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Product Citations

Ripak, Alexia ; De Kreijger, Simon ; Sampaio, Renato N. , et al. DOI: PubMed ID:

Abstract: Aryl diazonium salts are ubiquitous building blocks in chem., as they are useful radical precursors in organic synthesis as well as for the functionalization of solid materials. They can be reduced electrochem. or through a photo-induced electron transfer reaction. Here, we provide a detailed picture of the ground- and excited-state reactivity of a series of nine rare and earth-abundant photosensitizers with 13 aryl diazonium salts, which also included three macrocyclic calix[4]arene tetradiazonium salts. Nanosecond transient absorption spectroscopy confirmed the occurrence of excited-state electron transfer and was used to quantify cage-escape yields (i.e., the efficiency with which the formed radicals sep. and escape the solvent cage). Cage-escape yields were large; they increased when the driving force for photo-induced electron transfer increased and also tracked with the C-N+2 bond cleavage propensity, among others. A photo-induced borylation reaction was then investigated with all the photosensitizers and proceeded with yields between 9% and 74%.

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Product Details of [ 94-09-7 ]

CAS No. :94-09-7 MDL No. :MFCD00007892
Formula : C9H11NO2 Boiling Point : -
Linear Structure Formula :- InChI Key :BLFLLBZGZJTVJG-UHFFFAOYSA-N
M.W : 165.19 Pubchem ID :2337
Synonyms :
Ethyl 4-Aminobenzoate;NSC 41531;NSC 4688;H-4-Abz-OEt
Chemical Name :Ethyl 4-aminobenzoate

Calculated chemistry of [ 94-09-7 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 12
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.22
Num. rotatable bonds : 3
Num. H-bond acceptors : 2.0
Num. H-bond donors : 1.0
Molar Refractivity : 46.93
TPSA : 52.32 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.99 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.89
Log Po/w (XLOGP3) : 1.86
Log Po/w (WLOGP) : 1.45
Log Po/w (MLOGP) : 1.64
Log Po/w (SILICOS-IT) : 1.31
Consensus Log Po/w : 1.63

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.21
Solubility : 1.02 mg/ml ; 0.00619 mol/l
Class : Soluble
Log S (Ali) : -2.58
Solubility : 0.434 mg/ml ; 0.00263 mol/l
Class : Soluble
Log S (SILICOS-IT) : -2.51
Solubility : 0.509 mg/ml ; 0.00308 mol/l
Class : Soluble

Medicinal Chemistry

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

Safety of [ 94-09-7 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P272-P273-P280-P302+P352-P312-P333+P313-P362+P364-P501 UN#:N/A
Hazard Statements:H302-H317-H402 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 94-09-7 ]

* 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 [ 94-09-7 ]
  • Downstream synthetic route of [ 94-09-7 ]

