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[ CAS No. 99-76-3 ] {[proInfo.proName]}

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Chemical Structure| 99-76-3
Chemical Structure| 99-76-3
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Product Details of [ 99-76-3 ]

CAS No. :99-76-3 MDL No. :MFCD00002352
Formula : C8H8O3 Boiling Point : -
Linear Structure Formula :- InChI Key :LXCFILQKKLGQFO-UHFFFAOYSA-N
M.W : 152.15 Pubchem ID :7456
Synonyms :
Methyl 4-hydroxybenzoate;Methyl p-hydroxybenzoate;Septos;Maseptol;Methyl parahydroxybenzoate;Nipagin
Chemical Name :Methyl 4-hydroxybenzoate

Calculated chemistry of [ 99-76-3 ]

Physicochemical Properties

Num. heavy atoms : 11
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.12
Num. rotatable bonds : 2
Num. H-bond acceptors : 3.0
Num. H-bond donors : 1.0
Molar Refractivity : 39.74
TPSA : 46.53 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.84 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.63
Log Po/w (XLOGP3) : 1.96
Log Po/w (WLOGP) : 1.18
Log Po/w (MLOGP) : 1.32
Log Po/w (SILICOS-IT) : 1.21
Consensus Log Po/w : 1.46

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.29
Solubility : 0.781 mg/ml ; 0.00513 mol/l
Class : Soluble
Log S (Ali) : -2.56
Solubility : 0.417 mg/ml ; 0.00274 mol/l
Class : Soluble
Log S (SILICOS-IT) : -1.88
Solubility : 2.0 mg/ml ; 0.0132 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.02

Safety of [ 99-76-3 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P501-P261-P273-P272-P264-P280-P302+P352-P312-P362+P364-P333+P313 UN#:N/A
Hazard Statements:H303-H315-H317-H412 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 99-76-3 ]

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

  • Upstream synthesis route of [ 99-76-3 ]
  • Downstream synthetic route of [ 99-76-3 ]

