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CAS No. :53750-66-6 MDL No. :MFCD08447076
Formula : C6H3Cl2NO Boiling Point : -
Linear Structure Formula :- InChI Key :FYBNFLRGZHGUDY-UHFFFAOYSA-N
M.W : 176.00 Pubchem ID :11095146
Synonyms :

Safety of [ 53750-66-6 ]

Signal Word:Danger Class:8
Precautionary Statements:P260-P264-P280-P301+P330+P331-P303+P361+P353-P304+P340-P305+P351+P338-P310-P321-P363-P405-P501 UN#:3261
Hazard Statements:H314 Packing Group:
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Application In Synthesis of [ 53750-66-6 ]

* 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 [ 53750-66-6 ]
  • Downstream synthetic route of [ 53750-66-6 ]

[ 53750-66-6 ] Synthesis Path-Upstream   1~17

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Reference: [1] Heterocycles, 2000, vol. 53, # 4, p. 797 - 804
[2] Inorganic Chemistry, 2013, vol. 52, # 11, p. 6481 - 6501
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Reference: [1] European Journal of Medicinal Chemistry, 2014, vol. 76, p. 531 - 538
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  • [ 63071-13-6 ]
Reference: [1] Inorganic Chemistry, 2013, vol. 52, # 11, p. 6481 - 6501
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  • [ 53750-66-6 ]
  • [ 99586-65-9 ]
Reference: [1] Heterocycles, 2000, vol. 53, # 4, p. 797 - 804
[2] Journal of the Chemical Society. Perkin Transactions 1, 2001, # 17, p. 2012 - 2021
[3] Chemische Berichte, 1926, vol. 59, p. 1479,1482
[4] Chemische Berichte, 1928, vol. 61, p. 2211
[5] Patent: WO2004/85425, 2004, A1, . Location in patent: Page 210-211
[6] Patent: US2006/241104, 2006, A1, . Location in patent: Page/Page column 13-14
[7] Patent: WO2007/35428, 2007, A1, . Location in patent: Page/Page column 38
[8] European Journal of Medicinal Chemistry, 2014, vol. 76, p. 531 - 538
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  • [ 5470-22-4 ]
Reference: [1] Chemische Berichte, 1931, vol. 64, p. 21,26
[2] Chemische Berichte, 1926, vol. 59, p. 1479,1482
[3] Chemische Berichte, 1928, vol. 61, p. 2211
[4] Archiv der Pharmazie, 2009, vol. 342, # 7, p. 394 - 404
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Reference: [1] Patent: US2013/102601, 2013, A1,
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  • [ 67-56-1 ]
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YieldReaction ConditionsOperation in experiment
72% at 20℃; for 0.5 h; A mixture of picolinic acid (Aldrich) (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 (3x). The organic layers were combined and dried over [MGS04] and evaporated. The residue was purified by chromatography to give 4- chloropicolinic acid methyl ester as a white solid (19.9 g, 72percent) [: 1H] NMR (300 MHz, [CDC13)] 8 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). [[0217]] A mixture of 4-chloropicolinic acid methyl ester (2.4 g, 14.1 mmol), 57percent hydroiodic acid (13.3 mL) and 50percent aqueous hypophosphorous acid (0.66 mL) was stirred at 85 [°C] for 2 h and then was stirred at [107 °C] overnight. The mixture was cooled to 95 [°C.] At this temperature over 30 minutes 10 M sodium hydroxide aqueous solution (4.2 mL) was added, followed by the addition of water (15.2 mL). The mixture was cooled to rt and stirred at rt for [LH.] The precipitate was filtered, washed with cold water and dried under high vacuum overnight to give 4-iodopipecolinic acid 13a (3.5 g, [66percent) : 1H] NMR (300 MHz, DMSO d6) 8 8. [39] (d, [J=] 5.1, 1), [8. 