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Product Details of [ 99277-71-1 ]

CAS No. :99277-71-1 MDL No. :MFCD01013599
Formula : C7H4BrNO4 Boiling Point : -
Linear Structure Formula :- InChI Key :ZIRHHEZLJGORGU-UHFFFAOYSA-N
M.W : 246.02 Pubchem ID :3774467
Synonyms :
2-Nitro-4-bromobenzoic acid

Calculated chemistry of [ 99277-71-1 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 13
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 2
Num. H-bond acceptors : 4.0
Num. H-bond donors : 1.0
Molar Refractivity : 49.92
TPSA : 83.12 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
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) : 0.93
Log Po/w (XLOGP3) : 2.14
Log Po/w (WLOGP) : 2.06
Log Po/w (MLOGP) : 1.27
Log Po/w (SILICOS-IT) : -0.22
Consensus Log Po/w : 1.23

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.92
Solubility : 0.294 mg/ml ; 0.00119 mol/l
Class : Soluble
Log S (Ali) : -3.52
Solubility : 0.0747 mg/ml ; 0.000304 mol/l
Class : Soluble
Log S (SILICOS-IT) : -2.01
Solubility : 2.4 mg/ml ; 0.00977 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 2.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.94

Safety of [ 99277-71-1 ]

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

Application In Synthesis of [ 99277-71-1 ]

* 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 [ 99277-71-1 ]
  • Downstream synthetic route of [ 99277-71-1 ]

[ 99277-71-1 ] Synthesis Path-Upstream   1~29

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Reference: [1] ACS Medicinal Chemistry Letters, 2013, vol. 4, # 2, p. 288 - 292
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Reference: [1] Patent: WO2007/117607, 2007, A2,
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  • [ 3460-18-2 ]
Reference: [1] Tetrahedron Letters, 2010, vol. 51, # 50, p. 6646 - 6648
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  • [ 135484-83-2 ]
Reference: [1] Patent: EP1860098, 2007, A1,
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  • [ 16588-24-2 ]
Reference: [1] Tetrahedron Letters, 2010, vol. 51, # 50, p. 6646 - 6648
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YieldReaction ConditionsOperation in experiment
96% With iron(III) chloride; sodium hydroxide; hydrazine In water; isopropyl alcohol at 75℃; for 2 h; 2)
To 4-bromo-2-nitrobenzoic acid (1.80 g, 7.83 mmol) were added 0.88N aqueous sodium hydroxide solution (10 ML), iron(III) chloride (133 mg) and isopropyl alcohol (0.7 ML) and the mixture heated to 75° C.
While stirring the mixture, hydrazine (1.1 ML) was slowly added, and the mixture was reacted at 75° C. for 2 hrs.The reaction mixture was filtered and the filtrate was concentrated.The precipitated solid was washed with water to give 4-bromoanthranilic acid (1.73 g, 96percent).
1H NMR (DMSO-d6) δ ppm: 6.62 (dd, J=1.5, 8.5 Hz, 1H), 6.95 (d, J=1.5 Hz, 1H), 7.56 (d, J=8.5 Hz, 1H).
58% With hydrogen In tetrahydrofuran; ethanol for 66.5 h; EXAMPLE 14 7-(3-Amino-propyl)-3H-quinazolin-4-one14A. 2-Amino-4-bromo-benzoic acid; 4-Bromo-2-nitro-benzoic acid (0.5g, 2.03 mmol) (Matrix, 009241) was dissolved in a 1 : 1 mixture of ethanol/ tetrahydrofuran (22 ml). This solution was added to 5percent platinum on carbon (0.2g, 50percent water content) under an atmosphere of nitrogen. The reaction was shaken under an atmosphere of hydrogen for 2.5 hours. A further batch of platinum on carbon was added (0.2g) and the mixture was shaken for 64 hours under an atmosphere of hydrogen. The reaction mixture was filtered, washing through with a 1 : 1 mixture of ethanol/ tetrahydrofuran. The solvent was removed under reduced pressure and the residue was purified by flash silica chromatography, eluting with methanol/ dichloromethane (2:98) to yield the title compound as a yellow solid (0.253g, 58percent). LC/MS: (PS-Al) R12.62 [M+H]+ 215.88.