[ 94-09-7 ] Synthesis Path-Upstream   1~43

  • 1
  • [ 94-09-7 ]
  • [ 504-63-2 ]
  • [ 73987-38-9 ]
YieldReaction ConditionsOperation in experiment
45% at 150℃; for 12 h; Green chemistry Accurately weigh 0.005mmol (l. Lmg) of the transition metal, add 10mL has been put into the magnetic stirrer Young's reaction tube, The oxygen reaction was carried out in the Young's reaction tube, and the reaction was carried out under oxygen conditions. The syringe was applied to the Young's reaction tubeA solution of 0.04 mmol of co-catalyst I, 0.08 mmol of co-catalyst II, 0.2 mmol of 4-carboxylate and 1 ml of l-3'-propylene glycol, the above-mentioned Young's reaction tube was placed on a magnetic stirrer and stirred at 150 ° C for 12 h. After the reaction was completed,The pH of the solution was neutral, and the reaction solution was post-treated to obtain pure product of ethyl 6-formate quinoline in a yield of 45percent.
Reference: [1] Journal of Organic Chemistry, 2017, vol. 82, # 6, p. 3284 - 3290
[2] Patent: CN106543078, 2017, A, . Location in patent: Paragraph 0113; 0114
  • 2
  • [ 107-18-6 ]
  • [ 94-09-7 ]
  • [ 73987-38-9 ]
Reference: [1] Chemistry - A European Journal, 2017, vol. 23, # 63, p. 15874 - 15878
  • 3
  • [ 64-17-5 ]
  • [ 94-09-7 ]
  • [ 855763-77-8 ]
YieldReaction ConditionsOperation in experiment
65% at 150℃; for 36 h; Green chemistry Accurately weigh 0.005mmol (l. Lmg) of the transition metal, add 10mL has been put into the magnetic stirrer Young's reaction tube, The oxygen reaction was carried out in the Young's reaction tube, and the reaction was carried out under oxygen conditions. The syringe was applied to the Young's reaction tubeAdd 0.04 mmol of co-catalyst I, 0.08 mmol of co-catalyst II, 0.2 mmol of ethyl 4-aminobenzoate and lmlWater, the Young's reaction tube was placed on a magnetic stirrer and stirred at 150 ° C for 36 hours. After completion of the reaction, the reaction solutionThe pH was neutral, and the reaction solution was post-treated to give pure 2-methyl-6-quinolinecarboxylic acid ethyl ester in 65percent yield.
Reference: [1] Journal of Organic Chemistry, 2017, vol. 82, # 6, p. 3284 - 3290
[2] Patent: CN106543078, 2017, A, . Location in patent: Paragraph 0101; 0102
  • 4
  • [ 94-09-7 ]
  • [ 93-85-6 ]
Reference: [1] Collection of Czechoslovak Chemical Communications, 1962, vol. 27, p. 1533 - 1548
  • 5
  • [ 333-20-0 ]
  • [ 94-09-7 ]
  • [ 50850-93-6 ]
YieldReaction ConditionsOperation in experiment
100% at 19 - 20℃; Ethyl 4-aminobenzoate (4.9 g, 30.0 mmol) and potassium thiocyanate (11.6 g,120.0 mmol) are dissolved in acetic acid(180 mL), followed by dripping acetic acid solution(20 mL) with bromine (1.5 mL,30.0 mmol) at 19 °C in 20 min, then the temperature is increased to room temperature and the mixture continues to react overnight.
Then, the reaction solution is poured into water (100 mL), and stirred for 10 min, then ammonium hydroxide is dripped into the mixture to regulate pH to approximately 8, then the mixture is filtered, wherein filter cake is successively washed with water and petroleum ether, and finally the product is vacuumed to dryness, so as to obtain a yellow solid of 6.7 g, that is ethyl 2-aminobenzo[d]thiazole-6-carboxylate, with a yield of 100percent.
Spectrum is: 1H NMR (400 MHz, DMSO) δ: 8.28(d, J = 1.6 Hz, 1H), 7.88(s ,2H), 7.82(dd, J = 1.6 Hz, 8.4 Hz, 1H), 7.37(d, J = 8.4Hz, 1H), 4.29(q, J = 7.2 Hz ,2H), 1.32(t, J = 7.2 Hz, 3H).
97% With copper(ll) sulfate pentahydrate In methanol for 6 h; Reflux To methanol (800 mL) were added ethyl 4-aminobenzoate 4 (49.5 g, 0.3 mol), KSCN (291 g, 3 mol) and CuSO4*5H2O (275 g,1.5 mol). The mixture was heated to reflux by mechanical stir for 6 h. After cooling to room temperature, the precipitate was filtered, about 2/3 of the filtrate was evaporated under reduced pressure. Water (600 mL) was added, the precipitate obtained was filtered and added to 2 N NaOH solution (500 mL), stirred for 10 min at room temperature. The precipitate was filtered, washed with waterand dried to get 5 (52.6 g, 79percent) as white powder, mp: 242-243 °C([45], mp, 241-242 °C).
