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Product Details of [ 1072-97-5 ]

CAS No. :1072-97-5 MDL No. :MFCD00006323
Formula : C5H5BrN2 Boiling Point : -
Linear Structure Formula :- InChI Key :WGOLHUGPTDEKCF-UHFFFAOYSA-N
M.W :173.01 Pubchem ID :70622
Synonyms :

Calculated chemistry of [ 1072-97-5 ]

Physicochemical Properties

Num. heavy atoms : 8
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 1.0
Num. H-bond donors : 1.0
Molar Refractivity : 36.34
TPSA : 38.91 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) : -6.28 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.41
Log Po/w (XLOGP3) : 1.51
Log Po/w (WLOGP) : 1.43
Log Po/w (MLOGP) : 0.99
Log Po/w (SILICOS-IT) : 1.41
Consensus Log Po/w : 1.35

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.42
Solubility : 0.659 mg/ml ; 0.00381 mol/l
Class : Soluble
Log S (Ali) : -1.94
Solubility : 2.01 mg/ml ; 0.0116 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -2.51
Solubility : 0.531 mg/ml ; 0.00307 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.53

Safety of [ 1072-97-5 ]

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 [ 1072-97-5 ]

* 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 [ 1072-97-5 ]
  • Downstream synthetic route of [ 1072-97-5 ]

[ 1072-97-5 ] Synthesis Path-Upstream   1~152

  • 1
  • [ 1072-97-5 ]
  • [ 223463-13-6 ]
Reference: [1] Chemistry - A European Journal, 2018, vol. 24, # 55, p. 14622 - 14626
[2] Verslag van de Gewone Vergadering van de Afdeling Natuurkunde, Koninklijke Nederlandse Akademie van Wetenschappen, vol. 36, p. 517[3] Chem. Zentralbl., 1927, vol. 98, # II, p. 2198
  • 2
  • [ 39856-50-3 ]
  • [ 1072-97-5 ]
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
  • 3
  • [ 504-29-0 ]
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YieldReaction ConditionsOperation in experiment
98% With N-Bromosuccinimide In acetone at 0 - 20℃; To the mixture of pyridin-2-ylamine (10.0 g, 106 mmol) in acetone (200 mL), was added NBS (22.6 g, 127 mmol) portionwise at 0°C. The mixture was warmed to room temperature and stirred overnight. Solvent was evaporated in vacuum. The residue was purified by silica gel column (DCM/MeOH, 20/1) to afford 18 g (yield: 98percent) of 5-bromo-pyridin-2- ylamine as yellow solid. [00589] 1H NMR (DMSO-d6): δ = 7.94 (IH, d), 7.61 (IH, dd), 6.43 (IH, d), 6.10 (2H, brs).
98% With N-Bromosuccinimide In acetonitrile at 20℃; for 2 h; 4.5.4
5-Bromopyridin-2-amine
2-Aminopyridine (2.60 g, 0.028 mol) was dissolved in dry acetonitrile (100 mL), treated with N-bromosuccinimide (5.22 g, 0.029 mol) and stirred for 2 h at rt.
The solvent was removed and the resulting cream white solid purified by flash chromatography to give commercially available 2-amino-5-bromopyridine as a white solid (98percent).
1H NMR (300 MHz, CDCl3) δ 8.08 (s, 1H), 7.48 (dd, J = 8.7, 2.4, 1H), 6.41 (d, J = 8.7, 1H), 4.44 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 157.36, 148.88, 140.49, 110.42, 108.56.
91%
Stage #1: With bromine In acetone at -5 - 0℃; for 0.5 h;
Stage #2: at -1 - 4℃; for 1 h;
14.8 g (89.4 mmol) of potassium bromate was dissolved in the succinimide aqueous solution recovered in the previous step.In the condition of 25 °C, stirring, 17.5 mL of 50percent sulfuric acid aqueous solution was added dropwise. After the addition, the reaction was completed for 2.5 h. The reaction was completed, filtered and dried to obtain 42 g of N-bromosuccinimide.After dissolving 41.8 g of 2-aminopyridine in 175 mL of acetone, the solution was cooled to -5 to -3 °C, and a solution of bromine in acetone (35.4 g of bromine/160 mL of acetone) was added dropwise with stirring.The reaction temperature was controlled at -5 ~ 0 °C, and the reaction was completed for 0.5 h after the addition was completed until the raw materials reacted completely.The temperature of the solution was adjusted to -1 to 1 °C, and 42 g of self-made reconstituted N-bromosuccinimide was added in batches. The reaction temperature was 2 to 4 °C. The reaction was continued for 1 h after the addition was complete.After the reaction, the mixture was recovered with acetone, separated by adding an aqueous potassium hydroxide solution, and recrystallized to obtain 69.9 g of brown crystals of 2-amino-5-bromopyridine in a yield of 91percent and a purity of 99.0percent.
90% With N-Bromosuccinimide; ammonium acetate In acetonitrile at 20℃; for 0.0833333 h; [00159] Scheme 1. Preparation of relevant pyri(mi)dyl halides A-H. Key: (a) NBS, NH4OAc, MeCN, rt, 5 min, pyr: 85-90percent; pym: quant; (b) pyr: RCHO, Na(CN)BH3, MeCN, reflux, 1-12h (82percent, R = C5Hn); pym: NaH, Rl, THF, rt, overnight (85percent, R = Me); (c) Me3(Bn)NBr, f-BuONO, CH2Br2, rt, overnight, pyr: 77-83percent; pym: 30- 40percent; (d) pym: HI, CH2CI2, 0°C, 80-85percent; (e) i. NaOH, Br2, H20, rt, 50-60percent, ii. POCI3, PhNEt2, reflux, 4h, 75-85percent, iii. HI, CH2CI2, 0°C, 80-85percent; (f) ROH, Na, rt, 1-12 h, quant.; (g) RZnl, CI2Pd(PPh3)2, DMF/THF, rt, overnight, pyr (Br): 72percent (R = C6H13), pym (I) 81 percent, (R = C6H13); (h) alkyne, Cul, CI2Pd(PPh3)2, Et3N, MeCN, rt, 1-12 h, quant. [00160] Preparation of 3-pyridyl and 5-pyrimidyl halides. 2-Aminopyridine and 2-aminopyrimidine were employed as common starting materials for each of the pyridyl and pyrimidyl halides due to their commercial availability at very low cost. Synthesis of the various pyridyl bromides began with bromination of the 5-position of 2-aminopyridine using NBS/NH40AC (Das, B.; Venkateswarlu, K.; Majhi, A.; Siddaiah, V.; Reddy, K. R. J. Mol. Catal. A-Chem. 2007, 267, 30). This intermediate was either alkylated by reductive amination with appropriate aldehydes to prepare 5-bromo-2-N,N-dialkylaminopyridines (A) or subjected to aqueous (Bhasin, K. K.; Kumar, R.; Mehta, S. K.; Raghavaiah, P.; Jacob, C; Klapotke, T. M. Inorg. C im. Act. 2009, 362, 2386.) or non-aqueous (Nara, S. J.; Jha, M.; Brinkhorst, J.; Zemanek, T. J.; Pratt, D. A. J. Org. C em. 2008, 73, 9326.) diazotization/halo-dediazoniation to afford 2,5-dibromopyridine. This compound served as the precursor to all other substituted pyridines: 2-alkoxy-5-bromopyridines (C) were obtained by nucleophillic substitution with an appropriate sodium alkoxide17 and 2- alkynyl-5-bromopyridine (E) and 2-alkyl-5-bromopyridines (G) were prepared via Sonogoshira (Tilley, J. W.; Zawoiski, S. J. Org. Chem. 1988, 53, 386.) and Negeishi (Getmanenko, Y. A. ; Twieg, R. J. J. Org. Chem. 2008, 73, 830.) cross-coupling reactions, respectively.
86% With dihydrogen peroxide; 1-butylpyridinium bromide; toluene-4-sulfonic acid In 1,2-dimethoxyethane at 80℃; for 24 h; Schlenk technique; Inert atmosphere; Green chemistry General procedure: To a mixture of 2-aminopyridine (0.5 mmol, 1 equiv), p-TSA (0.4 mmol,0.8 equiv), 1-butylpyridinium bromide (1.5 mmol, 3 equiv) in a 50 mL Schlenk tube were added 1,2-dimethoxyethane (2 mL) under air. Then H2O2 (1.2 mmol, 2.4 equiv) was added. The mixture was stirred at 80°C for 24 h. And then the mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the products.
84.8% With N-Bromosuccinimide In acetonitrile at 5 - 20℃; for 24 h; 52.3 g (0.555 mol) of 2-aminopyridine and 500 mL of acetonitrile were added to a 1-necked 1 L flask.And 103.9 g (0.584 mol) of NBS (N-bromosuccinimide) was added thereto at a temperature of 5 ° C for 4 times. The temperature was gradually raised to room temperature and the mixture was stirred for 24 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, 1000 mL of water and 1000 mL of DCM were added, and the mixture was stirred for 2 hours. The separated organic layer was washed with 500 mL of brine, dried over anhydrous Na2SO4, and concentrated. The concentrate was recrystallized under DCM / Hexane conditions to obtain 81.5 g (yield: 84.8percent) of a compound as a white solid (Intermediate (14)).
84.8% With N-Bromosuccinimide In acetonitrile at 0 - 20℃; for 24 h; A 1L flask was charged with 52.3 g (0.555 mol) of 2-aminopyridine, and acetonitrile (500 mL) were added. At the temperature of 5 °C., 103.9 g (0.584 mol) of NBS (N-bromosuccinimide) And the temperature was gradually raised to room temperature and stirred for 24 hours. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, 1000 mL of water and 1000 mL of dichloromethane (DCM) were added, and the mixture was stirred for 2 hours. The separated organic layer was washed with 500 mL of brine, dried over anhydrous Na2SO4, and concentrated. The concentrate was recrystallized under dichloromethane (DCM) / hexane to obtain 81.5 g (yield: 84.8percent) of a white solid compound (Intermediate 40).
80% With N-Bromosuccinimide In N,N-dimethyl-formamide at -20 - 20℃; for 16 h; Inert atmosphere General procedure: To a - 20°C solution of 2-aminopyridineor 2-amino-4-chloropyridine(1 equiv) in DMF was added N-bromosuccinimide(1.1 or 2.2 equiv.) in two portions. The reaction mixture was stirred for 16 hat room temperature and was then poured withstirring into a 1M solution of NaOH (50 mL). The phases were separated and theaqueous layer was extracted with EtOAc. The combined organic phases were washedwith water (2 x 50 mL) and brine (50 mL), dried over MgSO4,filtered and concentrated underreduced pressure. The residue was obtained as pure compound withoutfurther purification or purified bychromatography on silica gel using Petroleumether/EtOAc as eluent.
54.37% With N-Bromosuccinimide In acetonitrile at -30℃; for 0.5 h; To a solution of pyridin-2-amine (10.0 g, 10.06 mmol) in acetonitrile (100 mL) at -30°C NBS (18.9 g, 106.2 mmol) was added and the resulting solution was stirred at -30°C for 30 mm. The reaction mixture was quenched with ice and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous Na2SO4. The organic layer was concentrated under vacuo. The product was purified by column chromatography to yield title compound (10.0 g, 54.37percent) as a yellow solid. LCMS: (M+2) = 175.0
54.37% With N-Bromosuccinimide In acetonitrile at -30℃; for 0.5 h; To a solution of pyridin-2-amine (10.0 g, 10.06 mmcl) in acetonitrile (100 mL) at 3000 NBS (18.9 g, 106.2 mmol) was added and it was stirred at 300C for 30 mm.The reaction mixture was quenched with ice and extracted with ethyl acetate. Theorganic layer was washed with water and dried over anhydrous Na2SO4. The organiclayer was concentrated under vacuo. The product was purified by column chromatography to yield title compound (10.0 g, 54.37percent) as a yellow solid. LCMS:(M+2) = 175.0

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[3] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 15, p. 4943 - 4951
[4] Synthetic Communications, 2009, vol. 39, # 2, p. 215 - 219
[5] Synthesis, 2001, # 14, p. 2175 - 2179
[6] Tetrahedron Letters, 2005, vol. 46, # 51, p. 8959 - 8963
[7] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 16, p. 4779 - 4783
[8] Synthesis, 2004, # 17, p. 2809 - 2812
[9] Patent: CN107540604, 2018, A, . Location in patent: Paragraph 0017; 0018; 0019; 0020; 0021; 0022
[10] Journal of Organic Chemistry, 2012, vol. 77, # 16, p. 6908 - 6916
[11] Patent: WO2012/162818, 2012, A1, . Location in patent: Page/Page column 45-46
[12] Chemical Communications, 2013, vol. 49, # 72, p. 7929 - 7931
[13] Journal of Organic Chemistry, 2008, vol. 73, # 23, p. 9326 - 9333
[14] Journal of Organic Chemistry USSR (English Translation), 1981, vol. 17, # 2, p. 353 - 357[15] Zhurnal Organicheskoi Khimii, 1981, vol. 17, # 2, p. 413 - 417
[16] Tetrahedron Letters, 2014, vol. 55, # 36, p. 5058 - 5061
[17] Patent: KR2017/103574, 2017, A, . Location in patent: Paragraph 0106; 0107; 0108; 0109
[18] Patent: KR2017/142950, 2017, A, . Location in patent: Paragraph 0384-0387
[19] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 1, p. 114 - 120
[20] RSC Advances, 2013, vol. 3, # 30, p. 12091 - 12095
[21] Patent: WO2014/202580, 2014, A1, . Location in patent: Page/Page column 107
[22] Patent: WO2014/202528, 2014, A1, . Location in patent: Page/Page column 102
[23] Synthesis, 1981, # 12, p. 987 - 989
[24] Journal of the American Chemical Society, 1944, vol. 66, p. 1479,1482
[25] Journal of Organic Chemistry, 1951, vol. 16, p. 73,79
[26] South African Journal of Chemistry, 2006, vol. 59, p. 125 - 128
[27] Patent: US4264605, 1981, A,
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[29] Journal of Medicinal Chemistry, 2012, vol. 55, # 7, p. 3201 - 3215
[30] Patent: WO2014/89324, 2014, A1, . Location in patent: Paragraph 0221
[31] Patent: CN105418343, 2016, A, . Location in patent: Paragraph 0056; 0057; 0058; 0059; 0060
[32] Patent: CN106083708, 2016, A, . Location in patent: Paragraph 0083
[33] Organic Process Research and Development, 2017, vol. 21, # 3, p. 451 - 459
[34] Patent: CN104016979, 2017, B, . Location in patent: Paragraph 0547; 0548; 0549
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YieldReaction ConditionsOperation in experiment
76% With bromine In ethanol at 20℃; To a solution of 2-aminopyridine (9.40 g, 0.1 mol) in EtOH (100 mL) was added dropwise Br2 (5.8 mL, 0.11 mol) maintaining the temperature below 20 °C. When the addition of bromine was completed, the mixture was stirred for 1 h. After removal of EtOH, the residue was made alkaline with a solution of NaOH (5.0 g, 0.13 mol) in H2O (50 mL) and cooled (10 °C). The solid was collected by filtration, slurry washed with cold H2O (10 mL), and then washed with boiling heptane (3 × 20 mL) to remove the 2-amino-3,5-dibromoaminopyridine, followed by air-drying to constant weight; yield: 13.15 g (76percent); off-white fine crystals; mp 135–136 °C (Lit.17 mp 132–135 °C); Rf = 0.4 (CHCl3–EtOAc). IR (KBr): 3452, 3292, 3153, 2924, 2852, 1628, 1587, 1550, 1481, 1387,1088, 999 cm–1.1H NMR (CDCl3): δ = 4.57 (br s, 2 H, NH2), 6.41 (d, J = 8.8 Hz, 1 H, H-3),7.48 (dd, J1 = 8.8 Hz, J2 = 2.4 Hz, 1 H, H-4), 8.09 (d, J = 2.4 Hz, 1 H, H-6).13C NMR (CDCl3): δ = 108.3, 110.1, 140.2, 148.7, 157.1.MS (EI, 70 eV): m/z (percent) = 174 (88, [M (81Br)]+), 172 (100, [M (79Br)]+),147 (46), 145 (49), 92 (97), 65 (67), 64 (60), 50 (49).Anal. Calcd for C5H5BrN2: C, 34.71; H, 2.91; N, 16.19. Found: C, 34.59;H, 3.01; N, 16.10.
67%
Stage #1: at 20 - 50℃;
28.2 g (0.3 moles) of 2-aminopyridine were dissolved in 50 ml of acetic acid. The solution is cooled to below 20° by immersion in an ice bath, and 48 g (15.4 ml, 0.3 moles) of bromine dissolved in 30 ml of acetic acid is added dropwise with vigorous stirring over a period of 1 h. Initially the temperature is maintained below 20°. After half the bromine solution has been added, it is allowed to rise to 50° to delay as long as possible the separation of the hydrobromide of 2-amino-5-bromopyridine. At 50° the hydrobromide usually begins to crystallize when about three-quarters of the bromine has been added. When addition of bromine is completed, the mixture is stirred for 1 h and is then diluted with 75 ml of water to dissolve the hydrobromide. The contents of the flask are transferred to a 500 ml beaker and are neutralized, with stirring and cooling, by the addition of 120 ml of 40percent sodium hydroxide solution. 2-Amino-5-bromopyridine, contaminated with some 2-amino-3,5-dibromopyridine,was filtered and dried. The 2-amino-3,5-dibromopyridine is removed from the product by washing with three 500-ml. portions of hot petroleum ether. The yield of 2-amino-5-bromopyridine, is 32-34.7 g (62-67percent). mp 134 °C (literature65 mp 132-135°C)
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[3] Synthesis (Germany), 2015, vol. 47, # 20, p. 3169 - 3178
[4] Journal of Organic Chemistry, 1983, vol. 48, # 7, p. 1064 - 1069
[5] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 7, p. 2455 - 2478
[6] Bioorganic and Medicinal Chemistry, 1999, vol. 7, # 3, p. 467 - 479
[7] Journal of Organic Chemistry USSR (English Translation), 1981, vol. 17, # 2, p. 353 - 357[8] Zhurnal Organicheskoi Khimii, 1981, vol. 17, # 2, p. 413 - 417
[9] Journal of the American Chemical Society, 1946, vol. 68, p. 2574,2576
[10] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1920, vol. 50, p. 489[11] Chem. Zentralbl., 1923, vol. 94, # III, p. 1021
[12] Organic Process Research and Development, 2017, vol. 21, # 3, p. 451 - 459
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YieldReaction ConditionsOperation in experiment
37%
Stage #1: With trimethylsilyl iodide In hexane at 0 - 20℃; for 8 h;
Stage #2: With hydrogenchloride; tin(ll) chloride In ethanol; water at 110℃; for 2 h;
General procedure: To a solutionof diazo-compound (1 mmol, 1 eq.) in n-hexane(10 mL) was added TMSI (1.3 eq.) dropwise at 0°C. After addition of TMSI, the suspension was stirred for 8h at rt. The suspension was then filtered and, the residue was dried and used as such for next step without purification.To a solutionof silyl-protected diazo-compound (1 eq.) in EtOH (1 ml) was added SnCl2(1.3 eq.) and conc. HCl (1.5 ml). The mixture was stirred at 110°Cfor 2h. The reaction mixture was quenched with NaOH (50percent) until pH10 and extracted with EtOAc (3 × 10mL). The combined organic layers were washed with brine (10 mL), dried (Na2SO4)and concentrated in vacuo. Flash column chromatography afforded the benzidene product.
Reference: [1] Tetrahedron Letters, 2014, vol. 55, # 29, p. 3950 - 3953
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[2] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 17, p. 3436 - 3441
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  • 9
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[2] Tetrahedron Letters, 1993, vol. 34, # 12, p. 2019 - 2020
  • 10
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Reference: [1] Organic Letters, 2006, vol. 8, # 17, p. 3805 - 3808
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Reference: [1] Tetrahedron, 1995, vol. 51, # 31, p. 8649 - 8654
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Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1953, vol. 72, p. 125,131
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  • [ 64500-11-4 ]
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  • [ 20511-12-0 ]
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[2] Organometallics, 2011, vol. 30, # 15, p. 4067 - 4073
  • 22
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  • [ 55717-46-9 ]
Reference: [1] Patent: JP2017/48131, 2017, A,
  • 23
  • [ 1072-97-5 ]
  • [ 13466-38-1 ]
Reference: [1] Heterocycles, 2002, vol. 57, # 1, p. 55 - 71
[2] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1920, vol. 50, p. 489[3] Chem. Zentralbl., 1923, vol. 94, # III, p. 1021
[4] Journal of Organic Chemistry USSR (English Translation), 1981, vol. 17, # 2, p. 353 - 357[5] Zhurnal Organicheskoi Khimii, 1981, vol. 17, # 2, p. 413 - 417
[6] Patent: WO2016/65582, 2016, A1, . Location in patent: Page/Page column 56
  • 24
  • [ 1072-97-5 ]
  • [ 1493-13-6 ]
  • [ 13466-38-1 ]
  • [ 475106-12-8 ]
Reference: [1] Tetrahedron Letters, 2014, vol. 55, # 28, p. 3771 - 3773
[2] Tetrahedron Letters, 2014, vol. 55, # 28, p. 3771 - 3773
  • 25
  • [ 1072-97-5 ]
  • [ 53939-30-3 ]
Reference: [1] Journal of Organic Chemistry, 2008, vol. 73, # 23, p. 9326 - 9333
[2] Tetrahedron, 2004, vol. 60, # 22, p. 4861 - 4865
[3] Tetrahedron, 2002, vol. 58, # 14, p. 2885 - 2890
[4] Tetrahedron Letters, 2001, vol. 42, # 15, p. 2779 - 2781
[5] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1920, vol. 50, p. 489[6] Chem. Zentralbl., 1923, vol. 94, # III, p. 1021
  • 26
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  • [ 624-28-2 ]
YieldReaction ConditionsOperation in experiment
87%
Stage #1: With hydrogen bromide; bromine In water at 0 - 20℃; for 0.166667 h;
Stage #2: With sodium nitrite In water at 0 - 5℃; for 0.5 h;
2-Amino-5-bromopyridine (2; 13.0 g, 75.1 mmol) was added over 10 min to a cold (10 °C) aq 47percent HBr (37 mL, 0.33 mol). Br2 (11 mL, 0.21mol) was added, keeping the temperature below 10 °C. Then, a solution of NaNO2 (16.1 g, 0.19 mol) in H2O (19 mL) was added dropwise, maintaining the temperature at 0–5 °C. The reaction mixture was stirred for an additional 30 min, then treated with a solution of NaOH (28.0 g, 0.70 mol) in H2O (30 mL) at such a rate that the temperature did not exceed 20–25 °C. The mixture was extracted with Et2O (3 × 40 mL) and the combined organic layers were dried (Na2SO4). The solvent was evaporated under vacuum, the residue was suspended in hexane (10 mL), and the solid formed was collected by filtration to afford a pale brown powder; yield: 15.49 g (87percent); mp 94–95 °C (Lit.19mp 96–97 °C); Rf = 0.55 (CHCl3). IR (KBr): 3411, 3022, 2924, 2852, 1549, 1437, 1356, 1090, 997 cm–1.1H NMR (CDCl3): δ = 7.39 (d, J = 8.4 Hz, 1 H, H-3), 7.67 (dd, J1 = 8.4 Hz,J2 = 2.5 Hz, 1 H, H-4), 8.45 (d, J = 2.4 Hz, 1 H, H-6). 13C NMR (CDCl3): δ = 120.1, 129.5, 140.4, 141.2, 151.3. MS (EI, 70 eV): m/z (percent) = 239 (36, [M (81Br, 81Br)]+), 237 (71, [M (79Br,81Br)]+), 235 (35, [M (79Br, 79Br)]+), 158 (85), 156 (85), 81 (57), 76 (78),50 (100).Anal. Calcd for C5H3Br2N: C, 25.35; H, 1.28; N, 5.91. Found: C, 25.46; H,1.13; N, 5.95.
83% With tert.-butylnitrite; trimethylbenzylammonium bromide In 1,2-dibromomethane at 20℃; [00159] Scheme 1. Preparation of relevant pyri(mi)dyl halides A-H. Key: (a) NBS, NH4OAc, MeCN, rt, 5 min, pyr: 85-90percent; pym: quant; (b) pyr: RCHO, Na(CN)BH3, MeCN, reflux, 1-12h (82percent, R = C5Hn); pym: NaH, Rl, THF, rt, overnight (85percent, R = Me); (c) Me3(Bn)NBr, f-BuONO, CH2Br2, rt, overnight, pyr: 77-83percent; pym: 30- 40percent; (d) pym: HI, CH2CI2, 0°C, 80-85percent; (e) i. NaOH, Br2, H20, rt, 50-60percent, ii. POCI3, PhNEt2, reflux, 4h, 75-85percent, iii. HI, CH2CI2, 0°C, 80-85percent; (f) ROH, Na, rt, 1-12 h, quant.; (g) RZnl, CI2Pd(PPh3)2, DMF/THF, rt, overnight, pyr (Br): 72percent (R = C6H13), pym (I) 81 percent, (R = C6H13); (h) alkyne, Cul, CI2Pd(PPh3)2, Et3N, MeCN, rt, 1-12 h, quant. [00160] Preparation of 3-pyridyl and 5-pyrimidyl halides. 2-Aminopyridine and 2-aminopyrimidine were employed as common starting materials for each of the pyridyl and pyrimidyl halides due to their commercial availability at very low cost. Synthesis of the various pyridyl bromides began with bromination of the 5-position of 2-aminopyridine using NBS/NH40AC (Das, B.; Venkateswarlu, K.; Majhi, A.; Siddaiah, V.; Reddy, K. R. J. Mol. Catal. A-Chem. 2007, 267, 30). This intermediate was either alkylated by reductive amination with appropriate aldehydes to prepare 5-bromo-2-N,N-dialkylaminopyridines (A) or subjected to aqueous (Bhasin, K. K.; Kumar, R.; Mehta, S. K.; Raghavaiah, P.; Jacob, C; Klapotke, T. M. Inorg. C im. Act. 2009, 362, 2386.) or non-aqueous (Nara, S. J.; Jha, M.; Brinkhorst, J.; Zemanek, T. J.; Pratt, D. A. J. Org. C em. 2008, 73, 9326.) diazotization/halo-dediazoniation to afford 2,5-dibromopyridine. This compound served as the precursor to all other substituted pyridines: 2-alkoxy-5-bromopyridines (C) were obtained by nucleophillic substitution with an appropriate sodium alkoxide17 and 2- alkynyl-5-bromopyridine (E) and 2-alkyl-5-bromopyridines (G) were prepared via Sonogoshira (Tilley, J. W.; Zawoiski, S. J. Org. Chem. 1988, 53, 386.) and Negeishi (Getmanenko, Y. A. ; Twieg, R. J. J. Org. Chem. 2008, 73, 830.) cross-coupling reactions, respectively.
58%
Stage #1: With hydrogen bromide; sodium nitrite In water at 0℃; for 0.166667 h;
Stage #2: With bromine In water at 0℃; for 0.25 h;
To a solution of 5-bromopyridin-2-amine (5.0 g, 28.9 mmol) in hydrogen bromide(50.0 mL, 46percent), sodium nitrite (15.0 g, 217.4 mmol) solution in water was slowlyadded at 0 °C. The resulting solution was stirred for 10 mm at the same temperature.Br2 (37.2 mL, 232.8 mmol) was slowly added to the reaction mixture at 0 °C andstirred for 15 mm at 0 °C. The reaction mixture was basified with sodium hydroxide and extracted with ethyl acetate, washed with sodium thiosulphate solution, water and brine solution. The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuo. The product was purified by column chromatography toyield title compound (4.0 g, 58.0percent) white solid. LCMS: (M+H) = 237.9;1H NMR:(DMSO-d6, 300MHz) 6 8.57-8.58 (d, 1 H), 8.00- 8.04 (dd, 1 H), 7.64- 7.67(d, 1 H).
58%
Stage #1: With hydrogen bromide; sodium nitrite In water at 0℃; for 0.166667 h;
Stage #2: With bromine In water at 0℃; for 0.25 h;
To a solution of 5-bromopyridin-2-amine (5.0 g, 28.9 mmol) in hydrogen bromide (50.0 mL, 46percent), sodium nitrite (15.0 g, 217.4 mmol) solution in water was slowly added at 0 00 abd then stirred for 10 mm at the same temperature. To the reaction mixture Br2 (37.2 mL, 232.8 mmol) was slowly added at 0 00 and stirred for 15 mm at0 00. The reaction mixture was basified with sodium hydroxide and extracted with ethyl acetate, washed with sodium thiosulphate solution, water and brine solution. The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuo. The product was purified by column chromatography to yield title compound (4.0 g, 58.0percent) white solid. LOMS: (M+H) = 237.9; 1H NMR: (DMSO-d6, 300MHz) 6 8.57-8.58 (d, 1 H), 8.00- 8.04 (dd, 1 H), 7.64- 7.67(d, 1 H).

