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Product Details of [ 99548-55-7 ]

CAS No. :99548-55-7 MDL No. :MFCD09954957
Formula : C9H9BrO2 Boiling Point : -
Linear Structure Formula :- InChI Key :CYEXEOXALMJXDI-UHFFFAOYSA-N
M.W : 229.07 Pubchem ID :22031226
Synonyms :

Calculated chemistry of [ 99548-55-7 ]

Physicochemical Properties

Num. heavy atoms : 12
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.22
Num. rotatable bonds : 2
Num. H-bond acceptors : 2.0
Num. H-bond donors : 0.0
Molar Refractivity : 50.39
TPSA : 26.3 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) : -5.25 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.51
Log Po/w (XLOGP3) : 3.44
Log Po/w (WLOGP) : 2.54
Log Po/w (MLOGP) : 2.97
Log Po/w (SILICOS-IT) : 2.84
Consensus Log Po/w : 2.86

Druglikeness

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

Water Solubility

Log S (ESOL) : -3.67
Solubility : 0.0495 mg/ml ; 0.000216 mol/l
Class : Soluble
Log S (Ali) : -3.67
Solubility : 0.0486 mg/ml ; 0.000212 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.72
Solubility : 0.0436 mg/ml ; 0.000191 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.55

Safety of [ 99548-55-7 ]

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 [ 99548-55-7 ]

* 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 [ 99548-55-7 ]
  • Downstream synthetic route of [ 99548-55-7 ]

[ 99548-55-7 ] Synthesis Path-Upstream   1~26

  • 1
  • [ 99548-55-7 ]
  • [ 17100-58-2 ]
YieldReaction ConditionsOperation in experiment
90% With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 1 h; At 0°C, lithium aluminum hydride (1.425 g, 37.5 mmol) was dropped into a solution of methyl 4-bromo-2-methylbenzoate (5.725 g, 25 mmol) in tetrahydrofuran (120 mL) slowly. The ice-salt bath used was removed after that dropping. The reaction was complete (detected by LCMS and TLC) after stirred for 1 hour at room temperature.
The mixture was cooled to 0°C again and the reaction was quenched with water (1.43 mL) and 10percent NaOH solution (14.3 mL) respectively. After stirred for 15 min at room temperature, the mixture was filtered and then the filter cake was washed with tetrahydrofuran (80 mL*2) and ethyl acetate EA (80 mL*2).
The filtrate was dried with anhydrous sodium sulfate, filtered, and then concentrated to obtain a colorless oil product (4.535 g, 90percent yield).
88.6% With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 2 h; L1AIH4 (0.37 g, 9.78 mmol) was suspended in THF (10 mL) and a solution of the product of Step A (1.12 g, 4.89 mmol) in THF (5 mL) was added dropwise at 0°C. After the addition, the reaction mixture was stirred for 2 hours at room temperature. The reaction was quenched with H20 (0.37 mL), a^.NaOH (15percent, 1 mL), H20 (1.11 mL), then filtered. The filtrate was concentrated to give target compound (0.88 g, 88.6 percent) as yellow oil.
65%
Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃;
Stage #2: With water; sodium hydroxide In tetrahydrofuranCooling with ice
Intermediate 15: (4-bromo-2-methylphenyl)methanol; LiAIH4 (30 g, 0.79 moL) was dissolved in THF (500 ml_), and the mixture was cooled to O0C. A solution of intermediate 14, methyl 4-bromo-2-methylbenzoate (70 g, 0.29 mol) in THF (200 ml.) was dropwise added at O0C, and the reaction mixture was stirred at room temperature overnight. After cooling with ice-bath, water (30 g) was dropwise added, followed by aqueous NaOH solution (15percent, 90 g). The solid was filtered and washed with THF (500 ml_). The filtrate was concentrated in vacuo to give a red solid, which was recrystallized from petroleum ether/EtOAc (30:1 ) to give the title compound (4-bromo-2-methylphenyl)methanol as a white solid (40 g, 65percent yield). 1H NMR (400 MHz, CDCI3) .pound. 7.32 (m, 2H), 7.23 (m, 1 H), 4.61 (s, 2H), 2.30 (s, 3H).
Reference: [1] Patent: US6359135, 2002, B1, . Location in patent: Page column 120
[2] Patent: US6369261, 2002, B1, . Location in patent: Page column 118
[3] Patent: US6369225, 2002, B1, . Location in patent: Page column 43, 119
[4] Patent: EP3048103, 2016, A1, . Location in patent: Paragraph 0091; 0092
[5] Patent: WO2014/206344, 2014, A1, . Location in patent: Page/Page column 114
[6] Patent: WO2010/15652, 2010, A2, . Location in patent: Page/Page column 37
[7] Patent: US6313107, 2001, B1,
[8] Patent: US6252090, 2001, B1,
[9] Patent: WO2013/43232, 2013, A2, . Location in patent: Paragraph 00618
[10] Patent: WO2015/35113, 2015, A1, . Location in patent: Page/Page column 263; 264
  • 2
  • [ 99548-55-7 ]
  • [ 24078-12-4 ]
Reference: [1] Journal of the Chemical Society, 1947, p. 690
[2] Patent: WO2015/35113, 2015, A1,
  • 3
  • [ 68837-59-2 ]
  • [ 18107-18-1 ]
  • [ 99548-55-7 ]
YieldReaction ConditionsOperation in experiment
100% at 0 - 20℃; for 1 h; STEP 1 : To a cooled (00C) solution of 4-bromo-2-methylbenzoic acid (15.1 g, 0.070 mol) in tetrahydrofuran (180 mL) and methanol (45 mL) was slowly added (trimethylsilyl)diazomethane (2.0M in hexanes, 42 mL, 0.084 mol). The reaction mixture was allowed to warm to room temperature and stirred for 1 h, at which time it was concentrated in vacuo to afford methyl 4-bromo-2-methylbenzoate (16 g, 100percent) as a yellow oil. The residue was taken to the next step without further purification. 1H NMR (400 MHz, CDCl3): 7.78 (d, IH), 7.42 (s, IH), 7.38 (d, IH), 3.88 (s, 3H), 2.58 (s, 3H). MS (EI) for C9H9BrO2: 230 (MH+).
89%
Stage #1: at 0℃; for 3 h;
Stage #2: With sodium hydroxide In methanol; hexane; dichloromethane; water at 20℃;
Step 1:
Methyl 4-bromo-2-methylbenzoate
A suspension of 4-bromo-2-methylbenzoic acid (4.98 g, 23 mmol) in dichloromethane and methanol at 0° C. was treated with a solution of trimethylsilyl-diazomethane (11.6 ml, 2.0 M solution in hexane), stirred at 0° C. for 3 h, allowed to warm to room temperature, diluted with 1.0 N sodium hydroxide and extracted with dichloromethane.
The combined extracts were dried over Na2SO4 and concentrated in vacuo.
The residue was purified by ISCO CombiFlash.(R). chromatography (silica, 0-5percent ethyl acetate in hexanes) to provide 4.72 g (89percent) of methyl 4-bromo-2-methylbenzoate as a colorless oil. MS (EI) m/z 228 [M]+.
85% at 20℃; for 0.333333 h; Example 1 : Example 1A: Part A:To a solution of 4-bromI"2~meihylbenzoic acid (1 ) (430 mg, 2 mmoi) in MeCN (5 ml) and MeOH (5 ml) was added trimethylsIydiazomethaI.euro.e (2Af, 3 mt, 6 mmoi). The <n="40"/>reaction mixture was stirred at room temperature for 20 minutes, quenched with the addition of AcOH (10 percent) in MeOH (5 ml), and concentrated to afford crude compound 2. This was further purified by flash column chromatography, gradient elution (0 to 100 percent) hexane / ethyl acetate, to afford compound 2 as a colorless oi. (388 mg, 85 percent yield).
89% at 0℃; for 3 h; Step 1:
Methyl 4-bromo-2-methylbenzoate
A stirred suspension of 4-bromo-2-methylbenzoic acid (4.98 g, 23 mmol) in dichloromethane (80 mL) and methanol (15 mL) was treated carefully with a 2.0 M solution of trimethylsilyldiazomethane (11.6 mL, 28 mmol) at 0° C.
The resulting solution was stirred at 0° C. for 3 hour.
The mixture was partitioned between dichloromethane and 1 N sodium hydroxide.
The combined organic phases were concentrated under reduced pressure and the residue was purified by ISCO CombiFlash.(R). chromatography (0-5percent ethyl acetate in hexanes) to afford 4.72 g (89percent) methyl 4-bromo-2-methylbenzoate as a colorless oil. MS (El) 228 [M]+.

Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 4, p. 999 - 1004
[2] Patent: WO2009/55077, 2009, A1, . Location in patent: Page/Page column 430
[3] Journal of Medicinal Chemistry, 2014, vol. 57, # 6, p. 2334 - 2356
[4] Patent: US2009/69370, 2009, A1, . Location in patent: Page/Page column 17-18
[5] Patent: WO2009/158369, 2009, A1, . Location in patent: Page/Page column 38; 39
[6] Patent: US2009/69300, 2009, A1, . Location in patent: Page/Page column 33
[7] Patent: WO2009/50522, 2009, A1, . Location in patent: Page/Page column 24
[8] Patent: WO2009/50523, 2009, A1, . Location in patent: Page/Page column 23
[9] Angewandte Chemie - International Edition, 2017, vol. 56, # 22, p. 6294 - 6297[10] Angew. Chem., 2017, vol. 129, # 22, p. 6391 - 6394,4
  • 4
  • [ 68837-59-2 ]
  • [ 74-88-4 ]
  • [ 99548-55-7 ]
YieldReaction ConditionsOperation in experiment
100% With sodium hydrogencarbonate In N,N-dimethyl-formamide at 80℃; 5.76 l-(3-CHIX)RO-4-METHYI^PHENYLV3-r2-f2.6-DIOXO-PIPERrom- 3-YU-I-OXO-Z^-DIHYDRO-IH-ISOINDOL-S-YLMETHYLI-TJREA <n="91"/>Step 1: A mechanically stirred mixture of 4-bromo-2-methyl-benzoic acid (100 g, 465 mmol), iodomethane (95 g, 670 mmol) and sodium bicarbonate (1 12 g, 1340 mmoi) in DMF (325 mL) was heated at 80 0C overnight. The reaction mixture was cooled to room temperature and partitioned between water (1500 mL) and 4: 1 hexanes:ethyl acetate (1500 mL). The organic layer was washed with water and dried (Na2SO4). The solvent was removed under vacuum to give HO g of 4-bromo-2-methyl-benzoic acid methyl ester as an oil, in 100percent yield; 1H NMR δ 2.51 (s, 3H), 3.84 (s, 3H), 7.40-7.78 (m, 3H).
100% With potassium carbonate In N,N-dimethyl-formamide at 20℃; Step 1.
methyl 4-bromo-2-methylbenzoate
A stirred mixture of 4-bromo-2-methylbenzoic acid (6 g, 27.9 mmol), iodomethane (5.21 mL, 84 mmol) and potassium carbonate (11.57 g, 84 mmol) in DMF (60 mL) was stirred at room temperature overnight.
The reaction mixture was partitioned between water (250 mL) and 4:1 hexanes:ethyl acetate (650 mL).
The organic layer was washed with water and dried over Na2SO4.
The solvent was removed under vacuum to give 6.39 g of desired product as an oil in 100percent yield. 1H NMR (400 MHz, CD3OD) δ ppm 7.86-7.65 (m, 7H) 7.50 (br. s., 2H) 3.88 (s, 3H) 2.56 (s, 3H).
100% With sodium hydrogencarbonate In N,N-dimethyl-formamide at 80℃; A mechanically stirred mixture of 4-bromo-2-methyl-benzoic acid (100 g, 465 mmol), iodomethane (95 g, 670 mmol) and sodium bicarbonate (112 g, 1340 mmol) in DMF (325 mL) was heated at 80 C overnight. The reaction mixture was cooled to room temperature and partitioned between water (1500 mL) and 4:1 hexanes:ethyl acetate (1500 mL). The organic layer was washed with water and dried (Na2SO4). The solvent was removed under vacuum to give 110 g of 4-bromo-2-methyl-benzoic acid methyl ester as an oil, in 100percent yield; 1H NMR (DMSO-d6) 2.51 (s, 3H), 3.84 (s, 3H), 7.40-7.78 (m, 3H).
100% With sodium hydrogencarbonate In N,N-dimethyl-formamide at 80℃; [00407j Step 1: A mechanically stirred mixture of 4-bromo-2-methyl-benzoic acid (100 g, 465 mmol), iodomethane (95 g, 670 mmol) and sodium bicarbonate (112 g, 1340 mmol) in DMF (325 mL) was heated at 80 °C overnight. The reaction mixture was cooled to room temperature and partitioned between water (1500 mL) and 4:1 hexanes : ethyl acetate (1500 mL). The organic layer was washed with water and dried (Na2SO4). The solvent was removed under vacuum to give 110 g of 4-bromo-2-methyl-benzoic acid methyl ester as an oil, in 100percent yield; 1H NMR (DMSO-d6) ö 2.51 (s, 3H), 3.84 (s, 3H), 7.40-7.78 (m, 3H).
100% With sodium hydrogencarbonate In N,N-dimethyl-formamide at 80℃; A mechanically stirred mixture of 4-bromo-2-methyl-benzoic acid (100 g, 465 mmol), iodomethane (95 g, 670 mmol) and sodium bicarbonate (112 g, 1340 mmol) in DMF (325 mL) was heated at 80 °C overnight. The reaction mixture was cooled to room temperature and partitioned between water (1500 mL) and 4: 1 hexanes:ethyl acetate (1500 mL). The organic layer was washed with water and dried (Na2S04). The solvent was removed under vacuum to give 110 g of 4-bromo-2-methyl -benzoic acid methyl ester as an oil, in 100percent yield; 1H MR (DMSO-i) δ 2.51 (s, 3H), 3.84 (s, 3H), 7.40-7.78 (m, 3H).
93.9% With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 1 h; Green chemistry To a 100 mL rbf was added 4-bromo-2-methyl-benzoic acid(2.0 g, 9.300 mmol), potassium carbonate (3.856 g, 27.90 mmol), and DMF (20.00mL). Iodomethane (1.452 g, 636.8 µL, 10.23 mmol) was added dropwise and thereaction was allowed to stir at rt for 1h. By lcms analysis, the reaction wascomplete. The reaction was quenched with brine and extracted with EtOAc 3times. The organic layer was dried over sodium sulfate and evaporated. Methyl4-bromo-2-methyl-benzoate (2.0 g, 8.731 mmol, 93.9percent) was used in the next stepwithout further purification. ESI-MS m/z calc. 227.97859, found 229.3 (M+1) +; Retention time: 1.93 minutes To a 100 mL rbf containing methyl 4-bromo-2-methyl-benzoate(2.0 g, 8.731 mmol) was added dmf (20.00 mL) and sodium propane-2-thiolate (2.282g, 23.25 mmol). The reaction was heated at 65°C for 3h. By lcms analysis, thereaction showed only conversion to the acid.
88% With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃; for 3 h; To a stirred solution of 4-bromo-2-methyl benzoic acid (10 g, 46.511 mmol) in DMF (50 ml) at 0°C, was added K2C03 (12.8 g, 93.023 mmol) and methyl iodide (3.4 ml, 55.813 mmol). The reaction mixture was slowly warmed to room temperature and stirred for about 3 h. The reaction mixture was diluted with ice cold water and the product was extracted with ethyl acetate. The combined organic layer was washed with brine, dried and concentrated to afford desired compound (10.0 g, 88 percent). 1H NMR (400 MHz, DMSO-d6) δ 7.74 (d, J=8.4 Hz, 1H), 7.60 (s, 1H), 7.52 (d, J=6.4 Hz, 1H), 3.82 (s, 3H), 2.50 (s, 3H); LC/MS: 230.9 (M+2)+.
82% With potassium carbonate In N,N-dimethyl-formamide at 25℃; for 12 h; Step 1. To 27 (3.0 g, 14.0 mmol) and CH3I (3.96 g, 27.9 mmol) in DMF (30 mL) was added K2C03 (2.89 g, 20.9 mmol). The reaction mixture was stirred at 25°C for 12 h and then quenched with H20 (20 mL). The solution was extracted with ethyl acetate (3 x 100 mL) and the organic layer was washed with H20 (3 x 100 mL) and concentrated to afford 28 (2.9 g, 82percent).

Reference: [1] Patent: WO2008/27542, 2008, A2, . Location in patent: Page/Page column 89-90
[2] Patent: US9242996, 2016, B2, . Location in patent: Page/Page column 379; 380
[3] Patent: WO2015/200795, 2015, A1, . Location in patent: Paragraph 00388
[4] Patent: WO2016/57503, 2016, A1, . Location in patent: Paragraph 00407
[5] Patent: WO2017/117118, 2017, A1, . Location in patent: Paragraph 00471
[6] Tetrahedron Letters, 2014, vol. 55, # 22, p. 3295 - 3298
[7] Patent: WO2014/125408, 2014, A2, . Location in patent: Page/Page column 24
[8] Patent: WO2018/49328, 2018, A1, . Location in patent: Page/Page column 35; 36
[9] Patent: WO2015/35113, 2015, A1, . Location in patent: Page/Page column 263; 264
  • 5
  • [ 68837-59-2 ]
  • [ 99548-55-7 ]
YieldReaction ConditionsOperation in experiment
100% With hydrogenchloride In methanol Example 33A
Methyl 4-bromo-2-methylbenzoate
A solution of 4-bromo-2-methyl benzoic acid (1.0 g, 4.7 mmol) in methanol (24 mL) was treated with 20 drops of HCl, heated at reflux for 6 hours, and concentrated to provide the desired product (1.07 g, 100percent).
100% With hydrogenchloride In methanol Example 263A
4-Bromo-2-methyl-benzoic Acid Methyl Ester
A solution of 4-bromo-2-methyl benzoic acid (1.0 g; 4.7 mmol) in MeOH (24 mL) with 20 drops conc. HCl was heated at reflux for 6 hrs. the concentrated to provide the desired product (1.1 g; 100percent).
86% for 3 h; Heating / reflux 4-Bromo-2-methyl-benzoic acid (4.6 g, 21.39 mmol) is dissolved in 2M HCl inMeOH and refluxed for 3 hours. The solvent is evaporated to give the 4-bromo-2-methyl-benzoic acid methyl ester (4.24 g, 86 percent). This intermediate (18.51 mmol) is dissolved in carbon tetrachloride (100 mL) and N-bromosuccinimide (NBS) (5.57 g, 24.06 mmol) is added. AIBN (122 mg, 740 μmol) is then added and the mixture purged with nitrogen for 5 min. The reaction mixture is then refluxed for 4 hours. After cooling to room temperature the reaction mixture is filtered and the filtrate is evaporated. The residue is purified by flash chromatography (silica gel, 2:1 petroleum ether/ethyl acetate) to give the title compound (3.42g, 60 percent).
78% With sulfuric acid In methanol; dichloromethane A.
4-Bromo-2-methylbenzoic acid, methyl ester A mixture of 4-bromo-2-methylbenzoic acid (14.77 g, 68.7 mmol) and sulfuric acid (5 mL) in methanol (200 mL) was heated at reflux for 3 h.
The solvent was evaporated and dichloromethane (200 mL) was added.
The solution was washed with water, 1 M NaOH, and brine (200 mL each), dried (MgSO4), filtered and evaporated to give 4-bromo-2-methylbenzoic acid, methyl ester (12.21 g, 78percent) as a colorless liquid.