Reference: [1] Patent: US2004/116422, 2004, A1, . Location in patent: Page/Page column 31
[2] Organic Letters, 2011, vol. 13, # 19, p. 5220 - 5223
[3] Journal of Organic Chemistry, 1997, vol. 62, # 5, p. 1240 - 1256
[4] Patent: WO2006/51290, 2006, A2, . Location in patent: Page/Page column 111; 144
[5] Collection of Czechoslovak Chemical Communications, 1935, vol. 7, p. 436,443
[6] Chemische Berichte, 1912, vol. 45, p. 2078
[7] Journal fuer Praktische Chemie (Leipzig), 1891, vol. <2> 43, p. 204
[8] Journal of the American Chemical Society, 1960, vol. 82, p. 5918 - 5923
[9] Patent: US2004/167128, 2004, A1, . Location in patent: Page 38
[10] Patent: WO2004/18419, 2004, A2, . Location in patent: Page 321
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Reference: [1] Patent: US2005/261307, 2005, A1,
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YieldReaction ConditionsOperation in experiment
91% With sodium nitrite In water; hydrogen bromide Step 1:
4-Bromo-2-nitro-benzoic acid
A modification of a procedure in the following reference which is herein incorporated by reference in its entirety, for all purposes as if fully set forth herein, was used: Boojamra, C. G.; Burow, K. M.; Thompson, L. A.; Ellman, J. A. J. Org. Chem., 1997, 62,1240-1256.
A solution of NaNO2 (1.9 g, 27.4 mmol) in water (65 mL) was added to a stirred solution of 4-amino-2-nitro-benzoic acid (1) (5 g, 27.4 mmol) in aqueous 48percent HBr (40 mL) and water (82 mL) at 0° C.
The cloudy reaction mixture turned into a clear orange-yellow solution after about 15 minutes.
After stirring for 25 minutes, the solution was added dropwise to a solution of CuBr (5.2 g, 36.3 mmol) in aqueous 48percent HBr (90 mL) at 0° C.
A yellow foam developed and gas was evolved from the purple-brown mixture.
After stirring at 0° C. for 1 hour, the mixture was concentrated under reduced pressure.
The aqueous layer was extracted with EtOAc (4*300 mL) which was dried with Na2SO4 and concentrated to dryness giving a dark solid.
The crude product was filtered through a plug of florisil (~20 g) eluding with EtOAc.
The combined organic fractions were evaporated to approx.
200 mL and washed with 1 M HCl (2*50 mL), brine (50 mL), dried with Na2SO4, filtered and concentrated to dryness giving 6.1 g of a light yellow solid product (2) in 91percent yield and >90percent purity by HPLC.
91% With sodium nitrite In water; hydrogen bromide Step 1:
4-Bromo-2-nitro-benzoic Acid
A modification of a procedure in the following reference which is herein incorporated by reference in its entirety, for all purposes as if fully set forth herein, was used: Boojamra, C. G.; Burow, K. M.; Thompson, L. A.; Ellman, J. A. J. Org. Chem., 1997, 62, 1240-1256.
A solution of NaNO2 (1.9 g, 27.4 mmol) in water (65 mL) was added to a stirred solution of 4-amino-2-nitro-benzoic acid (1) (5 g, 27.4 mmol) in aqueous 48percent HBr (40 mL) and water (82 mL) at 0° C.
The cloudy reaction mixture turned into a clear orange-yellow solution after about 15 minutes.
After stirring for 25 minutes, the solution was added dropwise to a solution of CuBr (5.2 g, 36.3 mmol) in aqueous 48percent HBr (90 mL) at 0° C.
