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Product Details of [ 99-94-5 ]

CAS No. :99-94-5 MDL No. :MFCD00002565
Formula : C8H8O2 Boiling Point : -
Linear Structure Formula :- InChI Key :LPNBBFKOUUSUDB-UHFFFAOYSA-N
M.W : 136.15 Pubchem ID :7470
Synonyms :
4-Methylbenzoic acid
Chemical Name :4-Methylbenzoic acid

Calculated chemistry of [ 99-94-5 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 10
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.12
Num. rotatable bonds : 1
Num. H-bond acceptors : 2.0
Num. H-bond donors : 1.0
Molar Refractivity : 38.37
TPSA : 37.3 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.52 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.47
Log Po/w (XLOGP3) : 2.27
Log Po/w (WLOGP) : 1.69
Log Po/w (MLOGP) : 1.93
Log Po/w (SILICOS-IT) : 1.68
Consensus Log Po/w : 1.81

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.56

Water Solubility

Log S (ESOL) : -2.49
Solubility : 0.438 mg/ml ; 0.00322 mol/l
Class : Soluble
Log S (Ali) : -2.69
Solubility : 0.278 mg/ml ; 0.00204 mol/l
Class : Soluble
Log S (SILICOS-IT) : -2.13
Solubility : 1.02 mg/ml ; 0.00746 mol/l
Class : Soluble

Medicinal Chemistry

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

Safety of [ 99-94-5 ]

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 [ 99-94-5 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Upstream synthesis route of [ 99-94-5 ]
  • Downstream synthetic route of [ 99-94-5 ]

[ 99-94-5 ] Synthesis Path-Upstream   1~55

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Reference: [1] Chemical and Pharmaceutical Bulletin, 1985, vol. 33, # 4, p. 1351 - 1359
  • 2
  • [ 77632-23-6 ]
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Reference: [1] Tetrahedron, 1986, vol. 42, # 4, p. 1139 - 1144
  • 3
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  • [ 19438-61-0 ]
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Reference: [1] Journal of applied chemistry of the USSR, 1987, vol. 60, # 1 pt 2, p. 136 - 138
[2] Journal of applied chemistry of the USSR, 1987, vol. 60, # 1 pt 2, p. 136 - 138
  • 4
  • [ 99-94-5 ]
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Reference: [1] Journal of Medicinal Chemistry, 2007, vol. 50, # 15, p. 3420 - 3422
  • 5
  • [ 79-19-6 ]
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  • [ 26907-54-0 ]
YieldReaction ConditionsOperation in experiment
98%
Stage #1: at 75℃; for 0.5 h;
Stage #2: for 4 h; Reflux
General procedure: 5.1.1
5-(4-Morpholinophenyl)-1,3,4-thiadiazol-2-amine (59)
A mixture of 4-morpholinobenzoic acid (5.18 g, 25 mmol) and N-aminothiourea (2.28 g, 25 mmol) in POCl3 (7 ml) was stirred vigorously at 75 °C for 0.5 h.
After addition of H2O (30 ml), the reaction mixture was heated under reflux for 4 h and basified to pH 8 by 50percent NaOH solution.
The mixture was filtered and the filter cake was recrystallized from ethanol to yield 3.90 g of compound 59 as a yellow crystal. Yield: 59percent; The synthetic procedures of compounds 60–81 were the same as that described above. 5.1.1.4
5-(p-Tolyl)-1,3,4-thiadiazol-2-amine (63)
Yield: 98percent, mp: 194-195 °C (EtOH). ESI-MS m/z: 192.3 [M+H]+; 1H NMR (DMSO-d6) δ 2.34 (s, 3H), 7.27 (d, J = 8.4 Hz, 2H), 7.35 (s, 2H), 7.64 (d, J = 8.4 Hz, 2H).