Reference: [1] Patent: US2003/187026, 2003, A1,
[2] Patent: US2003/187026, 2003, A1,
[3] Patent: WO2007/138072, 2007, A2, . Location in patent: Page/Page column 82
[4] Patent: US6331640, 2001, B1,
[5] Patent: US2003/212094, 2003, A1,
[6] Patent: WO2004/65351, 2004, A1, . Location in patent: Page 107
  • 6
  • [ 67-56-1 ]
  • [ 68837-59-2 ]
  • [ 99548-55-7 ]
YieldReaction ConditionsOperation in experiment
100% for 6 h; Heating / reflux Example 33A
methyl 4-bromo-2-methylbenzoate
A solution of 4-bromo-2-methyl benzoic acid (1.0 g, 4.7 mmol) in methanol (24 mL) was treated with 20 drops of HCl, heated at reflux for 6 hours, and concentrated to provide the desired product (1.07 g, 100percent).
100% at 70℃; for 6 h; To a solution of compound 1 (79.45 g, 369.5 mmol) in methanol (450 ml) was added thionyl chloride (53.6 ml, 739 mmol), and the mixture was stirred at 70 °C for 6 hs. The reaction mixture was concentrated to afford methyl 4-bromo-2-methylbenzoate (86.37 g, yield 100percent).
98% Heating / reflux REFERENCE EXAMPLE 1; Methyl 4-bromo-2-methylbenzoate; To a solution of 4-bromo-2-methylbenzoic acid (6.17 g, 0.29 mol) in MeOH (170 mL), H2SO4 95percent (3 mL) was added. It was heated to reflux overnight and allowed to cool to room temperature. The solvent was evaporated and EtOAc was added.The organic phase was washed with saturated NaHCO3, aq Na2CO3 and water.The combined organic phases were dried over Na2SO4 and the solvent was evaporated, to afford 6.43 g of the title compound as an oil (yield: 98percent). 1H NMR (300 MHz, CDCI3) δ (TMS): 2.58 (s, 3 H), 3.89 (s, 3 H), 7.36 (d, J = 1.8Hz, 1 H), 7.41 (dd, J = 8.1 Hz, J1= 1.8 Hz, 1 H), 7.78 (d, J= 8.1 Hz, 1 H).
98% Reflux Reference Example 1; Methyl 4-bromo-2-methylbenzoateTo a solution of 4-bromo-2-methylbenzoic acid (6.17 g, 0.29 mol) in MeOH (170 mL), H2SO4 95percent (3 mL) was added. It was heated to reflux overnight and allowed to cool to room temperature. The solvent was evaporated and EtOAc was added. The organic phase was washed with saturated NaHCO3, aq Na2CO3 and water. The combined organic phases were dried over Na2SO4 and the solvent was evaporated, to afford 6.43 g of the title compound as an oil (yield: 98percent).1H NMR (300 MHz, CDCl3) δ (TMS): 2.58 (s, 3H), 3.89 (s, 3H), 7.36 (d, J=1.8 Hz, 1H), 7.41 (dd, J=8.1 Hz, J'=1.8 Hz, 1H), 7.78 (d, J=8.1 Hz, 1H).
98% Heating / reflux REFERENCE EXAMPLE 1; Methyl 4-bromo-2-methylbenzoate; To a solution of 4-bromo-2-methylbenzoic acid (6.17 g, 0.29 mol) in MeOH (170 mL), H2SO4 95percent (3 mL) was added. It was heated to reflux overnight and allowed to cool to room temperature. The solvent was evaporated and EtOAc was added. EPO <DP n="31"/>The organic phase was washed with saturated NaHCψ3, aq Na2CO3 and water. The combined organic phases were dried over Na2SO4 and the solvent was evaporated, to afford 6.43 g of the title compound as an oil (yield: 98percent). 1H NMR (300 MHz, CDCI3) δ (TMS): 2.58 (s, 3 H), 3.89 (s, 3 H), 7.36 (d, J = 1.8 Hz, 1 H)1 7.41 (dd, J = 8.1 Hz, J1= 1.8 Hz, 1 H), 7.78 (d, J= 8.1 Hz, 1 H).
97% for 4 h; Reflux Compound 6.1. Methyl 4-bromo-2-methylbenzoate. To a solution of 4-bromo-2- methylbenzoic acid (5.1 1 g, 23.8 mmol, 1.0 equiv) in methanol (25 mL) was added dropwise ulfuric acid (2.0 mL) over about 3 minutes (mildly exothermic). The resulting mixture was refluxed for 4 hours. After cooling to room temperature, the reaction mixture was carefully quenched into saturated aqueous NaHC03 (100 mL) (note - significant gas evolution) and extracted with dichloromethane (200 mL x 1 then 50 mL x 1). The combined organic phases were washed with a mixture of brine/saturated NaHC03 (9: 1)(50 mL), dried (Na2S04), and concentrated under reduced pressure to yield the title compound as a colorless oil (5.28 g, 97percent). NMR (400 MHz, CDC13): δ 7.78 (d, J = 8.0 Hz, 1 H), 7.42 (d, J (dd, J = 1.6 Hz, 1 H), 3.89 (s, 3H), 2.58 (s, 3H).
97% for 4 h; Reflux Compound 6.1. Methyl 4-bromo-2-methylbenzoate.
To a solution of 4-bromo-2- methylbenzoic acid (5.11 g, 23.8 mmol, 1.0 equiv) in methanol (25 mL) was added dropwise ulfuric acid (2.0 mL) over about 3 minutes (mildly exothermic). The resulting mixture was refluxed for 4 hours. After cooling to room temperature, the reaction mixture was carefully quenched into saturated aqueous NaHCC>3 (100 mL) (note - significant gas evolution) and extracted with dichloromethane (200 mL x 1 then 50 mL x 1). The combined organic phases were washed with a mixture of brine/saturated NaHCC>3 (9: 1)(50 mL), dried (Na2S04), and concentrated under reduced pressure to yield the title compound as a colorless oil (5.28 g, 97percent). NMR (400 MHz, CDC13): δ 7.78 (d, J= 8.0 Hz, 1 H), 7.42 (d, J= 1.6 Hz, 1H), 7.38 (dd, J= 1.6 Hz, 1H), 3.89 (s, 3H), 2.58 (s, 3H).
97% at 70℃; for 6 h; 2-methyl-4-bromobenzoic acid 1,5 g dissolved in 30 ml methanol,To this was added 2 ml of thionyl chloride,The reaction was refluxed at 70 ° C for 6 hours,The solution was cooled to room temperature,Add 30 ml of saturated sodium carbonate solution,Fully agitated,Extracted with ethyl acetate 15 ml twice,The organic layer was washed twice with 10 ml of water,And saturated saline 10 ml washing,Dried over anhydrous magnesium sulfate,filter,Concentrated under reduced pressure,Get brownish red2-methyl-4-bromobenzoic acid methyl ester 2,5.17 g,Yield 97percent.
95.5% at 0 - 30℃; Heating; Reflux Stepl. Preparation of methyl 4-bromo-2-methylbenzoate - A IL 3 neck flask with mechanical stirrer, reflux condenser, internal temperature probe and a nitrogen bubbler was charged with 4- bromo-2-methylbenzoic acid (50.35 g, leq., Hongda) and methanol (350 mL). and the reactor contents were cooled to 0 C. Acetyl chloride (27.6g, leq.) was slowly added at a rate which maintained an internal temperature of less than 30 C. The reaction mixture was heated to reflux for 16 hours, until starting material was no longer detected by LC. Once reaction was complete, the reactor contents were cooled to room temperature and the reaction mixture was concentrated to an oil via rotary evaporator. The oil was then diluted with dichloromethane (100 mL) and washed with saturated sodium bicarbonate solution (100 mL). The organic layer was concentrated via rotary evaporator to afford methyl 4-bromo-2-methylbenzoate (51.22g, 95.5 percent) as a yellow oil.
95% at 80℃; for 5 h; Reference Example 9
Methyl 4-bromo-2-methylbenzoate
Concentrated sulfuric acid (500 μL) was added to a methanol (20.0 mL) solution of 4-bromo-2-methylbenzoic acid (2.00 g, 9.30 mmol), and the mixture was stirred for 5 hours at 80° C.
The reaction mixture was cooled to room temperature, subsequently a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the mixture was subjected to extraction two times with ethyl acetate.
The organic layer thus obtained was washed once with saturated brine, and was dried over anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure, and thus, the title compound (2.02 g, yield: 95percent) was obtained.
1H-NMR (400 MHz, CDCl3) δ ppm: 7.78 (1H, d, J=9 Hz), 7.41 (1H, d, J=2 Hz), 7.38 (1H, dd, J=9 Hz, 2 Hz), 3.89 (3H, s), 2.58 (3H, s).
95.7% for 5 h; Reflux C077C.H2SO4 (2 mL) was dissolved in MeOH (10 mL), then 4-bromo-2-methyl benzoic acid (1.1 g, 5.11 mmol) was added. After the addition, the reaction mixture was refluxed for 5 hours. The reaction mixture was concentrated to give the residue, which was dissolved in EtOAc (20 mL) and washed with a .NaHCC , brine, dried over Na2SC"4 and concentrated to give (1.12 g, 95.7percent) as yellow oil. 1H MR (400 MHz, CDC13) δ 7.78 (d, J= 8.4 Hz, 1H), 7.42 (s, 1H), 7.40 - 7.35 (d, J= 8.4 Hz, 1H), 3.98 - 3.80 (m, 3H), 2.58 (s, 3H).
95% at 65℃; for 18 h; 4-Bromo-2-methylbenzoic acid (100 g,465.02 mmol), concentrated sulfuric acid (52 mL) in methanol (1L) were combined and heated to 65 °C for 18 h. The reaction was concentrated and the residue diluted with ethyl acetate (500 mL), washed with saturated sodium bicarbonate solution (150 mL), water (200 mL), brine (250 mL) and dried over sodium sulfate. The organic phase was concentrated under reduced pressure and further dried under high vacuum to give methyl 4-bromo-2-methylbenzoate (102 g, 445.27 mmol, 95percent yield) as a red liquid. 1H NIVIR (400 MHz, Chloroform-di) 7.78 (d, J 8.3 Hz, 1H), 7.45 — 7.30 (m, 2H), 3.88 (s, 3H), 2.57 (s, 3H).
95% at 65℃; for 18 h; 4-Bromo-2-methylbenzoic acid(100 g, 465.02 mmol), concentrated sulfuric acid (52 mL) in methanol (1L) werecombined and heated to 65 °C for 18 hours. The reaction was concentrated and the residue diluted with ethyl acetate (500 mL), washed with saturated sodium bicarbonate solution (150 mL), water (200 mL), and brine (250 mL) and dried over sodium sulfate. The organic phase was concentrated under reduced pressure and further dried under highvacuum to give methyl 4-bromo-2-methylbenzoate (102 g, 445.27 mmol, 95percent yield) asa red liquid. 1H NMR (400 IVIFIz, Chloroform-dl) 7.78 (d, J= 8.3 Hz, 1H), 7.45 —7.30 (m, 2H), 3.88 (s, 3H), 2.57 (s, 3H).
94% at 0℃; Reflux The 2-methyl-4-bromobenzoic acid (3g, 13.4 mm, 1.0equiv) suspended in methanol (30 ml) in, cooling to 0 °C, drips thionylchloride (2.4 ml, 33.5 mm, 2.5equiv), stirring 15 min after in transferred to the oil bath boiler, heating to reflux, monitoring reaction is complete by TLC, cooling to room temperature, the solvent is concentrated under reduced pressure. Column chromatography (petroleum ether: ethyl acetate = 5:1) treatment to obtain pale brown oily liquid (2.995g, yield 94percent).
93.6% at 70℃; for 2 h; Inert atmosphere To a solution of 4-bromo-2-methyl-benzoic acid (30.0 g, 0.14mol) in 115 mL of methanol was added thionyl chloride (20.25 mL, 0.28 mol) slowly and the reaction mixture was stirred at 70 °C for 2 hours before it was concentrated to afford a crude product which was then purified by column chromatography to give the title compound (30.03 g, 93.6percent) as a solid
93% for 72 h; Reflux 4-Bromo-2-methylbenzoic acid (20.0 g,93.1 mmol) was suspended in dry MeOH (200 mL), to which was added c.H2S04 (1 mL).This mixture was heated at reflux for 72 h. Upon cooling, all solvent was removed under reduced pressure and the resulting oil dissolved in EtOAc (500 mL) then washed with sat. NaI-1C03 (3x100 mL), brine (100 mL) and dried (Na2SO4). The solution was filtered and the solvent removed under reduced pressure to afford the title compound as a pale yellowoil (19.92 g, 93percent). ‘H NMR [400 MHz, (CD3)2S0] 6 7.77(d, J 8.4 Hz, 1 H), 7.40-7.42 (m, I H), 7.35-7.39 (m, 1 H), 3.88 (s, 3 H), 2.57 (s, 3 H).
93.6% at 70℃; for 2 h; Inert atmosphere To a solution of 4-bromo-2-methyl-benzoic acid (30.0 g, 0.14 mol) in 115 mL of methanol was added thionyl chloride (20.25 mL, 0.28 mol) slowly and the reaction mixture was stilTed at 70 °C for 2 hours before it was concentrated to afford a crude product which was then purified by column chromatography to give the title compound (30.03 g, 93.6percent) as asolid.
