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Chemical Structure| 39856-50-3
Chemical Structure| 39856-50-3
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Product Details of [ 39856-50-3 ]

CAS No. :39856-50-3 MDL No. :MFCD00160411
Formula : C5H3BrN2O2 Boiling Point : -
Linear Structure Formula :- InChI Key :ATXXLNCPVSUCNK-UHFFFAOYSA-N
M.W :202.99 Pubchem ID :817620
Synonyms :

Calculated chemistry of [ 39856-50-3 ]

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 : 40.76
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) : -6.32 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.27
Log Po/w (XLOGP3) : 1.71
Log Po/w (WLOGP) : 1.75
Log Po/w (MLOGP) : 0.86
Log Po/w (SILICOS-IT) : -0.05
Consensus Log Po/w : 1.11

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.55
Solubility : 0.567 mg/ml ; 0.00279 mol/l
Class : Soluble
Log S (Ali) : -2.56
Solubility : 0.561 mg/ml ; 0.00276 mol/l
Class : Soluble
Log S (SILICOS-IT) : -2.26
Solubility : 1.11 mg/ml ; 0.00546 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 2.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.11

Safety of [ 39856-50-3 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P264-P271-P280-P302+P352-P304+P340+P312-P305+P351+P338-P332+P313-P337+P313-P403+P233-P405-P501 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 39856-50-3 ]

* 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 [ 39856-50-3 ]
  • Downstream synthetic route of [ 39856-50-3 ]

[ 39856-50-3 ] Synthesis Path-Upstream   1~43

  • 1
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YieldReaction ConditionsOperation in experiment
96% With tetrahydroxydiboron; 5%-palladium/activated carbon; water In acetonitrile at 50℃; for 24 h; General procedure: Nitrobenzene (0.6mmol), 5wtpercent Pd/C (0.5mmol percent, 0.003mmol), H2O (10 equiv, 6.0mmol), B2(OH)4 (3.3 equiv, 2.0mmol), and CH3CN (1.0mL) were added in a 10mL tube. The reaction mixture was stirred at 50°C for 24h. When the reaction was complete monitored by TLC, the mixture was cooled to room temperature. Water (5mL) was added, and extracted with EtOAc (3×5mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give aniline 2a (55mg, 99percent).
Reference: [1] Tetrahedron, 2017, vol. 73, # 27-28, p. 3898 - 3904
[2] Organic Process Research and Development, 2017, vol. 21, # 2, p. 247 - 252
[3] Organic Letters, 2016, vol. 18, # 11, p. 2774 - 2776
[4] ACS Catalysis, 2015, vol. 5, # 3, p. 1526 - 1529
[5] Yakugaku Zasshi, 1952, vol. 72, p. 381[6] Chem.Abstr., 1953, p. 6403
[7] Zhurnal Obshchei Khimii, 1940, vol. 10, p. 1105[8] Chem. Zentralbl., 1940, vol. 111, # II, p. 3474
[9] Chemical Communications, 2010, vol. 46, # 10, p. 1769 - 1771
[10] Chemical Communications, 2011, vol. 47, # 39, p. 10972 - 10974
[11] Green Chemistry, 2015, vol. 17, # 2, p. 898 - 902
  • 2
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  • [ 14916-65-5 ]
Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1953, vol. 72, p. 125,131
  • 3
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  • [ 14916-65-5 ]
Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1953, vol. 72, p. 125,131
  • 4
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  • [ 64-17-5 ]
  • [ 7664-41-7 ]
  • [ 1072-97-5 ]
  • [ 14916-65-5 ]
Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1953, vol. 72, p. 125,131
  • 5
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  • [ 13466-38-1 ]
Reference: [1] Organic Letters, 2005, vol. 7, # 4, p. 577 - 579
  • 6
  • [ 67-56-1 ]
  • [ 39856-50-3 ]
  • [ 13472-85-0 ]
YieldReaction ConditionsOperation in experiment
54% at 75℃; for 2 h; A solution of 5-bromo-2-nitropyridine (5.0 g, 24.63 mmol), in methanol (100 mL) was added sodium methoxide (2.67 g, 49.44 mmol) and stirred at 75 00 for 2 h. The reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (2 x 200 mL). The combined extracts were washed with water (200 mL), brine (200 mL), dried over anhydrous Na2SO4 and concentrated. The crude compound was purified by column chromatography over silica gel (100-200 mesh) using a solvent gradient mixture of 5percent ethyl acetate in pet-ether as eluant to afford 2.5 g (54percent) of 5-bromo-2-methoxypyridine 122-1 as a colorless liquid. 1H NMR (400 MHz, CDCI3): c5 8.19 (d, J= 2.2 Hz, 1 H), 7.63 (dd, J= 1.8, 8.8 Hz, 1H), 6.66 (d, J= 8.7 Hz, 1H), 3.90 (5, 3H). ESI-LC/MS: m/z190.13 [(M+2)H+]; R = 3.13 mm [Agilent [C with Ion trap Detector; Waters Symmetry 018, 3.5 pm, 4.6 X 75 mm column; gradient of 50:50 H20 (0.1percent H000H): CH3CN (0.1percent H000H) to 10:90 H20 (0.1percent H000H): CH3CN (0.1percent H000H) in 4mm and hold for 3mm with flow rate of 1.0 mL/min].