69%
Stage #1: at 20℃; for 0.333333 h;
Stage #2: at 10 - 20℃;
Ethyl 4-aminobenzoate (1 eq.) and KSCN (4 eq.) were dissolved in acetic acid (4 mL/mmol) and stirred at rt for 20mins. Then the reaction mixture was cooled to 10 °C and bromine (2 eq.) dissolved in small amount of acetic acid was added dropwise. Afterwards the reaction mixture was left to warm up to rt and stirred overnight. After the reaction was completed (monitored by TLC), reaction mixture was added dropwise into the sat. aq. NH3 solution (15 mL/mmol) while cooling in an ice bath. The product was extracted to EtOAc and the organic layer was washed with Na2S2O3, sat. aq. NaHCO3 and brine, dried using anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was recrystallized from diethyl ether to obtain ethyl 2-aminobenzo[d]thiazole-6-carboxylate in 69percent yield. 1H NMR (500 MHz, DMSO-d6): (ppm) 8.27 (d, J = 1.8Hz, 1H), 7.88 (s, 2H), 7.81 (dd, J = 8.4, 1.8 Hz, 1H), 7.36 (d,J = 8.4 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 1.30 (t, J = 7.1 Hz,3H).
67%
Stage #1: at 20℃;
Stage #2: With ammonium hydroxide In water
Compound 28 (2.0 g, 12 mmol) was dissolved in 16 mL of acetic acid, and to the resulting solution was suspended potassium thiocyanate (4.67 g, 48 mmol). A solution of 0.61 mL of bromine in 8 ml of acetic acid was slowly added, and the reaction mixture was stirred at room temperature overnight. Water was added and the mixture was made neutral by addition of aqueous ammonium hydroxide. The precipitation was collected by filtration and then washed with water and subsequently dried to afford compound 29 (1.80 g, 67percent) as light yellow solid. The compound was used, without structure determination, directly for the next step.
50% With copper(II) sulfate In methanol at 70℃; for 5 h; Step: 1 Preparation of ethyl 2-amino-l,3-benzothiazole-6-carboxylate.A mixture of ethyl-4-amino benzoate (1.65g, lOmmol), KCNS (9.72g, 100 mmol) and CuSO4 (8g, 50mmol) in methanol (3OmL) was stirred for 5 hours at 7O0C. Subsequently, the suspension was cooled and filtered; the filtrate was diluted with water (4OmL) and heated to boiling. Ethanol was added to the boiling filtrate until a clear, although slightly yellowish solution was formed. Cooling of this solution resulted in crystallization of the product (l.lg, 50percent yield) as a pale yellow solid. NMR <n="17"/>o(DMSO-de) 1H δ (ppm): 8.34 (IH, d, Ar-H), 7.87 (IH, dd, Ar-H), 7.42 (IH, d, Ar-H), 4.30 (2H, q, CH2), and 1.32 (3H, t, CH3). MS m/z: 223 (M+l)
46% at 10 - 20℃; [1067] Step 1: ethyl 2-aminobenzo[d]thiazol-6-carboxylate[1068] To a solution of ethyl 4-aminobenzoate (16.5 g, 100.0 mmol) and potassium thiocyanate (10.7 g, 110.0 mmol) in acetic acid (150 mL) was added dropwise a solution of bromine (5.1 mL, 100.0 mmol) in acetic acid (50 mL) at below 10 ℃. The reaction mixture was stirred at room temperature overnight. The resulting solid was filtered and then dissolved in warm water (50 ℃). The aqueous layer was washed with chloroform and then basified to pH 11 with solid sodium carbonate. The resulting solid was filtered, washed with water, and then dried under reduced pressure to give 10.2 g of the titled compound as a white solid (Yield: 46percent).
46% at 10 - 20℃; Step 1:
ethyl 4-aminobenzo[d]thiazol-6-carboxylate
To a solution of ethyl 4-aminobenzoate (16.5 g, 100.0 mmol) and potassium thiocyanate (10.7 g, 110.0 mmol) in acetic acid (150 mL) was added dropwise a solution of bromine (5.1 mL, 100.0 mmol) in acetic acid (50 mL) at below 10° C.
The reaction mixture was stirred at room temperature overnight.
The resulting solid was filtered and then dissolved in warm water (50° C.).
The aqueous layer was washed with chloroform and then basified to pH 11 with solid sodium carbonate.
The resulting solid was filtered, washed with water, and then dried under reduced pressure to give 10.2 g of the titled compound as a white solid (Yield: 46percent).