93.6% at 70℃; for 2 h; Inert atmosphere To a solution of 4-bromo-2-methyl-benzoic acid (30.0 g, 0.l4mol) in 115 mL of methanolwas added thionyl chloride (20.25 mL, 0.28 mol) slowly and the reaction mixture wasstilTed at 70 °C for 2 hours before it was concentrated to afford a crude product which was then purified by column chromatography to give the title compound (30.03 g, 93.6percent) assolid.
93.6% at 70℃; for 2 h; Inert atmosphere To a solution of 4-bromo-2-methyl-benzoic acid (30.0 g, 0.14 mol) in 115 mL of methanol was added thionyl chloride (20.25 mL, 0.28 mol) slowly and the reaction mixture was stilTed at 70 °C for 2 hours before it was concentrated to afford a crude product which wasthen purified by column chromatography to give the title compound (30.03 g, 93.6percent) assolid.
93.6% at 70℃; for 2 h; Inert atmosphere ΓΑ1 4-Bromo-2-methyl-benzoic acid methyl ester To a solution of 4-bromo-2-methyl-benzoic acid (30.0 g, 0.14mol) in 115 mL of methanol was added thionyl chloride (20.25 mL, 0.28 mol) slowly and the reaction mixture was stirred at 70 °C for 2 hours before it was concentrated to afford a crude product which was then purified by silica gel flash chromatography to give the title compound (30.03 g, 93.6percent) as a solid.
92% at 20℃; for 72 h; 4-Bromo-2-rnethylbenzoic acid (2.00 g, 9.30 mmol) was added to a solution of acetyl chloride (1.70 mL, 23.9 mmol) in methanol (30 mL). The mixture was allowed to stir at rt for 3 days and was then concentrated in vacuo. This gave 1.96 g (92percent) of the title compound as a light brown oil. 1H NMR (400 MHz, CD2Cl2) δ 2.61 (s, 3H), 3.90 (s, 3H), 7.38-7.42 (m, 2H), 7.78 (d, IH).
90% Reflux Intermediate 14: methyl 4-bromo-2-methylbenzoate; To a solution of commercially available 4-bromo-2-methylbenzoic acid (200 g, 0.87 mol) in methanol (500 ml.) was added sulphuric acid (98percent, 10 ml_). The reaction mixture was heated to reflux overnight. After cooling, the reaction mixture was concentrated, and then water and ethyl acetate were added. The organic layers were separated, dried over sodium sulfate and concentrated in vacuo to give the title compound, methyl 4-bromo-2-methylbenzoate as red oil (190 g, 90percent), which was used for next step without purification and characterization.
90%
Stage #1: at 20℃;
Stage #2: With sodium hydrogencarbonate In water; ethyl acetate
PREPARATION 46; 4-Bromo-2-bromomethyl-benzoic acid methyl ester.; 4-Bromo-2-methyl-benzoic acid (20.35 g, 94.6 mmol) in MeOH (200 mL) was saturated with HCI gas, cooled to rt, resaturated with HCI gas and stirred overnight. The reaction was concentrated and dissolved in EtOAc, washed with sat. NaHCO3 and brine, dried (MgSO4) and concentrated to a brown oil (20.5 g). Kugelrohr distillation (-0.3 torr, 80- 1000C) yielded 19.6 g (90percent) of 4-bromo-2-methyl-benzoic acid methyl ester as a colorless oil: NMR (CDCI3) 7.75 (d, J = 8.3 Hz, 1 H), 7.38 (s, 1 H), 7.34 (dd, J = 8.3, 2.1 Hz, 1 H), 3.85 (s, 3H), 2.54 (s, 3H).The ester (1.00 g, 4.37 mmol), N-bromosuccinimide (0.86 g, 4.83 mmol) and benzoylperoxide (0.10 g, 0.41 mmol) were refluxed in benzene (10 mL) for 4hrs, then cooled and concentrated. The residue was dissolved in ether and washed with water and brine, dried (MgSO4) and concentrated to a yellow-orange oil (1.42 g). NMR showed -70-75 percent pure PP46 which was used without purification: NMR (CDCI3) 7.81 (d, J = 8.7 Hz, 1 H), 7.60 (d, J = 2.1 Hz, 1 H), 7.48 (dd, J = 8.3, 2.1 Hz, 1 H), 4.86 (s, 2H), 3.91 (s, 3H).
89% With hydrogenchloride In dioxanes for 3 h; Heating / reflux [00260] To a round bottomed flask was added MeOH (25 mL) and commercially available 4-bromo-2-methyl benzoic acid (7.0 g, 32.8 mmol). Then 4N HCL/ dioxanes (25 mL) was added to the insoluble mixture and stirred under reflux for 3 h. The reaction was concentrated. EtOAc and H2O were added to the slurry and partitioned. The EtOAc layer was washed with NaHCO3 (sat.) 3X, washed with brine and dried with Na2SO4 and concentrated to give methyl 4-bromo-2-methylbenzoate as a light brown oil (6.7 g, 89percent yield).1H NMR (400 MHz, d6-DMSO) δ 7.64 (dd, 2H), 7.37 (s, 2H), 6.81 (d, IH), 6.42 (m, 2H),5.87 (d, 2H), 2.38 (d, 4H), 2.15 (s, 2H); MS (EI) for C7H17NO2: 268.2 (MH+).
89% at 80℃; for 2 h; Inert atmosphere Methyl 4-bromo-2-methylbenzoate
Under nitrogen, 4-bromo-2-methylbenzoic acid (5.0 g, 23.25 mmol) was disssolved in MeOH (100 mL), after which, SOCI2(1.697 mL, 23.25 mmol) was added dropwise to the solution. The mixture was refluxed at 80 °C for 2 h., and then concentrated to afford methyl 4-bromo-2-methylbenzoate (5.0 g, 20.74 mmol, 89 percent yield). LC-MS: m/z229(M+H)+1.28 min (ret. time).
86% for 3 h; Reflux Step 1:
4-Bromo-2-bromomethyl-benzoic Acid Methyl Ester
4-Bromo-2-methyl-benzoic acid (4.6 g, 21.39 mmol) is dissolved in 2M HCl in MeOH and refluxed for 3 hours.
The solvent is evaporated to give the 4-bromo-2-methyl-benzoic acid methyl ester (4.24 g, 86percent).
86% at 20℃; for 24 h; Cooling with ice In a round bottomed flask into ice-bath, were added methanol (15 mL), acetyl chloride (8.72 g,111 mmol) and 4-bromo-2-methylbenzoic acid (1.0 g, 4.65 mmol). The reaction mixture was stirred at room temperature for 24 h, and then concentrated under reduced pressure. The resulting residue was extracted with CH2Cl2. The organic layer was washed with 10percent sodium carbonate solution, dried over anhydrous Na2SO4, filtered and evaporated, giving the methyl 4-bromo-2-methylbenzoate 10 as a colorless oil in 86percent, which was directly used in cross coupling reaction. The compound 10 (0.30 g,1.31 mmol) was transferred to a round bottomed flask with a mixture of toluene-methanol (9:1,4.5–0.5 mL), followed by addition of phenylboronic acid (0.192 g, 1.57 mmol), PdCl2(PPh3)2 (0.037 g,4 mol percent) and potassium carbonate (0.543 g, 3.93 mmol). The reaction mixture was stirred at 60 °C for3 h, and after cooling to room temperature, was filtered over Celite. The resulting oil was purified bysilica gel column chromatography (n-hexane-EtOAc 0percent–1percent), affording the title compound as a white crystalline solid in 91percent yield, after evaporation under vacuum.
86% With hydrogenchloride In water for 3 h; Heating / reflux Step 1 4-Bromo-2-bromomethyl-benzoιc acid methyl ester <n="93"/>[00354] 4-Bromo-2-methyl-benzoic acid (4 6 g, 21 39 mmol) is dissolved in 2M HCl in MeOH and refluxed for 3 hours The solvent is evaporated to give the 4-bromo-2-methyl-benzoic acid methyl ester (4 24 g, 86 percent) This intermediate (18 51 mmol) is dissolved m carbon tetrachloride (100 mL) and N-bromosuccinimide (NBS) (5 57 g, 24 06 mmol) is added AIBN (122 mg, 740 mol) is then added and the mixture purged with nitrogen for 5 mm The reaction mixture is then refluxed for 4 hours After cooling to room temperature the reaction mixture is filtered and the filtrate is evaporated The residue is puπfied by flash chromatography (silica gel, 2 1 petroleum ether/ethyl acetate) to give the title compound (3 42g, 60 percent)
81% for 5 h; Reflux Ice bath,A solution of dichlorosulfoxide (5.50 mL, 70.00 mmol)Was added dropwise to a solution of 4-bromo-2-methylbenzoic acid (5.00 g, 23.2 mmol) in methanol (60 mL). After completion of the dropwise addition, the reaction was stirred at reflux for 5 hours.The mixture was cooled to room temperature and the reaction solution was concentrated under reduced pressure.The concentrate was adjusted to neutral with saturated sodium bicarbonate solution,Extracted with ethyl acetate, and the organic layer was washed with saturated brine,Dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 4.3 g of a pale yellow oil in 81percent yield.
81% at 0℃; for 60 h; Heating / reflux To a solution of compound 1 (208.8 g, 0.97 mol) in MeOH (1200 ml_) was added dropwise SOCI2 (210 ml_, 2.91 mol) at O0C. The mixture was heated to reflux for 60 hours. TLC EPO <DP n="104"/>(petroleum ether: ethyl acetate = 10:1) showed the reaction was complete, then the mixture was concentrated in vacuo. The residue was purified by column chromatography (eluting with petroleum ether) to afford compound 2 (179 g, 81 percent) as a yellow oil.1H NMR (400 MHz, CDCI3) δ 7.75-7.77 (d, J = 8.0 Hz, 1 H), 7.34-7.39 (m, 2H), 3.87 (s, 3H),2.56 (s, 3H).
78%
Stage #1: at 80℃; for 2 h;
Methyl 4-bromo-2-methylbenzoate. To 4-bromo-2-methylbenzoic acid (1 g, 4.7 mol), thionyl cloride (40 mL) was added. The mixture was stirred at 80°C for 2 hours. After cooling the reaction mixture to room temperature, the mixture was concentrated to dryness. Methanol (40 mL) was added and then the mixture was concentrated in vacuo to give methyl 4-bromo-2- methylbenzoate as a yellow oil (800 mg, 78percent).
78% at 80℃; for 2 h; To 4-bromo-2-methylbenzoic acid (1 g, 4.7 mol), thionyl chloride (40 mL) was added. The mixture was stirred at 80° C. for 2 hours. After cooling the reaction mixture to room temperature, the mixture was concentrated to dryness. Methanol (40 mL) was added and then the mixture was concentrated in vacuo to give methyl 4-bromo-2-methylbenzoate as a yellow oil (800 mg, 78percent).
62% at 60℃; for 16 h; To a stirring solution of 4-bromo-2-methylbenzoic acid (3 g) in methanol (70 mL) was added concentrated hydrochloric acid (5 mL) and the reaction mixture was heated to 60 °C for 16 h. The reaction mixture was concentrated under reduced pressure, the residue was basified with sodium bicarbonate solution and extracted with dichloromethane (3 x). The combined dichloromethane layers were washed with brine, dried over sodium sulphate and concentrated under reduced pressure to afford Methyl 4-bromo-2- methylbenzoate as a solid (2 g , 62percent)
15.3 g for 15 h; Reflux Step 1: Synthesis of methyl 4-bromo-2-methyl-benzoate To a stirred solution of 4-bromo-2-methyl-benzoic acid (15 g, 65 mmol) in methanol (50 mL) was added sulfuric acid (2 mL). The mixture was stirred and refluxed for 15 hours. After the completion of the reaction, the mixture was quenched by water (20 mL) and then basified to pH 8. After most of the methanol was evaporated, the mixture was extracted with ethyl acetate (50mL x 3). The organic layer was washed by brine (20 mL), and then dried over sodium sulfate and then concentrated to give 15.3 g of methyl 4-bromo-2-methyl-benzoate as a white solid.
15.3 g for 15 h; Reflux 10222] To a stirred solution of 4-bromo-2-methyl-benzoic acid (15 g, 65 mmol) in methanol (50 mE) was added sulthric acid (2 mE). The mixture was stirred and refluxed for 15 hours. Afier the completion of the reaction, the mixture was quenched by water (20 mE) and then basified to pH 8. Afier most of the methanol was evaporated, the mixture was extracted with ethyl acetate (50 mEx3). The organic layer was washed by brine (20 mE), and then dried over sodium sulfate and then concentrated to give 15.3 g of methyl 4-bromo-2-methyl-benzoate as a white solid.
26.6 g at 60℃; To a mixture of 4-bromo-2-methylbenzoic acid (25.0 g) and MeOH (200 mL) was added sulfuric acid (12.4 mL) at room temperature, and the mixture was stirred overnight at 60° C. The reaction mixture was neutralized with 1N aqueous sodium hydroxide solution at 0° C., and extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (26.6 g). (1063) 1H NMR (300 MHz, CDCl3) δ 2.51 (3H, s), 3.82 (3H, s), 7.31 (1H, dd, J=8.3, 1.5 Hz), 7.35 (1H, s), 7.71 (1H, d, J=8.3 Hz)

