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Chemical Structure| 4548-45-2
Chemical Structure| 4548-45-2
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Product Details of [ 4548-45-2 ]

CAS No. :4548-45-2 MDL No. :MFCD00006240
Formula : C5H3ClN2O2 Boiling Point : -
Linear Structure Formula :- InChI Key :BAZVFQBTJPBRTJ-UHFFFAOYSA-N
M.W : 158.54 Pubchem ID :78308
Synonyms :

Calculated chemistry of [ 4548-45-2 ]

Physicochemical Properties

Num. heavy atoms : 10
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 : 38.07
TPSA : 58.71 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.88 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.15
Log Po/w (XLOGP3) : 1.96
Log Po/w (WLOGP) : 1.64
Log Po/w (MLOGP) : -0.13
Log Po/w (SILICOS-IT) : -0.09
Consensus Log Po/w : 0.91

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -2.44
Solubility : 0.581 mg/ml ; 0.00367 mol/l
Class : Soluble
Log S (Ali) : -2.82
Solubility : 0.241 mg/ml ; 0.00152 mol/l
Class : Soluble
Log S (SILICOS-IT) : -2.01
Solubility : 1.55 mg/ml ; 0.00979 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 3.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.98

Safety of [ 4548-45-2 ]

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 [ 4548-45-2 ]

* 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 [ 4548-45-2 ]
  • Downstream synthetic route of [ 4548-45-2 ]

[ 4548-45-2 ] Synthesis Path-Upstream   1~45

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Reference: [1] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1920, vol. 50, p. 476[2] Chem. Zentralbl., 1923, vol. 94, # III, p. 1020
[3] Patent: WO2008/62182, 2008, A1,
  • 2
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  • [ 5350-93-6 ]
YieldReaction ConditionsOperation in experiment
96%
Stage #1: With hydrogenchloride; 1,1,1,3',3',3'-hexafluoro-propanol; iron In water at 20℃; for 0.5 h;
Stage #2: With sodium hydrogencarbonate In water
General procedure: The nitro compound (1 equiv), HFIP (10 equiv), Fe powder (5 equiv) were mixed in a tube. Then 2 N HCl aqueous solutions was added to the reaction mixture. After stirring at room temperature for 30 min, the reaction mixture was neutralized with sat. NaHCO3 (aq.) and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude product was then purified by column chromatography on silica gel to furnish the desired amine product.
94% With hydrogenchloride In ethanol; water at 20 - 90℃; for 1 h; [Referential Example 7] 1-(5-Methoxy-2-pyridyl)-5-phenyl-1H-pyrazole-3-carboxylic acid; [Show Image] 1) 5-Amino-2-chloropyridine; Conc. hydrochloric acid (1 ml) was added to a solution of 2-chloro-5-nitropyridine (20 g) in a mixture of ethanol (160 ml) and water (40 ml). Iron which was reduced by hydrogen (70.5 g) was added in several potions to this mixture at room temperature and the mixture was stirred at 90°C for 1 hour. After cooling with air, the reaction liquid was filtered through celite, and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on silica gel (ethyl acetate-hexane) to give the amine derivative (15.2 g, 94percent) as a solid. 1H-NMR (400 MHz, CDCl3)δ: 3.71 (2H, br s), 6.96 (1H, dd, J = 8.3, 2.9 Hz), 7.08 (1H, d, J = 8.3 Hz), 7.85 (1H, d, J = 2.9 Hz). LC-MSm/z: 129 (M+H)+.
92.8% With hydrogen In tetrahydrofuran at 100℃; for 20 h; COMPOUND EXAMPLE 1 4- [6- (4-METHOXY-BENZYLCARBAMOYL)-4-OXO-4H-PYRIDO [3,4-d] pyrimidin-3- ylmethyl]-benzoic acid Preparation Method 1: Step (a): 6-CHLORO-PYRIDIN-3-YLAMINE A solution of 2-chloro-5-nitropyridine (50. 00g, 315. 5MMOL) in THF (400mL) was treated with Ra Ni (8. 0G), and the reaction mixture was hydrogenated at 56 psi of hydrogen at 100°C for 20 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was evaporated, and the resulting solid was triturated with hexanes/ethyl acetate 9: 1. The solids were collected by filtration and dried to give 37. 61G of 6-CHLORO-PYRIDIN-3-YLAMINE as a brown solid (92.8percent yield). 