35] (d, [J= 1.] 8,1), 8.07 (dd, [J= 1.] 7,5. 2, [1) ;] MS (ESPOS): 250.2 [M + H] [+.] [[0218]] To a mixture of 7-Me MTL HCl salt 2b [(RAPOS;=ME,] R2=Me) (200 mg, 0.69 mmol, [1] equiv) in dry DMF (1.8 mL) at [0 °C] was added triethylamine (0.50 mL, 3.61 mmol, 5.2 equiv), followed by the addition of BSTFA (0.28 mL, 1.04 mmol, 1.5 equiv). The reaction mixture was stirred at [0 °C] for 10 minutes, and then was stirred at rt for 50 minutes. To the reaction mixture was added the acid 13a (341 mg, 0.90 mmol, 1.3 equiv) and HATU (423 mg, 1.11 mmol, 1.6 equiv). The reaction mixture was stirred at rt for 3 h. The reaction mixture was evaporated to dryness, taken up in ethyl acetate, washed with water [(1] x), sat. [NAHC03] [(1] x) and brine. The organic layer was dried over [NA2S04] and evaporated to give a yellow residue which was dissolved in methanol (20 mL) to which was added dry Dowex resin (250 mg). The reaction mixture was stirred at rt for 1 h. The resin was removed by filtration and the crude product eluted with 2M ammonia in methanol. The methanolic eluent was evaporated, and the resulting residue was purified by chromatography to provide a white solid 13b (Rl=Me, R2= Me, [R3=H)] (250 mg, 75percent) [: LH NMR] (300 MHz, CD30D) 8 8.46 (d, [J= 1.] 8,1), 8.30 (d, J= 5.4, 1), 7.98 (dd, J= 1.8, 5.1, 1), 5.25 (d, J= 6.0, 1), 4.32-4. 23 (m, 2), 4.09 (dd, J= 5.7, 10.2, 1), 3.87 (d, J= 3.0, 1), 3.54 (dd, J= 3.3, 10.2, 1), 2.24-2. 15 (m, 1), 2.11 (s, 3), 0.99-0. 96 (m, 6); MS (ESPOS): [483.] 5 [M + [H] +] ; MS (ESNEG): 481.4 [[M-H]-.] [0219] To a dry flask was added 13b [(RL=ME,] R2= Me, R3=H) (133.9 mg, [0.] 28 mmol, 1 equiv), triphenylphosphine (46.7 mg, 0.18 mmol, 0.64 equiv), copper (I) iodide [(33.] 9 mg, 0.18 mmol, 0.64 equiv), palladium acetate (20 mg, 0.09 mmol, 0.32 equiv) and triethylamine (1.6 mL). The mixture was deaerated with nitrogen, followed by addition of 3-prop-2-ynyl- cyclopentane (120 mg, [1.] 11 mmol, 4 equiv). The mixture was stirred at 50 oC overnight. The solvent was removed under vacuum to give a dark residue. The residue was purified by chromatography to give 13c (Rl=Me, R9'= 3-cyclopentyl-prop-1-ynyl, R2= Me, R3=H) as a yellow solid (106 mg, 83percent): 1H NMR (300 [MHZ, CD30D) 6] 8.55 (d, J= 4.8, 1), 7.98 (s, 1), 7.47 [(DD,] [J=] 1.7, 5.0, 1), 5.26 (d, [J=] 5.4, [1),] 4. [33-4.] 22 (m, 2), 4.10 (dd, [J=] 5.5, 10.4, 1), 3.86 (d, J= 3.3, 1), 3.55 (dd, J= 3.3, 10.5, 1), 2.49 (d, J= 6.9, 2), 2.26-2. 12 (m, 2), 2.11 (s, 3), 1.93- 1.82 (m, 2), 1.73-1. 55 (m, 4), 1.43-1. 31 (m, 2), 1.00-0. 96 (m, 6); MS (ESPOS): 463.6 [M [+ H] +] ; MS (ESNEG): 461.5 [M-H]-.
39.6% at 20 - 55℃; for 0.75 h; Anhydrous DMF (1 mL) was slowly added to sulfurous dichloride (30 mL) at 45 °C. The solution was stirred at room temperature for 10 mm, and then picolinic acid (10 g, 81 mmol) was added over 30 mm. The resulting solution was heated at 72 °C for 16 hours to generate 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. Theresulting solution and 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 mm, cooled to 5°C and treated with ethyl ether (20 mL) dropwisely. The resulting solid was filtered, washed with ethyl ether (20 mL) and dried under 35 °C to provide a white yellow solid. After the solid were solvated to hot water (50 mL, 45 °C), sodium bicarbonate aqueous solution was added to adjustpH to 89. 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: 3 9.6percent) as off-white solid.