Reference: [1] Patent: WO2014/78802, 2014, A1, . Location in patent: Page/Page column 199
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  • [ 13472-85-0 ]
Reference: [1] Organic Letters, 2005, vol. 7, # 4, p. 577 - 579
  • 8
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  • [ 124-41-4 ]
  • [ 13472-85-0 ]
Reference: [1] Yakugaku Zasshi, 1952, vol. 72, p. 381[2] Chem.Abstr., 1953, p. 6403
  • 9
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  • [ 141-52-6 ]
  • [ 55849-30-4 ]
Reference: [1] Yakugaku Zasshi, 1952, vol. 72, p. 381[2] Chem.Abstr., 1953, p. 6403
[3] Recueil des Travaux Chimiques des Pays-Bas, 1949, vol. 68, p. 275,282
  • 10
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Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1951, vol. 70, p. 182,190
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Reference: [1] Organic Process Research and Development, 2017, vol. 21, # 3, p. 451 - 459
[2] Organic Process Research and Development, 2017, vol. 21, # 3, p. 451 - 459
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Reference: [1] Organic Process Research and Development, 2017, vol. 21, # 3, p. 451 - 459
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YieldReaction ConditionsOperation in experiment
21.8%
Stage #1: With potassium acetate; palladium diacetate; bis(pinacol)diborane In N,N-dimethyl-formamide at 100℃; for 16 h;
Stage #2: With sodium perborate tetrahydrate In tetrahydrofuran; water at 20℃; for 16 h;
A suspension of 5-bromo-2-nitro-pyridine (10.0 g, 49 mmol), Boric acid ester (13.7 g, 54 mmol), Pd (OAc)2 (121 mg, 0.54 mmol) and KOAc (14.4 g, 147 mmol) in DMF (180 mL) was heated to 100 °C for 16 h. After the solvent was removed under vacuum, the remaining residue was mixed with EtOAc (600 mL). The EtOAc solution was washed with water (100 mL), brine (100 mL), and dried over Na2S04. It was concentrated to a residue that was mixed with NaBOs 4H20 (19.0g, 125 mmol), THF (180 mL) and H20 (180 mL). The resulting mixture was stirred at room temperature for 16 h. The aqueous phase was separated with the organic phase, and washed with EtOAc (100 mL x 2). The combined organic solution was then concentrated to give 6-nitro-pyridin-3-ol (1.5 g, 21.8 percent) as a yellow solid.
Reference: [1] Patent: WO2014/52365, 2014, A1, . Location in patent: Page/Page column 168
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Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1953, vol. 72, p. 125,131
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Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1953, vol. 72, p. 125,131
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  • [ 7664-41-7 ]
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Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1953, vol. 72, p. 125,131
  • 17
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YieldReaction ConditionsOperation in experiment
86.1%
Stage #1: at 20℃; for 0.5 h; Autoclave; Large scale
Stage #2: at 30 - 40℃; for 20 h; Large scale
500 L of glacial acetic acid and 150 L of acetic acid recovered in Example 1 were charged into a 1000 L autoclave, and the circulating water was stirred and stirred. After homogeneous mixing, 120 kg of 2-amino-5-bromopyridine was slowly added and the temperature was controlled at 20C. , Stirring 30min, slowly dropping 300kg peracetic acid, when dropping to about 50kg, the temperature began to slowly rise, stop dropping, when the temperature does not rise began to decline, and then dropping the remaining amount, until the peracetic acid plus Finished, the whole process temperature control at 30 . After completion of the dropwise addition, the temperature was controlled at 40 ° C and the reaction was carried out at constant temperature for 20 hours. When the reaction is complete, vacuum distillation, steaming about 600L acetic acid, to stop the distillation. The remaining liquid cooling to 25 , and then add 500L of water, with 40percent sodium hydroxide solution to adjust the pH value of the material to 8, cooled to -20 , filtration, drying, 125kg solid, crude The yield was 89.3percent. The recrystallized product was 120.5kg and the yield was 86.1percent.