[ 99-76-3 ] Synthesis Path-Upstream   1~56

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  • [ 40274-67-7 ]
Reference: [1] Journal of the American Chemical Society, 2018, vol. 140, # 24, p. 7647 - 7657
  • 2
  • [ 107-21-1 ]
  • [ 9003-39-8 ]
  • [ 94-13-3 ]
  • [ 99-76-3 ]
Reference: [1] Patent: US4728509, 1988, A,
  • 3
  • [ 51803-78-2 ]
  • [ 94-13-3 ]
  • [ 62-44-2 ]
  • [ 5422-92-4 ]
  • [ 99-76-3 ]
  • [ 99-96-7 ]
Reference: [1] Chemical Papers, 2010, vol. 64, # 3, p. 405 - 408
  • 4
  • [ 99-76-3 ]
  • [ 71-36-3 ]
  • [ 94-26-8 ]
Reference: [1] Journal of Organic Chemistry, 2008, vol. 73, # 13, p. 5147 - 5150
  • 5
  • [ 99-76-3 ]
  • [ 26845-47-6 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 23, p. 6309 - 6323
  • 6
  • [ 50-00-0 ]
  • [ 99-76-3 ]
  • [ 24589-99-9 ]
YieldReaction ConditionsOperation in experiment
58%
Stage #1: With triethylamine; magnesium chloride In acetonitrile for 24 h; Heating / reflux
Stage #2: With hydrogenchloride In water; acetonitrile
Methyl 4-hydroxybenzoate (3.00 g, 19.7 mmol) and magnesium chloride (2.81 g, 29.5 mmol) were stirred in 100 mL of acetonitrile. TEA (10.3 mL, 73.9 mmol) was added via syringe. Paraformaldehyde (12.0 g, 133 mmol) was added in a single portion and the reaction was heated to reflux. The reaction was stirred at reflux for 24 hours and cooled to rt. The reaction was quenched by the addition of approximately 100 mL of 1N HCl and poured into EtOAc. The layers were separated, and the organic layer was washed with brine. The combined aqueous layers were extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography. The clean fractions (by TLC) were concentrated in vacuo to afford 2.06 g (58percent) of the desired product. 1H NMR (400 MHz, DMSO-d6): δ 11.54 (s, 1H), 10.27 (s, 1H), 8.21 (d, J=2.4 Hz, 1H), 8.03 (dd, J=8.8, 2.4 Hz, 1H), 7.07 (d, J=8.8 Hz, 1H), 3.79 (s, 3H).
54% With triethylamine; magnesium chloride In acetonitrile at 20 - 82℃; for 19 h; A MIXTURE OF 4-HYDROXYMETHYLBENZOATE (64.8 G, 0.426 MOL, 1.0 EQ. ) AND ACETONITRILE (1 L) was stirred at room temperature while triethylamine (119 mL, 86.2 g, 0.852 mol, 2.0 EQ. ), MAGNESIUM CHLORIDE (60.8 G, 0.639 MOL, 1.5 EQ.) AND PARAFORMALDEHYDE (38.3 G, 1.28
MOL, 3.0 EQ. ) WERE ADDED SEQUENTIALLY. THE MIXTURE WAS HEATED AT 80 TO 82°C AND MONITORED by HPLC. Further quantities of magnesium chloride (20.3 g) and PARAFORMALDEHYDE (20 g) were added at 1.5 and 3.5 hours each. The mixture was heated a total of 19 hours and then concentrated. The residue was combined with ethyl acetate (500 mL) and 1M hydrochloric acid (1 L) added and the mixture stirred until a solution was obtained. The aqueous layer was separated and extracted with ethyl acetate (500 mL) and the combined organic phases were washed with 1M hydrochloric acid (500 ML) and then brine, dried (MGSO4) and concentrated. Purification of the product from the residue by filtration chromatography through silica gel (1000 mL), eluting first with DCM (3 x 1 L) and then 2percent MEOH/DCM (3 x 1 L), gave methyl 3-formyl-4-hydroxy-benzoate (41.2 g, 54percent) as a white solid. RP-HPLC (10-95S) RT = 3. 30 min ; 1H NMR (400 MHz, d6-DMSO): 8 11.54* (1H, s), 10.70 (1H, s), 8.22 (1H, d, J = 2.0 Hz), 8.03 (1H, dd, J = 8.0, 2.0 Hz), 7.08 (1H, dd, J = 8. 0,2. 0 Hz), 3.82 (3H, s); m/z (LCMS-ESI): Q-179 (M-H). [0211] A MIXTURE OF THE 3-FORMYL-4-HYDROXY-BENZOATE (41.2 G, 0.223 MOL, 1.0 EQ. ) AND N, N-
