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[ CAS No. 67443-38-3 ] {[proInfo.proName]}

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Chemical Structure| 67443-38-3
Chemical Structure| 67443-38-3
Structure of 67443-38-3 * Storage: {[proInfo.prStorage]}
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Product Details of [ 67443-38-3 ]

CAS No. :67443-38-3 MDL No. :MFCD00222270
Formula : C5H2BrClN2O2 Boiling Point : -
Linear Structure Formula :- InChI Key :WWQQPSDIIVXFOX-UHFFFAOYSA-N
M.W : 237.44 Pubchem ID :7019412
Synonyms :

Calculated chemistry of [ 67443-38-3 ]

Physicochemical Properties

Num. heavy atoms : 11
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 1
Num. H-bond acceptors : 3.0
Num. H-bond donors : 0.0
Molar Refractivity : 45.77
TPSA : 58.71 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.09 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.33
Log Po/w (XLOGP3) : 2.33
Log Po/w (WLOGP) : 2.41
Log Po/w (MLOGP) : 0.66
Log Po/w (SILICOS-IT) : 0.62
Consensus Log Po/w : 1.47

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -3.12
Solubility : 0.181 mg/ml ; 0.000763 mol/l
Class : Soluble
Log S (Ali) : -3.2
Solubility : 0.149 mg/ml ; 0.000628 mol/l
Class : Soluble
Log S (SILICOS-IT) : -2.88
Solubility : 0.312 mg/ml ; 0.00132 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 3.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.12

Safety of [ 67443-38-3 ]

Signal Word:Warning Class:
Precautionary Statements:P261-P264-P280-P305+P351+P338-P233 UN#:
Hazard Statements:H302-H315-H317-H319-H332-H335 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 67443-38-3 ]

* 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 [ 67443-38-3 ]
  • Downstream synthetic route of [ 67443-38-3 ]

[ 67443-38-3 ] Synthesis Path-Upstream   1~33

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Reference: [1] Journal of the Chemical Society, 1952, p. 2042,2044
  • 2
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  • [ 588729-99-1 ]
YieldReaction ConditionsOperation in experiment
100% With hydrogen; nickel In methanol Step 1:
5-bromo-2-chloro-3-aminopyridine
5-Bromo-2-chloro-3-nitropyridine (2.38 g, 10 mmol) was dissolved in methanol (50 mL), and raney nickel (0.5 g) was then added.
The mixture was stirred overnight under a hydrogen atmosphere.
Raney nickel was removed by filtration, and the filtrate was concentrated to give 5-bromo-2-chloro-3-aminopyridine (2.08 g, 100percent yield), which was directly used in the next step. MS m/z [ESI]: 208.9 [M+1].
89%
Stage #1: With hydrogenchloride; tin(ll) chloride In water at 20℃; for 20 h;
a) 3 -amino-5 -bromo-2-chloropyridineTo a stirred suspension of 5-bromo-2-chloro-3-nitropyridine (20.0 g, 84.2 mMol) in cone. HCl (90 mL) was added SnCl22H2O (60.0 g, 266 mMol) portionwise over 2 h. (The reaction got very warm to the touch.) The reaction was stirred at RT for 18 h, poured onto ice, and basified with aq. 6 N NaOH (300 mL). The resultant slurry was filtered, washed with H2O, and dried under vacuum to give the title compound (15.53 g, 89percent) as an off-white solid. MS (ES) m/e 206.7 (M + H)+.
89%
Stage #1: at 20℃; for 20 h;
Stage #2: With sodium hydroxide In water at 0℃;
To a stirred suspension of 5-bromo-2-chloro-3-nitropyridine (84.2 mmol) in cone. HCl (90 rtiL) was added SnCl22H2O (266 mmol) portionwise over 2 h (the reaction mixture grew very warm to the touch). The reaction mixture was stirred at room temperature for 18 h, poured onto ice, and basified with aq. 6 N NaOH (300 mL). The resultant slurry was filtered, washed with water, and dried under vacuum to give the title compound as an off-white solid (89percent). MS (ES) m/e 206.7 (M + H)+
73% for 1 h; Reflux To a solution of 5-bromo-2-chloro-3-nitropyridine (4.24 g, 17.86 mmol) in EtOH (89 ml) was added Tin(II) chloride (16.9 g, 89.0 mmol) at room temperature. The mixture was refluxed for 1 hour, and then cooled to room temperature, filtered through a Celite pad and washed with EtOAc. The filtrate was concentrated in vacuo. The residue was treated with saturated aq. NaHCO3, and extracted with EtOAc. The combined organic layers were washed brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=3:1) to give 5-bromo-2-chloropyridin-3-amine (2.7 g, 73percent) as a white solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 5.89 (2H, brs), 7.30 (1H, d, J=2.0 Hz), 7.66 (1H, d, J=2.4 Hz).

