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Product Details of [ 5794-88-7 ]

CAS No. :5794-88-7 MDL No. :MFCD00007823
Formula : C7H6BrNO2 Boiling Point : -
Linear Structure Formula :- InChI Key :CUKXRHLWPSBCTI-UHFFFAOYSA-N
M.W : 216.03 Pubchem ID :79858
Synonyms :

Calculated chemistry of [ 5794-88-7 ]

Physicochemical Properties

Num. heavy atoms : 11
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 1
Num. H-bond acceptors : 2.0
Num. H-bond donors : 2.0
Molar Refractivity : 45.51
TPSA : 63.32 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) : -6.46 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.45
Log Po/w (XLOGP3) : 1.63
Log Po/w (WLOGP) : 1.74
Log Po/w (MLOGP) : 0.64
Log Po/w (SILICOS-IT) : 1.18
Consensus Log Po/w : 1.13

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.56

Water Solubility

Log S (ESOL) : -2.54
Solubility : 0.617 mg/ml ; 0.00286 mol/l
Class : Soluble
Log S (Ali) : -2.57
Solubility : 0.578 mg/ml ; 0.00268 mol/l
Class : Soluble
Log S (SILICOS-IT) : -2.27
Solubility : 1.16 mg/ml ; 0.00536 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.22

Safety of [ 5794-88-7 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P301+P312-P302+P352-P304+P340-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 5794-88-7 ]

* 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 [ 5794-88-7 ]
  • Downstream synthetic route of [ 5794-88-7 ]

[ 5794-88-7 ] Synthesis Path-Upstream   1~59

  • 1
  • [ 3473-63-0 ]
  • [ 5794-88-7 ]
  • [ 32084-59-6 ]
YieldReaction ConditionsOperation in experiment
94% at 100℃; for 8 h; In a 100 mL round bottom flask, 2.16 g (10 mmol) of 2-amino-5-bromobenzoic acid was added.Formamidine acetate 1.04g (10mmol), isopropanol 30ml,Stir at 100 ° C for 8 hours, cool,Precipitated white solid was filtered off with suction, and dried to give 6-bromo -4 (3H) - quinazolinone 2.1g, 94percent yield.
Reference: [1] Patent: CN108239067, 2018, A, . Location in patent: Paragraph 0066-0068
[2] Patent: WO2008/89307, 2008, A2, . Location in patent: Page/Page column 44-45
[3] Patent: WO2008/89310, 2008, A2, . Location in patent: Page/Page column 47
  • 2
  • [ 5794-88-7 ]
  • [ 32084-59-6 ]
Reference: [1] Patent: US2005/282814, 2005, A1,
[2] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 3, p. 383 - 391
[3] Chemistry of Heterocyclic Compounds, 2002, vol. 38, # 7, p. 817 - 821
[4] Chemistry of Heterocyclic Compounds, 2002, vol. 38, # 7, p. 817 - 821
  • 3
  • [ 77287-34-4 ]
  • [ 5794-88-7 ]
  • [ 32084-59-6 ]
YieldReaction ConditionsOperation in experiment
81% for 12 h; Reflux In short,2-Amino-5-bromobenzoic acid (A, 50.0 g, 0.233 mmol, 1.0 equiv)Add formamide (50.0 mL, d = 1.133, 56.7 g, 1.26 mmol)The mixture was heated under reflux for 12 hours,The solution was lowered to 70 ° C,Add 100 ml of ethanol.The resulting precipitate was filtered and washed with 50 ml of ethanol,And dried to give 6-bromo-3H-quinazolin-4-one (B, 42.5 g, 0.189 mol)Yield 81percent
Reference: [1] Tetrahedron Letters, 2014, vol. 55, # 43, p. 6007 - 6010
[2] Organic Process Research and Development, 2010, vol. 14, # 3, p. 650 - 656
[3] Heterocyclic Communications, 2001, vol. 7, # 4, p. 337 - 340
[4] Patent: TWI557109, 2016, B, . Location in patent: Page/Page column 48; 83
[5] Tetrahedron Letters, 2002, vol. 43, # 21, p. 3911 - 3913
[6] Tetrahedron, 2003, vol. 59, # 9, p. 1413 - 1419
[7] Molecules, 2006, vol. 11, # 6, p. 383 - 392
[8] Journal of the Indian Chemical Society, 1959, vol. 36, p. 787,789, 790
[9] Journal of Organic Chemistry, 1952, vol. 17, p. 149,153
[10] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 22, p. 6373 - 6377
[11] Patent: WO2008/9077, 2008, A2, . Location in patent: Page/Page column 94
[12] Patent: WO2008/12326, 2008, A1, . Location in patent: Page/Page column 60
[13] Patent: US6339099, 2002, B1, . Location in patent: Page column 43, 44
[14] Monatshefte fur Chemie, 2015, vol. 146, # 10, p. 1723 - 1731
[15] Biochemistry, 2017, vol. 56, # 49, p. 6491 - 6502
  • 4
  • [ 195457-53-5 ]
  • [ 5794-88-7 ]
  • [ 32084-59-6 ]
Reference: [1] Patent: US5866572, 1999, A,
  • 5
  • [ 6313-33-3 ]
  • [ 5794-88-7 ]
  • [ 32084-59-6 ]
Reference: [1] Journal of Medicinal Chemistry, 1999, vol. 42, # 19, p. 3860 - 3873
  • 6
  • [ 20353-93-9 ]
  • [ 5794-88-7 ]
  • [ 32084-59-6 ]
Reference: [1] Journal of Medicinal Chemistry, 1991, vol. 34, # 4, p. 1492 - 1503
  • 7
  • [ 64-18-6 ]
  • [ 5794-88-7 ]
  • [ 32084-59-6 ]
Reference: [1] Journal of the American Chemical Society, 1906, vol. 28, p. 101
  • 8
  • [ 77287-34-4 ]
  • [ 5794-88-7 ]
  • [ 194851-16-6 ]
YieldReaction ConditionsOperation in experiment
41.24% at 150℃; for 1.5 h; Inert atmosphere; Microwave irradiation Around bottom two flask charged with 2-amino-5-bromobenzoicacid 12 (5.00 g, 23.14 mmol) was flushed with nitrogen and suspended in HCONH2 (80 mL, 2.01 mmol), the mixture was stirred at 150 °C for 1.5 h by atmospheric microwave heating. The product was extracted with AcOEt (50 mL x 3), washed with water, and dried over Na2SO4. After filtration and concentration in vacuo, the residue was purified by silica gel flash chromatography (PE/AcOEt = 5:1) affording 13 (1.46 g, 41.24percent) as white solid. mp: 259-261 °C.