73.4% With sulfuric acid; dihydrogen peroxide In water at 5 - 15℃; Add 1000ml of 30percent hydrogen peroxide solution to a 1000ml three-neck reaction flask, cool down to 15 °C with a low temperature reaction bath, and drop 320ml of 98percent concentrated sulfuric acid into the hydrogen peroxide water in the reaction bottle with a constant pressure dropping funnel. The temperature of the solution in the bottle is controlled at 5 In the range of -15 ° C, the solution B was added dropwise. At the same time, 160ml of 98percent concentrated sulfuric acid was added to another 1000ml three-neck reaction flask, and 60.00g of 2-amino-5-bromopyridine was added in batches by a low temperature reaction bath, and the temperature was controlled within the range of 5-15 °C.The solution A was obtained after the addition.The A and B solutions are all prepared, and the solution B is added dropwise to the solution A by a constant pressure dropping funnel, and the temperature of the reaction bottle is controlled by the low temperature reaction bath in the range of 0-10 ° C, and the optimum temperature is 5 ° C. The temperature change value was not more than 3 ° C. After the dropwise addition was completed, the reaction liquid was slowly heated to 50 ° C, the reaction was continued for 3 hours, and the sample was taken for TLC analysis to disappear.Add 5000 ml of water to a 5000 ml three-neck reaction flask, and cool to within 15 ° C. The above reaction solution is added to water with a constant pressure dropping funnel while stirring, and the temperature is controlled within a range of -15 ° C. After the dropwise addition is completed, Continue stirring for 18-20 minutes. At 5-15 ° C, 720 g of 30percent liquid alkali was added, stirring was continued for 0.5 hours, then filtered under reduced pressure, washed with 100 ml of water, and the filter cake was neutralized with a dilute alkali to pH = 7 and filtered again. The resulting solid was recrystallized from methanol and filtered hot.Dry to give a pale yellow solid of 51.13 g of product.Yield 73.4percent,The purity of the product liquid chromatography is greater than 99percent.
72% With dihydrogen peroxide In sulfuric acid at 0 - 20℃; Reference Example 11: 5-Bromo-2-nitro-pyridine. A solution of 2-amino-5-bromo-pyridine (5 g, 28.9 mmol) in cone, sulfuric acid (10 mL) was added dropwise to a cold (0 0C) mixture of hydrogen peroxide (10 mL, 38percent) and cone, sulfuric acid (10 mL). The mixture was warmed to r.t. and stirred overnight, then poured into ice cold water and filtered. The filtrate was basified with potassium hydroxide and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated to afford 5-bromo-2-nitro-pyridine (4.2 g, 72percent).
Reference: [1] Patent: CN106187867, 2016, A, . Location in patent: Paragraph 0035; 0044; 0045
[2] Bioorganic and Medicinal Chemistry, 1999, vol. 7, # 3, p. 467 - 479
[3] Patent: CN108558745, 2018, A, . Location in patent: Paragraph 0023; 0024; 0025; 0026
[4] Patent: WO2008/62182, 2008, A1, . Location in patent: Page/Page column 113
[5] Journal of Organic Chemistry, 2008, vol. 73, # 23, p. 9326 - 9333
[6] Journal of the American Chemical Society, 1945, vol. 67, p. 668
[7] Yakugaku Zasshi, 1952, vol. 72, p. 381[8] Chem.Abstr., 1953, p. 6403
[9] Recueil des Travaux Chimiques des Pays-Bas, 1949, vol. 68, p. 275,282
[10] Zhurnal Obshchei Khimii, 1940, vol. 10, p. 1105[11] Chem. Zentralbl., 1940, vol. 111, # II, p. 3474
[12] Patent: US2002/52349, 2002, A1,
[13] Organic Process Research and Development, 2017, vol. 21, # 3, p. 451 - 459
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Reference: [1] Asian Journal of Chemistry, 2013, vol. 25, # 8, p. 4632 - 4636
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Reference: [1] Organic Process Research and Development, 2017, vol. 21, # 3, p. 451 - 459
[2] Organic Process Research and Development, 2017, vol. 21, # 3, p. 451 - 459
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  • [ 35486-42-1 ]
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Reference: [1] Organic Process Research and Development, 2017, vol. 21, # 3, p. 451 - 459
[2] Organic Process Research and Development, 2017, vol. 21, # 3, p. 451 - 459
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Reference: [1] Asian Journal of Chemistry, 2013, vol. 25, # 8, p. 4632 - 4636
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Reference: [1] Organic Process Research and Development, 2017, vol. 21, # 3, p. 451 - 459
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Reference: [1] Organic Process Research and Development, 2017, vol. 21, # 3, p. 451 - 459
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Reference: [1] Organic Process Research and Development, 2017, vol. 21, # 3, p. 451 - 459
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  • [ 870521-31-6 ]
Reference: [1] Yakugaku Zasshi, 1952, vol. 72, p. 381[2] Chem.Abstr., 1953, p. 6403
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Reference: [1] Journal of Organic Chemistry, 2008, vol. 73, # 23, p. 9326 - 9333
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  • [ 766-11-0 ]
Reference: [1] Organic Letters, 2005, vol. 7, # 4, p. 577 - 579
[2] Organic Letters, 2015, vol. 17, # 8, p. 1866 - 1869
  • 28
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  • [ 775288-71-6 ]
YieldReaction ConditionsOperation in experiment
82% With N-ethyl-N,N-diisopropylamine In acetonitrile at 60℃; Inert atmosphere General procedure: A mixture of compound 7 (24.7 mmol), morpholine orsubstituted piperazine (29.2 mmol) and DIPEA (37.1 mmol) inacetonitrile (100 mL) was refluxed for 8 h. Progress of reaction wasmonitored by tlc and after complete conversion of starting materialreaction mixture was cooled to rt. The solvent was evaporated andthe residue was purified via column chromatography to affordcompounds 8c-8e.4.1.10.1. 1-(6-nitropyridin-3-yl)piperazine (8c). Yellow solid. Yield:82percent; 1H NMR (DMSO‑d6, 400 MHz) δ: 7.96 (d, J = 9.3 Hz, 1H, Pyr-H),7.88 (d, J = 2.9 Hz, 1H, Pyr-H), 7.26 (dd, J = 9.3, 3.0 Hz, 1H, Pyr-H),3.64 (t, 4H, Pyr-NCH2CH2N), 3.32 (t, 4H, Pyr-NCH2CH2N). 13C NMR(DMSO‑d6, 100 MHz): δ 151.7, 146.2, 136.6, 125.9, 118.4, 51.3, 45.8;HRMS (ESI): calcd for C9H12N4O2, [(M+H)+], 209.1039, found209.1030.