Reference: [1] Patent: EP2952510, 2015, A1, . Location in patent: Paragraph 0146
[2] Patent: WO2008/157191, 2008, A2, . Location in patent: Page/Page column 75
[3] Patent: WO2008/150827, 2008, A1, . Location in patent: Page/Page column 69
[4] Journal of Heterocyclic Chemistry, 2003, vol. 40, # 2, p. 261 - 268
[5] Patent: US2012/238587, 2012, A1, . Location in patent: Page/Page column 17
[6] Journal of the Chemical Society, 1952, p. 2042,2044
[7] Patent: US2011/245236, 2011, A1, . Location in patent: Page/Page column 107
[8] European Journal of Medicinal Chemistry, 2013, vol. 67, p. 243 - 251
[9] Patent: WO2007/129044, 2007, A1, . Location in patent: Page/Page column 77
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YieldReaction ConditionsOperation in experiment
55%
Stage #1: With hydrogenchloride; sodium nitrite In water at 0 - 5℃; for 1.75 h;
Stage #2: With hydrogenchloride; copper(l) chloride In water at 0 - 70℃;
EXAMPLE 1
6-(Furan-3-yl)-3-[3-(pyridin-3-yl)phenyl]-3 H -imidazo[4,5- b ]pyridine
2-Amino-5-bromo-3-nitropyridine (21.8 g, 0.1 mol) was ground to a fine powder using a mortar and pestle and then suspended in 6M hydrochloric acid (250 ml).
This mixture was cooled to 0°C and treated with solid NaNO2 (8.3 g, 0.12 mol) at such a rate that the internal temperature remained below 5°C (ca. 45 minutes).
Following the addition, stirring at 0°C was continued for a further 1 hour.
To the resultant suspension was added a solution of freshly prepared copper(I) chloride (12.9 g, 0.13 mol) in degassed 38percent hydrochloric acid and the reaction stirred to ambient temperature over 90 minutes before heating the reaction to 70°C to complete the decomposition of the diazonium salt.
The reaction was cooled, diluted with water (750 ml) and then air was passed through the mixture for 30 minutes before adding 0.88 ammonia to ca. pH 9.
The blue mixture was shaken with diethyl ether (600 ml) and any remaining solids removed by filtration.
The organic layer was then washed with 5percent aqueous ammonia, water, brine and dried over anhydrous sodium sulphate.
This solution was filtered and then pre-adsorbed on to silica.
Purification by dry flash chromatography eluding with isohexane and a gradient of ethyl acetate from 5percent to 20percent gave 5-bromo-2-chloro-3-nitropyridine as a pale yellow solid (13.1 g, 55percent) followed by recovered starting material (6.4 g); δH (400 MHz, CDCl3) 8.36 (1H, d, J 1, H-6), 8.69 (1H, d, J 1, H-4).
Reference: [1] Patent: WO2007/129044, 2007, A1, . Location in patent: Page/Page column 77
[2] Patent: EP1214319, 2003, B1, . Location in patent: Page/Page column 13
[3] Journal of Heterocyclic Chemistry, 2003, vol. 40, # 2, p. 261 - 268
[4] Journal of the Chemical Society, 1952, p. 2042,2044
[5] Journal of the Chemical Society, 1952, p. 2042,2044
[6] Tetrahedron, 2014, vol. 70, # 5, p. 1077 - 1083
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YieldReaction ConditionsOperation in experiment
89%
Stage #1: for 3 h; Heating / reflux
Stage #2: With sodium hydrogencarbonate In diethyl ether
Step B.
5-Bromo-2-chloro-3-nitropyridine
A mixture of 5-bromo-3-nitropyridin-2(1H)-one (Step A, 2.5 g, 10.4 mmol), phosphoryl chloride (25 mL) and N,N-dimethylformamide (2.5 mL) was stirred under reflux for 3 h.
After removal of solvent, the residue was dissolved in water (20 mL) and diethylether (20 mL) at 0° C. and the solution was separated.
The organic layer was washed with saturated sodium hydrogen carbonate, dried over sodium sulfate and concentrated to afford the title compound (2.5 g, 89percent) as a pale yellow solid.
1H-NMR (CDCl3) δ: 8.70 (d, J=1.7 Hz, 1H), 8.37 (d, J=1.7 Hz, 1H).
89% With trichlorophosphate In N,N-dimethyl-formamide for 2 h; Heating / reflux Step B. 5-Bromo-2-chloro-3-nitropyridineA mixture of 5-bromo-3-nitropyridin-2(1 H)-one (Step A, 7.2 g, 32.9 mmol), phosphoryl chloride(72 mL) and λ/,λ/-dimethylformamide (7.2 mL) was stirred under reflux for 2 h. After removal of solvent, the residue was dissolved in water (100 mL) and ethyl acetate(30 mL) and the solution was separated.The organic layer was washed with saturated sodium hydrogen carbonate, dried over sodium sulfate and concentrated to afford the title compound (6.97 g, 89percent) as a pale yellow solid.1H-NMR (CDCI3) δ: 8.70 (d, J= 1.7 Hz, 1 H), 8.37 (d, J= 1.7 Hz, 1 H).
85% With trichlorophosphate In N,N-dimethyl-formamide for 2 h; Reflux To a solution of 5-bromo-3-nitropyridin-2(1H)-one (4.62 g, 21.10 mmol) in POCl3 (46.2 ml) was added DMF (4.62 ml, 59.7 mmol) at room temperature. The mixture was refluxed for 2 hours, and then cooled to room temperature and concentrated in vacuo. The residue was treated with saturated aq. NaHCO3 and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=3:1) to give 5-bromo-2-chloro-3-nitropyridine (4.24 g, 85percent) as a yellow solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 8.37 (1H, d, J=2.4 Hz), 8.70 (1H, d, J=2.0 Hz).
Reference: [1] Patent: US2006/94750, 2006, A1, . Location in patent: Page/Page column 55
[2] Patent: WO2007/102059, 2007, A1, . Location in patent: Page/Page column 45
[3] Patent: US2012/238587, 2012, A1, . Location in patent: Page/Page column 17
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YieldReaction ConditionsOperation in experiment
82% With thionyl chloride In N,N-dimethyl-formamide for 1 h; Reflux N,N'-dimethylformamide (3 mL) was added to a mixture of 5-bromo-2-hydroxy-3-nitropyridine (16.54 g, 80 mmol) and thionyl chloride (43 mL) and the mixture was stirred and heated to reflux.
After 1 hour, the solution was cooled and the solvent was evaporated.
The mixture was co-evaporated with toluene to give a dark solid.
Purification by flash chromatography (10:1 hexanes/ethyl acetate) gave the title compound (14.63 g, 82percent) as a yellow solid.
1H-NMR δ (CDCl3): 8.38 (d, J=3.0 Hz, 1H), 8.70 (d, J=3.0 Hz, 1H).
82% With thionyl chloride In N,N-dimethyl-formamide for 1 h; Reflux N,N'-dimethylformamide (3 mL) was added to a mixture of 5-bromo-2-hydroxy-3-nitropyridine (16.54 g, 80 mmol) and thionyl chloride (43 mL) and the mixture was stirred and heated to reflux. After 1 hour, the solution was cooled and the solvent was evaporated. The mixture was co-evaporated with toluene to give a dark solid. Purification by flash chromatography (10:1 hexanes/ethyl acetate) gave the title compound (14.63 g, 82percent) as a yellow solid. 1H-NMR δ (CDCl3): 8.38 (d, J=3.0 Hz, 1H), 8.70 (d, J=3.0 Hz, 1H).
81% With trichlorophosphate In N,N-dimethyl-formamide for 3 h; Reflux A mixture of 5-bromo-2-hydroxy-3-nitropyridine (14) (28.8 g, 131.5 mmol), POCl3 (288 mL) and anhydrous DMF (30 mL) was stirred and heated at reflux for 3 h. After removal of POCl3, the residue was poured into ice water and extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (4:1 hexanes/EtOAc) to afford 15 (25.4 g, 81percent) as a pale yellow solid, mp 66-67 °C (lit32 68 °C). 1H NMR (CDCl3) δ 8.70 (d, J = 2.0 Hz, 1H, Ar-H), 8.37 (d, J = 2.5 Hz, 1H, Ar-H).
81% With trichlorophosphate In N,N-dimethyl-formamide for 12 h; Inert atmosphere; Reflux General procedure: 2-Hydroxy-3-nitropyridine 5 (0.015 mol) was suspended in POCl3 (15 mL). Anhydrous DMF (2 mL) was added and the resulting mixture was heated at reflux for 12 h. The excess of POCl3 was removed by distillation, the residue was taken up in a mixture of DCM with ice and the mixture was stirred for 30 min. The organic layer was separated, washed with water (3 x), dried over anhydrous Na2SO4, filtered and concentrated to yield analytically pure product.

