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Product Details of [ 150-13-0 ]

CAS No. :150-13-0 MDL No. :MFCD00007894
Formula : C7H7NO2 Boiling Point : -
Linear Structure Formula :- InChI Key :ALYNCZNDIQEVRV-UHFFFAOYSA-N
M.W : 137.14 Pubchem ID :978
Synonyms :
PABA;Vitamin Bx;Aminobenzoic acid;para-Aminobenzoic acid;p-Aminobenzoic acid;Vitamin H1

Calculated chemistry of [ 150-13-0 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 10
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 1
Num. H-bond acceptors : 2.0
Num. H-bond donors : 2.0
Molar Refractivity : 37.81
TPSA : 63.32 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) : -6.55 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.82
Log Po/w (XLOGP3) : 0.83
Log Po/w (WLOGP) : 0.98
Log Po/w (MLOGP) : -0.12
Log Po/w (SILICOS-IT) : 0.5
Consensus Log Po/w : 0.6

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.59
Solubility : 3.52 mg/ml ; 0.0256 mol/l
Class : Very soluble
Log S (Ali) : -1.74
Solubility : 2.48 mg/ml ; 0.0181 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -1.38
Solubility : 5.69 mg/ml ; 0.0415 mol/l
Class : Soluble

Medicinal Chemistry

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

Safety of [ 150-13-0 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 150-13-0 ]

* 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 [ 150-13-0 ]
  • Downstream synthetic route of [ 150-13-0 ]

[ 150-13-0 ] Synthesis Path-Upstream   1~131

  • 1
  • [ 150-13-0 ]
  • [ 95-86-3 ]
  • [ 13676-47-6 ]
Reference: [1] Patent: WO2010/111483, 2010, A1, . Location in patent: Page/Page column 83
  • 2
  • [ 137-09-7 ]
  • [ 150-13-0 ]
  • [ 13676-47-6 ]
Reference: [1] Journal of Heterocyclic Chemistry, 1969, vol. 6, p. 119 - 121
  • 3
  • [ 150-13-0 ]
  • [ 99071-54-2 ]
Reference: [1] Patent: US2011/281865, 2011, A1,
[2] Patent: WO2011/145035, 2011, A1,
[3] Patent: WO2013/144737, 2013, A2,
[4] Patent: US2015/57309, 2015, A1,
  • 4
  • [ 150-13-0 ]
  • [ 56-81-5 ]
  • [ 10349-57-2 ]
YieldReaction ConditionsOperation in experiment
95% at 140℃; Step 1.
Quinoline-6-carboxylic acid
Into a 500-mL 3-necked round-bottom flask, was placed 4-aminobenzoic acid (13.7 g, 100.00 mmol, 1.00 equiv), 4-nitrobenzoic acid (10.7 g, 64.07 mmol, 0.64 equiv), boric acid (5.9 g), FeSO4.7H2O (6.4 g), glycerol (38 mL), and concentrated sulfuric acid (18 mL).
The resulting solution was stirred overnight at 140° C.
The reaction mixture was cooled.
The pH value of the solution was adjusted to 10 with sodium hydroxide (10percent).
The resulting solution was extracted with 2*100 mL of ethyl acetate and the aqueous layers were combined.
The pH value of the aqueous layers was adjusted to pH 6 with conc. hydrochloric acid.
The solids were collected by filtration.
The resulting solution was diluted with 200 mL of methanol and the resulting solids were collected by filtration.
The solid was dried to afford 17.3 g (95percent) of quinoline-6-carboxylic acid as a dark-grey solid.
LC-MS: (ES, m/z):174 [M+H]+
56%
Stage #1: at 135℃; for 48 h;
Stage #2: at 0℃;
Step 1:
Quinoline-6-carboxylic acid
To a mixture of 4-aminobenzoic acid (175 g, 1.28 mol), 4-nitrophenol (88.75 g, 0.64 mol) and sulphuric acid (1.2 lit.), glycerol (234.8 g, 2.55 mol) was added dropwise at 135° C.
After 48 h, the reaction mixture was cooled to 0° C. and the pH adjusted to 3-5 with 10percent sodium hydroxide solution.
The resulting precipitate was collected by filtration and washed with water and dried under vacuum to afford the title compound as a black solid (125 g, 56percent).
56% at 135℃; for 48 h; To a mixture of 4-aminobenzoic acid (175 g, 1.28 mol), 4-nitrophenol (88.75 g, 0.64 mol) and sulphuric acid (1.2 lit.), glycerol (234.8 g, 2.55 mol) was added dropwise at 135°C. After 48h, the reaction mixture was cooled to 0°C and the pH adjusted to 3-5 with 10percent sodium hydroxide solution. The resulting precipitate was collected by filtration and washed with water and dried under vacuum to afford the title compound as a black solid (125 g, 56percent).
56% at 135℃; for 48 h; [252] Intermediates Intermediate 1: Quinolin-6-ylmethanamine: Stepl : Quinoline-6-carboxylic acid: To a mixture of 4-aminobenzoic acid: (175 g, 1.28 mol), 4-nitrophenol (88.75 g, 0.64 mol) and sulphuric acid (1.2 lit.), glycerol (234.8 g, 2.55 mol) was added drop wise at 135°C. After 48h, the reaction mixture was cooled to 0°C and the pH adjusted to 3-5 with 10percent sodium hydroxide solution. The resulting precipitate was collected by filtration and washed with water and dried under vacuum to afford the title compound as a black solid (125 g, 56percent).
56%
Stage #1: at 135℃; for 48 h;
Stage #2: With sodium hydroxide In water at 0℃;
Step 1:
Quinoline-6-carboxylic acid
To a mixture of 4-aminobenzoic acid: (175 g, 1.28 mol), 4-nitrophenol (88.75 g, 0.64 mol) and sulphuric acid (1.2 lit.), glycerol (234.8 g, 2.55 mol) was added drop wise at 135° C.
After 48 h, the reaction mixture was cooled to 0° C. and the pH adjusted to 3-5 with 10percent sodium hydroxide solution.
The resulting precipitate was collected by filtration and washed with water and dried under vacuum to afford the title compound as a black solid (125 g, 56percent).