17.5 g at 30℃; for 2 h; 2-Picolinic acid (15 g, 0.122 mol) was slowly added to thionyl chloride (50 mL) at a temperature range of 45-50 °C under stirring. Then the solution was heated to 72 °C, and kept refluxing for about 14 h. After cooled to room temperature, the mixture was diluted with toluene (100 mL), and concentrated to near dryness in vacuo. To the obtained oily residue, methanol (40 mL) was added. The contents were stirred for 2 h at 30 °C. After filtration, the filter cake was added 15percent Na2CO3 solution to adjust its pH value to neutral, filtrate and washed with cold methanol to obtained light yellow solid 17.5 g (83.7percent), mp: 52-54 °C. 1H NMR (400 MHz, DMSO-d6) δ 3.88 (s, 3H); 7.89 (dd, J = 5.4, 2.0 Hz, 1H); 8.10 (d, J = 2.1 Hz, 1H); 8.70 (d, J = 5.4 Hz, 1H).
10 g at 20℃; for 0.5 h; Step 1
Oxalyl chloride (6.7 mL, 76.8 mmol, 1.2 eq) was added to a solution of 4-chloro-pyridine-2-carboxylic acid (10.0 g, 63.4 mmol, 1 eq) in dichloromethane (270 mL).
The solution was cooled down to 0° C. and dimethylformamide (1.1 mL) was added drop wise.
The mixture was stirred at room temperature for 1.5 h and was evaporated to dryness.
The orange residue was diluted in methanol (110 mL) and the mixture was stirred at room temperature for 30 min and evaporated to dryness.
A 5percent solution of sodium bicarbonate (50 mL) was poured on the residue and the aqueous phase was extracted with ethyl acetate (2*40 mL).
The organic layers were washed with brine (3*20 mL), dried over magnesium sulfate, filtered and evaporated to afford 4-chloro-pyridine-2-carboxylic acid methyl ester as a beige powder (10.0 g, 92percent yield).
32.49 g at 0 - 5℃; for 1 h; Picolinic acid (1) (30.84g, 250mmol) was added dropwise to the stirring thionyl chloride (50mL). The resulting mixture was heated at reflux for 3 days giving a clear orange solution. After cooling to ambient temperature, the solution was concentrated to small volume and the residue coevaporated with toluene (2×20mL). The residue was dissolved in toluene (40mL) and cooled to 0–5°C. Methanol (16mL) was then added dropwise to the cold reaction mixture and stirred for 1h giving a white precipitate. This precipitate was collected by filtration, washed with toluene (3×10mL), and dried at 40°C for 24h to give compound methyl 4-chloropicolinate (2) as a white crystal [25]. Yield: 32.49g, 76percent. mp:131–132°C. 1H NMR (DMSO-d6, ppm) δ: 8.72 (d, 1H, J=5.4Hz, CH), 8.09 (s, 1H, CH), 7.84(d, 1H, J=2.0Hz, CH), 3.85(s, 3H, CH3). ESI-MS: m/z 172.1 (M+1), C7H6ClNO2 [171.01].
36.9 g at 20 - 30℃; for 2 h; 112.5 mL of thionyl chloride was added to a 250 mL reaction flask and 2-picolinic acid (34 g, 0.275 mol) was added in portions at 45 ° C with constant stirring,The reaction heated at reflux for 14h.Stop the reaction,Cooled to room temperature,Adding 200 mL of toluene,Recovery of toluene by distillation under reduced pressure,A yellow solid-liquid mixture was obtained.Add 60 mL of methanol,The reaction was stirred at room temperature (20-30 ) for 2h,Filter,neutralize,dry,To give 36.9 g of a pale yellow solid,Yield 78.5percentMp: 52-54 ° C,Content of 98.8percent (HPLC).