Reference: [1] European Journal of Medicinal Chemistry, 2017, vol. 141, p. 506 - 518
  • 9
  • [ 5794-88-7 ]
  • [ 38267-96-8 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 3, p. 383 - 391
[2] Tetrahedron, 2003, vol. 59, # 9, p. 1413 - 1419
[3] Journal of the Indian Chemical Society, 1959, vol. 36, p. 787,789, 790
[4] Patent: WO2014/151147, 2014, A1,
[5] Patent: US2015/30588, 2015, A1,
[6] Patent: US9295673, 2016, B2,
[7] Patent: WO2015/128873, 2015, A1,
[8] European Journal of Medicinal Chemistry, 2016, vol. 118, p. 276 - 289
[9] European Journal of Medicinal Chemistry, 2016, vol. 122, p. 731 - 743
[10] Patent: TWI557109, 2016, B,
[11] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 9, p. 1972 - 1977
[12] Patent: CN106565684, 2017, A,
[13] Letters in Drug Design and Discovery, 2017, vol. 14, # 2, p. 167 - 174
[14] Patent: WO2005/105761, 2005, A1,
  • 10
  • [ 108-24-7 ]
  • [ 5794-88-7 ]
  • [ 5426-59-5 ]
YieldReaction ConditionsOperation in experiment
60%
Stage #1: for 1 h; Heating / reflux
Stage #2: for 4 h; Heating / reflux
Stage #3: for 0.5 h; Heating / reflux
The bromoanthranilic acid was refluxed in liquid ammonia (10 mL/g) for 1 h. The solution was then evaporated to low bulk and the residue mixed with acetic anhydride (2 mL/g) and refluxed 4 h. Water was added, the mixture boiled for 30 min and 20percent sodium hydroxide sol. was then added until a clear solution formed. Ammonium carbonate was added to the hot solution until a precipitate formed. The mixture was held at 4° C. for 16 h before the precipitate was filtered out, washed with water and dried in vacuum (yield 60percent)
Reference: [1] Patent: US2009/69320, 2009, A1, . Location in patent: Page/Page column 76
[2] Journal of the American Chemical Society, 1906, vol. 28, p. 101
  • 11
  • [ 78-39-7 ]
  • [ 5794-88-7 ]
  • [ 5426-59-5 ]
Reference: [1] Journal of Medicinal Chemistry, 2018, vol. 61, # 16, p. 7261 - 7272
  • 12
  • [ 5794-88-7 ]
  • [ 5426-59-5 ]
Reference: [1] Journal of Chemical & Engineering Data, 1981, vol. 26, # 1, p. 103 - 104
[2] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 3, p. 308 - 312
  • 13
  • [ 57-13-6 ]
  • [ 5794-88-7 ]
  • [ 88145-89-5 ]
Reference: [1] Synlett, 2013, vol. 24, # 16, p. 2102 - 2106
[2] Pharmaceutical Chemistry Journal, 1987, vol. 21, # 7, p. 478 - 483[3] Khimiko-Farmatsevticheskii Zhurnal, 1987, vol. 21, # 7, p. 802 - 807
[4] Journal of the American Chemical Society, 1933, vol. 55, p. 4918,4920
[5] Patent: WO2008/12326, 2008, A1, . Location in patent: Page/Page column 63
[6] Chemical and Pharmaceutical Bulletin, 2015, vol. 63, # 2, p. 75 - 80
[7] Antimicrobial Agents and Chemotherapy, 2017, vol. 61, # 6,
  • 14
  • [ 590-28-3 ]
  • [ 5794-88-7 ]
  • [ 88145-89-5 ]
Reference: [1] Chinese Chemical Letters, 2012, vol. 23, # 4, p. 431 - 433
[2] Patent: WO2005/46698, 2005, A1, . Location in patent: Page/Page column 95-105
  • 15
  • [ 917-61-3 ]
  • [ 5794-88-7 ]
  • [ 88145-89-5 ]
Reference: [1] ACS Medicinal Chemistry Letters, 2016, vol. 7, # 9, p. 831 - 834
  • 16
  • [ 5794-88-7 ]
  • [ 88145-89-5 ]
Reference: [1] Chemistry of Heterocyclic Compounds, 2006, vol. 42, # 4, p. 540 - 545
[2] Journal of the Chemical Society, 1923, vol. 123, p. 3187
[3] Chemical and Pharmaceutical Bulletin, 2014, vol. 62, # 8, p. 824 - 829
  • 17
  • [ 32315-10-9 ]
  • [ 5794-88-7 ]
  • [ 4692-98-2 ]
YieldReaction ConditionsOperation in experiment
98% With pyridine In dichloromethane; acetonitrile at 50 - 55℃; for 2 h; a) Preparation of 6-bromo-1H-benzo[d][1,3]oxazine-2,4-dione A solution of 2-amino-5-bromo-benzoic acid (280 g, 1.3 mol) in acetonitrile (1.3 l) was warmed up to 50-55° C. Pyridine (206 g, 2.61 mol) and a solution of triphosgene (128.8 g, 0.43 mol) in dichloromethane (720 ml) were simultaneously added dropwise. After completion of the addition, the mixture was stirred at 50-55° C. for an additional 2 h. The solvent was removed under reduced pressure and water was added. The precipitate was collected by filtration, successively washed with water and chilled dichloromethane, and then dried under vacuum to afford the desired product 6-bromo-1H-benzo[d][1,3]oxazine-2,4-dione (304 g, 98percent). This material was used in the next step without further purification.
96% for 4 h; Reflux To a solution of 25 g (116 mmol) of 2-amino-5-bromobenzoic acid (3a) in 350 mL of THF was added 24.4 g (82 mmol) of bis(trichloromethyl) carbonate was added, and the resulting suspension was stirred at reflux temperature for 4 h. The reaction mixture was poured onto ice, and the precipitate was collected by filtration, washed with methanol and dried to afford 27.1 g (96percent) of 6-bromo-2H-3,1-benzoxazine-2,4(1H)-dione as a white powder. 1H NMR (200 MHz, CDCl3) δ: 7.19 (d, J = 8.4 Hz, 1H), 7.96-8.02 (m, 1H), 8.09 (d, J = 2.6 Hz, 1H).
94.6% at 80℃; for 4 h; Inert atmosphere The 2-amino-5-bromobenzoic acid (10.00g, 46 . 29mmol) dissolved in tetrahydrofuran (100 ml) and triphosgene was also added (9.80g, 33 . 00mmol) under nitrogen atmosphere which is heated to 80 °C stirring 4 hours. Cooling to room temperature, the reaction solution the ice water (120 ml) in, filtering, the filter cake are sequentially water, ether washing, drying, get white solid (10.6g, 94.6percent).
93% With pyridine In dichloromethane; acetonitrile at 55℃; for 3 h; b)
Preparation of 6-bromo-1H-benzo[d][1,3]oxazine-2,4-dione
To a suspension of 2-amino-5-bromo-benzoic acid (270 g, 1.25 mol) in acetonitrile (1250 mL) was added a solution of triphosgene (123.8 g, 416.7 mmol) in dichloromethane (DCM) (500 mL) and pyridine (197.5 g, 2.5 mol) simultaneously at 55° C.
The resultant mixture was stirred for another 3 hours then cooled to room temperature.
The precipitate was collected by filtration, washed with acetonitrile and dried to afford 6-bromo-1H-benzo[d][1,3]oxazine-2,4-dione as a pale powder (280 g, 93percent).
1H NMR (DMSO-d6): δ 11.83 (s, 1H), 7.98 (s, 1H), 7.89-7.87 (d, 1H,), 7.09-7.07 (d, 1H).