1H NMR (400 MHz, CHLOROFORM-D) d ppm 3.7 (s, 2H), 6.9 (m, 1H), 7.1 (d, J=9. OHz, 1H), 7.8 (s, 1H) MS (APCI) M+l = 129.0; Preparation Method 2 : It should be appreciated that the starting material and intermediates described above in Preparation Method 1 are also used below in Preparation Method 2. However, reagents, reaction times and temperatures, work-ups, purifications, and the like may differ between Preparation Methods 1 and 2. Step (a): Preparation of 6-chloro-pyridin-3-ylamine A 5 gallon stirred stainless steel pressure reactor was charged with 2-chloro-5- nitropyrimidine (571.8 g, 3.61 moles), 8.5 L of THF, and Raney Nickel (150 g). The vessel was pressurized to 50 psi with hydrogen gas, and the mixture was stirred at room temperature overnight. An aliquot checked by mass spectrometry showed the reaction was complete. The solvent was reduced to about 750 mL and left sitting at room temperature overnight. A first crop of solid had formed in the about 750 mL of solvent remaining. The solid was collected by filtration, and the filtercake was washed 1 time with THF, 2 times with heptane, and dried overnight in a vacuum oven at 45°C. Separately, about 1.5 L of heptane were added to the filtrate from above, and the mixture was refrigerated for 2 hours. A second crop of solids that formed were collected by filtration, and the filtercake was washed 1 time with heptane and dried overnight in the vacuum oven at 45°C. Meanwhile, the filtrate from the second crop was rotary evaporated, and a residual solid third crop was collected and dried overnight in the vacuum oven at 45°C. The reaction yielded 432 g (93percent total yield in 3 crops) of 6-chloro-pyridin- 3-ylamine that was sufficiently pure by NMR to carry on in the next reaction without further purification. OH (DMSO) 7.64 (1 H, M), 7.03 (1 H, d), 6.93 (1 H, d), 5.44 (2 H, s)
83% With hydrogen In methanol at 20℃; for 26 h; a) Preparation of 6-chloro-pyridin-3-ylamine 2-Chloro-5-nitro-pyridine (15 g, 94.9 mmol) was hydrogenated over Raney nickel (2 g) in methanol (200 mL) at 70 psi and r.t. for 26 h. The mixture was filtered through Celite and concentrated to afford 6-chloro-pyridin-3-ylamine (10.4 g, 83percent).
78% With hydrogen In methanol at 25℃; for 16 h; Step 1.
Preparation of 6-chloro-pyridin-3-ylamine (B4-1): A solution of 2-chloro-5-nitro pyridine (30 g, 189 mmol) in MeOH (600 mL) was charged to a Parr reactor.
The contents of the reactor were treated with Raney nickel (2 g) and hydrogenated at 60 Psi hydrogen pressure and 25° C. for 16 hours.
The contents of the reactor were then filtered through a Celite.(R). bed and washed with MeOH (100 mL).
The combined filtrates were concentrated, and the resultant residue was purified by column chromatography (60-120 mesh silica gel column; 10percent MeOH in CHCl3 as eluding solvent) to provide B4-1 as a pale yellow solid. Yield: 19 g, 78percent. 1H NMR (CDCl3) δ: 7.85 (d, 1H), 7.1 (d, 1H), 6.95 (dd, 1H) and 3.52-3.98 (broad s, 2H).

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Reference: [1] Synlett, 2014, vol. 25, # 10, p. 1403 - 1408
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Reference: [1] Journal of Organic Chemistry, 2011, vol. 76, # 23, p. 9841 - 9844
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  • [ 126553-00-2 ]
Reference: [1] Patent: EP1591443, 2005, A1,
  • 6
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[5] Patent: WO2013/91502, 2013, A1,
[6] Patent: US2014/329800, 2014, A1,
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  • [ 456-24-6 ]
YieldReaction ConditionsOperation in experiment
84% With potassium fluoride In dimethyl sulfoxide at 70℃; for 18 h; Heating / reflux To 100 g of 2-chloro-5-nitropyridine (Aldrich) in 600 mL of dimethyl sulfoxide under an inert atmosphere was added 100 g of anhydrous KF. The reaction was heated at 70° C. for 18 hours before cooling and diluting with 500 mL each of brine, ethyl acetate, and hexanes. This mixture was filtered through a pad of celite, the organic phase was separated, and the aqueous phase was extracted three times with equal volumes of ethyl acetate and hexanes. The pooled organic phases were washed with brine, dried with anhydrous sodium sulfate, and stripped of the solvents. This crude product was passed through a plug of silica gel with a gradient of 10-30percent ethyl acetate/hexanes and stripped to constant weight on a rotary evaporator to give 76 g (84percent) of 2-fluoro-5-nitropyridine as an oil, which was used in the following procedure. To 76 g of 2-fluoro-5-nitropyridine in 500 ml of ethyl acetate under nitrogen was added 100 g of Raney nickel which had been washed three times with ethanol and three times with ethyl acetate. The nitrogen was replaced with hydrogen and the reaction was allowed to proceed for 18 hours at 30 lb/in2. After the hydrogen atmosphere had been replaced by nitrogen, the reaction was filtered through celite and stripped of solvent. The product was purified by passing through a plug of silica gel with chloroform and recrystallized from chloroform to give 42 g (70percent) of 6-fluoro-pyridin-3-ylamine in two crops as white platelets: melting point 90-91° C.; mass spectrum (m/e): M+H 112.7.