Reference: [1] Synthesis (Germany), 2015, vol. 47, # 20, p. 3169 - 3178
[2] Journal of Organic Chemistry, 2012, vol. 77, # 16, p. 6908 - 6916
[3] Patent: WO2012/162818, 2012, A1, . Location in patent: Page/Page column 45-46
[4] Patent: WO2014/202580, 2014, A1, . Location in patent: Page/Page column 107
[5] Patent: WO2014/202528, 2014, A1, . Location in patent: Page/Page column 102
[6] Journal of the American Chemical Society, 1946, vol. 68, p. 2574,2576
[7] Journal of Organic Chemistry, 2008, vol. 73, # 23, p. 9326 - 9333
  • 27
  • [ 504-29-0 ]
  • [ 1072-97-5 ]
  • [ 408352-48-7 ]
Reference: [1] Canadian Journal of Chemistry, 1989, vol. 67, p. 2061 - 2066
  • 28
  • [ 1072-97-5 ]
  • [ 13472-85-0 ]
Reference: [1] Yakugaku Zasshi, 1952, vol. 72, p. 381[2] Chem.Abstr., 1953, p. 6403
  • 29
  • [ 1072-97-5 ]
  • [ 74-88-4 ]
  • [ 84539-30-0 ]
Reference: [1] Patent: WO2011/54841, 2011, A1, . Location in patent: Page/Page column 40
[2] Patent: US2012/208798, 2012, A1, . Location in patent: Page/Page column 16
  • 30
  • [ 1072-97-5 ]
  • [ 74-88-4 ]
  • [ 84539-30-0 ]
  • [ 26163-07-5 ]
YieldReaction ConditionsOperation in experiment
34% With NaH In N,N-dimethyl-formamide; mineral oil a)
5-Bromo-2-(methylamino)pyridine and 5-bromo-2-(dimethylamino)pyridine To a suspension of NaH (60percent dispersion in mineral oil, 0.44 g, 11 mmole) in dry DMF (40 mL) was added solid 2-amino-5-bromopyridine (1.73 g, 10 mmole) in portions over 5-10 min.
Gas evolution was allowed to subside between additions.
The resulting amber mixture was stirred for 15 min, then' methyl iodide (0.61 mL, 10 mmole) was added all at once.
The reaction mixture was stirred at RT overnight, then was concentrated in vacuo.
The residue was diluted with 5percent NH4Cl (30 mL) and the mixture was extracted with CH2Cl2.
The combined organic extracts were washed with brine, dried (MgSO4), and concentrated.
Flash chromatography on silica gel (3percent MeOH/CH2Cl2) separated the products. 5-Bromo-2-(methylamino)pyridine (0.60 g, 32 percent) was obtained as a semisolid: TLC (3percent MeOH/CH2Cl2) Rf 0.35; MS (ES) m/e 187 (M + H)+. 5-Bromo-2-(dimethylamino)pyridine (0.70 g, 34percent) was obtained as a semisolid: TLC (3percent MeOH/CH2Cl2) Rf 0.77; MS (ES) m/e 201 (M + H)+.
Reference: [1] Patent: EP1226138, 2004, B1,
  • 31
  • [ 1072-97-5 ]
  • [ 67-56-1 ]
  • [ 84539-30-0 ]
Reference: [1] Journal of Catalysis, 2017, vol. 347, p. 57 - 62
  • 32
  • [ 1072-97-5 ]
  • [ 28539-02-8 ]
  • [ 84539-30-0 ]
Reference: [1] Acta Chemica Scandinavica, 1993, vol. 47, # 8, p. 805 - 812
  • 33
  • [ 1072-97-5 ]
  • [ 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
  • 34
  • [ 1072-97-5 ]
  • [ 64-17-5 ]
  • [ 1493-13-6 ]
  • [ 55849-30-4 ]
  • [ 475106-12-8 ]
Reference: [1] Tetrahedron Letters, 2014, vol. 55, # 28, p. 3771 - 3773
  • 35
  • [ 1072-97-5 ]
  • [ 74-88-4 ]
  • [ 26163-07-5 ]
YieldReaction ConditionsOperation in experiment
94%
Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 0.166667 h;
Stage #2: for 1 h;
Step 64a: 5-Bromo-N,N-dimethylpyridin-2-amine (cCompound 0601-114)To a solution of 5-bromopyridin-2-amine (1.0 g, 5.8 mmol) in THF (25 mL) was added NaH (0.92 g, 23.1 mmol) at 0 °C and stirred for 10 min. followed by the addition of CH3I (1 mL, 16 mmol) and stirred fori h. Water (30 mL) was added and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine, dried over Na2S04, concentrated and purified by column chromatography on silica gel (ethyl acetate in petroleum ether, 10percent v/v) to give the title compound (1.1 g, 94percent) as a white solid LCMS: 203 [M+2]+; 1HNMR (400 MHz, DMSO-<3/4) δ 2.99 (s, 6H), 6.61 (d, J= 9.6 Hz, 1H), 7.62 (dd, J= 9.2, 2.8 Hz, 1H), 8.12 (d, J= 2.4 Hz, 1H).
94%
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.166667 h;
Stage #2: for 1 h;
Step 64a: 5-Bromo-N,N-dimethylpyridin-2-amine (compound 0601-114)[0486]To a solution of 5-bromopyridin-2-amine (1.0 g, 5.8 mmol) in THF (25 mL) was added NaH (0.92 g, 23.1 mmol) at 0° C. and stirred for 10 min. followed by the addition of CH3I (1 mL, 16 mmol) and stirred for 1 h. Water (30 mL) was added and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by column chromatography on silica gel (ethyl acetate in petroleum ether, 10percent v/v) to give the title compound (1.1 g, 94percent) as a white solid LCMS: 203 [M+2]+; 1HNMR (400 MHz, DMSO-d6) δ 2.99 (s, 6H), 6.61 (d, J=9.6 Hz, 1H), 7.62 (dd, J=9.2, 2.8 Hz, 1H), 8.12 (d, J=2.4 Hz, 1H).
94%
Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 0.166667 h;
Stage #2: for 1 h;
THF (25mL) in 5-bromo-2-amine (1.0g, 5.8mmol) to a solution of NaH (0.92g, 23.1mmol) was stirred addition to 10 minutes at 0 , then CH3I (1mL, 16mmol) and the mixture was stirred for 1 hour with the addition of. With the addition of water (30mL) and extracted with ethyl acetate (3x30mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated and purified by column chromatography (petroleum ether in ethyl acetate, 10percent v / v) on silica gel to give the white solid title compound obtained as (1.1g, 94percent).
Reference: [1] Patent: WO2011/130628, 2011, A1, . Location in patent: Page/Page column 206
[2] Patent: US2013/102595, 2013, A1, . Location in patent: Paragraph 0485; 0486
[3] Patent: JP2015/187145, 2015, A, . Location in patent: Paragraph 0418
  • 36
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  • [ 50-00-0 ]
  • [ 26163-07-5 ]
YieldReaction ConditionsOperation in experiment
43%
Stage #1: at 20℃;
Stage #2: With sodium cyanoborohydride; zinc(II) chloride In methanol; water at 20℃; for 4 h;
37 percent Aqueous formaldehyde (13.55 ml, 180.3 mmol) was added dropwise to a solution of 2-amino-5-bromopyrydine (2.0 g, 11.56 mmol) in methanol (465 ml)at room temperature. To the mixture was added dropwise a solution of zinc chloride (3.94 g, 28.90 mmol) and sodium cyanoborohydride (3.63 g, 57.80 mmol) in methanol (155 ml)and the mixture was stirred at room temperature for 4 hrs. To the reaction mixture was added ice water (300 ml) at 5 °C and then methanol was distilled off under reduced pressure. The residue was extracted with ethyl acetate - tetrahydrofuran (1/1) and the extract was washed with water and brine in turn and dried. The solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate = 24 and 5) to give 5-bromo-2-dimethylamino-pyridine (1.00 g, 43 percent) as colorless crystals. m.p.: 39 - 41 °C; IR (Nujol): 1588 cm-1; APCI-MS m/z: 201/203 [M+H]+.
43% With sodium cyanoborohydride; zinc(II) chloride In methanol; water at 20℃; for 4 h; (Preparation 27) (0109) 1) 37percent Aqueous formaldehyde (13.55 ml, 180.3 mmol) was added dropwise to a solution of 2-amino-5-bromopyrydine (2.0 g, 11.56 mmol) in methanol (465 ml)at room temperature. To the mixture was added dropwise a solution of zinc chloride (3.94 g, 28.90 mmol) and sodium cyanoborohydride (3. 63 g, 57.80 mmol) in methanol (155 ml) and the mixture was stirred at room temperature for 4 hrs. To the reaction mixture was added ice water (300 ml) at 5° C. and then methanol was distilled off under reduced pressure. The residue was extracted with ethyl acetate-tetrahydrofuran (1/1) and the extract was washed with water and brine in turn and dried. The solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=24 and 5) to give 5-bromo-2-dimethylamino-pyridin- e (1.00 g, 43percent) as colorless crystals. m.p.: 39-41° C.; IR (Nujol): 1588 cm-1; APCI-MS m/z: 201/203 [M+H]+.
Reference: [1] Patent: EP1481965, 2004, A1, . Location in patent: Page 29
[2] Patent: EP2959918, 2015, A1, . Location in patent: Paragraph 0109
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  • [ 74-88-4 ]
  • [ 84539-30-0 ]
  • [ 26163-07-5 ]
YieldReaction ConditionsOperation in experiment
34% With NaH In N,N-dimethyl-formamide; mineral oil a)
5-Bromo-2-(methylamino)pyridine and 5-bromo-2-(dimethylamino)pyridine To a suspension of NaH (60percent dispersion in mineral oil, 0.44 g, 11 mmole) in dry DMF (40 mL) was added solid 2-amino-5-bromopyridine (1.73 g, 10 mmole) in portions over 5-10 min.
Gas evolution was allowed to subside between additions.
The resulting amber mixture was stirred for 15 min, then' methyl iodide (0.61 mL, 10 mmole) was added all at once.
The reaction mixture was stirred at RT overnight, then was concentrated in vacuo.
The residue was diluted with 5percent NH4Cl (30 mL) and the mixture was extracted with CH2Cl2.
The combined organic extracts were washed with brine, dried (MgSO4), and concentrated.
Flash chromatography on silica gel (3percent MeOH/CH2Cl2) separated the products. 5-Bromo-2-(methylamino)pyridine (0.60 g, 32 percent) was obtained as a semisolid: TLC (3percent MeOH/CH2Cl2) Rf 0.35; MS (ES) m/e 187 (M + H)+. 5-Bromo-2-(dimethylamino)pyridine (0.70 g, 34percent) was obtained as a semisolid: TLC (3percent MeOH/CH2Cl2) Rf 0.77; MS (ES) m/e 201 (M + H)+.
Reference: [1] Patent: EP1226138, 2004, B1,
  • 38
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  • [ 78-95-5 ]
  • [ 4044-99-9 ]
YieldReaction ConditionsOperation in experiment
80.6% at 90℃; for 16 h; INTERMEDIATE 186-Bromo-2-methylimidazo [1,2-al pyridine2-Amino-5-bromopyridine (6.2 g) was dissolved in ethanol (60 mL) andchloroacetone (5.7 mL) was added. The mixture was heated to reflux at 90°C for 16 h with stirring. The cooled reaction mixture was concentrated under vacuum and the residue was purified on silica (Biotage, 100 g), eluting with a gradient of 2-15percent methanol in DCM, to afford the title compound (6.1 g, 80.6percent) as a yellow solid. H (500 MHz, CD3OD) 9.03 (s, 1H), 8.02 (m, 1H), 7.93 (s, 1H), 7.79 (d, J 9.4 Hz, 1H), 2.56 (d, J 1.0Hz, 3H).
80.6% at 90℃; for 16 h; 5-Bromopyridin-2-amine (6.2 g) was dissolved in ethanol (60 mL) and chloroacetone (5.7 mL) was added. The mixture was heated under reflux at 90°C for 16 h with stirring. The reaction mixture was cooled and concentrated in vacuo. The resulting crudeyellow solid was purified on silica gel, eluting with a gradient of 2-15percent methanol in dichloromethane, to afford the title compound (6.1 g, 80.6percent) as a yellow solid. H (500 MHz, CD3OD) 9.03 (s, 1H), 8.02 (m, 1H), 7.93 (s, 1H), 7.79 (d,J9.4 Hz, 1H), 2.56 (d,J 1.0 Hz, 3H).
53.4% for 16 h; Reflux A solution of 5-bromopyridin-2-amine (20 g, 115.6 mmol) in ethanol (200 mL) was treated with 1-chloropropan-2-one (18.6 mL, 231.2 mmol), added portionwise, andthe reaction mixture was stirred under reflux for 16 h. The reaction mixture was concentrated under vacuum. The resulting yellow solid was re-dissolved in DCM (150 mL) and 1M aqueous sodium hydroxide solution (150 mL) was added. The two-phase mixture was stirred at ambient temperature for 20 minutes. The organic phase was separated and washed with brine (50 mL), then dried over Na2SO4 and concentrated todryness under vacuum. The crude residue was purified by chromatography on silica gel(eluting with 0-100percent EtOAc in heptane) to afford the title compound (13.75 g, 53.4percent) asa white solid. H (250 MHz, CDC13) 8.18 (s, 1H), 7.41 (d, J9.5 Hz, 1H), 7.30 (s, 1H),7.18 (d,J9.5 Hz, 1H), 2.44 (s, 3H). LCMS m/z211/213 [M+H].
19% for 24 h; Reflux Intermediate I-74 (800 mg, 4.2 mmol, 1.0 eq) and chloroacetone (3.0 g, 13 mmol, 3.0 eq) were mixed in ethanol (10 mL) and the reaction mixture was refluxed for 24 hours. The crude reaction mixture was concentrated by evaporation; the residue was dissolved in ethyl acetate and washed with water. The combined organic layers were dried over anhydrous Na2SO4, the solids were removed by filtration and the filtrate was concentrated by evaporation. The crude reaction product was purified by silica gel column chromatography to give intermediate I-75 (188 mg, 19percent). MS (ESI): m/z 212 (M+H+).
9 g at 90℃; for 20 h; 2-Amino-5-bromopyridine (10 g, 57.8 mmol) was dissolved in ethanol (100 mL)and chloroacetone (9.3 mL, 115.59 mmol) was added. The mixture was heated to reflux at 90°C for 16 h. The reaction mixture was concentrated under vacuum and the residuewas purified by flash chromatography, eluting with a gradient of 0-20percent methanol in DCM, to afford the title compound (9 g, 66.4percent) as a yellow solid. OH (500 MHz, CD3OD) 9.03 (s, 1H), 8.02 (m, 1H), 7.93 (s, 1H), 7.79 (d, J9.4 Hz, 1H), 2.56 (s, 3H).

