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Chemical Structure| 62621-09-4
Chemical Structure| 62621-09-4
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Product Details of [ 62621-09-4 ]

CAS No. :62621-09-4 MDL No. :MFCD03618407
Formula : C9H9NO4 Boiling Point : -
Linear Structure Formula :- InChI Key :JJHCLPDHYBSSHC-UHFFFAOYSA-N
M.W :195.17 Pubchem ID :15088700
Synonyms :

Calculated chemistry of [ 62621-09-4 ]

Physicochemical Properties

Num. heavy atoms : 14
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.22
Num. rotatable bonds : 3
Num. H-bond acceptors : 4.0
Num. H-bond donors : 0.0
Molar Refractivity : 51.51
TPSA : 72.12 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.09 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.77
Log Po/w (XLOGP3) : 1.97
Log Po/w (WLOGP) : 1.69
Log Po/w (MLOGP) : 1.16
Log Po/w (SILICOS-IT) : 0.03
Consensus Log Po/w : 1.32

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.41
Solubility : 0.759 mg/ml ; 0.00389 mol/l
Class : Soluble
Log S (Ali) : -3.11
Solubility : 0.152 mg/ml ; 0.000776 mol/l
Class : Soluble
Log S (SILICOS-IT) : -2.25
Solubility : 1.11 mg/ml ; 0.00568 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 2.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.79

Safety of [ 62621-09-4 ]

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 [ 62621-09-4 ]

* 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 [ 62621-09-4 ]
  • Downstream synthetic route of [ 62621-09-4 ]

[ 62621-09-4 ] Synthesis Path-Upstream   1~14

  • 1
  • [ 1975-51-5 ]
  • [ 74-88-4 ]
  • [ 62621-09-4 ]
YieldReaction ConditionsOperation in experiment
100% With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 2 h; Method L:Step a: [00293] A mixture of 2-methyl-4-nitrobenzoic acid (l eq.) iodomethane (1.1 eq.), K2CO3 (1.5 eq.), and 10 mL of DMF is stirred for 2hrs at room temperature, then poured into water and extracted with AcOEt. The extract is washed with water and brine, dried over anhydrous MgSψ4, and evaporated to afford the expected compound in quantative yield.
89% With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 3 h; A solution of 2-methyl-4-nitro-benzoic acid (10 g, 55 mmol), MeI (3.8 ml, 61 mmol) and K2CO3 (11.4 g, 83 mmol) in DMF was stirred for 3 h at RT after which the reaction was poured onto water and extracted in EtOAc. The organic fractions were washed with water and brine, dried over Na2SO4 and concentrated to give the desired product as an orange solid (9.57g, 89percent). 1H NMR (400 MHz, DMSO-^6) δ ppm 2.60 (s, 3 H), 3.88 (s, 3 H), 8.00 (d, J=8.70 Hz, 1 H), 8.10 - 8.16 (m, 1 H), 8.21 (d, J=2.29 Hz, I H).
Reference: [1] Patent: WO2010/10184, 2010, A1, . Location in patent: Page/Page column 59
[2] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 22, p. 7625 - 7651
[3] Patent: WO2009/122180, 2009, A1, . Location in patent: Page/Page column 101
[4] Patent: WO2015/81891, 2015, A1, . Location in patent: Page/Page column 138
  • 2
  • [ 67-56-1 ]
  • [ 1975-51-5 ]
  • [ 62621-09-4 ]
YieldReaction ConditionsOperation in experiment
100% at 70℃; for 18 h; Intermediate 5; Methyl 2-methyl-4-nitrobenzoate; SOCI2 was added to a solution of 2-methyl-4-nitrobenzoic acid (3 g, 16.5 mmol) in methanol dropwise. The reaction mixture was stirred at 70°C for 18 hours. The mixture was evaporated and the residue was diluted with diethyl ether, washed with water and NaOH 1 N. The organic phase was dried over Na2SO4, filtered and evaporated to give the title compound as dark yellow solid (3.25 g, quantitative yield). NMR1H NMR (300 MHz), CDCI3 δ: 7.95 (m, 3H), 3.86 (s, 3H), 2.59 (s, 3H).