84% With potassium fluoride In dimethyl sulfoxide at 70℃; for 18 h; To 100 g of 2-chloro-5-nitropyridine (Aldrich) in 600 mL of dimethyl sulfoxide under an inert atmosphere was added 100 g of anhydrous KF. The reaction was heated at 70C for 18 hours before cooling and diluting with 500 mL each of brine, ethyl acetate, and hexanes. This mixture was filtered through a pad of celite, the organic phase was separated, and the aqueous phase was extracted three times with equal volumes of ethyl acetate and hexanes. The pooled organic phases were washed with brine, dried with anhydrous sodium sulfate, and stripped of the solvents. This crude product was passed through a plug of silica gel with a gradient of 10-30percent ethyl acetate/hexanes and stripped to constant weight on a rotary evaporator to give 76 g (84percent) of 2-fluoro-5-nitropyridine as an oil, which was used in the following procedure. To 76 g of 2-fluoro-5-nitropyridine in 500 ml of ethyl acetate under nitrogen was added 100 g of Raney nickel which had been washed three times with ethanol and three times with ethyl acetate. The nitrogen was replaced with hydrogen and the reaction was allowed to proceed for 18 hours at 30 lb/in2. After the hydrogen atmosphere had been replaced by nitrogen, the reaction was filtered through celite and stripped of solvent. The product was purified by passing through a plug of silica gel with chloroform and recrystallized from chloroform to give 42 g (70percent) of 6-fluoro-pyridin-3-ylamine in two crops as white platelets: melting point 90-91C; mass spectrum (m/e): M+H 112.7.
83% With cesium fluoride In 1,2-dimethoxyethane Method A
Preparation of 2-Fluoro-5-nitropyridine
A suspension of 160 g (1.01 mol) of 2-chloro-5-nitropyridine and 379 g of dry cesium fluoride was placed in a dry stainless steel bomb which was then charged with 1 L of anhydrous ethylene glycol dimethyl ether.
The bomb was sealed, and the reaction was heated at 130° C. with vigorous stirring for 18 hours.
The reactor was cooled, vented, and the contents suspended by vigorous agitation.
The solids were collected by filtration, then washed well with dichloromethane.
The resulting dark brown filtrate was concentrated at 45° C. to give a thick oily brown residue that was distilled through a 4-inch Vigreux column at 61° C./0.05 mm Hg (literature bp 86-87° C./7 mm Hg; Finger G. C. and Starr L. D., J. Am. Chem. Soc., 81:2674-2675 (1959)) to afford 119.4 g (83percent) of the product as a clear pale yellow oil, >96percent pure by gas chromatography (GC).
Nuclear magnetic resonance spectroscopy (1H NMR) in deuterated chloroform (CDCl3): δ9.15 (dd, J=2.7, 0.7 Hz, 1H), 8.63 (td, J=7.7, 2.9 Hz, 1H), and 7.15 (dd, J=9.3, 3.4 Hz, 1H).
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YieldReaction ConditionsOperation in experiment
54% With potassium fluoride In acetonitrile 8b.
2-fluoro-5-nitropyridine
2-Chloro-5-nitropyridine (100 g, 0.656 mol, Aldrich), potassium fluoride (84.1 g, 1.45 mol, Aldrich), tetraphenylphosphonium bromide (95.3 g, 0.227 mol, Aldrich), and acetonitrile (1.5 L) were combined and heated at reflux until consumption of the 2-chloro-5-nitropyridine was complete.
The volume of the mixture was reduced to 750 mL, diluted with 2 L of ether, filtered and concentrated.
The resultant residue was triturated with hot hexane, and the combined hexane extracts were concentrated to give of the title compound (48 g, 54percent): 1 H NMR (CDCl3, 300 MHz) δ 7.15 (dd, J=3, 6 Hz, 1 H), 8.64 (m, 1 H), 9.15 (d, J=1.6 Hz, 1 H).
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YieldReaction ConditionsOperation in experiment
54% With KF In acetonitrile 12a.
2-Fluoro-5-nitropyridine
2-Chloro-5-nitropyridine (100 g, 0.656 mol, Aldrich), KF (84.1 g, 1.448 mol), Ph4 PBr (95.3 g, 0.227 mol) and acetonitrile (1.5 L) were combined and heated at reflux until no starting material remained.
The volume was reduced to 750 mL, and the mixture was diluted with 2 L of ether, filtered and concentrated.
The residue was triturated with hot hexane (5*1 L).
The hexane extracts were combined and concentrated to afford 48 g (54percent).
1 H NMR (CDCl3, 300 MHz) δ7.15 (dd, J=3, 6 Hz, 1H), 8.64 (m, 1H), 9.15 (d, J=1.6 Hz, 1H).
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YieldReaction ConditionsOperation in experiment
87 % With hydrazine In methanol; water 2-Hydrazino-5-nitropyridine.
To a slurry of 47.6 g (0.3 mol) of 2-chloro-5-nitropyridine in a mixture of 400 ml methanol and 60 ml water and cooled to 10° C. was added with cooling below 30° 86 g hydrazine (95 percent) over about 10 minutes.