Reference: [1] Patent: EP3401315, 2018, A1, . Location in patent: Paragraph 0062; 0063
[2] Synlett, 2012, vol. 23, # 15, p. 2219 - 2222
[3] European Journal of Medicinal Chemistry, 2013, vol. 63, p. 702 - 712
[4] Medicinal Chemistry, 2017, vol. 13, # 4, p. 345 - 358
[5] European Journal of Medicinal Chemistry, 2013, vol. 61, p. 26 - 40
[6] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1991, vol. 30, # 5, p. 494 - 498
[7] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 7, p. 2509 - 2522
[8] Patent: WO2007/113644, 2007, A2, . Location in patent: Page/Page column 15-16
[9] Patent: WO2013/43001, 2013, A1, . Location in patent: Paragraph 1067; 1068
[10] Patent: US2015/11528, 2015, A1, . Location in patent: Paragraph 0600
[11] Journal of Medicinal Chemistry, 1999, vol. 42, # 15, p. 2828 - 2843
[12] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 23, p. 5561 - 5565
  • 6
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YieldReaction ConditionsOperation in experiment
31% With bromine In acetic acid (195-1)
A solution of ethyl p-aminobenzoate (23.2 g) and potassium thiocyanate (40.9 g) in acetic acid (280 mL) was cooled to 0° C., and thereto was added dropwise bromine (22.4 g), and the mixture was stirred at 0° C. for 20 minuts, and stirred at room temperature for 135 minutes, and stirred for 5 hours.
The precipitated solid was collected by filtration to give ethyl 2-amino-1,3-benzothiazole-6-carboxylate (9.62 g, 31percent)
1H NMR (DMSO-d6, 400 MHz) δ 8.65 (brs, 2H), 8.38 (d, 1H, J=1.7 Hz), 7.89 (dd, 1H, J=8.5, 1.7 Hz), 7.44 (d, 1H, J=8.5 Hz), 4.30 (q, 2H, J=7.1 Hz), 1.32 (t, 3H, J=7.1 Hz).
31% With bromine In acetic acid (195-1)
A solution of ethyl p-aminobenzoate (23.2 g) and potassium thiocyanate (40.9 g) in acetic acid (280 mL) was cooled to 0°C, and thereto was added dropwise bromine (22.4 g), and the mixture was stirred at 0°C for 20 minuts, and stirred at room temperature for 135 minutes, and stirred for 5 hours.
The precipitated solid was collected by filtration to give ethyl 2-amino-1,3-benzothiazole-6-carboxylate (9.62 g, 31 percent).
1H NMR (DMSO-d6, 400MHz) δ 8.65 (brs, 2H), 8.38 (d, 1H, J=1.7Hz), 7.89 (dd, 1H, J=8.5, 1.7Hz), 7.44 (d, 1H, J=8.5Hz), 4.30 (q, 2H, J=7.1Hz), 1.32 (t, 3H, J=7.1Hz).
Reference: [1] Patent: US2003/181496, 2003, A1,
[2] Patent: EP1479384, 2004, A1,
[3] Patent: US5496816, 1996, A,
[4] Archiv der Pharmazie (Weinheim, Germany), 1928, p. 215[5] Archiv der Pharmazie (Weinheim, Germany), 1929, p. 205
[6] Patent: US5498777, 1996, A,
[7] Patent: US5538964, 1996, A,
  • 7
  • [ 540-72-7 ]
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Reference: [1] Collection of Czechoslovak Chemical Communications, 1962, vol. 27, p. 1533 - 1548
[2] Journal of Medicinal Chemistry, 1997, vol. 40, # 1, p. 105 - 111
[3] Tetrahedron, 2005, vol. 61, # 38, p. 9075 - 9081
  • 8
  • [ 1147550-11-5 ]
  • [ 94-09-7 ]
  • [ 50850-93-6 ]
Reference: [1] Farmaco, 1994, vol. 49, # 3, p. 153 - 166
[2] Yakugaku Zasshi, 1950, vol. 70, p. 271,276[3] Chem.Abstr., 1951, p. 10212
  • 9
  • [ 15192-76-4 ]
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  • [ 50850-93-6 ]
Reference: [1] Chemische Berichte, 1934, vol. 67, p. 944,947
[2] Yakugaku Zasshi, 1946, vol. 66, p. Ausg. B, S. 75[3] Chem.Abstr., 1952, p. 112
  • 10
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  • [ 582-80-9 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 1, p. 39 - 44
[2] Patent: CN106588914, 2017, A,
[3] Patent: CN107056789, 2017, A,
[4] Patent: CN106588913, 2017, A,
[5] Patent: CN106317057, 2017, A,
  • 11