A yellow foam developed and gas was evolved from the purple-brown mixture.
After stirring at 0° C. for 1 hour, the mixture was concentrated under reduced pressure.
The aqueous layer was extracted with EtOAc (4*300 mL) which was dried with Na2SO4 and concentrated to dryness giving a dark solid.
The crude product was filtered through a plug of florisil (-20 g) eluding with EtOAc.
The combined organic fractions were evaporated to approx.
200 mL and washed with 1 M HCl (2*50 mL), brine (50 mL), dried with Na2SO4, filtered and concentrated to dryness giving 6.1 g of a light yellow solid product (2) in 91percent yield and >90percent purity by HPLC.
Reference: [1] Patent: US2005/256157, 2005, A1,
[2] Patent: US2005/261307, 2005, A1,
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YieldReaction ConditionsOperation in experiment
32.8%
Stage #1: With potassium permanganate In pyridine; water at 60℃; for 32 h;
Stage #2: for 0.5 h; Heating / reflux
1.1.a.
4-Bromo-2-nitro-benzoic acid
To a reaction mixture of 82 g (0.379 mol) 4-bromo-2-nitro-toluene in 700 ml of pyridine and 500 ml of water are added batchwise 174.5 g (1.104 mol) of potassium permanganate within eight hours.
The reaction mixture is stirred for 12 hours at 60° C. Then a further 20 g (0.092 mol) of 4-bromo-2-nitro-toluene, 50 ml of pyridine and 30 g (0.189 mol) of potassium permanganate are added one after another.
The reaction mixture is stirred for 12 hours at 60° C., combined with 200 ml of ethanol and refluxed for 30 minutes.
Then the reaction mixture is filtered hot and the filtrate is evaporated down in the rotary evaporator.
The residue remaining is made alkaline with 10percent sodium hydroxide solution and extracted with diethyl ether.
The aqueous phase is separated off and acidified with dilute hydrochloric acid.
The crystals formed are filtered off, washed with water, azeotropically dried with tetrahydrofuran and stirred with diisopropylether.
26% With potassium permanganate; sodium carbonate In water at 105℃; Heating / reflux Sodium carbonate (4.53 g, 42 mmol) was added to a suspension of 4-bromo-2- nitrotoluene (2.00 g, 9.26 mmol) in 140 mL of water. The mixture was heated to 80°C. Potassium permanganate (5.85 g, 37 mmol) was added and the temperature was raised to 105°C and heating was continued under a reflux condenser overnight. The reaction mixture was cooled to room temperature and filtered through Celite. The filtrate was acidified with 6N aqueous HCI and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated to give 0.59 g (26percent yield) of desired product as a beige solid.
22% With potassium permanganate In waterHeating / reflux A. 4-bromo-2-nitrobenzoic acid A mixture of 4-bromo-2-nitrotoluene (5.0 g, 23 mmol), KMnO4 (10.9 g, 69 mmol), and water (250 mL) was heated at reflux overnight in a 1 L round-bottom flask fitted with a reflux condenser. The brown suspended MnO2 was removed by filtration through a pad of diatomaceous earth. The filter cake was washed with water. The basic filtrate was acidified to pH1 with concentrated HCl and extracted with EtOAc (3.x.300 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo to provide pure benzoic acid (1.22 g, 22percent). 1H NMR (400 MHz, CD3OD): 8.07 (d, J=1.9 Hz, 1H), 7.85 (dd, J=8.2, 1.9 Hz, 1H), 7.65 (d, J=8.2 Hz, 1H). MS (ESI): neg. ion m/z 244 [M-H]-.