98% at 70℃; for 7 h; Under ice bath was added SOCl2 dropwise anhydrous methanol (100ml) in. And then a solution of 2-methyl-4-nitrobenzoic acid (10.0 g, 55.2 mmol) in anhydrous methanol (70mL) solution, 1 hour addition was complete. This mixed system placed in an oil bath at 70 ° C 7 hours, TLC the reaction was complete. Cooling, the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate (100 mL) was added saturated sodium bicarbonate (100 mL), separated, the aqueous phase was extracted once with ethyl acetate (50mL). The combined organic phase was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure, and dried under high vacuum to give a white solid 10.5g, 98percent yield
96% for 15 h; Reflux Example 1) l-MethyI-lH-imidazole-4-suIfonic acid (4-chloro-benzyI)-(2-ethyI-l- oxo-2,3-dihydro-lH-isoindol-5-yl)-amide (Method A)i) 2-Methyl-4-nitro-benzoic acid methyl ester2-Methyl-4-nitrobenzoic acid (2.00 g, 11.00 mmol) was stirred in concentrated sulfuric acid (0.6 ml) and methanol (25 ml) at reflux for 15 hrs. Reaction was cooled and the solvent evaporated. The resulting residue was partitioned between water and dichloromethane and the organic phase separated. The aqueous phase was extracted with dichloromethane (x3) and the combined organics washed with brine, then dried (MgSO4) and evaporated in vacuo to yield the title compound as a pale yellow solid (1.89 g, 96percent). HPLC retention time 4.39min.
95.3% at 0 - 70℃; for 24.5 h; Step 1:
Synthesis of 2-Methyl-4-nitro-benzoic acid methyl ester
To a solution of 2-methyl-4-nitro-benzoic acid (3 g, 16.56 mmole) in 30 ml methanol was added at 0° C. sulfuric acid (95-98percent, 10 ml) slowly for ½ hr.
The reaction mixture was stirred at 70° C. for 24 hrs.
Mixture was cooled down, a solid precipitated out, then the mixture was concentrated, diluted with 50 ml water, stirred for 10 minutes, filtered off, the solid was washed with water, dried to afford 3.08 g of brown solid, 95.3percent yield, pure by H NMR.
94.65% for 15 h; Reflux In a 250 mL, 3-neck round-bottomed flask, 2-methyl-4-nitrobenzoic acid (20 g, 93.8 mmol) was charged with methanol (100 mL) and sulfuric acid (4 mL). The reaction mixture was refluxed for 15 h. After completion, the reaction mixture was concentrated to obtain the crude product which was added water (200 mL) and basified to pH 7-8 with aqueous NaHC03 solution. Aqueous solution was extracted with dichloromethane (250 mL X 3), the organic layer was washed with saturated brine solution followed by drying over anhydrous sodium sulphate. The solvent was removed to obtain methyl 2-methyl-4- nitrobenzoate 1), 20 g; Yield: 94.65percent.
93% at 0 - 80℃; for 2 h; SOCl2 (2.6 g, 22.0 mmol) was slowly added to the solution of 2-methyl-4- nitrobenzoic acid (61.1) (2.0 g, 11.0 mmol) in MeOH (20 mL) at 0 °C. The resulting mixture was heated at 80 °C for 2 h. After cooling to room temperature, the reaction mixture was concentrated to afford methyl 2-methyl-4-nitrobenzoate (61.2) as a yellow oil (2.0 g, 93percent).
91.3% at 12 - 20℃; for 12 h; Thionyl chloride (4.3 g, 36.45 mmol) was added dropwise to a stirred solution of 18 (3 g, 16.57 mmol) in MeOH (25 mL) while maintaining the internal temperature below 12 °C. When the addition was complete the mixture was left to stand at room temperature for 12 h to result a white precipitation. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford white solid. The solid was washed with hexane and ethyl ether to afford 19 (2.95 g, 91.3percent); mp 153.7-154.4 °C (lit.39 mp 153-154 °C); Rf 0.43 (hexane/EtOAc 3:1); 1H NMR (CDCl3) δ 2.69 (s, 3H, CH3), 3.95 (s, 3H, COOCH3), 8.02-8.11 (m, 3H, C6H3).
90.9% at 20 - 60℃; EXAMPLE 75
2-Methyl-4-nitro-benzoic acid methyl ester (1)
In accordance with general method S, 5.00 g (27.60 mmol) of 2-methyl-4-nitro-benzoic acid are dissolved in 20 ml of methanol, with heating, and 6 ml of concentrated sulfuric acid are added.