Reference: [1] Patent: US2012/277224, 2012, A1, . Location in patent: Page/Page column 82
[2] Patent: US2011/281865, 2011, A1, . Location in patent: Page/Page column 83
[3] Patent: WO2011/145035, 2011, A1, . Location in patent: Page/Page column 107-108
[4] Patent: WO2013/144737, 2013, A2, . Location in patent: Paragraph 252
[5] Patent: US2015/57309, 2015, A1, . Location in patent: Paragraph 0504
[6] Journal of the American Chemical Society, 1946, vol. 68, p. 2721
  • 5
  • [ 7664-93-9 ]
  • [ 150-13-0 ]
  • [ 62-23-7 ]
  • [ 10349-57-2 ]
Reference: [1] Patent: US5134148, 1992, A,
[2] Patent: EP381375, 1990, A1,
  • 6
  • [ 150-13-0 ]
  • [ 56-81-5 ]
  • [ 62-23-7 ]
  • [ 10349-57-2 ]
Reference: [1] Monatshefte fuer Chemie, 1891, vol. 12, p. 309
[2] Monatshefte fuer Chemie, 1881, vol. 2, p. 519
  • 7
  • [ 7664-93-9 ]
  • [ 150-13-0 ]
  • [ 56-81-5 ]
  • [ 62-23-7 ]
  • [ 10349-57-2 ]
Reference: [1] Monatshefte fuer Chemie, 1881, vol. 2, p. 519
  • 8
  • [ 150-13-0 ]
  • [ 123-73-9 ]
  • [ 635-80-3 ]
YieldReaction ConditionsOperation in experiment
44%
Stage #1: With hydrogenchloride In water for 2 h; Reflux
Stage #2: for 12.75 h;
Intermediate 13: (2-methylquinolin-6-yl)methanamine Stepl : 2-methylquinoline-6-carboxylic acid: To 4-aminobenzoic acid (5 g, 36.45 mmol) , 6N HCl (73 ml) was added and refluxed for 2h. Crotonaldehyde (3.06 g, 43.75 mmol) was added dropwise over 45 min.. After 12h, the reaction mixture was cooled to 0°C and the pH adjusted to 3-5 with aqueous ammonia solution. The aqueous layer containing solid was washed with dichloromethane and acidified with 2N HCl, filtered and dried under vacuum to afford the title compound as brown solid (3.0 g, 44percent).
44%
Stage #1: With hydrogenchloride In water for 2 h; Reflux
Stage #2: for 12 h;
Step 1:
2-methylquinoline-6-carboxylic acid
To 4-aminobenzoic acid (5 g, 36.45 mmol), 6N HCl (73 ml) was added and refluxed for 2 h.
Crotonaldehyde (3.06 g, 43.75 mmol) was added dropwise over 45 min.
After 12 h, the reaction mixture was cooled to 0° C. and the pH adjusted to 3-5 with aqueous ammonia solution.
The aqueous layer containing solid was washed with dichloromethane and acidified with 2N HCl, filtered and dried under vacuum to afford the title compound as brown solid (3.0 g, 44percent).
Reference: [1] Patent: WO2013/144737, 2013, A2, . Location in patent: Paragraph 252
[2] Patent: US2015/57309, 2015, A1, . Location in patent: Paragraph 0524
[3] Journal of Medicinal Chemistry, 2002, vol. 45, # 21, p. 4647 - 4654
[4] Chemistry - A European Journal, 2018, vol. 24, # 61, p. 16368 - 16378
[5] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 22, p. 6138 - 6141
[6] Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy, 2015, vol. 151, p. 184 - 197
  • 9
  • [ 123-73-9 ]
  • [ 150-13-0 ]
  • [ 635-80-3 ]
Reference: [1] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 19, p. 817,819
[2] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 19, p. 817
  • 10
  • [ 150-13-0 ]
  • [ 38896-30-9 ]
Reference: [1] Patent: US2011/281865, 2011, A1,
[2] Patent: WO2011/145035, 2011, A1,
[3] Patent: WO2013/144737, 2013, A2,
[4] Patent: US2015/57309, 2015, A1,
  • 11
  • [ 110-86-1 ]
  • [ 150-13-0 ]
  • [ 4385-62-0 ]
Reference: [1] Journal of the Chemical Society, 1940, p. 355,357
  • 12
  • [ 150-13-0 ]
  • [ 73987-38-9 ]
Reference: [1] Journal of the American Chemical Society, 1946, vol. 68, p. 2721
  • 13
  • [ 150-13-0 ]
  • [ 22090-27-3 ]
Reference: [1] Journal of Medicinal Chemistry, 2012, vol. 55, # 19, p. 8524 - 8537,14
  • 14
  • [ 150-13-0 ]
  • [ 95-54-5 ]
  • [ 2963-77-1 ]
YieldReaction ConditionsOperation in experiment
82% at 200℃; for 5 h; A mixture of 4-aminobenzoic acid (5 g, 5.78 mmol) and o-phenylenediamine (3.9 g, 3.68 mmol) were stirred in polyphosphoric acid (12.5 gm) at 200 °C for 5 h. The reaction mixturewas cooled and poured into crushed ice. The precipitate was thenstirred in cold water. Ammonium hydroxide solution was added until the pH 7 was achieved. The resulting solid was filtered andwashed several times with methanol and column chromatographedon silica gel in ethyl acetate: hexane (4:1) to afford thedesired product 4-(1H-benzimidazol-2-yl)-phenylamine (5) aswhite solid; yield: 82percent; mp: 207-209 °C; 1H NMR (400 MHz, DMSO-d6): δ = 7.96 (d, 2H, J = 8.72 Hz, ArH), 7.55-7.51 (m, 2H, ArH), 7.16-7.14 (m, 2H, ArH), 6.75 (d, 2H, J = 8.24 Hz, ArH), 4.45 (bs, 2H,NH2); 13C NMR (100 MHz, CDCl3 DMSO-d6): δ = 152.2, 148.4,127.5, 120.9, 118.6, 113.8 (ArC); MS (ESI), m/z: 210.2 (M++1).
82% With polyphosphoric acid In hexane; water at 200℃; for 5 h; A mixture of 4-aminobenzoic acid (5 g, 5.78 mmol) and o-phenylenediamine (3.9 g, 3.68 mmol) were stirred in a syrupy polyphosphoric acid (12.5 gm) at 200 °C for 5 h.
The reaction was monitored by TLC.
The reaction mixture was cooled and poured into crushed ice.
The white precipitate was then stirred in cold water.
Ammonium hydroxide solution was added until the pH 7.0 was achieved.
The resulting solid was filtered and washed several times with methanol and column chromatographed on silica gel in hexane:
ethylacetate to afford the desired product 4-(1H-benzimidazol-2-yl)-phenylamine (3) as white solid; (82percent); mp: 207-209 °C; 1H NMR (400 MHz, DMSO-d6): δ = 7.96 (d, 2H, J = 8.72 Hz, ArH), 7.55-7.51 (m, 2H, ArH), 7.16-7.14 (m, 2H, ArH), 6.75 (d, 2H, J = 8.24 Hz, ArH), 4.45 (bs, 2H, NH2); 13C NMR (100 MHz, CDCl3 + DMSO-d6): δ = 152.2, 148.4, 127.5, 120.9, 118.6, 113.8 (ArC); MS(ESI), m/z: 209.2 (M++1).
74% at 0 - 130℃; General procedure: Eaton’s reagent (10 vol; wt/vol)) was added drop wise to a wellpulverised mixture of the corresponding 1,2-phenylenediamine(2a–e)/1,2-diaminopyridine (2f) (1 equiv) and 4-amino benzoicacid (1 equiv) at 0 C. The reaction mixture was then heated at130 C for 5–6 h (monitored by TLC and LCMS for completion).The reaction mixture was cooled and neutralised with 10percent sodiumhydroxide solution to pH of 6–7, the precipitate formed was filteredand washed repeatedly with water and dried. The solidobtained was recrystallized from ethanol to afford the desiredproduct in good yield as described below.
70% at 200℃; for 2 h; Amixture of o-phenylenediamine 1 (1.08 g, 0.01 mol) and paminobenzoicacid 2 (1.37 g, 0.01 mol) were stirred in asyrupy o-phosphoric acid (15 ml) at 200 °C for 2 h. Thereaction mixture was cooled and poured on crushed ice. Thebulky white precipitate obtained was stirred in cold water(150 ml) and sodium hydroxide solution (5 M) was addeduntil the pH 7. The resulting solid obtained 3 was filteredand recrystallized from methanol. Yield = 70percent, m.p.246–248 °C. IR (KBr) cm−1: 3357 (NH), 2985 (Ar–CH),1675 (C=N), 1586 (C=C). 1H-NMR (CDCl3, 500 MHz) δppm: 7.09–8.24 (m, 8H, Ar–CH), 5.78 (s, 1H, NH ofbenzimidazole), 4.30 (s, 2H, NH2). 13C-NMR (CDCl3, 500 MHz) δ ppm: 155.2 (C-2), 148.5 (C′-1), 139.6 (C-8 and C-9), 130.3 (C′-3 and C′-5), 124.7 (C-5 and C-6), 122.2 (C′-4),119.5 (C′-2 and C′-6), 118.1 (C-4 and C-7). EI-MS m/z: 209(M+). Anal. calcd for C13H11N3: C, 74.62; H, 5.30; N,20.08. Found: C, 74.86; H, 5.28; N, 20.01.
61% at 220℃; for 5 h; 4-Aminobenzoic acid (5.00 g, 36.46 mmol), o-phenylenediamine (3.94 g, 36.46 mmol) andPPA (50.0 g, 10 eq.) were added to a 50 mL reaction vessel with a drying tube and heated at220 °C, with stirring for 5 h. The reaction progress was monitored by TLC using a 6:94mixture of MeOH:DCM. The resulting mixture was washed with 200 mL hot water into a10percent NaHCO3 solution (200 mL) and basified yielding a brown solid. This solid was washedwith water (3 x 400 mL) and crystallized from methanol and water to yield light brown needlecrystals of 1 (4.68 g, 61percent yield).ATR-FTIR max /cm-1 3360, 3441 (NH2); m.p. 240 - 241 °C (lit. 240 - 241 °C) [1]; Rf(MeOH/DCM 6:94) 0.49; δH (DMSO-d6, 400 MHz) 5.54 (s, 2H, NH2), 6.68 (d, J = 8.6 Hz,2H), 7.11 (m, 2H), 7.49 (m, 2H), 7.86 (d, J = 8.6 Hz, 2H); δC (DMSO-d6, 100.6 MHz) 113.5,113.5, 114.2 (Cquat), 117.3 (Cquat), 121.2, 127.7, 150.5 (Cquat), 152.6 (Cquat); HRMS-ES+Calculated: 210.1031 [M+H]+ for C13H12N3, Observed: 210.1031; C18 HPLC, flow rate: 1mL/min, H2O / acetonitrile (40:60), 99.1percent.
55% at 180 - 200℃; for 4 h; 4-(1H-Benzo[d]imidazol-2-yl)aniline was synthesized from o-phenylenediamine and p-aminobenzoic acid in the presence of an acid as a dehydrating agent. A mixture of o-phenylenediamine (30 mmol) and p-aminobenzoic acid (45 mmol) was refluxed in o-phosphoric acid (30 mL) at 180-200 °C for 4 h on an oil bath. After that, the reaction mixture was cooled to 50-60 °C and poured onto crushed ice. The reaction mixture was then neutralized with a sodium hydroxide solution (10percent, 70 mL) and the precipitate was collected by filtration. The raw product was washed with an excess 10percent sodium hydroxide solution and water and then dried. The product was further puried by crystallization from ethanol. Mp: 248.1-249.8 °C (lit. mp: 248 °C ; yield = 55percent; IR (KBr) νmax /cm-1: 3438 (NH benzimidazole), 3360, 3216 (NH2 aminophenyl), 3050 (CH arom), 1621 (C=N), 1605 (C=C arom). 1H NMR (DMSO-d6) δ/ppm: 5.66 (2H, s, NH2 aminophenyl), 6.73 (2H, d, J = 8 Hz, Ar), 7.14-7.20 (2H, m, Ar), 7.51-7.58 (2H, m, Ar), 7.91 (2H, d, J = 8 Hz, Ar), 12.42 (1H, brs, NH benzimidazole).
33% at 20 - 220℃; for 4 h; 1,2-phenlendiamine (6.5 g, 60 mmol), 4-aminobenzoic acid (7.0 g, 51 mmol) and polyphosphoric acid (25 g) were placed into a flask and were stirred at 220 C for 4 hrs. After the mixture was cooled to ambient temperature, to the dark lump was added aq. K2CO3 (10 percent, 400 mL). The lump was neutralized with aq. NaHCO3 to pH ca. 7, and the formed solid was collected by filtration. The solid was washed with hot water (50-70 C) till the water was colorless. recrystallization in ethyl acetate (800 ml, Charcoal 3g) gave a white solid (4.2 g, 33 percent) as pure product. MS m/z = 210 (M+1)
33% With phosphoric acid In neat (no solvent) for 0.25 h; Microwave irradiation o-Phenylenediamine (8.8 mmol,1.0 g) and p-aminobenzoicacid (8.2 mmol, 1.1 g) were mixed with 12 mL oforthophosphoric acid in an Erlenmeyer flask and irradiatedin a microwave oven for 15 minutes at 170W with intermediateshaking. The reaction mixture was diluted with colddistilled water and was rendered alkaline with ammoniumhydroxide solution. The crude product separated was filteredunder vacuum and recrystallized from ethanol-water. (0.4 g,33percent) mp 250°C. IR: 3500-3400 (N-H str., br), 3048, 3001(Ar-H str.), 1606 (C=N 1441 (C=C str.), 1273 (C-N str.), 834(N-H wagging), 745 (Ar-H bending); 1H-NMR (CDCl3): 7.9 (dap, 2H, J=9.0, ArH), 7.55 (m, 2H, ArH), 7.15 (m, 2H,ArH), 6.7 (dap, 2H, J=9.08, ArH), 4.7 (br s, 1H, NH), 3.9(br s, 2H, NH2).