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  • [ 32996-16-0 ]
Reference: [1] Angewandte Chemie - International Edition, 2007, vol. 46, # 12, p. 2074 - 2077
  • 12
  • [ 94-09-7 ]
  • [ 14685-90-6 ]
Reference: [1] Berichte der Deutschen Pharmazeutischen Gesellschaft, vol. 31, p. 71[2] Chem. Zentralbl., 1921, vol. 92, # I, p. 584
[3] Journal and Proceedings of the Royal Society of New South Wales, 1938, vol. 71, p. 418[4] Chem. Zentralbl., 1938, vol. 109, # II, p. 4062
[5] Polish Journal of Chemistry, 2003, vol. 77, # 3, p. 329 - 332
[6] Patent: WO2011/47156, 2011, A1, . Location in patent: Page/Page column 77
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  • [ 100-37-8 ]
  • [ 59-46-1 ]
Reference: [1] CIOS Rep. XXIII-23 &lt;1945&gt; 9,
[2] Journal of the Society of Chemical Industry, London, 1945, vol. 64, p. 177
[3] Pharmaceutical Chemistry Journal, 2001, vol. 35, # 10, p. 556 - 559
  • 14
  • [ 55305-43-6 ]
  • [ 94-09-7 ]
  • [ 7153-22-2 ]
Reference: [1] Tetrahedron Letters, 2016, vol. 57, # 11, p. 1205 - 1209
  • 15
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  • [ 94-09-7 ]
  • [ 7153-22-2 ]
Reference: [1] Chemische Berichte, 1938, vol. 71, p. 335,338
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  • [ 94-09-7 ]
  • [ 3084-40-0 ]
  • [ 10287-54-4 ]
  • [ 74763-68-1 ]
  • [ 114416-19-2 ]
Reference: [1] Pharmaceutical Chemistry Journal, 1988, vol. 22, # 2, p. 142 - 145[2] Khimiko-Farmatsevticheskii Zhurnal, 1988, vol. 22, # 2, p. 191 - 195
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  • [ 122-52-1 ]
  • [ 3084-40-0 ]
  • [ 10287-54-4 ]
  • [ 74763-68-1 ]
  • [ 114416-19-2 ]
Reference: [1] Pharmaceutical Chemistry Journal, 1988, vol. 22, # 2, p. 142 - 145[2] Khimiko-Farmatsevticheskii Zhurnal, 1988, vol. 22, # 2, p. 191 - 195
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  • [ 94-09-7 ]
  • [ 66493-39-8 ]
Reference: [1] Patent: WO2017/219800, 2017, A1,
[2] Patent: US6639107, 2003, B1,
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  • [ 94-09-7 ]
  • [ 100-61-8 ]
  • [ 57834-33-0 ]
YieldReaction ConditionsOperation in experiment
93%
Stage #1: With toluene-4-sulfonic acid In toluene at 50 - 60℃; for 2 h; Green chemistry
Stage #2: for 5 h; Reflux; Green chemistry
165 g (1 mol) of ethyl p-aminobenzoate, 117.7 g (1.1 mol) of N-methylaniline, 10 g of p-toluenesulfonic acid,200mL with toluene toluene added to the 1000mL reaction flask, stirred and warmed to 50-60 ° C, 2h dropwise 59.53g (1.1mol) formic acid(Content of 85percent),Heating to reflux reaction, continue to separate the generated water, the reaction of about 5h to stop water when there is no water. The reaction solution was distilled off with atmospheric toluene recovery agent, toluene was recovered, the remaining vacuum distillation reaction solution,A pale yellow viscous liquid N- (4-ethoxycarbonylphenyl) -N'-methyl-N'-phenyl formamidine 262g, yield 93percent, purity 99.4percent.
Reference: [1] Patent: CN107235859, 2017, A, . Location in patent: Paragraph 0012-0018
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  • [ 100-61-8 ]
  • [ 57834-33-0 ]
YieldReaction ConditionsOperation in experiment
95.7% at 50 - 60℃; for 2 h; A mixture of 165 g (1 mol) of ethyl p-aminobenzoate, 112.35 g (1.05 mol) of N-methylaniline, 159 g (1.5 mol) of trimethyl orthoformate and 10.2 g (0.1 mol) of a specific surface area of 137 m2 / g Γ-type activated alumina into the 500ml reaction flask,Stirring and heating to 50 ~ 60 , incubation reaction 2h. Open the vacuum pump, and gradually increase the vacuum, vacuum distillation of the resulting methanol, to no methanol distillation.The reaction solution was filtered while hot, the recovered active alumina was repeatedly used and the mother liquor was distilled under reduced pressure to give a pale yellow viscous liquid N- (4-ethoxycarbonylphenyl) -N'-methyl-N'-phenyl Formamidine 270 g, yield 95.7percent, purity 99.5percent.