Reference: [1] Journal of Medicinal Chemistry, 2018, vol. 61, # 10, p. 4528 - 4560
[2] European Journal of Medicinal Chemistry, 2018, vol. 157, p. 935 - 945
[3] Journal of Medicinal Chemistry, 2005, vol. 48, # 6, p. 1857 - 1872
[4] Journal of Medicinal Chemistry, 2005, vol. 48, # 7, p. 2388 - 2406
[5] Patent: WO2006/95159, 2006, A1, . Location in patent: Page/Page column 77
[6] Patent: WO2006/8545, 2006, A2, . Location in patent: Page/Page column 153
[7] Journal of Medicinal Chemistry, 2010, vol. 53, # 22, p. 7938 - 7957
[8] Patent: WO2011/112995, 2011, A1, . Location in patent: Page/Page column 47
[9] Patent: US2014/148430, 2014, A1, . Location in patent: Paragraph 0321
[10] Patent: EP3305785, 2018, A1, . Location in patent: Paragraph 0171-0173
[11] British Journal of Pharmacology, 2018, vol. 175, # 12, p. 2399 - 2413
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Reference: [1] Patent: WO2013/90497, 2013, A1,
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[2] Patent: WO2011/140488, 2011, A1,
[3] Patent: US2013/237534, 2013, A1,
[4] Patent: WO2016/40858, 2016, A1,
[5] Journal of Medicinal Chemistry, 2014, vol. 57, # 3, p. 578 - 599
[6] Patent: WO2014/44846, 2014, A1,
[7] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 2, p. 348 - 364
[8] Journal of Medicinal Chemistry, 2015, vol. 58, # 1, p. 512 - 516
[9] Patent: WO2014/144326, 2014, A1,
[10] Patent: WO2016/40848, 2016, A1,
[11] Journal of Medicinal Chemistry, 2017, vol. 60, # 5, p. 1892 - 1915
[12] Patent: US2017/313683, 2017, A1,
[13] European Journal of Medicinal Chemistry, 2018, vol. 144, p. 1 - 28
[14] Patent: WO2018/5533, 2018, A1,
[15] Patent: WO2018/5860, 2018, A1,
[16] Patent: WO2018/5863, 2018, A1,
[17] British Journal of Pharmacology, 2018, vol. 175, # 12, p. 2399 - 2413
[18] European Journal of Medicinal Chemistry, 2018, vol. 157, p. 935 - 945
[19] Patent: TW2018/29406, 2018, A,
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Reference: [1] Patent: WO2014/52365, 2014, A1,
[2] Patent: CN106905245, 2017, A,
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[2] Journal of Medicinal Chemistry, 2010, vol. 53, # 22, p. 7938 - 7957
[3] Patent: WO2011/140488, 2011, A1,
[4] Patent: US2013/116262, 2013, A1,
[5] European Journal of Medicinal Chemistry, 2014, vol. 81, p. 341 - 349
[6] Patent: WO2014/128588, 2014, A1,
[7] Patent: WO2014/195274, 2014, A1,
[8] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 2, p. 348 - 364
[9] Patent: WO2015/131080, 2015, A1,
[10] Patent: EP2773638, 2015, B1,
[11] Patent: WO2016/30439, 2016, A1,
[12] Patent: EP2429566, 2016, B1,
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[14] Patent: CN106608879, 2017, A,
[15] Patent: CN106749259, 2017, A,
[16] ACS Medicinal Chemistry Letters, 2017, vol. 8, # 6, p. 608 - 613
[17] European Journal of Medicinal Chemistry, 2018, vol. 144, p. 1 - 28
[18] Patent: EP3284746, 2018, A1,
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[20] Patent: EP3269715, 2018, A1,
[21] Patent: EP3305785, 2018, A1,
[22] Medicinal Chemistry Research, 2018, vol. 27, # 6, p. 1666 - 1678
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[24] Patent: EP3385262, 2018, A1,
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Reference: [1] Patent: CN105153149, 2017, B,
[2] Patent: CN106905245, 2017, A,
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YieldReaction ConditionsOperation in experiment
93% With triethylamine; lithium chloride In dimethyl sulfoxide at 60 - 65℃; for 12 h; To a vessel was added 5-bromo-2-nitropyridine (10.0 g, 1.0 equiv.) along with DMSO (25 ml_, 2.5 vol). N-Boc piperazine (13.8 g, 1.5 equiv.) was added, followed by triethylamine (7.5 g, 1.5 equiv.) and LiCI (2.1 g, 1.0 equiv.). The mixture was warmed to 60-65°C for a minimum of 12 hours.Water (5 ml_, 0.5 vol) was added slowly to the vessel at 60-65°C. The mixture was kept at 60-65 °C for one hour, then cooled to room temperature. The slurry was kept at 20-25 °C for 1 hour and then filtered onto a 2 Whatman™ paper filter. The cake was rinsed with water (50 ml_, 5 vol.). The crude solids were collected and transferred back to a clean vessel. Water (100 mL, 10 vol.) was added to the vessel containing the solids and the mixture was warmed to 35-40°C for 2 hours, then filtered while warm onto a 2 Whatman paper™ filter. The solids were rinsed with water (40 mL, 4 vol.) and allowed to dry overnight in the vacuum oven at 50-55°C. The 4-(6-nitro-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester was isolated as a yellow solid (14.1 g collected; -93percent yield).