90% at 20℃; for 4.5 h; Reflux General procedure: 4.2.2.1. 5-(4-Fluorophenyl)-1,3,4-thiadiazol-2-amine (2b). A mixture of 4-fluoro benzoic acid (5.0 g, 35.70 mmol), thiosemicarbazide (3.25 g, 35.70 mmol) and POCl3 (9.25 ml)was heated to 75 °C and maintained same temperature for 30 min under stirring. The reaction mixture cooled to room temperature, water (55 ml) was added and refluxed for 4 h. After cooling, the mixture was basified with 50percent NaOH to pH 8 by the drop wise addition under stirring. The obtained solid was filtered and recrystallized from ethanol to give the target compound 2b as a colorless solid. Yield: 5.69 g, 82percent
90% at 75℃; for 0.5 h; General procedure: A mixture of appropriate carboxylic acid (5.0 g, 1 eq), thiosemicarbazide(1 eq) and POCl3 (1.85 eq) was heated to 75C andmaintained at the same temperature for 30 min under stirring. Thereaction mixture was then cooled to room temperature, water (11v) was added and the mixture was refluxed for 4 h. After cooling,the mixture was basified with 50percent NaOH to pH 8 by the drop wiseaddition under stirring. The obtained solid was filtered andrecrystallized from ethanol to give the target compounds 4b-g
Reference: [1] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 21, p. 5766 - 5775
[2] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 14, p. 6663 - 6668
[3] European Journal of Medicinal Chemistry, 2015, vol. 95, p. 49 - 63
[4] European Journal of Medicinal Chemistry, 2015, vol. 106, p. 75 - 84
[5] Medicinal Chemistry Research, 2012, vol. 21, # 6, p. 816 - 824
[6] Bulletin of the Korean Chemical Society, 2010, vol. 31, # 8, p. 2345 - 2350
[7] Bulletin of the Korean Chemical Society, 2011, vol. 32, # 3, p. 1011 - 1016
[8] Asian Journal of Chemistry, 2010, vol. 22, # 7, p. 5289 - 5296
[9] Journal of the Chinese Chemical Society, 2007, vol. 54, # 3, p. 771 - 777
[10] Journal of the Chinese Chemical Society, 2010, vol. 57, # 6, p. 1327 - 1330
[11] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 15, p. 4292 - 4295
[12] Journal of Chemical Research, 2011, vol. 35, # 8, p. 442 - 443
[13] Nucleosides, Nucleotides and Nucleic Acids, 2011, vol. 30, # 4, p. 280 - 292
[14] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 3, p. 1181 - 1187
[15] Oriental Journal of Chemistry, 2011, vol. 27, # 2, p. 373 - 383
[16] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 9, p. 2789 - 2795
[17] Journal of Chemical Research, 2012, vol. 36, # 4, p. 218 - 221
[18] RSC Advances, 2014, vol. 4, # 99, p. 55827 - 55831
[19] Medicinal Chemistry Research, 2015, vol. 24, # 12, p. 4058 - 4069
[20] Oriental Journal of Chemistry, 2015, vol. 31, # 4, p. 1873 - 1885
[21] Pharmazie, 2018, vol. 73, # 3, p. 123 - 127
[22] Bioorganic Chemistry, 2018, vol. 81, p. 88 - 92
  • 6
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Reference: [1] Angewandte Chemie - International Edition, 2008, vol. 47, # 28, p. 5215 - 5219
  • 7
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Reference: [1] Patent: EP1197491, 2002, A1, . Location in patent: Page 25
  • 8
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Reference: [1] Patent: US5153335, 1992, A,
  • 9
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Reference: [1] Environmental Science and Technology, 1998, vol. 32, # 16, p. 2357 - 2370
  • 10
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YieldReaction ConditionsOperation in experiment
84% With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); potassium carbonate In tetrachloromethane at 90℃; In a 100 mL round bottom flask, 40 mL of carbon tetrachloride, 3.00 g of p-toluic acid, 4.00 g of NBS and 0.1 g of AIBN were added, and the mixture was stirred and refluxed at 90 ° C, and the TLC was traced to the end point.After cooling to room temperature, it was suction filtered, and the filter cake was washed with warm water to remove the succinimide produced by the reaction, followed by drying to obtain a product of 4.02 g.Melting point: 231-232 ° C, yield 84percent.
84% With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane at 90℃; for 1.5 h; 3.00 g of p-toluic acid, 4.00 g of NBS and 0.1 g of AIBN, in a 100 ml roundIn the bottom flask, 40 ml of carbon tetrachloride was added, and the reaction was refluxed at 90 ° C. The plate was traced until the reaction of the starting material was complete, about 1.5 h, and cooled.After suction filtration, the filter cake was washed with warm water to remove the succinimide produced by the reaction, and then dried to obtain 4.02 g of a white solid product.The yield was 84percent.