22%
Stage #1: With potassium permanganate In waterHeating / reflux
Stage #2: With hydrogenchloride In water
A mixture of 4-bromo-2-nitrotoluene (5.0 g, 23 mmol), KMnO4 (1 g, 70 mmol), and H2O (250 mL) was heated at reflux overnight in a 1 L round-bottom flask fitted with a reflux condenser. The brown suspended MnO2 was removed by filtration through a pad of diatomaceous earth. The filter cake was washed with H2O. The basic filtrate was acidified to pH 1 with concentrated HCl and extracted with EtOAc (3.x.300 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo to provide the pure benzoic acid (1.22 g, 22percent). MS (ESI) calculated for C7H4BrNO4, 244.9; found, m/z 244 [M-H]-. 1H NMR (400 MHz, CD3OD): 8.07 (d, J=1.9 Hz, 1H), 7.85 (dd, J=8.2, 1.9 Hz, 1H), 7.65 (d, J=8.2 Hz, 1H).
22% Heating / reflux A. 4-Bromo-2-nitrobenzoic acid. ; A mixture of 4-bromo-2-nitrotoluene (5.0 g, 23 mmol), KMnO4 (10.9 g, 69 mmol), and water (250 mL) was heated at reflux overnight. The mixture was filtered through a pad of diatomaceous earth, washing with water. The basic filtrate was acidified to pH1 with conc. HCl and extracted with EtOAc (3.x.300 mL). The combined organic layers were dried (MgSO4) and concentrated to provide the desired benzoic acid (1.22 g, 22percent). MS (ESI-): mass calcd. for C7H4BrNO4, 244.9; m/z found, 244 [M-H]-. 1H NMR (400 MHz, CD3OD): 8.07 (d, J=1.9, 1H), 7.85 (dd, J=8.2, 1.9, 1H), 7.65 (d, J=8.2, 1H).

Reference: [1] Journal of Medicinal Chemistry, 2006, vol. 49, # 21, p. 6371 - 6390
[2] Patent: US2004/242572, 2004, A1, . Location in patent: Page/Page column 34
[3] Patent: WO2006/52722, 2006, A1, . Location in patent: Page/Page column 87-88
[4] Patent: US2004/224983, 2004, A1, . Location in patent: Page 13
[5] Patent: US2005/38032, 2005, A1, . Location in patent: Page/Page column 11
[6] Patent: US2006/69286, 2006, A1, . Location in patent: Page/Page column 29; 61
[7] Journal of the Chemical Society, 1926, p. 1803
[8] Journal of the Chemical Society, 1926, p. 1803
[9] Collection of Czechoslovak Chemical Communications, 1935, vol. 7, p. 436,443
[10] Journal of the American Chemical Society, 1952, vol. 74, p. 5621
[11] Journal of the American Chemical Society, 1960, vol. 82, p. 5918 - 5923
[12] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 24, p. 6905 - 6909
[13] Patent: US2004/167128, 2004, A1, . Location in patent: Page 38
[14] Patent: US6323155, 2001, B1,
[15] Patent: US2004/157836, 2004, A1,
[16] Organic Process Research and Development, 2006, vol. 10, # 6, p. 1287 - 1291
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Reference: [1] Journal of Organic Chemistry, 1997, vol. 62, # 5, p. 1240 - 1256
[2] Patent: WO2004/18419, 2004, A2, . Location in patent: Page 320-321
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Reference: [1] Patent: US2004/116422, 2004, A1, . Location in patent: Page/Page column 30-31
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Reference: [1] Patent: US2005/256157, 2005, A1,
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Reference: [1] Journal of the American Chemical Society, 1960, vol. 82, p. 5918 - 5923
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Reference: [1] Collection of Czechoslovak Chemical Communications, 1935, vol. 7, p. 436,443
[2] Journal fuer Praktische Chemie (Leipzig), 1891, vol. <2> 43, p. 204
[3] Journal fuer Praktische Chemie (Leipzig), 1891, vol. <2> 43, p. 204
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Reference: [1] Journal fuer Praktische Chemie (Leipzig), 1891, vol. <2> 43, p. 204
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Reference: [1] Journal of the Chemical Society, 1926, p. 1803
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Reference: [1] Tetrahedron Letters, 2004, vol. 45, # 4, p. 817 - 819
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YieldReaction ConditionsOperation in experiment
96%
Stage #1: With borane-THF In tetrahydrofuran at 20℃; for 72 h;
Stage #2: With water; sodium hydrogencarbonate In tetrahydrofuran
Step 1. Borane tetrahydrofuran complex solution (1 M in tetrahydrofuran, 13 mL, 13 mmol) was added over 5 min to a solution of 4-bromo-2-nitrobenzoic acid (2.00 g, 8.13 mmol) at room temperature, then after 72 h the reaction mixture was carefully poured upon sat. aq. sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layer was dried (MgSO4) and evaporated to produce (4-bromo-2-nitro-phenyl)-methanol (1.85 g, 96percent). White solid, 1H-NMR (300 MHz, CDCl3): 8.25 (d, J=1.8, 1H), 7.80 (dd, J=8.1, 1.8, 1H), 7.67 (d, J=8.1, 1H), 4.96 (d, J=6.3, 2H), 2.37 (t, J=6.3, 1H).