The mixture is refluxed for 5 h. Yield: 4.90 g (90.9percent); melting point: 73.6° C.
C9H9NO3(Mr=195.18); GC (method 1) 9.55 min
1H-NMR (CDCl3) in ppm: 8.19-8.09 (m, 2H, aryl H), 7.99 (d, 1H, J=8.52 Hz, aryl H), 3.87 (s, 3H, -OCH3), 2.59 (s, 3H, -CH3)
13C-NMR (CDCl3) in ppm: 166.35 (-C=O), 159.29 (C4), 141.79 (C2), 135.14 (C1), 131.43 (C6), 126.06 (C3), 120.48 (C5), 52.37 (-OCH3), 21.50 (-CH3)
IR (ATR) (cm-1): 1722, 1523, 1432, 1348, 1260, 1081, 896, 821, 786, 730
MS m/z (percent): 195 (70), 164 (100), 134 (21), 118 (29), 63 (15). General Method SFor esterification of the acid group of the starting compound 2-methyl-4-nitro-benzoic acid, the stated amount is dissolved in methanol in a 100 ml one-necked flask at room temperature, concentrated H2SO4 is added and the mixture is refluxed at approx. 60° C. for 6 h. The excess alcohol is removed in vacuo, the residue is taken up in EtOAc and the mixture is deacidified repeatedly with 20percent strength sodium hydroxide solution. After drying (Na2SO4), the combined organic phases are concentrated in vacuo.

Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 3, p. 942 - 945
[2] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 3, p. 946 - 949
[3] Patent: WO2009/47240, 2009, A1, . Location in patent: Page/Page column 28
[4] Journal of Medicinal Chemistry, 1999, vol. 42, # 18, p. 3510 - 3519
[5] Patent: CN103804358, 2016, B, . Location in patent: Paragraph 0117
[6] Patent: WO2010/139953, 2010, A1, . Location in patent: Page/Page column 31-32
[7] Patent: US9138427, 2015, B2, . Location in patent: Page/Page column 286
[8] Patent: WO2016/81464, 2016, A1, . Location in patent: Paragraph 00117
[9] Patent: WO2016/90079, 2016, A1, . Location in patent: Paragraph 00866
[10] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 11, p. 3585 - 3594
[11] Patent: US2012/115862, 2012, A1, . Location in patent: Page/Page column 34-35
[12] Patent: WO2005/80388, 2005, A1, . Location in patent: Page/Page column 63
[13] Patent: WO2006/17443, 2006, A2, . Location in patent: Page/Page column 155-156
[14] Patent: US2010/15141, 2010, A1, . Location in patent: Page/Page column 26
[15] Patent: WO2011/19538, 2011, A1, . Location in patent: Page/Page column 127
[16] Patent: CN105218397, 2016, A, . Location in patent: Paragraph 0011
  • 3
  • [ 67-56-1 ]
  • [ 201230-82-2 ]
  • [ 5326-38-5 ]
  • [ 62621-09-4 ]
Reference: [1] Patent: WO2006/7542, 2006, A1, . Location in patent: Page/Page column 24
  • 4
  • [ 67-56-1 ]
  • [ 30459-70-2 ]
  • [ 62621-09-4 ]
YieldReaction ConditionsOperation in experiment
100% at 0℃; for 0.5 h; [00147] To 2-methyl-4-nitrobenzoic acid (10.5 g, 58.0 mmol) in CH2C12 (80 ml) was added 2.0 M oxalyl chloride in methylene chloride (39.9 ml, 80 mmol), followed by DMF (0.224 ml, 2.90 mmol). The mixture was stirred at 40 °C for 1.5 h and then at rt for 0.5 h. Solvent was removed and the residue was put on high vacuum for 0.5 h. The acyl chloride prepared was then dissolved in methylene chloride (40mL) and cooled at 0 °C, MeOH (40mL) was added and the mixture was stirred at 0 °C for 0.5 h. Solvent was removed, the crude was diluted with EtOAc, washed with sat. sodium bicarbonate, brine. The organic layer was dried over sodium sulfate and concentrated to give Intermediate 3A (1 1.35 g, 58.2 mmol, 100percent yield) as a white solid.1 NMR (400 MHz, chloroform-d) δ ppm 7.98 - 8.1 1 (m, 3 H) 3.93 (s, 3 H) 2.67 (s, 3 H).