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YieldReaction ConditionsOperation in experiment
89% at 100℃; for 16 h; Inert atmosphere Example 3.6: Preparation of 4-cvano-2-methylbenzoic acid methyl ester; To a solution of 4-bromo-2-methylbenzoic acid methyl ester (108 g, 471 mmol) in Λ/,Λ/-dimethylformamide (4 1) under a nitrogen atmosphere was added zinc (II) cyanide (88.5 g, 753.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (65 g, 56.60 mmol). The reaction mixture was stirred at 1000C for 16 hours. The reaction mixture was diluted with toluene and the phases were separated. The aqueous phase was extracted twice with toluene. The combined organic phases were washed with brine and saturated aqueous ammonium hydroxide, dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate / cyclohexane 1 :5) to give 4-cyano-2- methylbenzoic acid methyl ester (73 g, 89percent yield). 1H NMR (400 MHz, CDCl3): 7.78 (d, IH), 7.52 (m, 2H), 3.92 (s, 3H), 2.62 (s, 3H).
89% at 100℃; for 16 h; Inert atmosphere Example 17: 4-cyano-2-methylbenzoic acid methyl ester; To a solution of 4-bromo-2-methylbenzoic acid (108 g, 471 mmol) inΛ/,Λ/-dimethylformamide (4 L) under a nitrogen atmosphere was added zinc (II) cyanide (88.5 g, 753.6 mmol) and tetrakis(triphenylphosphine)palladium (65 g, 56.60 mmol). The reaction mixture was stirred at 1000C for 16 hours. The reaction mixture was diluted with toluene and the phases were separated. The aqueous phase was extracted twice with toluene. The combined organic phases were washed with brine and saturated aqueous ammonium hydroxide, dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate / cyclohexane 1 :5) to give 4-cyano-2- methylbenzoic acid methyl ester (73 g, 89percent yield). 1H NMR (400 MHz, CDCl3): 7.78 (d, IH), 7.52 (m, 2H), 3.92 (s, 3H), 2.62 (s, 3H) ppm.
73%
Stage #1: at 90℃; for 2 h;
Stage #2: With ammonium chloride In ISOPROPYLAMIDE; water
Reference Example 10
Methyl 4-cyano-2-methylbenzoate
To a dimethylacetamide (4.62 mL) solution of the compound obtained in Reference Example 9 (498 mg, 2.32 mmol), zinc cyanide (163 mg, 1.39 mmol), tris(dibenzylideneacetone)dipalladium(0) (42 mg, 46.3 μmol) and 1,1'-bis(diphenylphosphino)ferrocene (51 mg, 92.6 μmol) were added, and the mixture was stirred for 2 hours at 90° C.
The reaction mixture was cooled to room temperature, subsequently a saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was subjected to extraction two times with ethyl acetate.
The organic layer thus obtained was washed with water and saturated brine, and was dried over anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1 (1:1, v/v).
Thus, the title compound (294 mg, yield: 73percent) was obtained.
1H-NMR (400 MHz, CDCl3) (ppm: 7.97 (1H, d, J=8 Hz), 7.55-7.53 (2H, m), 3.93 (3H, s), 2.62 (3H, s).
26% With tetrakis(triphenylphosphine) palladium(0) In N,N-dimethyl-formamide at 140℃; for 12 h; Inert atmosphere Methyl 4-cyano-2-methylbenzoate. A mixture of methyl 4-bromo-2-methylbenzoate (1 g, 4.4 mmol), zinc cyanide (0.7 g, 6.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (100 mg, 0.086 mmol) in Ν,Ν-dimethylformamide was heated to 140°C under nitrogen atmosphere. And then the mixture stirred under reflux condition for 12 hours. The mixture was cooled to room temperature, and partitioned between dichloromethane (20 mL * 3) and brine (60 mL). The organic layer was concentrated to dryness and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 15: 1) to give methyl 4-cyano-2-methylbenzoate as a white solid (200 mg, 26percent). LRMS (M + H ) mlz: calcd 175.06; found 175. 1H NMR (300 MHz, CDC13): δ 7.97 (d, J= 8.7 Hz, 1H), 7.57-7.53 (m, 2H), 3.93 (s, 3H), 2.62 (s, 3H).
26% With tetrakis(triphenylphosphine) palladium(0) In N,N-dimethyl-formamide at 140℃; for 12 h; Inert atmosphere; Reflux A mixture of methyl 4-bromo-2-methylbenzoate (1 g, 4.4 mmol), zinc cyanide (0.7 g, 6.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (100 mg, 0.086 mmol) in N,N-dimethylformamide was heated to 140° C. under nitrogen atmosphere. And then the mixture stirred under reflux condition for 12 hours. The mixture was cooled to room temperature, and partitioned between dichloromethane (20 mL*3) and brine (60 mL). The organic layer was concentrated to dryness and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=15:1) to give methyl 4-cyano-2-methylbenzoate as a white solid (200 mg, 26percent). LRMS (M+H+) m/z: calcd 175.06. found 175. 1H NMR (300 MHz, CDCl3): δ 7.97 (d, J=8.7 Hz, 1H), 7.57-7.53 (m, 2H), 3.93 (s, 3H), 2.62 (s, 3H).