90% With triethylamine; lithium chloride In dimethyl sulfoxide at 60 - 65℃; for 12 h; 500 mL of the reaction flask was added to the starting material III20.3 g (0.1 mol) and IV27.9 g (0.15 mol) of starting material,200mL DMSO,15.2 g (0.15 mol) of triethylamine and 4.2 g (0.1 mol) of lithium chloride were added with stirring,System temperature to 60-65 incubation reaction 12h.65 ° C to the system slowly adding 200mL of water,Stir for 1 h. The system was cooled to room temperature and stirred for 1 h. The mixture was filtered and washed thoroughly with water at 50-55 ° C overnight to give 27.7 g of pure product as a pale yellow solid. Yield: 90.0percent
88.87% With triethylamine In dimethyl sulfoxide at 60℃; for 18 h; Inert atmosphere Step 1
tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate
To a solution of 5-bromo-2-nitropyridine (20.00 g, 98.53 mmol, 1.00 equivalent) in dimethylsulfoxide (52 mL) were added tert-butyl piperazine-1-carboxylate (24.00 g, 128.86 mmol, 1.31 equivalentalents) and triethylamine (20.00 g, 197.65 mmol. 2.01 equivalents).
The solution was heated to 60°C and stirred for 18 hours. TLC (petroleum ether: ethyl acetate = 3: 1) showed completion of the reaction.
The solution was diluted with water (200 mL), stirred for 30 minutes, and then filtered.
The filter cake was washed with water and dried in vacuo to give a crude product.
The crude product was purified by silica gel column (petroleum ether: ethyl acetate = 50: 1 to 20: 1) to give the title compound (27.00 g, 87.57 mmol, 88.87percent yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 9.03 Hz, 1H), 8.13 (d, J = 2.89 Hz, 1H), 7.21 (dd, J = 9.10, 2.95 Hz, 1H), 3.69-3.59 (m, 4H), 3.51-3.40 (m, 4H), 1.49 (s, 9H).
84.1% With potassium carbonate In water; dimethyl sulfoxide at 70℃; for 28 h; Inert atmosphere Step a): synthesis of 1-Boc-4-(6-nitro-3-pyridyl)piperazine (formula 3)Step b): A 1 -L RBF, was charged with 50 g of 5-Bromo-2-nitro-pyridine (0.246 mol, 1 .00 eq.), 175 ml DMSO and 35 ml water. To the resulting mixture was added 37.45 g potassium carbonate (0.271 mol, 1 .1 eq.) followed by 59.64 g boc-piperazine (0.320 mol, 1 .3 eq.). The mixture was heated to 70^ and stirred under argon until completion (approx. 28 h). The reaction was diluted with 315 ml of water and allowed to cool down to RT. After 2 h stirring, the solid was collected by filtration, washed with water (2 x 250 ml) and left in air at RT overnight to give crude wet 1 -Boc-4-(6-nitro-3- pyridyl)piperazine as yellow solid. HPLC (Method 1 ): 6.49 min (96.4percent) (230 nm)Crude product was suspended in 250 ml toluene, followed by concentrated under reduced pressure. The residue was dissolved in 200 ml toluene, under reflux. Resulting orange solution was allowed to cool down slowly to RT without stirring. After 3 h, precipitated solid was filtered, washed with toluene (50 ml), TBME (2 x 100 ml) and dried at 50<C/20 mbar for 7 h to yield 63.88 g of 1 -Boc-4-(6-nitro-3-pyridyl)piperazine as yellow solid (84.1 percent yield). HPLC (Method 1 ): 6.49 min (99.1 percent) (230 nm).
82% With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 80℃; To a solution of 5-bromo-2-nitropyridine (40.0 g,197 mmol) in DMSO (150 mL) were added 1-Bocpiperazine(47.4 g, 252 mmol) and DIPEA (38 mL,219 mmol) . The reaction mixture was heated at 80 °C for11 h. The reaction mixture was poured into ice-water andthen extracted with EtOAc. The combined extracts werewashed with water and brine. The organic layer was driedover Na2SO4, filtered, and concentrated under reducedpressure. Purification by column chromatography (1:9methanol/ dichloromethane) gave 1-Boc- 4-(6-nitro-pyridin-3-yl)-piperazine (49.9 g, 82percent) as yellow solid. 1H NMR(400 MHz, CDCl3): δ 8.11 (d, J = 9.1 Hz, 1H), 8.08 (d, J =2.7 Hz, 1H), 7.18 (dd, J = 9.1, 2.8 Hz, 1H), 3.65–3.56 (m,4H), 3.48–3.38 (m, 4H), 1.45 (s, 9H).