90% at 70℃; for 12 h; A 500 mL single neck round-bottomed flask equipped with a football-shaped PTFE stirring bar (16 mm × 37 mm) was chargedwith 2-amino-5-bromobenzoic acid (10.0 g, 46.3 mmol,1.0 equiv) followed by the addition of tetrahydrofuran (230 mL,0.2 molar) and solid triphosgene (13.7 g, 46.3 mmol, 1.0 equiv)resulting in a suspension. The reaction vessel was placed into afitted metal heating mantle and the neck was equipped with a24/40 Liebig condenser. The suspension was stirred (500 rpm)and the heating mantle set to 70 °C. The suspension becamehomogenous before a white solid precipitated out after about30 minutes at 70 °C. The heterogeneous reaction mixture wasaged for 12 hours then cooled to room temperature (25 °C). Theslurry was poured into a 600 mL beaker equipped with overheadmechanical stirrer (PTFE 75 mm paddle) containing250 mL of deionized water. With vigorous stirring, the mixturebecame homogenous followed by precipitation of a pale whitesolid. The solid was collected by vacuum filtration on aBüchner funnel (7.6 cm diameter) with Whatman 1 filter paper(70 mm) and air pulled through for 5 minutes. The material was transferred to a 250 mL Erlenmeyer flask equipped with cylindricalstir bar and 50 mL of methanol was added. The slurrywas stirred for 10 minutes and then collected by vacuum filtration.The filter cake was dried under vacuum (0.1 mmHg at 25 °C) for 12 hours to afford 9b as a white powder (90percent yield).Physical characteristics of 9b: white powder with 95.4percent purityas determined by quantitative 1H NMR using maleic acid as theinternal standard; mp > 270 °C; IR (solid) cm−1: 3170, 1751;1H NMR (DMSO-d6, 400 MHz) δ 11.86 (s, 1H, N-H), 7.98 (d,J = 2.3 Hz, 1H, Ce-H), 7.88 (dd, J = 8.7, 2.3 Hz, 1H, Cd-H),7.19 (d, J = 8.7 Hz, 1H, Cf-H); 13C NMR (DMSO-d6,100 MHz) δ 158.8 (s, Ca), 146.7 (s, Cb), 140.6 (s, Cc), 139.3(d, Cd), 130.5 (d, Ce), 117.6 (d, Cf), 114.5 (s, Cg), 112.4 (s,Ch); HRMS (ESI): calcd for [C8H4BrNO3 + Na]+ 263.926677;found: 263.926475; anal. calcd for C8H4BrNO3: C, 50.34; H,3.90; found: C, 49.98; H, 3.80.
72% for 3 h; Heating / reflux To a dry, 4-L round bottom flask was added [175] g [(810 MMOL) OF 2-AMINO-5-] bromobenzoic acid (19), triphosgene (83 g, 278 [MMOL),] and dioxane (3 L). The suspension was stirred under N2 and heated to reflux. The reaction was found to be complete by TLC and NMR after stirring at reflux for 3 h, but did not become homogenous at any time. After cooling to room temperature, the reaction was filtered and the precipitate washed with ether. The solid was dried in the vacuum oven at 40 [°C] to afford 5-bromoisatoic anhydride (20,151. 1 g, 72percent) as a white solid [:APOS;H NMR] [(DMSO-D6) 8] 7.29 (d, J= 8.7, [1H),] 7.91 (dd, [J = 2.] 5,8. 7, [1H),] 8.09 (d, J= 2.3, 1H).

Reference: [1] Patent: US2006/63804, 2006, A1, . Location in patent: Page/Page column 11
[2] Journal of Medicinal Chemistry, 2011, vol. 54, # 3, p. 831 - 850
[3] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 15, p. 4482 - 4498
[4] European Journal of Organic Chemistry, 2014, vol. 2014, # 3, p. 564 - 574
[5] Patent: CN105384687, 2016, A, . Location in patent: Paragraph 0302; 0303; 0304; 0305; 0306; 0307
[6] Patent: US2006/84804, 2006, A1, . Location in patent: Page/Page column 12
[7] Beilstein Journal of Organic Chemistry, 2018, vol. 14, p. 2529 - 2536
[8] Patent: WO2004/18414, 2004, A2, . Location in patent: Page 135
[9] European Journal of Medicinal Chemistry, 1994, vol. 29, # 12, p. 925 - 940
[10] Chemical Biology and Drug Design, 2010, vol. 75, # 5, p. 444 - 454
[11] Biochemistry, 2017, vol. 56, # 49, p. 6491 - 6502
[12] Journal of Organic Chemistry, 2018, vol. 83, # 4, p. 2006 - 2017
  • 18
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  • [ 5794-88-7 ]
  • [ 4692-98-2 ]
YieldReaction ConditionsOperation in experiment
78% With hydrogenchloride In tetrahydrofuran; water; toluene A.
5-Bromoisatoic Anhydride
To a stirred solution of 5-bromo-2-amino-benzoic acid (25 g, 0.115 mmol) in a mixed solvent of THF:H2O:conc. HCl (4:2:1, 350 mL), was added a solution of phosgene (0.23 mmol, 20percent in toluene) dropwise.
The reaction mixture was allowed to stir at room temperature for 4 h.
The resulting precipitate was filtered, washed with water and dried under reduced pressure to give the title compound (22.5 g, 78percent) as a gray solid.
Reference: [1] Medicinal Chemistry Research, 1997, vol. 7, # 1, p. 25 - 35
[2] Patent: US6458783, 2002, B1,
  • 19
  • [ 541-41-3 ]
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  • [ 4692-98-2 ]
Reference: [1] Journal of Chemical Research, Miniprint, 1987, # 7, p. 1839 - 1868
  • 20
  • [ 5794-88-7 ]
  • [ 29632-82-4 ]
  • [ 62473-92-1 ]
Reference: [1] Patent: US2011/98311, 2011, A1,
  • 21
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  • [ 853908-50-6 ]
Reference: [1] Patent: WO2012/116237, 2012, A2,
[2] Patent: WO2014/151147, 2014, A1,
[3] Patent: US2015/320727, 2015, A1,
[4] MedChemComm, 2016, vol. 7, # 2, p. 297 - 310
[5] Patent: US9295673, 2016, B2,
[6] Patent: WO2006/122806, 2006, A2,
[7] Patent: WO2009/155527, 2009, A2,
  • 22
  • [ 5794-88-7 ]
  • [ 39859-36-4 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 15, p. 4482 - 4498
  • 23
  • [ 5794-88-7 ]
  • [ 71-43-2 ]
  • [ 39859-36-4 ]
Reference: [1] Chemical Communications, 2017, vol. 53, # 9, p. 1482 - 1485
  • 24
  • [ 109-04-6 ]
  • [ 5794-88-7 ]
  • [ 1563-56-0 ]
YieldReaction ConditionsOperation in experiment
89.3%
Stage #1: at -40℃; for 1.5 h;
Stage #2: at 0℃; for 2 h;
To a -40°C solution of 2.5 M n-butyllithium in hexane (400 mL, 1000 mmol, 4 eq) and diethyl ether (1 L) was added 2-bromopyridine (173.93 g, 1101 mmol, 4.4 eq) over approximately 30 min. The reaction was stirred for 1 h at -40°C, and then treated with 5-bromoanthranilic acid (54.14 g, 250.6 mmol, 1 eq) in THF (1 L). The reaction was warmed to 0°C and stirred 2 h at 0°C, then quenched with chlorotrimethylsilane (625 mL, 4924 mmol, 20 eq). The reaction was stirred 30 min at ambient temperature, then cooled to 0°C and quenched with 3N HCI (625 mL). The aqueous layer was separated, and the organic layer was extracted once with 3N HCl. The combined aqueous layers were neutralized with solid sodium hydroxide pellets, with cooling via ice bath. The resulting mixture was extracted with diethyl ether (3 .x. 1 L). The combined ether layers were dried over sodium sulfate, filtered and concentrated to a black oil, which was subsequently purified by flash chromatography (1 L silica gel, 20-30percent ethyl acetate/hexane) to give the required compound as a brown solid (62 g, 224 mmol, 89.3percent).