The solids first went into solution, then a greenish-yellow precipitate separated.
The mixture was stirred at reflux for 30 minutes.
The greenish solid was filtered off and washed with cold methanol.
The solid was slurried in 200 ml of cold water, washed and vacuum dried.
The yield was 40.1 g (87 percent).
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  • [ 52023-68-4 ]
YieldReaction ConditionsOperation in experiment
93%
Stage #1: With triethylamine In dichloromethane at 20℃; for 12 h;
Stage #2: With palladium on activated charcoal; hydrogen In ethanol for 2 h;
A mixture of 2-chloro-5-nitropyridine (303 mg, 1.91 mmol, 1.0 equiv), morpholine (0.5 mL,5.74 mmol, 3.0 equiv) and Et3N (483 mg, 0.67 mL, 2.5 equiv) in CH2Cl2 (4 mL) was stirred at roomtemperature overnight. The reaction mixture was diluted with water (10 mL) and extracted withCH2Cl2 (30 mL 3). The combined organic layers were washed with water (30 mL 6) and brine(1x30 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to give a yellow solid. 70 mg ofthe yellow solid (0.335 mmol, 1.0 eq) were diluted in EtOH (5 mL) and a spatula tip of catalyst Pd/Cwas added. The obtained mixture was hydrogenated for 2 h, using a Hypem XP hydrogen generator(h2planet, Milan, Italy), Pressure was set at 1.5 bar. The crude mixture was filtered on Celite, and thefiltrate was evaporated to obtain a red solid. Yield: 93percent over two steps. TLC (hexane:ethyl acetate =4:6 v/v + Et3N): Rf = 0.15. 1H-NMR (CDCl3) δ 7.79 (d, J = 2.7 Hz, 1H), 7.01 (dd, J = 8.8, 2.7 Hz, 1H),6.73 (brs, 2H, NH2), 6.56 (d, J = 8.8 Hz, 1H), 3.82 (m, 4H), 3.33 (m, 4H). 13C-NMR (CDCl3) δ 154.02,135.09, 134.58, 126.42, 108.41, 66.80 (2C), 47.08 (2C). ESI()MS: m/z 178 [M-H]-.
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[9] Patent: WO2015/131080, 2015, A1,
[10] Patent: US2015/336982, 2015, A1,
[11] Chinese Chemical Letters, 2015, vol. 26, # 10, p. 1307 - 1310
[12] Chinese Chemical Letters, 2016, vol. 27, # 1, p. 1 - 6
[13] RSC Advances, 2016, vol. 6, # 9, p. 6896 - 6904
[14] European Journal of Medicinal Chemistry, 2017, vol. 125, p. 1036 - 1050
[15] Patent: WO2018/19252, 2018, A1,
[16] Bioorganic Chemistry, 2018, vol. 81, p. 689 - 699
[17] Patent: WO2009/154769, 2009, A1,
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Reference: [1] Liebigs Annalen der Chemie, 1991, # 9, p. 875 - 878
  • 26
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  • [ 5418-51-9 ]
  • [ 27048-04-0 ]
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Reference: [1] Journal of Organic Chemistry, 1984, vol. 49, # 20, p. 3681 - 3684
  • 28
  • [ 110-85-0 ]
  • [ 4548-45-2 ]
  • [ 82205-58-1 ]
YieldReaction ConditionsOperation in experiment
9.10 g With potassium carbonate In ethanol at 20℃; Under stirring at room temperature, To 2-chloro-5-nitropyridine (0.04 mol), anhydrous potassium carbonate (0.04 mol) and ethanol (80 mL) was added piperazine (0.042 mol) Of ethanol (10 mL). The reaction mixture was stirred for 2-4h, Pour into water, ethyl acetate extraction, The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 9.10 g of the title compound as a yellow solid.
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 16, p. 4779 - 4783
[2] European Journal of Medicinal Chemistry, 2005, vol. 40, # 2, p. 209 - 214
[3] Archiv der Pharmazie, 2009, vol. 342, # 7, p. 377 - 385
[4] Patent: CN107298652, 2017, A, . Location in patent: Paragraph 0081; 0083
  • 29
  • [ 4548-45-2 ]
  • [ 82205-58-1 ]
Reference: [1] Patent: US5120843, 1992, A,
[2] Patent: WO2011/31628, 2011, A1,
[3] Patent: US2011/224137, 2011, A1,
[4] Patent: WO2012/24179, 2012, A1,
[5] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 4, p. 985 - 988
  • 30
  • [ 4548-45-2 ]
  • [ 52382-48-6 ]
Reference: [1] Synthetic Communications, 1999, vol. 29, # 19, p. 3341 - 3352
  • 31
  • [ 4548-45-2 ]
  • [ 31040-15-0 ]
Reference: [1] Tetrahedron, 2015, vol. 71, # 3, p. 407 - 418
  • 32
  • [ 109-01-3 ]
  • [ 4548-45-2 ]
  • [ 55403-34-4 ]
YieldReaction ConditionsOperation in experiment
90% With potassium carbonate In DMF (N,N-dimethyl-formamide) at 100℃; for 24 h; [0133] A stirred mixture of 2-chloro-5-nitropyridine (3.16 g, 20.0 mmol), 1-methyl-piperazine (2.00 g, 2.00 mmol) and potassium carbonate (2.76 g, 20.0 mmol) in DMF is heated at 100 C. for 24 h, cooled, poured into water and extracted with CH2Cl2. The combined extracts are dried over MgSO4 and concentrated in vacuo. The resultant residue is purified by flash chromatography (SiO2, 2percent ammonia in 10:90 ethanol:ethyl acetate as eluent) affords the title compound as an off-white solid, 4.0 g (90percent yield), identified by NMR analysis
86.6% With potassium carbonate In 1,4-dioxaneReflux Step 1
To a solution of 2-chloro-5-nitropyridine (LVII) (3.17 g, 20.0 mmol) in dioaxane (50 mL) was added 1-methylpiperazine (LVIII) (4.00 g, 40.0 mmol) and potassium carbonate.