DIMETHYLFORMAMIDE (225 ML) WAS COOLED TO 0°C AND N-BROMOSUCCINIMIDE (39.6 G, 1.0 EQ. ) was added in a single portion to the mixture. The mixture was cooled for 10 minutes and then allowed to stir at room temperature for 30 minutes. The mixture was poured into water (1.8 L), upon which a white precipitate formed. The precipitate was collected and washed with water (-2 L). Drying the damp solid azeotropically with toluene gave 3-bromo-5- FORMYL-4-HYDROXY-BENZOIC acid methyl ester (52.2 g, 89percent) as an off-white solid. RP-HPLC (10-95S) RT = 4. 50 MIN.APOS;H NMR (400 MHz, d6-DMSO): 8 10. 12 (1H, s), 8.32 (1H, d, J = 2.0 Hz), 8.28 (1H, d, J = 2.0 Hz), 3.85 (3H, s). [0212] A mixture OF 3-BROMO-5-FORMYL-4-HYDROXY-BENZOIC acid methyl ester (26.0 g, 100 mmol, 1.0 eq) and N, N DIMETHYLFORMAMIDE (400 mL) was stirred at room temperature WHILE POTASSIUM CARBONATE (20.73 G, 150 MMOL, 1.5 EQ. ) AND THEN BENZYL BROMIDE (15 ML,
21.6 G, 125 MMOL, 1.25 EQ. ) IN A SINGLE PORTION WAS ADDED TO THE MIXTURE. THE REACTION mixture was stirred for 24 hours and then poured into water (1 L). The precipitate was collected by filtration and the filtrate extracted with diethyl ether (x 3). The precipitate was dissolved with the ether extracts and the solution was washed with water and then brine, dried (MGSO4) and concentrated. Purifiction of product from the residue via filtration chromatography on a silica gel plug (1 L), loaded in 25percent DCM/Hexane and eluted successively with 1 L portions of 25 percent DCM/Hexane (x 2), then 50 percent DCM/HEXANE (x 1) and finally 100percent DCM (x 3), gave methyl 4-BENZYLOXY-3-BROMO-5-FORMYL-BENZOATE (25.2 g, 72percent) as an off-white solid. RP-HPLC (10-95S) RT = 4.47 min ; 1H NMR (400 MHz, d6- DMSO): 8 10.00 (1H, s), 8.42 (1H, d, J = 2.0 Hz), 8.21 (1H, d, J = 2.0 Hz), 3.88 (3H, s); M/Z (LCMS-ESI): Q+ 371/373 (M+Na).
40% With triethylamine; magnesium chloride In tetrahydrofuran for 89 h; Reflux Parafomaldehyde (0.42 g, 13.5 mmol) was added to a mixture of the methyl 4-hydroxybenzoate (10 mmol), anhydrous MgCl2 (2.86 g, 30 mmol) and Et3N (5.3 ml, 37.5 mmol) in THF (50 mL) and the mixture was heated to reflux for 89 h. After the reaction mixture was cooled to r.t., the reaction was quenched with 10percent HCl aq. and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (hexane/ethyl acetate = 5 : 1) to afford methyl 3-formyl-4-hydroxybenzoate5. Yield 40percent, colorless solid. 1H NMR (300 MHz, CDCl3): δ 11.41 (s, 1H), 9.96 (s, 1H), 8.33 (d, J = 2.3 Hz, 1H), 8.20 (dd, J = 2.6, 4.9 Hz, 1H), 7.05 (d, J = 9.0 Hz, 1H), 3.94 (s, 3H).
35% With triethylamine; magnesium chloride In tetrahydrofuran for 24 h; Reflux Parafomaldehyde (2.1g, 67.5 mmol) was added to a mixture of methyl 4-hydroxybenzoate (10 mmol), anhydrous MgCl2 (1.43g, 15 mmol) and Et3N (5.3 ml, 37.5 mmol) in THF (50 mL) and the mixture heated to reflux for 24 h. After the reaction mixture was cooled to r.t. the reaction was quenched with 1 M HCl and the product was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (hexane/ethylacetate = 5 : 1) to afford methyl 3-formyl-4-hydroxybenzoate5. Yield 35 percent, colorless solid. 1H NMR (300 MHz, CDCl3) δ 11.39 (s, 1H), 9.95 (s, 1H), 8.32 (s, 1H), 8.18-8.21 (d, J = 9 Hz, 1H), 7.02-7.05 (d, J= 9 Hz, 1H).