Reference: [1] Molecules, 2012, vol. 17, # 4, p. 4533 - 4544
[2] Patent: EP2108641, 2009, A1, . Location in patent: Page/Page column 46
[3] Patent: EP2113503, 2009, A1, . Location in patent: Page/Page column 29
[4] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 4, p. 1569 - 1574
[5] Tetrahedron, 2014, vol. 70, # 5, p. 1077 - 1083
[6] Yakugaku Zasshi, 1951, vol. 71, p. 169,171[7] Chem.Abstr., 1952, p. 8108
[8] Journal of the Chemical Society, 1952, p. 2042,2044
[9] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1980, vol. 16, # 12, p. 1234 - 1238[10] Khimiya Geterotsiklicheskikh Soedinenii, 1980, vol. 16, # 12, p. 1632 - 1636
[11] Patent: US2003/162968, 2003, A1,
[12] Journal of Organic Chemistry, 2009, vol. 74, # 12, p. 4547 - 4553
[13] Patent: US2004/63744, 2004, A1, . Location in patent: Page/Page column 31; 32
[14] Patent: US2010/204214, 2010, A1, . Location in patent: Page/Page column 117
[15] Patent: WO2005/121140, 2005, A1, . Location in patent: Page/Page column 28-29
[16] Patent: WO2005/121140, 2005, A1, . Location in patent: Page/Page column 45
[17] Patent: WO2006/101456, 2006, A1, . Location in patent: Page/Page column 56
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  • [ 68-12-2 ]
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Reference: [1] Patent: US6465484, 2002, B1,
[2] Patent: US6162804, 2000, A,
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Reference: [1] Patent: US6200976, 2001, B1,
  • 8
  • [ 15862-34-7 ]
  • [ 7440-44-0 ]
  • [ 67443-38-3 ]
Reference: [1] Patent: US4665078, 1987, A,
[2] Patent: US4532252, 1985, A,
[3] Patent: US4537890, 1985, A,
[4] Patent: US4537891, 1985, A,
  • 9
  • [ 1072-97-5 ]
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Reference: [1] Tetrahedron, 2014, vol. 70, # 5, p. 1077 - 1083
  • 10
  • [ 13466-38-1 ]
  • [ 67443-38-3 ]
Reference: [1] Patent: WO2007/102059, 2007, A1,
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  • [ 67443-38-3 ]
  • [ 89415-54-3 ]
Reference: [1] Patent: WO2011/15343, 2011, A1,
[2] Patent: WO2012/37108, 2012, A1,
[3] Patent: WO2018/67786, 2018, A1,
[4] Patent: US2010/261714, 2010, A1,
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  • [ 37805-78-0 ]
Reference: [1] Patent: WO2011/15343, 2011, A1,
  • 13
  • [ 67443-38-3 ]
  • [ 623-50-7 ]
  • [ 105544-30-7 ]
YieldReaction ConditionsOperation in experiment
82% With sodium hydride In tetrahydrofuran at 0 - 20℃; for 1 h; Method I: 5-bromo-2-chloro-3-nitropyridine (100 mg, 0.42 mmol) and Ethyl glycolate (0.044 mL, 0.46 mmol) were dissolved in THF (5 mL) and cooled to 0°C. Sodium hydride (0.015 mL, 0.46 mmol) was added and the mixture was stirred for 1hr at room temperature. Reaction mixture was poured in ice water and extracted with EtOAc (2 x 10ml). The organiclayer was washed with brine (10ml), dried over sodium sulphate and concentrated. The crude product was purified by flash column using 100-200 silica gel to ethyl 2-(5-bromo-3-nitropyridin-2-yloxy)acetate (105 mg, 82 percent) 9(b). 1H NMR (300 MHz, DMSO-d6) δ = 1.27 (s, 3H), 4.25 (q, 2 H), 5.12 (s, 2H) 8.40 (d, J = 2.07 Hz, 1 H), 8.47 (d, J = 2.07 Hz, 1 H); ESMS: m/z 306.8 [M+1]
49%
Stage #1: With sodium hydride In 1,4-dioxane at 70℃; for 1 h;
Stage #2: at 20 - 70℃; for 17 h;
Step 1. Sodium hydride (55percent dispersion in mineral oil, 603 mg, 13.8 mmol) was added to a solution of ethyl glycolate (1.43 g, 13.8 mmol) in 1,4-dioxane, and the reaction mixture was heated at 70° C. for 1 h, then 5-bromo-2-chloro-3-nitropyridine (Eur. Pat. Appl. EP 122109 (1984); 1.64 g, 6.91 mmol) was added, and stirring was continued at 70° C. for 1 h and at room temperature for 16 h. The reaction mixture was then neutralized with sat. aq. sodium hydrogencarbonate solution and extracted three times with dichloromethane. The organic layers were pooled, dried (Na2SO4), and evaporated. Chromatography (SiO2, hexane-ethyl acetate gradient) furnished (5-bromo-3-nitro-pyridin-2-yloxy)-acetic acid ethyl ester (1.03 g, 49percent). Light yellow liquid, MS (ISP)=305.1 (M+H)+.
44%
Stage #1: With sodium hydride In 1,4-dioxane at 20 - 30℃; for 0.75 h;
Stage #2: at 0 - 80℃;
To a suspension of sodium hydride (5.31 g, 133 mmol) in 1 ,4-dioxane (250 ml), ethyl glycolate (12.56 ml, 133 mmol) was added drop wise over a period of 30 minutes ensuring that the temperature was maintained below 30°C. The resulting thick suspension was stirred at room temperature for 15 minutes. In a separate 11 round- bottomed flask was added 5-bromo-2-chloro-3-nitropyridine (21 g, 88 mmol) in 1 ,4- dioxane (150 ml) to give a brown solution. The suspension of sodium hydride and ethyl glycolate was added drop wise over a period of 30 minutes at 0°C. The resulting reaction mixture was heated to 80°C overnight. The reaction mixture was concentrated under reduced pressure and the crude residue was purified by Biotage silica chromatography (gradient 0percent to 10percent ethyl acetate in n- hexanes) to give the title compound (1 .8g, 44percent). N R (500 MHz, CDCI3): 8.48 (1 H, s), 8.42 (1 H, s), 5.07 (2H, s), 4.28-4.24 (2H, q), 1.31-1.28 (3H, t).