62.7%
Stage #1: With n-butyllithium In tetrahydrofuran at -40℃;
Stage #2: at -40 - 0℃; for 2 h;
Stage #3: With chloro-trimethyl-silane In tetrahydrofuran at 20℃; for 0.5 h;
To a -40 °C solution of 2.5 M n-BuLi (18 mL) in THF (300 mL) is added 2- bromopyridine (5.0 g, 32 mmol) over 15 min. The reaction is stirred for 1 h at -40 °C, and then treated with 2-Amino-5-bromo-benzoic acid (6.9 g, 32 mmol) in THF (300 mL). The reaction is warmed to 0 °C and stirred for 2 h then quenched with TMSC1 (3.4 g, 32 mmol). The reaction is stirred at room temperature for 30 min then cooled to 0 °C and quenched with 3M HCl (20 mL). The aqueous layer is separated and the organic layer is extracted with 3M HCl. The organic layer is basified with solid NaOH, the resulting mixture is extracted with EtOAc, and the organic layer is dried over Na2S04, filtered and concentrated. The residue is purified by column chromatography on silica gel to give the desired product as a yellow solid. Yield: 5.50 g (62.7percent) HPLC-MS: M+H=277/279; tRet =3.16 min; AM6
62.7%
Stage #1: With n-butyllithium In tetrahydrofuran at -40℃; for 1.25 h;
Stage #2: at 0℃; for 2 h;
To a -40° C. solution of 2.5 M n-BuLi (18 mL) in THF (300 mL) is added 2-bromopyridine (5.0 g, 32 mmol) over 15 min. The reaction is stirred for 1 h at -40° C., and then treated with 2-Amino-5-bromo-benzoic acid (6.9 g, 32 mmol) in THF (300 mL). The reaction is warmed to 0° C. and stirred for 2 h then quenched with TMSCl (3.4 g, 32 mmol). The reaction is stirred at room temperature for 30 min then cooled to 0° C. and quenched with 3M HCl (20 mL). The aqueous layer is separated and the organic layer is extracted with 3M HCl. The organic layer is basified with solid NaOH, the resulting mixture is extracted with EtOAc, and the organic layer is dried over Na2SO4, filtered and concentrated. The residue is purified by column chromatography on silica gel to give the desired product as a yellow solid. Yield: 5.50 g (62.7percent) HPLC-MS: M+H=277/279; tRet=3.16 min; AM6
50.7%
Stage #1: With n-butyllithium In tetrahydrofuran at -40℃; for 1 h; Inert atmosphere
Stage #2: at 0 - 10℃; for 3 h; Inert atmosphere
Add tetrahydrofuran (44 mL) to the reaction flask, protect with nitrogen, add n-butyl lithium (51 mL) at -40 ° C, control the internal temperature not to exceed -20 ° C, lower the temperature to -40 ° C, and slowly add 2-bromopyridine ( 15.8g), the reaction was incubated for 1 hour, the temperature was controlled below -40 ° C, and a solution of 2-amino-5-bromo-benzoic acid (6.7 g) dissolved in (44 mL) tetrahydrofuran was added dropwise.After the dropwise addition, the temperature was naturally raised to about 0 ° C for 3 hours.The internal temperature was kept below 10 °C, and a saturated ammonium chloride solution (11 mL) was slowly added dropwise to terminate the reaction. Water (50 mL) was added thereto, and the mixture was partitioned. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (50mL) The organic layers were combined and washed with saturated aqueous sodium chloride (40 mL×2).Drying over anhydrous sodium sulfate, filtration, and concentrated under reduced pressure to give an oily substance, purified by column chromatography (eluent PE: EA = 3:1 to 1:1, volume ratio), and the positive component was collected and concentrated to give a solid product ( 4.37 g, yield 50.7percent).

Reference: [1] Patent: EP1183243, 2006, B1, . Location in patent: Page/Page column 11
[2] Patent: WO2014/154762, 2014, A1, . Location in patent: Page/Page column 62
[3] Patent: US2014/296230, 2014, A1, . Location in patent: Paragraph 0303-0306
[4] Patent: CN108264499, 2018, A, . Location in patent: Paragraph 0050-0051; 0075; 0076; 0077-0079
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  • [ 5794-88-7 ]
  • [ 1563-56-0 ]
YieldReaction ConditionsOperation in experiment
58%
Stage #1: With n-butyllithium In tetrahydrofuran at -40℃;
Stage #2: at 0℃;
(2-Amino-5-bromo-phenyl)-pyridin-2-yl-methanone 123; The anion of 2-bromo-pyridine 121 and 2-amino-5-bromobenzoic acid 122 were condensed to provide the 2'-pyridylketone 123.
Reference: [1] Patent: US2006/3995, 2006, A1, . Location in patent: Page/Page column 60-61
  • 26
  • [ 77-78-1 ]
  • [ 5794-88-7 ]
  • [ 52727-57-8 ]
YieldReaction ConditionsOperation in experiment
56% With triethylamine In N,N-dimethyl-formamide at 20℃; for 48 h; Step a:
Methyl 2-amino-5-bromobenzoate
MeSO4 (26.3 mL, 0.280 mol) was added to a solution of 2-amino-5-bromobenzoic acid (50.0 g, 0.230 mol) in DMF and Et3N (40 mL, 0.28 mol).
The reaction mixture was stirred at rt for 48 h.
The mixture was quenched with water, extracted with EtOAc and dried over MgSO4.
The solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel (5percent EtOAc in petroleum ether) to afford methyl 2-amino-5-bromobenzoate (30 g, 56percent yield).
1H NMR (300 MHz, DMSO) δ 7.74 (d, J=2.7, 1H), 7.35 (dd, J=9.0, 2.1, 1H), 6.78-6.73 (m, 3H), 3.77 (s, 3H).
56% With triethylamine In N,N-dimethyl-formamide at 20℃; for 48 h; MeSO4 (26.3 mL, 0.280 mol) was added to a solution of 2-amino-5-bromobenzoic acid (50.0 g, 0.230 mol) in DMF and Et3N (40 mL, 0.28 mol).
The reaction mixture was stirred at rt for 48 h.
The mixture was quenched with water, extracted with EtOAc and dried over MgSO4.
The solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel (5percent EtOAc in petroleum ether) to afford methyl 2-amino-5-bromobenzoate (30 g, 56percent yield).
1H NMR (300 MHz, DMSO) δ 7.74 (d, J=2.7, 1H), 7.35 (dd, J=9.0, 2.1, 1H), 6.78-6.73 (M, 3H), 3.77 (s, 3H).