Reference: [1] Patent: WO2015/86498, 2015, A1, . Location in patent: Page/Page column 94
[2] Patent: WO2015/86506, 2015, A1, . Location in patent: Page/Page column 99
[3] Patent: WO2015/86512, 2015, A1, . Location in patent: Page/Page column 97
[4] Patent: US2010/204214, 2010, A1, . Location in patent: Page/Page column 112
[5] Patent: WO2014/9295, 2014, A1, . Location in patent: Page/Page column 115
  • 39
  • [ 1072-97-5 ]
  • [ 598-31-2 ]
  • [ 4044-99-9 ]
Reference: [1] Journal of Medicinal Chemistry, 2017, vol. 60, # 21, p. 8781 - 8800
[2] Journal of the Chemical Society, 1951, p. 2411,2415
[3] Yakugaku Zasshi, 1946, vol. 66, p. Ausg. B, S. 75[4] Chem.Abstr., 1952, p. 112
  • 40
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  • [ 4044-99-9 ]
Reference: [1] Green Chemistry, 2016, vol. 18, # 17, p. 4623 - 4627
  • 41
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  • [ 1072-97-5 ]
  • [ 35486-42-1 ]
YieldReaction ConditionsOperation in experiment
76% With bromine In ethanol at 20℃; To a solution of 2-aminopyridine (9.40 g, 0.1 mol) in EtOH (100 mL) was added dropwise Br2 (5.8 mL, 0.11 mol) maintaining the temperature below 20 °C. When the addition of bromine was completed, the mixture was stirred for 1 h. After removal of EtOH, the residue was made alkaline with a solution of NaOH (5.0 g, 0.13 mol) in H2O (50 mL) and cooled (10 °C). The solid was collected by filtration, slurry washed with cold H2O (10 mL), and then washed with boiling heptane (3 × 20 mL) to remove the 2-amino-3,5-dibromoaminopyridine, followed by air-drying to constant weight; yield: 13.15 g (76percent); off-white fine crystals; mp 135–136 °C (Lit.17 mp 132–135 °C); Rf = 0.4 (CHCl3–EtOAc). IR (KBr): 3452, 3292, 3153, 2924, 2852, 1628, 1587, 1550, 1481, 1387,1088, 999 cm–1.1H NMR (CDCl3): δ = 4.57 (br s, 2 H, NH2), 6.41 (d, J = 8.8 Hz, 1 H, H-3),7.48 (dd, J1 = 8.8 Hz, J2 = 2.4 Hz, 1 H, H-4), 8.09 (d, J = 2.4 Hz, 1 H, H-6).13C NMR (CDCl3): δ = 108.3, 110.1, 140.2, 148.7, 157.1.MS (EI, 70 eV): m/z (percent) = 174 (88, [M (81Br)]+), 172 (100, [M (79Br)]+),147 (46), 145 (49), 92 (97), 65 (67), 64 (60), 50 (49).Anal. Calcd for C5H5BrN2: C, 34.71; H, 2.91; N, 16.19. Found: C, 34.59;H, 3.01; N, 16.10.
67%
Stage #1: at 20 - 50℃;
28.2 g (0.3 moles) of 2-aminopyridine were dissolved in 50 ml of acetic acid. The solution is cooled to below 20° by immersion in an ice bath, and 48 g (15.4 ml, 0.3 moles) of bromine dissolved in 30 ml of acetic acid is added dropwise with vigorous stirring over a period of 1 h. Initially the temperature is maintained below 20°. After half the bromine solution has been added, it is allowed to rise to 50° to delay as long as possible the separation of the hydrobromide of 2-amino-5-bromopyridine. At 50° the hydrobromide usually begins to crystallize when about three-quarters of the bromine has been added. When addition of bromine is completed, the mixture is stirred for 1 h and is then diluted with 75 ml of water to dissolve the hydrobromide. The contents of the flask are transferred to a 500 ml beaker and are neutralized, with stirring and cooling, by the addition of 120 ml of 40percent sodium hydroxide solution. 2-Amino-5-bromopyridine, contaminated with some 2-amino-3,5-dibromopyridine,was filtered and dried. The 2-amino-3,5-dibromopyridine is removed from the product by washing with three 500-ml. portions of hot petroleum ether. The yield of 2-amino-5-bromopyridine, is 32-34.7 g (62-67percent). mp 134 °C (literature65 mp 132-135°C)
Reference: [1] Synthetic Communications, 1986, vol. 16, # 13, p. 1641 - 1646
[2] Canadian Journal of Chemistry, 2005, vol. 83, # 2, p. 146 - 149
[3] Synthesis (Germany), 2015, vol. 47, # 20, p. 3169 - 3178
[4] Journal of Organic Chemistry, 1983, vol. 48, # 7, p. 1064 - 1069
[5] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 7, p. 2455 - 2478
[6] Bioorganic and Medicinal Chemistry, 1999, vol. 7, # 3, p. 467 - 479
[7] Journal of Organic Chemistry USSR (English Translation), 1981, vol. 17, # 2, p. 353 - 357[8] Zhurnal Organicheskoi Khimii, 1981, vol. 17, # 2, p. 413 - 417
[9] Journal of the American Chemical Society, 1946, vol. 68, p. 2574,2576
[10] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1920, vol. 50, p. 489[11] Chem. Zentralbl., 1923, vol. 94, # III, p. 1021
[12] Organic Process Research and Development, 2017, vol. 21, # 3, p. 451 - 459
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Reference: [1] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 22, p. 7155 - 7164
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YieldReaction ConditionsOperation in experiment
88% With N,N'-N,N'-[1-(benzo[d]thiazol-2-yl)ethanone O-4-[1-(benzo[d]thiazol-2-yl)ethylideneaminooxy]butyl oxime]bis[dichloropalladium(II)] trihydrate; tetrabutylammomium bromide; potassium hydroxide In water at 160℃; for 0.166667 h; Microwave irradiation; Green chemistry General procedure: A mixture of the appropriate aryl bromides 4–8 (1 mmol), boronic acid 9a, 9b (1.2 mmol), 194 mg TBAB (0.6 mmol), palladium complex 3 (0.15 molpercent), 112 mg KOH (2 mmol), and 3 cm3 distilled water was mixed in a process glass vial. The vial was capped properly, and there after the mixture was heated under microwave irradiating conditions at 160 C and 250 W for the appropriate reaction time as listed in Table 1. After the reaction was almost complete (monitored by TLC), the reaction mixture was extracted with EtOAc (3 9 20 cm3). The combined organic extracts were dried over anhydrous MgSO4 then filtered and the solvent was evaporated under reduced pressure. The products were purified with flash column chromatography to give the corresponding pure crosscoupled products 10–14 (from aryl bromides and chloride,Table 1).
76% With potassium carbonate In water at 70℃; for 9 h; Inert atmosphere General procedure: In a typical run, h-BN(at)Fur(at)Pd(OAc)2 (0.05 mmol) was added to a mixture of arylboronic acid 1 (1.0 mmol), aryl bromide 2 (1.5 mmol) and K2CO3 (1.5 mmol) in water (1 mL). The resulting mixture was stirred at 70 °C under Ar protection, and the progress of the reaction was monitored by TLC. After completion of the reaction, ethyl acetate was added to the reaction mixture and the catalyst was separated. The organic phase was washed with water, dried over anhydrous Na2SO4 and the solvent was evaporated under reduced pressure. Finally, the residue was isolated by chromatography on a column of silica gel to afford the corresponding product 3.
70% With potassium phosphate; tetrakis(triphenylphosphine) palladium(0) In water; ethylene glycol at 80℃; for 16 h; Inert atmosphere General procedure: To a solution of 2a, 2c or 2h (3 mmol, 0.5 g) in ethylene glycol (5 mL) was added successively the boronic acid (4.5 or 9.0 mmol, 1.5 or 3 equiv), Pd(PPh3)4 (1molpercent), and a solution of K3PO4 (6 mmol, 2 equiv) inwater (2 mL). The reaction mixture was heated at 80°C for 16 h and was then hydrolyzed with a 1 M solution of sodium hydroxide (20 mL). The aqueous phase was extracted with ethylacetate (3 x 30 mL) and the combined organic layers were washed with brine (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with petroleum ether/EtOAc (60/40) as eluent.
61% With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In water; acetonitrile at 90℃; for 16 h; To a stirred solution of 5-bromopyridin-2-amine (1) (5.0 g, 28.9 mmol) in acetonitrile (75 mL) at room temperature was added phenylboronic acid (4.93 g, 40.5 mmol), Na2C03 (4.59 g, 43.4 mmol), H20 (25 mL) and Pd(PPh3)4 (3.30 g, 2.89 mmol). The resulting mixture was heated at 90°C for 16 h. After cooling to room temperature the reaction mixture was filtered through a pad of celite, and the filtrate was partitioned and extracted with EtOAc (5x100 mL). The combined organic layers were dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue obtained was purified by column chromatography (silica gel, 0 to 20percent EtOAc/hexanes) to afford 5-phenylpyridin-2-amine (2) (3.0 g, 61 percent) as an off-white solid: MS (Multi-mode, ESI/APCI) m/z 172 [M + H]+.
1.8 g With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,4-dioxane; water at 80℃; for 16 h; Inert atmosphere To a stirred solution of 5-bromopyridin-2-amine (2.0 g, 11.55 mmol) in Dioxane: H2O (20:4 mL) was added phenylboronic acid (1.26 g, 10.40 mmol) and Na2CO3 (2.45 g, 23.14 mmol) at 25° C.
The reaction mixture was degassed with Argon for 30 minutes.
Tetrakis (668.5 mg, 0.578 mmol) was added.
The reaction mixture was heated at 80° C. for 16 h.
Then the reaction mixture was cooled, diluted with water (50 mL) and extracted in EtOAc (150 mL*2) The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate and distilled off to give crude product which was purified by Flash chromatography to give pure 5-phenylpyridin-2-amine (1.8 g).
1H NMR: (400 MHz, DMSO) (31196) δ: 6.07 (s, 2H), 6.51-6.53 (m, 2H), 7.24-7.28 (m, 2H), 7.38-7.42 (m, 2H), 7.55-7.57 (m, 2H), 7.62-7.71 (m, 1H), 8.24-8.25 (d, J=2.0 Hz, 1H).

Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 21, p. 6122 - 6126
[2] European Journal of Organic Chemistry, 2014, vol. 2014, # 27, p. 5901 - 5905
[3] Monatshefte fur Chemie, 2003, vol. 134, # 4, p. 573 - 583
[4] New Journal of Chemistry, 2016, vol. 40, # 8, p. 6568 - 6572
[5] Monatshefte fur Chemie, 2016, vol. 147, # 7, p. 1197 - 1205
[6] Synthesis, 2010, # 18, p. 3163 - 3173
[7] ACS Catalysis, 2013, vol. 3, # 12, p. 2776 - 2789
[8] Patent: WO2014/174397, 2014, A2, . Location in patent: Paragraph 0046; 0051; 0052
[9] Journal of Organometallic Chemistry, 2003, vol. 687, # 2, p. 327 - 336
[10] European Journal of Organic Chemistry, 2010, # 29, p. 5548 - 5551
[11] Heterocycles, 1987, vol. 26, # 10, p. 2711 - 2716
[12] Applied Organometallic Chemistry, 2017, vol. 31, # 12,
[13] Tetrahedron, 2016, vol. 72, # 52, p. 8557 - 8564
[14] Advanced Synthesis and Catalysis, 2017, vol. 359, # 3, p. 454 - 466
[15] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 1, p. 114 - 120
[16] Patent: WO2014/187922, 2014, A1, . Location in patent: Page/Page column 157
[17] Journal of Medicinal Chemistry, 2008, vol. 51, # 15, p. 4724 - 4729
[18] Patent: EP1582516, 2005, A1, . Location in patent: Page/Page column 87
[19] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 15, p. 3057 - 3061
[20] Patent: US2016/96835, 2016, A1, . Location in patent: Paragraph 0159
[21] Organic Process Research and Development, 2016, vol. 20, # 8, p. 1489 - 1499
[22] New Journal of Chemistry, 2017, vol. 41, # 24, p. 15420 - 15432
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  • [ 92-52-4 ]
YieldReaction ConditionsOperation in experiment
56.3% With (+/-)-7-(2,3-diacetoxypropyl)theophylline; palladium diacetate; lithium carbonate In water at 120℃; for 0.166667 h; Microwave irradiation; Green chemistry General procedure: Suzuki–Miyaura couplings were performed in glass tubes suitable for microwave. Halopyridines (0.44 mmol), phenyl boronic acid (65.17 mg, 0.53 mmol), Li2CO3 (63.7 mg, 0.89 mmol), 1 mol percent of Pd(OAc)2 (1 mg, 4.45 ϰ 10-3 mol), and 2 mol percent of the corresponding ligand in 3 mL of distilled water. The mixtures were stirred and heated at 120 °C under microwave radiation during 10 min with a ramp of 1 min in a CEM Discover reactor coupled to a CEM Explorer robotic system. The resulting reaction mixture was cooled to room temperature and the mixture extracted with CH2Cl2 (3 ϰ 2 mL), the organic phase was treated with anhydrous Na2SO4 after filter over celite and analyzed by Gas Chromatography (GC–MS) on an Agilent 6890N GC with a 30.0 m DB-1MS capillary column coupled to an Agilent 5973 Inert Mass Selective detector. Additional experiments of catalysis were carried out under the same reaction conditions using different bases Na2CO3, K2CO3, Li2CO3, Cs2CO3, Rb2CO3, NaOH, KOH, Et3N, and DIPEA.
Reference: [1] Tetrahedron Letters, 2014, vol. 55, # 42, p. 5841 - 5845
[2] Russian Journal of General Chemistry, 1996, vol. 66, # 12, p. 1925 - 1938
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Reference: [1] European Journal of Organic Chemistry, 2012, # 3, p. 595 - 603
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Reference: [1] Advanced Synthesis and Catalysis, 2017, vol. 359, # 4, p. 616 - 622
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Reference: [1] European Journal of Organic Chemistry, 2012, # 3, p. 595 - 603
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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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Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1953, vol. 72, p. 125,131
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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] Yakugaku Zasshi, 1952, vol. 72, p. 381[2] Chem.Abstr., 1953, p. 6403
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YieldReaction ConditionsOperation in experiment
99.04% at 20℃; Industrial scale To a 1 L four-necked flask equipped with a magnetic stirrer and thermometer, 46.04 g (0.267 mol) of 2-amino-5-Bromopyridine, was added 500mL dichloromethane at room temperature with stirring to dissolve slowly added dropwise 53.80g (0.527mol) acetic anhydride,Should be 2 to 5 hours, TLC control to the end of the reaction, vacuum distillation, the residue was dissolved in ethyl acetate, 200mL saturated sodium bicarbonateWashed twice and evaporated to dryness to give 56.41 g of 2-acetylamino-5-bromopyridine in a yield of 99.04percent.
92% With pyridine In tetrahydrofuran at 20℃; Step 63a: N-(5-bromopyridin-2-yl)acetamide (Compound 0601-112)To a solution of 2-amino-5-bromopyridine (0.50 g, 2.9 mmol) in THF (10 mL) was added pyridine (343 mg, 4.3 mmol) and acetic anhydride (295 mg, 2.9 mmol) at room temperature and stirred overnight. To the mixture water (30 mL) was added, extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with saturated aqueous NaHC03 and brine, dried over Na2S04, concentrated to give the title compound (0.58 g, 92percent) as a white solid LCMS: 215 [M+2]+; 1HNMR (400 MHz, OMSO-d6) δ 2.09 (s, 3H), 7.97 (dd, J= 8.8, 2.4 Hz, 1H), 8.06 (d, J= 8.8 Hz, 1H), 8.41 (d, J= 1.2 Hz, 1H), 10.64 (s, 1H).
92% With pyridine In tetrahydrofuran at 20℃; Step 63a: N-(5-bromopyridin-2-yl)acetamide (Compound 0601-112)[0481]To a solution of 2-amino-5-bromopyridine (0.50 g, 2.9 mmol) in THF (10 mL) was added pyridine (343 mg, 4.3 mmol) and acetic anhydride (295 mg, 2.9 mmol) at room temperature and stirred overnight. To the mixture water (30 mL) was added, extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, concentrated to give the title compound (0.58 g, 92percent) as a white solid LCMS: 215 [M+2]+; 1HNMR (400 MHz, DMSO-d6) δ 2.09 (s, 3H), 7.97 (dd, J=8.8, 2.4 Hz, 1H), 8.06 (d, J=8.8 Hz, 1H), 8.41 (d, J=1.2 Hz, 1H), 10.64 (s, 1H).
92% With pyridine In tetrahydrofuran at 20℃; Solution of pyridine (343mg, 4.3mmol) in THF (10mL) solution of 2-amino-5-bromopyridine (0.50g, 2.9mmol) and acetic anhydride (295mg, 2.9mmol) was stirred overnight then added at room temperature . With the addition of water (30mL) to the mixture, and the mixture was extracted with ethyl acetate (3x30mL). The combined organic layers were washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, to afford the title compound as a white solid (0.58g, 92percent).
81% at 80℃; for 5 h; Synthesis of N-(5-bromopyridin-2-yl) acetamide [0293] A solution of 5-bromopyridin-2-amine (5.0 g, 28.90 mmol) in acetic anhydride (30 mL) was stirred at 80 °C for 5 h. After the consumption of the starting materials (monitored by TLC), the reaction was diluted with water (50 mL). The obtained solid was filtered and washed with hexane and dried in vacuo to afford N-(5-bromopyridin-2-yl) acetamide (5.0 g, 81percent) as a white solid. 1H-NMR (DMSO-<, 500 MHz): δ 10.61 ( s, 1H), 8.42 (s, 1H), 8.07 (d, 1H), 7.94 (d, 1H), 2.13 (s, 3H); LC-MS: 99.35percent; 217 (M+1); (column; X-bridge C-18, (50x3.0 mm, 3.5μ); RT 3.10 min. 5mM NH4OAc in water: ACN; 0.50 ml/min); TLC: 50percent EtOAc:hexane (R/. 0.3).
80% at 20℃; for 12 h; To a stirred solution of 5-Bromo-pyridin-2-ylamine (100 mg, 0.578 mmol) in dry THF was added acetic anhydride (70.25 mg, 0.693 mmol).
The reaction mixture was stirred at 20° C. for 12 hrs.
THF was distilled out and to it was added ethyl acetate.
The organic layer was washed with saturated NaHCO3 solution and dried over anhy sodium sulphate.
Removal of the solvent afforded N-(5-Bromo-pyridin-2-yl)-acetamide (100 mg, 80percent).
This was carried to next step without further purification.
75.4% at 100℃; for 9 h; A 2000 mL single-neck round bottom flask was charged with 2-amino-5-bromopyridine (86.50 g, 500 mmol)Acetic anhydride (153 g, 1500 mmol) and 850 ml of acetic acid,Start magnetic stirrer,The mixture in the reaction flask was stirred at 100 ° C for 9 hours.The TLC and GC tests confirmed that the starting 2-amino-5-bromopyridine was completely reacted,Water was added to the reaction solution,The reaction was then suction filtered, the filter cake was washed with ethyl acetate:N-hexane = 1: 4 to give the pure product 2-acetylamino-5-bromopyridine,The filtrate was extracted with ethyl acetate, the extract was removed by rotary evaporation,The crude product was obtained and recrystallized from ethyl acetate: n-hexane = 1: 4 to give the pure product2-acetamido-5-bromopyridine,After drying, the yield was calculated to be 75.40percent with a purity of 99.68percent (HPLC).