Reference: [1] Synthetic Communications, 2013, vol. 43, # 24, p. 3315 - 3321
[2] Patent: US2007/191603, 2007, A1, . Location in patent: Page/Page column 37
[3] Patent: WO2011/77098, 2011, A1, . Location in patent: Page/Page column 157-158
[4] Patent: WO2007/77961, 2007, A2, . Location in patent: Page/Page column 358
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Reference: [1] Zeitschrift fuer Chemie (Stuttgart, Germany), 1986, vol. 26, # 3, p. 99
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Reference: [1] Zeitschrift fuer Chemie (Stuttgart, Germany), 1986, vol. 26, # 3, p. 99
[2] Synthetic Communications, 2013, vol. 43, # 24, p. 3315 - 3321
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YieldReaction ConditionsOperation in experiment
98%
Stage #1: at 20℃; Cooling
Stage #2: at 0 - 20℃; for 17 h;
To a cooled solvent of MeOH (50.0 mL) was added Na (2.90 g, 126.4 mmol) portion-wise, then the mixture was warmed to rt and stirred until Na was all dissolved, then the solution was added to a suspension of 5-bromo-2-chloro-3-nitropyridine (10.0 g, 42.12 mmol, Shanghai long sheng hua gong, china) in MeOH (100 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour, then warmed up to rt and stirred further for 16 hours, then concentrated to 80 mL and quenched with water (100 mL). The precipitate was filtered, washed with water (50 mL*2) and dried under infrared light to give the title compound as a pale yellow solid (9.62 g, 98percent). MS (ESI, pos. ion) m/z: 233.0 [M+H]+.
82% for 2 h; Reflux Sodium methoxide (17.2 g, 318.4 mmol)was added to a stirred solution of 5-bromo-2-chloro-3-nitropyridine (15.0 g, 64.2 mmol) inmethanol (125 mL). After addition, the reaction mixture was heated at reflux for 2 h. Themixture was concentrated under reduced pressure, and the residue was diluted with water (200mL). The resulting precipitate was collected by filtration, washed with water, and dried underreduced pressure to give the title compound (12.0 g, 82percent yield) as a brown solid.
71.4% at 0 - 20℃; for 19 h; To a solution of sodium methanolate (0.52 g, 9.64 mmol) in MeOH (10 mL) wasadded 5-bromo-2-chloro-3-nitropyridine (0.57 g, 2.41 mmol) at 0°C. The reaction was stirred at0°C for 1 h, then warmed up to rt and stired further for 18 h. The reaction was quenched withH20 (20 mL), adjusted to pH 7 with 3M HCl and then filtered. The seperated organic phase wasconcentrated in vacuo to give the title compound as a light yellow solid (0.4 g, 71.4percent). Thetitle compound was characterized by LC-MS and 1H NMR as shown below:LC-MS (ESI, pos. ion) m/z: 233 [M+Ht;1H NMR (400 MHz, CDCh) 8 (ppm): 3.93 (s, 3H), 8.08 (s, 1H), 8.89 (s, 1H).
Reference: [1] Patent: US2014/134133, 2014, A1, . Location in patent: Paragraph 0384
[2] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 15, p. 3534 - 3541
[3] ACS Medicinal Chemistry Letters, 2017, vol. 8, # 7, p. 737 - 741
[4] Patent: WO2014/22128, 2014, A1, . Location in patent: Paragraph 0149
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YieldReaction ConditionsOperation in experiment
98% at 0 - 20℃; for 19.1667 h; 5 -Bromo-2-chloro-3 -nitropyridineTo a stirred solution of 5 -bromo-2-chloro-3 -nitropyridine (20.4 g, 86 mMol) in methanol (75 rnL) at 0 0C in an ice bath was added dropwise a solution of 25 wtpercent sodium methoxide in methanol (20 mL, 87 mMol) and methanol (20 mL) over 10 minutes. After stirring at 0 0C for 1 h the reaction was allowed to warm to RT and stirred for 18 h. The reaction was concentrated under vacuum to aproximately half its volume then poured into ice water (-500 mL). The precipitate that formed was filtered off , washed with cold water, and dried under vacuum to give the title product (19.7 g, 98percent) as a pale yellow solid: MS(ES)+ m/e 233.2 [M+H]+.
71.4% at 0 - 20℃; for 19 h; To a solution of sodium methanolate (0.52 g, 9.64 mmol) in MeOH (10 mL) was added 5-bromo-2-chloro-3-nitropyridine (0.57 g, 2.41 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hour, then warmed to rt and stirred for 18 hours. The mixture was quenched with water (20 mL), adjusted to pH=7 with aq. HCl (3 M), and then filtered. The organic phase was separated and concentrated in vacuo to give the title compound as a light yellow solid (0.4 g, 71.4percent).
Reference: [1] Patent: WO2008/157191, 2008, A2, . Location in patent: Page/Page column 78
[2] Patent: US2014/234254, 2014, A1, . Location in patent: Paragraph 0297; 0298; 0299
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  • [ 152684-30-5 ]
YieldReaction ConditionsOperation in experiment
98% at 0 - 20℃; for 19 h; a) 5 -bromo-2-(methyloxy)-3 -nitropyridine. To a stirred solution of 5-bromo-2-chloro-3-nitropyridine (86 mmol) in methanol (75 mL) at 0 0C was added drop wise a solution of 25percent w/w sodium methoxide in methanol (20 mL, 87 mmol) and methanol (20 mL) over 10 min. After stirring at 0 0C for 1 h the reaction was allowed to warm to room temperature and stirred for 18 h. The reaction was concentrated under vacuum to approximately half its volume then poured into ice water (-500 mL). The precipitate that formed was filtered, washed with cold water, and dried under vacuum to give the title product (98percent) as a pale yellow solid. MS(ES)+ m/e 233.2 [M+H]+.