80% With N-ethyl-N,N-diisopropylamine In acetonitrile for 72 h; Reflux To a stirred solution of 5-bromo-2-nitropyridine (4.93 g, 24.3 mmol) and piperazine-1-carboxylic acid tert-bλxtyl ester (4.97 g, 26.7 mmol) in CH3CN (60 ml) is added DIPEA (4.65 mL, 26.7 mmol). The mixture is heated at reflux for 72 hours then cooled to room temperature and the precipitated product collected by filtration. The filtrate is concentrated and purified by flash column chromatography eluting with 30percent EtO Ac/petrol. The combined products are re-crystallized from EtO Ac/petrol to give 4-(6-nitro-pyridin-3-yl)-piperazine-1-carboxylic acid tert-huty\\ ester, (4.50 g, 80percent yield). MS(ESI) m/z 308 (M+H)+
80% at 120℃; for 3 h; A solution of 1-Boc-piperazine (15.0 mmol) and 5-bromo-2-nitropyridine (5.00 mmol) in N-methyl pyrrolidone (15 mL) was stirred at 120 °C for 3 h. The reaction mixture was diluted with water and the precipitate was collected by filtration to give 2 (80percent) as a colorless powder. 1H NMR (400 MHz, DMSO-d6): δ 8.10–8.08 (d, J = 9.2 Hz, 1H, ArH), 7.96–7.95 (d, J = 3.0 Hz, 1H, ArH), 7.33–7.30 (dd, J = 3.4 Hz, 1H, ArH), 3.66–3.63 (m, 4H, piperazine-CH2), 3.43–3.41 (m, 4H, piperazine-CH2), 1.47 (s, 9H, t-butyl-CH3).
80% With N-ethyl-N,N-diisopropylamine In acetonitrile for 72 h; Reflux Nitrile analogues can be made by the following. To a stirred solution of 5-bromo-2-nitropyridine (4.93 g, 24.3 mmol) and piperazine-1-carboxylic acid tert-butyl ester (4.97 g, 26.7 mmol) in CH3CN (60 ml) is added DIPEA (4.65 mL, 26.7 mmol). The mixture is heated at reflux for 72 hours then cooled to room temperature and the precipitated product collected by filtration. The filtrate is concentrated and purified by flash column chromatography eluting with 30percent EtOAc/petrol. The combined products are re-crystallized from EtOAc/petrol to give 4-(6-nitro-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester, (4.50 g, 80percent yield). MS(ESI) m/z 308 (M+H)+
79% With triethylamine In dimethyl sulfoxide at 65 - 70℃; for 30 h; EXAMPLE 2: Preparation of 4-(6-Nitro-pyridin-3yl)-piperazine-1-carboxylic acid tert-butyl ester; B Exampl e 2A: Preparation of 4-(6-Nitro-pyridin-3yl)-piperazine-1-carboxylic acid tert-butyl ester To 1.0 kg (5 mol) 5-bromo-2-nitropyridine was added 1.2 kg {6.4 mol) boc piperazine (tert-Butyl piperazine-1-carboxylate) in 2.6L DMSO and 0.5 kg triethylamine under nitrogen. The mixture was heated to 65-700C and held for 30~hours after which some solids precipitated. Water was added and the reaction cooled to 25°C over 2hrs. The resulting slurry was filtered, washed and dried at 45°C to give 1.2kg (79percent crude yield) of canary yellow solid intermediate (2A), which was used without further purification in the subsequent step.
79% With tetra-(n-butyl)ammonium iodide; potassium carbonate In dimethyl sulfoxide at 120℃; for 16 h; Synthesis of compound 107.1 To a solution of 78.4(1. Og, 4.92mmol, 1.0 eq) in DMSO (10 ml) was added Bu4NI (0.18g, 0.049 mmol, 0.1 eq), tert-butyl piperazine-1- carboxylate (1.37g, 7.38mmol, 1.5eq), and K2CO3 (1.36g, 9.85mmol, 2eq). Reaction mixture was heated at 120° C for 16 hours.Upon completion reaction mixture was poured into water and product was extracted with ethyl acetate. Organic layers were combined, dried over sodium sulphate and concentrated under reduced pressure. The crude was purified using column chromatography to provide 107.1 (1.2 g, 79percent). MS (ES): m/z 279.23 [M+H]+.
67% for 72 h; Heating / reflux Preparation XX <n="116"/>Synthesis of 4-r6-amino-pyridin-3-ylVpiperazine-l-carboxylic acid tert-butyl ester Step 1. Synthesis of 4-f6-nitro-pyridin-3-yl)-piperazine-l-carboxyric acid tert-butyl ester; A mixture of 5-bromo-2-nitropyridine (4.93g, 24.30 mmol) and tert-butyl piperazine-1-carboxylate (5.Og, 26.7 mmol) in acetonitrile (60ml) was heated at refluxed for 3 days. The solvent was evaporated and the solid residue purified by flash chromatography on silica eluting with EtO Ac/Petrol (1:3) and recrystallised from EtO Ac/Petrol to afford the title compound as an orange solid (5.Og, 67percent) (LCMS: Rt 2.8, [M+H]+ 309).