Reference: [1] Patent: US2008/9524, 2008, A1, . Location in patent: Page/Page column 410
[2] Patent: US2015/231142, 2015, A1, . Location in patent: Paragraph 1269
  • 27
  • [ 67-56-1 ]
  • [ 5794-88-7 ]
  • [ 52727-57-8 ]
YieldReaction ConditionsOperation in experiment
90.8% Reflux The commercially available material 2-amino-5-bromobenzoic acid (G-0) (0.2g, 0.93mmol) was dissolved in methanol (10mL) and concentrated H2SO4 (0.2ml, 3.72mmol) was slowly added. The reaction mixture was refluxed for 6h. After cooling, the solvent was evaporated mostly under reduced pressure and then aqueous NaHCO3 was used to adjust the pH to 9–10. The residue was extracted with ethyl acetate (3×20mL) and then the combined organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was recrystallized from ethyl acetate and petroleum ether or purified by column chromatography using ethyl acetate and petroleum ether (1:8) as an eluent to give G-1 as white solid. yield 90.8percent, mp: 64–65°C 1H NMR (400MHz, d6-DMSO) δ 7.77 (s, 1H, PH-H), 7.38 (d, J=8.6Hz, 1H, Ph-H), 6.82 (s, 2H, NH2-H), 6.77 (d, J=8.9Hz, 1H, Ph-H), 3.80 (s, 3H, CH3-H). 13C NMR (100MHz, d6-DMSO) δ 167.14, 150.86, 136.90, 132.76, 119.37, 110.65, 105.22, 52.15
76%
Stage #1: for 72 h; Reflux
2-Amino-5-bromobenzoic acid (8Og, 0.37mmol) was dissolved in MeOH (600 ml.) and a solution of H2SO4 (50 ml.) was slowly added. The reaction mixture was refluxed for 72 h, then concentrated. NaOH solution was added to adjust the pH to 10-11. The mixture was extracted with EtOAc (3 x 500 ml_). The combined organic layer was dried over MgSO4, concentrated to afford the desired compound (65 g, yield: 76 percent) as a colorless oil, which is used directly in the next step without purification.
76%
Stage #1: for 72 h; Reflux
Example 8D: 2-Amino-5-bromo-/V-methylbenzamide2-Amino-5-bromobenzoic acid (80 g, 0.37 mol) was dissolved in MeOH (600 mL) and cone. H2S04 (50 mL) was slowly added. The reaction mixture was refluxed for 72 h, then concentrated. NaOH solution was added to adjust the pH to 10-1 1 . The mixture was extracted with EtOAc (3 χ 500 mL). The combined organic layer was dried over MgS04, concentrated to afford the desired compound (65 g, yield: 76 percent) as a colorless oil, which is used directly in the next step without purification. A mixture of methyl 2-amino-5-bromobenzoate and CH3NH2.H2O (1000 mL) was stirred at 80 C overnight in a pressure tube. The mixture was diluted with H20 (1000 mL) and extracted with EtOAc (3 χ 500 mL). The combined organic layers were dried over MgS04, concentrated to afford the title compound (55 g, yield: 87 percent) as a gray solid. 1H NMR (CDCI3, 400 MHz): δ 2.93 (d, J = 5.2 Hz, 3H), 5.48 (s, br, 2H), 6.04 (s, br, 1 H), 6.54 (d, J == 2.0, 8.4 Hz, 1 H), 7.38 (d, J = 2.0 Hz, 1 H).
Reference: [1] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 20, p. 5779 - 5789
[2] Patent: WO2010/141406, 2010, A2, . Location in patent: Page/Page column 97
[3] Patent: WO2012/74951, 2012, A1, . Location in patent: Page/Page column 50-51
[4] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 13, p. 3574 - 3577
[5] Chemistry of Heterocyclic Compounds, 2006, vol. 42, # 1, p. 64 - 69
[6] Journal of Heterocyclic Chemistry, 2010, vol. 47, # 2, p. 415 - 420
[7] Journal of Medicinal Chemistry, 2013, vol. 56, # 21, p. 8332 - 8338
[8] European Journal of Medicinal Chemistry, 2014, vol. 76, p. 343 - 351
  • 28
  • [ 5794-88-7 ]
  • [ 52727-57-8 ]
YieldReaction ConditionsOperation in experiment
56% With triethylamine In ethyl acetate; N,N-dimethyl-formamide; Petroleum ether Step a:
Methyl 2-amino-5-bromobenzoate
MeSO4 (26.3 mL, 0.280 mol) was added to a solution of 2-amino-5-bromobenzoic acid (50.0 g, 0.230 mol) in DMF and Et3N (40 mL, 0.28 mol).
The reaction mixture was stirred at rt for 48 h.
The mixture was quenched with water, extracted with EtOAc and dried over MgSO4.
The solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel (5percent EtOAc in petroleum ether) to afford methyl 2-amino-5-bromobenzoate (30 g, 56percent yield).
1H NMR (300 MHz, DMSO) δ 7.74 (d, J=2.7, 1H), 7.35 (dd, J=9.0, 2.1, 1H), 6.78-6.73 (m, 3H), 3.77 (s, 3H).
Reference: [1] Patent: US2011/98311, 2011, A1,
  • 29
  • [ 186581-53-3 ]
  • [ 5794-88-7 ]
  • [ 52727-57-8 ]
Reference: [1] Green Chemistry, 2017, vol. 19, # 6, p. 1449 - 1453
  • 30
  • [ 67-56-1 ]
  • [ 87-48-9 ]
  • [ 5794-88-7 ]
  • [ 52727-57-8 ]
Reference: [1] Angewandte Chemie, 1981, vol. 93, # 10, p. 914 - 915
  • 31
  • [ 19165-25-4 ]
  • [ 95-54-5 ]
  • [ 34801-09-7 ]
  • [ 5794-88-7 ]
Reference: [1] Monatshefte fur Chemie, 1996, vol. 127, # 1, p. 103 - 110
  • 32
  • [ 5794-88-7 ]
  • [ 610-71-9 ]
Reference: [1] Justus Liebigs Annalen der Chemie, 1884, vol. 222, p. 113
[2] Chemische Berichte, 1877, vol. 10, p. 1705
[3] Pharmazie, 1982, vol. 37, # 2, p. 115 - 117
  • 33
  • [ 5794-88-7 ]
  • [ 39263-32-6 ]
Reference: [1] European Journal of Medicinal Chemistry, 2014, vol. 76, p. 343 - 351
  • 34
  • [ 6941-75-9 ]
  • [ 20776-50-5 ]
  • [ 5794-88-7 ]
Reference: [1] Molecules, 2010, vol. 15, # 8, p. 5561 - 5580
  • 35
  • [ 5794-88-7 ]
  • [ 61954-80-1 ]
Reference: [1] Journal of Organic Chemistry, 1997, vol. 62, # 26, p. 9361 - 9364
[2] Journal of Medicinal Chemistry, 2002, vol. 45, # 2, p. 344 - 359
[3] Chemical and Pharmaceutical Bulletin, 2007, vol. 55, # 4, p. 613 - 624
[4] Journal of Medicinal Chemistry, 2015, vol. 58, # 16, p. 6678 - 6696
  • 36
  • [ 5794-88-7 ]
  • [ 21739-92-4 ]
Reference: [1] Journal of the Chemical Society, 1953, p. 232,236
  • 37
  • [ 5794-88-7 ]
  • [ 29124-57-0 ]
Reference: [1] Chemistry - A European Journal, 2012, vol. 18, # 18, p. 5530 - 5535
[2] Patent: WO2014/11900, 2014, A2,
[3] Patent: US2015/197519, 2015, A1,
[4] Advanced Synthesis and Catalysis, 2017, vol. 359, # 13, p. 2191 - 2195
[5] Patent: US9695165, 2017, B2,
[6] Organic and Biomolecular Chemistry, 2017, vol. 15, # 31, p. 6474 - 6477
[7] Patent: CN107304201, 2017, A,
  • 38
  • [ 5794-88-7 ]
  • [ 74-88-4 ]
  • [ 33922-96-2 ]
Reference: [1] Journal of Organic Chemistry, 2007, vol. 72, # 2, p. 583 - 588
  • 39
  • [ 5794-88-7 ]
  • [ 16313-66-9 ]
YieldReaction ConditionsOperation in experiment
84% With ammonia; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In water; N,N-dimethyl-formamide at 20℃; for 15 h; Compound 26 (9.1 g, 42.1 mmol), HOBT (13.6 g, 101.1 mmol) and EDC.HC1 (19.4 g, 101.1 mmol) were dissolved in DMF (60 mL) and NH3.H20 (30 mL) was added slowly. The reaction mixture was stirred for 15 hours at room temperature. The solvent was then removed in vacuo. The residue was dissolved in ethyl acetate (100 mL) and washed with 1 N NaOH (20 mL), followed by brine, dried over Na2S04 andconcentrated under vacuum resulting in compound 27 (7.6 g, 84percent yield).