Reference: [1] Organic Syntheses, 2005, vol. 82, p. 64 - 68
[2] Journal of the American Chemical Society, 2009, vol. 131, # 43, p. 15608 - 15609
[3] Patent: US2008/300242, 2008, A1, . Location in patent: Page/Page column 36
[4] Patent: WO2004/62661, 2004, A1, . Location in patent: Page/Page column 35-36
[5] Tetrahedron Letters, 2016, vol. 57, # 52, p. 5914 - 5918
[6] Tetrahedron Letters, 2016, vol. 57, # 22, p. 2448 - 2450
[7] Journal of Medicinal Chemistry, 2017, vol. 60, # 24, p. 10188 - 10204
[8] Acta Chemica Scandinavica, 1999, vol. 53, # 4, p. 258 - 262
[9] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 17, p. 2253 - 2256
[10] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 6, p. 1939 - 1943
[11] Journal of Natural Products, 2016, vol. 79, # 5, p. 1407 - 1414
[12] Patent: CN106674053, 2017, A, . Location in patent: Paragraph 0008; 0017
[13] Patent: CN106674044, 2017, A, . Location in patent: Paragraph 0018; 0019
  • 7
  • [ 100-97-0 ]
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YieldReaction ConditionsOperation in experiment
80% at 85℃; for 2 h; 50g of phosphorus pentoxide is added1L MeS03H,Heated to clarify (90 degrees Celsius),Down to 80 ° CSlow to join1- (4-hydroxyphenyl) ethanone (190 g, 1.25 mol)Hexamethylenetetramine(255 g, 1.82 mol)mixture,Feeding finished, 85 degrees Celsius reaction 2 hours, into the ice water to filter 180g products. Yield: 80.0percent
75% at 85 - 90℃; for 2 h; A.
Methyl 3-formyl-4-hydroxybenzoate
2 g of phosphoric anhydride and 40 ml of methanesulfonic acid are placed in a three-necked round-bottomed flask.
The mixture is heated to approximately 85° C., the heating is then stopped and an intimate mixture of 7.6 g (0.05 mol) of methyl 4-hydroxybenzoate and of 10.22 g (0.073 mol) of hexamethylenetetramine is added in fractions, at a temperature of 85° C. to 90° C.
Once the addition has been completed, the mixture is heated at 85°/90° C. for 2 hours and allowed to cool to 70° C., and then 60 ml of water are added.
The mixture is allowed to gradually return to ambient temperature, and then extracted with ethyl acetate.
It is then washed with water, an aqueous sodium bicarbonate solution, water, a potassium acid sulfate solution, again with water to neutrality and, finally, with a saturated sodium chloride solution.
In this way, 6.73 g of desired compound are obtained in the crude form.
Yield: 75percent
M.p.: 80-81° C.
31% at 20 - 100℃; for 3.5 h; Reference Example 4; Preparation of methyl 3-(4-ethylbenzyl)-4-hydroxybenzoate To a mixture of methyl 4-hydroxybenzoate (20 g, 131 mmol) and methanesulfonic acid (80 mL), hexamethylenetetramine (20 g, 144 mmol) was added in small portions at room temperature. After stirring at 100°C for 3.5 hours, concentrated hydrochloric acid (10 mL) and water (300 mL) were added. The reaction mixture was extracted twice with ethyl acetate and the organic phase was dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 80:20-65:35) to give methyl 3-formyl-4-hydroxy-benzoate (7.24 g, 31percent, mp 87.5-89.0°C) as a colorless powder. To a mixture of methyl 3-formyl-4-hydroxybenzoate (4.0 g, 22.2 mmol) and tetrahydrofuran (100 mL), 4-ethylphenyllithium [which had been prepared by stirring t-butyllithium (66 mmol) into a mixture of 1-bromo-4-ethylbenzene (12.3 g, 66 mmol) and tetrahydrofuran (200 mL) at -70°C for 30 minutes] was added at -70°C and stirred for 1 hour. After addition of saturated aqueous ammonium chloride, the reaction mixture was extracted with ethyl acetate, and the organic phase was washed with saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 65:35-50:50) to give methyl 3-[(4-ethylphenyl)hydroxymethyl]benzoate (2.92 g, 46 percent) as a light-yellow gum. The thus obtained methyl 3-[(4-ethylphenyl)hydroxymethyl]benzoate (2.88 g, 10.0 mmol), 10percent palladium carbon (200 mg), concentrated hydrochloric acid (0.5 mL) and methanol (15 mL) were mixed and stirred under a hydrogen atmosphere at room temperature for 14 hours. After filtration to remove the insoluble materials, the solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 80:20) to give methyl 3-(4-ethylbenzyl)-4-hydroxybenzoate (2.38 g, 88percent) as a colorless powder. mp 134.0-137.0°C
24.7% at 100℃; Inert atmosphere A solution of methyl p-hydroxybenzoate (13.7 g, 90.0 mmol) was dissolved in methanesulfonic acid (150 mL)Was added hexamethylenetetramine (HMTA) (25.2g, 180mmol),The resulting mixture was stirred at 100 deg.] C and nitrogen overnight.Cooled to room temperature,Concentrated hydrochloric acid (24 mL) and water (300 mL) were added,Stir at room temperature for 30 minutes.Extracted with ethyl acetate (100 mL x 2) and dried over anhydrous sodium sulfate.The solvent was distilled off under reduced pressure and the product was purified by column chromatography (200 to 300 mesh silica gel, ethyl acetate: petroleum ether = 1: 20)To a solution of methyl 3-formyl-4-hydroxybenzoate (1) (4.0 g).The yield was 24.7percent.