95%
Stage #1: With borane In tetrahydrofuran at 0 - 20℃; for 48 h;
Stage #2: With methanol In tetrahydrofuran at 0℃;
Example 25 Synthesis of 4-(7-( 1 -isobutyl- 1 H-pyrazol-4-yl)quinazolin-2-ylamino)-N-(3-(pyrrolidin- 1 - yl)propyl)benzenesulfonamide (Compound 709)Stepl. (4-Bromo-2-nitrophenyl)methanolTo a 0.5M suspension of 4-bromo-2-nitrobenzoic acid in THF in an ice bath was slowly added borane (1.0M /THF, 4eq). The reaction mixture was stirred at ambient temperature for 48 h. LCMS showed the reaction was complete. The mixture was recooled to 00C and quenched with methanol and concentrated to remove solvent. The residue was taken into ethyl acetate and organic phase was washed with water, saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated to give yellow solid in 95percent yield.
Reference: [1] Patent: US2007/191603, 2007, A1, . Location in patent: Page/Page column 40
[2] Patent: WO2007/117607, 2007, A2, . Location in patent: Page/Page column 333
[3] MedChemComm, 2018, vol. 9, # 5, p. 862 - 869
[4] Journal of Medicinal Chemistry, 2018, vol. 61, # 18, p. 8402 - 8416
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Reference: [1] Patent: WO2007/117607, 2007, A2,
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Reference: [1] Journal of Organic Chemistry, 1995, vol. 60, # 18, p. 5814 - 5819
[2] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 24, p. 6905 - 6909
[3] Journal of Medicinal Chemistry, 2006, vol. 49, # 21, p. 6371 - 6390
[4] Patent: US2004/224983, 2004, A1, . Location in patent: Page 13
[5] Patent: US2005/38032, 2005, A1, . Location in patent: Page/Page column 13
[6] Patent: US2006/25460, 2006, A1, . Location in patent: Page/Page column 124
[7] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 22, p. 6373 - 6375
[8] Patent: US2010/160314, 2010, A1, . Location in patent: Page/Page column 69
[9] Patent: WO2012/162254, 2012, A1, . Location in patent: Page/Page column 151
[10] Patent: US2013/143907, 2013, A1, . Location in patent: Paragraph 0315; 0316; 0317
[11] European Journal of Medicinal Chemistry, 2013, vol. 70, p. 233 - 247
[12] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 9, p. 2488 - 2500
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YieldReaction ConditionsOperation in experiment
97% With caesium carbonate In N,N-dimethyl-formamide at 20℃; Compound 7 A (10.0 g, 40.7 mmol) was dissolved in DMF (100 mL). Cs2CO3 (27.0g, 81.3 mmol) and methyl iodide (7.60 mL, 122.0 mmol) were added. The solution was stirred at room temperature overnight. EtOAc (250 mL) and water (100 mL) were added. The organic phase was separated and washed with water (100 mL) three times and brine (50 mL), then dried over Na2SO4) filtered, and concentrated using a rotary evaporator. The product was dried under vacuum to give compound 7B (10.3 g, 97percent).