84% With benzotriazol-1-ol; ammonium hydroxide; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 15 h; 12464] To a suspension of compound 69-4 (9.1 g, 42.1 mmol), HOST (13.6 g, 101.1 mmol) and EDC.HC1 (19.4 g, 101.1 mmol) in DMF (60.0 mE) was added NH3.H20 (30.0 mE) dropwise. At the end of addition, the mixture was stirred at rt for 15 irs. After the reaction was completed, the solvent was removed. The residue was dissolved in EtOAc (100 mE). The resulting mixture was washed with NaOH aqueous solution (20 mE, 1 M) and brine, dried over anhydrous Na2504 and concentrated in vacuo to give the title compound 69-5 (7.6 g, 84percent). The compound was characterized by the following spectroscopic data:12465] MS (ESI, pos.ion) mlz: 216.5 [M+H]12466] ‘H NMR (400 MHz, CDC13) ö (ppm): 7.57 (d, 1H),7.22,7.19 (d, d, 1H), 6.58, 6.56 (d, d, 1H), 6.40 (s, 2H), 5.98 (brs, 2H).
82%
Stage #1: With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; for 20 h;
Stage #2: With ammonium hydroxide In tetrahydrofuran at 20℃; for 14 h;
To a stirred solution of 2-amino-5-bromobenzoic acid (14.0 g, 0.065 mol) dissolved in THF (230 mL) was added CDI (12.6 g, 0.077 mol). The reaction mixture was stirred for 2 h at rt. To this mixture ammonia (321 mL, 25percent solution in water) wasadded and the mixture was stirred at room temperature for 14 h. The volatiles were evaporated to dryness; water (100 mL) was added and the mixture was extracted with ethyl acetate (2 x 150 mL). The combined organic extracts were concentrated under reduced pressure to afford a residue. The product was purified by silica gel colunm chromatography using 70percent ethyl acetate in hexanes. The required fractions werecollected and concentrated under reduced pressure to afford 2-amino-5- bromobenzamide (14.0 g, 0.065 mol, 82percent yield) as a brown solid. LCMS (ESI) m/e 215.0 (bromo pattern) [(M+H), calcd for C7H8BrN2O, 214.97]; LC/MS retention time (method B): ti = 0.93 mm.
80%
Stage #1: With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; for 2 h; Inert atmosphere; Sealed tube
Stage #2: With ammonium hydroxide In tetrahydrofuran at 0 - 20℃; Inert atmosphere; Sealed tube
To a suspension of compound 28-7 (1.52 g, 7.00 mmol) in dry THF (5.0 mL) was added CDI (0.83 g, 5.12 mmol) dropwise. At the end of the addition, the mixture was stirred at rt for 2.0 hrs, and then NH3.H2O (20 mL) was added dropwise at 0 °C. At the end of the addition, the mixture was stirred at rt overnight. After the reaction was completed, the THF solvent was removed. The residue was dissolved in EtOAc (100 mL). The resulting mixture was washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo to give the title compound as a pale yellow solid (1.2 g, 80percent). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 215 [M+H] ; and *H NMR (400 MHz, CDC13) δ (ppm): 7.78 (s, 1H), 7.45 (d, 1H, J = 8.0 Hz), 7.15 (s, 1H), 6.89 (d, 1H, J = 2.0 Hz), 6.79 (s, 1H), 6.61 (dd, 1H, J= 8.0 Hz, 2.0 Hz).
80%
Stage #1: With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; for 2 h;
Stage #2: With ammonium hydroxide In tetrahydrofuran at 0 - 20℃;
To a mixture of compound 1-18 (1.51 g.7.00 mmol) in dry THF (5.0 mL) was added CD1 (0.83 g.5.12 mmol). At the end of the addition, the mixture was stirred at rt for 2.0 hrs. And then NH3.H2O (20 mL) was added dropwise at 0 °C. At the end of the addition, the mixture was stirred at rt overnight. After the reaction was completed, the solvent was removed. The residue was dissolved in EtOAc (100 mL). The resulting mixture was washed with brine, dried over anhydrous a^SC^ and concentrated in vacuo to give the title compound as a pale yellow solid (1.2 g. 80percent). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 217 [M+H] : and NMR (400 MHz. CDCL) δ (ppm): 7.78 (s, 1H), 7.45 (d, 1H. J= 8.0 Hz), 7.15 (s.1H).6.89 (d. \W.J = 2.0 Hz), 6.79 (s.1H).6.61 (dd.1 H. J= 8.0 Hz.2.0 Hz).
80%
Stage #1: With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; for 2 h;
Stage #2: With ammonium hydroxide In tetrahydrofuran; water at 20℃;
To a solution of compound 24-2 (1.51 g, 7.00 mmol) in anhydrous THF (5 mL) was added CDI (0.83 g, 5.12 mmol). After the mixture was stirred at rt for 2 hours, the mixure was cooled to 0 °C and ammonium hydroxide (20 mL) was added dropwise. At the end of the addition, the mixture was stirred at rt overnight. After the reaction was completed, the THF was removed in vacuo and the rediue was dissolved in EtOAc (100 mL). The solution was washed with a saturated aqueous solution of NaCl, dried over anhydrous Na2S04 and concentrated in vacuo to afford a pale yellow solid (1.2 g, 80 percent). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 217 [M+H]+; and lU NMR (400 MHz, CDC13): δ 7.78 (s, 1H), 7.45 (d, 1H, J = 8.0 Hz), 7.15 (s, 1H), 6.89 (d, 1H, J = 2.0 Hz), 6.79 (s, 1H), 6.61 (dd, 1H, J = 8.0 Hz, 2.0 Hz) ppm.

Reference: [1] Patent: WO2012/13643, 2012, A1, . Location in patent: Page/Page column 43
[2] Patent: US2015/79028, 2015, A1, . Location in patent: Paragraph 2454; 2463; 2464; 2465; 2466
[3] Patent: WO2016/53794, 2016, A1, . Location in patent: Page/Page column 132
[4] Patent: WO2014/82380, 2014, A1, . Location in patent: Paragraph 00585; 00592
[5] Patent: WO2014/82379, 2014, A1, . Location in patent: Page/Page column 112; 1113; 118
[6] Patent: WO2014/131315, 2014, A1, . Location in patent: Page/Page column 187; 188
[7] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 3, p. 383 - 391
[8] Journal of Chemical Research, Miniprint, 1987, # 7, p. 1839 - 1868
[9] European Journal of Medicinal Chemistry, 2014, vol. 76, p. 343 - 351
[10] Organic Letters, 2016, vol. 18, # 14, p. 3342 - 3345
[11] Biochemistry, 2017, vol. 56, # 49, p. 6491 - 6502
  • 40
  • [ 64-17-5 ]
  • [ 5794-88-7 ]
  • [ 63243-76-5 ]
YieldReaction ConditionsOperation in experiment
44% Reflux Into a 100-mL 3 -necked round-bottom flask, were placed compound 1.1 (5 g, 23.14 mmol, 1.00 equiv) and ethanol (100 mL). Hydrogen chloride gas was introduced and resulting solution was refluxed overnight. The reaction was then quenched by the addition of saturated sodium bicarbonate and solvents were removed under vacuum. Crude was purified using flash column chromatography to provide 2.5 g (44percent) of compound 1.2 as a yellow solid.