80% With tribromo-isocyanuric acid In ethyl acetate for 6 h; Reflux; Green chemistry General procedure: a solution of the arene (2.0 mmol) and TBCA (0.25 g, 0.68 mmol) in EtOAc (20 mL) was refluxed for 6 h with stirring. At the end of the reaction, the precipitated cyanuric acid was then separated by filtration and the filtrate was evaporated to dryness under reduced pressure. The residue was passed through a short chromatographic column (SiO2, eluted with 15:1 hexane–ethyl acetate) to give the purified products.
77.9% With N-Bromosuccinimide; dibenzoyl peroxide In water; benzene EXAMPLE 117
4-[2-Cyclopentyl-1-(thiazol-2-ylcarbamoyl)-ethyl]-benzoic Acid Methyl Ester
A solution of 4-methyl-benzoic acid (10 g, 73.4 mmol) in benzene (133 mL) was treated with benzoyl peroxide (72 mg, 0.29 mmol).
This mixture was heated to reflux until it became homogeneous.
At this time, the reaction was treated with N-bromosuccinimide (13 g, 73.4 mmol) and additional benzoyl peroxide (72 mg, 0.29 mmol).
This mixture was heated at reflux for 2.5 h.
At this time, the reaction was cooled to 25° C.
The resulting precipitate was collected by filtration and washed with hot water (50 mL).
The solid was taken up in water (150 mL).
This slurry was heated at 80° C. and then filtered while hot.
The solid that was collected was dried in vacuo to afford 4-bromomethyl-benzoic acid (12.3, 77.9percent) as a white solid: mp 224-226° C.; EI-HRMS m/e calcd for C8H7BrO2 (M+) 213.9629, found 213.9628.
77.9% With N-Bromosuccinimide; dibenzoyl peroxide In water; benzene EXAMPLE 117
4-[2-Cyclopentyl-1-(thiazol-2-ylcarbamoyl)-ethyl]-benzoic acid methyl ester
A solution of 4-methyl-benzoic acid (10 g, 73.4 mmol) in benzene (133 mL) was treated with benzoyl peroxide (72 mg, 0.29 mmol).
This mixture was heated at reflux until it became homogeneous.
At this time, the reaction was treated with N-bromosuccinimide (13 g, 73.4 mmol) and additional benzoyl peroxide (72 mg, 0.29 mmol).
This mixture was heated at reflux for 2.5 h.
At this time, the reaction was cooled to 25° C.
The resulting precipitate was collected by filtration and washed with hot water (50 mL).
The solid was taken up in water (150 mL).
This slurry was heated at 80° C. and then filtered while hot.
The solid that was collected was dried in vacuo to afford 4-bromomethyl-benzoic acid (12.3, 77.9percent) as a white solid: mp 224-226° C.; EI-HRMS m/e calcd for C8H7BrO2 (M+) 213.9629, found 213.9628.
77%
Stage #1: With sodium bromate In water; ethyl acetate
Stage #2: With sodium hydrogensulfite In water for 4.33333 h;
[00216] Step 1 : A solution of 4-methylbenzoic acid (10.0 g, 73.5 mmol) in ethyl acetate (142 mL) was treated with a solution of BrC^Na (28.2 g, 220.4 mmol) in water (1 10 mL). A solution of aHS03 (22.9 g, 220.4 mmol) in water (220 mL) was then added dropwise over 20 min to the reaction mixture [Caution: exotherm] and the reaction mixture stirred for 4 h. The aqueous layer was extracted with Et20. The combined organics were washed with 1 M a2S203, dried over a2S04, filtered and concentrated in vacuo. The resulting solid was recrystallized from methanol to provide 4-(bromomethyl)benzoic acid (12.2 g, 77percent yield) as a white solid. XH NMR (400 MHz, DMSO-i3/4) δ 13.05 (s, 1H), 7.93 (d, J= 8.2 Hz, 2H), 7.58 (t, J= 9.2 Hz, 2H), 4.76 (s, 2H).
65% With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane First Stage
39.7 g (287 mmol) of p-toluylic acid, 51.2 g (287 mmol) of N-bromosuccinimide and 2.8 g (11.5 mmol) of dibenzoyl peroxide were suspended in 350 ml of carbon tetrachloride.