Reference: [1] Patent: CN106431990, 2017, A, . Location in patent: Paragraph 0014; 0015; 0017; 0018; 0020; 0021
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  • [ 1678-68-8 ]
  • [ 1678-68-8 ]
Reference: [1] Patent: JP2005/350392, 2005, A, . Location in patent: Page/Page column 9-10
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  • [ 51934-41-9 ]
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[2] Organic Letters, 2017, vol. 19, # 10, p. 2518 - 2521
[3] Organic Letters, 2010, vol. 12, # 8, p. 1696 - 1699
[4] Organic Letters, 2018, vol. 20, # 17, p. 5167 - 5171
[5] Chemical Science, 2018, vol. 9, # 46, p. 8731 - 8737
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Reference: [1] Patent: US2002/58809, 2002, A1,
[2] Patent: US4544654, 1985, A,
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  • [ 94-09-7 ]
  • [ 51-06-9 ]
Reference: [1] Yakugaku Zasshi, 1953, vol. 73, p. 294,296[2] Chem.Abstr., 1954, p. 2003
[3] Farmaco, Edizione Scientifica, 1954, vol. 9, p. 384
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  • [ 94-24-6 ]
Reference: [1] Journal of the Society of Chemical Industry, London, 1945, vol. 64, p. 177
[2] Journal of the Society of Chemical Industry, London, 1945, vol. 64, p. 177
[3] Journal of the Society of Chemical Industry, London, 1945, vol. 64, p. 177
[4] Journal of the Society of Chemical Industry, London, 1945, vol. 64, p. 177
  • 26
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  • [ 4740-24-3 ]
Reference: [1] Zeitschrift fuer Chemie (Stuttgart, Germany), 1980, vol. 20, # 7, p. 259 - 260
[2] Journal of the Society of Chemical Industry, London, 1945, vol. 64, p. 177
[3] Journal of the Society of Chemical Industry, London, 1945, vol. 64, p. 177
  • 27
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  • [ 56961-25-2 ]
Reference: [1] Journal of the American Chemical Society, 1960, vol. 82, p. 3454 - 3456
  • 28
  • [ 108-22-5 ]
  • [ 94-09-7 ]
  • [ 73013-51-1 ]
Reference: [1] Green Chemistry, 2018, vol. 20, # 6, p. 1290 - 1296
[2] Journal of Organic Chemistry, 2012, vol. 77, # 22, p. 10347 - 10352
  • 29
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  • [ 4334-88-7 ]
YieldReaction ConditionsOperation in experiment
65%
Stage #1: With hydrogenchloride; sodium nitrite In methanol; water at 0 - 5℃; for 0.5 h;
Stage #2: With tetrahydroxydiboron In methanol; water at 20℃; for 1 h;
General procedure: To a solution of arylamine (0.5 mmol, 1.0 equiv) in MeOH(1.0 mL) was added HCl (0.5 mL, 1.5 mmol, 3.0 equiv), followed by H2O (0.5 ml). This mixture was stirred 2 min,and the NaNO2 solution (0.25 mL) was then added. The NaNO2 solution was prepared by dissolving 35 mg ofNaNO2 in H2O (0.25 mL). This mixture was stirred 30 minat 0–5 °C, followed by HCl (135 mg, 1.5 mmol, 3.0 equivalents) in MeOH (1.0 mL). This mixture was stirred 60min. H2O (10 mL) was added to reaction mixture, then extracted with CH2Cl2 (50 mL, 3×). The combined organic layer was dried over Na2SO4, followed by evaporation to give the products.
Reference: [1] Synlett, 2014, vol. 25, # 11, p. 1577 - 1584
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  • [ 249647-25-4 ]
Reference: [1] Angewandte Chemie - International Edition, 2012, vol. 51, # 8, p. 1958 - 1961