The reaction was refluxed overnight, cooled to room temperature and concentrated under vacuum.
The residue was treated with water and sonicated followed by stirring for 30 min.
The solid was filtered, washed with cold water and dried to give 1-methyl-4-(5-nitropyridin-2-yl)piperazine (LIX) as a yellow solid (3.85 g, 17.3 mmol, 86.6percent yield). ESIMS found for C10H14N4O2 m/z 223.1 (M+H).
76.5% With potassium carbonate In tetrahydrofuran at 50℃; for 3 h; General procedure: To a solution of C-1∼C-3 (5.3mmol) or 2-chloro-5-nitropyridine (5.3mmol) in THF (5mL) was added K2CO3 (10.6mmol) and different alicyclic amines (0.011mol). The reaction mixture was heated and stirred for 3.0hat 50°C. The solvent was evaporated under reduced pressure whereafter water was poured into the mixture and stirring for 1h. Production D-1∼D-16 was gained after filtration.
Reference: [1] Molecules, 2012, vol. 17, # 4, p. 4703 - 4716
[2] Patent: US2004/167030, 2004, A1, . Location in patent: Page 9
[3] Patent: US2015/266825, 2015, A1, . Location in patent: Paragraph 1279; 1280
[4] European Journal of Medicinal Chemistry, 2018, vol. 158, p. 322 - 333
[5] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 5, p. 1362 - 1365
[6] Patent: US3947434, 1976, A,
[7] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 14, p. 4186 - 4190
[8] Patent: US6297375, 2001, B1,
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  • [ 4548-45-2 ]
  • [ 28020-36-2 ]
Reference: [1] Chinese Chemical Letters, 2016, vol. 27, # 1, p. 1 - 6
[2] Patent: WO2006/100588, 2006, A1,
  • 34
  • [ 4548-45-2 ]
  • [ 171178-45-3 ]
Reference: [1] Inorganic Chemistry, 2017, vol. 56, # 14, p. 8381 - 8389
[2] Patent: WO2008/76425, 2008, A1,
  • 35
  • [ 4548-45-2 ]
  • [ 171178-46-4 ]
Reference: [1] Patent: WO2008/76425, 2008, A1,
[2] Patent: WO2008/130600, 2008, A2,
  • 36
  • [ 4548-45-2 ]
  • [ 42726-73-8 ]
  • [ 292600-22-7 ]
YieldReaction ConditionsOperation in experiment
42.8%
Stage #1: With sodium hydride In tetrahydrofuran at 0 - 20℃; for 0.25 h;
Stage #2: at 20℃; for 4 h;
Tert-butyl methyl malonate (2.64 g, 15.14 mmol) was dissolved in THF (50 mL). Sodium hydride (0.605 g, 15.14 mmol) was added portion-wise at 0 °C and the reaction mixture was allowed to stir for 15 mm at room temperature. 2-chloro-5-nitropyridine (2.012.61 mmol) dissolved in 10 mL of THF was then added to the mixture and the mixture was allowed to stir for 4 hours at room temperature before being quenched withsaturated aqueous ammonium chloride and extracted with EtOAc (3x). The combined organic layer was washed with brine, dried with sodium sulfate, filtered and concentrated. The resulting residue was dissolved in 30 mL of 2:1 DCMITFA and stirred for 1.5 hours. The reaction mixture was then diluted with 1.5 M potassium phosphate solution and extracted with EtOAc (3x). The combined organic layer was washed with brine, driedwith sodium sulfate, filtered and concentrated. The resulting residue was dissolved in methylene chloride before being charged to an 80 g silica gel cartridge which was eluted with a 30 mm gradient from 0-100percent EtOAc in hexane. Fractions containing the desired product were concentrated to yield Intermediate I-109A (1.06 g, 5.40 mmol, 42.8 percent yield), as a yellow oil. LC-MS: Method H, MS (ESI) m/z: 197.0 (M+H). ‘H NMR(400MHz, CDC13) 9.41 (d, J=2.6 Hz, 1H), 8.49 (dd, J8.6, 2.6 Hz, 1H), 7.56 (d, J8.6 Hz, 1H), 4.02 (s, 2H), 3.78 (s, 3H).