Reference: [1] Patent: WO2004/16632, 2004, A2, . Location in patent: Page 57-58
[2] Patent: WO2014/206343, 2014, A1, . Location in patent: Page/Page column 99
[3] Chemische Berichte, 1926, vol. 59, p. 1479,1482
[4] Chemische Berichte, 1928, vol. 61, p. 2211
[5] Journal of Organic Chemistry, 1955, vol. 20, p. 283,285
[6] Organic Preparations and Procedures International, 1997, vol. 29, # 1, p. 117 - 122
[7] Heterocycles, 2000, vol. 53, # 4, p. 797 - 804
[8] Patent: US2005/277652, 2005, A1, . Location in patent: Page/Page column 73
[9] Patent: EP1897880, 2008, A1, . Location in patent: Page/Page column 15-16
[10] Patent: US2006/19853, 2006, A1, . Location in patent: Page/Page column 19
[11] Patent: WO2006/24034, 2006, A1, . Location in patent: Page/Page column 31
[12] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 9, p. 2923 - 2929
[13] Patent: US2013/102601, 2013, A1, . Location in patent: Paragraph 0173-0174
[14] Inorganic Chemistry, 2013, vol. 52, # 11, p. 6481 - 6501
[15] Medicinal Chemistry Research, 2013, vol. 22, # 8, p. 3959 - 3968
[16] European Journal of Medicinal Chemistry, 2014, vol. 76, p. 531 - 538
[17] Patent: CN104045598, 2017, B, . Location in patent: Paragraph 0067; 0068; 0069
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Reference: [1] Patent: US2005/277652, 2005, A1, . Location in patent: Page/Page column 117-118
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Reference: [1] Patent: EP2314588, 2011, A1,
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Reference: [1] Organic Preparations and Procedures International, 1997, vol. 29, # 1, p. 117 - 122
[2] Patent: EP2314588, 2011, A1, . Location in patent: Page/Page column 16-17
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Reference: [1] Organic Preparations and Procedures International, 1997, vol. 29, # 1, p. 117 - 122
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Reference: [1] European Journal of Medicinal Chemistry, 2014, vol. 76, p. 531 - 538
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  • [ 220000-86-2 ]
YieldReaction ConditionsOperation in experiment
90% With pyridine In 1,2-dichloro-ethane at -40 - 50℃; for 24 h; To a solution of t-butanol (25 mL), pyridine (20 mL) and 1,2-dichloroethane (80 mL) at -40° C., was added a solution of 4-chloropicolinyl chloride (9.0 g, 51.1 mmol) in dichloroethane (60 mL).
The mixture was heated at 50° C. for 24 h.
The mixture was diluted with dichloromethane, washed with 5percent citric acid, and sat. K2HPO4 aq. solution.
The organic layer was dried over MgSO4.
The product was purified by flash column chromatography (SiO2, eluding with 20percent EtOAc/CH2Cl2) to give a clear oil (9.8 g, 90percent). LC-MS: m/z 213 (M+), 158 (M-Bu+).
78% With pyridine In dichloromethane at -40 - 50℃; for 16 h; 4-chloropicolinic acid (10.5 g, 66.64 mmol) was suspended in thionyl chloride (40 mL), and the mixture was heated to 80° C. and refluxed. N,N-dimethylformamide (0.2 mL) was added dropwise, and the mixture was refluxed for 2 hours. The excess of thionyl chloride was removed under reduced pressure to give the pale yellow acyl chloride, followed by addition of dichloromethane (60 mL). The resulted solution was added into a mixed solution of tert-butanol (25 mL), pyridine (20 mL) and dichloromethane (80 mL) at -40° C. The reraction mixture was heated to 50° C. and stirred for 16 hours. The solvents were removed under reduced pressure and ethyl acetate (150 mL) was added. The resulted mixture was washed with saturated brine (50 mL*2) and a sodium hydroxide solution (1 N, 50 mL*2), and separated. The organic phase was dried over anhydrous sodium sulfate and concentrated under the reduced pressure. The residue was dried under vacuum to give the title compound (11.1 g, purity 95percent, yield 78percent) as a pale yellow solid. 1H NMR(DMSO-d6, 400 MHz): δ1.56 (s, 9H), 7.80 (dd, J=2.4 Hz, 5.2 Hz, 1H), 8.02 (d, J=2 Hz, 1H), 8.69 (d, J=5.2 Hz, 1H).
