* 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.
A magnetically stirred solution of N-phenylanthranilic acid (5.45 g,26 mmol) in phosphorus oxychloride (100 mL, 1.07 mol) was treated with concentrated sulfuric acid (0.5mL), then brought to reflux for 12 h. The solution was cooled to rt, added slowly to cracked ice (650 g), and made slightly alkaline with concentrated ammonium hydroxide. A light tan solid was collected by filtration, washed with water, and air dried for 24 h. Flash chromatography (silica gel/75percent hexane, 20percentTHF, 5percent triethylamine) afforded 4.67 g (84percent yield) of 10 as fine yellow needles having one medium Rf spot by TLC; mp 117–119 °C (lit.15 mp 119–120 °C); 1H NMR (CDCl3): 8.50–8.10 (m, 4H),7.95–7.50 (m, 4H); IR (THF): 3075, 1622, 1562, 1438, 1404, 1324, 1287, 1014, 831, 767, 647, 608cm-1; Vis (CHCl3): λmax (") 360.5 nm (10,000); MS EI: m/e (relative intensity) 215 (33, M++2), 213(100, M+), 178 (21), 177 (16). Anal. Calcd for C13H8ClN: C, 73.07; H, 3.77; N, 6.55; Cl, 16.59. Found: C, 72.99; H, 3.80; N, 6.55; Cl, 16.58.
69%
Reflux
General procedure: The phenyl amino benzoic acid derivatives (47 mmol) (2a–c) were cyclized intra molecularly to 9-chloroacridine derivatives(3a–c) by refluxing them in 60 mL of POCl3 for 4 h and the reaction was monitored by TLC. After completion, the excess POCl3 was removed by rota evaporator under reduced pressure to the crude reaction mass crushed ice was added, pH was adjusted 7 by adding saturated bicarbonate solution. The solid separated was filtered,dried and purified by flash column chromatography using 5–10percent ethyl acetate: hexane as eluent in 60–120 mesh silica gelto get the corresponding 9-chloroacridine derivatives in good yield. These intermediates were confirmed by mass analysis (ESI mode) and proceed to next step.
56%
at 110℃; for 3 h;
In a 100ml eggplant type bottle,N-phenylanthranilic acid (5.0 g, 23.5 mmol) was added,Phosphorus oxychloride (50 ml, 537 mmol). Put it in a 110°C oil bath and stir for 3 hours.TLC (developer: dichloromethane/methanol=20/1) detects complete disappearance of compound III-14.Withdraw from the oil bath and naturally cool to room temperature.The reaction mixture was slowly added to 150 g of ice and stirred vigorously. After the heat is released,The pH was adjusted with saturated sodium bicarbonate solution until bubbles ceased to form.After filtration, the filter cake is washed with water 2 or 3 times and drained.This gave the solid, 9-chlorohydrazine, 2.8 g (brown solid, yield 56percent).
Reference：
[1] Journal of Physical Organic Chemistry, 2010, vol. 23, # 4, p. 382 - 389
[2] Journal of the American Chemical Society, 2010, vol. 132, # 40, p. 14006 - 14008
[3] Journal of Heterocyclic Chemistry, 1987, vol. 24, # 5, p. 1405 - 1408
[4] Heterocycles, 2014, vol. 88, # 1, p. 535 - 546
[5] Journal of Heterocyclic Chemistry, 2012, vol. 49, # 4, p. 748 - 754
[6] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 4, p. 877 - 885
[7] Electrochimica Acta, 2010, vol. 55, # 9, p. 3348 - 3354
[8] Patent: CN107721925, 2018, A, . Location in patent: Paragraph 0092; 0093
[9] Organic Syntheses, 1942, vol. 22, p. 5
[10] Journal of the Indian Chemical Society, 1998, vol. 75, # 10-12, p. 716 - 724
[11] European Journal of Medicinal Chemistry, 2010, vol. 45, # 2, p. 745 - 751
[12] Archiv der Pharmazie, 2009, vol. 342, # 12, p. 699 - 709
[13] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 12, p. 3491 - 3494