100% at 0℃; for 0.5 h; Intermediate 3A: 2-Methyl-4-nitro-benzoic acid methyl ester j00129j To 2-methyl-4-nitrobenzoic acid (6.5 g, 35.9 mmol) in DCM (40 mL) was added 2.0 M oxalyl chloride in DCM (24.67 mL, 49.3 mmol), followed by DMF (0.139 mL, 1.794 mmol). The mixture was stirred at 40 °C for 1.5 h and then at rt for 0.5 h. The solvent was removed and the residue was stored under high vacuum for 0.5 h. The intermediate acid chloride was then dissolved in DCM (40 mL) and cooled to 0 °C,MeQH (40 mL) was then added and the mixture was stirred at 0 °C for 0.5 h. Solvent was removed, the crude reaction mixture was diluted with EtOAc, washed with saturated NaHCO3 and brine. The organic layer was dried over sodium sulfate and concentrated to give Intermediate 3A (7.0 g, 35.9 mmol, 100 percent yield) as a white solid. ‘H NMR (400 MHz, CHLOROFORIVI-d) ö ppm 7.98 - 8.11 (m, 3 H) 3.93 (s, 3 H) 2.67 (s, 3 H).
Reference: [1] Patent: WO2013/184734, 2013, A1, . Location in patent: Paragraph 00146; 00147
[2] Patent: WO2014/201073, 2014, A1, . Location in patent: Paragraph 00129
  • 5
  • [ 1975-51-5 ]
  • [ 62621-09-4 ]
Reference: [1] Patent: WO2013/184734, 2013, A1,
[2] Patent: WO2014/201073, 2014, A1,
  • 6
  • [ 99584-16-4 ]
  • [ 62621-09-4 ]
Reference: [1] Journal of Medicinal Chemistry, 1999, vol. 42, # 18, p. 3510 - 3519
  • 7
  • [ 89001-53-6 ]
  • [ 62621-09-4 ]
Reference: [1] Journal of Medicinal Chemistry, 1999, vol. 42, # 18, p. 3510 - 3519
  • 8
  • [ 99-52-5 ]
  • [ 62621-09-4 ]
Reference: [1] Journal of Medicinal Chemistry, 1999, vol. 42, # 18, p. 3510 - 3519
  • 9
  • [ 124-41-4 ]
  • [ 62621-09-4 ]
  • [ 10268-12-9 ]
Reference: [1] Helvetica Chimica Acta, 1998, vol. 81, # 2, p. 251 - 267
  • 10
  • [ 62621-09-4 ]
  • [ 6933-47-7 ]
YieldReaction ConditionsOperation in experiment
100% With ammonium formate In ethanol at 40℃; for 2 h; Intermediate 7; Methyl 4-amino-2-methylbenzoate; To a solution of methyl 2-methyl-4-nitrobenzoate (Intermediate 5) (3.25 g, 16.6 mmol) in ethanol was added Pd/C 10percent (catalytic quantity) and ammonium formate (10.5 g, 0.17 mmol). The mixture was stirred at 400C for 2 hours. The mixture was filtered on celite, washed with diethyl ether. The filtrate was evaporated and the residue was diluted with diethyl ether, washed with water. The organic phase was dried over Na2SC>4, filtered and evaporated to give the title compound as brown oil (2.8 g, quantitative yield). NMR1H NMR (300 MHz), CDCI3 δ: 7.74 (d, 1 H, J=9.20 Hz), 6.41 (m, 2H), 3.75 (s, 3H), 2.47 (s, 3H).