94% With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 3 h; Example I-XVIIPreparation of Compound 321General Procedure I-ESTo a mixture of 4-bromo-2-nitrobenzoic acid (10 g, 41 mmol) and K2CO3 (11.3 g, 82 mmol) in 100 mL of DMF was added CH3I (7.1 g, 50 mmol) dropwise and the mixture was stirred at 80° C. for 3 hrs. After cooling to r.t, the mixture was filtered, the filtrated was concentrated under reduced pressure to remove DMF, and the residue was dissolved with EtOAc (50 mL), washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography to give methyl 4-bromo-2-nitrobenzoate (I-XVIIa, 10 g, yield 94percent). 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.66 (d, J=8.0 Hz, 1H), 3.92 (s, 3H).
94% With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 3 h; To a mixture of 4-bromo-2-nitrobenzoic acid (10 g, 41 mmol, 1 eq) and K2CO3 (11.3 g, 82 mmol, 2 eq) in 100 mL of DMF was added CH3I (7.1 g, 50 mmol, 1.2 eq) dropwise and the mixture was stirred at 80 °C for 3 hrs. After cooling to rt, the mixture was filtered, the filtrated was poured into water and extracted with EtOAc (150 mL x 3), washed with water (150 mL x 3) and brine (150 mL x 2), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography to give methyl 4-bromo-2-nitrobenzoate (10 g, 94percent). 1HNMR (300 MHz, DMSO-d6): G 8.34 (s, 1H), 8.08- 8.05 (m, 1 H), 7.85- 7.82 (m, 1 H), 3.85 (s, 3 H).
90% With 1,8-diazabicyclo[5.4.0]undec-7-ene In DMF (N,N-dimethyl-formamide) at 0 - 20℃; A. Methyl 2-amino-4-bromobenzoate To a stirred solution of 4-bromo-2-nitrobenzoic acid (EXAMPLE 5) (3.81 g, 15 mmol) in DMF (30 mL) at 0° C. was added 1,8-diazabicycloundecane (DBU) (10.3 mL, 75 mmol) followed by methyl iodide (4.67 mL, 75 mmol).
The reaction mixture was stirred 15 min at 0° C. then allowed to warm to room temperature and stir overnight.
The mixture was poured into water and extracted with EtOAc (2*).
The combined organic extracts were washed with water (2*), dried (MgSO4), and concentrated in vacuo.
The residue was purified by flash chromatography (hexanes/EtOAc) to afford methyl 4-bromo-2-nitrobenzoate as a pale yellow solid (3.52 g, 90percent).
90% With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide at 0 - 20℃; B. Methyl 2-amino-4-bromobenzoate. ; To a stirred solution of 4-bromo-2-nitrobenzoic acid (3.81 g, 15 mmol) in DMF (30 mL) at 0° C. was added 1,8-diazabicycloundecane (DBU; 10.3 mL, 75 mmol) followed by Mel (4.67 mL, 75 mmol). The mixture was stirred for 15 min at 0° C., then was allowed to warm to rt and was stirred overnight. The mixture was poured into water and extracted with EtOAc (2.x.). The combined organic extracts were washed with water (2.x.), dried (MgSO4), and concentrated. The residue was purified by flash chromatography (hexanes/EtOAc) to afford methyl 4-bromo-2-nitrobenzoate as a pale yellow solid (3.52 g, 90percent). To a solution of the nitrobenzoate (3.52 g, 13.5 mmol) in 1:1 EtOAc/DCM (30 mL) at rt was added SnCl2.2H2O (15.27 g, 67 mmol). After 18 h, the mixture was concentrated, diluted with satd. aq. NaHCO3, and extracted with DCM (3.x.). The combined organic layers were dried (MgSO4) and concentrated to provide the desired aminobenzoate as a white solid (2.89 g, 93percent). 1H NMR (400 MHz, CDCl3): 7.70(d, J=8.6, 1H), 6.84 (d, J=1.9, 1H), 6.75 (dd, J=8.6, 1.9, 1H), 5.78 (br s, 2H), 3.86 (s, 3H).