Then, the resultant mixture was heated with vigorously stirring to perform a reaction under reflux for 2 hours.
After completion of the reaction, the reaction mixture was cooled in ice bath.
The deposited crystalline product was collected by filtration, which was then washed with hexane and water, followed by drying.
The resultant crystalline product was recrystallized from ethanol to obtain 40.3 g of 4-bromomethylbenzoic acid as a white needle crystal (isolated yield: 65percent).
63% With N-Bromosuccinimide; dibenzoyl peroxide In chloroform for 20 h; Reflux p-Toluic acid (200g, 1 .46moles) was charged in chloroform(2L), N-Bromo succinimide(261 .4, 1 .46moles) and dibenzoyl peroxide(2.8g, 0.01 17moles) were added successively. The temperature of the reaction mass was raised to reflux and maintained at that temperature for 20hours. It was brought to room temperature, filtered and washed with chloroform (I L) and water (2L) successively. The crude 4-brommethyl benzoic acid was dried in oven at 50-60°C for two hours. The dried product(320g) was suspended in ethyl acetate (960ml) and stirred at room temperature for 3hours. The product was filtered, washed with ethyl acetate(320ml) and dried to yield 4-bromomethyl benzoic acid (200g, 63percent) of 97.5percent purity by HPLC.
60% With N-Bromosuccinimide; dibenzoyl peroxide In chloroform for 2.5 - 3 h; Heating / reflux 200 Lts Chloroform is charged into the reactor. 27.4 Kgs of N-bromo succinimide ischarged. 0.370 Kgs of benzoyl peroxide is charged. Reaction mass is heated to refluxtemperature and maintained reflux for2.5-3 hours. Cooled to 25-35C. the compound offormula (XIV) is filtered and water washed thoroughly. Ethyl Acetate is charged to thewet material and water washed. Ethyl acetate is distilled off under vacuum to a residualvolume of 60-70 L and cooled to 25-35C. The compound of the formula (XIV) isfiltered and washed with a ethyl acetate It is dried at 30-40C.Drywt. : 19.7 Kg (60percent)MR: 226-230C.Purity by HPLC: 99.9percent
60% With hydrogen bromide; sodium bromide In chloroform; water at 10 - 25℃; Electrolysis General procedure: A solution of 4-methoxy toluene (0.625 g, 5 mmol) in 25ml chloroform wastaken in a beaker-type undivided cell. A 25percent aqueous sodium bromide solution(50 ml) containing 5ml of 47percent HBr was added to it. Platinum electrodes (each of10 cm2 area) were placed in the upper layer of the aqueous phase. The organic phasealone was stirred with a magnetic stirrer at a rate of 40 rpm in such a way that theorganic layer did not touch the electrodes. The electrolysis was conducted galvanostaticallyat a current density of 30mA=cm2 until the quantity of charge indicated inTable 1 was passed at 15 C.After completion of electrolysis, the lower organic phase was separated,washed with 10percent sodium thiosulfate solution followed by water (225 ml), anddried with anhydrous Na2SO4. The solvent was removed under reduced pressureto afford 1.46 g (86percent yield) of 3-bromo 4-methoxy benzylbromide as product.

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YieldReaction ConditionsOperation in experiment
67.7% With dibenzoyl peroxide In tetrachloromethane Third Step
Synthesis of 4-(Bromomethyl)benxoic acid (III) STR18
13.6 g (100 mmol) of p-toluic acid STR19 17.8 g (100 mmol) of N-bromo succinoimide STR20 and 1 g (4.1 mmol) of dibenzoyl peroxide were suspended in 125 ml of carbon tetrachloride, and the mixture was heated under vigorous stirring and reacted under reflux (oil bath 93° C., inner temp. 74° C.) for 2 hours to obtain a reaction mixture of yellow milky liquid.
The reaction mixture was cooled in an ice bath, and the precipitated crystalline product was filtered and washed with hexane.
The crystalline product was further washed with water, and recrystallized from ethanol to obtain 14.6 g of white needle crystals of 4-(bromomethyl)benzoic acid (III).
Yield 67.7percent.