Reference: [1] Patent: CN103601745, 2017, B, . Location in patent: Paragraph 0029; 0030
[2] Tetrahedron Letters, 2002, vol. 43, # 17, p. 3121 - 3123
[3] Patent: WO2011/130628, 2011, A1, . Location in patent: Page/Page column 205
[4] Patent: US2013/102595, 2013, A1, . Location in patent: Paragraph 0480; 0481
[5] Patent: JP2015/187145, 2015, A, . Location in patent: Paragraph 0414
[6] CrystEngComm, 2010, vol. 12, # 12, p. 4231 - 4239
[7] ACS Medicinal Chemistry Letters, 2017, vol. 8, # 8, p. 875 - 880
[8] Patent: WO2015/66697, 2015, A1, . Location in patent: Paragraph 0293
[9] Patent: US2010/222325, 2010, A1, . Location in patent: Page/Page column 126
[10] Patent: CN106632016, 2017, A, . Location in patent: Paragraph 0013; 0014; 0015; 0016; 0017; 0018; 0019-0024
[11] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 8, p. 1077 - 1080
[12] Angewandte Chemie - International Edition, 2007, vol. 46, # 6, p. 930 - 933
[13] Patent: US6657063, 2003, B1, . Location in patent: Page column 92
[14] Patent: WO2006/79791, 2006, A1, . Location in patent: Page/Page column 42
[15] Patent: WO2009/145360, 2009, A1, . Location in patent: Page/Page column 68-69
[16] Patent: EP842924, 1998, A1,
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YieldReaction ConditionsOperation in experiment
39% for 48 h; The 5-bromo-2-aminopyridine(5.8 mmol) and acetyl chloride (7.6 mmol) dissolved in 10 ml ofacetone, stirring 48 hours. After concentrating by get the crude product bycolumn chromatography (dichloromethane/methanol =250/1) title compoundseparated to obtain 480 mg (39percent). 1 H-NMR (CDCl 3) δ 9.08(1H, brs), 8.30 (2H, s), 7.92 (1H, m), 2.27 (3H, s).
Reference: [1] Organic and Biomolecular Chemistry, 2015, vol. 13, # 25, p. 7050 - 7066
[2] Patent: US2003/166620, 2003, A1,
[3] Patent: CN103130792, 2016, B, . Location in patent: Paragraph 0204-0206
[4] Patent: WO2004/814, 2003, A1, . Location in patent: Page 84
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YieldReaction ConditionsOperation in experiment
91% at 10 - 20℃; General procedure: Phosphoric acid (0.7 mL, 12 mmol) was added to acetonitrile (0.5 mL, 9.5 mmol), the resulting mixture was cooled to 10-15 °C. Then, a mixture of aminopyridine 1a-g (2 mmol) and sodium nitrite (0.56 g, 8 mmol) pretriturated in a mortar was added in small portions at such a rate that allowed us to avoid vigorous liberation of nitrogen oxides. The resulting paste was thoroughly triturated and allowed to stand at 10-15 °C for 10 min and then at 20 °C for the period of time indicated in Table 1. The reaction progress was monitored by TLC (eluent hexane-acetone, 1 : 3) and GCMS. Upon completion, the reaction mixture was diluted with water, neutralized with NaHCO3, and extracted with ethyl acetate. The organic layer was separated and dried with Na2SO4, the solvent was evaporated. Compounds 2a-g were purified by recrystallization from ethanol. Yields and m.p. of compounds 2a-g are summarized in Table 1. NMR spectra and m.p. of compounds obtained correspond to the data published for authentic samples.
Reference: [1] Russian Chemical Bulletin, 2016, vol. 65, # 9, p. 2312 - 2314[2] Izv. Akad. Nauk, Ser. Khim., 2016, # 9, p. 2312 - 2314,3
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Reference: [1] Patent: US2002/173506, 2002, A1,
[2] Patent: US6001856, 1999, A,
[3] Patent: EP887079, 1998, A1,
[4] Patent: US6291489, 2001, B1,
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Reference: [1] New Journal of Chemistry, 2015, vol. 39, # 11, p. 8329 - 8336
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Reference: [1] Patent: WO2007/124345, 2007, A2, . Location in patent: Page/Page column 24-25
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Reference: [1] Patent: US2004/102450, 2004, A1, . Location in patent: Page/Page column 79
[2] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 4, p. 1407 - 1412
  • 63
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  • [ 104-15-4 ]
  • [ 7169-97-3 ]
Reference: [1] Synthesis, 2007, # 1, p. 81 - 84
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  • [ 1493-13-6 ]
  • [ 75-05-8 ]
  • [ 7169-97-3 ]
  • [ 475106-12-8 ]
Reference: [1] Tetrahedron Letters, 2014, vol. 55, # 28, p. 3771 - 3773
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  • [ 67443-38-3 ]
Reference: [1] Tetrahedron, 2014, vol. 70, # 5, p. 1077 - 1083
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  • [ 15862-37-0 ]
Reference: [1] Tetrahedron, 2003, vol. 59, # 43, p. 8555 - 8570
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  • [ 6945-68-2 ]
YieldReaction ConditionsOperation in experiment
71% at 0 - 20℃; Inert atmosphere General procedure: 2-Aminopyridine 7 (0.020 mol) was added to ice-cold concentrated sulfuric acid and the resulting solution was treated with concentrated nitric acid (1.09 mL, 0.024 mol), which was added slowly so as to maintain the reaction temperature in 0-5 °C range.The resulting solution was stirred at 0-5 °C for 1 h, warmed up to rt and stirred at that temperature overnight. It was then poured over ice and the pH was adjusted to 7-8 with 10percent aq NaOH solution. The resulting precipitate was collected by filtration, washed with water and dried at 60 °C overnight to provide analytically pure 2-amino-3-nitropyridines.
63% With sodium hydroxide; sulfuric acid; nitric acid In ice-water Step AAA: 2-Amino-5-bromo-3-nitropyridine
Sulfuric acid (290 mL) was cooled to 0° C., followed by the slow addition of 2-amino-5-bromopyridine (50 g, 289 mmol).
Nitric acid (15 mL) was added dropwise over 30 min with the aid of a pressure-equalized dropping funnel.
After 90 min at 0° C., the reaction mixture was heated to 75° C. for 2 h.
After cooling to ambient temperature, the reaction mixture was poured into 1500 mL of ice-water and neutralized to pH 8 with 50percent NaOH (w/w).
The precipitate formed was collected on a fritted funnel, washed with 1000 mL cold water, and dried in vacuo, which provided 39.7 g of the title compound (63percent yield).
Reference: [1] Chemical Communications, 2013, vol. 49, # 72, p. 7929 - 7931
[2] Tetrahedron, 2003, vol. 59, # 43, p. 8555 - 8570
[3] Tetrahedron, 2014, vol. 70, # 5, p. 1077 - 1083
[4] Patent: US6025366, 2000, A,
[5] Journal of the Chemical Society, 1948, p. 1389,1392
[6] Yakugaku Zasshi, 1959, vol. 79, p. 1129,1132[7] Chem.Abstr., 1960, p. 3418
[8] Patent: US6110931, 2000, A,
[9] Patent: US5624935, 1997, A,
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Reference: [1] Yakugaku Zasshi, 1959, vol. 79, p. 1129,1132[2] Chem.Abstr., 1960, p. 3418
  • 69
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Reference: [1] Yakugaku Zasshi, 1959, vol. 79, p. 1129,1132[2] Chem.Abstr., 1960, p. 3418
[3] Patent: US5445763, 1995, A,
[4] Patent: US4665078, 1987, A,
[5] Patent: US4532252, 1985, A,
[6] Patent: US4537890, 1985, A,
[7] Patent: US4537891, 1985, A,
[8] Tetrahedron, 2014, vol. 70, # 5, p. 1077 - 1083
[9] Patent: US2018/44335, 2018, A1, . Location in patent: Paragraph 0441
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Reference: [1] Yakugaku Zasshi, 1959, vol. 79, p. 1129,1132[2] Chem.Abstr., 1960, p. 3418
  • 71
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  • [ 77992-44-0 ]
Reference: [1] Synthesis (Germany), 2015, vol. 47, # 20, p. 3169 - 3178
  • 72
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  • [ 557-20-0 ]
  • [ 19842-07-0 ]
YieldReaction ConditionsOperation in experiment
99% at 20℃; for 75 h; Heating / reflux 2-Amino-5-ethylpyridineDiethylzinc (24 mL of IM solution in hexane; 24 mmol) was added dropwise to a solution of 2-amino-5-bromopyridine (2.0 g, 11.6 mmol) and Pd(dppf)Cl2*CH2Cl2(225 mg, 0.28 mmol) in degassed dioxane (45 mL). The mixture was stirred at rt for 2 h, heated at reflux for 3 h and stirred at rt for 70 h under argon. The mixture was poured into NaCl (sat., aq.; 150 mL) and extracted with EtOAc (4x100 mL).The combined organic phases were washed with NaCl (sat., aq.; 100 mL), dried(Na2SO4) and concentrated. The residue was purified by chromatography(EtO Ac/heptane, then MeOH/EtOAc) to give the title compound. Yield: 1.40 g (99 percent).1H NMR (DMSO-d6, 400 MHz) δ 7.74 (s, IH), 7.25 (dd, IH), 6.40 (d, IH)5 5.67 (br. s, 2H), 2.39 (q, 2H), 1.10 (t, 3H).
99% at 20℃; for 75 h; Heating / reflux Diethylzinc (24 mL of IM solution in hexane, 24 mmol) was added dropwise to a solution of 2-amino-5-bromopyridine (2.0 g, 11.6 mmol) and Pd(dppf)Cl2-CH2Cl2 (225 mg, 0.28 mmol) in degassed dioxane (45 mL). The mixture was stirred at rt for 2 h, then heated at reflux for 3 h and stirred at rt for 70 h under an argon atmosphere. The mixture was poured into NaCl (aq., sat.; 150 mL) and extracted with EtOAc (4x100 mL). The combined extracts were washed with NaCl (aq., sat.; 100 mL), dried (Na2SO4) and concentrated. The crude product was purified by chromatography (EtO Ac/heptane, then MeOH/EtOAc) to give the title compound (1.40 g, 99 percent).1H NMR (DMSO-d6, 400 MHz) δ 7.74 (s, IH), 7.25 (dd, IH)5 6.40 (d, IH), 5.67 (br. s, 2H), 2.39 (q, 2H), 1.10 (t, 3H).
Reference: [1] Patent: WO2007/51981, 2007, A1, . Location in patent: Page/Page column 60
[2] Patent: WO2007/51982, 2007, A1, . Location in patent: Page/Page column 52
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  • [ 124-41-4 ]
  • [ 10167-97-2 ]
YieldReaction ConditionsOperation in experiment
36% at 135℃; for 14 h; 5-methoxypyridin-2-amine (P5).; Method a: 2-Amino-4-bromopyridine (0.10 g; 0.58 mmol), sodium methoxide (0.16 g; 2.9 mmol) and copper powder nanosized activated (0.11 g; 1.74 mmol) were introduced in a screw cap vial (Pyrex glass) together with 2.0 mL of anhydrous MeOH and a stirrer bar. The vial was closed and put in an oil bath at 135°C and stirred for 14 h. The mixture was cooled, diluted with MeOH (5.0 mL) and filtered through an SPE silica gel cartridge and the product eluted with AcOEt. The fractions were <n="13"/>collected and evaporated obtaining a crude of 92 mg of product which was further purified by FCC (DCM/AcOEt = 1:1) to give 26 mg (yield 36percent) of the title compound as brown oil.; Attempts to improve the result were made by increasing the equivalents of catalyst used. It was believed that copper could be coordinated and thus inactivated by the nitrogen atoms of the substrate. By this means the expected product was achieved in 36percent yield (eq 3). The reaction mixture, after being heated for 14 hrs, still contained a significant amount of starting material together with black polymers. The reaction was quenched to avoid further formation of polymers and degradation of the formed product.
34.3% at 100℃; for 48 h; Sealed tube A mixture of 2-amino-5-bromopyridine (5.0 g, 28.9 mmol), sodium methoxide (6.3 g, 116.6 mmol) and copper powder (1.85 g, 28.9 mmol) in methanol (30 mL) was heated in sealed tube for 48 h at 100° C. The reaction mixture was cooled to room temperature, diluted with dichloromethane (50 mL), filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The residue was diluted with water, extracted with dichloromethane (2.x.100 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The crude material was purified over silica gel column chromatography eluting with EtOAc:Hexane (6:4) to afford Int-1 (1.2 g, 34.3percent) as brown color oil. To a solution of Int-1 (3.0 g, 24.2 mmol) in dimethoxy ethane (30 mL) was added 3-chloro-2,4-pentanedione (4.9 g, 36.4 mmol) at room temperature and the mixture was stirred at reflux temperature for 16 hours. The volatile was concentrated under reduced pressure. The residue was purified over silica gel column chromatography eluting with MeOH:DCM (1:9) to afford Int-2 (2.3 g, 46.6percent) as brown color oil. A solution of Int-2 (1.5 g, 7.35 mmol) in DMF DMA (15 mL) was stirred at reflux temperature for 24 hours. The reaction mixture was cooled to room temperature and diluted with diethyl ether (15 mL) and stirred for 15 minutes. The precipitated solid was filtered, washed with ether (2.x.10 mL) and dried under vacuum to afford Int-3 (1.2 g, 63percent) as brown solid. Mass (m/z): 260 [M++1]. 1H NMR (200 MHz, CDCl3): δ 9.43 (d, J=2.2 Hz, 1H), 7.8 (d, J=12.4 Hz, 1H), 7.44 (d, J=9.8 Hz, 1H), 7.09 (dd, J=2.2, 9.6 Hz, 1H), 5.58 (d, J=12 Hz, 1H), 3.86 (s, 3H), 3.06 (brs, 6H), 2.75 (s, 3H). To a solution of Int-3 (1.6 g, 6.17 mmol) in DMF (25 mL) was added Int-3B (2.38 g, 12.3 mmol) followed by K2CO3 (2.13 g, 15.4 mmol) at room temperature under inert atmosphere and the reaction mixture was stirred at 100° C. for 16 hours. The reaction mixture was cooled to room temperature, poured into ice water (70 mL) and stirred for 15 minutes. The precipitated solid was filtered, washed with water (2.x.10 mL) and dried under vacuum to afford Int-4 (1.2 g, 50percent) as brown solid. Mass (m/z): 390 [M++1]. 1H NMR (200 MHz, dmso-d6): δ 10.13 (s, 1H), 9.17 (s, 1H), 8.59 (d, J=5.6 Hz, 1H), 8.-6.90 (m, 4H), 7.55 (d, J=10 Hz, 1H), 7.25-7.14 (m, 2H), 3.8 (s, 3H), 3.66 (s, 3H), 2.6 (s, 3H). A mixture of Int-4 (0.8 g, 2.05 mmol) and 4 N HCl (30 mL) was stirred at reflux temperature for 4 hours. The reaction mixture was cooled to room temperature and pH adjusted to about 5 using NaHCO3 and stirred for 20 minutes. The precipitated solid was filtered, washed with water (2.x.10 mL) and dried under vacuum to afford Int-5 (0.7 g, 90.9percent yield) as brown color solid. Mass (m/z): 376 [M++1]. 1H NMR (200 MHz, dmso-d6): δ 10.29 (s, 1H), 9.18 (d, J=1.8 Hz, 1H), 8.72 (d, J=5.2 Hz, 1H), 8.-7.78 (m, 6H), 7.64 (dd, J=2.2, 10 Hz, 1H), 3.71 (s, 3H), 2.69 (s, 3H). To a stirred solution of Int-5 (0.7 g, 1.86 mmol) in DMF (10 mL) were added HOBt (0.25 g, 1.86 mmol), EDCI (0.71 g, 3.7 mmol), N-ethyldiisopropylamine (0.7 mL, 5.58 mmol) at 0° C. After being stirred for 10 minutes, and then added o-phenylenediamine (0.2 g, 1.86 mmol) to the reaction mixture at 0° C. The reaction mixture was warmed to room temperature and stirring was continued for 16 hours. The reaction mixture was poured into ice cold water (50 mL) and stirred for 10 minutes. The precipitated solid was filtered, washed with water (3.x.10 mL) and dried under vacuum. The crude material was purified over silica gel column chromatography eluting with 4percent MeOH/DCM to afford the title compound (0.27 g, 31.1percent yield) as off white solid. Mass (m/z): 465.2 [M++1]. 1H NMR (200 MHz, dmso-d6): δ 10.02 (s, 1H), 9.53 (s, 1H), 9.18 (s, 1H), 8.59 (d, J=5.6 Hz, 1H), 7.86-7.98 (m, 4H), 7.60 (d, J=9.6 Hz, 1H), 7.13-7.25 (m, 3H), 6.85-7.0 (m, 1H), 6.75 (d, J=8.0 Hz, 1H), 6.45-6.61 (m, 1H), 4.86 (brs, 2H), 3.69 (s, 3H), 2.60 (s, 3H). 13C NMR (125 MHz, dmso-d6): δ 164.69, 159.26, 158.17, 156.83, 148.74, 146.45, 143.33, 143.03, 142.42, 128.49, 127.05, 126.55, 126.21, 123.65, 120.66, 118.59, 118.10, 116.37, 116.29, 116.15, 110.27, 110.15, 55.90, 16.36.
17% at 140℃; for 0.5 h; Microwave irradiation (75W) in a sealed tube Method b:; 2-Amino-4-bromopyridine (0.10 g; 0.58 mmol), sodium methoxide (0.16 g; 2.9 mmol) and copper powder nanosized activated (0.11 g; 1.74 mmol) were introduced in a microwave glass tube with 1.5 mL of anhydrous DMF and sealed. The tube was introduced in the microwave cavity and heated for 30 min at 140°C (140C30M75W300Psi). Although DMF is a high boiling solvent, high pressure was observed, probably caused by the partial methanolysis of the DMF resulting in low boiling products such as methyl formate and dimethylamine. The mixture was diluted with 10 mL of 2 M NH4Cl solution and extracted 3 times with AcOEt. The organic phase was washed 2 times with 2 M NH4Cl solution and 1 time with water to remove the remaining DMF, dried on NaSO4, and filtered. After the solvent was removed, the crude product was purified by FCC (AcOEt) to afford 12 mg (yield 17percent) of the title compound as brown oil. 1H NMR (270 MHz; CDCl3), δ 7.74 (1 H, d, 3JHH = 3.0 Hz), 7.06 ( IH, dd, 3JHH = 9.0 Hz, 4JHH = 3.0 Hz), 6.45 (1 H, d, 3JHH = 9.0 Hz), 3.95 (2H, bs, NH2), 3.74 (3H, s, OCH3); m/z (EI-MS): 124 (M+), 109 ([M-CH3]+).; Substitution of halide by OCH3 and SEt group is more challenging. The first attempts to prepare P5 by a nucleophilic aromatic displacement of the bromide with a methoxy group catalyzed by Cu powder in a conventional way11 or with microwave heating or an ultrasound bath were frustrated by the apparent unreactivity of the substrate.; In order to decrease the reaction time, the transformation in eq 3 was carried out with microwave irradiation according to Table 3.
Reference: [1] Heterocycles, 2002, vol. 57, # 1, p. 55 - 71
[2] Journal of Medicinal Chemistry, 2007, vol. 50, # 19, p. 4746 - 4758
[3] Patent: WO2007/124345, 2007, A2, . Location in patent: Page/Page column 10; 25
[4] Patent: US2010/29638, 2010, A1, . Location in patent: Page/Page column 96
[5] Patent: WO2007/124345, 2007, A2, . Location in patent: Page/Page column 11; 24-25
[6] Patent: WO2003/76442, 2003, A1, . Location in patent: Page/Page column 83
[7] Patent: WO2007/124345, 2007, A2, . Location in patent: Page/Page column 25
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  • [ 98-86-2 ]
  • [ 4044-98-8 ]
YieldReaction ConditionsOperation in experiment
60% With iodine In cyclohexane at 60℃; for 0.25 h; Green chemistry General procedure: Initially, 2-amino pyridine (0.25 mmol), substituted acetophenones (0.25 mmol), iodine(20 molpercent, 13 mg), and cyclohexane (2 mL) were taken in 25-mL round-bottomed flaskand stirred at 60 °C. The stirring was continued for 15 min under this condition. Later,the reaction mixture diluted with 30 mL of water and collected the organic layer with ethylacetate. The organic layer was dried over Na2SO4 and concentrated under reduced pressure.The crude product was purified through column chromatography using petroleumether and ethyl acetate as an eluant.
Reference: [1] Journal of Organic Chemistry, 2013, vol. 78, # 24, p. 12494 - 12504
[2] Advanced Synthesis and Catalysis, 2013, vol. 355, # 9, p. 1741 - 1747
[3] Synthetic Communications, 2018, vol. 48, # 9, p. 1076 - 1084
[4] Advanced Synthesis and Catalysis, 2013, vol. 355, # 11-12, p. 2217 - 2221
[5] European Journal of Organic Chemistry, 2015, vol. 2015, # 29, p. 6526 - 6533
[6] Patent: CN107629050, 2018, A, . Location in patent: Paragraph 0200; 0202
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  • [ 70-11-1 ]
  • [ 4044-98-8 ]
YieldReaction ConditionsOperation in experiment
81% With sodium hydrogencarbonate In ethanol for 6 h; Heating / reflux Dissolving 5.8 g (29 mmol) of phenacyl bromide and 5.0 g (29 mmol) of 2-amino-5-bromopyridine into 50 milliliter of ethanol, adding 3.6 g of sodium hydrogen carbonate, the resultant suspension was refluxed under heating for 6 hours. After completion of the reaction, separation with filtration was carried out and resultant crystals were washed with water and ethanol, thereby obtaining 6.4 g of 6-bromo-2-phenyl-imidazo [1,2-a] pyridine (yield: 81 percent).
50% at 80℃; A solution of 5-bromopyridin-2-amine (1.0 g, 5.78 mmol), 2-bromoacetophenone (1.4 g, 7.03 mmol) in MeOH (20 mL) was heated at 80 °C overnight. The reaction mixture was concentrated in vacuo. The residue was suspended with water, and extracted with EtO Ac. The organic layer was washed with brine, dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by column chromatography (PE : EtO Ac = 5 : 1 to 2 : 1) to give product of 6-bromo-2-phenylimidazo[l,2-a]pyridine (800 mg, yield: 50percent). 1H- MR (CDC13, 400 MHz) δ 8.27 (d, J= 0.8 Hz, 1H), 7.93-7.95 (m, 2H), 7.84 (s, 1H), 7.53 (d, J= 9.6 Hz, 1H), 7.42-7.47 (m, 2H), 7.33-7.37 (m, 1H), 7.22-7.25 (m, 1H). MS (M+H)+: 273 / 275.
34% at 25℃; General procedure: To a solution of 2-aminopyridine (1 equiv.) in acetone was added the appropriate α-bromoketone (1 equiv.). The solution was stirred at 25 °C with reaction times ranging from 2 to 6 hours. After completion of the reaction (monitored by LC-MS), the formed precipitate was filtered off and washed with acetone (15 mL). The solid was neutralized with a saturated NaHCO3 or ammonia solution. The aqueous phase was extracted with DCM (3 x 20 mL). The combined organic layers were dried on Na2SO4, filtered and concentrated) under vacuum to give the pure imidazo[1,2-a]pyridine.
8.8 g With sodium hydrogencarbonate In ethanol at 20 - 80℃; for 6 h; To a 250 mL round bottom flask was added E1 (8.70 g, 50.29 mmol),A2 (10.01 g, 50.29 mmol) and sodium hydrogen carbonate (NaHCO3)(5.07 g, 60.34 mmol) was dissolved in ethanol (200 mL) After stirring at room temperature for 4 hours, the mixture was stirred in a bath at 80 ° C for 2 hours. After completion of the reaction, the ethanol was removed, and the mixture was extracted with dichloromethane and water and then distilled under reduced pressure. Ethyl acetate and n-hexane column.Then, the precipitate was prepared by using dichloromethane and petroleum ether,Filtration gave Compound E2 (8.80 g, 32.22 mmol).