Reference: [1] Patent: WO2009/47240, 2009, A1, . Location in patent: Page/Page column 29
[2] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 3, p. 942 - 945
[3] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 3, p. 946 - 949
[4] Bulletin de la Societe Scientifique de Bretagne, 1956, vol. 31, p. Sonderheft S.9,41
[5] Patent: WO2006/7542, 2006, A1, . Location in patent: Page/Page column 24
  • 11
  • [ 62621-09-4 ]
  • [ 133446-99-8 ]
YieldReaction ConditionsOperation in experiment
96% With N-Bromosuccinimide In tetrachloromethane for 2 h; Reflux U) 2-Bromomethyl-4-nitro-benzoic acid methyl esterN-Bromosuccinimide (2.18 g, 12.30 mmol) was added to a stirred solution of 2- methyl-4-nitro-benzoic acid methyl ester (2 g, 10.25 mmol) and ABCN (626 mg, 2.56 mmol) in carbon tetra-chloride (80 ml) at room temperature. The reaction was heated at reflux for 2 hrs and then allowed to cool to room temperature and stirred for 15 hrs. The solvent was evaporated in vacuo and the resulting residue filtered through a pad of silica (eluting with dichloromethane). The solvent was evaporated in vacuo to afford the title compound as a yellow solid (2.70 g, 96percent). HPLC retention time 4.49min. Mass spectrum (ES+) m/z 256 (M+H).
88.8% With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane at 70℃; Reflux; Irradiation EXAMPLE 76
2-Bromomethyl-4-nitro-benzoic acid methyl ester (2)
In accordance with general method T, 4.70 g (24.00 mmol) of (1) are dissolved in 30 ml of carbon tetrachloride, with heating, and 5.00 g (28.00 mmol) of N-bromosuccinimide and 2 spatula tips of azobisisobutyronitrile are then added.
The mixture is refluxed for 6 h with irradiation with a 500 W spotlight.
On cooling to room temperature, succinimide separates out, and is filtered off.
The filtrate is evaporated on a rotary evaporator in order to obtain the product as a yellow oil. Yield: 5.85 g (88.8percent)
C9H8BrNO4 (Mr=274.07); GC (method 3) 7.98 min
1H-NMR (CDCl3) in ppm: 4.96 (s, 2H, -CH2-Br), 2.71 (s, 3H, -CH3)
MS m/z (percent): 274 (100), 193 (38), 178 (46), 147 (12), 132 (18), 88 (9). General Method TThe substance to be halogenated is dissolved in carbon tetrachloride in a 250 ml three-necked flask with a reflux condenser and drying tube at approx. 70° C. and the stated amounts of N-bromosuccinimide and azobisisobutyronitrile are added. The mixture is refluxed for 5 h, if necessary with irradiation with a 500 W spotlight. At the end of the reaction, the N-bromosuccinimide has dissolved and has been converted into succinimide, which settles on the surface. After cooling to room temperature, the mixture is filtered with suction. The filtrate is evaporated on a rotary evaporator in order to obtain the product as a yellow - orange oil.
78.7% With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane for 20 h; Reflux In a 500 mL, 3-neck round-bottomed flask, the intermediate (1) (20 g, 88.01 mmol) was charged with CC14 (100 mL). N-bromosuccinimide (39.16g, 220.03 mmol) and AIBN (2.16 g, 13.20 mmol) were added and the resulting mixture was refluxed for 20 h. The reaction mixture was quenched with water (500 mL), extracted with dichloromethane (200 mL X 3), and the combined organic layer was washed with saturated brine solution followed by drying over anhydrous sodium sulphate. The organic layer was evaporated under reduced pressure and the crude product obtained was purified by silica gel column chromatography to obtain pure methyl 2-(bromomethyl)-4-nitrobenzoate (2), 19 g; Yield: 78.7percent; Η NMR (400 MHz, OMSO-de) : δ 8.52 (s, 1H), 8.27-8.3(dd, 1H), 8.07-8. l(d, 1H), 5.1 (s, 2H), 3.94 (s, 1H).
65% With N-Bromosuccinimide; 1,1'-azobis(1-cyanocyclohexanenitrile) In tetrachloromethane for 5 h; Reflux To a solution of 2-methyl-4-nitrobenzoic acid methyl ester (2.0 g, 10.36 mmol) in carbon tetrachloride (80 mL) and l , azobis(cyclohexanecarbonitrile) (0.63 g, 2.56 mmol) was added N-bromosuccinimide (2.18 g, 12.25 mmol) and the resulting solution was heated at reflux for 5h and allowed to sit at room temperature overnight. The reaction was concentrated under reduced pressure and to the resulting residue was added DCM. The solid was filtered off and washed several times with DCM. The combined filtrate and washes were loaded onto a silica column and eluted with 10percent EtOAc/hexane to provide slightly impure methyl 2-(bromomethyl)-4-nitrobenzoate (1.82 g, 65percent yield) which was carried on as is to the next step.