MS (ESI, m/z) calcd. for C10H12ClNO2: 213, found: 158 [M-But+H]+
49% With pyridine; dmap In dichloromethane at 30℃; A solution of 4-chloro-pyridine-2-carbonyl chloride (150 g, 0.857 mol) in DCM (750 ml) was slowly added to a solution of 2-methyl-propan-2-ol (158.8 g, 2.14 mol) and DMAP (21 g, 0.171 mol) in DCM (750 mL) and pyridine (750 mL). The resultant mixture was stirred at 30 °C overnight. The reaction mixture was concentrated in vacuo and the residue was purified by chromatography to give A- chloro-pyridine-2-carboxylic acid t-butyl ester (90 g, 49percent yield) as a yellow solid. 1H NMR (CDC13): δ 8.63 (d, J = 8.0 Hz, 1 H), 8.03 (s, 1 H), 7.44 (d, J = 8.0 Hz 1 H), 1.63 (s, 9 H); MS (ESI) m/z: 214 (M+H+).
11.1 g With pyridine In dichloromethane at -40 - 50℃; for 16 h; [0176]   4-chloropicolinic acid (10.5 g, 66.64 mmol) was suspended in   thionyl chloride (40 mL). The resulted mixture was heated to 80° C. and refluxed.   N,N-dimethyl formamide (0.2 mL) was dropwise added, and the resulted mixture was refluxed for 2 h. Thionyl chloride was removed under reduced pressure to give light yellow acyl chloride. The residue was dissolved in   dichloromethane (60 mL). At −40° C., the dichloromethane solution prepared above was added dropwise to a mixed solution of   tert-butanol (25 mL),   pyridine (20 mL) and dichloromethane (80 mL). The reaction solution was heated to 50° C. and stirred for 16 h. The solvent was removed under reduced pressure, and to the residue was added   ethyl acetate (150 mL). The resulted mixture was washed with saturated brine (50 mL×2) and a solution of   sodium hydroxide (1 N, 50 mL×2), and then separated. The organic phase was dried over anhydrous sodium sulfate. The solvent in the organic phase was removed under reduced pressure. The residue was dried in vacuum to give the   title compound (11.1 g, purity 95percent, yield 78percent) as a light yellow solid. [0177] 1H NMR (DMSO-d6, 400 MHz): δ1.56 (s, 9H), 7.80 (dd, J=2.4 Hz, 5.2 Hz, 1H), 8.02 (d, J=2 Hz, 1H), 8.69 (d, J=5.2 Hz, 1H). [0178] MS (ESI, m/z) calcd. for C10H12ClNO2:213, found: 158 (M-But+H)+.

Reference: [1] Patent: US2005/239820, 2005, A1, . Location in patent: Page/Page column 17
[2] Patent: US2013/35492, 2013, A1, . Location in patent: Paragraph 0173
[3] Patent: WO2010/51373, 2010, A1, . Location in patent: Page/Page column 65
[4] Patent: WO2012/112570, 2012, A1, . Location in patent: Page/Page column 49
[5] Patent: US2013/60043, 2013, A1, . Location in patent: Paragraph 0176; 1077; 0178
[6] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 13, p. 3732 - 3737
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Reference: [1] Patent: US2004/122237, 2004, A1, . Location in patent: Page 88
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Reference: [1] Molecules, 2011, vol. 16, # 6, p. 5130 - 5141
[2] Archiv der Pharmazie, 2011, vol. 344, # 6, p. 349 - 357
[3] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 9, p. 2923 - 2929
[4] Archiv der Pharmazie, 2012, vol. 345, # 5, p. 360 - 367
[5] Patent: US2013/225641, 2013, A1,
[6] Patent: CN105753841, 2016, A,
[7] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 23, p. 6166 - 6173
[8] Patent: CN106543077, 2017, A,
[9] Patent: CN104496896, 2017, B,
[10] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 3, p. 254 - 259
[11] Patent: CN107573340, 2018, A,
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Reference: [1] Patent: WO2013/36232, 2013, A2,
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  • [ 1020172-07-9 ]
Reference: [1] Patent: WO2013/36232, 2013, A2,
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