[14] Heterocycles, 2010, vol. 80, # 2, p. 1047 - 1066
[15] European Journal of Medicinal Chemistry, 2012, vol. 56, p. 217 - 224
[16] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 14, p. 4170 - 4177
[17] Tetrahedron Letters, 2014, vol. 55, # 22, p. 3308 - 3311
[18] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 14, p. 3014 - 3017
[19] Medicinal Chemistry, 2014, vol. 10, # 5, p. 506 - 511
[20] Chinese Chemical Letters, 2014, vol. 25, # 7, p. 1021 - 1024
[21] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 8, p. 1800 - 1807
[22] Patent: CN103755634, 2016, B,
[23] European Journal of Medicinal Chemistry, 2017, vol. 138, p. 1135 - 1146
[24] Chemical Biology and Drug Design, 2017, vol. 90, # 5, p. 926 - 935
[25] RSC Advances, 2018, vol. 8, # 68, p. 38995 - 39004
2
[ 91-40-7 ]
[ 10025-87-3 ]
[ 1207-69-8 ]
Reference：
[1] Chemische Berichte, 1933, vol. 66, p. 866,869[2] Zhurnal Obshchei Khimii, 1933, vol. 3, p. 615,618
3
[ 91-40-7 ]
[ 10026-13-8 ]
[ 71-43-2 ]
[ 1207-69-8 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1933, vol. 504, p. 297,302
4
[ 91-40-7 ]
[ 6267-02-3 ]
Reference：
[1] Patent: WO2011/93609, 2011, A1,
[2] Patent: WO2012/39561, 2012, A1,
[3] Patent: WO2013/45411, 2013, A1,
[4] Patent: WO2014/165307, 2014, A2,
[5] Journal of the American Chemical Society, 2014, vol. 136, # 52, p. 18070 - 18081
[6] Patent: CN105585577, 2016, A,
[7] Patent: KR2018/30860, 2018, A,
[8] Patent: CN108191739, 2018, A,
[9] Patent: US2018/166636, 2018, A1,
5
[ 91-40-7 ]
[ 494-19-9 ]
Reference：
[1] Australian Journal of Chemistry, 2013, vol. 66, # 6, p. 635 - 645
6
[ 91-40-7 ]
[ 38609-97-1 ]
Reference：
[1] Acta Poloniae Pharmaceutica - Drug Research, 2010, vol. 67, # 2, p. 211 - 214
Reference：
[1] Tetrahedron Letters, 2000, vol. 41, # 27, p. 5229 - 5232
[2] Bioscience, biotechnology, and biochemistry, 2001, vol. 65, # 8, p. 1761 - 1765
[3] Journal of Medicinal Chemistry, 1968, vol. 11, # 1, p. 111 - 117
[4] Journal of Heterocyclic Chemistry, 1996, vol. 33, # 4, p. 1163 - 1170
[5] Journal of the American Chemical Society, 1933, vol. 55, p. 4294,4297, 4298
9
[ 67-56-1 ]
[ 91-40-7 ]
[ 35708-19-1 ]
Yield
Reaction Conditions
Operation in experiment
92%
Stage #1: for 0.166667 h; Cooling with ice Stage #2: at 0 - 90℃; for 12 h;
Preparation of Compound 1-1 [95] After 2-(phenylamino)benzoic acid (50 g, 0.23 mol) was dissolved in MeOH (1 L) and put into an ice bath, the mixture was stirred for 10 minutes. After slowly adding SOCl2 (60 mL, 0.58 mol) thereto at 0 , the mixture was stirred under reflux for 12 hours at 90 . Upon completion of the reaction, the reaction mixture was washed with distilled water and extracted with ethylacetate. After drying an organic layer with MgSO4 and removing solvent by a rotary type evaporator, Compound 1-1 (47 g, 92percent) was obtained through purification by column chromatography using ethylacetate as a developing solvent.
92%
at 0 - 90℃; for 12 h; Reflux
2-(phenylamino)benzoic acid (50g, 0.23mol) was dissolved in MeOH 1L, placed in an ice bath and then stirred at 0°C for 10 minutes. SOCl2 (60mL, 0.58mol) was slowly added at 0°C and the mixture was stirred under reflux at 90°C for 12 hours. After termination of the reaction, the mixture was washed with distilled water and extracted with EA. The organic layer was dried with anhydrous MgSO4, and the solvent was removed using a rotary evaporator. Subsequently, column chromatography purification was conducted using EA as a developer, yielding Compound 3-1 (47g, 92percent).