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  • [ 2963-77-1 ]
Reference: [1] Chemical and Pharmaceutical Bulletin, 2007, vol. 55, # 1, p. 115 - 117
  • 16
  • [ 58338-59-3 ]
  • [ 2963-77-1 ]
  • [ 150-13-0 ]
  • [ 95-54-5 ]
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  • 17
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  • [ 150-13-0 ]
  • [ 93-85-6 ]
YieldReaction ConditionsOperation in experiment
42% With bromine In methanol at -10 - -5℃; for 2 h; Synthesis of 2-aminobenzothiazole-6-carbolic Acid(2)NaSCN (65 g, 0.8 mol) was added to a suspension of commercially available 4-amino-benzoic acid (1, 100 g, 0.73 mol) in MeOH followed by the addition of Br2 (38 ml, 0.73 mol) in portions. The above solution was allowed to cool to -10° C. and stirred for 2 h while keeping the inner temperature below -5° C. The precipitate was then filtered and suspended in 350 ml of 1 M HCl. The suspension was heated to reflux for 30 min. After immediate filtration, 150 ml concd HCl was added to the hot filtrate to give 70 g (yield 42percent) of 2-amino-benzothiazole-6-carboxylic acid (2) (as a white solid), which was dried and used without further purification.
Reference: [1] Patent: US2009/123373, 2009, A1, . Location in patent: Page/Page column 14-15
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  • [ 333-20-0 ]
  • [ 150-13-0 ]
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[2] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1991, vol. 30, # 5, p. 494 - 498
[3] Patent: WO2010/62171, 2010, A2, . Location in patent: Page/Page column 156
[4] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 23, p. 5561 - 5565
[5] Patent: KR2018/81285, 2018, A, . Location in patent: Paragraph 0132; 0144-0147
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  • [ 150-13-0 ]
  • [ 93-85-6 ]
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[2] Arzneimittel Forschung, 1952, vol. 2, p. 455,460
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Reference: [1] Yakugaku Zasshi, 1946, vol. 66, p. Ausg. B, S. 75[2] Chem.Abstr., 1952, p. 112
  • 23
  • [ 108-31-6 ]
  • [ 150-13-0 ]
  • [ 17057-04-4 ]
YieldReaction ConditionsOperation in experiment
92% at 20℃; for 1 h; (1) equipped with a mechanical stirrer, thermometer,Constant pressure injector 500mL three-necked flask followed by 35g of maleic anhydride (0.357mol)And 100mL acetone, stirring at 20 until dissolved, at the same time,49 g (0.357 mol) p-aminobenzoic acid was dissolved in 250 mL acetone,Forming a transparent solution to be used; then,The preparation of p-aminobenzoic acid acetone solution was added dropwise to 500mL three-necked flask,After the dropwise addition, continue the reaction 1h, suction filtration (solvent recovery), washing,Recrystallization, dried to give yellow crystalsN- (4-carboxyphenyl) maleimide acid77.28g,Yield 92percent, purity 99.3percent (HPLC)
37%
Stage #1: at 20℃; for 4 h;
Stage #2: With sodium acetate In acetic anhydride at 80℃; for 6 h;
A solution of p-aminobenzoic acid (128 mg, 0.94 mmol) and excess maleic anhydride (137 mg, 1.40 mmol) was added to ethyl acetate (20 mL), the reaction was stirred at room temperature for 4 h. After the reaction was completed, the precipitate was filtered, washed with a small amount of ethyl acetate (8 mL), dried, finally, a white powder was obtained. The crude white powder (220 mg, 0.94 mmol) was added to acetic anhydride (10 mL). A catalytic amount of sodium acetate (25 mg, 0.30 mmol) was added, the reaction temperature was controlled at 80 ° C, reaction time was 6 h, after completion of the reaction, the reaction mixture was poured into 40 mL of ice water, stirring for 30min, precipitation of white solid, filtered, the precipitate was washed with deionized water until neutral, vacuum drying, column chromatography on silica gel yielded a light yellow solid (75 mg, 37percent). Compound 31H NMR and 13C NMR are shown in Fig. 1 and Fig. 2, respectively.
Reference: [1] Patent: CN107286072, 2017, A, . Location in patent: Paragraph 0017; 0018; 0019
[2] Revue Roumaine de Chimie, 2008, vol. 53, # 9, p. 743 - 752
[3] Acta Crystallographica Section C: Crystal Structure Communications, 2011, vol. 67, # 2, p. o67-o70
[4] Patent: CN106243118, 2016, A, . Location in patent: Paragraph 0029
[5] Revue Roumaine de Chimie, 2001, vol. 46, # 10, p. 1167 - 1173
[6] Revue Roumaine de Chimie, 2002, vol. 47, # 3-4, p. 257 - 262
[7] Patent: US5198551, 1993, A,
[8] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 22, p. 5926 - 5931
[9] Organic and Biomolecular Chemistry, 2009, vol. 7, # 17, p. 3400 - 3406
[10] Revue Roumaine de Chimie, 2012, vol. 57, # 11, p. 929 - 937
[11] Journal of Polymer Science, Part A: Polymer Chemistry, 2015, vol. 53, # 1, p. 123 - 132
[12] RSC Advances, 2016, vol. 6, # 104, p. 101900 - 101910
  • 24
  • [ 150-13-0 ]
  • [ 110-16-7 ]
  • [ 17057-04-4 ]
Reference: [1] Journal of the American Chemical Society, 2005, vol. 127, # 22, p. 8036 - 8043
[2] Journal of the Chemical Society, 1957, p. 4133
  • 25
  • [ 150-13-0 ]
  • [ 17057-04-4 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 1, p. 521 - 530
[2] Tetrahedron Letters, 2012, vol. 53, # 32, p. 4245 - 4247
[3] Molecules, 2012, vol. 17, # 7, p. 7927 - 7940
[4] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 3, p. 797 - 801
[5] European Journal of Medicinal Chemistry, 2015, vol. 96, p. 259 - 268
[6] Journal of Agricultural and Food Chemistry, 2016, vol. 64, # 24, p. 4876 - 4881
[7] Patent: WO2017/177316, 2017, A1,
  • 26
  • [ 150-13-0 ]
  • [ 6285-57-0 ]
Reference: [1] Letters in Drug Design and Discovery, 2011, vol. 8, # 8, p. 717 - 724
  • 27
  • [ 109-01-3 ]
  • [ 150-13-0 ]
  • [ 55121-99-8 ]
YieldReaction ConditionsOperation in experiment
42% With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; To a mixture of 4-aminobenzoic acid (5g, 36.5 mmol), 1-methylpiperazine (3.7 mL, 32.8 mmol) and TEA (16.0 mL, 114.8 mmol) in DCM (100 mL) was added EDC.HCl (10.5 g, 54.8 mmol) and the mixture was stirred at room temperature overnight. The sovent was removed and the residue was purified by silica flash chromatography with 0 to 10percent MeOH in DCM. The light yellow oil obtained was dissolved in DCM and filtered. The yellow solid obtained was dissolved in DCM washed with brine then with Na2CO32M. The organic phase was dried and evaporated to give 4-(4-methylpiperazine-1-carbonyl)aniline (3 g, 42percent yield). MS found for C12H17N3O as (M+H)+ 220.2.
Reference: [1] Patent: WO2016/196776, 2016, A2, . Location in patent: Paragraph 001074
  • 28
  • [ 111-24-0 ]
  • [ 150-13-0 ]
  • [ 22090-24-0 ]
Reference: [1] Chemische Berichte, 1907, vol. 40, p. 857
[2] Chemische Berichte, 1907, vol. 40, p. 857
  • 29
  • [ 150-13-0 ]
  • [ 50850-93-6 ]
Reference: [1] Yakugaku Zasshi, 1946, vol. 66, p. Ausg. B, S. 75[2] Chem.Abstr., 1952, p. 112
[3] European Journal of Medicinal Chemistry, 2013, vol. 61, p. 26 - 40
  • 30
  • [ 150-13-0 ]
  • [ 119-24-4 ]
Reference: [1] Journal of the American Chemical Society, 1948, vol. 70, p. 23
  • 31
  • [ 1004-75-7 ]
  • [ 5221-17-0 ]
  • [ 150-13-0 ]
  • [ 119-24-4 ]
Reference: [1] Journal of the American Chemical Society, 1948, vol. 70, p. 20,21,22
  • 32
  • [ 1004-75-7 ]
  • [ 3475-39-6 ]
  • [ 150-13-0 ]
  • [ 119-24-4 ]
Reference: [1] Chemische Berichte, 1949, vol. 82, p. 333,336
  • 33
  • [ 150-13-0 ]
  • [ 619-67-0 ]
Reference: [1] Chemische Berichte, 1953, vol. 86, p. 1073,1075
[2] Patent: US2010/216853, 2010, A1, . Location in patent: Page/Page column 19
[3] Chemistry and Biology, 2010, vol. 17, # 5, p. 471 - 482
[4] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 2, p. 813 - 826
  • 34
  • [ 150-13-0 ]
  • [ 64-19-7 ]
  • [ 556-08-1 ]
YieldReaction ConditionsOperation in experiment
91% With magnesia In neat (no solvent) at 70℃; for 0.583333 h; Green chemistry General procedure: In an oven dried round bottomed flask (50 mL) nano-MgO (5.0 molpercent) were added and then alky/aryl amines (5.0 mmol) and aromatic/aliphatic acid (5.0 mmol) was added. After that it was allowed to stir on a pre heated oil bath at 70 °C under aerobic condition till the required time (the progress of the reaction was judged by TLC). After the completion, the reaction mixture was brought to room temperature and ethyl acetate (3 × 10 mL) was added to it and then centrifuged at 3500 rpm to recover the nano catalyst. Having done this, the reaction mixture was washed with water and brine, dried over anhydrous Na2SO4, concentrated in a rotary evaporator and finally the crude product was charged to column chromatography (ethylacetate:hexane (3:7) as an eluent) for purification and wherever necessary the products were recrystallized from hot ethanol.
Reference: [1] Synthetic Communications, 2008, vol. 38, # 7, p. 1028 - 1035
[2] Applied Catalysis A: General, 2013, vol. 456, p. 118 - 125
[3] Green Chemistry, 2012, vol. 14, # 3, p. 847 - 854
[4] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2010, vol. 49, # 9, p. 1274 - 1281
[5] Synthetic Communications, 2008, vol. 38, # 17, p. 2929 - 2940
  • 35
  • [ 108-24-7 ]
  • [ 150-13-0 ]
  • [ 556-08-1 ]
YieldReaction ConditionsOperation in experiment
99%
Stage #1: at 20℃; for 5 h;
Stage #2: With hydrogenchloride In water
General procedure: Ac2O (5.7 mL, 60.3 mmol) was added to the solution of 4-amino-benzoic acid (1) (6.86 g, 50.0 mmol) in pyridine (25 mL). The reaction was stirred at room temperature for 5 h. The solvent was removed in vacuo and the residue dispersed in water (100 mL) and acidified to pH 2-3 with concentrated hydrochloric acid. The resulting precipitate was collected by filtration, washed with water (30 mL) and dried to give 4-acetamido-benzoic acid (3) as a pale yellow powder (7.80 g, 99percent).
99% at 20℃; for 5 h; Step 1: Ac20 (5.7 ml, 60.3 mmol) was added to the solution of 4-amino-benzoic acid(6.86 g, 50.0 mmol) in pyridine (25 ml). The reaction was stirred at room temperature for 5 h. The solvent was removed in vacuo, and the residue was dispersed in water (100 ml) and acidified to pH 2-3 with concentrated hydrochloric acid. The resulting precipitate was collected by filtration, washed with water (30 ml) and dried to give 4-acetamido-benzoic acid as a pale yellow powder (7.80 g, 99percent).
96% at 55℃; for 2.66667 h; 5mol of p-aminobenzoic acid was dissolved in 1.8L mass fraction of 85percent formic acid solution,Control the stirring speed 150rpm, adding 6.5mol of acetic anhydride,Raise the temperature of the solution to 55 ° C,Continue stirring 90min,Distillation under reduced pressure 60kPa 70min,The remaining solution was added 3L mass fraction of 20percent potassium chloride solution,Reduce the temperature of the solution to 15 ° C,Crystal precipitation,filter,With a mass fraction of 15percent sodium bromide solution was washed,The mass fraction of 95percent ether solution was recrystallized,Solid sodium hydroxide dehydration agent dehydration,The final productAcetamidobenzoic acid 859.20g, yield 96percent.
Reference: [1] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 18, p. 5352 - 5360
[2] Patent: WO2016/57779, 2016, A2, . Location in patent: Page/Page column 80
[3] Patent: CN106631858, 2017, A, . Location in patent: Paragraph 0006; 0010-0015
[4] Monatshefte fur Chemie, 2007, vol. 138, # 1, p. 95 - 99
[5] Journal of Organic Chemistry, 2012, vol. 77, # 21, p. 9553 - 9561
[6] Journal of Chemical Research, 2010, # 6, p. 354 - 357
[7] Mikrochemie, 1951, vol. 38, p. 358,365
[8] Organic Letters, 2005, vol. 7, # 22, p. 5087 - 5090
[9] Synthesis, 2006, # 19, p. 3316 - 3340
[10] Analytical Biochemistry, 2010, vol. 398, # 2, p. 150 - 160
[11] Journal of the American Society for Mass Spectrometry, 2011, vol. 22, # 9, p. 1515 - 1525
[12] Journal of Molecular Catalysis A: Chemical, 2012, vol. 357, p. 175 - 176
  • 36
  • [ 60-35-5 ]
  • [ 150-13-0 ]
  • [ 556-08-1 ]
YieldReaction ConditionsOperation in experiment
71% at 150℃; for 24 h; General procedure: In a typical procedure, a mixture of amine (1 mmol), amide (1 mmol) and 50 mg GO was taken in a round-bottom flask (50 mL) and stirred the mixture using a magnetic stirring bar under open air at 150 °C for 24 h. After the reaction was completed, ethyl acetate (5 mL) was added to the reaction mixture and the catalyst was filtered off. The filtered catalyst was further washed with ethyl acetate and the combined organic layer was evaporated to afford nearly pure product. The residue was further purified by passing through a silica gel columnand eluting with ethyl acetate petroleum ether mixture. All products were characterized by spectral data as well as melting points (for solid compounds).
Reference: [1] Tetrahedron Letters, 2018, vol. 59, # 10, p. 899 - 903
  • 37
  • [ 108-24-7 ]
  • [ 150-13-0 ]
  • [ 64-19-7 ]
  • [ 556-08-1 ]
YieldReaction ConditionsOperation in experiment
90% for 0.25 h; Reflux 4-aminobenzoic acid (10) (4 g, 29 mmol) was added to a mixture (1:1)of acetic acid and acetic anhydride (20 mL), stirred, and the reaction mixture was refluxed for 15 min.After the completion of the reaction, the mixture was poured into ice-cooled water and a solid residue was obtained after filtration. The crude was washed three times with 100 mL H2O to remove excessacid. The crude was recrystallized in MeOH, yielding (24) (90percent). IR (KBr): 3340 (NH); 2539 (CH); 1700and 1607 (C=O), cm1. 1H-NMR (400 MHz, DMSO-d6) δ ppm: 2.08 (s, 3H, CH3); 7.68 (d, 2H, C6H4);7.87 (d, 2H, C6H4); 10.24 (s, 1H, NH); 12.68 (s, 1H, COOH). Calculated analysis for C9H9NO3: C, 60.33;H, 5.06; N, 7.82. Found: C, 59.80; H, 4.90; N, 7.52.