Reference: [1] Patent: US5143644, 1992, A,
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YieldReaction ConditionsOperation in experiment
69.7 mmol, 71.1% With N-Bromosuccinimide In water; benzene EXAMPLE 74
2-(p-Aminomethylphenyl)penem-3-carboxylic Acid (via mercaptide intermediate) STR880 Parabromomethylbenzoic acid STR881
A mixture (suspension) of p-toluic acid (13.6 g, 98 mmol), N-bromosuccinimide (17.8 g, 99 mmol) and benzoylperoxide (0.2 g, 0.826 mmol) in dry benzene (100 ml) was heated at reflux for 21 h.
After evaporation of the solvent in vacuo, the white residual solid was suspended in boiling water (100 ml), collected by filtration and washed with boiling water (4*100 ml).
The crude dried product was crystallized from hot MeOH, yielding 15.0 g (69.7 mmol, 71.1percent) of p-bromomethylbenzoic acid as white crystals mp 223°-225° C.; 1 Hmr (DMSO-d6) δ: 4.75 (2H, s, --CH2 Br), 7.47-7.62-7.88-8.02 ppm (4H, A2' B2', aromatic Hs); ir (nujol) νmax:2500-2600(br.--CO2 H), and 1670cm-1 (C=O --CO2 H).
Reference: [1] Patent: US4272437, 1981, A,
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Reference: [1] Journal of Organic Chemistry USSR (English Translation), 1986, vol. 22, p. 24 - 32[2] Zhurnal Organicheskoi Khimii, 1986, vol. 22, # 1, p. 30 - 39
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  • [ 100-51-6 ]
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  • [ 78504-88-8 ]
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[2] Chemical Communications, 2013, vol. 49, # 95, p. 11155 - 11157
[3] Patent: WO2009/109999, 2009, A1,
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[2] Technol. Rep. Kyushu Univ., 1951, vol. 24, p. 16,19[3] Chem.Abstr., 1953, p. 4867
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Reference: [1] Journal of Organic Chemistry USSR (English Translation), 1981, vol. 17, # 4, p. 583 - 591[2] Zhurnal Organicheskoi Khimii, 1981, vol. 17, # 4, p. 673 - 681
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Reference: [1] Journal of Organic Chemistry USSR (English Translation), 1981, vol. 17, # 4, p. 583 - 591[2] Zhurnal Organicheskoi Khimii, 1981, vol. 17, # 4, p. 673 - 681
[3] Patent: FR835727, 1938, ,
[4] Organic Process Research and Development, 1999, vol. 3, # 3, p. 196 - 200
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Reference: [1] Tetrahedron, 1988, vol. 44, # 6, p. 1631 - 1636
[2] Tetrahedron, 1988, vol. 44, # 6, p. 1631 - 1636
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Reference: [1] Journal of Organic Chemistry USSR (English Translation), 1986, vol. 22, p. 24 - 32[2] Zhurnal Organicheskoi Khimii, 1986, vol. 22, # 1, p. 30 - 39
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Reference: [1] Journal of Organic Chemistry USSR (English Translation), 1981, vol. 17, # 4, p. 583 - 591[2] Zhurnal Organicheskoi Khimii, 1981, vol. 17, # 4, p. 673 - 681
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Reference: [1] Tetrahedron Letters, 1987, vol. 28, # 6, p. 679 - 682
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Reference: [1] Macromolecules, 2014, vol. 47, # 13, p. 4136 - 4143
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Reference: [1] Chemische Berichte, 1893, vol. 26, p. 1733
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Reference: [1] Chemistry - A European Journal, 2015, vol. 21, # 28, p. 10179 - 10184
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YieldReaction ConditionsOperation in experiment
87% at 0 - 100℃; for 2.16667 h; p-Toluic acid (500 mg, 3.67 mmol) was added portionwise to ClSO3H (1.5 mL, 23 mmol) at 0 °C. After 10 min, the reaction mixture was heated to 100 °C for 2 h. The solution was dripped slowly onto ice and stood until all of the ice had melted. The precipitated product was then filtered off, washed with water and dried to leave 3-(chlorosulfonyl)-4-methylbenzoic acid as a pale brown solid (746 mg, 87percent). 1H NMR δ (400 MHz, d6-DMSO) 8.32 (d, J = 1.9 Hz, 1H), 7.76 (dd, J = 7.8, 1.9 Hz, 1H), 7.25 (d, J = 7.8 Hz, 1H), 5.55 (br s, 1H), 2.58 (s, 3H). LC-MS (APCI-) 233 (M-H+ with 35Cl, 100percent), 235 (M-H+ with 37Cl, 40percent). Reaction of 2 (30 mg, 0.18 mmol) and the above sulfonyl chloride (82 mg, 0.35 mmol) using NaHCO3, after chromatography (eluting with CH2Cl2:MeOH 98:2 to 19:1 to 9:1) gave 6h as a yellow solid (42 mg, 60percent).