Reference: [1] Patent: WO2010/127926, 2010, A1, . Location in patent: Page/Page column 46
[2] Patent: WO2010/127928, 2010, A1, . Location in patent: Page/Page column 32
[3] ChemBioChem, 2016, vol. 17, # 8, p. 759 - 767
[4] Patent: US2012/129832, 2012, A1, . Location in patent: Page/Page column 11-12
[5] Patent: WO2013/75083, 2013, A1, . Location in patent: Paragraph 00467; 00469
[6] Patent: US9206128, 2015, B2, . Location in patent: Page/Page column 216; 217
  • 11
  • [ 99548-55-7 ]
  • [ 557-21-1 ]
  • [ 103261-67-2 ]
YieldReaction ConditionsOperation in experiment
89% With tetrakis(triphenylphosphine) palladium(0) In N,N-dimethyl-formamide at 100℃; for 2 h; STEP 2: To a solution of methyl 4-bromo-2-methylbenzoate (26.6 g, 0.1 16 mol) in DMF (300 mL) was added zinc cyanide (8.1 g, 0.07 mol) followed by tetrakis(triphenylphosphine)palladium(0) (6.7 g, 0.0058 mol). The reaction mixture was placed in a 1000C oil bath and stirred for 2 h, at which time it was filtered through a bed of celite and the filter cake rinsed with ethyl acetate. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (10percent ethyl acetate in hexanes) to afford methyl 4-cyano-2-methylbenzoate (18.1 g, 89percent) as a white powder. 1H NMR (400 MHz, CDCl3): 7.97 (d, IH), 7.55 (s, IH), 7.53 (br m, IH), 3.93 (s, 3H), 2.62 (s, 3H).
Reference: [1] Patent: WO2009/55077, 2009, A1, . Location in patent: Page/Page column 430
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YieldReaction ConditionsOperation in experiment
63% at 180℃; for 5 h; Inert atmosphere A mixture of 4-bromo-2-methyl-benzoic acid methyl ester (26.0 g, 113.5 mmol) and CuCN (12.48 g, 140.7 mmol) was heated at 180 °C for 5 hours before it was poured into ice-water. The solid precipitate was collected by vacuum filtration to give a crude product which was then purified by column chromatography to afford the title compound (12.53 g, 63percent) as a solid.
63% at 180℃; for 5 h; A mixture of 4-bromo-2-methyl-benzoic acid methyl ester (26.0 g, 113.5 mmol) and CuCN (12.48 g, 140.7 mmol) was heated at 180 °C for 5 hours before it was poured intoice-water. The solid precipitate was collected by vacuum filtration to give a crude product which was then purified by column chromatography to afford the title compound (12.53 g, 63percent) as a solid.
63% at 180℃; for 5 h; Inert atmosphere A mixture of 4-bromo-2-methyl-benzoic acid methyl ester (26.0 g, 113.5 mmol) and CuCN (12.48 g,140.7 mmol) was heated at 180 °C for 5 hours before it was poured into ice-water. The solid precipitate was collected by vacuum filtration to give a crude product which was then purified by column chromatography to afford the title compound (12.53 g,63percent)asasolid.
63% at 180℃; for 5 h; Inert atmosphere A mixture of 4-bromo-2-methyl-benzoic acid methyl ester (26.0 g, 113.5 mmol) andCuCN (12.48 g, 140.7 mmol) was heated at 180 °C for 5 hours before it was poured intoice-water. The solid precipitate was collected by vacuum filtration to give a crude product which was then purified by column chromatography to afford the title compound (12.53 g, 63percent) as a solid.
63% at 180℃; for 5 h; Inert atmosphere ΓΒ1 4-Cyano-2-methyl-benzoic acid methyl ester A mixture of 4-bromo-2-methyl-benzoic acid methyl ester (26.0 g, 113.5 mmol) and CuCN (12.48 g, 140.7 mmol) was heated at 180 °C for 5 hours before it was poured into ice- water. The solid precipitate was collected by vacuum filtration to give a crude product which was then purified by silica gel flash chromatography to afford the title compound (12.53 g, 63percent) as a solid.
58.7% for 8 h; Reflux A mixture of methyl 4-bromo-2-methylbenzoate (84.65 g, 369.5 mmol) and cuprous cyanide (45 g, 502.5 mmol) in dimethylformamide (60 ml) was refluxed for 8 h. After being cooled down to room temperature, the reaction mixture was diluted with water (400 ml), and the resulting mixture was filtered. The filter cake was washed with ethyl acetate (200 mlx3). The filtrate was washed with water (400 ml), and the aqueous layer was extracted with ethyl acetate (200 mlx2). The combined organic layer was washed with brine (400 ml), dried over anhydrous sodium sulfate (40 g), and evaporated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 15:1) to afford methyl 4-cyano-2-methylbenzoate (38 g, yield 58.7percent) as a yellow solid.
0.9 g at 220℃; for 0.333333 h; Sealed tube; Microwave irradiation Step 2: Synthesis of methyl 4-cyano-2-methyl-benzoate To a solution of methyl 4-bromo-2-methyl-benzoate (2.5 g, 11.0 mmol) in NMP (12 mL)was added cyanocopper (1.95 g, 22.0 mmol) in a sealed vial, the sealed vial was irradiated in themicrowave on a Biotage Smith Synthesizer at 220°C for 20 minutes. After the reaction was completed, the mixture was cooled to 0°C, and then 20 mL of ammonia was added dropwise. The mixture was stirred for 30 minutes at 0°C and then was quenched by water / ethyl acetate (100 mL, 1/1). The mixture was filtered through a celite pad. The filtrate was partitioned betweenwater/ethyl acetate. The aqueous layer was extracted with ethyl acetate (50 mL x 3). The organic layer was washed with brine (30 mL), and then dried over sodium sulfate and evaporated to dryness. The residue was purified by column chromatography eluting with a gradient from 0percent to 10percent ethyl acetate in petroleum ether to give 0.9 g of methyl 4-cyano-2-methyl-benzoate as a white solid.
0.9 g at 220℃; for 0.333333 h; Sealed tube; Microwave irradiation 10224] To a solution of methyl 4-bromo-2-methyl-benzo- ate (2.5 g, 11.0 mmol) in NMP (12 mE) was added cyanocopper (1.95 g, 22.0 mmol) in a sealed vial, the sealed vial was irradiated in the microwave on a l3iotage Smith Synthesizer at 220° C. for 20 minutes. After the reaction was completed, the mixture was cooled to 0° C., and then 20 mE of ammonia was added dropwise. The mixture was stirred for 30 minutes at 0° C. and then was quenched by water ethyl acetate (100 mE, 1/1). The mixture was filtered through a celite pad. The filtrate was partitioned between water/ethyl acetate. The aqueous layer was extracted with ethyl acetate (50 mEx3). The organic layer was washed with brine (30 mE), and then dried over sodium sulfate and evaporated to dryness. The residue was purified by column chromatography eluting with a gradient from 0percent to 10percent ethyl acetate in petroleum ether to give 0.9 g of methyl 4-cyano-2-methyl-benzoate as a white solid.