Reference: [1] Patent: WO2018/13774, 2018, A1, . Location in patent: Page/Page column 246
  • 37
  • [ 4548-45-2 ]
  • [ 292600-22-7 ]
Reference: [1] Tetrahedron Letters, 2001, vol. 42, # 37, p. 6441 - 6445
[2] Patent: US2014/142081, 2014, A1,
[3] Patent: WO2014/79136, 2014, A1,
[4] Patent: WO2014/79150, 2014, A1,
[5] Angewandte Chemie - International Edition, 2015, vol. 54, # 51, p. 15545 - 15549[6] Angew. Chem., 2015, vol. 127, # 51, p. 15766 - 15770,5
  • 38
  • [ 4548-45-2 ]
  • [ 400777-00-6 ]
Reference: [1] Inorganic Chemistry, 2017, vol. 56, # 14, p. 8381 - 8389
  • 39
  • [ 4548-45-2 ]
  • [ 119285-07-3 ]
Reference: [1] Journal of Medicinal Chemistry, 2011, vol. 54, # 7, p. 2433 - 2446
[2] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 16, p. 4779 - 4783
[3] Chinese Chemical Letters, 2013, vol. 24, # 4, p. 303 - 306
[4] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 23, p. 6410 - 6414
  • 40
  • [ 4548-45-2 ]
  • [ 1227862-58-9 ]
  • [ 57260-71-6 ]
  • [ 119285-07-3 ]
Reference: [1] Patent: US2011/224137, 2011, A1,
  • 41
  • [ 4548-45-2 ]
  • [ 57260-71-6 ]
  • [ 193902-78-2 ]
YieldReaction ConditionsOperation in experiment
100% With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 100℃; for 16 h; Step 1 : t-Butyl 4-(5-nitropyridin-2-yl)piperazine-1-carboxylate (B-2) To 5-nitro-2-chloropyridine (10.0 g, 0.0631 mol) and N-BOC-piperazine (17.6 g, 0.0946 mol) dissolved in DMF (200 ml_) was added N1N- diisopropylethylamine (24.5 g, 31.3 ml_, 0.189 mol). The reaction mixture was heated at 100 0C for 16 h then cooled to RT and concentrated. Water (300 ml_) was added, and the aqueous solution was extracted with CH2CI2. The combined organic extract was dried (MgSO4), filtered, and concentrated. Purification by vacuum filtration through silica gel (eluant: 5percent EtOAc-CH2CI2) gave t-butyl 4-(5-nitropyridin-2-yl)piperazine-1 -carboxylate (B-2) as a yellow solid (19.45 g, 100percent yield). MS (M+1): 309.
100% With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 100℃; for 16 h; Intermediate B-54-(5-Aminopyridin-2-yl)-N-(2-fluorophenyl)piperazine- 1 -carboxamide (B-5) Step 1 : t-Butyl 4-(5-nitropyridin-2-yl)piperazine-l-carboxylate (B-2)To 5-nitro-2-chloropyridine (10.0 g, 0.0631 raol) and N-BOC-piperazine (17.6 g, 0.0946 mol) dissolved in DMF (200 mL) was added N,N-diisopropylethylamine (24.5 g, 31.3 mL, 0.189 mol). The reaction mixture was heated at 100 °C for 16 h then cooled to RT and concentrated. Water (300 mL) was added, and the aqueous solution was extracted with CH2G2. The combined organic extract was dried (MgS0 ), filtered, and concentrated.Purification by vacuum filtration through silica gel (eluant: 5percent EtOAc-CFkCL.) gave t-butyl 4-(5-nitropyridin-2-yl)piperazine-l-carboxylate (B-2) as a yellow solid (19.45 g, 100percent yield). MS (M+l): 309.
95% With potassium carbonate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 120℃; for 4 h; N-BOC piperazine (0.5g) and 2-chloro-5-nitropyridine (0.424g) in DMF (16ml) were treated with potassium carbonate (0.744g) and DIPEA (1.41ml). The resulting mixture was heated at 1200C for 4 hours.After cooling to room temperarure, the solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. Organic layer washed again with water then dried over anhydrous magnesium sulphate. After filtration, the solvent evaporated to dryness in vacuo to afford the title compound as a pale brown solid in 95percent.LCMS (ES+) 209.05 (MH+-BOC)
95% With potassium carbonate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 120℃; for 4 h; N-BOC piperazine (0.5g) and 2-chloro-5-nitropyridine (0.424g) in DMF (16ml) were treated with potassium carbonate (0.744g) and DIPEA (1.41ml). The resulting mixture was heated at 1200C for 4 hours.After cooling to room temperarure, the solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. Organic layer washed again with water then dried over anhydrous magnesium sulphate. After filtration, the solvent evaporated to dryness in vacuo to afford the title compound as a pale brown solid in 95percent. LCMS (ES+) 209.05 (MH+-BOC).