60% With N-ethyl-N,N-diisopropylamine In acetonitrile at 110℃; for 72 h; To the reaction flask was added 5-bromo-2-nitropyridine (4.93 g, 24.3 mmol), Piperazine-1-carboxylic acid tert-butyl ester (4.97 g, 26.7 mmol)Diisopropylethylamine (4.65 mL, 26.7 mmol) and acetonitrile (60 mL)The mixture was stirred at 110 ° C for 72 hours.Cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH = 10/1)The resulting residue was purified to give the title compound (4.5 g, white solid) in 60percent yield.
60% With potassium carbonate; potassium iodide In dimethyl sulfoxide at 120℃; Compound 11a (13.7 g, 73.9 mmol), compound 11b (10 g, 49.3 mmol), potassium iodide (81.8 mg, 0.493 mmol)and potassium carbonate (13.6 g, 98.6 mmol) were added into DMSO (100 mL). The reaction solution was stirred at120 °C overnight and then cooled to room temperature, adjusted to pH 7 with hydrochloric acid (1 mol) and then extractedwith dichloromethane. The aqueous phase was alkalize by saturated solution of sodium carbonate, and then extractedwith dichloromethane again. The organic phase was combined and dried over anhydrous Na2SO4, concentrated andthen slurried by water to give compound 11c (9.2 g, 60percent). LCMS:309(M+H)+, RT=1.710min.
50% With N-ethyl-N,N-diisopropylamine In acetonitrile for 2 h; Reflux N,N-Diisopropylethylamine (4.77g, 36.94mmol) was added to a solution of 82 5-bromo-2-nitropyridine (5.00g, 24.63mmol) and 100 tert-butyl piperazine-1-carboxylate (5.10g, 27.09mol) in 101 acetonitrile ([ACN] 30mL). The mixture was refluxed for 2h, cooled to RT, concentrated under a vacuum, and purified by silica gel column chromatography (from 102 PE/86 EA=1:1 to 103 DCM/87 MeOH=20:1) to obtain 104 tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate (3.80g; yield, 50percent) as a yellow solid. Pd/C (100.0mg) was added to a solution of tert-butyl 4-(6-nitropyridin-3-yl) piperazine-1-carboxylate (925.0mg, 3.0mmol) in EA/MeOH (10 mL/10mL). The mixture was degassed by flushing with H2, stirred at RT under a H2 atmosphere for 2h, and filtered and concentrated under a vacuum to obtain INT-3 (792.0mg; yield, 95percent) as an off-white solid. ESI-MS: m/z 279.2 [M+H]+.
45.2% With triethylamine In dimethyl sulfoxide for 12 h; Heating 4.1.39
Tert-Butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate (10a)
A mixture of 5-bromo-2-nitropyridine (3.4 g, 16.9 mmol), tert-butyl piperazine-1-carboxylate (3.2 g, 16.9 mmol) and Et3N (3.4 g, 33.8 mmol) in DMSO (20 mL) was stirred at 75 °C for 12 h.
The reaction mixture was cooled down to room temperature and diluted with water (10 mL), and then the product was extracted three times with EtOAc (25 mL).
The combined organic layer was dried over Na2SO4, and the solvent was removed in vacuo.
The residue product was purified on a silica gel column using petroleum ether/EtOAc (4:1, v/v) as eluent to afford 10a (2.19 g, 45.2percent) as a white solid. MS (ESI) m/z 309.2 [M+H]+; 1H NMR (400 MHz, CDCl3): δ 8.19 (d, J = 9.10 Hz, 1H), 8.13 (d, J = 3.00 Hz, 1H), 7.22 (dd, J = 3.20 Hz, 9.20 Hz, 1H), 3.65 (t, J = 5.00 Hz, 4H), 3.46 (t, J = 5.00 Hz, 4H), 1.49 (s, 9H).
40.63% With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 50℃; Compound 38 (10.2 g, 49.52 mmol) was added to the reaction flask, respectively,Compound 36 (10.40 g, 54.47 mmol)Dissolved in DMF,DIPEA (7.78 g, 59.42 mmol) was added.50 ° C under the conditions of reaction,TLC tracking, to be completely complete,The reaction system is poured into ice water,There is a yellow solid precipitation,Filter solids, beat with EA,Dried to obtain 6.20 g of compound 39,Yield: 40.63percent.
37% With potassium carbonate In dimethyl sulfoxide at 65℃; Into a solution of 5-bromo-2-nitropyridine (30 g, 148 mmol) in DMSO (1 L) were added K2CO3 (40 g, 296 mmol) and teri-butyl piperazine-l-carboxylate (28g, 148 mmol). The mixture was stirred at 65 degree for overnight. After cooling down, it was poured into water (2 L). The solid precipitated was collected and dried under vacuum. It was then further purified by flash column eluting with 20:1 petroleum ether/ethyl acetate and then with methylene chloride to give 188a as a yellow solid (17 g, 37percent). MS: [M+H]+ 309.