83% at 0 - 100℃; [CHLOROSULFONIC] acid (50 [ML,] 752 mmol) was added to a [250-ML] round-bottom flask and cooled to [0 °C IN THE] presence of nitrogen. p-Toluic acid (1,10 g, 73.7 mmol) was added in small portions over 5 min to give a yellow solution. The solution was warmed to room temperature and heated to [100 °C] overnight. The reaction mixture was then cooled to room temperature and poured over ice (ca 750 g). The resulting precipitate was filtered, washed with water and dried in a vacuum oven at [70 °C] for 8 h to afford 14.38 g (83percent) of 2 as an off-white solid [: 1H] NMR (DMSO-d6) [8 2.] 60 (s, [3H),] 7.28 (d, [J =] 7.9 Hz, [1H),] 7.79 (d, [J =] 7.8 Hz, 1H), 8.31 (s, 1H), 13.87 (br s, 1H).
58% at 100℃; for 3 h; To a well-stirred solution of chlorosulfonic acid wasadded to the compound 1 (3.0 g, 22.0 mmol) in portionwise. The mixture was heated for 3 h at 100 °C. The mixture was cooled, poured into crushed ice and extracted with CH2Cl2. The organic layer was washed with ice water, dried over anhydrous Na2SO4 and concentrated to yield compound 6 as off white solid (Rf value: 0.4; Yield: 3.0 g (58percent)).
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 5, p. 1725 - 1729
[2] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 1, p. 58 - 68
[3] Patent: WO2004/18414, 2004, A2, . Location in patent: Page 132
[4] Journal of Medicinal Chemistry, 2013, vol. 56, # 15, p. 6146 - 6155
[5] ChemMedChem, 2016, vol. 11, # 8, p. 893 - 899
[6] Journal of the Korean Chemical Society, 2013, vol. 57, # 6, p. 731 - 737
[7] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 9, p. 2430 - 2433
[8] Patent: WO2008/98025, 2008, A1, . Location in patent: Page/Page column 20-21; 48-49
[9] ChemMedChem, 2018, vol. 13, # 12, p. 1165 - 1171
[10] Patent: WO2009/110985, 2009, A2, . Location in patent: Page/Page column 65
[11] Patent: WO2009/118292, 2009, A1, . Location in patent: Page/Page column 46-47
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Reference: [1] Patent: US2006/47152, 2006, A1, . Location in patent: Page/Page column 39-41
[2] Patent: US2006/47153, 2006, A1, . Location in patent: Page/Page column 39-41
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Reference: [1] Tetrahedron, 1988, vol. 44, # 6, p. 1631 - 1636
[2] Tetrahedron, 1988, vol. 44, # 6, p. 1631 - 1636
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Reference: [1] Tetrahedron Letters, 1989, vol. 30, # 8, p. 899 - 902
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YieldReaction ConditionsOperation in experiment
80.6% With hydrogenchloride; dichloro-acetic acid; sodium tungstate (VI) dihydrate; dihydrogen peroxide In water at 50 - 60℃; for 10 h; To a 1000 ml four-neck reaction flask (with mechanical agitation, thermometer, dropping funnel and reflux condenser), 136 g of p-methylbenzoic acid, Followed by the addition of 272 g of dichloroacetic acid as a solvent, Then add 0.2 g of sodium tungstate dihydrate, Then add 365 grams of 30percent hydrochloric acid, stir, Heated to 50 to 60 ° C, 136 g of 30percent hydrogen peroxide was added dropwise, the dropping time was 6 hours, and the temperature was maintained at 50 to 60 ° C during the dropping. After completion of the dropwise addition, the reaction was continued for 4 hours, and the mixture was subjected to liquid chromatography (HPLC) analysis, and the raw material content (9.5percent) After the reaction is completed, the reaction solution is distilled under reduced pressure. When there is no fraction, the temperature is lowered to 20 to 30 ° C, 250 g of methanol is added, heated to reflux and then cooled again to 10 ° C The residue was filtered, filtered and the cake was washed with methanol. The cake was dried to give the product: 165.2 g, yield: 80.6percent, HPLC content: 98.5percent.