88% With potassium carbonate In 1,4-dioxane for 4 h; Heating / reflux Potassium carbonate (1.7g, 12.31 mmol) was added to a solution of 2-Chloro- 5-nitropyridine (1.33g,8.38mmol) and piperazine-1-carboxylic acid tert-butyl ester (1.57g, 8.42mmol) in dioxane (10ml) then stirred at reflux for 4hours. The reaction was cooled, and solvent evaporated. The residue was extracted with MeCI2 (100ml) washed with H2O (50ml), separated organic layer washed with brine (50ml) dried over MgSO4, filtered and solvent evaporated yielding a residue which chromatographed on silica gel eluting with 10percent v/v EtOAc/hexanes yielding desired product as a pale yellow solid (2.3g,88percent)Partial 1H NMR (400MHz, CDCI3)σ 9.0 (s,1H) 8.20(d,1H)6.50 (d,1 H) .
87% With potassium carbonate In acetonitrile for 4 h; Heating / reflux A suspension of 2-chloro-5-nitropyridine (7.90 g), piperazine-1-carboxylic acid tert-butyl ester (11.2 g) and potassium carbonate (6.90 g) in acetonitrile (250 mL) was heated under reflux for four hours. The reaction mixture was concentrated and diluted with ethyl acetate and washed with water and saturated brine and dried over sodium sulfate and filtered and concentrated. The residue was vigorously stirred in ethyl acetate/isopropyl ether, collected by filtration and dried under reduced pressure, and 16.1 g (87percent) of the title compound was obtained as a yellow solid. MS(FAB) m/z:309 (M + H)+.
83%
Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 0.25 h;
Stage #2: at 20 - 50℃; for 4 h;
To a solution of tert-butyl piperazine-1-carboxylate (64 g, 346 mmol) in 600 ml. of THF at O0C was added NaH (16.4 g, 409 mmol, 60percent in mineral oil) portionwise. The reaction mixture was stirred for 15 min and 2-chloro-5-nitropyridine (50 g, 314 mmol) was added. The reaction mixture was allowed to warm to rt and then heated to 5O0C for 4 h. The reaction was quenched by water (30 ml.) and extracted with DCM (1.5 Lx 3). The combined organic layers were dried over Na2SO4 and the solvent was removed under reduced pressure. The residue was subjected to wash with petroleum ether to give the desired product of Step A (80 g, yield 83percent). 1H NMR (CDCI3, 400 MHz) δ 8.95 (d, J = 2.4 Hz, 1 H), 8.24 (d, J = 12 Hz, 1 H), 6.92 (d, J = 6.0 Hz, 1 H), 3.75 (s, 4 H), 3.44 (s, 4H), and 1.41 (s, 9 H).
58% With potassium carbonate In butan-1-ol at 120℃; for 17 h; Place 2-chloro-5-nitro-pyridine (1.0 g, 6.31 mmol), piperazine-1-carboxylic acid tert-butyl ester (1.76 g, 9.45 mmol), and triethylamine (1.76 mL, 12.6 mmol) in ra-butanol (20 mL). Heat to 120 °C for 17 hours. Cool to room temperature and add ethyl acetate and water. Separate organic layer and wash with water and saturated aq. sodium chloride. Collect organic layer, dry over Mg2SO4, filter, and concentrate under reduced pressure. Subject residue to silica gel chromatography eluting with 20percent EtOAc:hexane to yield 1.14 g (58percent) of 4-(5-nitro-pyridin-2-yl)-piperazine-l-carboxylic acid tert-butyl ester. MS(ES): m/z = 309 [M+H].
50%
Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 0.333333 h;
Stage #2: at 50℃;
To a solution containing 5.8 g (31.5 mmol) of tert-butyl 1-piperazinecarboxylate and 20 mL of THF at 00C was added 1.5 g (37 mmol) of a 60percent dispersion of NaH in mineral oil. The reaction mixture was allowed to stir for 20 min and 5.0 g (31.5 mmol) of 2-chloro-5-nitropyridine was added. The reaction mixture was heated at 500C <n="96"/>overnight, quenched by the addition of water, and extracted with DCM. The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure. The residue was subjected to silica gel chromatography to give 4.89 g (50percent) of tert-butyl 4-(5-nitro-2-pyridinyl)-1-piperazinecarboxylate as a yellow solid: 1H NMR (400 MHz, DMSOd6) δ 8.25 (dd, J = 9.5 and 2.9 Hz, 1 H), 6.93 (d, J = 9.5 Hz, 1 H), 3.76 -3.78 (m, 4 H), 3.41 - 3.48 (m, 4 H), and 1.42 (s, 9 H).