Reference: [1] Patent: WO2013/79452, 2013, A1, . Location in patent: Page/Page column 165
[2] Patent: WO2014/191336, 2014, A1, . Location in patent: Page/Page column 43
[3] Patent: WO2014/191340, 2014, A1, . Location in patent: Page/Page column 40
[4] Patent: WO2014/191338, 2014, A1, . Location in patent: Page/Page column 41
[5] Patent: WO2016/55394, 2016, A1, . Location in patent: Page/Page column 41
[6] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 12, p. 3671 - 3675
[7] Patent: US5591752, 1997, A,
[8] Patent: US2014/45855, 2014, A1, . Location in patent: Paragraph 0551
[9] Patent: WO2015/110369, 2015, A1, . Location in patent: Page/Page column 37
[10] Patent: US2016/326148, 2016, A1, . Location in patent: Paragraph 0223; 0224
[11] Patent: EP2272835, 2011, A1, . Location in patent: Page/Page column 14
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  • [ 544-92-3 ]
  • [ 103261-67-2 ]
Reference: [1] Patent: US2009/82368, 2009, A1, . Location in patent: Page/Page column 41-42
  • 14
  • [ 99548-55-7 ]
  • [ 1975-53-7 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 12, p. 3671 - 3675
[2] Patent: WO2010/127928, 2010, A1,
[3] Patent: EP2272835, 2011, A1,
  • 15
  • [ 99548-55-7 ]
  • [ 35598-05-1 ]
Reference: [1] Patent: US2003/212094, 2003, A1,
  • 16
  • [ 99548-55-7 ]
  • [ 156001-49-9 ]
Reference: [1] Patent: WO2013/43232, 2013, A2,
  • 17
  • [ 99548-55-7 ]
  • [ 78471-43-9 ]
YieldReaction ConditionsOperation in experiment
97% With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane at 85℃; for 2 h; A mixture of methyl 4-bromo-2-methylbenzoate (1 g, 4.4 mmol), NBS (0.80 g, 4.4 mmol), BPO (56 mg, 0.23 mmol), and CCl4 (20 mL) was stirred at 85 °C for 2 hours. The mixture was filtered with a pad of silica gel and concentrated to afford the desired product (1.3 g, 97percent yield).
92% With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane at 20℃; for 4 h; 250 W lamp irradiation REFERENCE EXAMPLE 2; Methyl 4-bromo-2-(bromomethyl)benzoate; To a solution of methyl 4-bromo-2-methylbenzoate (9.60 g, 0.42 mol, obtained in reference example 1) in CCI4 (150 mL), Λ/-bromosuccinimide (7.46g, 0.42mol) and benzoyl peroxide (0.19g, 0.79mmol) were added. The reaction mixture was stirred EPO <DP n="37"/>4h at room temperature while irradiated with a 250 Watt lamp and it was then filtered to remove the precipitated solids. The filtrate was washed with 1 N NaOH and water and it was dried over Na2SO4. The solvent was evaporated to afford11.87 g of the desired compound as an oil that solidified on standing (yield: 92percent, uncorrected).1H NMR (300 MHz, CDCI3) δ (TMS): 3.94 (s, 3 H), 4.90 (s, 2 H)1 7.51 (dd, J = 8.4Hz1 J1 = 2.1 Hz, 1 H), 7.63 (d, J = 1.8 Hz, 1 H), 7.84 (d, J = 8.4 Hz, 1 H).
92% With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane at 20℃; for 4 h; Light irradiation Reference Example 2; Methyl 4-bromo-2-(bromomethyl)benzoateTo a solution of methyl 4-bromo-2-methylbenzoate (9.60 g, 0.42 mol, obtained in reference example 1) in CCl4 (150 mL), N-bromosuccinimide (7.46 g, 0.42 mol) and benzoyl peroxide (0.19 g, 0.79 mmol) were added. The reaction mixture was stirred 4 h at room temperature while irradiated with a 250 Watt lamp and it was then filtered to remove the precipitated solids. The filtrate was washed with 1N NaOH and water and it was dried over Na2SO4. The solvent was evaporated to afford 11.87 g of the desired compound as an oil that solidified on standing (yield: 92percent, uncorrected).1H NMR (300 MHz, CDCl3) 8 (TMS): 3.94 (s, 3H), 4.90 (s, 2H), 7.51 (dd, J=8.4 Hz, J'=2.1 Hz, 1H), 7.63 (d, J=1.8 Hz, 1H), 7.84 (d, J=8.4 Hz, 1H).
92% With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane at 20℃; for 4 h; Irradiation REFERENCE EXAMPLE 2; Methyl 4-bromo-2-(bromomethyl)benzoate; To a solution of methyl 4-bromo-2-methylbenzoate (9.60 g, 0.42 mol, obtained in reference example 1) in CCI4 (150 mL), Λ/-bromosuccinimide (7.46g, 0.42mol) and benzoyl peroxide (0.19g, 0.79mmol) were added. The reaction mixture was stirred 4h at room temperature while irradiated with a 250 Watt lamp and it was then filtered to remove the precipitated solids. The filtrate was washed with 1 N NaOH and water and it was dried over Na2SO4. The solvent was evaporated to afford 11.87 g of the desired compound as an oil that solidified on standing (yield: 92percent, uncorrected).1H NMR (300 MHz, CDCI3) δ (TMS): 3.94 (s, 3 H), 4.90 (s, 2 H), 7.51 (dd, J = 8.4 Hz, J' = 2.1 Hz, 1 H), 7.63 (d, J = 1.8 Hz, 1 H), 7.84 (d, J = 8.4 Hz, 1 H).
90% With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 2 h; Inert atmosphere; Reflux Example 1295-{2-[2-Amino-6-(4-methylpiperazin-l-yl)pyrimidin-4-yl]-3-methy1-l^^,4-tetrahydroisoquinolin-7- yll-Σ-cyclopropylisoindolin-l-oneStep I methyl 4-bromo-2-(bromomethyl)benzoate; A mixture of methyl 4-bromo-2-methylbenzoate (0.7 g, 0.003 mol), N-bromosuccinimide (0.65 g, 0 0037 mol) and benzoyl peroxide (0 038 g, 0.00016 mol) in carbon tetrachloride (30 niL) was refluxed under an atmosphere of nitrogen for 2 h. The mixture was cooled to RT, and filtered through silica gel eluting with dichloromethane followed by diethyl ether. The mixture was concentrated and the residue was purified by chromatography on silica gel with 30percent EtOAc in hexanes to afford the desired product (0.86 g, 90percent).
79% With N-Bromosuccinimide; azobisisobutyronitrile In tetrachloromethane Example 33B
Methyl 4-bromo-2-(bromomethyl)benzoate
A solution of Example 33A (1.02 g, 4.47 mmol) in CCl4 (22 mL) was treated with AIBN (0.065 g, 0.4 mmol) and NBS (0.955 g, 5.4 mmol), heated to reflux for 4 hours, washed with water, dried (Na2SO4), filtered, and concentrated to provide the desired product (1.1 g, 79percent).
79% With azobisisobutyronitrile In tetrachloromethane Example 263B
4-Bromo-2-bromomethyl-benzoic acid methyl Ester
A solution of Example 263A (1.02 g; 4.5 mmol) in CCl4 (22 mL) was treated with AIBN (65 mg; 0.4 mmol), heated at reflux for 4 hrs., washed with water, dried (Na2SO4) and concentrated to provide the desired product (1.1 g; 79percent).
79% With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane for 4 h; Heating / reflux Example 33B
methyl 4-bromo-2-(bromomethyl)benzoate
A solution of Example 33A (1.02 g, 4.47 mmol) in CCl4 (22 mL) was treated with AIBN (0.065 g, 0.4 mmol) and NBS (0.955 g, 5.4 mmol), heated to reflux for 4 hours, washed with water, dried (Na2SO4), filtered, and concentrated to provide the desired product (1.1 g, 79percent).
74% With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane at 85℃; for 5 h; Step 2:
Methyl 4-Bromo-2-(bromomethyl)benzoate
A solution of methyl 4-bromo-2-methylbenzoate (1.0 g, 4.3 mmol) in CCl4 was treated with N-bromosuccinimide (0.93 g, 5.2 mmol) and benzoyl peroxide (0.53 g, 2.2 mmol), heated at 85° C. for 5 h, cooled to room temperature and filtered The filtercake was washed with CCl4 and the filtrates were combined and concentrated in vacuo to provide an oil residue.
The residue was purified by ISCO CombiFlash.(R). chromatography (silica, 0-5percent ethyl acetate in hexanes) to afford the title compound, 1.59 g (74percent), MS (EI) m/z 308 [M]+.
74% With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane at 85℃; for 5 h; Step 2:
Methyl 4-bromo-2-(bromomethyl)benzoate
A solution of methyl 4-bromo-2-methylbenzoate (1.0 g, 4.3 mmol) in carbon tetrachloride was treated with N-bromosuccinimide (0.93 g, 5.2 mmol) and benzoyl peroxide (0.53 g, 2.2 mmol), heated at 85° C. for 5 h, cooled to room temperature and filtered.
The filtercake was washed with methylene chloride.
The combined filtrates were concentrated in vacuo.
The residue was purified by ISCO CombiFlash.(R). chromatography (silica, 0-5percent ethyl acetate in hexanes) to afford 1.59 g (74percent) of methyl 4-bromo-2-(bromomethyl)benzoate as a light yellow oil. MS (EI) m/z 308 [M]+.
72% With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In acetonitrile at 80℃; [00528] Intermediate 51 a: methyl 4-bromo-2-(bromomethyl)benzoate [00529] A mixture of methyl 4-bromo-2-methylbenzoate (2.5g, 10.91 mmol) and NBS (1 .94g, 10.91 mmol) in acetonitrile (22mL) was degassed and AIBN (72mg, 0.44mmol) added. The mixture was stirred and heated at 80 °C overnight and then cooled to room temperature and concentrated in vacuo. The residue was purified by column chromatography using an eluent of 0-25percent EtOAc inheptane to give methyl 4-bromo-2-(bromomethyl)benzoate (2.44g, 7.91 mmol, 72percent) as a colourlessoil that solidified upon standing.1H NMR (CDCI3, 400MHz) O/ppm: 7.87 (1H, d, J= 8.4Hz), 7.65 (1H, d, J= 2.0Hz), 7.53 (1H, dd, J=8.4Hz, 2.0Hz), 4.92 (2H, 5), 3.96 (3H, 5).MS Method 2: RT: 1 .90 mi mlz 226.8/228.8 [M-Br]
72% With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethaneInert atmosphere; Reflux To 2-methyl-4-bromobenzoic acid methyl ester (2.995g, 12,584 mm, 1 . 0equiv) of carbon tetrachloride (40 ml) is added to solution N-bromo succinimide (2.338g, 13.2 mm, 1 . 05equiv), benzoyl peroxide (152 mg, 0 . 629 mm, 0 . 05equiv), and heated to reflux in a nitrogen atmosphere. The TLC monitoring the reaction is complete, cooling to room temperature, filtered, concentrated under reduced pressure the solvent. Column chromatography (petroleum ether: ethyl acetate = 10:1) treatment to obtain pale brown solid (2.78g, yield 72percent).
72.9% With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In acetonitrile at 85℃; for 18 h; Methyl 4-bromo-2-methylbenzoate (102 g, 445.27 mmol), NBS (79.2 g, 445.27 mmol), Azo-isobutyronitrile (2.58 g, 16 mmol) in acetonitrile (600 mL) were combined and refluxed at 85 °C for 18 h. The mixture was concentrated, and to the residue was added dichloromethane (150 mL). The resultant solid was removed by filtration. The filtrate was concentrated and purified by flash column chromatography (0-4percent EtOAc in Hexanes). Fractions containing product was concentrated under reduced pressure and further dried under high vacuum to give Methyl-4-bromo-2- (bromomethyl) benzoate (100 g, 324.70 mmol, 72.9 percent yield) as an off-white solid. 1H NIVIR (300 MHz, Dimethylsulfoxide-d6) 7.88 (d, J 2.2 Hz, 1H), 7.82 (dd, J 8.4, 2.1 Hz, 1H), 7.72— 7.64 (m, 1H), 5.00 (s, 2H), 3.88 (s, 3H).
72.9% With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In acetonitrile at 85℃; for 18 h; Methyl 4-bromo-2-methylbenzoate (102 g, 445.27 mmol), NBS (79.2 g, 445.27 mmol), Azo-isobutyronitrile(2.58 g, 16 mmol) in acetonitrile (600 mL) were combined and refluxed at 85°C for 18hours. The mixture was concentrated, and to the residue was added dichloromethane (150 mL). The resultant solid was removed by filtration. The filtrate was concentrated and purified by flash column chromatography (0-4percent EtOAc in Hexanes). Fractions containing product was concentrated under reduced pressure and further dried under highvacuum to give Methyl-4-bromo-2-(bromomethyl) benzoate (100 g, 324.70 mmol, 72.9percent yield) as an off-white solid. 1HNMR (300 IVIHz, Dimethylsulfoxide-d6) 7.88 (d, J2.2 Hz, 1H), 7.82 (dd, J= 8.4, 2.1 Hz, 1H), 7.72—7.64 (m, 1H), 5.00 (s, 2H), 3.88 (s,3H).