Reference: [1] Patent: US5254584, 1993, A,
[2] Patent: US5304572, 1994, A,
[3] Patent: CN105859549, 2016, A, . Location in patent: Paragraph 0006; 0011-0012
[4] Organic Process Research and Development, 1999, vol. 3, # 1, p. 10 - 16
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Reference: [1] Patent: WO2011/143426, 2011, A1,
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Reference: [1] Journal of the Iranian Chemical Society, 2012, vol. 9, # 3, p. 321 - 326
[2] Bulletin of the Chemical Society of Japan, 2000, vol. 73, # 4, p. 951 - 956
[3] Journal of applied chemistry of the USSR, 1984, vol. 57, # 1 pt 2, p. 121 - 123
[4] Journal of Organic Chemistry, 2009, vol. 74, # 16, p. 6287 - 6290
[5] Synthesis, 2004, # 3, p. 441 - 445
[6] Molecules, 2005, vol. 10, # 3, p. 671 - 675
[7] Molecules, 2004, vol. 9, # 7, p. 595 - 601
[8] Molecules, 2005, vol. 10, # 10, p. 1307 - 1317
[9] Synthesis, 2006, # 7, p. 1195 - 1199
[10] Molecules, 2005, vol. 10, # 2, p. 394 - 400
[11] Tetrahedron, 2004, vol. 60, # 41, p. 9113 - 9119
[12] Tetrahedron Letters, 1989, vol. 30, # 8, p. 899 - 902
[13] Chemische Berichte, 1893, vol. 26, p. 1733
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Reference: [1] Journal of Organic Chemistry, 1953, vol. 18, p. 707,708
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Reference: [1] Russian Journal of Organic Chemistry, 1998, vol. 34, # 7, p. 997 - 999
[2] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1974, p. 2405 - 2409
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Reference: [1] ACS Catalysis, 2018, vol. 8, # 11, p. 10173 - 10179
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Reference: [1] Journal of Organic Chemistry, 1952, vol. 17, p. 1035,1040
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Reference: [1] Chlorine Alkali News, 1953, # 11, p. 44[2] Chem.Abstr., 1955, p. 7523
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Reference: [1] Justus Liebigs Annalen der Chemie, 1890, vol. 258, p. 15
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Reference: [1] Patent: CN107915582, 2018, A,
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Reference: [1] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 10, p. 3156 - 3172
[2] European Journal of Medicinal Chemistry, 2018, vol. 152, p. 175 - 194
[3] Patent: CN108329259, 2018, A,
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YieldReaction ConditionsOperation in experiment
98%
Stage #1: at 0℃; for 0.166667 h;
Stage #2: With phosphorus trichloride In toluene at 20 - 60℃; for 0.5 h;
General procedure: A solution of NHMe(OMe) (0.360 g, 6.0 mmol) and benzoic acid (0.244 g, 2.0 mmol) was stirred in dry toluene (10 mL) at 0 °C for 10 min. A solution of PCl3 (0.137 g, 1.0 mmol) in dry toluene (2 mL) was then added dropwise to the mixture. The mixture was warmed to r.t. slowly and then stirred at 60 °C for 0.5 h. When the reaction was complete (TLC monitoring), the mixture was cooled to r.t. The mixture was then quenched with sat. NaHCO3 soln (20 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried (anhyd MgSO4). The solvent was removed in vacuo.The product was purified by column chromatography (silica gel, petroleum ether–EtOAc, 3:2) to give pure 3a as a colorless oil; yield: 320 mg (97percent).
Reference: [1] Synthesis (Germany), 2014, vol. 46, # 3, p. 320 - 330
[2] Organic Letters, 2000, vol. 2, # 25, p. 4091 - 4093
[3] Chimia, 1995, vol. 49, # 10, p. 381 - 385
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Reference: [1] Synlett, 2007, # 18, p. 2841 - 2846
[2] Patent: WO2016/192083, 2016, A1,
[3] Journal of Organic Chemistry, 2017, vol. 82, # 2, p. 1114 - 1126
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Reference: [1] Journal of Organic Chemistry, 2009, vol. 74, # 2, p. 795 - 809
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