92%
at 0 - 90℃; for 12 h;
2-(phenylamino)benzoic acid (50 g, 0.23 mol) was dissolved in methanol (1 L), put in an ice bath and stirred for ten minutes. After slowly adding SOCI2 (60 ml_, 0.58 mol) thereto at 0°C, the mixture was stirred under reflux for 12 hours at 90°C.Upon completion of the reaction, the reaction mixture was washed with distilled water and extracted with ethyl acetate. After drying the organic layer with magnesium sulfate and removing the solvent by a rotary type evaporator, 2-(phenylamino) methyl benzoate (47 g, 92percent) was obtained through purification by column chromatography using ethyl acetate as developing solvent.
90%
for 5 h;
2.5 grams (g) (0.12 moles (mol)) of 2-(phenylamino)benzoic acid, 1.39 g (0.13 mol) of thionyl chloride, and 50 milliliters (ml) of methanol were added to a flask, and these reactants were allowed to react for 5 hours. After the reaction was completed, the reaction mixture was filtered to obtain solid products. Then, the solid products were washed out with water, thereby obtaining 2.4 g (yield: 90percent) of Intermediate I-3-1
90%
for 5 h;
2-(phenylamino)benzoic acid (2.5 grams (g), 0.12 moles (mol)), thionyl chloride (1.39 g, 0.13 mol), and 50 milliliters (mL) of methanol were added to a flask, and the mixture was allowed to react for 5 hours. Once the reaction was completed, the reaction mixture was filtered, and the remaining solid was washed with water to obtain Intermediate I-3-1 (2.4 g, 90percent).
81%
Stage #1: at 0℃; for 0.166667 h; Inert atmosphere Stage #2: at 90℃;
In N2in the gas purification system, mixing and stirring N-phenyl-O-aminobenzoic acid (46.9mmol) and methanol solvent. The mixture at 0 °C restiring at a temperature of 10 minutes, and is slow to instillment thionyl chloride (21.2mmol). In the mixed solution is 90 °C temperature stirring 12 hours or more. After the completion of reaction, to remove the solvent, and distilled water and for the mixed solution is then extracted with ethyl acetate. From the extraction of using magnesium sulphate remove the moisture in the organic layer, and removing the solvent. The material through the use of hexane and ethyl acetate to carry out wet refining column chromatography, thereby obtaining compound crocatus of the liquid is "b". (Yield: 81percent)
80%
at 0 - 90℃; Inert atmosphere
Compound 1A(4.52 g, 21.2 mmol) was mixed with a methanol solvent(100ml) and then stirred under a nitrogen atmosphere. After further stirring at 0° C. for 10 minutes, 1 equivalent of thionyl chloride (21.2 mmol) was slowly added dropwise. The mixed solution was stirred at 90° C. for 12 hours or longer. After completion of the reaction, the solvent was removed, and distilled water and ethyl acetate were added to extract an organic layer. The moisture remaining in the extracted organic layer was removed using magnesium sulfate, followed by removal of the solvent, and then a crude product was subjected to wet purification using column chromatography using hexane and ethyl acetate to obtain a dark yellow liquid 1B(3.84 g, yield 80percent).