68% With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane at 80℃; for 16 h; To a solution of methyl 4-bromo-2-methylbenzoate (5.0 g, 21.83 mmol) in carbon tetrachloride (100 mL) was added BS (4.3 g, 24.01 mmol), the suspension was heated at 80 °C for 5 min, then AIBN (1.07 g, 6.55 mmol) was added. The suspension continued to stir at 80 °C for 16 h, then cooled to RT and filtered. The filtrate was concentrated to give the crude product, which was purified by silica-gel column to give methyl 4-bromo-2-methylbenzoate (4.6 g, 68percent) as a white solid.
66% With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In acetonitrile for 21.75 h; Heating / reflux Step 2: A mechanically stirred mixture of 4-bromo-2-methyl-benzoic acid methyl ester (1 15 g, 500 mmol), N-bromosuccinimide (90 g, 500 mmol) and AIBN (3.1 g) in acetonitrile (700 mL) was warmed over 45 minutes to a gentle reflux, and held at reflux for 21 hours. The reaction mixture was cooled to room temperature, diluted with saturated aqueous sodium bisulfite, and concentrated in vacuo. The residue was partitioned between water and 1 :1 hexanes:ethyl acetate. The organic phase was washed with water, brine, and filtered through a pad of silica gel. The solvent was removed under vacuum to give an oil/solid mixture, which was digested in ether and filtered. The filtrate was chromatographed on silica gel using a hexanes-ethyl acetate gradient, eluting the product at 4:1 hexanes-ethyl acetate and providing 102 g of 4-bromo-2-bromomethyl- benzoic acid methyl ester, in 66percent yield; 1H NMR (DMSCMs) δ 3.87 (s, 3H), 4.99 (s, 2H), 7.67-7.97 (m, 3H).
66% With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In acetonitrile for 21 h; Reflux A mechanically stirred mixture of 4-bromo-2-methyl-benzoic acid methyl ester (115 g, 500 mmol), N-bromosuccinimide (90 g, 500 mmol) and AIBN (3.1 g) in acetonitrile (700 mL) was warmed over 45 minutes to a gentle reflux, and held at reflux for 21 hours. The reaction mixture was cooled to room temperature, diluted with saturated aqueous sodium bisulfite, and concentrated in vacuo. The residue was partitioned between water and 1:1 hexanes:ethyl acetate. The organic phase was washed with water, brine, and filtered through a pad of silica gel. The solvent was removed under vacuum to give an oil/solid mixture, which was digested in ether and filtered. The filtrate was chromatographed on silica gel using a hexanes-ethyl acetate gradient, eluting the product at 4:1 hexanes-ethyl acetate and providing 102 g of 4-bromo-2-bromomethyl-benzoic acid methyl ester, in 66percent yield; 1H NMR (DMSO-d6) 3.87 (s, 3H), 4.99 (s, 2H), 7.67-7.97 (m, 3H).
66% With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In acetonitrile for 21.75 h; Reflux [00408j Step 2: A mechanically stirred mixture of 4-bromo-2-methyl-benzoic acid methyl ester (115 g, 500 mmol), N-bromosuccinimide (90 g, 500 mmol) and AIBN (3.1 g) in acetonitrile (700 mL) was warmed over 45 minutes to a gentle reflux, and held at reflux for 21 hours. The reaction mixture was cooled to room temperature, diluted with saturated aqueous sodium bisulfite, and concentrated in vacuo. The residue was partitioned between water and 1:1 hexanes:ethyl acetate. The organic phase was washed with water, brine, and filtered through a pad of silica gel. The solvent was removed under vacuum to give an oil/solid mixture, which was digested in ether and filtered. The filtrate was chromatographed on silica gel using a hexanes-ethyl acetate gradient, eluting the product at 4:1 hexanes-ethyl acetate and providing 102 g of 4-bromo-2-bromomethyl-benzoic acid methyl ester, in 66percent yield; 1H NMR (DMSO-d6) ö 3.87 (s, 3H), 4.99 (s, 2H), 7.67-7.97 (m, 3H).
66% With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In acetonitrile for 21.75 h; Reflux A mechanically stirred mixture of 4-bromo-2-methyl -benzoic acid methyl ester (115 g, 500 mmol), N-bromosuccinimide (90 g, 500 mmol) and AIBN (3.1 g) in acetonitrile (700 mL) was warmed over 45 minutes to a gentle reflux, and held at reflux for 21 hours. The reaction mixture was cooled to room temperature, diluted with saturated aqueous sodium bisulfite, and concentrated in vacuo. The residue was partitioned between water and 1 : 1 hexanes:ethyl acetate. The organic phase was washed with water, brine, and filtered through a pad of silica gel. The solvent was removed under vacuum to give an oil/solid mixture, which was digested in ether and filtered. The filtrate was chromatographed on silica gel using a hexanes-ethyl acetate gradient, eluting the product at 4: 1 hexanes-ethyl acetate and providing 102 g of 4-bromo-2-bromomethyl-benzoic acid methyl ester, in 66percent yield; 1H MR (DMSO-i) δ 3.87 (s, 3H), 4.99 (s, 2H), 7.67-7.97 (m, 3H).
62.5% With N-Bromosuccinimide; dibenzoyl peroxide In chloroform at 100℃; for 2 h; Inert atmosphere Methyl 4-bromo-2-(bromomethyl)benzoate
To a solution of methyl 4-bromo-2-methylbenzoate (5.0 g, 21.83 mmol) in chloroform (20 mL), under nitrogen, was added NBS (3.88 g, 21.83 mmol) and benzoyl peroxide (0.264 g, 1.091 mmol). The mixture was refluxed at 100 °C for 2 h., filtered and concentrated to afford methyl 4-bromo-2-(bromomethyl)benzoate (5.0 g, 13.64 mmol, 62.5 percent yield). LC-MS: m/z 307 (M+H)+1.28 min (ret. time).
60% With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane for 4.08333 h; Inert atmosphere; Reflux This intermediate (18.51 mmol) is dissolved in carbon tetrachloride (100 mL) and N-bromosuccinimide (5.57 g, 24.06 mmol) is added. AIBN (122 mg, 740 μmol) is then added and the mixture purged with nitrogen for 5 minutes.
The reaction mixture is then refluxed for four hours.
After cooling to room temperature the reaction mixture is filtered and the filtrate is evaporated.
The residue is purified by flash chromatography (silica gel, 2:1 petroleum ether/ethyl acetate) to give the title compound (3.42 g, 60percent).
60% With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane for 4.08333 h; Heating / reflux Step 1 4-Bromo-2-bromomethyl-benzoιc acid methyl ester <n="93"/>[00354] 4-Bromo-2-methyl-benzoic acid (4 6 g, 21 39 mmol) is dissolved in 2M HCl in MeOH and refluxed for 3 hours The solvent is evaporated to give the 4-bromo-2-methyl-benzoic acid methyl ester (4 24 g, 86 percent) This intermediate (18 51 mmol) is dissolved m carbon tetrachloride (100 mL) and N-bromosuccinimide (NBS) (5 57 g, 24 06 mmol) is added AIBN (122 mg, 740 mol) is then added and the mixture purged with nitrogen for 5 mm The reaction mixture is then refluxed for 4 hours After cooling to room temperature the reaction mixture is filtered and the filtrate is evaporated The residue is puπfied by flash chromatography (silica gel, 2 1 petroleum ether/ethyl acetate) to give the title compound (3 42g, 60 percent)
60% With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane for 4.08333 h; Heating / reflux 4-Bromo-2-methyl-benzoic acid (4.6 g, 21.39 mmol) is dissolved in 2M HCl inMeOH and refluxed for 3 hours. The solvent is evaporated to give the 4-bromo-2-methyl-benzoic acid methyl ester (4.24 g, 86 percent). This intermediate (18.51 mmol) is dissolved in carbon tetrachloride (100 mL) and N-bromosuccinimide (NBS) (5.57 g, 24.06 mmol) is added. AIBN (122 mg, 740 μmol) is then added and the mixture purged with nitrogen for 5 min. The reaction mixture is then refluxed for 4 hours. After cooling to room temperature the reaction mixture is filtered and the filtrate is evaporated. The residue is purified by flash chromatography (silica gel, 2:1 petroleum ether/ethyl acetate) to give the title compound (3.42g, 60 percent).
60% With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 18 h; Reflux Part B:A solution of compound 2 (3S8 mg, 1.69 mmol), W-bromosuccinimide ( NBS, 302 mg,1 ,69 mmol) and benzoyl peroxide (12.3 mg, 0.05 mmol) in carbon tetrachloride (6 mL) was heated to reflux for 18 hours. LC-MS analysis indicated the reaction was complete. The reaction mixture was diluted with diethyl ether (10 mL) and passed through a plug of ceSite to remove precipitates. The filtrate was washed with saturated NaHCO3, dried over magnesium sulfate, concentrated and purified by flash column chromatography, gradient elution (0 to 100 percent) hexane / ethyl acetate, to afford compound 3 as a colorless oil (310 mg, 60 percent yield). HPLC-MS tR = 2.00 min (UV254 nm); mass calculated for formula C9H8Br2O2 SOS-Q, observed LCMS m/z 306.9 (M+H).
41% With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane at 80℃; for 5 h; Step 2. To a solution of 28 (1.0 g, 4.37 mmol) and NBS (0.93 g, 5.24 mmol) in CC14 (10 mL) was added BPO (106 mg, 0.44.00 mmol). The reaction mixture was stirred at 80°C for 5 h. Upon completion, the reaction was quenched with H20 (10 mL) and extracted with ethyl acetate (3 x 20 mL). The the organic layer was washed with H20 (3 x 10 mL), concentrated, and purified by prep-TLC (petroleum : ethyl acetate = 20: 1) to afford 29 (610 mg, 41percent).
37.5% With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane at 20℃; for 4 h; To a stirring solution of methyl 4-bromo-2-methylbenzoate (600 mg, 2.62 mmol) in carbon tetrachloride (70 mL) was added /V-bromo succinimide (466 mg, 2.62 mmol) and benzoyl peroxide (12 mg) and the resultant reaction mixture was stirred in presence of sodium lamp at RT for 4 h. The reaction mixture was filtered through celite and washed with 2N sodium hydroxide solution, dried over sodium sulphate and concentrated under reduced pressure to afford Methyl 4-bromo-2-(bromomethyl)benzoate as a solid (300 mg, 37.5percent).
1.8 g With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethaneInert atmosphere; Reflux Synthesis of methyl 4-bromo-2-(bromomethyl)benzoate (46): A solution of methyl 4-bromo-2-methylbenzoate 45 (2000 mg, 8.77 mmol), N-bromosuccinimide (NBS) (3035 mg, 17.54 mmol), benzoyl peroxide (BPO) (1061 mg, 4.39 mmol) in CC14 (20 mL) was refluxed overnight under nitrogen atmosphere. After cooling to room temperature, the mixture was washed with brine (20 mL X 2) and dried over anhydrous Na2S04. The solvent was removed under reduced pressure to give the crude product, which was purified by silica gel chromatography (2-5percent EtO Ac/petroleum ether) to give methyl 4-bromo-2- (bromomethyl)benzoate 46 as a white solid (yield: 1.8 g, 67percent). LCMS: m/z 308.7 [M+H]+; tR = 1.88 min.
75 g With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane at 20 - 60℃; for 4 h; Irradiation To a solution of 6D (50 g, 0.22 mol) in CC14 (750 mL) was added N-bromosuccinimide(38.9 g, 0.22 mol) and benzoyl peroxide(1.1 g, 4.4 mmol) at room temperature. The reaction mixture was stirred 4 hr at 60 °C while irradiatedwith a 250 watt lamp. The mixturewas cooled to room temperature, washedwith 1 M aq. NaOH, water, and dried over Na2S04.The solvent wasevaporated to afford the crude 6E (75g) as oil ' which wastaken to next step directly.
33.1 g at 80℃; for 18 h; Inert atmosphere To a mixture of methyl 4-bromo-2-methylbenzoate (25.0 g) and (trifluoromethyl)benzene (400 mL) were slowly added N-bromosuccinimide (19.4 g) and 2,2′-azobis(isobutyronitrile) (1.79 g) at room temperature. The mixture was heated under reflux under nitrogen atmosphere at 80° C. for 18 hr, and cooled to room temperature. The insoluble substance was filtered off, the obtained filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (33.1 g). (1065) 1H NMR (300 MHz, DMSO-d6) δ 3.87 (3H, s), 4.99 (2H, s), 7.65-7.73 (1H, m), 7.78-7.84 (1H, m), 7.89 (1H, d, J=2.3 Hz)

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