98% at 0 - 20℃; for 19.1667 h; To a stirred solution of 5-bromo-2-chloro-3-nitropyridine (86 mmol) in methanol (75 mL) at 0 0C was added dropwise a solution of 25 wtpercent sodium methoxide in methanol (87 mmol) and methanol (20 mL) over 10 min. After stirring at 0 0C for 1 h the reaction was allowed to warm to room temperature and was stirred for 18 h. The reaction was concentrated under vacuum to aproximately half its volume then poured into ice water (-500 mL). The precipitate that formed was filtered, washed with cold water, and dried under vacuum to give the title product (98percent) as a pale yellow solid. MS(ES)+ m/e 233.2 [M+H]+.
95% at 0 - 20℃; for 24 h; Reflux A solution of 20.0 g (84.2 mmol) 5-bromo-2-chloro-3-nitro-pyridine in 50 mL MeOH is cooled to 0°C and 15.8 mL (84.2 mmol) of a NaOMe solution in MeOH (30percent) is added drop wise. The mixture is stirred at RT over night and then stirred under reflux for 24 h. The precipitate is filtered off, suspended in water and the suspension is stirred for lh. The product is filtered off and dried und vacuum at 60°C. Yield: 18.7 g (95percent).
95% at 0 - 20℃; Reflux A solution of 20.0 g (84.2 mmol) 5-bromo-2-chloro-3-nitro-pyridine in 50 mL MeOH is cooled to 0°C and 15.8 mL (84.2 mmol) of a NaOMe solution in MeOH (30percent) is added drop wise. The mixture is stirred at RT over night and then stirred under reflux for 24 h. The precipitate is filtered off, suspended in water and the suspension is stirred for lh. The product is filtered off and dried und vacuum at 60°C. Yield: 18.7 g (95percent).
95% at 0 - 20℃; Reflux A solution of 20.0 g (84.2 mmol) 5-bromo-2-chloro-3-nitropyridine in 50 mL MeOH is cooled to 0°C and 15.8 mL (84.2 mmol) of a NaOMe solution in MeOH (30percent) is added drop wise. The mixture is stirred at RT over night and then stirred under reflux for 24 h. The precipitate is filtered off, suspended in water and the suspension is stirred for 1h. The product is filtered off and dried und vacuum at 60°C. Yield: 18.7 g (95percent).
95% at 0 - 20℃; Reflux A solution of 20.0 g (84.2 mmol) 5-bromo-2-chloro-3-nitro-pyridine in 50 mL MeOH is cooled to 0° C. and 15.8 mL (84.2 mmol) of a NaOMe solution in MeOH (30percent) is added drop wise.
The mixture is stirred at RT over night and then stirred under reflux for 24 h.
The precipitate is filtered off, suspended in water and the suspension is stirred for 1 h.
The product is filtered off and dried and vacuum at 60° C. Yield: 18.7 g (95percent).
90% at 0 - 20℃; for 16.16 h; Intermediate 1; λ/-[5-Bromo-2-(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide; a) 5-bromo-2-(methyloxy)-3-nitropyridine; To a cooled (0 0C) solution of S-bromo-l-chloro-S-nitropyridine (50 g, 211 mmol) in methanol (200 mL) was added dropwise over 10 minutes 20percent sodium methoxide (50 mL, 211 mmol) solution. The reaction, which quickly became heterogeneous, was allowed to warm to ambient temperature and stirred for 16 h.The reaction was filtered and the precipitate diluted with water (200 mL) and stirred for 1 h. The solids were filtered, washed with water (3 x 100 mL) and dried in a vac oven (40 0C) to give 5-bromo-2-(methyloxy)-3-nitropyridine (36 g, 154 mmol, 73.4percent yield) as a pale yellow powder. The original filtrate was concentrated in vacuo and diluted with water (150 mL). Saturated ammonium chloride (25 mL) was added and the mixture stirred for 1 h. The solids were filtered, washed with water, and <n="87"/>dried in a vac oven (40 0C) to give a second crop of 5-bromo-2-(methyloxy)-3- nitropyridine (9 g, 38.6 mmol, 18.34 percent yield). Total yield = 90percent. MS(ES)+ m/e 232.8, 234.7 [M+H]+.
90% at 0 - 20℃; for 16 h; a)
5-bromo-2-(methyloxy)-3-nitropyridine
To a cooled (0° C.) solution of 5-bromo-2-chloro-3-nitropyridine (50 g, 211 mmol) in methanol (200 mL) was added dropwise over 10 minutes 20percent sodium methoxide (50 mL, 211 mmol) solution.
The reaction, which quickly became heterogeneous, was allowed to warm to ambient temperature and stirred for 16 h.
The reaction was filtered and the precipitate diluted with water (200 mL) and stirred for 1 h.
The solids were filtered, washed with water (3*100 mL) and dried in a vac oven (40° C.) to give 5-bromo-2-(methyloxy)-3-nitropyridine (36 g, 154 mmol, 73.4percent yield) as a pale yellow powder.
The original filtrate was concentrated in vacuo and diluted with water (150 mL).Saturated ammonium chloride (25 mL) was added and the mixture stirred for 1 h. The solids were filtered, washed with water, and dried in a vac oven (40° C.) to give a second crop of 5-bromo-2-(methyloxy)-3-nitropyridine (9 g, 38.6 mmol, 18.34percent yield). Total yield=90percent. MS(ES)+m/e 232.8, 234.7 [M+H]+.
83% at 0 - 50℃; for 12 h; 4.1.1