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 19, p. 5746 - 5752
[2] Patent: WO2014/182951, 2014, A1, . Location in patent: Paragraph 00281
[3] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 23, p. 6481 - 6488
[4] Patent: EP1180514, 2002, A1, . Location in patent: Example 75
[5] Journal of Organic Chemistry, 2018, vol. 83, # 3, p. 1154 - 1159
  • 41
  • [ 5794-88-7 ]
  • [ 63243-76-5 ]
Reference: [1] Patent: US2003/55042, 2003, A1,
[2] Patent: US6429205, 2002, B1,
  • 42
  • [ 118-92-3 ]
  • [ 20776-51-6 ]
  • [ 5794-88-7 ]
Reference: [1] Journal of the Chemical Society. Perkin Transactions 2, 2000, # 6, p. 1113 - 1118
[2] Tetrahedron Letters, 2000, vol. 41, # 13, p. 2083 - 2085
[3] Synthetic Communications, 2004, vol. 34, # 12, p. 2143 - 2152
  • 43
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  • [ 181765-86-6 ]
Reference: [1] Tetrahedron, 2011, vol. 67, # 1, p. 125 - 143
[2] RSC Advances, 2013, vol. 3, # 38, p. 17271 - 17280
[3] Chemistry--A European Journal, 2014, vol. 20, # 36, p. 11336 - 11339,4
  • 44
  • [ 5794-88-7 ]
  • [ 21740-00-1 ]
YieldReaction ConditionsOperation in experiment
60%
Stage #1: With hydrogenchloride; sodium hydroxide; sodium nitrite In water at 0℃; for 2 h; Inert atmosphere
Stage #2: With sulfuric acid; potassium iodide In water at 35 - 90℃; for 0.833333 h; Inert atmosphere
A solution of 8 (3.9 g, 0.018 mol), NaNO2 (1.5 g, 0.022 mol) and NaOH (0.90 g, 0.023 mmol) in H2O (55 mL) was added dropwise to a stirred solution of conc. HCl (6.4 mL) in H2O (9 mL) cooled at 0 °C over a period of 1.5 h. After addition the stirring was continued for another 30 min at 0 °C. The formed suspension of diazonium salt was added to a stirred solution of KI (4.5 g, 0.027 mol) and conc. H2SO4 (1.1 mL) in H2O (7.4 mL) at 35 to 40 °C over 20 min. The mixture was then heated to 90 °C and stirred for 30 min. Unreacted iodine was removed by steam distillation. The mixture was stirred and cooled. The crude product was filtered and washed with H2O, and then dissolved in NaOH solution (aq. 40percent). The polymeric components were separated by decantation and the clear solution was acidified with conc. HCl. The product was extracted by Et2O. The extract was dried over MgSO4 and concentrated under vacuum. The residue was crystallized from MeOH/H2O (1:1, v/v) to give compound 9 (3.56 g, 0.0109 mol, 60percent) as a pale yellow solid.
Reference: [1] Angewandte Chemie - International Edition, 2011, vol. 50, # 46, p. 10851 - 10854
[2] Organic Letters, 2008, vol. 10, # 14, p. 3001 - 3004
[3] Tetrahedron, 2011, vol. 67, # 1, p. 125 - 143
[4] Angewandte Chemie - International Edition, 2012, vol. 51, # 12, p. 2925 - 2929
[5] Collection of Czechoslovak Chemical Communications, 1984, vol. 49, # 1, p. 86 - 109
[6] Synthesis, 1997, # 11, p. 1301 - 1304
[7] Chemical Communications, 2013, vol. 49, # 31, p. 3254 - 3256
[8] RSC Advances, 2013, vol. 3, # 38, p. 17271 - 17280
[9] Organic and Biomolecular Chemistry, 2014, vol. 12, # 27, p. 5031 - 5037
[10] Chemistry--A European Journal, 2014, vol. 20, # 36, p. 11336 - 11339,4
[11] Patent: WO2014/189370, 2014, A1, . Location in patent: Page/Page column 28
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  • [ 5794-88-7 ]
  • [ 130148-53-7 ]
Reference: [1] Journal of Organic Chemistry, 1991, vol. 56, # 18, p. 776 - 785
  • 46
  • [ 5794-88-7 ]
  • [ 102393-82-8 ]
Reference: [1] Pharmaceutical Chemistry Journal, 1987, vol. 21, # 7, p. 478 - 483[2] Khimiko-Farmatsevticheskii Zhurnal, 1987, vol. 21, # 7, p. 802 - 807
[3] Chemical and Pharmaceutical Bulletin, 2015, vol. 63, # 2, p. 75 - 80
[4] Antimicrobial Agents and Chemotherapy, 2017, vol. 61, # 6,
  • 47
  • [ 57-13-6 ]
  • [ 5794-88-7 ]
  • [ 102393-82-8 ]
Reference: [1] Journal of Heterocyclic Chemistry, 2017, vol. 54, # 5, p. 2755 - 2766
  • 48
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  • [ 111218-89-4 ]
Reference: [1] Pharmaceutical Chemistry Journal, 1987, vol. 21, # 7, p. 478 - 483[2] Khimiko-Farmatsevticheskii Zhurnal, 1987, vol. 21, # 7, p. 802 - 807
  • 49
  • [ 5794-88-7 ]
  • [ 99767-45-0 ]
YieldReaction ConditionsOperation in experiment
57% With hydrogenchloride; iron(III) chloride In 1-methyl-pyrrolidin-2-one; water at 60℃; for 1 h; Reflux 2-araino-5-broraobenzoic acid (2,31 mmol) and CuCN (2.78 mmol) were heated to reflux in NMP (5 ml,) for 3 h. The reaction mixture was poured into a solution of FeC-3 3H20 (3.0 g) in H20 (3 mL) and HC1 (0.5 mL) and stirred at 60 °C for lh. After cooling the reaction down, Et20 (100 mL) was added and the two phases were separated. The organic layer was washed with HCi I (50 mL) and H20 (2x50 mL), dried over a2S04, filtered and evaporated under reduced pressure. 2 -amino-5-cyanobenzoic acid (3) was obtained (57percent of yield) by triturating from CH2C12. NMR (300 MHz, CDCI3) δ 8.32 (d, 1H, J= 1.8 Hz), 7.71 (dd, 1R J= 1.8, J2= 8.7 Hz), 7.32 (br s, 1 H), 6.75 (d, 1H, J= 8.7 Hz).
57% for 3 h; Reflux 2-amino-5-cyanobenzoic [00144] 2-amino-5-bromobenzoic acid (2.31 mmol) and CuCN (2.78 mmol) were heated to reflux in NMP (5 mL) for 3 h. The reaction mixture was poured into a solution of FeCl3 3H20 (3.0 g) in H20 (3 mL) and HC1 (0.5 mL) and stirred at 60 °C for lh. After cooling the reaction down, Et20 (100 mL) was added and the two phases were separated. The organic layer was washed with HC1 IN (50 mL) and H20 (2x50 mL), dried over Na2S04, filtered and evaporated under reduced pressure. 2-amino-5-cyanobenzoic acid (3) was obtained (57percent of yield) by triturating from CH2C12. 1H NMR (300 MHz, CDC13) δ 8.32 (d, 1H, J= 1.8 Hz), 7.71 (dd, lH, Ji= 1.8, J2= 8.7 Hz), 7.32 (br s, 1H), 6.75 (d, 1H, J= 8.7 Hz).
