preparation 3 (11.4 g, 70.3percent) as a yellow solid. The product had an analytical HPLC retention time = 3.18 min. (Column: YMC ODS 4.6 x 50 mm (4 min.); Solvent A = 10percent MeOH, 90percent H2O, 0.2percent H3PO4; Solvent B = 90percent MeOH, 10percent H2O, 0.2percent H3PO4) and a LCMS M+1 = 214. The purity of the product was about 96percent. The major impurity was the iso- propyl 6-chloronicotinate with an analytical HPLC retention time = 2.88 min. and a LOMS M+1 = 200.
Reference: [1] Patent: WO2006/65908, 2006, A1, . Location in patent: Page/Page column 65; 66
  • 18
  • [ 5326-23-8 ]
  • [ 67098-46-8 ]
  • [ 115309-57-4 ]
YieldReaction ConditionsOperation in experiment
11.66 g for 16 h; Reflux General procedure: To 6-chloronicotinic acid 19a (10 g) in methylene chloride(100 ml) solution, N,N’-diisopropyl-O-tert-butylisourea (50 g) wasadded and the mixture was stirred under heating and reflux for16 h. The insoluble compound was filtered out, and the filtratewas concentrated. The residue was purified by silica gel column chromatography (chloroform/ethyl acetate = 6/1) to obtain the compound 20a (11.66 g). To the compound 20a (6.0 g) in dimethylacetoamide (30 ml) solution, tris(dibenzylideneacetone)dipalladium (0.51 g), zinc cyanide (0.22 g), diphenylphosphinoferrocene (0.62 g), and zinc powder (1.98 g) were added and the mixture was stirred under argon atmosphere at 120 °C for 3 h. The reaction solution was filtered by sellite, which was then washed with ethyl acetate. Then, the filtrate was washed with distilled water and saturated saline, then the organic layer was dried over with anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate= 5/1) to obtain the compound 21a (3.59 g). To copper(I) iodide(0.93 g) in tetrahydrofuran (50 ml) suspension, ethylmagnesium bromide (0.86 M tetrahydrofuran solution)(12.5 ml) was added dropwise under cooling at 0 °C, the mixture was stirred at 0 °C for 30 min, then the compound 21a (1.0 g) obtained above in tetrahydrofuran (10 ml) solution was added atthe 20 °C. After stirring for 30 min at that temperature, 28percent ammonia solution in water and ethyl acetate were added to the mixture and the solution separated. The aqueous layer was extracted with ethyl acetate, while the combined organic layer was washed with saturated saline, then was dried over with anhydrous sodium sulfate and concentrated. The obtained residue was purifiedby silica gel column chromatography (hexane/ethyl acetate= 8/1) to obtained the compound 22a (0.47 g). To the compound 22a (200 mg) in tetrahydrofuran (1 ml) solution, (-)-B-chlorodiisopinocampheylborane (65percent hexane solution) (0.92 ml) was added dropwise under cooling at 20 °C, then the mixture was stirred at that temperature for 18 h. Then, ether and distilled water were added to the reaction mixture, and the solution was separated. The organic layer was extracted with distilled water and 1 M hydrogen chloride. Then, the combined aqueous layer was neutralized by sodium hydrogen carbonate, and extracted with ethyl acetate. Organic layer was washed with saturated saline, then was dried over with anhydrous sodium sulfate and concentrated to obtained the title compound (150 mg, 84percent ee). The optical purity was determined using CHIRALCEL AD-H(Daicel Chemical Industries) (movement phase: hexane/ethanol= 98/2, 1.0 ml/min).
Reference: [1] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 14, p. 4233 - 4249
  • 19
  • [ 5326-23-8 ]
  • [ 75-64-9 ]
  • [ 115309-58-5 ]
Reference: [1] Patent: WO2004/67007, 2004, A1, . Location in patent: Page/Page column 3
[2] Tetrahedron, 2008, vol. 64, # 14, p. 3236 - 3245
[3] Patent: US6384033, 2002, B1,
  • 20
  • [ 5326-23-8 ]
  • [ 115309-58-5 ]
Reference: [1] Journal of Organic Chemistry, 2006, vol. 71, # 5, p. 2000 - 2008
[2] Organic Process Research and Development, 2006, vol. 10, # 6, p. 1157 - 1166
  • 21
  • [ 5326-23-8 ]
  • [ 1765-93-1 ]
  • [ 223127-24-0 ]
Reference: [1] Patent: EP1657242, 2006, A1, . Location in patent: Page/Page column 31
  • 22
  • [ 5326-23-8 ]
  • [ 128632-03-1 ]
Reference: [1] Journal of Labelled Compounds and Radiopharmaceuticals, 2007, vol. 50, # 5-6, p. 613 - 615
  • 23
  • [ 5326-23-8 ]
  • [ 3612-20-2 ]
  • [ 1017598-71-8 ]
YieldReaction ConditionsOperation in experiment
66%
Stage #1: With 2,2,6,6-tetramethyl-piperidine; n-butyllithium In tetrahydrofuran; hexane at -78℃; for 3 h;
Stage #2: at -78℃; for 2 h;
The synthesis of the intermediate I-11.1 is described in EP2072519 A1, p. 36. At −78° C., a hexane solution (94 mL, 150.81 mmol) of 1.6 M n-butyllithium is added dropwise to a THF solution (110 mL) of 2,2,6,6-tetramethylpiperidine (16.14 g, 113.10 mmol) and obtained solution is stirred for 1 hour. Afterwards a THF solution (50 mL) of 6-chloronicotinic acid (6.0 g, 37.70 mmol) is added dropwise over 1 hour and the reaction mixture is stirred for 2 hours. A THF solution (50 mL) of 1-benzyl-4-piperidone (21.6 g, 113.10 mmol) is added dropwise at −78° C. After stirred for 2 hours, water (70 mL) is added, and the reaction mixture is warmed to room temperature. The aqueous layer is separated, and the organic layer is extracted with aqueous 1 N sodium hydroxide solution (2×75 mL). The obtained aqueous layer is extracted with diethyl ether (100 mL), and the aqueous layer is acidified (pH-1) by adding concentrated hydrochloric acid. After stirring for 1 hour, the precipitate is filtered off, washed with water, and dissolved in ethyl acetate. The organic layer is washed with aqueous saturated sodium hydrogen carbonate solution, dried over Na2SO4 and concentrated in vacuo. The residue is washed with diethyl ether. Yield 66percent, m/z 329 [M+H]+, rt 0.72 min, LC-MS Method Z012_S04.
Reference: [1] Patent: US2016/75704, 2016, A1, . Location in patent: Paragraph 0267-0271
[2] Patent: EP2072519, 2009, A1, . Location in patent: Page/Page column 36
  • 24
  • [ 5326-23-8 ]
  • [ 163213-19-2 ]
Reference: [1] Journal of Heterocyclic Chemistry, 2012, vol. 49, # 2, p. 442 - 445
Historical Records