5-Bromo-2-methoxy-3-nitropyridine (2)
To a solution of 5-bromo-2-chloro-3-nitropyridine (1) (10.0 g, 42.37 mmol) in anhydrous methanol (40 mL) was added sodium methoxide solution (20 mL, 63.56 mmol) slowly at 0 °C.
The reaction mixture was then heated to 50 °C and stirred for 12 h.
After the completion of reaction, the mixture was filtered and the precipitate was washed with water.
The obtained solids were then dried under reduced pressure to give the title compound (8.12 g, 35.0 mmol, 83percent yield) with light yellow. ESI-MS: m/z = 233 [M+H]+.
81.5% for 2 h; Reflux Sodium methoxide (17.2 g, 318.4 mmol) was added to a stirred solution of 5-bromo-2-chloro- 3-nitropyridine (15.0 g, 64.2 mmol) in methanol (125 mL). After addition, the reactionmixture was heated at reflux for 2 h. The mixture was concentrated under reduced pressure, and the residue was diluted with water (200 mL). The resulting precipitate was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (12.0 g, 8 1.5percent yield) as a brown solid. 44 NMR (400MHz, CDCI3): 6 8.43 (d, Jr 2.4 Hz, 1 H), 8.38 (d,J 2.0 Hz, 1 H), 4.09 (s, 311).
81.5% for 2 h; Reflux Sodium methoxide (17.2 g, 318.4 mmol) was added to a stirred solution of 5-bromo-2-chloro-3- nitropyridine (15.0 g, 64.2 mmol) in methanol (125 mL). After addition, the reaction mixture was heated at reflux for 2 h, at which time TLC indicated the reaction had gone to completion. The mixture was concentrated under reduced pressure, and the residue was diluted with water (200 mL). The resulting precipitate was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (12,0 g, 81.5percent yield) as a brown solid. H NMR (400MHz, CDC13): δ 8.43 (d, J= 2.4 Hz, 1 H), 8.38 (d, J = 2.0 Hz, 1 H), 4.09 (s, 3 H)
81.5% for 2 h; Reflux Sodium methoxide (17.2 g, 318.4 mmol) was added to a stirred solution of 5-bromo-2-chloro-3- nitropyridine (15.0 g, 64.2 mmol) in methanol (125 mL). After addition, the reaction mixture was heated at reflux for 2 h. The mixture was concentrated under reduced pressure, and the residue was diluted with water (200 mL). The resulting precipitate was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (12.0 g, 81.5percent yield) as a brown solid. 1H NMR (400MHz, CDC13): δ 8.43 (d, J= 2.4 Hz, 1 H), 8.38 (d, J= 2.0 Hz, 1 H), 4.09 (s, 3 H).
81.5% for 2 h; Reflux Sodium methoxide (17.2 g, 318.4 mmol) was added to a stirred solution of 5-bromo-2-chloro-3-nitropyridine (15.0 g, 64.2 mmol) in MeOH (125 mL). The reaction was heated at refluxtemperature for 2 h and then concentrated under reduced pressure. The residue was diluted with water (200 mL). The resulting precipitate was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (12.0 g, 8 1.5percent yield) as a brown solid.‘H NMR (400MHz, CDC13): 6 8.43 (d, J= 2.4 Hz, 1 H), 8.38 (d, J= 2.0 Hz, 1 H), 4.09 (s, 3 H).
71.4% at 0 - 20℃; for 19 h; At 0 , sodium methoxide (0.52g, 9.64mmol) in MeOH (10mL) was added 5-bromo-2-chloro-3-nitropyridine (0.57g, 2.41mmol).The reaction was maintained with stirring at 0 1 hour and then cooled to room temperature, stirring was continued for 18 hours.The reaction solution was added water (20 mL) after being quenched with 3M hydrochloric acid and adjusted to pH 7, and filtered.The separated organic phase was concentrated under reduced pressure to give the title compound as a pale yellow solid (0.4g, 71.4percent)
62% at 0 - 20℃; Method A: to a cooled suspension of 15 (15.0 g, 63.2 mmol) in anhydrous MeOH (60 mL) was added 20percent NaOMe in MeOH (15 mL, 66.4 mmol) dropwise at 0 °C. After the reaction mixture was allowed to warm to rt and stirred overnight, the pale yellow precipitate was filtered off to give the crude product. The crude product was diluted with water and stirred for 1 h. The solid was collected by filtration, washed with water and dried to afford 16 (9.22 g, 62percent) as a pale yellow solid. The original filtrate was concentrated in vacuo and diluted with water. Saturated aqueous NH4Cl was added and the mixture was stirred for 1 h. The solid was collected by filtration, washed with water and dried in a vacuum oven (40 °C) to give the second crop of 16 (4.74 g, 32percent) as a pale yellow solid, mp 88-90 °C. 1H NMR (CDCl3) δ 8.45 (d, J = 2.5 Hz, 1H, Ar-H), 8.39 (d, J = 2.0 Hz, 1H, Ar-H), 4.11 (s, 3H, OCH3).
1.37 kg at 0 - 10℃; for 2.75 h; Inert atmosphere; Large scale 5-Bromo-2-(methyloxy)-3-nitropyridine
Method A
A solution of 25percent wt sodium methoxide in methanol (2.1 L) was added to a suspension of 5-bromo-2-chloro-3-nitropyridine (1.70 kg) in methanol (6.6 L), stirred under nitrogen at 0-5° C.
The reaction mixture was stirred at 5-10° C. for 2.75 hours and then water (8.5 L) was added.
The reaction mixture was cooled to 20-25° C.
The mixture was then concentrated under vacuum and the resultant suspension was filtered, washed with water (8.5 L then 2*4.25 L) and the solid dried under vacuum to give the title compound as an off-white solid (1.37 kg).
1H NMR (400 MHz, Chloroform-d) δ (ppm) 8.46 (s, 1H), 8.40 (s, 1H).