Reference：
[1] Patent: WO2011/93609, 2011, A1, . Location in patent: Page/Page column 15
[2] Patent: WO2012/39561, 2012, A1, . Location in patent: Page/Page column 23
[3] Patent: WO2013/45411, 2013, A1, . Location in patent: Paragraph 0097
[4] Journal of the American Chemical Society, 2014, vol. 136, # 52, p. 18070 - 18081
[5] Patent: US2017/5275, 2017, A1, . Location in patent: Paragraph 0283; 0284; 0285
[6] Patent: US2017/25620, 2017, A1, . Location in patent: Paragraph 0324; 0325; 0326
[7] Archiv der Pharmazie, 1984, vol. 317, # 7, p. 595 - 606
[8] Patent: CN105585577, 2016, A, . Location in patent: Paragraph 0101; 0102; 0103; 0104
[9] Patent: US2018/166636, 2018, A1, . Location in patent: Paragraph 0109; 0110
[10] Journal of the American Chemical Society, 1935, vol. 57, p. 195,196
[11] Journal of the American Chemical Society, 1933, vol. 55, p. 4294,4297, 4298
[12] Helvetica Chimica Acta, 1944, vol. 27, p. 616,617
[13] Journal of Materials Chemistry, 2007, vol. 17, # 12, p. 1209 - 1215
[14] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 8, p. 1971 - 1985
10
[ 91-40-7 ]
[ 77-78-1 ]
[ 35708-19-1 ]
Yield
Reaction Conditions
Operation in experiment
94%
With potassium carbonate In acetone for 2 h; Reflux
To a flask charged with N-phenyl-anthranilic acid (10.0 g, 46.9 mmol) and potassium carbonate (6.48 g, 46.9 mmol) in acetone (140 mL) was added dimethyl sulfate (7.56 mL, 79.7 mmol) at room temperature. The flask was attached to a reflux condenser and heated to reflux. After 2 h, the was cooled to rt, and poured onto 10 crushed ice. The resulting mixture was extracted with dichloromethane and then dried over Na2S04. The resulting solution was filtered and concentrated. The resulting residue was purified via silica gel chromatography, eluted with hexane:ethyl acetate = 6:4, to afford the product as a yellow oil in 94percent yield.
92%
With potassium carbonate In acetone for 2 h; Reflux
Commercially available N-phenyl anthranilic acid (1) (2.0 g, 10 mmol) in acetone (30 mL) was refluxed with dimethyl sulphate (2.0 gr, 1.55 mL, 15 mmol) and potassium carbonate (1.38 g, 10 mmol) for 2 hrs. The progress of the reaction was monitored by TLC and when reaction was judged complete, the reaction mixture was allowed to cool to room temperature and poured into crushed ice. The aqueous layer was extracted with CH2C12 (2 x 30mL), dried over anhydrous MgS04, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with gradient elution (10 to 40percent EtOAc-hexane) to afford the title compound as light yellow oil (2.1 g, 92percent yield). 1H NMR (300 MHz, DMSO- 6): δ 9.29 (s, 1H), 7.88 (d, 1H, J = 7.8 Hz), 7.45-7.30 (m, 3H), 7.28-7.18 (m, 3H), 7.07 (t, 1H, J = 7.5 Hz), 6.80 (t, 1H, J = 7.5 Hz), 3.85 (s, 3H). LCMS (ESI) m/z 228 (MH+).
Reference：
[1] Patent: KR2018/30860, 2018, A, . Location in patent: Paragraph 0043-0045
[2] Patent: WO2014/165307, 2014, A2, . Location in patent: Paragraph 0314
[3] Journal of the American Chemical Society, 1935, vol. 57, p. 195,196
11
[ 91-40-7 ]
[ 74-88-4 ]
[ 35708-19-1 ]
Reference：
[1] Journal of Organic Chemistry, 2007, vol. 72, # 2, p. 583 - 588
12
[ 91-40-7 ]
[ 150389-84-7 ]
Reference：
[1] Chemical Communications, 2011, vol. 47, # 15, p. 4472 - 4474
[2] Organic and Biomolecular Chemistry, 2014, vol. 12, # 19, p. 3071 - 3079
With potassium carbonate;copper(l) iodide; dipyridyl; bis(acetylacetonato)palladium(II); In 1-methyl-pyrrolidin-2-one; at 160℃; for 24h;Molecular sieve;Product distribution / selectivity;
EXAMPLES 26-55; Examples 26-55 from Table 3, which were performed according to scheme 5 on a scale of 1 mmol, demonstrate the wide applicability of the process according to the invention. To determine the yields, after aqueous workup, the products were chromatographed on silica gel and characterized unambiguously with the aid of NMR, MS, HRMS.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
Life Science
For Research Only
100K+ Compounds
Competitive Price
1-2 Day Shipping