Reference: [1] Patent: EP1582516, 2005, A1, . Location in patent: Page/Page column 86
[2] European Journal of Medicinal Chemistry, 2011, vol. 46, # 9, p. 4252 - 4257
[3] Patent: WO2013/34048, 2013, A1, . Location in patent: Page/Page column 72
[4] European Journal of Organic Chemistry, 2014, vol. 2014, # 21, p. 4643 - 4650
[5] Tetrahedron Letters, 2017, vol. 58, # 28, p. 2771 - 2773
[6] Journal of Organic Chemistry, 2007, vol. 72, # 20, p. 7650 - 7655
[7] Patent: US2009/253735, 2009, A1, . Location in patent: Page/Page column 5
[8] Tetrahedron, 2011, vol. 67, # 37, p. 7128 - 7138
[9] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 11, p. 3368 - 3372
[10] Green Chemistry, 2016, vol. 18, # 6, p. 1455 - 1458
[11] Synthetic Communications, 2016, vol. 46, # 21, p. 1741 - 1746
[12] Advanced Synthesis and Catalysis, 2017, vol. 359, # 13, p. 2215 - 2221
[13] Patent: KR2018/61825, 2018, A, . Location in patent: Paragraph 0194-0197
[14] European Journal of Organic Chemistry, 2018, vol. 2018, # 26, p. 3432 - 3436
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Reference: [1] Chemical Communications (Cambridge, United Kingdom), 2012, vol. 48, # 90, p. 11073 - 11075,3
[2] Chemical Communications, 2012, vol. 48, # 90, p. 11073 - 11075
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Reference: [1] Organic and Biomolecular Chemistry, 2012, vol. 10, # 5, p. 1093 - 1101
[2] Chinese Chemical Letters, 2015, vol. 26, # 7, p. 881 - 884
[3] Synthetic Communications, 2017, vol. 47, # 4, p. 285 - 290
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  • [ 4545-21-5 ]
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Reference: [1] Catalysis Communications, 2017, vol. 90, p. 43 - 46
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  • [ 102-96-5 ]
  • [ 4044-98-8 ]
Reference: [1] Advanced Synthesis and Catalysis, 2013, vol. 355, # 6, p. 1065 - 1070
  • 80
  • [ 107-20-0 ]
  • [ 1072-97-5 ]
  • [ 6188-23-4 ]
YieldReaction ConditionsOperation in experiment
100%
Stage #1: for 3 h; Reflux
Stage #2: With sodium hydrogencarbonate In water
(1)
Preparation of 6-bromoimidazo[1,2-a]pyridine (4)
2.00 g of 2-amino-5-bromopyridine (3) is dissolved in ethanol (35 mL), and chloroacetaldehyde in water (2.52 mL, 6.1 mol/L) was added and the reaction mixture was heated at reflux for 3 hours.
The reaction mixture was concentrated, and saturated aqueous NaHCO3 was added to the residue, and it is extracted with ethyl acetate.
After conventional workup afford 2.30 g of the titled compound as a brown powder (yield: 100percent).
LCMS (ESI) m/z (M+H)+: 368.93
100% at 80℃; for 15 h; To a solution of 5-bromopyridin-2-amine (10.0 g, 57.7 mmol) in EtOH/H2O (100 mL/20 mL) was added 2-chloroacetaldehyde (10.5 g, 86.7 mmol) slowly. The mixture was heated to 80° C. and stirred further for 15 hours, then cooled to rt and concentrated in vacuo. The saturated aqueous NaHCO3 solution (200 mL) was added to the residue. The resulted mixture was extracted with DCM (200 mL*3). The combined organic phases were concentrated in vacuo to give the title compound as a brown solid (11.3 g, 100percent). MS (ESI, pos. ion) m/z: 197.1 [M+H]+.
98% for 6 h; Reflux The scheme above describes the synthesis of a compound of the invention. A substituted pyridine such as compound 1-1 is reacted with 2-chloroacetaldehyde, resulting in the halogenated imidazopyridine compound 1-2.
98% for 6 h; Reflux j0554] The scheme above describes the synthesis of a compound of the invention. A substituted pyridine such as compound 1-1 is reacted with 2-chloroacetaldehyde, resulting in the halogenated imidazopyridine compound 1-2. Compound 1-2 is coupled to a benzoxazolyl boronic acid ester in Suzuki conditions to produce compound 1-4. Further derivatization of compound 1-4 using, for example, NBS, DMF results in halogenation of the imidazopyridine moiety, which is then further reacted in an additional Suzuki coupling using pyridine boronic acid to result in compound 1-6.
83% With sodium hydrogencarbonate In water; isopropyl alcohol at 80℃; for 72 h; 2-Amino-5-bromopyridine (Aldrich, 18.8 g, 108.7 mmol), chloroacetaldehyde (34 mL of 50percent solution in water, 217.4 mmol), NaHCO3 (20.1 g, 239.1 mmol) and i-PrOH (150 mL) were combined in a sealed tube, purged with N2, sealed and heated to 80 0C. After 72 h, the mixture was cooled to rt and concentrated under reduced pressure. The residue was diluted with EtOAc, washed with water and brine and the combined aqueous layers were back-extracted with EtOAc. The combined extracts were dried over Na2SO4 and decolorizing carbon, filtered through a pad of Celite.(R). and concentrated under reduced pressure. The residue was purified by silica gel chromatography (75 to 85percent EtOAc/hexanes to give 17.85 g (83percent) of the title compound as a tan solid. MS(ES)+ m/e 198.7 [M+H]+.
83% for 14 h; Heating / reflux Reflux a solution OF 2-AMINO-5-BROMO-PYRIDINE (Maybridge; 1.0 g, 5.78 mmol), 50percent aqueous chloroacetaldehyde (2 mL, 12.7 mmol) in acetonitrile (100 mL) for 14 h. Dilute the reaction with saturated aqueous sodium bicarbonate and extract into ethyl acetate. Flash chromatography using appropriate ethyl acetate/hexane mixtures gives 0.95 g (83percent) of the subtitled compound as a tan solid. MS (electrospray, m/z) 196.7, 198.7 (M+1). 1H NMR (400 MHz, DMSO-d6) 8 8.9 (d, J= 1. 5 Hz, 1H), 7.90 (s, 1H), 7.58 (d, J = 1.5 Hz, 1H), 7.53 (d, J = 9. 2 HZ, 1H), 7.29 (dd, J = 9. 2, 2 HZ, 1H).