Reference: [1] Patent: CN102757444, 2016, B, . Location in patent: Paragraph 0073-0074
[2] Patent: US2004/10011, 2004, A1, . Location in patent: Page/Page column 18
[3] Chemical & Pharmaceutical Bulletin, 1983, vol. 31, # 5, p. 1751 - 1753
[4] Bioorganic and Medicinal Chemistry Letters, 1997, vol. 7, # 17, p. 2289 - 2294
[5] Synlett, 2005, # 20, p. 3131 - 3135
[6] Patent: EP1528066, 2005, A1, . Location in patent: Page/Page column 19-20
[7] Patent: CN106478619, 2017, A, . Location in patent: Paragraph 0083; 0084
[8] Patent: EP1489078, 2004, A1, . Location in patent: Page 149
[9] Patent: EP1666478, 2006, A1, . Location in patent: Page/Page column 64-65
[10] Russian Chemical Bulletin, 2014, vol. 63, # 9, p. 2026 - 2035[11] Izv. Akad. Nauk, Ser. Khim., 2014, # 9, p. 2026 - 2035,10
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YieldReaction ConditionsOperation in experiment
36% With sulfuric acid; trifluoroacetic acid In water (a)
Preparation of methyl 3-formyl-4-hydroxybenzoate:
Methyl-4-hydroxybenzoate (4.56 g, 30 mmol) was mixed with trifluoroacetic acid (24 ml) and hexamethyl-enetetramine (8.41 g, 60 mmol) (Duff reaction).
The reaction medium was heated to 80° C. for three hours and cooled to 0° C., followed by successive addition of 15 ml of 50percent sulfuric acid and 90 ml of demineralized water.
After stirring for one hour at room temperature, the medium was extracted with ethyl ether, washed with water, dried over magnesium sulfate and filtered, and the solvents were evaporated off.
The product was purified by passage through a column of silica and was eluted with dichloromethane.
After evaporation of the solvents, 1.92 g of a crystallized white solid are obtained, equivalent to a yield of 36percent.
Its properties were as follows:
White solid.
Mass: 1.92 g.
Yield: 36percent.
1 H NMR (CDCl3, 250 Mhz): 3.93 (3H, s), 7.04 (1H, Ar, d) 8.19 (1H, Ar, Dd), 8.32 (1H, Ar, d), 11.40 (1H, s), 9.96 (1H, s).
Reference: [1] Patent: US5849798, 1998, A,
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Reference: [1] Patent: US2014/161729, 2014, A1, . Location in patent: Page/Page column
[2] Synthetic Communications, 2014, vol. 44, # 24, p. 3552 - 3562
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  • [ 67-56-1 ]
  • [ 106-44-5 ]
  • [ 5355-17-9 ]
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  • [ 99-76-3 ]
  • [ 99-96-7 ]
Reference: [1] Advanced Synthesis and Catalysis, 2004, vol. 346, # 6, p. 633 - 638
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  • [ 6297-22-9 ]
Reference: [1] Australian Journal of Chemistry, 1963, vol. 16, p. 112 - 122
[2] Tetrahedron, 2006, vol. 62, # 42, p. 10000 - 10004
[3] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 23, p. 6309 - 6323
[4] Canadian Journal of Chemistry, 1982, vol. 60, p. 1996 - 2001
[5] Journal of Organic Chemistry, 1991, vol. 56, # 5, p. 1758 - 1763
[6] Bulletin de la Societe Chimique de France, 1969, p. 781 - 787
[7] Patent: US4755616, 1988, A,
[8] Patent: US4785132, 1988, A,
[9] Patent: US4755617, 1988, A,
[10] Patent: EP240362, 1991, B1,
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  • [ 99-76-3 ]
  • [ 30131-16-9 ]
Reference: [1] Journal of Medicinal Chemistry, 1988, vol. 31, # 1, p. 84 - 91
[2] New Journal of Chemistry, 2017, vol. 41, # 11, p. 4672 - 4679
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  • [ 57009-12-8 ]
Reference: [1] Patent: US2011/98271, 2011, A1,
[2] Patent: WO2011/51704, 2011, A1,
[3] Patent: WO2012/140419, 2012, A1,
[4] Patent: US2012/264731, 2012, A1,
[5] Journal of Medicinal Chemistry, 2015, vol. 58, # 2, p. 943 - 962
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  • [ 25978-74-9 ]
Reference: [1] Journal of Materials Chemistry C, 2016, vol. 4, # 19, p. 4269 - 4277
[2] Patent: US2012/184587, 2012, A1,
[3] Patent: WO2009/158393, 2009, A1,
  • 15