49% With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane at 85℃; for 21 h; A solution of Intermediate 58 (9.57 g, 49 mmol), NBS (9.6g, 54 mmol), benzoyl peroxide (121 mg,0.5 mmol) in carbon tetrachloride was heated at 85°C for 18 h. The reaction was concentrated under vaccum, analysed by TLC and 1H NMR and found to have some remaining starting material. <n="103"/>The residues were added to CCl4 (40 ml) with NBS (4.4 g) and benzoyl peroxide (60 mg) then stirred at 85°C for 3h. The reaction was concentrated, taken up in DCM then washed with aqueous NaHCO3 and brine. The organic phase was dried over Na2SO4 and concentrated under vacuum. The residues were purified by flash chromatography using a Biotage SP4. The desired product was isolated as an orange solid (6.58 g, 49percent). 1H NMR (400 MHz, DMSO-^6) δ ppm 3.93 (s, 3 H), 5.10 (s, 2 H), 8.08 (d, 7=8.24 Hz, 1 H), 8.25 - 8.30 (m, 1 H), 8.51 (d, /=2.29 Hz, 1 H).
48.2% With N-Bromosuccinimide; dibenzoyl peroxide In 1,2-dichloro-ethane for 48 h; Reflux A solution of 19 (2.57 g, 13.19 mmol) in 1,2-dichloroethane (100 mL) was treated with N-bromosuccinimide (2.3 g, 13.19 mmol) and benzoyl peroxide (0.26 g), and the mixture was kept at reflux for 2 days, then cooled, washed with water, and evaporated to a yellow oil (3.52 g). The oil was dissolved in acetone and silica gel (4.0 g) was added. A dry silica gel plug was obtained after evaporation of the solvent. The plug was loaded on to a silica gel column and eluted with 10percent ethyl acetate in hexane to afford 20 (1.73 g, 48.2percent) as a yellow oil; Rf 0.53 (hexane/EtOAc 3:1); 1H NMR (CDCl3) δ 3.89 (s, 3H, COOCH3), 4.86 (s, 2H, CH2Br), 7.98-8.23 (m, 3H, C6H3).
44% With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 7 h; Inert atmosphere; Heating 2 - methyl-4-nitrobenzoate (. 200mg, 1 OmmoL), benzoyl peroxide (48.5mg,0.2mmoL), N_-bromosuccinimide (213mg, 1.2mmoL) was added to the CCl4 (15mL), and under protection of Ar gas, the reaction was heated at reflux for 7 hours, cooled, washed with saturated sodium bicarbonate (3 X20mL ), saturated brine (20 mL), dried and the solvent was distilled off under reduced pressure, the residue was purified by flash column chromatography, eluent PE: ΕΑ = 20: 1, to give a white solid 124mg, 44percent yield
39% With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane at 80℃; Azobisisobutyronitrile (AIBN) (0.17 g, 1.02 mmol) was added to the solution of methyl 2-methyl-4-nitrobenzoate (61.2) (2.0 g, 10.2 mmol) and N-bromosuccinimide (NBS) (2.7 g, 15.2 mmol) in CCl4 (50 mL). The mixture was stirred at 80 °C overnight. After cooling to room temperature, the reaction mixture was filtered and, the filtrate was concentrated to afford methyl 2-(bromomethyl)-4-nitrobenzoate (61.3) as a white solid (1.1 g, 39percent). [00869] LCMS: 314.0 [M+CH3CN]+.
1.9 g With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 10 h; Reflux 2-Methyl-4-nitro - benzoic acid methyl ester (3.0 g, 15 mmol) wasdissolved in carbon tetrachloride (50 mL), and then were added N- bromosuccinimide (3.0 g, 17 mmol) and benzoyl peroxide (100mg, 0.4 mmol), the addition was complete the reaction was refluxed for 10hours. Completion of the reaction, the reaction solution was cooled toroom temperature, filtered, and the filtrate was washed with saturated sodiumbicarbonate solution and water, dried over anhydrous sodium sulfate, filteredand concentrated. Was purified by silica gel column chromatography usingconcentrated to give the intermediate 2-bromomethyl-4-nitro - benzoic acidmethyl ester (pale yellow solid, 1.9 g).