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[8] Journal of Organic Chemistry, 2007, vol. 72, # 20, p. 7650 - 7655
[9] Patent: WO2008/82487, 2008, A2, . Location in patent: Page/Page column 104
[10] Patent: WO2010/108074, 2010, A2, . Location in patent: Page/Page column 53
[11] Tetrahedron, 2011, vol. 67, # 37, p. 7128 - 7138
[12] Patent: WO2014/151147, 2014, A1, . Location in patent: Paragraph 00641
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[16] Patent: WO2009/140128, 2009, A2, . Location in patent: Page/Page column 154
  • 81
  • [ 1072-97-5 ]
  • [ 97-97-2 ]
  • [ 6188-23-4 ]
YieldReaction ConditionsOperation in experiment
64.28%
Stage #1: With hydrogenchloride; sodium acetate In ethanol; water for 2.5 h; Reflux
Stage #2: With sodium hydrogencarbonate In water
To a stirred solution of 5-bromo-pyridin-2-amine (5 g, 28.9 mmol) and sodium acetate (4.0 g, 48.76 mmol) in 100 mL of 60 percent ethanol in water, was added a refluxed solution of sodium acetate (2.0 g, 24.38 mmol) followed by 2-chloro-1 ,1 -dimethoxyethane (6.66 g, 53.5 mmol) in concentrated hydrochloric acid (1 .0 mL) in water (6 mL) and the reaction mass was refluxed for 2.5 h. The solvent was removed, residue obtained was diluted with cold water and pH adjusted to neutral (~7) with saturated sodium bicarbonate solution. The reaction mixture was extracted with ethyl acetate (2x100 mL), washed with water (2x100 mL) and brine (2x100 mL) and dried over anhydrous sodium sulphate. The crude material obtained was purified by trituration using 2 percent ethyl acetate in petroleum ether. Yield: 3.6 g (64.28 percent); 1H NMR (DMSO-d6, 300 MHz): δ 7.33 (dd, 1 H, J=1 .8, 9.6 Hz, Ar), 7.55 (d, 1 H, J=9.6 Hz, Ar), 7.60 (s, 1 H, Ar), 7.92 (s, 1 H, Ar), 8.91 (s, 1 H, Ar); MS (ES+): m/e 198 (M+1 ).
Reference: [1] Patent: WO2014/80241, 2014, A1, . Location in patent: Page/Page column 33
[2] Patent: US4105767, 1978, A,
[3] Patent: US4177274, 1979, A,
[4] Patent: US4237300, 1980, A,
[5] Patent: US4096264, 1978, A,
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  • [ 621-62-5 ]
  • [ 6188-23-4 ]
Reference: [1] Patent: WO2015/188369, 2015, A1, . Location in patent: Page/Page column 88
  • 83
  • [ 1072-97-5 ]
  • [ 2032-35-1 ]
  • [ 6188-23-4 ]
Reference: [1] Journal of Medicinal Chemistry, 2015, vol. 58, # 21, p. 8713 - 8722
[2] Chemical and Pharmaceutical Bulletin, 1991, vol. 39, # 6, p. 1556 - 1567
[3] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 9, p. 2245 - 2248
  • 84
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Reference: [1] Journal of Medicinal Chemistry, 2006, vol. 49, # 12, p. 3614 - 3627
[2] Patent: US2011/98471, 2011, A1,
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  • [ 38696-21-8 ]
Reference: [1] Journal of Organic Chemistry, 2012, vol. 77, # 16, p. 6908 - 6916
  • 86
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  • [ 31970-30-6 ]
Reference: [1] Applied Organometallic Chemistry, 2013, vol. 27, # 4, p. 232 - 238
[2] Journal of Medicinal Chemistry, 2014, vol. 57, # 15, p. 6403 - 6418
  • 87
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  • [ 23536-76-7 ]
Reference: [1] Chemistry of Heterocyclic Compounds, 2002, vol. 38, # 7, p. 836 - 839
[2] Patent: TW2016/2107, 2016, A,
[3] ACS Medicinal Chemistry Letters, 2018, vol. 9, # 3, p. 256 - 261
  • 88
  • [ 1072-97-5 ]
  • [ 64064-71-7 ]
Reference: [1] Patent: US4096264, 1978, A,
  • 89
  • [ 1072-97-5 ]
  • [ 39590-27-7 ]
  • [ 6160-65-2 ]
  • [ 613-69-4 ]
Reference: [1] Patent: US5593993, 1997, A,
  • 90
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  • [ 63785-87-5 ]
Reference: [1] Journal of Organic Chemistry USSR (English Translation), 1981, vol. 17, # 2, p. 353 - 357[2] Zhurnal Organicheskoi Khimii, 1981, vol. 17, # 2, p. 413 - 417
  • 91
  • [ 1072-97-5 ]
  • [ 76053-45-7 ]
Reference: [1] Monatshefte fur Chemie, 2003, vol. 134, # 4, p. 573 - 583
  • 92
  • [ 1072-97-5 ]
  • [ 136117-71-0 ]
Reference: [1] Chemical and Pharmaceutical Bulletin, 1991, vol. 39, # 6, p. 1556 - 1567
[2] Patent: WO2017/216292, 2017, A1,
  • 93
  • [ 1072-97-5 ]
  • [ 106730-54-5 ]
Reference: [1] Chemical and Pharmaceutical Bulletin, 1991, vol. 39, # 6, p. 1556 - 1567
  • 94
  • [ 1072-97-5 ]
  • [ 2032-35-1 ]
  • [ 69214-09-1 ]
YieldReaction ConditionsOperation in experiment
59%
Stage #1: With hydrogenchloride In 1,4-dioxane; water for 0.5 h; Heating / reflux
Stage #2: With sodium hydrogencarbonate In 1,4-dioxane; water for 24 h; Heating / reflux
Method 32
5-Bromoimidazo[1,2a]pyridine
A solution of bromoacetaldehyde diethylacetyl (50ml, 0.332mol) in dioxane (143ml), water (85ml) and conc. hydrochloric acid (5ml) was heated at reflux for 30 minutes and the mixture allowed to cool.
Sodium hydrogen carbonate (53g) was added followed by a solution of 5-bromo-2-aminopyridine (30g, 0.174mol) in dioxane (230ml) and water (85ml) and the mixture was heated at reflux for 24 hours.
The mixture was allowed to cool, poured into water and acidified with 2M hydrochloric acid.
The mixture was washed with ethyl acetate and the aqueous layer was basified with 2M aqueous sodium hydroxide solution.
The aqueous mixture was extracted with ethyl acetate.
The extracts were combined, dried and the volatiles removed by evaporation.
The residue was purified by chromatography eluding with hexane/ethyl acetate (50:50) in creasing in polarity to (25:50) to give the title compound 20g (59percent). NMR: 7.30 (dd, 1H), 7.54 (d, 1H), 7.59 (s, 1H), 7.90 (s, 1H), 8.89 (s, 1H); m/z: 197 [MH]+.
Reference: [1] Patent: EP1214318, 2003, B1, . Location in patent: Page/Page column 38
  • 95
  • [ 1072-97-5 ]
  • [ 96166-00-6 ]
Reference: [1] Patent: JP2017/48131, 2017, A,
  • 96
  • [ 1072-97-5 ]
  • [ 79-10-7 ]
  • [ 167837-43-6 ]
YieldReaction ConditionsOperation in experiment
62% With sodium carbonate In water a)
(E)-3-(6-Aminopyridin-3-yl)acrylic acid
Acrylic acid (23 mL, 0.33 mole) was added carefully to a solution of 2-amino-5-bromopyridine (25.92 g, 0.15 mole) and Na2CO3 (55.64 g, 0.53 mole) in H2O (600 mL). PdCl2 (0.53 g, 0.003 mole) was then added, and the mixture was heated at reflux.
After 24 hr, the reaction was cooled to RT and filtered, and the filtrate was adjusted to pH 6 with aqueous HCl. Additional H2O (0.5 L) was added to improve mixing, and the mixture was stirred for 1 hr.
The pH was readjusted to 6, then the solid was collected by suction filtration.
The filter pad was washed sequentially with H2O (2 x 0.5 L), cold absolute EtOH (100 mL), and Et2O (2 x 250 mL).
Drying in high vacuum at elevated temperature gave the title compound (15.38 g, 62percent) as a tan solid: 1H NMR (300 MHz, DMSO-d6) δ 8.11 (d, J = 2.0 Hz, 1 H), 7.75 (dd, J = 8.7, 2.0 Hz, 1 H), 7.43 (d, J = 15.8 Hz, 1 H), 6.53 (s, 2 H), 6.45 (d, J = 8.7 Hz, 1 H), 6.22 (d, J = 15.8 Hz, 1 H); MS (ES) m/e 165 (M + H)+.
Reference: [1] Journal of Medicinal Chemistry, 2002, vol. 45, # 15, p. 3246 - 3256
[2] Patent: EP1226138, 2004, B1,
[3] RSC Advances, 2018, vol. 8, # 42, p. 23698 - 23710
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  • [ 167837-43-6 ]
Reference: [1] Journal of Medicinal Chemistry, 2002, vol. 45, # 15, p. 3246 - 3256
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Reference: [1] Patent: WO2012/10538, 2012, A2,
[2] Patent: WO2012/10538, 2012, A2,
[3] Patent: US2012/22258, 2012, A1,
[4] Angewandte Chemie - International Edition, 2013, vol. 52, # 38, p. 10093 - 10096[5] Angew. Chem., 2013, vol. 52, # 38, p. 10093 - 10096,4
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  • [ 381233-75-6 ]
Reference: [1] Heterocycles, 2002, vol. 57, # 1, p. 55 - 71
  • 100
  • [ 1072-97-5 ]
  • [ 444120-91-6 ]
Reference: [1] Tetrahedron, 2004, vol. 60, # 22, p. 4861 - 4865
[2] Tetrahedron, 2002, vol. 58, # 14, p. 2885 - 2890
  • 101
  • [ 1072-97-5 ]
  • [ 444120-94-9 ]
Reference: [1] Tetrahedron, 2002, vol. 58, # 14, p. 2885 - 2890
  • 102
  • [ 1072-97-5 ]
  • [ 504413-35-8 ]
Reference: [1] Patent: WO2018/17435, 2018, A1,
[2] Patent: WO2009/133127, 2009, A1,
  • 103
  • [ 1072-97-5 ]
  • [ 129686-16-4 ]
Reference: [1] Organic Letters, 2013, vol. 15, # 13, p. 3460 - 3463
  • 104
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  • [ 227939-01-7 ]
Reference: [1] Journal of Labelled Compounds and Radiopharmaceuticals, 2003, vol. 46, # 11, p. 1055 - 1065
[2] ACS Medicinal Chemistry Letters, 2018, vol. 9, # 7, p. 623 - 628
  • 105
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  • [ 356560-80-0 ]
Reference: [1] Journal of Medicinal Chemistry, 2006, vol. 49, # 12, p. 3614 - 3627
[2] European Journal of Organic Chemistry, 2005, # 17, p. 3761 - 3765
[3] Patent: WO2013/127266, 2013, A1,
[4] Patent: WO2013/127267, 2013, A1,
[5] Patent: WO2013/127268, 2013, A1,
[6] Patent: WO2013/130935, 2013, A1,
[7] Patent: WO2013/130943, 2013, A1,
[8] Patent: WO2008/128953, 2008, A1,
[9] Patent: WO2004/43940, 2004, A1,
[10] Patent: WO2005/116029, 2005, A1,
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  • [ 1072-97-5 ]
  • [ 571189-49-6 ]
Reference: [1] RSC Advances, 2017, vol. 7, # 70, p. 44366 - 44370
  • 107
  • [ 1072-97-5 ]
  • [ 57260-71-6 ]
  • [ 571188-59-5 ]
Reference: [1] RSC Advances, 2017, vol. 7, # 70, p. 44366 - 44370
  • 108
  • [ 1072-97-5 ]
  • [ 571188-59-5 ]
Reference: [1] Patent: CN108558745, 2018, A,
  • 109
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  • [ 82454-61-3 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 4, p. 1586 - 1605
[2] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 4, p. 1586 - 1605
[3] Dalton Transactions, 2006, vol. 6, # 13, p. 1627 - 1635
[4] Letters in Drug Design and Discovery, 2011, vol. 8, # 5, p. 401 - 405
[5] Patent: US2013/85278, 2013, A1,
  • 110
  • [ 1072-97-5 ]
  • [ 73183-34-3 ]
  • [ 827614-64-2 ]
YieldReaction ConditionsOperation in experiment
99% With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium acetate In 1,4-dioxane at 80℃; for 16 h; Inert atmosphere equipped with a mechanical stirring in a 5L three flask, 300g2--amino-5-bromopyridine, 528 g of boronic acid pinacol ester-linked, 3L1,4- dioxane, 42.4gPd (dppf)2Cl2, 593 g of anhydrous potassium acetate, purged with nitrogen three times, heated to about 80 open 16 hours.TLC the reaction was complete, cooled, suction filtered, the filter cake was washed twice with 200mL of dichloromethane, the filtrate was concentrated to dryness, 2L of methanol and stirred overnight at room temperature and 200g active carbon, filtration.Concentrated to dryness to give an oil, and petroleum ether was added 150mL 2L MTBE beating overnight, filtered to give 380g2- aminopyridine-5-boronic acid pinacol ester, 99percent yield.
10% With potassium acetate In N,N-dimethyl-formamide for 0.333333 h; Microwave irradiation A different strategy was designed using 5-pyridyl boronate and subsequently oxidized to P5 in the presence OfNaOCH3. After a first attempt to prepare the boronate P6 in DMSO13 with conventional heating failed, the same coupling was tried with microwave <n="28"/>heating using DME as the solvent.14 This procedure gave the desired boronate in 20 min instead of 20 h, but only in 10percent yield due to problems found in the work-up (eq 5).
1.8 g With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,4-dioxane; water for 4 h; Reflux; Inert atmosphere 10167] 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2 -amine, made in laboratory. The preparation methodwas as follows:10168] 2-amino-5-bromopyridine (5.1 g, 30 mmol), bis(pinacolato)diboron (10.7 g, 45 mmol), potassium carbonate(8.3 g, 60 mmol), and tetrakis(triphenylphosphine)palladium(693 mg, 0.6 mmol) were added to 150 mL dioxane and 2 mLwater. The resulting mixture was reacted under reflux in thenitrogen protection for 4 hours, cooled to room temperature,filtered and concentrated. The crude product was dissolved in300 mL dichioromethane, washed with water, dried overanhydrous sodium sulfate, and concentrated. When only asmall amount of solvent retained, petroleum ether was addedthereto. A yellow solid was separated out and filtered to obtaina product (1.8 g).
Reference: [1] Patent: CN102786543, 2016, B, . Location in patent: Paragraph 0037-0043
[2] Patent: WO2007/124345, 2007, A2, . Location in patent: Page/Page column 25-26
[3] European Journal of Organic Chemistry, 2012, # 3, p. 595 - 603
[4] Patent: US2015/239885, 2015, A1, . Location in patent: Paragraph 0167; 0168
[5] European Journal of Medicinal Chemistry, 2016, vol. 108, p. 154 - 165
[6] European Journal of Medicinal Chemistry, 2018, vol. 157, p. 1031 - 1050
  • 111
  • [ 1072-97-5 ]
  • [ 749849-14-7 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 21, p. 5598 - 5601
[2] Patent: WO2011/50245, 2011, A1,
  • 112
  • [ 1072-97-5 ]
  • [ 2065-75-0 ]
  • [ 30384-96-4 ]
YieldReaction ConditionsOperation in experiment
53% for 2 h; Reflux Step 1: 6-bromoimidazo [1, 2-a] pyridine-3-carbaldehydeBromomalonaldehyde (5230 mg, 34.68 mmol) was added to a solution of 5-bromopyridin-2- amine in acetonitrile (5000 mg, 28.90 mmol). The reaction mixture was refluxed for 2 hours. After completion of the reaction, the reaction mixture was quenched with sodium bicarbonate solution and extracted with EtOAc. The organic layer was washed with brine and dried over sodium sulfate. The organic layer was concentrated in vacuo and the product was purified by column chromatography using EtOAc -petroleumether gradient to obtain the title compound. Yield: 53 percent; H NMR (DMSO-d6; 300 MHz): δ 9.94 (s, 1H), 9.50 (s, 1H), 8.54 (s, 1H), 7.86-7.85 (m, 2H); MS (m/z): 226 (M+l) +.
Reference: [1] Patent: WO2011/55320, 2011, A1, . Location in patent: Page/Page column 44
[2] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 17, p. 5837 - 5844
[3] Journal of Medicinal Chemistry, 2017, vol. 60, # 21, p. 8781 - 8800
[4] Chinese Chemical Letters, 2015, vol. 26, # 1, p. 118 - 120
  • 113
  • [ 1072-97-5 ]
  • [ 381233-96-1 ]
YieldReaction ConditionsOperation in experiment
90%
Stage #1: at 100℃;
Stage #2: With potassium iodide In water for 1.5 h;
Preparation 9-Benzenesulfonyl-3-bromo-5-hvdroxy-9H-dipyridor2,3-b;4\\3,-dlpyrrole-6- carbonitrileStep 1 : 5-Bromo-3-iodo-pyridin-2-ylamineA stirred solution of 5-bromo-pyridin-2-ylamine (50 g, 289 mmol) in 2M sulfuric acid (500 mL) was treated portionwise with potassium iodate (30.8 g, 144 mmol) and the mixture heated to 100 °C. A solution of potassium iodide (26.5 g, 160 mmol) in water (50 mL) was added dropwise over ca. 1 hour. The mixture was allowed to stir for a further 30 minutes then cooled to ambient temperature. The pH of the aqueous phase was adjusted to 8-9 and the mixture extracted with ethyl acetate (x 3). The combined organic layer was washed with aqueous sodium thiosulfate solution, water and brine, dried(Na2S04) and evaporated to afford the title compound as a brown solid (77.4 g, 90percent). NMR (300 MHz, CDC13): 8.06 (d, J = 2.2 Hz, 1H), 7.96 (d, J = 2.2 Hz, 1H), 4.96 (s, 2H).
90% With N-iodo-succinimide; trifluoroacetic acid In N,N-dimethyl-formamide at 50℃; for 3 h; Example 62-amino-5-bromo-3-iodopyridine (11 )2 CHgCN (75percent) 11 a) NIS procedure:To a solution of 2-amino-5-bromopyridine (2) in DMF was added tnfluoroacetic acid (1 .2 equiv). At room temperature, N-iodosuccinimide (1 .1 equiv) was added and the reaction mixture was heated at 50°C for 3 h. HPLC indicated complete conversion. After cooling to room temperature the product was precipitated by adding the reaction mixture to water. After neutralization with sodiumthiosulfate and 1 N NaOH the title compound (11 ) was collected by filtration as a brown solid in 90percent yield.
90%
Stage #1: With N-iodo-succinimide; trifluoroacetic acid In N,N-dimethyl-formamide at 20 - 50℃; for 3 h;
Stage #2: With sodium thiosulfate; sodium hydroxide In water; N,N-dimethyl-formamide
a) NIS Procedure:To a solution of 2-amino-5-bromopyridine (2) in DMF was added trifluoroacetic acid (1.2 equiv). At room temperature, N-iodosuccinimide (1.1 equiv) was added and the reaction mixture was heated at 50° C. for 3 h. HPLC indicated complete conversion. After cooling to room temperature the product was precipitated by adding the reaction mixture to water. After neutralization with sodiumthiosulfate and 1N NaOH the title compound (11) was collected by filtration as a brown solid in 90percent yield.
90% With sulfuric acid; iodine; iodic acid In water; acetic acid at 80℃; for 8 h; 4.5.5
5-Bromo-3-iodopyridin-2-amine (3)
A mixture of 2-amino-5-bromopyridine (45.0 g, 0.260 mol), iodic acid (11.86 g, 0.068 mol), iodine (26.40 g, 0.104 mol), sulfuric acid (4.50 mL), acetic acid (150 mL) and water (30 mL) was heated to 80 °C for 8 h.
After this time, the reaction mixture was concentrated under vacuum and then made basic with an aqueous 12 M sodium hydroxide solution.
The resulting basic solution was extracted with dichloromethane (3 * 200 mL), washed with an aqueous saturated solution of sodium thiosulfate and then brine, dried over magnesium sulfate and the excess organic solvent was removed.
The resulting cream white solid was purified by flash silica chromatography to give 2-amino-5-bromo-3-iodopyridine 3
16
as a white solid (69.94 g, 90percent).
1H NMR (300 MHz, CDCl3) δ 8.05 (s, 1H), 7.95 (s, 1H), 5.03 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 156.75, 148.72, 148.57, 107.58, 77.93.
90% With N-iodo-succinimide; trifluoroacetic acid In N,N-dimethyl-formamide at 50℃; for 19 h; To a solution of 2-amino-5-bromo pyridine in DMF, trifluoro acetic acid (1.1 equiv) wasadded at room temperature, followed by addition of N-Iodo succinimide (1 .1 equiv) and the reaction mixture was heated at 50°C for 180min. After completion of the reaction, reaction mass was cooled to room temperature and the product was precipitated by adding the reaction mixture to water. After neutralization with sodium thiosulfate and iN NaOH the title compound was collected by filtration as a brown solid with 90percent yield.
86%
Stage #1: With sulfuric acid; iodine; acetic acid; periodic acid In water; acetonitrile at 65 - 82℃; Inert atmosphere
Stage #2: With sodium hydroxide In water; acetonitrile at 60 - 70℃;
Example 5; Preparation of 2-amino-5-bromo-3-iodopyridine (IIa); In a 1000 mL double-jacket reactor (under a nitrogen atmosphere) 38.28 g iodine is suspended in 21 g acetic acid and 62 g acetonitrile. To the brown mixture is added at 20 to 40° C. 14.6 g sulfuric acid 96percent. The addition is strongly exothermic. The dropping funnel is rinsed with 20 g water. The resulting mixture is heated with a jacket temperature of 90° C. When the temperature of the mixture is 70° C., the mixture is treated within 3 to 6 minutes with 45.20 g periodic acid (50percent in water). The addition is endothermic. The funnel is rinsed with 10 g water. The solution is then treated at 65 to 75° C. within 5 to 10 minutes with a previously prepared solution of 58.00 g 2-amino-5-bromopyridine in 67 g acetonitrile and 31.5 g acetic acid. The dropping funnel is rinsed with 15 g acetonitrile. The resulting solution is heated to 77 to 82° C. and stirred under slightly reflux conditions for 3 to 4 hours (approx. 90° C. jacket temperature). In-process control (proposed target value: <2.0percent starting material). Upon complete conversion the mixture is immediately cooled down and treated at 60 to 70° C. drop wise with 66 g sodium hydrogen sulfite (38-40percent in water). Immediately after the addition, the mixture is diluted at 60 to 70° C. within 30 to 60 minutes with 360 g water. The mixture is then treated at 60 to 70° C. within 50 to 90 minutes with approximately 202 g sodium hydroxide 28percent to adjust the pH to 7.3 to 7.6. When the desired pH is reached the suspension is stirred at 60 to 70° C. for 30 to 60 minutes. The suspension is cooled to 20 to 25° C. within 2 to 5 hours and then stirred at this temperature for 2 to 5 hours. The crystals are filtered off and washed in two portions with a mixture of 270 g water and 23 g acetonitrile. The wet crystals (approx. 120 g) are dried at 40 to 50° C./<30 mbar until constant weight. Yield: 90.5 g of slightly brownish crystals with an assay of 95.0percent (m/m). This corresponds to a corrected yield of 86percent.
75% With sodium periodate; iodine; trifluoroacetic acid In acetonitrile at 80℃; Example 62-amino-5-bromo-3-iodopyridine (11 ) b) l2/NalO4 procedure:To a solution of 2-amino-5-bromopyridine (2) in acetonitrile was added sodiumpenodate (0.4 equiv) and iodine (0.65 equiv). Tnfluoroacetic acid (0.65 equiv) was added over 15 min and the reaction mixture was heated at 80°C overnight. HPLC indicated 96percent conversion at this point. An aqueous solution of sodium sulfite was added, followed by more water to precipitate the product which was filtered off and washed with water. The title compound (11 ) was isolated as a brown crystalline solid in 75percent yield. MS (Turbo Spray): 298 (M+H+, 100percent)
73.8% With N-iodo-succinimide; trifluoroacetic acid In N,N-dimethyl-formamide at 50℃; for 16 h; To a stirred solution of 5-bromopyridin-2-amine (4.0 g, 23.12 mmol), TFA (2.316 mL, 30.1 mmol) in DMF (100 mL) at 0 °C were added portion wise NIS (6.76 g, 30.1 mmol). The reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was quenched with ice cold water and sodium thiosulphate solution (3 : 1), the product was precipitated by adding the saturated NaHCCb solution (adjust pH-8), stirred for 10 min at 0 °C. The resulting solid compound was collected by filtration to afford 5-bromo-3-iodopyridin-2 -amine (5.1 g, 17.06 mmol, 73.8 percent yield) as a brown solid. MS (E+) m/z: 298.9(M). Retention time: 1.16 min. [K].
70% With sulfuric acid; iodine; acetic acid; periodic acid In water at 75℃; for 7 h; I2, HI04.H20, AcOH, H2S04.H20, 75°C, 7h, 70percent
68% With sulfuric acid; iodine; periodic acid In water; acetic acid for 24 h; Inert atmosphere; Reflux A solution of iodine (2.6 g, 10.8 mmol) in glacial acetic acid (25 mL) wasprepared and was added dropwise to a solution of 2a(3 g, 17.3 mmol) and periodic acid (0.7 g, 5.2 mmol) inglacial acetic acid (10 mL). After addition of concentrated sulfuric acid (0.4mL) and water (2 mL), the reaction mixture was refluxed for 24h. The mixturewas quenched with a saturated solution of Na2S2O3and then alkalinized with a 10M solution of NaOH. The resulted suspension wasfiltered and washed with water to give a light brown solid. This residue waspurified by chromatographyon silica gel with Petroleum ether/EtOAc (2:8) as eluent to afford the 2gas an orange solid (3.8 g, 68percent yield).
46% With iodine In dimethyl sulfoxide at 25 - 100℃; for 16 h; The corresponding starting material was prepared as follows:I2 (8.81 g, 34.7 mmol, 1.2 equiv.) was added to a solution of 5-bromopyridin-2-amine (5.00 g, 28.9 mmol) in DMSO (30 mL), and the resulting mixture was stirred at 100°C for 4h. After standing at 25°C for 12h, the reaction mixture was poured onto a saturated Na2S205 aqueous solution (20 mL), and extracted with EtOAc (3 X 50 mL). The combined organic layers were washed with brine, dried over anhydrous MgS04 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane/EtOAc, EtOAc 15 to 25percent) providing 5-bromo-3-iodopyridin-2-amine (4.00 g, 46 percent) as a pale yellow solid. H1 NMR (300MHz, CDC13): δ 8.07 (s, 1H), 7.98 (s, 1H) and 5.05 (bs, 2H).
40.5% With sodium periodate; iodine In N,N-dimethyl-formamide at 80 - 90℃; Example B-5: Preparation of (2S)-1-(4-(1-isopropyl-3-(3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H- pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ol (B-5) <n="68"/>B-5-1 B-5-2 B-5-3Preparation of 5-bromo-3-iodopyridin-2-amine (B-5-2)B-5-1 B-5-2A mixture of 5-bromopyridin-2-amine (B-5-1) (50 g, 0.29 mol), I2 (59 g, 0.233 mol) and NaIO4 (24.8 g, 0.116 mol) in DMF 600 mL) was stirred at 80-900C overnight. TLC (EtOAc: Petroleum ether = 1 :5) showed that the reaction was complete. The mixture was concentrated under reduced pressure to remove the solvent. The residue was dissolved in EtOAc (500 mL), washed with water (100 mL) and saturated aqueous NaCI (100 mL), dried over Na2SO4 and concentrated to give crude compound B-5-2, which was purified via a silica gel column eluted with EtOAc/Petroleum ether (12:1 ) to afford pure 5-bromo-3- iodopyridin-2-amine (B-5-2) (35 g, 40.5percent) as an orange solid.