90% With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide at 0 - 20℃; for 48.25 - 72.25 h; Example 62:; N-[7-ethyI-6-(l-methyI-lH-pyrazol-4-yl)-2,4-dioxo-l,4-dihydro-2H-quinazoIin-3-yI]- methanesulfonamide; 4-Bromo-2-nitro-benzoic acid methyl ester; To a solution of 4-bromo-2-nitrobenzoic acid (25.3 g, 103 mmol) in DMF (200 mL) at 0 0C were added DBU (79.1 mL, 514.8 mmol) and MeI (32.2 mL, 515 mmol). The reaction mixture was stirred for 15 min at this temperature and for 72 h at r.t. The mixture was poured into water and extracted with EtOAc (2X). The combined organic layers were washed with water (2X), dried (Na2SO4) and the solvent was removed in vacuo. The residue was purified by flash chromatography (silica gel, 7:3 hexanes:EtOAc) to provide the title compound (26.24 g, 98percent) as a yellow oil.; Example 71:; N-[7-(l,l-difluoro-ethyl)-6-(2-isopropyl-2H-pyrazol-3-yl)-2,4-dioxo-l,4-dihydro-2H- quinazolin-3-yl]-methanesulfbnamide; 4-Bromo-2-nitro-benzoic acid methyl ester; To solution of 4-bromo-2-nitro-benzoic acid (9 g, 36.58 mmol) in dimethylforrnamide (36 mL) cooled to 0 0C were added l,8-diazabicyclo[5.4.0]und-7-ene (28.09 mL, 182.9 mmol) and MeI (11.4 mL, 182.5 mmol). The reaction mixture was stirred at 0 0C for 15 min and at r.t. for 48 h. The mixture was poured into water and extracted with EtOAc (2X). The combined organic phases were washed with water (2X), dried (Na2SO4) and concentrated to dryness. The crude product was purified by flash chromatography (hexanes to EtOAc / hexanes (4:6)) to give 4-bromo-2-nitro-benzoic acid methyl ester (8.62 g, 33.147 mmol, 90percent). 1H-NMR (CDCl3, 400 MHz) 8.02 (s, 1 H), 7.81 (dd, J= 2.3, 10.5Hz IH), 7.66 (d, J= 8.2 Hz, IH), 3.92 (s, 3H).
0.9% With 1,8-diazabicyclo[5.4.0]undec-7-ene In DMF (N,N-dimethyl-formamide) at 0 - 20℃; To a stirred solution of 4-bromo-2-nitrobenzoic acid (3.8 g, 15 mmol) in DMF (30 mL) at 0° C. was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (10.0 mL, 75.0 mmol) followed by iodomethane (4.7 mL, 75 mmol). The reaction mixture was stirred 15 min at 0° C., then was allowed to warm to room temperature and was stirred overnight. The mixture was poured into H2O and extracted with EtOAc (2.x.). The combined organic extracts were washed with H2O (2.x.), dried (MgSO4), and concentrated in vacuo. The residue was purified by flash chromatography (hexanes/EtOAc) to afford methyl 4-bromo-2-nitrobenzoate as a pale yellow solid (3.52 g, 0.90percent). To a solution of the nitrobenzoate (3.52 g, 13.5 mmol) in 1:1 EtOAc/DCM (30 mL) at room temperature was added SnCl2.2H2O (15 g, 67 mmol). The reaction mixture was allowed to stir overnight. The solvents were evaporated in vacuo, and the residue was partitioned between satd. aq. NaHCO3 and DCM. The layers were separated, and the aqueous layer was further extracted with DCM (2.x.). The combined organic layers were dried (MgSO4) and concentrated in vacuo to provide the pure aminobenzoate as a white solid (2.89 g, 93percent). 1H NMR (400 MHz, CDCl3): 7.70 (d, J=8.6 Hz, 1H), 6.84 (d, J=1.9 Hz, 1H), 6.75 (dd, J=8.6, 1.9 Hz, 1H), 5.78 (br s, 2H), 3.86 (s, 3H).