Reference: [1] Patent: WO2013/109738, 2013, A1, . Location in patent: Paragraph 00140; 00141
[2] Patent: WO2015/9930, 2015, A2, . Location in patent: Paragraph 00143-00144
  • 50
  • [ 5794-88-7 ]
  • [ 20712-12-3 ]
YieldReaction ConditionsOperation in experiment
100% With borane-THF In tetrahydrofuran at 20℃; Inert atmosphere; Cooling with ice 500mLAdd three bottles1A (10 g, 46.3 mmol), dissolved in anhydrous THF (100 mL),Nitrogen protection,Under ice-cooling, a borane tetrahydrofuran solution (1M) (231 mL, 231 mmol) was added dropwise. After the addition was completed, the mixture was warmed to room temperature, stirred overnight and quenched with water (150 mL) under ice-cooling. The resulting mixture was extracted with ethyl acetate, washed with water, Sodium hydride solution, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 1B (9.7 g, 100percent yield) as a white solid
96% With lithium aluminium tetrahydride In tetrahydrofuran at 20℃; for 3.5 h; General procedure: To a suspension of lithium aluminum hydride (20.4 mmol) in THF (10 mL) was added benzoic acid (8.5 mmol) dissolved in THF (24 mL) dropwise over 20 minutes at room temperature. The reaction continued to stir at room temperature for 3.5 h, and then was quenched at 0 °C with H2O (10 mL). The suspension was filtered through a Celite plug with EtOAc (100 mL), washed with brine (30 mL), dried with MgSO4 and concentrated in vacuo.
Reference: [1] ACS Catalysis, 2013, vol. 3, # 4, p. 622 - 624
[2] Chemical Communications, 2017, vol. 53, # 1, p. 216 - 219
[3] Organic Letters, 2017, vol. 19, # 12, p. 3219 - 3222
[4] Patent: CN107304201, 2017, A, . Location in patent: Paragraph 0061; 0064
[5] Tetrahedron Letters, 2017, vol. 58, # 40, p. 3795 - 3799
[6] Journal of Medicinal Chemistry, 2018,
[7] Journal of Medicinal Chemistry, 2010, vol. 53, # 17, p. 6506 - 6510
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[15] Tetrahedron, 2014, vol. 70, # 34, p. 5114 - 5121
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[17] Patent: US2015/197519, 2015, A1, . Location in patent: Paragraph 0125; 0216
[18] Organic Letters, 2015, vol. 17, # 19, p. 4750 - 4753
[19] Advanced Synthesis and Catalysis, 2017, vol. 359, # 13, p. 2191 - 2195
[20] Patent: US9695165, 2017, B2, . Location in patent: Page/Page column 37; 38
[21] Organic and Biomolecular Chemistry, 2017, vol. 15, # 31, p. 6474 - 6477
  • 51
  • [ 13292-87-0 ]
  • [ 5794-88-7 ]
  • [ 20712-12-3 ]
YieldReaction ConditionsOperation in experiment
100% With sodium hydroxide In tetrahydrofuran REFERENCE EXAMPLE 285
In THF (350 ml) was dissolved 5-bromoanthranilic acid (40.06 g), and the mixture was cooled to 0° C.
To the mixture was added dropwise a solution of 10.0M borane dimethylsulfide in THF (54.5 ml), and the mixture was stirred at room temperature for 4.5 hours.
The mixture was cooled to 0° C., and to the mixture was added dropwise 3N sodium hydroxide solution.
The mixture was stirred at room temperature overnight, and to the mixture was added granulated sodium hydroxide to adjust the mixture to pH 11.
The aqueous layer was saturated with potassium carbonate, and the THF layer was separated.
The aqueous layer was extracted with ether (100 ml*5).
The organic layers were combined and dried with magnesium sulfate.
The solvent was evaporated under reduced pressure to give (2-amino-5-bromophenyl)methanol (36.66 g, 100percent).
1 H NMR (200 MHz, CDCl3) δ 4.62 (2H, s), 7.20 (1H, s), 7.23-7.26 (1H, m).
Reference: [1] Patent: US6166006, 2000, A,
  • 52
  • [ 5794-88-7 ]
  • [ 199786-58-8 ]
Reference: [1] Synthesis, 1997, # 11, p. 1301 - 1304
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[4] Organic and Biomolecular Chemistry, 2014, vol. 12, # 27, p. 5031 - 5037
[5] Patent: WO2014/189370, 2014, A1,
  • 53
  • [ 24424-99-5 ]
  • [ 5794-88-7 ]
  • [ 306937-20-2 ]
Reference: [1] European Journal of Organic Chemistry, 2007, # 16, p. 2643 - 2649
  • 54
  • [ 5794-88-7 ]
  • [ 689291-89-2 ]
Reference: [1] Tetrahedron, 2011, vol. 67, # 1, p. 125 - 143
[2] Chemical Communications, 2013, vol. 49, # 31, p. 3254 - 3256
  • 55
  • [ 5794-88-7 ]
  • [ 723281-72-9 ]
Reference: [1] Patent: WO2012/116237, 2012, A2,
[2] Patent: WO2014/151147, 2014, A1,
[3] Patent: US2015/320727, 2015, A1,
[4] MedChemComm, 2016, vol. 7, # 2, p. 297 - 310
[5] Patent: US9295673, 2016, B2,
[6] Patent: WO2006/122806, 2006, A2,
[7] Patent: WO2009/155527, 2009, A2,
  • 56
  • [ 5794-88-7 ]
  • [ 882672-05-1 ]
Reference: [1] Patent: WO2014/11900, 2014, A2,
[2] Patent: US2015/197519, 2015, A1,
[3] Patent: US9695165, 2017, B2,
[4] Patent: CN107304201, 2017, A,
  • 57
  • [ 3473-63-0 ]
  • [ 5794-88-7 ]
  • [ 155690-79-2 ]
YieldReaction ConditionsOperation in experiment
91% for 16 h; Heating / reflux To a 1.2 M solution of 5-bromoanthranilic acid (1 equiv) in N,N-dimethylformamide was added formamidine acetate (1 equiv). The mixture was heated to reflux and stirred at this temperature for 16 hours. After this time, the reaction was cooled and NaHCO3 solution (5 percent in H2O) (3 volumes) were carefully added and the mixture stirred vigorously. The resulting <n="113"/>precipitate was collected by filtration and then washed with water (2 X 1 volume) and then t- butyl methylether (2 X 1 volume) before being dried in a vacuum oven to give the desired product which required no further purification.6-Bromo-3H-pyrido[2,3-d]pyriniidin-4-one: (91 percent yield, insert) m/z (LC-MS,ESP):225 [M- H]- R/T = 2.31 minutes)
Reference: [1] Patent: WO2008/23161, 2008, A1, . Location in patent: Page/Page column 111-112
  • 58
  • [ 5794-88-7 ]
  • [ 1266728-34-0 ]
Reference: [1] Patent: WO2011/20193, 2011, A1,
  • 59
  • [ 5794-88-7 ]
  • [ 1538604-68-0 ]
Reference: [1] Patent: WO2014/11900, 2014, A2,
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