50%
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.333333 h; Inert atmosphere
Stage #2: at 50℃;
To a solution containing 5 8 g (31 5 mmol) of fert-butyl 1-pιperazιnecarboxylate and 20 mL of THF at 0 °C was added 1 5 g (37 mmol) of a 60percent dispersion of NaH in mineral oil The reaction mixture was allowed to stir for 20 mm and 5 0 g (31 5 mmol) of 2-chloro-5-nιtropyrιdιne was added The reaction mixture was heated at 50 °C overnight, quenched by the addition of H2O, and extracted with DCM The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure The residue was subjected to silica gel chromatography to give 4 89 g (50percent) of fert-butyl 4-(5-nιtro-2-pyrιdιnyl)-1-pιperazιnecarboxylate as a yellow solid 1H-NMR (400 MHz, DMSO-d6) δ 8 25 (dd, J =9 5 and 2 9 Hz, 1 H), 6 93 (d, J =9 5 Hz, 1 H), 3 76 -3 78 (m, 4 H), 341 - 3 48 (m, 4 H), and 1 42 (s, 9 H)
4.94 g at 70℃; for 16 h; To a solution of 2-chloro-5-nitropyridine (LXV) (2.0 g, 12.6 mmol) in EtOH (20 mL) was added tert-butyl piperazine-l-carboxylate (XCVI) (7.05 g, 37.9 mmol). The reaction was headed at 70°C for 16 h. The reaction was concentrated under vacuum and then dissolved in EtOAc. The EtOAc was washed with 1 M NaOH, brine and then dried over MgS04 to give tert-butyl 4-(5-nitropyridin-2-yl)piperazine-l- carboxylate (XCVII) as a yellow solid (4.94 g). ESIMS found for C14H20N4O4 mlz 309.0 (M+H).
4.94 g at 70℃; for 16 h; Step 1
To a solution of 2-chloro-5-nitropyridine (LVII) (2.0 g, 12.6 mmol) in EtOH (20 mL) was added tert-butyl piperazine-1-carboxylate (LXXII) (7.05 g, 37.9 mmol).
The reaction was headed at 70° C. for 16 h.
The reaction was concentrated under vacuum and then dissolved in EtOAc.
The EtOAc was washed with 1 M NaOH, brine and then dried over MgSO4 to give tert-butyl 4-(5-nitropyridin-2-yl)piperazine-1-carboxylate (LXXIII) as a yellow solid (4.94 g). ESIMS found for C14H20N4O4 m/z 309.0 (M+H).
4.94 g at 70℃; for 16 h; To a solution of 2-chloro-5-nitropyridine (LXV) (2.0 g, 12.6 mmol) in EtOH (20 mL) was added fert-butyl piperazine-l-carboxylate (XCVI) (7.05 g, 37.9 mmol). The reaction was headed at 70°C for 16 h. The reaction was concentrated under vacuum and then dissolved in EtOAc. The EtOAc was washed with 1 M NaOH, brine and then dried over MgS04 to give tert-butyl 4-(5-nitropyridin-2-yl)piperazine-l-carboxylate (XCVII) as a yellow solid (4.94 g). ESIMS found for C14H20N4O4 mlz 309.0 (M+H).

Reference: [1] Patent: WO2010/59606, 2010, A2, . Location in patent: Page/Page column 182
[2] Patent: WO2011/31628, 2011, A1, . Location in patent: Page/Page column 66-67
[3] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 4, p. 985 - 988
[4] Patent: WO2006/94840, 2006, A1, . Location in patent: Page/Page column 43
[5] Patent: WO2006/94843, 2006, A1, . Location in patent: Page/Page column 53
[6] Chinese Chemical Letters, 2013, vol. 24, # 4, p. 303 - 306
[7] Patent: WO2007/97937, 2007, A1, . Location in patent: Page/Page column 195
[8] Patent: EP1764360, 2007, A1, . Location in patent: Page/Page column 105
[9] Patent: WO2009/32667, 2009, A1, . Location in patent: Page/Page column 149-150
[10] Patent: WO2007/53394, 2007, A1, . Location in patent: Page/Page column 14
[11] Patent: WO2009/32667, 2009, A1, . Location in patent: Page/Page column 94-95
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[13] Patent: WO2006/131835, 2006, A2, . Location in patent: Page/Page column 50
[14] Patent: WO2008/29266, 2008, A1, . Location in patent: Page/Page column 26-27
[15] Journal of Medicinal Chemistry, 2011, vol. 54, # 7, p. 2433 - 2446
[16] Patent: WO2012/24179, 2012, A1, . Location in patent: Page/Page column 62
[17] Patent: WO2013/40215, 2013, A1, . Location in patent: Paragraph 00319
[18] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 23, p. 6410 - 6414
[19] Patent: US2015/266825, 2015, A1, . Location in patent: Paragraph 1294; 1295
[20] Patent: WO2018/75858, 2018, A1, . Location in patent: Paragraph 0351; 0352
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[2] Patent: JP2015/86180, 2015, A,
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[2] Drugs of the Future, 2014, vol. 39, # 10, p. 677 - 684
[3] Patent: CN103893184, 2016, B,
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