Reference: [1] Angewandte Chemie - International Edition, 2013, vol. 52, # 38, p. 10093 - 10096[2] Angew. Chem., 2013, vol. 52, # 38, p. 10093 - 10096,4
[3] Patent: WO2011/73263, 2011, A1, . Location in patent: Page/Page column 78
[4] Patent: WO2012/10538, 2012, A2, . Location in patent: Page/Page column 28
[5] Patent: US2012/22258, 2012, A1, . Location in patent: Page/Page column 13-14
[6] Organic and Biomolecular Chemistry, 2014, vol. 12, # 2, p. 307 - 315
[7] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 15, p. 4943 - 4951
[8] Patent: WO2015/186137, 2015, A1, . Location in patent: Page/Page column 15
[9] Patent: CN104761491, 2018, B, . Location in patent: Paragraph 0017-0027; 0029-0032
[10] Patent: US2011/28511, 2011, A1, . Location in patent: Page/Page column 10-11
[11] Journal of Medicinal Chemistry, 2012, vol. 55, # 23, p. 10584 - 10600
[12] Patent: WO2012/10538, 2012, A2, . Location in patent: Page/Page column 28
[13] Patent: WO2018/5586, 2018, A1, . Location in patent: Page/Page column 154; 155
[14] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 19, p. 5913 - 5917
[15] Patent: WO2012/6680, 2012, A1, . Location in patent: Page/Page column 24
[16] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 1, p. 114 - 120
[17] Patent: WO2011/86531, 2011, A2, . Location in patent: Page/Page column 35-36
[18] Beilstein Journal of Organic Chemistry, 2013, vol. 9, p. 1426 - 1431
[19] Journal of Labelled Compounds and Radiopharmaceuticals, 2016, vol. 59, # 14, p. 680 - 688
[20] Patent: WO2009/16460, 2009, A2, . Location in patent: Page/Page column 66-67
[21] Journal of Medicinal Chemistry, 2012, vol. 55, # 24, p. 11022 - 11030
[22] Patent: WO2008/74997, 2008, A1, . Location in patent: Page/Page column 96-97
[23] Patent: US2008/261921, 2008, A1, . Location in patent: Page/Page column 70
[24] Patent: US2006/30583, 2006, A1, . Location in patent: Page/Page column 74
[25] Journal of Medicinal Chemistry, 2013, vol. 56, # 21, p. 8860 - 8871
[26] Patent: WO2015/114452, 2015, A2, . Location in patent: Paragraph 0246; 0247
[27] Patent: WO2008/124849, 2008, A2, . Location in patent: Page/Page column 90
  • 114
  • [ 1072-97-5 ]
  • [ 381233-96-1 ]
YieldReaction ConditionsOperation in experiment
76% With sodium hydroxide; sulfuric acid; iodine In diethyl ether; water; acetic acid; ethyl acetate Referential Example 1
5-Bromo-3-iodo-1,2-dihydropyridin-2-one
2-Amino-5-bromopyridine (CAS No. 1072-97-5) (300 g) was dissolved in a mixed solvent consisting of 1000 ml of acetic acid and 200 ml of water, 30 ml of concentrated sulfuric acid were gradually dropped thereinto under stirring.
Then, 79.1 g of periodic acid hydrate and 176 g of iodine were added thereto, followed by stirring at 80°C for 4 hours.
To the reaction mixture were added periodic acid hydrate (40g) and iodine (22g), followed by further stirring at 80°C for 2 hours.
After cooling to room temperature, the reaction mixture was poured onto ice(3000ml) and neutralized to pH 7.0 with 5N aqueous sodium hydroxide.
The resulting crystals were collected by filtration, dissolved in a mixed solvent of ethyl acetate/diethyl ether, successively washed with aqueous sodium thiosulfate, water, 1N aqueous sodium hydroxide and brine, and dried over anhydrous magnesium sulfate.
Then, the solvent was evaporated, to give 392g of 2-amino-5-bromo-3-iodopyridine (yield: 76percent).
Reference: [1] Patent: EP1300396, 2003, A1,
  • 115
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  • [ 1004550-24-6 ]
  • [ 372198-69-1 ]
YieldReaction ConditionsOperation in experiment
55% With sulfuric acid In ethanol at 90℃; for 18 h; To a solution of cone. H2SO4 (2.7 mL) in EtOH (140 mL) were added 2- amino-5-bromopyridine (Aldrich, 5.92 g, 34.2 mmol) and ethyl 2-chloro-3- oxopropanoate potassium salt (20.0 g, 106.0 mmol; see Tetrahedron, 56, 7915-7921 <n="43"/>(2000)) in a sealed tube. The reaction vessel was purged with N2, sealed and heated to 90 0C. After 18 h, the resultant slurry was cooled to rt, filtered and concentrated under reduced pressure. The residue was diluted with EtOAc, washed with IN NaOH followed by brine and the combined aqueous layers were back-extracted with 95:5 EtOAc/MeOH. The combined extracts were dried over Na2SO4 and decolorizing carbon, filtered through a pad of Celite.(R). and concentrated under reduced pressure. The residue was recrystallized from 1 : 1 EtOAc/hexanes (100 mL) to give 5.09 g (55percent) of the title compound as an off- white solid. MS(ES)+ m/e 271.2 [M+H]+.
Reference: [1] Patent: WO2008/14219, 2008, A2, . Location in patent: Page/Page column 41-42
  • 116
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  • [ 372198-69-1 ]
YieldReaction ConditionsOperation in experiment
32% With sulfuric acid In ethanol at 0 - 80℃; for 5 h; To a solution of H2S04 (1.81 g, 18.50 mmol, 986 uL, 1.6 eq) and EtOH (25 mL) at 0 °C was added Example 102A (6.76 g, 35.8 mmol, 3.1 eq) and 2-amino-5- bromopyridine (2.00 g, 11.56 mmol, 1 eq). The reaction was stirred at 80 °C for 5 hr. The reaction was cooled to 25 °C. To the mixture was added water and the pH of the solution was adjusted to 7 with saturated NaHC03. The mixture was extracted with ethyl acetate (300 mL*3). The combined organic phase was washed with brine (200 mL*2), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel (0343) chromatography (Petroleum ether: Ethyl acetate=10/l, 3/1). Example 112A (1.00 g, 3.72 mmol, 32 percent yield) was obtained as a white solid. ESI m/z 268.9[M +1]+. (0344) [0175] MR: (CDC13, 400MHz): ppm 9.56 (s, 1H), 8.38 (s, 1H), 8.03 (d, J=8.8 Hz, 1H), 7.6 (dd, J=1.6, 9.6 Hz, 1H), 4.47-4.42 (m, 2H), 1.43(t, J=7.2 Hz, 3H).
Reference: [1] Patent: WO2017/214413, 2017, A1, . Location in patent: Paragraph 0174-0175
[2] Patent: US2013/59832, 2013, A1, . Location in patent: Paragraph 0435; 0436
  • 117
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  • [ 33142-21-1 ]
  • [ 372198-69-1 ]
YieldReaction ConditionsOperation in experiment
21% Reflux To a solution of ethyl formylchloroacetate (prepared according to the procedure described by Plouvier et al. Heterocycles 1991, 32, 693) (2.41 g, 16.0 mmol) in ethanol (60 mL) was added 5-bromopyridin-2-amine (2.77 g, 16.0 mmol), and the mixture was heated to reflux overnight. After cooling, the solvent was removed by rotary evaporation, and the residue was treated with CHCI3 (50 mL) and a saturated solution of aqueous NaHC03. The layers were separated and the aqueous layer was further extracted with CHC13 (2 x 30 mL). The combined organic layer was dried over Na2S04, filtered, and concentrated to dryness. Purification by flash column chromatography (20-35percent ethyl acetate in hexane) gave the title compound (0.9 g, 21percent). 1H-NMR (DMSO-d6, 400 MHz) δ 9.61 (s, 1 H), 8.32 (s, 1 H), 8.00 (d, J = 9.6 Hz, 1 H), 7.74 (d, J = 9.6 Hz, 1 H), 4.48 (q, J = 7.2 Hz, 2 H), 1.45 (t, J = 7.2 Hz, 3 H). LC-MS: single peak at 254 nm, MH+ calcd. for C10H10BrN2O2: 269, obtained: 269.
Reference: [1] Patent: WO2011/50245, 2011, A1, . Location in patent: Page/Page column 104-105
[2] Patent: WO2012/87519, 2012, A1, . Location in patent: Page/Page column 112; 113
[3] Patent: WO2013/71272, 2013, A1, . Location in patent: Paragraph 00298-00320
[4] Patent: WO2014/151147, 2014, A1, . Location in patent: Paragraph 00641
[5] Patent: US2015/30588, 2015, A1, . Location in patent: Page/Page column 67
[6] Patent: US9295673, 2016, B2, . Location in patent: Page/Page column 345
  • 118
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  • [ 372198-69-1 ]
YieldReaction ConditionsOperation in experiment
55% With sulfuric acid In ethanol for 2 h; Heating / reflux Add concentrated sulfuric acid (0.56 g, 5.78 mmol) to a suspension of 2-chloro-3- oxo-propionic acid ethyl ester potassium salt (Tetrahedron 2000, 58 (40), 7915-7921 ; 3.27 g, 17.3 mmol) and 2-amino-5-bromopyridine (1.0 g, 5.78 mmol) in ethanol (100 mL). Reflux for 2 h, cool, and carefully dilute with saturated aqueous sodium bicarbonate. Extract in ethyl acetate, combine organic extracts, and concentrate. Flash chromatography using appropriate ethyl acetate/methanol mixtures gives 0.85 g (55percent) of the subtitled compound as a white solid. MS ES+m/e 269.0, 271.0 (M+1) bromine isotopes NMR (400 MHz, DMSO-d6) B 9.32 (m, 1H), 8.28 (s, 1H), 7.79 (d, J = 10 Hz, 1H), 7.70 (dd, J = 10,2 Hz, 1H), 4.36 (q, J = 7.0 Hz, 2H), 1.33 (t, J = 7.0 Hz, 3H).
Reference: [1] Patent: WO2004/50659, 2004, A1, . Location in patent: Page 41
  • 119
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  • [ 372198-69-1 ]
Reference: [1] Patent: US2013/59846, 2013, A1, . Location in patent: Paragraph 0433; 0434; 0435; 0436; 0437
[2] Patent: WO2013/33116, 2013, A1, . Location in patent: Page/Page column 95; 96; 97
  • 120
  • [ 1072-97-5 ]
  • [ 913287-11-3 ]
  • [ 372198-69-1 ]
YieldReaction ConditionsOperation in experiment
48% for 16 h; Reflux A. To a suspension of 2-chloro-3-oxopropanoate potassium salt (6.3 g, 33 mmol) (prepared according to Ikemoto, T. er a/., Tetrahedron 2000, 56, 7915-7921) and 2-amino-5-bromopyridine (1.93 g, 11.1 mmol) in ethanol (150 mL) was added concentrated sulfuric acid (1.1 g) and the reaction mixture was heated at reflux for 16 h, allowed to cool to ambient temperature and concentrated in vacuo. The residue was partitioned between ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate (100 mL) and the aqueous phase was extracted with ethyl acetate (2 x 50 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with a 0-50percent gradient of ethyl acetate in hexanes to afford ethyl 6-bromoimidazo[1 ,2-a]pyridine-3-carboxylate as a yellow solid in 48percent yield (1.45 g): 1H NMR (300 MHz, CDCI3) δ 9.48-9.42 (m, 1 H), 8.26-8.19 (m, 1H), 7.63- 7.55 (m, 1 H), 7.49-7.40 (m, 1 H), 4.45-^.31 (m, 2H), 1.44-1.31 (m, 3H); MS (ES+) m/z 268.9 (M + 1), 270.9 (M + 1).
Reference: [1] Patent: WO2013/64984, 2013, A1, . Location in patent: Page/Page column 81
  • 121
  • [ 1072-97-5 ]
  • [ 105-39-5 ]
  • [ 109-94-4 ]
  • [ 372198-69-1 ]
Reference: [1] Journal of Medicinal Chemistry, 2011, vol. 54, # 7, p. 2455 - 2466
  • 122
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  • [ 372198-69-1 ]
Reference: [1] Journal of Chemical Sciences, 2018, vol. 130, # 5,
  • 123
  • [ 1072-97-5 ]
  • [ 911115-16-7 ]
Reference: [1] Patent: US2013/85278, 2013, A1,
[2] Patent: US2013/85278, 2013, A1,
  • 124
  • [ 1072-97-5 ]
  • [ 110-13-4 ]
  • [ 228710-82-5 ]
YieldReaction ConditionsOperation in experiment
92% With toluene-4-sulfonic acid In toluene for 14 h; Heating / reflux 5-Bromopyridin-2-yl-amine (13. 8g, 0. 08MOL), acetonylacetone (14. 1 ml, 0. 12mol) and p-toluenesulphonic acid (100MG) were dissolved in toluene (180ML) and REFLUXED under Dean Stark conditions for 14 hours. After cooling, the brown solution was poured into water (200MOI) and extracted with toluene (2 x 200ml). The organic extracts were combined and washed with brine (50MI) then dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give crude product. This was purified by column chromatography on silica eluting with ethyl acetate: pentane (1: 3) to give the title compound as a brown oil (18. 4g, 0. 073MOL, 92percent). 1H NMR (CDC13, 400MHZ) 8 : 2.18 (s, 6H), 5.90 (s, 2H), 7.11 (d, 1 H), 7.92 (d, 1 H), 8.62 (s, 1 H). LRMS: M/Z 253 (M-H+, Br isotope).
92% for 14 h; Heating / reflux; Dean Stark conditions 5-Bromopyridin-2-yl-amine (13.8g, O.Oβmol), acetonylacetone (14.1 ml, 0.12mol) and p-toluenesulphonic acid (100mg) were dissolved in toluene (180ml) and refluxed under Dean Stark conditions for 14 hours. After cooling, the brown solution was poured into water (200ml) and extracted with toluene (2 x 200ml). The organic extracts were combined and washed with brine (50ml) then dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give crude product. This was purified by column chromatography on silica eluting with ethyl acetate: pentane (1 :3) to give the title compound as a brown oil (18.4g, 0.073mol, 92percent). 1H NMR (CDCI3, 400MHz) δ: 2.18 (s, 6H), 5.90 (s, 2H), 7.11 (d, 1 H), 7.92 (d, 1 H), 8.62 (s, 1 H). LRMS: m/z 253 (M-H+, Br isotope).
91.2% With toluene-4-sulfonic acid In tolueneReflux; Dean-Stark 2-Amino-5-bromopyridine (2) (10 mmol, 1.73 g), 2,5-hexanedione (12 mmol, 1.13 g) and p-toluene sulfonic acid (3 mmol, 0.52 g) was dissolved in toluene (30 mL) and heated to reflux in a Dean-Stark apparatus for 8-10 h until compound 2 can not be detected by TLC. After cooling to room temperature, the reaction mixture was washed with a saturated aqueous NaHCO3 solution, water and brine. The organic phase was dried with MgSO4 and concentrated in vacuum. The resulting orange liquid was dried under high vacuum and cooled to orange solid 3 (2.28 g, yield = 91.2 percent), m.p. 67.6-68.9 °C (lit. [9] 69 °C); 1H NMR (400 Hz, CDCl3), δ (ppm): 2.130 (s, 6H, 2*CH3), 5.905 (s, 2H, CH), 7.115-7.132 (d, 1H, pyr-H), 7.922-7.944 (dd, 1H, pyr-H), 8.651-8.656 (d, 1H, pyr-H); 13C NMR (100 MHz, CDCl3), δ (ppm): 13.19, 107.40, 118.91, 123.01, 128.59, 140.51, 150.41, 150.70.
80% With toluene-4-sulfonic acid In n-heptaneHeating / reflux 2-Amino-5-bromopyridine (6.0 Kg, 34.7 mol), 2,5-hexanedione (4.35 Kg, 38.2 mol) and p- toluenesulfonic acid (12 g) were dissolved in heptane (36 L) and refluxed under Dean Stark conditions overnight. The equipment was set for distillation and heptane (18 L) was removed by distillation. The mixture was cooled to 2O0C for 60 minutes. Seed crystals were added and the mixture granulated at 200C for 2 hours and then at 5°C overnight. The product was collected by filtration, washed with heptane (2*6 L) and dried at 45°C under vacuum overnight. Yield = 80percent (7.0 Kg) δH (CDCI3 300MHz) 2.20 (6H, s), 5.95 (2H, s), 7.15 (1H, d), 7.95 (1 H, d), 8.70 (1 H, s) ppm. MS m/z 253 (MH+, Br isotope).
80% With toluene-4-sulfonic acid In n-heptaneHeating / reflux 5-Bromo-2-(2,5-dimethylpyrrol-1-yl)pyridine
2-Amino-5-bromopyridine (6.0 Kg, 34.7 mol), 2,5-hexanedione (4.35 Kg, 38.2 mol) and p-toluenesulfonic acid (12 g) were dissolved in heptane (36 L) and refluxed under Dean Stark conditions overnight.
The equipment was set for distillation and heptane (18 L) was removed by distillation.
The mixture was cooled to 20° C. for 60 minutes.
Seed crystals were added and the mixture granulated at 20° C. for 2 hours and then at 5° C. overnight.
The product was collected by filtration, washed with heptane (2*6 L) and dried at 45° C. under vacuum overnight. Yield=80percent (7.0 Kg) δH (CDCl3 300 MHz) 2.20 (6H, s), 5.95 (2H, s), 7.15 (1H, d), 7.95 (1H, d), 8.70 (1 H, s) ppm. MS m/z 253 (MH+, Br isotope).
80% With acetic acid In cyclohexaneHeating / reflux Example 138
5-Bromo-2-(2,5-dimethyl-pyrrol-1-yl)-pyridine
Hexane-2,5-dione (97 mL, 831 mmol) was added to a solution of 2-amino-5-bromo-pyridine (125 g, 722 mmol) in cyclohexane (625 mL) and acetic acid (20 mL).
The solution was heated to reflux under argon atmosphere with a Dean-Stark trap.
A total of 30 mL of water was collected from the Dean-Stark trap.
The mixture was allowed to cool to room temperature, diluted with water, and extracted with diethyl ether.
The organic phase was washed with 1N hydrochloric acid (4 x), saturated aqueous sodium bicarbonate solution (2x) and saturated aqueous sodium chloride solution (2x).
The organic phase was dried (MgSO4) and concentrated in vacuo to yield a yellow solid.
The product was dissolved in hot hexanes (200 mL).
Charcoal was added and the mixture filtered.
Crystallization proceeded over three hours at 0°C.
The solid was collected by filtration to yield yellow crystals (145 g, 80percent).
Mp = 69°C; 1H NMR (CDCl3, 300MHz) δ 8.66 (d, 9 Hz, 1 H), 7.96 (dd, 9 Hz, 8 Hz, 1 H), 7.15 (d, 8 Hz, 1 H), 5.91 (s, 2 H), 2.14 (s, 6 H); MS (CI) m/z 251 (MH+); Anal. Calcd. for C11H11BrN2: C, 52.61; H, 4.42; N, 11.16; Br, 31.82. Found: C, 52.62; H, 4.56; N, 11.18; Rf = 0.4 (60:40 dichloromethane / hexanes).