Reference: [1] Patent: WO2009/39140, 2009, A1, . Location in patent: Page/Page column 52
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  • 19
  • [ 67443-38-3 ]
  • [ 1826-67-1 ]
  • [ 425380-38-7 ]
YieldReaction ConditionsOperation in experiment
40% at -78 - -20℃; for 8 h; Vinyl magnesium bromide (400 ml, 1.0 M in THF) was added slowly to a stirred solution of 5-bromo-2-chloro-3-nitropyridine (20 g, 84.74 mmol) in dry THF (800 ml) at -78°C. The reaction mixture was slowly warmed to -20°C and stirred at same temperature for a period of 8 h. Reaction mixture was quenched with 20 percent of NH4CI (600 ml) and the product was extracted with ethyl acetate (2 x 500 ml). The combined organic layers were washed with water (200 ml) and brine (200 ml), dried and concentrated. The obtained crude was triturated with diethyl ether (2 x 100 ml) to afford the title compound as a brown solid (8 g, 40 percent). 1H NMR (400 MHz, DMSO-dg) δ 12.48 (bs, 1H), 8.07 (s, 1H), 7.82 (t, J=3.2 Hz, 1H), 6.61 (s, 1H); LC/MS: 232 (M+l)+.
31% at -50 - -30℃; for 2 h; To a solution of 5-bromo-2-chloro-3-nitropyridine (10 g, 0.042 mol) in anhydrous THF (150 mL), a solution of vinylmagnesium bromide (17 g, 0.127 mol) in THF was added dropwise at -30 to -50 °C. The reaction mixture was stilTed at -30 to -40 °C for 2 h. Then the reaction mixture was poured into saturated aqueous NH4C1 solution and the mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2504, filtered and concentrated under reduced pressure and the residue was purified by column chromatography to provide 4-bromo-7-chloro-]H-pyrrolo[2,3-c]pyridine ( 3 g, 3 1percent): ‘H NMR: (DMSO-d6) 3 12.45 (s, 1H), 8.04 (s, 1H), 7.79-7.78 (m, 1H), 6.59-6.58 (d, J = 2.0, 1H).
29% at -78℃; for 1.5 h; Inert atmosphere To a solution of compound 10 (250 mg; 1.05 mmol) in dry THF (10 ml) under argon at -78 °C was added dropwise a 1.42 M solution of vinylmagnesium bromide in THF (6 ml, 8.4 mmol; prepared by dilution of 1.7 M solution of in THF (50 ml) with THF (12 ml)). The reaction mixture was stirred at the same temperature for another 1.5 h and then it was quenched by addition of NH4Cl sat. (30 ml). The THF-layer was separated and the aqueous layer was extracted with EtOAc (2×10 ml). Combined organic layers (THF with EtOAc extracts) were dried over Na2SO4 and concentrated to afford 270 mg of yellow oily material which was treated with DCM (10 ml). Light-yellow solid was filtered and dried in oven (45 °C) to give compound 11 (70 mg, 29percent).
21% at -78℃; for 4 h; Inert atmosphere 5-Bromo-2-chloro-3-nitro-pyridine (20.2 g, 85.07 mmol, 1 equiv.) was dissolved in dry tetrahydrofuran (100 mL) under nitrogen atmosphere, and the solution was cooled to -78° C. Bromo(vinyl)magnesium (1 M, 340 mL, 4 equiv.) was added to the solution, and the reaction mixture was stirred at -78° C. for 4 h. LCMS analysis showed that the reaction was completed.
The reaction was quenched with saturated ammonium chloride (150 mL).
The aqueous phase was extracted with ethyl acetate (3*150 mL), and the combined organic layers were dried over magnesium sulfate, filtered and concentrated.
The crude product was purified by flash column chromatography (silica gel, eluting with a 1/1 mixture of ethyl acetate and petroleum ether) to afford 4-bromo-7-chloro-1H-pyrrolo[2,3-c]pyridine as a yellow solid (4.12 g, 21percent yield).
17% at -78℃; for 3 h; The solution of compound 1 (30 g, 0.13 mol) in THF (1.5 L) was cooled to -78 °C. Then a solution of vinyl magnesium in THF (508 mL, 1N, 0.51 mol) was added dropwise to the above solution maintained below -40 °C. The mixture was stirred for 3 hrs at -78 °C before being quenched with saturated aqueous NH4Cl solution. The layers were separated, the aqueous layer was extracted with EtOAc (3×500 mL) and the combined organic layer was washed with brine and concentrated. The crude product was purified by silica gel column chromatography to obtain compound 2 (5 g, 17percent). Compound 2 (4.0 g, 17.2 mmol) was dissolved in freshly prepared NaOMe (20 mL). CuI (3.2 g, 17.2 mmol) was added to the above solution. The mixture was stirred at 110 °C under microwave for 3 hrs. After the mixture was completed, the mixture was added EtOAc and H2O, then the suspension was filtered, the filtrate was separated. The organic layer was concentrated to give crude product which was purified by column chromatography to give compound 3 (1.8 g, 45percent). A mixture of compound 3 (0.7 g, 3.8 mmol) and 3-methyl-1,2,4-triazole (6.4 g, 76.8 mmol) was added copper powder (0.49 g, 7.68 mmol) and KOH (0.43 g, 7.68 mmol). The mixture was heated tomelt at 170-175 °C under N2. After the starting material was consumed completely, the mixture was added EtOAc and H2O, then the suspension was filtered, the filtrate was separated. The organic layer was concentrated to give crude product which was purified by column chromatography to give compound 4 (0.23 g, 26percent). A solution of compound 4 (0.23 g, 1 mmol) in THF (12 mL) was cooled to -10 °C, EtMgBr (0.47 g, 3.5 mmol)was added dropwise at -10 °C followed by the addition of pyridine(0.3 mL). The slurry was cooled to -45 °C, and the ethyl 2-chloro-2-oxoacetate (0.55 g, 4 mmol) was added dropwise at -45 °C. The slurry was allowed to -10 °C and stirred at this temperature for 1h. After the reaction was completed, the mixture was quenched with IPA (2mL) and H2O (20 mL). The mixture was extracted with EtOAc, the organic layer was washed with brine and concentrated to give crude product which was purified by column chromatographyto give compound 5 (0.17 g, 52percent). A solution of compound 5 (0.17 g, 0.52mmol) in MeOH (5 mL) was added NaOH (0.041 g, 1.03 mmol) and H2O (2mL). The mixture was stirred at 25 °C for 6 hrs and then added 1N HCl to adjusted pH 6, the mixture was concentratedto give compound 6 (0.29 g) as crude product.
17% at -78 - -40℃; for 3 h; A solution of compound 1 (30 g, 0.13 mol) in THF (1.5 L) was cooled to 78 °C. Vinylmagnesium in THF (508 mL, 1N, 0.51 mol) was added dropwise to the above solution and the temperature was maintained below 40 °C. The mixture was stirred for 3 h at 78 °C before being quenched with saturated aqueous NH4Cl solution. The layers were separated, the aqueous layer was extracted with EtOAc (3 500 mL), and the combined organic layer was washed with brine and concentrated.The crude product was purified by silica gel column chromatography to obtain compound 2 (5 g,17percent). Compound 2 (4.0 g, 17.2 mmol) was dissolved in freshly prepared NaOMe (20 mL). CuI(3.2 g, 17.2 mmol) was added and the mixture was microwave-irradiated at 110 °C and stirred for3 h. After reaction completion, EtOAc and H2O were added, then the suspension was filtered andthe filtrate was separated. The organic layer was concentrated to give crude product, which waspurified by column chromatography to give compound 3 (1.8 g, 45percent). A mixture of compound 3(0.7 g, 3.8 mmol), 3-methyl-1,2,4-triazole (6.4 g, 76.8 mmol), copper powder (0.49 g, 7.68 mmol), and KOH (0.43 g, 7.68 mmol) was heated to melt at 170–175 °C while being protected by N2 atmosphere. After consumption of the starting material, EtOAc and H2O were added to the mixture, and the suspension was filtered and the filtrate was collected. The organic layer was concentrated to give the crude product, which was purified by column chromatography to give compound 4 (0.23 g, 26percent).A solution of compound 4 (0.23 g, 1 mmol) in THF (12 mL) was cooled to 10 °C, and EtMgBr (0.47 g,3.5 mmol) was added dropwise at 10 °C, followed by the addition of pyridine (0.3 mL). The slurrywas cooled to 45 °C, and the ethyl 2-chloro-2-oxoacetate (0.55 g, 4 mmol) was added dropwise at 45 °C. The temperature was allowed to rise to 10 °C and the mixture was stirred for 1h. Afterreaction completion, the mixture was quenched with IPA (2 mL) and H2O (20 mL). The mixture wasextracted with EtOAc, and the organic layer was washed with brine and concentrated to the givecrude product which was purified by column chromatography to give compound 5 (0.17 g, 52percent).Compound 5 (0.17 g, 0.52 mmol) was dissolved in MeOH (5 mL). NaOH (0.041 g, 1.03 mmol) and H2O(2 mL) were added and the mixture was stirred at 25 C for 6 h. HCl (1N) was added to adjust the pH to 6, and the mixture was concentrated to give compound 6 (0.29 g) as crude product.