Reference: [1] Molecules, 2017, vol. 22, # 11,
  • 38
  • [ 150-13-0 ]
  • [ 556-08-1 ]
YieldReaction ConditionsOperation in experiment
68% With sodium acetate In acetic acid EXAMPLE 4 STR8 4-Acetylaminobenzoic acid.
A mixture of 4-aminobenzoic acid (Aldrich, 50.0 g, 0.365 mol) and anhydrous sodium acetate (35.0 g, 0.427 mol) in glacial acetic acid (150 mL) was heated to reflux for 15 h.
The mixture was poured into cold water (1 L).
The precipitate was separated by filtration and washed several times with cold water.
The cake was dried in oven at 70° C. and recrystallized from 2:1 water:ethanol to give 43.0 g (68percent) of the title compound as off-white flakes, mp 258° C.
Analysis:
Calculated for C9 H9 NO3: C, 60.32; H, 5.06; N, 7.82 Found: C, 60.51; H, 5.14; N, 7.81
Reference: [1] Patent: US5602277, 1997, A,
  • 39
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  • [ 75-36-5 ]
  • [ 556-08-1 ]
Reference: [1] European Journal of Medicinal Chemistry, 1995, vol. 30, # 7-8, p. 561 - 568
[2] Journal of the Indian Chemical Society, 2012, vol. 89, # 2, p. 261 - 268
[3] Journal of the American Chemical Society, 1956, vol. 78, p. 2870
[4] Journal of Organic Chemistry, 2013, vol. 78, # 23, p. 11765 - 11771
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  • [ 150-13-0 ]
  • [ 507-09-5 ]
  • [ 556-08-1 ]
Reference: [1] Journal of Organic Chemistry, 2013, vol. 78, # 11, p. 5550 - 5555
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  • [ 150-13-0 ]
  • [ 556-08-1 ]
Reference: [1] Journal of Chemical Research - Part S, 2003, # 3, p. 121 - 123
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  • [ 150-13-0 ]
  • [ 556-08-1 ]
Reference: [1] Journal of Chemical Research, 2010, # 5, p. 288 - 295
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  • [ 830-03-5 ]
  • [ 14609-74-6 ]
  • [ 556-08-1 ]
Reference: [1] Journal of the American Chemical Society, 1993, vol. 115, # 20, p. 8980 - 8984
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Reference: [1] Food and Chemical Toxicology, 1998, vol. 36, # 9-10, p. 761 - 770
[2] Food and Chemical Toxicology, 1999, vol. 37, # 6, p. 655 - 661
[3] Drug Metabolism and Disposition, 2014, vol. 42, # 3, p. 377 - 383
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  • [ 556-08-1 ]
Reference: [1] Journal of the Indian Chemical Society, 2009, vol. 86, # 2, p. 179 - 182
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Reference: [1] Journal of Applied Toxicology, 1998, vol. 18, # 2, p. 117 - 123
[2] Journal of Applied Toxicology, 1998, vol. 18, # 3, p. 179 - 185
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Reference: [1] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 16, p. 239
[2] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 16, p. 237
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Reference: [1] Roczniki Chemii, 1958, vol. 32, p. 277,279, 280[2] Chem.Abstr., 1958, p. 19893
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Reference: [1] Patent: DE151725, , ,
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  • [ 20350-26-9 ]
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Reference: [1] Indian Journal of Chemistry, Section A: Inorganic, Bio-inorganic, Physical, Theoretical & Analytical Chemistry, 1990, vol. 29, # 8, p. 757 - 760
  • 52
  • [ 71-50-1 ]
  • [ 150-13-0 ]
  • [ 556-08-1 ]
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Reference: [1] Patent: DE151725, , ,
  • 54
  • [ 98-88-4 ]
  • [ 150-13-0 ]
  • [ 582-80-9 ]
YieldReaction ConditionsOperation in experiment
96.7%
Stage #1: With sodium carbonate In water
Stage #2: at 20℃;
PREPARATION EXAMPLE EX45 (0284) This example demonstrates the production of 4-benzoylamino benzoic acid having the following structure (0285) (0286) In a 1 L beaker with mechanical stirring, 27.4 g of 4-aminobenzoic acid (0.2 mol) was mixed in 300 mL of DI H2O. Then, 21.2 g (0.2 mol) of sodium carbonate was added until the pH value became 9.1 and all the 4-amino benzoic acid dissolved in the water. (0287) Then, 56.24 g (0.4 mol) of benzoyl chloride was added dropwise to the beaker at room temp. The reaction was stirred overnight. A solid formed during the reaction, and the pH stabilized at 4.0. The pH was further lowered to about 2 with hydrochloric acid. The product was collected by filtration and washed with hot water to remove excess benzoic acid. The solid product was dried in an oven at 110° C. and 44.21 g of the product was obtained (yield 96.7percent).
81% at 20℃; General procedure: Aromatic halides (1.0 equivalent) were added dropwise to the stirred solution of aminobenzoic acids (200 mg) in pyridine. Mixtures were stirred at room temperature for about all target derivatives except of benzyl based derivative. The pH of reaction mixtures was kept basic using pyridine. Progress of the reaction was monitored using TLC plates. Upon complete formation of target compounds, the desired products were filtered as white precipitates. For benzyl based derivatives reaction mixture was refluxed for more than 24 hours and product was obtained by evaporating the solvent under vacuum.
Reference: [1] Patent: US9200142, 2015, B2, . Location in patent: Page/Page column 50
[2] Acta Poloniae Pharmaceutica - Drug Research, 2018, vol. 75, # 2, p. 385 - 396
[3] Synthetic Communications, 2008, vol. 38, # 23, p. 4068 - 4075
[4] Chemische Berichte, 1910, vol. 43, p. 2578
[5] Journal of the American Chemical Society, 1956, vol. 78, p. 2570
[6] Bulletin de la Societe Chimique de France, 1951, p. 220,222
[7] Chemische Berichte, 1910, vol. 43, p. 2578
[8] Journal of Medicinal Chemistry, 1988, vol. 31, # 3, p. 590 - 603
[9] Journal of Organic Chemistry USSR (English Translation), 1981, vol. 17, # 11, p. 2139 - 2141[10] Zhurnal Organicheskoi Khimii, 1981, vol. 17, # 11, p. 2394 - 2396
[11] Russian Journal of Physical Chemistry A, 1996, vol. 70, # 12, p. 2004 - 2006
[12] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 4, p. 1739 - 1742
[13] Journal of Organic Chemistry, 2013, vol. 78, # 23, p. 11765 - 11771
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Reference: [1] Bulletin of the Chemical Society of Japan, 1988, vol. 61, # 1, p. 247 - 254
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  • [ 582-80-9 ]
Reference: [1] Journal of Chemical Research - Part S, 2003, # 3, p. 121 - 123
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  • [ 65-85-0 ]
  • [ 582-80-9 ]
Reference: [1] Journal of Chemical Research - Part S, 1998, # 5, p. 268 - 269
  • 60
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  • [ 150-13-0 ]
  • [ 582-80-9 ]
Reference: [1] Chemische Berichte, 1910, vol. 43, p. 2578
  • 61
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Reference: [1] Chemische Berichte, 1910, vol. 43, p. 2578
  • 62
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  • [ 2374-03-0 ]
Reference: [1] Journal of the Chemical Society, 1954, p. 980,984
  • 63
  • [ 110-91-8 ]
  • [ 150-13-0 ]
  • [ 51207-86-4 ]
YieldReaction ConditionsOperation in experiment
46.54% With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 0 - 20℃; for 12 h; Synthesis of compound 177.2. To a solution of 177.1 (0.5g, 3.72 mmol, 1.0 eq) in DMF (10 ml) were added morpholine (0.409g, 4.74mmol, 1.3eq), and HATU (2.8g, 7.29mmol, 2.0eq). Reaction mixture was cooled to 0°C. DIPEA(1.8ml, 32.8mmol, 3.0eq) was added at 0° C. Reaction mixture was stirred at room temperature for 12 h.Upon completion mixture was poured into water and product was extracted with EtOAC. Organic layers were combined and dried over Na2S04 and concentrated under reduced pressure to obtain crude which was purified using column chromatography to get pure 177.2 (0.350g, 46.54percent). MS (ES): m/z 206.2 [M+H]+.
Reference: [1] Patent: WO2015/131080, 2015, A1, . Location in patent: Paragraph 00953; 00954
[2] Journal of Medicinal Chemistry, 2012, vol. 55, # 11, p. 5536 - 5545
[3] European Journal of Medicinal Chemistry, 2017, vol. 131, p. 107 - 125
  • 64
  • [ 75-15-0 ]
  • [ 150-13-0 ]
  • [ 3855-95-6 ]
Reference: [1] Comptes Rendus des Seances de l'Academie des Sciences, Serie C: Sciences Chimiques, 1976, vol. 283, p. 319 - 321
  • 65
  • [ 869-24-9 ]
  • [ 150-13-0 ]
  • [ 59-46-1 ]
Reference: [1] Farmaco, Edizione Scientifica, 1956, vol. 11, p. 3,6
  • 66
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  • [ 100-37-8 ]
  • [ 59-46-1 ]
Reference: [1] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 8, p. 998
[2] Patent: DE180291, , ,
[3] Patent: DE180291, , ,
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  • [ 56-91-7 ]
Reference: [1] Journal of the Chemical Society, 1944, p. 678
  • 68
  • [ 150-13-0 ]
  • [ 71-36-3 ]
  • [ 94-25-7 ]
YieldReaction ConditionsOperation in experiment
76%
Stage #1: at 50 - 65℃; Inert atmosphere
Stage #2: With sodium hydrogencarbonate In water for 0.75 h;
General procedure: Acid 2 or 3 (1.5 g, 10.94 mmol) was dissolved in the corresponding alcohol (150 mL) at temperature about 50 °C. Then the solution was cooled to rt and thionyl chloride (15 mL, 206.77 mmol) was added. The reaction mixture was heated at 30 °C (MeOH), 50 °C (EtOH), or 65 °C (BuOH). The reaction course was monitored by TLC (toluene/EtOAc/formic acid 25:25:1). When the starting acid was consumed (4–10 h), water (20 mL) was added. The reaction mixture was stirred for 30 min and concentrated. The resulting residue was stirred with satd NaHCO3 (30 mL) for 45 min and extracted with EtOAc (3 × 30 mL). The organic extracts were pooled, dried (Na2SO4), and concentrated to obtain esters 5a,43 5b,32,44 5c,32 6a,45 6b,32,46,47 and 6c32 as an oil. All esters were used in the next step without purification. Analytical data (HRMS) and yields are in Table 1 (Supplementary data). 1H and 13C NMR data for 5f and 6f are in Table 2 (Supplementary data).#10;#10;
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[2] Carbohydrate Research, 2012, vol. 361, p. 1 - 6
[3] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 14, p. 1245
[4] Russian Journal of Organic Chemistry, 1995, vol. 31, # 11, p. 1529 - 1532[5] Zhurnal Organicheskoi Khimii, 1995, vol. 31, # 11, p. 1701 - 1704
[6] Chemical Biology and Drug Design, 2010, vol. 76, # 1, p. 25 - 33
[7] Journal of Polymer Science, Part A: Polymer Chemistry, 2013, vol. 51, # 13, p. 2759 - 2768
[8] Journal of Mass Spectrometry, 2016, vol. 51, # 3, p. 245 - 253
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[2] Synthetic Communications, 1989, vol. 19, # 9-10, p. 1787 - 1800
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YieldReaction ConditionsOperation in experiment
70% With N-Bromosuccinimide In N,N-dimethyl-formamide at 20℃; for 18 h; 4-Amino-benzoic acid (100 mmol) was dissolved in DMF (50 mL) and iV-bromosuccinimide(100 mmol) was added. Stirred at ambient temperature for 18h, the reaction mixture was then poured into water (100 mL). The product was removed by filtration, washed with water and dried in vacuo to give 4-amino-3-bromo-benzoic acid.Yield: 70percentIH NMR (D6-DMSO): 6.10 (s, 2H); 6.78 (d, IH); 7.63 (dd, IH); 7.89 (d, IH); 12.39 (br s,IH).
65% With N-Bromosuccinimide In DMF (N,N-dimethyl-formamide) at 20℃; for 18 h; 4-Amino-benzoic acid (100 mmol) was dissolved in DMF (50 mL) and N-bromo- succinimide (100 mmol) was added. Stirred at ambient temperature for 18h, the reaction mixture was then poured into water (100 mL). The product was removed by filtration, washed with water and dried in vacuo. Yield: 70percent 1H NMR (D6-DMSO) : 6.10 (s, 2H); 6.78 (d, 1H); 7.63 (dd, 1H); 7.89 (d, 1H) ; 12.39 (br s, 1H).4-Amino-benzoic acid (100 mmol) was dissolved in DMF (100 mL) and N-bromo succinimide (100 mmol) was added portion wise. The orange reaction mixture was stirred over night at ambient temperature, then poured into water. The product was collected by filtration and re-crystallized from MeOH. Yield: 65percent 1H NMR (D6-DMSO) : 6.09 (s, 2H); 6.81 (d, 1H); 7.13 (dd, 1H); 7.89 (d, 1H) ; 12.37 (br, 1H).
61% at 90℃; for 12 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.
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YieldReaction ConditionsOperation in experiment
96% With sodium hydroxide In 1,4-dioxane; water at 20℃; for 24 h; To a mixture of 4-aminobenzoic acid 1a (5.00g, 36.5mmol) in dioxane (70mL) and water (35mL) were added NaOH (1.46g, 36.5mmol) followed by di-tert-butyl dicarbonate (11.9g, 54.8mmol). The reaction mixture was stirred at room temperature for 24h. Solvent was removed by rotary evaporation, and 3N aqueous hydrochloric acid was added dropwise to the residue to adjust pH 3. A precipitate was obtained, collected, washed with water, and dried to provide 2a (8.28g, 96percent) as a solid.
94%
Stage #1: at 20℃; for 0.0833333 h; Inert atmosphere
Stage #2: for 24 h; Inert atmosphere
4-(tert-butoxycarbonylamino)benzoic acid
4-Aminobenzoic acid (1.00 g, 7.29 mmol) was dissolved in 1,4-dioxane (15 mL) and H2O (7 mL). Et3N (2.0 mL, 14.58 mmol) was added to the solution and the reaction mixture was stirred for 5 minutes at room temperature. Di-tert-butyl dicarbonate (3.18 g, 14.58 m mol) was then added to the solution in one portion and the reaction mixture was stirred for 24 hours.
Following removal of the solvent in vacuo, 3M HCl was added to the residue yielding a white precipitate.
The slurry was then filtered and washed with H2O before drying in under high vacuum.
Recrystallization from hot methanol yielded the titled compound as a colorless solid (1.63 g, 6.85 mmol, 94percent yield).