Reference: [1] Organic Process Research and Development, 2004, vol. 8, # 4, p. 587 - 592
[2] Patent: WO2004/52372, 2004, A1, . Location in patent: Page 85-86
[3] Patent: WO2008/87512, 2008, A1, . Location in patent: Page/Page column 51-52
[4] Asian Journal of Chemistry, 2016, vol. 28, # 6, p. 1403 - 1404
[5] Patent: WO2006/82511, 2006, A1, . Location in patent: Page/Page column 6; 36-37
[6] Patent: US2006/183740, 2006, A1, . Location in patent: Page/Page column 15
[7] Patent: EP1054881, 2008, B1, . Location in patent: Page/Page column 56
[8] Patent: WO2005/115985, 2005, A1, . Location in patent: Page/Page column 68
[9] Patent: WO2006/44405, 2006, A1, . Location in patent: Page/Page column 89
[10] Patent: WO2004/108675, 2004, A1, . Location in patent: Page 97
[11] Patent: WO2010/22307, 2010, A2, . Location in patent: Page/Page column 16
[12] Patent: WO2004/108676, 2004, A1, . Location in patent: Page 132
  • 125
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  • [ 7440-44-0 ]
  • [ 110-13-4 ]
  • [ 228710-82-5 ]
YieldReaction ConditionsOperation in experiment
80% With acetic acid In cyclohexane; water EXAMPLE 138 STR91 5-Bromo-2-(2,5-dimethyl-pyrrol-1-yl)-pyridine
Hexane-2,5-dione (97 mL, 831 mmol) was added to a solution of 2-amino-5-bromo-pyridine (125 g, 722 mmol) in cyclohexane (625 mL) and acetic acid (20 mL).
The solution was heated to reflux under argon atmosphere with a Dean-Stark trap.
A total of 30 mL of water was collected from the Dean-Stark trap.
The mixture was allowed to cool to room temperature, diluted with water, and extracted with diethyl ether.
The organic phase was washed with 1N hydrochloric acid (4*), saturated aqueous sodium bicarbonate solution (2*) and saturated aqueous sodium chloride solution (2*).
The organic phase was dried (MgSO4) and concentrated in vacuo to yield a yellow solid.
The product was dissolved in hot hexanes (200 mL).
Charcoal was added and the mixture filtered.
Crystallization proceeded over three hours at 0° C.
The solid was collected by filtration to yield yellow crystals (145 g, 80percent). Mp=69° C.; 1 H NMR (CDCl3, 300 MHz) δ 8.66 (d, 9 Hz, 1 H), 7.96 (dd, 9 Hz, 8 Hz, 1 H), 7.15 (d, 8 Hz, 1 H), 5.91 (s, 2 H), 2.14 (s, 6 H); MS (CI) m/z 251 (MH+); Anal. Calcd. for C11 H11 BrN2: C, 52.61; H, 4.42; N, 11.16; Br, 31.82. Found: C, 52.62; H, 4.56; N, 11.18; Rf =0.4 (60:40 dichloromethane/hexanes).
Reference: [1] Patent: US6051586, 2000, A,
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Reference: [1] Journal of Medicinal Chemistry, 2011, vol. 54, # 7, p. 2455 - 2466
[2] Tetrahedron, 2011, vol. 67, # 37, p. 7128 - 7138
[3] Patent: WO2015/188369, 2015, A1,
  • 127
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  • [ 19255-60-8 ]
  • [ 603311-76-8 ]
Reference: [1] Patent: WO2004/50659, 2004, A1, . Location in patent: Page 39
  • 128
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  • [ 603310-75-4 ]
Reference: [1] Patent: US2011/301148, 2011, A1,
[2] Patent: EP3372601, 2018, A1,
  • 129
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  • [ 2032-35-1 ]
  • [ 865156-68-9 ]
YieldReaction ConditionsOperation in experiment
62%
Stage #1: With hydrogen bromide In ethanol at 80℃; for 16 h;
Stage #2: With sodium hydroxide In ethanol; water
A suspension of 2-amino-5-bromopyrimidine (3.0 g, 17.2 mmol), bromoacetaldehyde diethyl acetal (3.2 mL, 20.7 mmol) and 48percent HBr (1.7 mL) in EtOH was heated was heated to 80 0C in a sealed tube for 16 h. After cooling to rt, the reaction was adjusted to pH ~12 with 6N NaOH and the resultant precipitate was collected by filtration, rinsed with water followed by hexanes and dried to a constant weight to give 2.12 g (62percent) of 6-bromoimidazo[l,2-α]pyrimidine as a white solid. MS(ES)+ m/e 199.7 [M+H]+.
Reference: [1] Patent: WO2008/14219, 2008, A2, . Location in patent: Page/Page column 48
  • 130
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  • [ 910543-72-5 ]
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[2] Patent: WO2012/10538, 2012, A2,
[3] Patent: WO2012/10538, 2012, A2,
[4] Patent: WO2012/10538, 2012, A2,
[5] Patent: US2012/22258, 2012, A1,
[6] Patent: US2012/22258, 2012, A1,
[7] Patent: US2012/22258, 2012, A1,
[8] Patent: US2012/22258, 2012, A1,
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  • [ 100-39-0 ]
  • [ 935687-49-3 ]
Reference: [1] Electrochimica Acta, 2010, vol. 55, # 20, p. 5741 - 5745
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  • [ 72754-05-3 ]
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  • [ 947248-52-4 ]
Reference: [1] Patent: WO2018/17435, 2018, A1,
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[2] Journal of Medicinal Chemistry, 2008, vol. 51, # 15, p. 4724 - 4729
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Reference: [1] Patent: WO2011/63908, 2011, A1,
[2] Patent: WO2012/143329, 2012, A1,
[3] Patent: EP2343295, 2011, A1,
[4] Patent: WO2011/64328, 2011, A1,
[5] Patent: EP2343297, 2011, A1,
[6] Patent: WO2012/160029, 2012, A1,
[7] Patent: WO2011/157688, 2011, A1,
[8] Patent: EP2426135, 2012, A1,
[9] ChemMedChem, 2011, vol. 6, # 12, p. 2214 - 2224
[10] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 16, p. 5257 - 5263
[11] Patent: WO2012/130299, 2012, A1,
[12] Patent: WO2013/87579, 2013, A1,
[13] Patent: WO2014/9219, 2014, A1,
[14] Patent: WO2014/20041, 2014, A1,
[15] Patent: WO2014/195276, 2014, A1,
[16] Patent: WO2014/198647, 2014, A2,
[17] Patent: US2015/148542, 2015, A1,
[18] Patent: WO2013/41472, 2013, A1,
[19] Patent: WO2009/133127, 2009, A1,
[20] Bioorganic and Medicinal Chemistry Letters, 2019, vol. 29, # 2, p. 257 - 261
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Reference: [1] Patent: WO2011/73263, 2011, A1,
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  • [ 97674-02-7 ]
  • [ 1189169-37-6 ]
YieldReaction ConditionsOperation in experiment
66% With bis-triphenylphosphine-palladium(II) chloride In toluene at 130℃; for 16 h; Inert atmosphere 5-Bromo-2-iodopyrimidine (10 g, 35.1 mmol) and tributyl(1-ethoxyethenyl)- stannane (15.85 g, 43.88 mmol) were dissolved in anhydrous toluene (500 mL) and purged with nitrogen for 10 minutes. Dichlorobis(triphenylphosphine)palladium(II) (1.23 g, 1.76 mmol) was added and the mixture was stirred at 130°C for 16 h. The reaction mixture was cooled to room temperature and water (29 mL) was added, followed by 6MHC1 (106 mL), then the mixture was stirred vigorously at room temperature for 4 h. The solvent was removed in vacuo and the pH of the mixture was adjusted to pH 7 by the addition of saturated aqueous sodium hydrogencarbonate solution (500 mL). The mixture was extracted with ethyl acetate (3 x 350 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material waspurified on silica gel, eluting with 20-100percent ethyl acetate in heptane, to afford the title compound (2.99 g, 66 percent) as a gold-coloured solid. LCMS m/z 20 1/203.
Reference: [1] Patent: WO2015/86506, 2015, A1, . Location in patent: Page/Page column 125
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Reference: [1] Journal of Medicinal Chemistry, 2010, vol. 53, # 22, p. 7938 - 7957
[2] Patent: US9242996, 2016, B2,
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  • [ 375853-82-0 ]
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Reference: [1] Patent: CN107759563, 2018, A,
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Reference: [1] Journal of Medicinal Chemistry, 2011, vol. 54, # 7, p. 2455 - 2466
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  • [ 2579-22-8 ]
  • [ 1284293-40-8 ]
Reference: [1] Journal of Organic Chemistry, 2014, vol. 79, # 22, p. 11209 - 11214
[2] Advanced Synthesis and Catalysis, 2015, vol. 357, # 1, p. 46 - 50
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Reference: [1] Journal of Chemical Sciences, 2018, vol. 130, # 5,
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  • [ 411235-57-9 ]
  • [ 893738-68-6 ]
YieldReaction ConditionsOperation in experiment
85%
Stage #1: With potassium phosphate In water; toluene for 0.166667 h; Inert atmosphere
Stage #2: Reflux
General procedure: The corresponding bromopyridine (1 mmol) and cyclopropylboronic acid (1.3 mmol)were dissolved in toluene (10 mL) under argon atmosphere. Then, anhydrous K3PO4 (3 mmol)and water (1 mL) were added and reaction mixture stirred for 10 min under an argon flow.Tricyclohexylphosphine (10 molpercent) and Pd(OAc)2 (5 molpercent) were added and reaction mixture stirred at reflux until GC-MS analysis of the reaction mixture indicated full consumption of thestarting material. The reaction mixture was cooled to room temperature, filtered through a pad of Celite, diluted with EtOAc (25 mL), washed with water (3 × 20 mL), dried (Na2SO4) andevaporated to dryness. The crude product was purified by column chromatography on silica gel,eluting with a methanol and CH2Cl2 mixture. 2-Amino-5-cyclopropylpyridine (1a):1 yield 85percent. Rf = 0.26 (MeOH-CH2Cl21:19). 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 2.4 Hz, 1H), 7.11 (dd, J =8.4, 2.4 Hz, 1H), 6.42 (d, J = 8.4 Hz, 1H), 4.19 (s, 2H), 1.80 – 1.73 (m, 1H),0.93 – 0.81 (m, 2H), 0.62 – 0.51 (m, 2H). 13C NMR (100 MHz, CDCl3) δ156.4, 146.2, 135.6, 129.0, 108.4, 12.2, 7.5. GC-MS: tR= 6.724 min (m/z (rel.in.)) 134 (64.41percent).
83% With potassium phosphate tribasic heptahydrate; C45H53ClFeNO2PPd In water; toluene at 100℃; for 6 h; Inert atmosphere General procedure: Potassium phosphate (0.75 mmol) and IIe (1 mol percent) was added to the solution of aryl halides (0.25 mmol) and cyclopropylboronic acid (0.5 mmol) in toluene (2.0 mL) and water (100 μL). The mixture was heated to 100 °C for a proper time under nitrogen atmosphere and cooled to room temperature. Water (10 mL) was added and the mixture was extracted with EtOAc (3.x.15 mL), evaporated and purified by chromatography on silica gel.
71% With potassium phosphate In water; toluene at 80℃; for 16 h; Inert atmosphere a) 5-Cyclopropyl-pyridin-2-ylamine; To a solution of 5-bromo-pyridin-2-ylamine (2 g, 11.55 mmol) and cyclopropyl boronic acid (2.98 g, 34.68 mmol) in toluene (40 mL) and water (2 mL) was added K3PO4 (8.59 g, 40.46 mmol) under an argon atmosphere. A balloon containing argon was affixed, and the reaction flask was purged to ensure a argon atmosphere. To this were added Pd(OAc)2, (259.52 mg, 1.16 mmol) and tricyclohexylphosphene (647.3 mg, 2.3 mmol) and stirred at 80° C. for 16 h. The reaction mixture was cooled to room temperature and water was added. The aqueous phase was extracted with ethyl acetate, the combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue purified by silica gel chromatography using ethyl acetate/hexane as eluent. The title compound was obtained as an off white solid (1.1 g, 71percent).1H NMR (DMSO, 400 MHz): δ(ppm)=7.73 (s, 1H), 7.04-7.02 (dd, J=8.48 2.04 Hz, 1H), 6.34 (d, J=8.48 2.04 Hz, 1H), 5.60 (s, 2H), 1.78-1.66 (m, 1H), 0.822-0.77 (m, 2H), 0.52-0.313 (m, 2H)
71% With potassium phosphate In water; toluene at 80℃; for 16 h; Inert atmosphere To a solution of 5-bromo-pyridin-2-ylamine (2 g, 11.55 mmol) and cyclopropyl boronic acid (2.98 g, 34.68 mmol) in toluene (40 mL) and water (2 mL) was added K3P04 (8.59 g, 40.46 mmol) under an argon atmosphere. A balloon containing argon was affixed, and the reaction flask was purged to ensure a argon atmosphere To this were added Pd(OAc)2, (259.52 mg,1.16 mmol) and tricyclohexylphosphene (647.3mg, 2.3mmol) and stirred at 80°C for 16 h. The reaction mixture was cooled to room temperature and water was added. The aqueous phase was extracted with ethyl acetate, the combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue purified by silica gel chromatography using ethyl acetate/hexane as eluent. The title compound was obtained as an off white solid (l . lg, 71percent). 1H NMR (DMSO, 400 MHz): <5 (ppm) = 7.73 (s, 1H), 7.04-7.02 (dd, J = 8.48 2.04 Hz, 1H), 6.34 (d, J = 8.48 2.04 Hz, 1H), 5.60 (s, 2H), 1.78-1.66 (m, 1H), 0.822-0.77 (m, 2H), 0.52- 0.313 (m,2H)
71% With potassium phosphate In water; toluene at 80℃; for 16 h; Inert atmosphere a) 5-Cyclopropyl-pyridin-2-ylamine; To a solution of 5-bromo-pyridin-2-ylamine (2 g, 11.55 mmol) and cyclopropyl boronic acid (2.98 g, 34.68 mmol) in toluene (40 mL) and water (2 mL) was added K3PO4 (8.59 g, 40.46 mmol) under an argon atmosphere. To this were added Pd(OAc)2 (259.52 mg, 1.16 mmol) and tricyclohexylphosphene (647.3 mg, 2.3 mmol) and stirred at 80° C. for 16 hours. The reaction mixture was cooled to room temperature and water was added. The aqueous phase was extracted with ethyl acetate, the combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue purified by silica gel chromatography using ethyl acetate/hexane as eluent. The title compound was obtained as an off white solid (1.1 g, 71percent).1H NMR (DMSO-D6, 400 MHz): δ (ppm)=7.73 (s, 1H), 7.04-7.02 (dd, J=8.48 2.04 Hz, 1H), 6.34 (d, J=8.48 2.04 Hz, 1H), 5.60 (s, 2H), 1.78-1.66 (m, 1H), 0.82-0.77 (m, 2H), 0.52-0.31 (m, 2H)
71% With potassium phosphate; tricyclohexylphosphine In water; toluene at 80℃; for 16 h; Inert atmosphere To a solution of 5-bromo-pyridin-2-ylamine (2 g, 11.55 mmol) and cyclopropyl boronic acid (2.98 g, 34.68 mmol) in toluene (40 mL) and water (2 mL) was added K3P04 (8.59 g, 40.46 mmol) under an argon atmosphere. To this were added Pd(OAc)2 (259.52 mg, 1.16 mmol) and tricyclohexylphosphene (647.3 mg, 2.3 mmol) and stirred at 80°C for 16 hours. The reaction mixture was cooled to room temperature and water was added. The aqueous phase was extracted with ethyl acetate, the combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue purified by silica gel chromatography using ethyl acetate/hexane as eluent. The title compound was obtained as an off white solid (1.1 g, 71percent).1H NMR (DMSO-D6, 400 MHz): <5 (ppm) = 7.73 (s, 1H), 7.04-7.02 (dd, J = 8.48 2.04 Hz, 1H), 6.34 (d, J = 8.48 2.04 Hz, 1H), 5.60 (s, 2H), 1.78-1.66 (m, 1H), 0.82-0.77 (m, 2H), 0.52- 0.31 (m,2H)
64.47% With potassium phosphate; palladium diacetate; tricyclohexylphosphine In toluene at 110℃; for 3 h; Inert atmosphere To a solution of 5-bromopyridin-2-amine (lg, 5.78mmol, l .Oeq) in mixture of toluene (12mL) and water (lmL) were added cyclopropyl boronic acid (0.65g, 7.51mmol, 1.3eq) and potassium phosphate (2.45g, 11.56mmol, 2.0eq). The reaction mixture was degassed for 10 min under argon atmosphere, and palladium acetate (0.13g, 0.578mmol, O. leq) and Tricyclohexylphosphine (0.324g, 1.15mmol, 0.2eq) were added. Reaction mixture was again degassed for 10 min and stirred at 110°C for 3h. After completion of reaction, reaction mixture was transferred into water and extracted with ethyl acetate. Organic layer was combined, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography and compound was eluted in 20percent ethyl acetate in hexane as eluent to obtain 101.1. (0.5g, 64.47 percent). MS(ES): m/z 135.18 [M+H]+
1.33 g With potassium phosphate; palladium diacetate; tricyclohexylphosphine In water; toluene at 80℃; Inert atmosphere To a mixture of 5-bromopyridin-2-amine (5.0 g) in a mixed solvent of toluene (100 mL) and water (5 mL) were added cyclopropylboronic acid (4.59 g), tricyclohexyl phosphine (1.62 g), palladium(II) acetate (0.649 g) and tripotassium phosphate (21.5 g) at room temperature.
The mixture was stirred overnight at 80° C. under argon atmosphere.
The reaction mixture was allowed to be cooled to room temperature, and the insoluble substance was removed by filtration.
To the filtrate was added ethyl acetate, and the mixture was extracted with ethyl acetate.
The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (1.33 g).
1H NMR (300 MHz, DMSO-d6) δ 0.44-0.55 (2H, m), 0.72-0.86 (2H, m), 1.73 (1H, tt, J=8.4, 5.2 Hz), 5.62 (2H, s), 6.35 (1H, d, J=9.1 Hz), 7.03 (1H, dd, J=8.5, 2.5 Hz), 7.73 (1H, d, J=2.7 Hz).
1.28 g With (bis(tricyclohexyl)phosphine)palladium(II) dichloride; caesium carbonate In 1,4-dioxane for 10 h; Inert atmosphere A mixture of 2-amino-5-bromopyridine (3.00 g), cyclopropylboronic acid (2.23 g), cesium carbonate (16.9 g) and dichlorobis(tricyclohexylphosphine)palladium (1.28 g) in 1,4-dioxane (11.5 mL) was heated under reflux under a nitrogen atmosphere for 10 h
After cooling to room temperature, water was added, and the mixture was extracted twice with ethyl acetate.
The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated, and the obtained residue was purified by silica gel column chromatography (solvent; hexane/ethyl acetate=70/30 - 0/100) to give the title compound (1.28 g).
MS(ESI)m/z; 135[M+H]+

Reference: [1] Tetrahedron Letters, 2017, vol. 58, # 17, p. 1681 - 1683
[2] Tetrahedron, 2012, vol. 68, # 3, p. 900 - 905
[3] Patent: US2011/190269, 2011, A1, . Location in patent: Page/Page column 63
[4] Patent: WO2011/92272, 2011, A1, . Location in patent: Page/Page column 132; 133
[5] Patent: US2011/201605, 2011, A1, . Location in patent: Page/Page column 43
[6] Patent: WO2011/101304, 2011, A2, . Location in patent: Page/Page column 88
[7] Patent: WO2018/71794, 2018, A1, . Location in patent: Paragraph 00567; 00568
[8] Patent: US2015/266872, 2015, A1, . Location in patent: Paragraph 0773; 0774
[9] Patent: EP3372601, 2018, A1, . Location in patent: Paragraph 0586; 0587
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Reference: [1] Tetrahedron Letters, 2017, vol. 58, # 17, p. 1681 - 1683
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Reference: [1] Tetrahedron Letters, 2017, vol. 58, # 17, p. 1681 - 1683
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Reference: [1] Tetrahedron Letters, 2017, vol. 58, # 17, p. 1681 - 1683
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Reference: [1] Tetrahedron Letters, 2017, vol. 58, # 17, p. 1681 - 1683
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Reference: [1] Tetrahedron Letters, 2017, vol. 58, # 17, p. 1681 - 1683
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  • [ 33142-21-1 ]
  • [ 944896-42-8 ]
YieldReaction ConditionsOperation in experiment
83.3%
Stage #1: at 20℃; Inert atmosphere; Reflux; Large scale
Stage #2: With water; sodium hydroxide In ethanol at 35℃; Reflux; Large scale
Example 4 Preparation of compound 8: 1. An ethanol solution of compound 5 (12400 g in 51 L of ethanol) was added to an appropriately sized stainless steel reactor at room temperature under nitrogen atmosphere. 2. Compound 6 (9500 g) was added as a solid in one portion at room temperature. 3. The reaction mixture was heated to reflux (∼78°C) and stirred for 1-2 days. 4. The reaction was monitored by HPLC. 5. Upon completion, the reaction mixture was allowed to cool to room temperature. 6. NaOH solution (9884 g solid pellets dissolved in 38 L of water) was added as a stream over a 30 min period at an internal temperature below 35 °C. 7. The reaction mixture was heated to reflux (∼78°C) for 3 to 4 hours. 8. The reaction was monitored by HPLC. 9. Upon completion, the reaction mixture was cooled to an appropriate temperature to start solvent removal. 10. All ethanol (approximately 5 volumes of ethanol) was removed under vacuum at 40 to 45 °C. 11. The reaction mixture was cooled to room temperature. 12. Water (57 L; 6 vol) was added at room temperature. 13. The aqueous solution was washed with ethyl acetate (2 x 38 L) to remove all organic impurities. 14. The lower aqueous layer was cooled to 0-5 °C and acidified with cone. HCl (∼15 L) until reaching pH 1-2. 15. The reaction mixture was stirred for 1 to 2 hours at 0 to 5 °C. 16. The mixturewas filtered and the cake was washed with water (2 x 38 L) and acetone (2 x 19L) followed by drying for 1-2 hours. 17. The solid collectedwas transferred back into an appropriately sized reactor. 18. Heptane (95 L; 10 vol) was addedto the reactor; the suspension was stirred for 4 to 5 hours at roomtemperature. 19. The solidwas collected by filtration and washed with heptane (2 x 19 L). 20. The solid (15 kg) was suspended in methanol (75 L; 5 vol) at room temperature for 2 hours. 21. The suspension was filtered and the solid collected was washed with methanol (2x 5L). 22. The solid was dried under vacuum at 50°C to constant weight to give compound 8 as an off-white to white solid (10169 g, 83.3 percent yield; HPLC purity 99.2percent;1HNMR (DMSO-d6, 300 MHz) δ 9.4 (s, 1H), 8.3 (s, 1H), 7.85-7.67 (m, 2H)).
Reference: [1] Patent: EP2792360, 2014, A1, . Location in patent: Paragraph 0223-0224
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Reference: [1] Patent: WO2011/50245, 2011, A1,
[2] Patent: US9295673, 2016, B2,
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[2] Patent: WO2013/127267, 2013, A1,
[3] Patent: WO2013/127268, 2013, A1,
[4] Patent: WO2013/130935, 2013, A1,
[5] Patent: WO2013/130943, 2013, A1,
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