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  • [ 7149-03-3 ]
YieldReaction ConditionsOperation in experiment
91% With N-Bromosuccinimide In N,N-dimethyl-formamide at 0 - 20℃; for 18.5 h; Darkness To a solution of ethyl 4-aminobenzoate (10 g, 61 mmol) in DMF (150 mL) cooled in ice-bath was added NBS (10.8 g, 61 mmol) portionwise and the mixture was stirred for 30 min at the same temperature. Then the ice-bath was removed and the stirring was continued at rt overnight (18 h). The mixture was poured into water (500 mL) and filtered, the orange solid was washed with water (50 mL × 2) and recrystallized from EtOH to afford pale-yellow crystals (13.3 g, 91percent) Rf = 0.38 (PE : EtOAc = 5 : 1); m.p. 86 - 88 °C; 1H-NMR (CDCl3, 300 MHz) δ: 8.07 (s, 1H), 7.79 (t, J = 11.55 Hz,1H), 6.70 (d, J = 8.10 Hz,1H), 4.58 (br, 2H), 4.37 (dd, J = 6.6 Hz, J = 6.6 Hz , 2H), 1.34 (t, J = 7.2 Hz, 3H).
88% With bromine In dichloromethane at -10 - 20℃; for 18 h; EXAMPLE 1
Preparation of Ethyl 4-amino-3-bromobenzoate
A solution of bromine (7.0 mL, 137.3 mmol) in dichloromethane is added dropwise to a cold (-10° C.) solution of ethyl 4-aminobenzoate (22.0 g, 133.3 mmol) in dichloromethane.
The reaction mixture is allowed to come to room temperature, stirred for 18 h and diluted with water.
The organic phase is separated, washed twice with brine, dried over MgSO4 and concentrated in vacuo.
The resultant residue is purified by flash chromatography (SiO2, 8/1 hexanes/EtOAc as eluent) to afford the title compound as a white solid, 28.6 g (88percent yield), identified by H-NMR and mass spectral analyses. MS m/e 242 (M-H)+; 1H NMR (400 MHz, DMSO-d6) δ 1.28 (t, J=7.01 Hz, 3 H), 4.22 (q, J=7.16 Hz, 2 H), 6.18 (brs, 2 H), 6.81 (d, J=7.91 Hz, 1H), 7.65 (dd, J=8.54, 1.98 Hz 1 H), 7.89 (d, J=1.83 Hz, 1H).
77% at 90℃; for 8 h; Green chemistry General procedure: To a round bottom flask was added 5 mmol of acetophenone, 0.5 mmol of 2-methylpyridine nitrate and 5.5 mmol of 40 wtpercent HBr, 60 ° C under the open flask stir reaction 6h, The yield of α-bromoacetophenone was 95percent The product was isolated by silica gel column chromatography (ethyl acetate / boiling point 60-90 ° C petroleum ether) at 200-300 mesh, The isolated yield was 88percent.
4.0 g With N-Bromosuccinimide In chloroform at 0℃; for 3 h; Inert atmosphere To a solution of ethyl 4-aminobenzoate (8.0 g, 0.048 mol) in chloroform (100 ml) was addedN-bromosuccinamide (8.62 g, 0.048 mol) at 0°C under inert atmosphere and reaction masswas stirred for 3 h at 0°C. Then the reaction mixture was diluted with EtOAc. The reaction mixture was quenched with water, extracted with EtOAc and organic layer was separated, dried over Na2504 and concentrated to afford 4.0 g of title product. ‘H NMR (300 MHz, DMSO-d6): 7.87 (s, 1H), 7.65-7.62 (d, J = 9.0 Hz, 1H), 6.80-6.78 (d, J = 8.7 Hz, 1H), 6.18(s, 2H), 4.28-4.18 (d, J= 6.9Hz, 2H), 1.29-1.24 (t, J= 6.9Hz, 3H); MS [M+Hf’: 244.
11.8 g With bromine In methanol at 0 - 20℃; for 2 h; Inert atmosphere Compound 11a (15.00 g, 90.81 mmol) was dissolved in anhydrous methanol (200 mL) at 0° C. and a solution of liquid bromine (13.06 g, 81.72 mmol) in methanol (100 mL) was added dropwise under nitrogen.The resulting reaction solution was reacted at 20°C for 2 hours. After the reaction is complete, directly concentrate, add water (100 mL), and extract with ethyl acetate (200 mL×3). Dry the organic phase over anhydrous sodium sulfate, filter, and concentrate.The mixture was purified by flash silica gel column chromatography (petroleum ether/ethyl acetate=100-0percent) to give compound 11b (11.8 g).