Reference: [1] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 22, p. 7625 - 7651
[2] Patent: WO2010/139953, 2010, A1, . Location in patent: Page/Page column 32
[3] Patent: US2012/115862, 2012, A1, . Location in patent: Page/Page column 34-35
[4] Patent: WO2016/81464, 2016, A1, . Location in patent: Paragraph 00118
[5] ACS Medicinal Chemistry Letters, 2018, vol. 9, # 3, p. 250 - 255
[6] Patent: WO2018/136935, 2018, A1, . Location in patent: Paragraph 00500
[7] Patent: WO2009/122180, 2009, A1, . Location in patent: Page/Page column 101-102
[8] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 11, p. 3585 - 3594
[9] Patent: CN103804358, 2016, B, . Location in patent: Paragraph 0120
[10] Patent: WO2016/90079, 2016, A1, . Location in patent: Paragraph 00868-00869
[11] Journal of Medicinal Chemistry, 1991, vol. 34, # 7, p. 2209 - 2218
[12] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 11, p. 1625 - 1630
[13] Journal of Medicinal Chemistry, 1999, vol. 42, # 18, p. 3510 - 3519
[14] Journal of Medicinal Chemistry, 2006, vol. 49, # 26, p. 7912 - 7915
[15] Patent: WO2006/17443, 2006, A2, . Location in patent: Page/Page column 155
[16] Patent: WO2010/10184, 2010, A1, . Location in patent: Page/Page column 59
[17] Patent: US2007/49603, 2007, A1, . Location in patent: Page/Page column 62
[18] Patent: WO2011/17296, 2011, A1, . Location in patent: Page/Page column 66
[19] Patent: WO2011/19538, 2011, A1, . Location in patent: Page/Page column 131
[20] Patent: WO2012/92880, 2012, A1, . Location in patent: Page/Page column 56-57
[21] Patent: WO2014/85210, 2014, A1, . Location in patent: Page/Page column 43
[22] Patent: WO2015/81891, 2015, A1, . Location in patent: Page/Page column 138; 139
[23] Patent: US9138427, 2015, B2, . Location in patent: Page/Page column 286-287
[24] Patent: CN103420977, 2016, B, . Location in patent: Paragraph 0275-0278
[25] Patent: CN105218397, 2016, A, . Location in patent: Paragraph 0012
[26] Tetrahedron, 2017, vol. 73, # 20, p. 2913 - 2922
  • 12
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  • [ 110568-64-4 ]
Reference: [1] Patent: US2010/15141, 2010, A1, . Location in patent: Page/Page column 26
[2] Patent: WO2011/19538, 2011, A1, . Location in patent: Page/Page column 127-128
[3] Patent: WO2015/81891, 2015, A1,
[4] Patent: US9138427, 2015, B2,
[5] Patent: CN103804358, 2016, B,
[6] Patent: WO2012/92880, 2012, A1,
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  • [ 98475-07-1 ]
YieldReaction ConditionsOperation in experiment
98% With azobisisobutyronitrile In tetrachloromethane; hexane; dichloromethane b
Synthesis of methyl-2-bromomethyl-3-nitro-benzoate:
To a well stirred solution of methyl-4-nitro-2-methyl-benzoate (5 gm, 0.025 mol.) in carbon tetrachloride or CH2Cl2 (75 ml) was added N-bromo-succinimide (NBS) (4.950 gm, 0.03 mol) and AIBN (50 mg) and the homogeneous reaction mixture was refluxed for 16 hr or until the starting material had completely reacted.
The reaction mixture was then cooled to room temperature, and the succinimide was removed by filtration.
The filtrate was concentrated to give crude product, which after treatment with hexane provided methyl-2-bromomethyl-3-nitro-benzoate as a white solid (6.9 gm, 98percent yield).
Reference: [1] Patent: US2002/95044, 2002, A1,
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  • [ 222036-66-0 ]
Reference: [1] Patent: WO2011/19538, 2011, A1,
[2] Patent: WO2015/81891, 2015, A1,
[3] Patent: US9138427, 2015, B2,
[4] Patent: CN103804358, 2016, B,
[5] Patent: WO2012/92880, 2012, A1,
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