37% With potassium carbonate In dimethyl sulfoxide at 65℃; To a solution of 5-bromo-2-nitropyridine (30 g, 148 mmol) in DMSO (1 L) was added K2CO3 (40 g, 296 mmol) and tert-butyl piperazine-1-carboxylate (28 g, 148 mmol).
The mixture was stirred at 65° C. overnight.
After cooling down, it was poured into water (2 L).
The precipitated solid was collected and dried under vacuum.
It was then further purified by flash column eluting with 20:1 petroleum ether/ethyl acetate and then with methylene chloride to give 115a as a yellow solid (17 g, 37percent). MS: [M+H]+309.
37% With potassium carbonate In dimethyl sulfoxide at 65℃; Example 101g
tert-Butyl 4-(6-Nitropyridin-3-yl)piperazine-1-carboxylate 101g
Into a solution of 5-bromo-2-nitropyridine (30 g, 148 mmol) in DMSO (1 L) were added K2CO3 (40 g, 296 mmol) and tert-butyl piperazine-1-carboxylate (28g, 148 mmol).
The mixture was stirred at 65 °C overnight.
After cooling down, it was poured into water (2 L).
The solid precipitated was collected and dried under vacuum.
It was then further purified by flash column eluting with 20:1 petroleum ether/ethyl acetate and then with methylene chloride to give 101g as a yellow solid (17 g, 37percent). MS: [M+H]+ 309.
33% With potassium carbonate In N,N-dimethyl-formamide at 120℃; for 36 h; 4-(6-nitro-3-pyridinyl)-1-piperazinecarboxylic acid, 1,1-dimethylethyl ester
A solution is prepared of 1 g (4.9 mM) of 2-nitro-5-bromopyridine and 917 mg (4.9 mM) of N-Boc-piperazine in 10 ml of dimethylformamide and 1.02 g (7.4 mM) of potassium carbonate are added.
The reaction mixture is agitated at 120° C. for 36 hours and then cooled.
50 ml of water are then added and extraction is carried out with ethyl acetate.
The organic phase obtained is washed with water, dried and concentrated under reduced pressure.
The crude product is purified by silica gel chromatography in eluding with the aid of a toluene/isopropanol mixture (98/2; v/v).
The product sought after is thus obtained as a yellow solid (yield=33percent).
1H NMR (250 MHz, DMSO) δ: 8.24 (d, 1H); 8.17 (d, 1H); 7.46 (dd, 1H); 3.50 (m, 8H); 1.42 (s, 9H).
400 mg at 120℃; for 18 h; Dissolved 5-bromo-2-nitropyridine (1.0 g, 4.92 mmol) and tert-butyl piperazine-1- carboxylate (1.1 g, 5.91 mmol) in N-methylpyrrolidine and stirred at 120 C for 18 h. Thereafter the reaction mixture was cooled to 30 C and diluted with water and extracted with ethyl acetate (2 x 200 mL). The combined organic extract was washed with brine (50 mL). The organic layer was dried over sodium sulfate and concentrated under vacuum to give crude product. The crude product was purified by column chromatography to give 400 mg of the desired product. LC-MS: m/z calcd for C14H20N4O4, 308.33, no ionization 1H NMR (500 MHz, CDC13): δΗ 1.4 (9H, s, 0(CH3)3), 3.38 (4H, t, J = 5 Hz, NCH2CH2N), 3.58 (4H, t, J = 5 Hz, NCH2CH2N), 7.14 (1H, dd, Jl = 5 Hz, J2 = 10 HZ, ArCH), 8.06 (1H, d, J = 5 Hz, ArCH) and 8.11 (1H, d, J = 10 Hz, ArCH).

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YieldReaction ConditionsOperation in experiment
77%
Stage #1: With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 80 - 90℃; Inert atmosphere
Stage #2: With hydrogen In 1,4-dioxane at 20℃;
Under nitrogen protection, 550 mL of dioxane and 2-nitro-5-bromopyridine (20.3 g, After 0.10 mol) of pinacol borate (25.4 g, 0.10 mol) and potassium acetate (14.7 g, 0.15 mol), after stirring uniformly, the catalyst PdCl2dppf (0.74 g, 0.001 mol) was finally added, and the temperature was slowly raised to 80- 90 °C, Stir the reaction for 2-3 h. After the completion of the GC reaction, the reaction was stopped by cooling, and the reaction solution was filtered through celite to obtain a dark-black reaction solution. After charging at 1 atm of hydrogen, the mixture was reacted at room temperature overnight. After the reaction was completed, the activated carbon was decolorized, and the filtrate was distilled under reduced pressure until no liquid was poured. /Heptane mixed solvent was cooled and beaten for half an hour, filtered to obtain 18.5 g of light gray product, heated again with ethanol, and then cooled down, and the filter cake was rinsed with -20 ° C anhydrous ethanol, and dried to obtain 16.9 g, yield 77 percent HPLC purity 99.6percent
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