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[5] Patent: EP2546249, 2013, A1,
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  • 22
  • [ 67443-38-3 ]
  • [ 105-53-3 ]
  • [ 911434-05-4 ]
YieldReaction ConditionsOperation in experiment
63.3%
Stage #1: With sodium hydride In tetrahydrofuran at 20℃; for 3.5 h;
Stage #2: Heating / reflux
Intermediate 7; Preparation of N-(5-bromo-2-methyl-3-pyridinyl)cyclopropanesulfonamide; a) 5-bromo-2-methyl-3-nitropyridine; Sodium hydride (1.31 g, 54.8 mmol, 2.19 g of 60percent in mineral oil) was suspended in dry THF (70 mL) and to this suspension was added 5-bromo-2-chloro-3-nitropyridine as a solid. An ambient water bath was placed under the reaction and a solution of diethyl malonate in dry THF (15 mL) was added carefully via addition funnel. Observed a vigorous evolution of gas. After 2 hours additional sodium hydride (0.202 g, 8.42 mmol, 0.337 g of 60percent in mineral oil) was added and the reaction was stirred for 1.5 hours. The reaction was concentrated in vacuo, diluted with 6N HCl (100 ml), and refluxed overnight. The reaction was concentrated in vacuo and diluted with saturated sodium carbonate to pH 9. The basic aqueous mixture was diluted with dichloromethane and filtered through filter paper to remove an insoluble green solid. The filtrate was transferred to a separatory funnel and the layers were separated. The dichloromethane was washed with saturated sodium chloride (aq), dried over sodium sulfate, filtered and concentrated to give the title compound (5.79 g, 63.3percent) as an orange oil. MS (ES)+ m/e 217 [M+H].
63.3%
Stage #1: With sodium hydride In tetrahydrofuran at 20℃; for 3.5 h;
Stage #2: Heating / reflux
Example 66; N- [2-Methyl-5 -(6-quinolinyl)-3 -pyridinyljmethanesulfonamide; a) 5-bromo-2-methyl-3-nitropyridine; Sodium hydride (1.31 g, 54.8 mmol; 2.19 g of 60percent in mineral oil) was suspended in dry THF (70 mL) and to this suspension was added 5-bromo-2-chloro- 3-nitropyridine as a solid. An ambient water bath was placed under the reaction and a solution of diethyl malonate in dry THF (15 mL) was added carefully via addition funnel. A vigorous evolution of gas was observed. After 2 hours additional sodium hydride (0.202 g, 8.42 mmol, 0.337 g of 60percent in mineral oil) was added and the reaction was stirred for 1.5 hours. The reaction was concentrated in vacuo, diluted with 6 N HCl (100 mL), and heated at reflux overnight. The reaction was concentrated in vacuo and diluted with saturated sodium carbonate until the pH = 9. The basic aqueous mixture was diluted with dichloromethane and filtered through filter paper to remove an insoluble green solid. The filtrate was transferred to a separatory funnel and the layers were separated. The dichloromethane was washed <n="79"/>with brine, dried over Na2SO4, filtered and concentrated to give the title compound (5.79 g, 63.3percent) as an orange oil. MS(ES)+ m/e 217 [M+H].
63.3%
Stage #1: With sodium hydride In tetrahydrofuran at 20℃; for 3.5 h;
Stage #2: Heating / reflux
5 -Bromo-2-methyl-3 -nitropyridineSodium hydride (1.31 g, 54.8 mmol, 2.19 g of 60percent in mineral oil) was suspended in dry THF (70 mL) and to this suspension was added 5 -bromo-2-chloro-3 -nitropyridine as a solid. An ambient water bath was placed under the reaction and a solution of diethyl malonate in dry THF (15 mL) was added carefully via addition funnel. Observed a vigorous evolution of gas. After 2 hours additional sodium hydride (0.202 g, 8.42 mmol, 0.337 g of 60percent in mineral oil) was added and the reaction was stirred for 1.5 hours. The reaction was concentrated in vacuo, diluted with 6N HCl (100 ml), and refluxed overnight. <n="85"/>The reaction was concentrated in vacuo and diluted with saturated sodium carbonate until the pH = 9. The basic aqueous mixture was diluted with dichloromethane and filtered through filter paper to remove an insoluble green solid. The filtrate was transferred to a separatory funnel and the layers were separated. The dichloromethane was washed with saturated NaCl, dried over Na2SO4, filtered and concentrated to give the title compound (5.79 g, 63.3percent) as an orange oil. MS(ES)+ m/e 217 [M+H].
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