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[16] Patent: US2002/19527, 2002, A1,
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[18] Patent: WO2016/55947, 2016, A1, . Location in patent: Page/Page column 76
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[22] Patent: EP1726580, 2006, A1, . Location in patent: Page/Page column 120
  • 32
  • [ 94-09-7 ]
  • [ 40566-85-6 ]
YieldReaction ConditionsOperation in experiment
2.2 g With hydrogenchloride; sodium nitrite In water at -20 - -10℃; for 0.5 h; Step 1 : Ethyl 4-hydrazinylbenzoate. hydrochloride: To a stirred and cooled (-20°C) solution of ethyl 4-aminobenzoate (2 g, 12.181 mmol) in cone. HC1 (22 mL) was added aqueous solution of sodium nitrite (925 mg, 13.40 mmol). This mixture was added very slowly to a precooled (-10 °C) mixture of tin chloride (13.8 g, 60.905 mmol) in cone. HC1 (15 mL) and stirred at the same temperature for 30 min. The precipitate obtained was filtered and washed with diethyl ether (2 x 20 mL) to yield 2.2 g of the title product as off white solid; 1H NMR (300 MHz, DMSO-i) δ 1.29 (t, J = 7.2 Hz, 3H), 4.26 (q, J = 7.5 Hz, 2H), 6.99 (d, = 7.8 Hz, 2H), 7.87 (d, = 8.4 Hz, 2H), 8.95 (br s, 1H), 10.48 (br s, 2H); APCI-MS (m/z) 181 (M+H)+.
Reference: [1] Journal of Medicinal Chemistry, 1993, vol. 36, # 11, p. 1529 - 1538
[2] Patent: WO2015/87234, 2015, A1, . Location in patent: Page/Page column 39
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Reference: [1] Patent: US5317103, 1994, A,
[2] Patent: EP438230, 1991, A2,
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  • [ 555-06-6 ]
Reference: [1] Chemische Berichte, 1986, vol. 119, # 5, p. 1627 - 1639
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  • [ 10602-03-6 ]
Reference: [1] Organic and Biomolecular Chemistry, 2018, vol. 16, # 16, p. 2865 - 2869
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  • [ 78485-37-7 ]
Reference: [1] Farmaco, 1994, vol. 49, # 3, p. 153 - 166
[2] Patent: EP3401315, 2018, A1,
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  • [ 437707-51-2 ]
Reference: [1] Journal of the American Chemical Society, 2002, vol. 124, # 19, p. 5350 - 5364
[2] Tetrahedron Letters, 1996, vol. 37, # 52, p. 9325 - 9328
  • 38
  • [ 94-09-7 ]
  • [ 82765-44-4 ]
YieldReaction ConditionsOperation in experiment
86% With N-chloro-succinimide In acetonitrile for 5 h; Inert atmosphere; Reflux To a solution of ethyl 4-aminobenzoate (2.0 mmol) inacetonitrile (2 mL mmol-1), NCS (2.05 mmol) was added.The mixture was refluxed for 5 h. Extraction was performedwith ethyl acetate and the organic layer was washed with 5percentNaOH, dried over anhydrous MgSO4, and the solvent wasremoved under reduced pressure. The product was purifiedby crystallization in hexane, which furnished 4-amino-3‑chlorobenzoate 27c as a purple crystal (mp 81-83 °C)in 86percent yield. 1H NMR (300 MHz, CDCl3) δ 1.33 (t, 3H,J 7.0 Hz, CH3), 4.29 (q, 2H, J 7.0 Hz, CH2), 6.70 (d, 1H,J 8.5 Hz, Ar‑H), 7.72 (dd, 1H, J 8.4, 1.9 Hz, Ar-H), 7.92 (d, 1H,J 1.9 Hz, Ar-H); 13C NMR (75 MHz, CDCl3) δ 14.30, 60.62,114.35, 118.06, 120.63, 129.52, 131.12, 146.97, 165.74.
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[2] Journal of the Brazilian Chemical Society, 2018, vol. 29, # 1, p. 109 - 124
[3] Journal of Medicinal Chemistry, 2004, vol. 47, # 27, p. 6973 - 6982
[4] Patent: US5502073, 1996, A,
[5] Patent: US5516774, 1996, A,
[6] Patent: US5733905, 1998, A,
[7] Patent: US5736540, 1998, A,
  • 39
  • [ 94-09-7 ]
  • [ 82765-44-4 ]
YieldReaction ConditionsOperation in experiment
76% With N-chloro-succinimide In dichloromethane (CH2 Cl2); acetonitrile (CH3 CH) Ethyl p-aminobenzoate, 49.50 g (0.30 moles) was dissolved in 500 ml of acetonitrile (CH3 CH) and heated to reflux.
When the mixture became homogeneous, 42.0 g (0.315 moles) of N-chlorosuccinimide was added in several portions over one hour and the mixture was stirred at reflux overnight.
By TLC (Hexane: EtOAc, 3:1), the mixture contained no starting material but only the desired product (Rf=0.55) and a minor impurity, which was probably dichlorinated material (Rf=0.65).
The mixture was concentrated on a rotary evaporator and the residue was redissolved in 250 mL of dichloromethane (CH2 Cl2) and washed twice with 100 mL of 5percent sodium hydroxide (NaOH).
The organic layer was dried over anhydrous potassium carbonate (K2 CO3) and concentrated on a rotary evaporator to yield 62.0 g of a reddish brown solid.
The solid was recrystallized from 1.25 L of boiling hexane to give 52 g of a brown solid.
The solid was recrystallized twice more from 1 L of boiling hexane to give 45.5 g (76percent) of tan solid ethyl 4-amino-3-chlorobenzoate (2), mp 82-83° C. and homogeneous by TLC. Additional material, 9.6 g (16percent) of like quality, was obtained by repeated recrystallization from hexane.
The total yield of pure ethyl 4-amino-3-chlorobenzoate (2) was 92percent. 1H NMR (CDCl3) d 7.97-7.96 (t, 1H, J=0.7 Hz, ArH), 7.80-7.75 (dt, 1H, J=0.7 Hz, ArH), 6.77-6.73 (dd, 1H, J=0.5 Hz, ArH), 4.40-4.29 (q, 2H, J=2.8 Hz, OCH2), 1.41-1.34 (t, J=2.8 Hz, 2H, OCH2 CH3). IR (KBr) cm-1, 3500, 3370 (NH2, m), 1695, (C=O, s) 1630. MS (El) m/e 199 (M+), 201 (M+2), Anal. Calc'd for C9 H10 NO2 Cl: C, 54.15; H, 5.05: N, 7.02. Fd. C, 54.14; H, 5.17, N, 6.93.
The formula is: STR2 4-Amino-3-chlorobenzoic acid (3)
Reference: [1] Patent: US6028111, 2000, A,
  • 40
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  • [ 362527-61-5 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 1, p. 153 - 158
  • 41
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  • [ 406233-26-9 ]
Reference: [1] Journal of Medicinal Chemistry, 2006, vol. 49, # 3, p. 1165 - 1181
  • 42
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  • [ 406233-25-8 ]
Reference: [1] Journal of Medicinal Chemistry, 2006, vol. 49, # 3, p. 1165 - 1181
  • 43
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  • [ 1020149-73-8 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 6, p. 1631 - 1635
[2] Journal of Medicinal Chemistry, 2014, vol. 57, # 3, p. 701 - 713
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Chemical Structure| 23239-88-5

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Ethyl 4-aminobenzoate hydrochloride

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