mp: 192-194° C.
1H NMR (400 MHz, DMSO) δ 9.73 (s, 1H-CO2H), 7.83 (d, 2H, J=8.9 Hz), 7.55 (d, 2H, J=8.9 Hz), 1.47 (s, 9H) ppm.
13C NMR (100 MHz, CDCl3) δ 167.1, 152.6, 143.8, 130.4, 124.0, 117.2, 79.7, 28.1 ppm.
HRMS (ESI): Calculated for C12H15NnaO4 (M+Na)+: 260.0893. found: 260.0897.
93% With triethylamine In 1,4-dioxane; water at 23℃; for 48 h; 4-N-tert-Butoxycarbonylaminobenzoic Acid (7). To a solution of 4-aminobenzoic acid 6 (520 mg, 3.8 mmol) in dioxane/H2O (2:1) (13 mL) was added triethylamine (0.79 mL, 5.7 mmol) and Boc2O(1.31 mL, 5.7 mmol) at 23° C. and it was allowed to stir for 48 h at same temperature. The solvent was removed under reduced pressure, and 3 M HCl (5 mL) was added dropwise to the residue at 0° C. A precipitate was obtained, collected, washed with water, and dried to give corresponding acid 7 (836 mg, 93percent) as slightly yellow solid, Rf=0.78 (CH2Cl2:Me-OH=9:1). 1H NMR (400 MHz, CDCl3): δ 9.25 (brs, 1H), 7.91 (d, 2H, J=8.7 Hz), 7.50 (d, 2H, J=8.7 Hz), 1.51 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 169.7, 154.8, 131.8, 125.3, 118.6, 118.5, 81.3, 28.6. MS (Ei): m/z 237.10 [M]+. HRMS (EI), calcd for C12H15NO4 237.1001, found [M]+ 237.1004.
91.3% With triethylamine In methanol at 20℃; for 16 h; More specifically, Compound B-2 was obtained as follows. 4-amino benzoic acid (B-1) (2.00g, 14.6mmol) was dissolved in 140mL of methanol. Then, (Boc)2O (6.7mL, 29.1 mmol) and triethylamine (3.06mL, 21.9mmol) were added therein and stirred for 16 hours at room temperature. The reaction solution was concentrated under reduced pressure, thereby obtaining a residue. Hexane and saturated sodium hydrogen carbonate aqueous solution (50mL) was added to the residue thereby performing extraction to obtain a water layer. The water layer was mixed with 10percent sodium citric acid aqueous solution until pH 4 was obtained, thereby precipitating out white solid. The thus obtained solid was dissolved in ethyl acetate and washed with water. The resultant was concentrated under reduced pressure. The residue from the concentration was recrystalized in ethyl acetate-hexane, thereby obtaining Compound B-2 (3.25g, Yield: 91.3percent) in the form of colorless crystals. 1H-NMR (270MHz, CD3OD) analysis of the thus obtained Compound B-2 showed that δ9.24 (1H, s, NH), 7.96 (2H, d, J = 8.9 Hz, aromatic), 7.55 (2H, d, J = 8.6 Hz, aromatic), 1.56 (9H, s, t-butyl). Moreover, ESI-MS (negative) analysis of Compound B-2 showed that m/z was 236.20 [(M-H)-]. These results confirmed the structure of Compound B-2. In addition, Compound B-2 was found to have a molecular mass of 237.25.
91% With triethylamine In 1,4-dioxane; water at 20℃; iert-Butyl 4-(qumolin-8-ylcarbamoyl)phenylcarbamate (45); A solution of 4-aminobenzoic acid (1.0 g, 7.3 mmol) and triethylamine (3.0 mL, 21.8 mmol) in l,4-dioxane H20 was treated di-iert-butyl carbonate (2.5 mL, 10.9 mmol) at room temperature overnight. After removing the solvent in vacuo, the residue was dissolved in EtOAc and washed with 1M HC1 solution. The organic phase was then extracted with 1M NaOH solution three times. The aqueous layer was then acidified by 1M HC1 solution and the precipitation was collected and washed with H20 to give 4-(fert-butoxycarbonylamino)benzoic acid (1.58 g, 91 percent). To a solution of 4-(rert-butoxycarbonylamino)benzoic acid (150 mg, 0.63 mmol) and pyridine (108 pL, 1.26 mmol) in C3/4C12 was added oxalyl chloride (57 pL, 0.63 mmol) at 0 °C for 15 min. 8-Aminoquiniline (90 mg, 0.63 mmol) was then added to the mixture. After kept at room temperature for lh, then reaction was quenched with MeOH and poured into H20 and extracted with CH2C12, dried over Na2S0 and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel (MeOH:CH2Cl2= 1:40 - 1:30) to give compound 45 (150 mg, 65 percent) NMR (300 MHz, CDC13) 610.72 (s, 1H), 8.95-8.87 (m, 2H), 8.21-8.04 (m, 4H), 7.63-7.47 (m, 4H), 6.82 (s, 1H), 1.55 (s, 9H); HR-MS Calcd. for (C2,H2iN303+H) 364.1661, found 364.1673.
90% With guanidine hydrochloride In ethanol at 35 - 40℃; for 2 h; General procedure: Amine (1 mmol) was added to a magnetically stirred solution of guanidine hydrochloride (15 molpercent) and di-tert-butyl dicarbonate (1.2 mmol) in EtOH (1 mL), at 35-40°C and stirred for appropriate time (Table 1). After completion of the reaction (followed by TLC or GC), EtOH was evaporated under vacuum and the residue either was washed with water to remove the catalyst or was dissolved in CH2Cl2 (or EtOAc) and filtered off to separate out the catalyst. Evaporation of the organic solvent (if used in work up) gives almost a pure product. In the cases of using an excess (Boc)2O the product was washed with petroleum ether or hexane to recover the residual (Boc)2O. If necessary, the product was further purified either by crystallization (hexane and dichloromethane, or diethyl ether and petroleum ether) or silica gel column chromatography using EtOAc-hexane (1: 6) as eluent.
89% With triethylamine In 1,4-dioxane; water at 20℃; for 24 h; Triethylamine (0.4 ml, 3 mmol) followed by di-tert-butyldicarbonate (0.6 g, 3 mmol) is added to a mixture of 4-aminobenzoic acid (0.2 g, 1.5 mmol) in dioxane (4 ml) and H2O (2 ml). The reaction mixture is stirred at room temperature for 24 h. The solvent is removed at reduced pressure, and the residue is acidified with 1N HCl. The precipitate obtained is washed with H2O, obtaining I as a white solid (0.4 g, 89percent). 1H NMR (300 MHz, DMSO-d6) δ 9.71 (s, 1H, COOH), 7.82 (d, J=8.7 Hz, H-2,6), 7.54 (d, J=9 Hz, H-3,5), 1.44 (s, 9H, 3CH3). 13C NMR (75 MHz, DMSO-d6) δ 167.4 (CO), 152.9 (CO), 144.1, 130.3 (2CHar), 124.4, 117.6 (2CHar), 80.0 (C(CH3)3), 28.4 (3CH3). HPLC gradient of 15-95percent CH3CN/H2O in 10 min, tr=4.25 min, m/z [M+H]+=237. Theoretical elemental analysis C12H15NO4: C, 60.75; H, 6.37; N, 5.90; experimental elemental analysis C, 60.84; H, 6.09; N, 5.95.
87% With sodium hydroxide In 1,4-dioxane; water at 0 - 20℃; To a stirred solution of 4-aminobenzoic acid 6a (5.00 g, 36.5 mmol) and sodium hydroxide (1.56 g, 39.3 mmol) in 1:1 water/dioxane (60 mL) at 0 °C was added di-tert-butyl dicarbonate (14.3 g, 65.4 mmol). The resulting mixture was stirred for 3 h, then warmed to room temperature and stirred overnight. The aqueous mixture was then washed with ethyl acetate (60 mL) before further ethyl acetate (60 mL) was added and the resulting mixture neutralised with 1 M aqueous KHSO4. The organic layer was separated, washed with water (60 mL), dried (MgSO4) and the solvent removed in vacuo to give the title product 73a (7.53 g, 87percent) as an off-white solid, which was used without further purification. Mp 186-187 °C [lit.8 Mp 191-192 °C]; Rf=0.70 (CH2Cl2/MeOH=9:1); δH (400 MHz, DMSO-d6) 1.17 (9H, s, C(CH3)3), 7.23 (2H, d, J=8.6 Hz, Ar-H), 7.53 (2H, d, J=8.6 Hz, Ar-H), 9.38 (1H, s, NH). Spectroscopic data were in agreement with literature values.8
86% at 100℃; for 0.2 h; Microwave irradiation; Green chemistry General procedure: Amine (1 mmol) and di-tert-butyl dicarbonate [(Boc)2O] (1.1 mmol) were placed in a microwave reaction vial. The LG microwave oven MG 555f was programmed to 300 W at 100 °C. The reaction was monitored using TLC. After the reaction, ice water was added to the reaction mixture which resulted in the precipitation of the product. The solid product was merely filtered off and washed with excess cold water. The product was pure enough for all practical purposes. For characterization purpose, it was further purified by column chromatography (Neutral Alumina as adsorbent, solvent system: Hexane: Ethyl acetate (7.5:2.5)).#10;
86%
Stage #1: With triethylamine In 1,4-dioxane; water at 20℃; for 0.0833333 h;
Stage #2: at 20℃; for 26 h;
General procedure: To a solution of 12a (2.0 g, 14.6 mmol) in 67percent 1.4-dioxane/water(48 mL) was added triethylamine (4.07 mL, 29.2 mmol) at room temperature and allowed to stir for 5 min. Di-tert-butyl decarbonate(6.37 mL, 29.2 mmol) was then added to the solution. After beingstirred for 26 h, the reaction mixture was concentrated and acidified with 2M hydrochronic acid to yield a white precipitate. The slurry wasthen filtered, washed with water and dried over in vacuo to afford 13a(2.94 g, 86percent) as a white solid.4-((tert-Butoxycarbonyl)amino)benzoic acid (13a). Yield: 86percent.1H NMR (300 MHz, CDCl3)δ 8.03 (2H, dt, J=8.8, 2.1 Hz), 7.46 (2H, dt,J=8.9, 2.0 Hz), 6.71 (1H, s, H-N), 1.54 (9H, s, tBu-O).
79% With sodium hydrogencarbonate In 1,4-dioxane; water at 0 - 20℃; for 22 h; Step-1: To a solution of 4-aminobenzoic acid (5.0 g, 36.44 mmol) in 1,4-dioxan/10percent aq. NaHCO3 soln (1:1, 20 mL) was added a cat. amount of TBAB (0.58 g, 1.82 mmol) and the reaction mixture was stirred at 0° C. To it was added BOC anhydride (11.91 g, 54.6 mmol) and the reaction was allowed to stir at rt for 22 h. The reaction mixture was then acidified with 10percent aq. citric acid soln. when 4N-Boc-aminobenzoic acid precipitated out as a white solid. It was filtered, washed with water (100 mL), dried to get 4N-Boc-aminobenzoic acid (6.8 g, 79percent) as a white solid, which was used for next step.
72%
Stage #1: With sodium hydroxide In 1,4-dioxane; water at 20℃;
Stage #2: With hydrogenchloride In water
Commercially available 4-amino benzoic acid (5 g, 36 mmol) was dissolved in 1 M sodium hydroxide solution (40 mL, 40 mmol) and 1,4 dioxane (30 mL). After the addition of di-tert-butyl dicarbonate (7.85 g, 36 mmol), the mixture was stirred at room temperature over the weekend. The dioxane was removed in vacuo and the residue was diluted with water (100 mL). Then concentrated hydrochloric acid (37percent) was added until pH3. The precipitate was collected by filtration, washed with water (100 mL) and air-dried to afford the title compound as a white solid (6.3 g, 72percent).
71% With sodium hydroxide In 1,4-dioxane; water at 0 - 20℃; for 24 h; To a solution of 4-aminobenzoic acid (ig, 7.29mmol) in a mixture of dioxane:water (2OmL:lOmL) was added sodium hydroxide (2M, 35mL). The mixture was stirred until complete dissolution and then it was added di-tert-butyl dicarbonate (3.18g, 14.S7mmol) at 0°C. The reaction mixture was stirred 24 hours at room temperature. The solvent was removed under reduced pressure and the crude was acidified with hydrogen chloride SN. The precipitate obtained was filtered and washed with water to obtain the title compound as a white solid (1 .23g, 71percent).LRMS (mlz): 238 (M+1)+
69.4% With triethylamine In 1,4-dioxane; water at 0 - 20℃; for 48 h; STEP-5:Synthesis of compound 10
Procedure:To a solution of 4-amino benzoic acid (50 g, 364.9 mmol) and TEA (66.35g, 656.9 mmol) in 1,4-dioxane: H20 (1000 mL) was added (Boc)20 (89.2 g, 401.3 mmol) at 0°C and warmed to rt stirred for 48h at rt. The reaction mixture was diluted with water (250mL), adjusted the reaction mixture to acidic (PH~5) using saturated citric acid solution, then extracted the aq acidic solution with ethyl acetate (1000 mL), separated the organic layer washed with brine solution (100 mL), dried over anhydrous Na2S04 and evaporated under the reduced pressure. The crude product was triturated with 500 mL of hexane, filtered and dried under vacuum to yield 60 g (69.4 percent) of compound 4b as a half white solid.TLC system: Methanol: CHC13(1: 9) Rf value: 0.6
70.6% With sodium hydroxide In 1,4-dioxane A.
N-BOC-4-aminobenzoic acid
4-amino-benzoic acid (10 g, 72.9 mmol) was placed into a mixture of dioxane (145.8 ml) and 0.5M NaOH (145.8 ml).
The solution was cooled to 0° C. and di-t-butyl dicarbonate (23.87 g, 109.5 mmol) was added.
The reaction mixture was allowed to warm to room temperature and stirred overnight.
The next day, the dioxane was removed, the residue was made acidic and extracted into ethyl acetate.
The ethyl acetate fractions were combined and washed with 1N HCl to remove any unreacted starting material.
The solution was dried over Na2 SO4 and the solvent was removed in vacuo.
The crude material was recrystallized from ethyl acetate/hexanes to yield 12.2 g (70.6percent) of pure product. mp 189-190° C.; 1 H NMR (CD3 OD) 1.52 (9H, s), 7.49 (2H, d, J=8.6 Hz), 7.91 (2H, d, J=8.6 Hz), 9.28 (1H, s); 13 C NMR (CD3 OD) 28.59, 81.29, 118.54, 125.30, 131.81, 145.70, 155.00, 169.80; anal. calc. for C12 H15 NO4, C: 60.76, H: 6.37, N: 5.90; found, C: 60.52, H: 6.43, N: 5.83; HRMS calc. for C12 H15 NO4, 237.0961, found, 237.1001.
70.6% With sodium hydroxide In 1,4-dioxane N-BOC-4-aminobenzoic acid
4-amino-benzoic acid (10 g, 72.9 mmol) was placed into a mixture of dioxane (145.8 ml) and 0.5M NaOH (145.8 ml).
The solution was cooled to 0° C. and di-t-butyl dicarbonate (23.87 g, 109.5 mmol) was added.
The reaction mixture was allowed to warm to room temperature and stirred overnight.
The next day, the dioxane was removed, the residue was made acidic and extracted into ethyl acetate.
The ethyl acetate fractions were combined and washed with 1N HCl to remove any unreacted starting material.
The solution was dried over Na2 SO4 and the solvent was removed in vacuo.
The crude material was recrystallized from ethyl acetate/hexanes to yield 12.2 g (70.6percent) of pure product. mp 189°-190° C.; 1 H NMR (CD3 OD) 1. 52 (9 H,s), 7.49 (2 H, d, J=8.6 Hz), 7.91 (2 H, d, J=8.6 Hz), 9.28 (1 H, s); 13 C NMR (CD3 OD) 28.59, 81.29, 118.54, 125.30, 131.81, 145.70, 155.00, 169.80; anal. calc. for C12 H15 NO4, C: 60.76, H: 6.37, N: 5.90; found, C: 60.52, H: 6.43, N: 5.83; HRMS calc. for C12 H15 NO4, 237.0961, found, 237.1001.