Reference: [1] Patent: WO2006/19768, 2006, A1, . Location in patent: Page column 87
[2] Patent: US2011/152246, 2011, A1, . Location in patent: Page/Page column 186-187
[3] Patent: WO2017/120429, 2017, A1, . Location in patent: Page/Page column 300
[4] Journal of Medicinal Chemistry, 2006, vol. 49, # 21, p. 6371 - 6390
[5] Patent: US2004/224983, 2004, A1, . Location in patent: Page 15
[6] Patent: US2006/69286, 2006, A1, . Location in patent: Page/Page column 29
[7] Patent: WO2006/108591, 2006, A1, . Location in patent: Page/Page column 125-126; 130
[8] Patent: US2005/38032, 2005, A1, . Location in patent: Page/Page column 11
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  • [ 158580-57-5 ]
YieldReaction ConditionsOperation in experiment
78% With sulfuric acid In water for 16 h; Heating / reflux Step 1. Preparation of Methyl 4-bromo-2-nitrobenzoate Add concentrated sulfuric acid (7 mL) to a solution of commercially available 4- bromo-2-nitrobenzoic acid (25.0 g, 102 mmol) in methanol (150 mL), and heat at reflux for 16 hours. Cool the reaction to room temperature and pour into water (500 mL) and adjust the pH of the suspension to 9 with solid sodium carbonate. Extract the solution with ethyl acetate (2 x 250 mL), then combine the organic extracts and wash with brine (100 mL), dry over sodium sulfate, filter and remove the solvent under reduced pressure to afford the title compound as a pale amber oil, which crystallizes upon standing (20.5 g, 78percent)
Reference: [1] Patent: WO2005/37796, 2005, A1, . Location in patent: Page/Page column 50-51
[2] Patent: EP2471792, 2012, A1, . Location in patent: Page/Page column 65
[3] Journal of the American Chemical Society, 2018, vol. 140, # 33, p. 10553 - 10561
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  • [ 158580-57-5 ]
Reference: [1] Patent: WO2006/62093, 2006, A1, . Location in patent: Page/Page column 55-56
[2] Patent: EP1860098, 2007, A1, . Location in patent: Page/Page column 40
  • 24
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Reference: [1] Patent: EP1820795, 2007, A1,
  • 25
  • [ 507-19-7 ]
  • [ 99277-71-1 ]
  • [ 890315-72-7 ]
Reference: [1] Patent: WO2006/62093, 2006, A1, . Location in patent: Page/Page column 56
[2] Patent: EP1820795, 2007, A1,
[3] Patent: EP1860098, 2007, A1, . Location in patent: Page/Page column 40-41
  • 26
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  • [ 953039-66-2 ]
Reference: [1] Patent: WO2007/117607, 2007, A2,
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  • [ 1826-67-1 ]
  • [ 1211594-25-0 ]
Reference: [1] Patent: WO2014/210255, 2014, A1, . Location in patent: Page/Page column 94; 95
  • 28
  • [ 99277-71-1 ]
  • [ 1224724-39-3 ]
Reference: [1] Patent: US2011/152246, 2011, A1,
[2] Patent: WO2014/210255, 2014, A1,
[3] Patent: WO2017/120429, 2017, A1,
  • 29
  • [ 99277-71-1 ]
  • [ 1211596-82-5 ]
Reference: [1] Patent: WO2014/210255, 2014, A1,
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