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[45] RSC Advances, 2014, vol. 4, # 76, p. 40444 - 40448
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Reference: [1] Synthetic Communications, 2001, vol. 31, # 21, p. 3273 - 3280
[2] Patent: US5534537, 1996, A,
[3] Journal of Medicinal Chemistry, 2016, vol. 59, # 22, p. 10299 - 10314
[4] Patent: US6639107, 2003, B1,
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  • [ 150-13-0 ]
  • [ 66493-39-8 ]
Reference: [1] European Journal of Medicinal Chemistry, 2013, vol. 63, p. 231 - 238
  • 84
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Reference: [1] Patent: US4507283, 1985, A,
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Reference: [1] Patent: US2012/128592, 2012, A1,
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  • [ 7151-76-0 ]
Reference: [1] Journal of Organic Chemistry, 2001, vol. 66, # 25, p. 8293 - 8296
[2] Synthetic Communications, 2004, vol. 34, # 20, p. 3807 - 3819
[3] Patent: US5081261, 1992, A,
  • 87
  • [ 150-13-0 ]
  • [ 100-36-7 ]
  • [ 51-06-9 ]
Reference: [1] Chemical Communications, 2015, vol. 51, # 96, p. 17132 - 17135
[2] Green Chemistry, 2018, vol. 20, # 2, p. 375 - 381
  • 88
  • [ 150-13-0 ]
  • [ 3337-66-4 ]
Reference: [1] American Chemical Journal, 1909, vol. 42, p. 457
  • 89
  • [ 80657-95-0 ]
  • [ 943-80-6 ]
  • [ 150-13-0 ]
  • [ 97279-80-6 ]
  • [ 97279-79-3 ]
Reference: [1] Journal of the American Chemical Society, 1985, vol. 107, # 17, p. 5008 - 5009
  • 90
  • [ 150-13-0 ]
  • [ 1776-53-0 ]
  • [ 3685-23-2 ]
YieldReaction ConditionsOperation in experiment
64.286 % ee With 5% active carbon-supported ruthenium; hydrogen; sodium hydroxide In water at 100℃; for 20 h; Autoclave p-Aminobenzoic acid (10.0 g, 0.07mol, leq.), 5 percent Ru/C (2,50 g) and 10percent NaOH (lOO.OmL) were mixed in autoclave. The mixture was stirred at 100°C under 15 bar of hydrogen. After 20h of stirring no Starting material was observed on TLC (DCM/MeOH/NH3 = 5/5/1, v/v/v, stain: ninhydrine). According to the NMR - full conversion and cis:trans ratio = 1 :4.6 . Reaction was stopped.
Reference: [1] European Journal of Medicinal Chemistry, 2001, vol. 36, # 3, p. 265 - 286
[2] Biochemische Zeitschrift, 1933, vol. 262, p. 462
[3] Journal of the American Chemical Society, 1938, vol. 60, p. 2341,2343
[4] Chemische Berichte, 1942, vol. 75, p. 425,428
[5] Chemische Berichte, 1943, vol. 76, p. 1019,1023
[6] Chemische Berichte, 1963, vol. 96, p. 2377 - 2386
[7] Journal of Medicinal Chemistry, 1993, vol. 36, # 8, p. 1100 - 1103
[8] Arzneimittel-Forschung/Drug Research, 1999, vol. 49, # 1, p. 6 - 12
[9] Synthetic Communications, 2002, vol. 32, # 13, p. 1985 - 1995
[10] Patent: WO2017/134212, 2017, A1, . Location in patent: Page/Page column 10
  • 91
  • [ 150-13-0 ]
  • [ 3685-23-2 ]
Reference: [1] Journal of Fluorine Chemistry, 1996, vol. 80, # 1, p. 35 - 40
  • 92
  • [ 150-13-0 ]
  • [ 51498-33-0 ]
Reference: [1] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 4, p. 1317
  • 93
  • [ 150-13-0 ]
  • [ 6406-74-2 ]
Reference: [1] Patent: CN105461659, 2016, A,
  • 94
  • [ 150-13-0 ]
  • [ 18144-47-3 ]
Reference: [1] Patent: US4730050, 1988, A,
[2] Patent: EP283563, 1991, B1,
[3] Angewandte Chemie - International Edition, 2013, vol. 52, # 38, p. 10084 - 10088[4] Angew. Chem., 2013, vol. 125, # 38, p. 10268 - 10272,5
[5] Patent: WO2015/179956, 2015, A1,
  • 95
  • [ 59247-47-1 ]
  • [ 18144-47-3 ]
  • [ 150-13-0 ]
Reference: [1] Organic Letters, 2002, vol. 4, # 26, p. 4689 - 4692
  • 96
  • [ 150-13-0 ]
  • [ 75-65-0 ]
  • [ 18144-47-3 ]
Reference: [1] Synthetic Communications, 2004, vol. 34, # 8, p. 1489 - 1497
[2] Patent: EP2947074, 2015, A1, . Location in patent: Paragraph 0042; 0043
  • 97
  • [ 506-59-2 ]
  • [ 150-13-0 ]
  • [ 6331-71-1 ]
YieldReaction ConditionsOperation in experiment
65%
Stage #1: With triethylamine In dichloromethane at 10℃; for 0.166667 h;
Stage #2: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃;
To a 500 ml three-mouth bottle by adding 200 ml of methylene chloride, will be under stirring 25.0g (0.18mol, 1 . 0eq) of the P-aminobenzoic acid in reaction adds the human, cooling to 10 °C the following, then adding dimethylamine hydrochloride 17.8g (0.21mol, 1 . 2eq), triethylamine 36.1g (0.36mol, 2 . 0eq), stirring 10 min later, is added in batches EDCI40.0g (0.21mol, 1 . 2eq), after stirring at room temperature for overnight. TLC detection reaction end, in the poured into a saturated sodium bicarbonate aqueous solution, ethyl acetate extraction, combined with the phase, wash once salt water, organic phase with sodium sulfate drying, filtering, turned to the raped drying Canada petroleum ether filtration, the white solid obtained product 19.0 g. Yield: 65.0percent, MP (°C) 151.0-153.0 °C,
Reference: [1] Patent: CN105461659, 2016, A, . Location in patent: Paragraph 0035; 0036; 0037; 0038
  • 98
  • [ 150-13-0 ]
  • [ 68-12-2 ]
  • [ 6331-71-1 ]
Reference: [1] RSC Advances, 2013, vol. 3, # 40, p. 18283 - 18287
[2] Inorganic Chemistry, 2017, vol. 56, # 17, p. 10596 - 10608
  • 99
  • [ 150-13-0 ]
  • [ 6331-71-1 ]
Reference: [1] Patent: US2011/280808, 2011, A1,
  • 100
  • [ 150-13-0 ]
  • [ 123-72-8 ]
  • [ 4740-24-3 ]
YieldReaction ConditionsOperation in experiment
88% With 2-picoline borane complex In methanol at 20℃; 4-(Butylamino)benzoic Acid (Compound 3)
Compound 2 (about 3 mmol) was dissolved in 15 mL of methanol with R-picoline-borane (1.1 mol equiv) and butanal (1.1 mol equiv).
The mixture was stoppered with a vent needle and stirred overnight at room temperature.
After 16-24 hours, solvent was removed in vacuo, 10 mL 1 M HCl was added to the flask, and the mixture was stirred at room temperature for an additional 30 minutes.
The pH was adjusted to neutral using NaHCO3, and the intermediate product was extracted with ethyl acetate (2*60 mL).
The organic layer was washed with brine (1*45 mL), dried with magnesium sulfate, filtered, removed in vacuo, and subsequently purified via column chromatography with 30percent ethyl acetate in hexane to yield compound 3 (88percent) as a white powder. 1H NMR (500 MHz) (CD3OD): δ 7.92 (d, J=8.8 Hz, 2H), 6.55 (d, J=8.8 Hz, 2H), 3.18 (t, J=7.2 Hz, 2H), 1.63 (m, 2H), 1.44 (m, 2H), 0.97 (t, J=7.4 Hz, 3H).
13C NMR (125 MHz) (CD3OD): δ 172.6, 153.1, 132.7, 117.3, 111.6, 43.4, 31.7, 20.5, 14.1.
Reference: [1] Journal of Organic Chemistry, 2007, vol. 72, # 25, p. 9815 - 9817
[2] Journal of Medicinal Chemistry, 2011, vol. 54, # 13, p. 4904 - 4912
[3] Patent: US2014/18422, 2014, A1, . Location in patent: Paragraph 0098
  • 101
  • [ 109-65-9 ]
  • [ 150-13-0 ]
  • [ 4740-24-3 ]
Reference: [1] Molecular Crystals and Liquid Crystals (1969-1991), 1984, vol. 103, p. 177 - 180
  • 102
  • [ 150-13-0 ]
  • [ 75-31-0 ]
  • [ 774-67-4 ]
YieldReaction ConditionsOperation in experiment
38.5% With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 0 - 20℃; for 2 h; Synthesis of compound 178.1. To a solution of 177.1 (0.6g, 4.37mmol, l .Oeq) in DMF (6 mL) were added isopropyl amine (0.73 mLl, 8.75 mmol, 2.0 eq), HATU (2.49 g,6.55 mmol,1.5 eq). Reaction mixture was cooled to 0 °C. DIPEA (1.4 ml, 8.74 mmol, 2.0 eq) was added at 0 °C. Reaction mixture was stirred at room temperature for 2 hours. Upon reaction completion, mixture was poured into water and product was extracted with EtOAC. Organic layers were combined, dried over sodium sulphate and concentrated under reduced pressure to obtain crude which was purified to get pure 178.1 (0.30 g, 38.5 percent). MS (ES): m/z 176.2 [M+H]+.
Reference: [1] Patent: WO2015/131080, 2015, A1, . Location in patent: Paragraph 00957; 00958
[2] Journal of Medicinal Chemistry, 2007, vol. 50, # 20, p. 4898 - 4908
  • 103
  • [ 150-13-0 ]
  • [ 7366-56-5 ]
Reference: [1] Journal of the American Chemical Society, 1934, vol. 56, p. 1408
[2] European Journal of Medicinal Chemistry, 2015, vol. 102, p. 387 - 397
[3] Research on Chemical Intermediates, 2017, vol. 43, # 11, p. 6299 - 6315
  • 104
  • [ 150-13-0 ]
  • [ 7366-56-5 ]
Reference: [1] Journal of Heterocyclic Chemistry, 2011, vol. 48, # 3, p. 529 - 532
  • 105
  • [ 150-13-0 ]
  • [ 532-55-8 ]
  • [ 7366-56-5 ]
Reference: [1] Bulletin of the Korean Chemical Society, 2012, vol. 33, # 1, p. 111 - 114
  • 106
  • [ 1147550-11-5 ]
  • [ 150-13-0 ]
  • [ 7366-56-5 ]
Reference: [1] Chemical and Pharmaceutical Bulletin, 1993, vol. 41, # 1, p. 117 - 125
[2] Medicinal Chemistry Research, 2011, vol. 20, # 6, p. 705 - 713
  • 107
  • [ 150-13-0 ]
  • [ 56961-25-2 ]
Reference: [1] Organic Process Research and Development, 1999, vol. 3, # 1, p. 10 - 16
[2] Farmaco, 1990, vol. 45, # 6, p. 617 - 630
[3] Justus Liebigs Annalen der Chemie, 1947, vol. 558, p. 10,30
[4] Gazzetta Chimica Italiana, 1955, vol. 85, p. 1405,1408
[5] Chemische Berichte, 1941, vol. 74, p. 807,821
  • 108
  • [ 150-13-0 ]
  • [ 619-45-4 ]
  • [ 56961-25-2 ]
Reference: [1] Patent: EP279698, 1990, A3,
  • 109
  • [ 150-13-0 ]
  • [ 56961-25-2 ]
  • [ 634-93-5 ]
Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1925, vol. 44, p. 1108[2] E., vol. 42, p. 176
  • 110
  • [ 7782-50-5 ]
  • [ 150-13-0 ]
  • [ 64-19-7 ]
  • [ 56961-25-2 ]
  • [ 634-93-5 ]
Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1925, vol. 44, p. 1108[2] E., vol. 42, p. 176
  • 111
  • [ 150-13-0 ]
  • [ 41727-48-4 ]
Reference: [1] Chemische Berichte, 1941, vol. 74, p. 807,821
  • 112
  • [ 59-30-3 ]
  • [ 4271-30-1 ]
  • [ 150-13-0 ]
  • [ 948-60-7 ]
  • [ 712-30-1 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 1, p. 67 - 71
  • 113
  • [ 150-13-0 ]
  • [ 2486-71-7 ]
Reference: [1] Organic Process Research and Development, 1999, vol. 3, # 3, p. 196 - 200
  • 114
  • [ 150-13-0 ]
  • [ 19718-49-1 ]
Reference: [1] Acta Chemica Scandinavica (1947-1973), 1968, vol. 22, p. 538 - 548
[2] European Journal of Medicinal Chemistry, 2019, p. 234 - 248
  • 115
  • [ 150-13-0 ]
  • [ 7149-03-3 ]
Reference: [1] Patent: WO2016/55947, 2016, A1,
  • 116
  • [ 150-13-0 ]
  • [ 24589-77-3 ]
Reference: [1] Journal of Heterocyclic Chemistry, 2002, vol. 39, # 1, p. 179 - 184
[2] Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy, 2009, vol. 71, # 5, p. 2030 - 2039
[3] Advanced Synthesis and Catalysis, 2014, vol. 356, # 7, p. 1571 - 1576
  • 117
  • [ 420-04-2 ]
  • [ 150-13-0 ]
  • [ 42823-46-1 ]
YieldReaction ConditionsOperation in experiment
53%
Stage #1: With hydrogenchloride In water at 20 - 100℃;
Stage #2: With potassium carbonate In water for 0.5 h;
To a stirred suspension of 4-aminobenzoic acid (50 g, 0.364 mole) in a mixture of concentrated HCl/water (46 mL/283 mL) was added cyanamide (35 g, 0.839 mole) at room temperature. The reaction mixture was heated at 100° C. for 6 hours. The reaction mixture was then allowed stand at room temperature (without stirring) for 16 hours. The precipitated solid was filtered and washed with water (100 mL). The solid was taken in aqueous K2CO3 solution (30 g in 400 mL of water) and stirred for 30 minutes. The solid was filtered, washed with water (2.x.50 mL) and dried under vacuum to provide Int-2A (35 g, 53percent) as white solid. 1H NMR (200 MHz, dmso-d6): δ 8.40-8.21 (bs, 2H), 7.93 (d, J=8.4 Hz, 2H), 7.18 (d, J=8.4 Hz, 2H). Mass (m/z): 180.1 [M++1]. To a stirred suspension of Int-2A (35 g, 195.5 mmol) in methanol (350 mL) was added acetyl chloride (35 mL, 490 mmol) dropwise at 0° C. under inert atmosphere over a period of 20 minutes. The reaction mixture was stirred at room temperature for 16 hours. After consumption of starting material (by thin layer chromatography (TLC)), the reaction mixture was neutralized using solid NaHCO3 at 0° C. Solid (excess NaHCO3) was filtered and filtrate was evaporated under vacuum to get crude compound. The crude compound was washed with EtOAc (100 mL) to afford pure Int-2B (35 g, 92percent) as white solid. 1H NMR (200 MHz, dmso-d6): δ 8.45-8.23 (bs, 2H), 7.98 (d, J=8.4 Hz, 2H), 7.34 (d, J=8.8 Hz, 2H), 3.83 (s, 3H). Mass (m/z): 194.1 [M++1].
Reference: [1] Patent: US2010/29638, 2010, A1, . Location in patent: Page/Page column 62
[2] European Journal of Medicinal Chemistry, 1996, vol. 31, # 11, p. 895 - 899
  • 118
  • [ 156-62-7 ]
  • [ 150-13-0 ]
  • [ 42823-46-1 ]
YieldReaction ConditionsOperation in experiment
45.8% With hydrogenchloride In water at 80℃; for 3 h; Cooling with ice 1) 100 mL of concentrated hydrochloric acid was added to 250 mL of a three-necked reaction flask and mechanically stirred.2) 10 g of p-aminobenzoic acid and 30 g of lime nitrogen were mixed uniformly.3) The mixture was slowly added to the reaction flask under ice-water bath and stirred into a mixture (insoluble).4) The reaction mixture was allowed to warm to 80 ° C for 3 hours.5) 20 g of lime nitrogen was slowly added to the reaction flask and incubated for 3 hours.6) Check whether the pH of the reaction solution is neutral.7) The reaction solution in the reaction flask was concentrated under reduced pressure at 80 ° C to dryness to give a dark brown solid.8) The solid was subjected to Soxhlet extraction for 3 to 4 hours using 200 mL of methyl tert-butyl ether.9) The methyl tert-butyl ether solution was added to dry anhydrous sodium sulfate.10) A solution of dried methyl tert-butyl ether was passed through the dry HCl gas at room temperature to precipitate a solid.11) The above-mentioned precipitated solid was carefully filtered and the precipitated solid was washed with an appropriate amount of methyl t-butyl ether to obtain a wet product.12) The wet product was poured into a vacuum oven at 45 ° C to give a solution of guanidinobenzoate (7.2 g, 45.8percent).
Reference: [1] Patent: CN106543041, 2017, A, . Location in patent: Paragraph 0023-0037
  • 119
  • [ 150-13-0 ]
  • [ 42823-46-1 ]
Reference: [1] Patent: US5086069, 1992, A,
  • 120
  • [ 150-13-0 ]
  • [ 555-06-6 ]
YieldReaction ConditionsOperation in experiment
90% With sodium hydroxide In water NaOH (1.2 g, 0.03 mol) was dissolved in 10 mL of distilled water and then 4.11 g (0.03 mol) p-aminobenzoic acid was added. After complete dissolution of the p-aminobenzoic acid, the water was evaporated and the yellow powder obtained was dried in oven at 80°C for 2 h. The resulting sodium salt (4.3 g, 90percent yield) was first analysed by IR spectroscopy.
Reference: [1] Organic and Biomolecular Chemistry, 2011, vol. 9, # 4, p. 1126 - 1132
[2] Supramolecular Chemistry, 2013, vol. 25, # 8, p. 490 - 502
  • 121
  • [ 150-13-0 ]
  • [ 108166-01-4 ]
Reference: [1] Patent: WO2013/144737, 2013, A2,
[2] Patent: US2015/57309, 2015, A1,
  • 122
  • [ 16867-03-1 ]
  • [ 150-13-0 ]
  • [ 95331-56-9 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 13, p. 1647 - 1650
[2] Journal of Enzyme Inhibition and Medicinal Chemistry, 2017, vol. 32, # 1, p. 513 - 521
[3] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 8, p. 2350 - 2353
  • 123
  • [ 150-13-0 ]
  • [ 70261-82-4 ]
Reference: [1] Patent: WO2016/196776, 2016, A2,
  • 124
  • [ 24424-99-5 ]
  • [ 150-13-0 ]
  • [ 144072-29-7 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 20, p. 5591 - 5593
  • 125
  • [ 150-13-0 ]
  • [ 102359-00-2 ]
Reference: [1] Medicinal Chemistry Research, 2018, vol. 27, # 1, p. 161 - 170
  • 126
  • [ 28920-43-6 ]
  • [ 150-13-0 ]
  • [ 185116-43-2 ]
YieldReaction ConditionsOperation in experiment
94% for 24 h; Inert atmosphere p-­Aminobenzoic acid (10 g, 73 mmol) was dissolved in dry NMP (50 ml) under an inert atmosphere followed by the dropwise addition of Fmoc-­Cl (18.9 g, 73 mmol) in dry NMP (50 ml). After 24 hrs, the reaction mixture was poured slowly into 400 ml water. The colorless precipitate was collected by filtration, washed with water and dried in vacuum at 120 ºC to give N‐Fmoc-­p-­amino benzoic acid (24.8 g, 94percent). mp: 215 ºC (dec.) 1H-­NMR: δ (300 MHz, DMSO-d6) 4.33 (t, 3J = 6.25 Hz, 1 H); 4.54 (d, 3J = 6.25 Hz, 2 H); 7.33-­7.45 (m, 4 H); 7.57 (d, 3J = 7.35 Hz, 2 H); 7.76 (d, 3J = 7.35 Hz, 2 H); 7.89 (m, 4 H), 10.08 (s, 1H); 12.69 (s, 1H). 13C-­NMR and DEPT: δ (300 MHz, DMSO-­d6) 46.61 (+); 65.83 (-­); 117.5 (+); 120.22 (+); 124.48; 125.14 (+); 127.17 (+); 127.74 (+); 130.48 (+); 140.86; 143.31; 143.74; 153.31; 167.03. IR ν (cm-­‐1): 3344, 2970, 2887, 2660, 2544, 1709, 1673, 1610, 1592, 1526, 1511, 1411, 1311, 1282, 1221, 1052, 850, 736. RP-­HPLC (min): 26.6 min. M (FD): m/z (percent) = 359.1 (100); 360.1 (17.4); calc.[C22H17NO4] = 359.1
Reference: [1] Tetrahedron Letters, 2013, vol. 54, # 8, p. 753 - 756
[2] Chemical Communications, 2013, vol. 49, # 40, p. 4555 - 4557
[3] Journal of Chemical Research, Miniprint, 1998, # 10, p. 2736 - 2753
[4] Chemical Communications, 2014, vol. 50, # 14, p. 1691 - 1693
  • 127
  • [ 82911-69-1 ]
  • [ 150-13-0 ]
  • [ 185116-43-2 ]
Reference: [1] European Journal of Organic Chemistry, 2008, # 9, p. 1582 - 1588
[2] Biological Chemistry, 2015, vol. 396, # 1, p. 45 - 52
  • 128
  • [ 150-13-0 ]
  • [ 73183-34-3 ]
  • [ 180516-87-4 ]
YieldReaction ConditionsOperation in experiment
74% With tert.-butylnitrite; eosin In acetonitrile at 20℃; for 2 h; Irradiation General procedure: tert-Butyl nitrite (155 mg, 1.1 mmol) wasadded drop wise to a mixture of bis(pinacolato)diborane (127 mg, 0.5 mmol),4-anisidine (61 mg, 0.5 mmol) and eosin Y (0.01 mmol) in acetonitrile (3 mL).The resulting mixture was stirred at room temperature under irradiation withblue LED for 2 h (TLC). This mixture after being diluted with ethyl acetate(5 mL) was ltered through celite and the ltrate was extracted with ethylacetate (3 10 mL). The extract was washed with brine, dried over anhydrousNa 2 SO 4 , and evaporated to leave the crude product which was puried bycolumn chromatography over silica gel with hexane–ethyl acetate (98:2) aseluent to furnish pure 2-(4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as a light yellow viscous liquid (3d, 208 mg, 88percent); IR (neat)2978, 2933, 2839, 2526, 2050, 1950, 1911, 1724, 1605, 1570 cm1;1H NMR(500 MHz, CDCl 3 ) d 1.33 (s, 12H), 7.82 (s, 3H), 6.89 (d, J = 8.0 Hz, 2H), 7.75 (d,J = 8.0 Hz, 2H);13C NMR (125 MHz, CDCl 3 ) d 24.9 (4C), 55.2, 83.6 (2C), 113.4(2C), 136.6 (2C), 162.3. The spectroscopic data is in full agreement with thosereported for an authentic sample.14This procedure was followed for all thereactions listed in Table 2. All of these products (3a,143b,143c,16a3d,143e,143f,8a3g,143h,143i,143j,8a3k,8a3l,8a3m,143n,8c3o,16b) are known compounds,and their spectroscopic data are in agreement with those previously reported.
Reference: [1] Synlett, 2012, vol. 23, # 9, p. 1394 - 1396
[2] Tetrahedron Letters, 2016, vol. 57, # 14, p. 1551 - 1554
[3] Journal of Organic Chemistry, 2013, vol. 78, # 5, p. 1923 - 1933
  • 129
  • [ 150-13-0 ]
  • [ 57260-71-6 ]
  • [ 350684-49-0 ]
YieldReaction ConditionsOperation in experiment
87% With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; butan-1-ol In DMF (N,N-dimethyl-formamide) at 20℃; for 22 h; To a solution of 4-aminobenzoic acid (411 mg, 3.00 mmol) in DMF (3.0 mL) at room temperature was added EDC (862 mg, 4.50 mmol), HOBt (608 mg, 4.50 mmol), triethylamine (606 mg, 0.835 mL, 6.00 mmol) and tert-butyl piperazinecarboxylate (671 mg, 3.60 mmol). The mixture was stirred for 22 h, and then 2 N aq. NaOH was added to adjust the PH>10. The mixture was extracted with ethyl acetate, and the organic layer was dried over MgSO4, concentrated. The residue was purified by silica gel column chromatograghy eluted with EtOAc:hexanes (50 to 90percent EtOAc) to give 4-(4-amino-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester (796 mg, 87percent) as a colorless oil. MS (ES+): m/z = 306.2
Reference: [1] Patent: WO2004/46120, 2004, A2, . Location in patent: Page 179
[2] Patent: WO2014/26242, 2014, A1, . Location in patent: Page/Page column 95
[3] Patent: WO2009/138438, 2009, A1, . Location in patent: Page/Page column 26
  • 130
  • [ 150-13-0 ]
  • [ 95-83-0 ]
  • [ 39861-21-7 ]
YieldReaction ConditionsOperation in experiment
64% at 0 - 130℃; General procedure: Eaton’s reagent (10 vol; wt/vol)) was added drop wise to a wellpulverised mixture of the corresponding 1,2-phenylenediamine(2a–e)/1,2-diaminopyridine (2f) (1 equiv) and 4-amino benzoicacid (1 equiv) at 0 C. The reaction mixture was then heated at130 C for 5–6 h (monitored by TLC and LCMS for completion).The reaction mixture was cooled and neutralised with 10percent sodiumhydroxide solution to pH of 6–7, the precipitate formed was filteredand washed repeatedly with water and dried. The solidobtained was recrystallized from ethanol to afford the desiredproduct in good yield as described below.
Reference: [1] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 21, p. 5970 - 5987
  • 131
  • [ 150-13-0 ]
  • [ 892242-64-7 ]
Reference: [1] Patent: US2015/218132, 2015, A1,
[2] Patent: WO2016/43975, 2016, A1,
[3] Patent: WO2017/27465, 2017, A1,
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4-Aminobenzoic acid potassium salt

Similarity: 0.98

Amines

Chemical Structure| 555-06-6

[ 555-06-6 ]

Sodium 4-aminobenzoate

Similarity: 0.98

Chemical Structure| 99-31-0

[ 99-31-0 ]

5-Aminoisophthalic acid

Similarity: 0.98

Chemical Structure| 99-05-8

[ 99-05-8 ]

3-Aminobenzoic acid

Similarity: 0.98

Chemical Structure| 2305-37-5

[ 2305-37-5 ]

3-Amino-5-methylbenzoic acid

Similarity: 0.98

Chemical Structure| 138-84-1

[ 138-84-1 ]

4-Aminobenzoic acid potassium salt

Similarity: 0.98

Carboxylic Acids

Chemical Structure| 2840-04-2

[ 2840-04-2 ]

5-Amino-2-methylbenzoic acid

Similarity: 0.98

Chemical Structure| 99-31-0

[ 99-31-0 ]

5-Aminoisophthalic acid

Similarity: 0.98

Chemical Structure| 99-05-8

[ 99-05-8 ]

3-Aminobenzoic acid

Similarity: 0.98

Chemical Structure| 2305-37-5

[ 2305-37-5 ]

3-Amino-5-methylbenzoic acid

Similarity: 0.98

Chemical Structure| 535-87-5

[ 535-87-5 ]

3,5-Diaminobenzoic acid

Similarity: 0.95