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  • [ 3337-59-5 ]
YieldReaction ConditionsOperation in experiment
65% With N-chloro-succinimide; titanium tetrachloride In dichloromethane at 20℃; for 5 h; To a mixture of 4-hydroxybenzoic acid (0.2 g; 1 .3 mmol) and N-chlorosuccinimide (0.37 g; 2.76 mmol) in dry CH2CI2 (15 ml) TiCI_4 (0.1 ml; 0.9 mmol) was added at room temperature and the resulting mixture was stirred for 5h. To it ice (-10 g) was added and the resulting slurry was stirred for 30 min at room temperature, diluted to 100 ml with EtOAc. The organic phase was washed with H20 (2 x 10 ml), brine (10 ml), dried over anhydrous MgS04, filtered and the filtrate evaporated to dryness, The residue was purified by FCC (Si02, CH2CI2) to give the title compound (0.19 g; 65percent), as colourless solid. 1 H-NMR (CDCI3) 7.96 s, 2H) ; 6.18 (s, 1 H): 3.89 (s, 3H).
Reference: [1] Patent: WO2014/63199, 2014, A1, . Location in patent: Page/Page column 89
[2] Gazzetta Chimica Italiana, 1899, vol. 29 I, p. 387,388
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  • [ 25458-44-0 ]
Reference: [1] Patent: WO2015/185142, 2015, A1,
[2] Bulletin of the Korean Chemical Society, 2017, vol. 38, # 1, p. 70 - 77
[3] Journal of Chemical Research, 2017, vol. 41, # 5, p. 296 - 300
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  • [ 99-76-3 ]
  • [ 29415-97-2 ]
YieldReaction ConditionsOperation in experiment
94% With bromine In dichloromethane at 0 - 20℃; Inert atmosphere Dibromine (0.185 L, 3614.92 mmol) was added dropwise a stirred suspension of methyl 4- hydroxybenzoate (500 g, 3286 mmol) in DCM (4 L) at 0°C under N2. The mixture was left to stir for 24 hrs at RT under N2 (need to trap HBr). A solution of sodiummetabisulfite (62.5 g, 329 mmol) in 2L of water was then added, while keeping the temperature around 15°C, followed by 500 mL of MeOH. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered and concentrated to dryness to afford methyl 3-bromo-4-hydroxybenzoate (710 g, 94percent) as a white solid. NMR Spectrum (CDC13): 3.89 (s, 3H), 5.95 (s, 1H), 7.05 (d, 1H), 7.92 (dd, 1H), 8.19 (d, 1H).
94% With bromine In dichloromethane at 0 - 20℃; for 36 h; Inert atmosphere Step 1Dibromine (0.185 L, 3614.92 mmol) was added dropwise a stirred suspension of methyl 4- hydroxybenzoate (500 g, 3286 mmol) in DCM (4 L) at 0°C under N2. The mixture was left to stir for 24 h at r.t. under N2. A solution of sodium metabisulfite (62.5 g, 329 mmol) in 2L of water was then added, while keeping the temperature around 15°C, followed by 500 mL of MeOH. The organic layer was washed with water, brine, dried over MgS04, filtered and concentrated to dryness to afford methyl 3-bromo-4-hydroxybenzoate (710 g,94percent) as a white solid. Proton NMR Spectrum (CDC13): 3.89 (s, 3H), 5.95 (s, 1H), 7.05 (d, 1H), 7.92 (dd, 1H), 8.19 (d, 1H).
81% With bromine In dichloromethane at 0 - 20℃; for 6 h; The compound (5 g, 32.9 mmol) obtained in was dissolved in dichloromethane (350 mL), and a solution obtained by dissolving Br2 (1.7 mL, 32.9 mmol) in dichloromethane (50 mL) was slowly added thereto at 0°C, and stirred at ambient temperature for 1 hour. The mixture was stirred at ambient temperature for another 5 hours, and water and a Na2S2O3 aqueous solution were added thereto. The mixture was extracted with dichloromethane, washed with saline, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified using silica gel chromatography to obtain the title compound (white solid, 6.18 g, and 81 percent yield). (0110) 1H NMR (300 MHz, CDCl3) δ 8.19 (d, 1H), 7.92 (dd, 1H), 7.05 (d, 1H), 5.93 (s, 1H), 3.89 (s, 3H).
78.2% With bromine; acetic acid In dichloromethane at 20 - 30℃; for 32 h; To methylparaben (21.42g, 0.148mol, 1eq) in dichloromethane (300ml) was added glacial acetic acid (90ml, 0.155mol, 1.1eq), stirring until completely dissolved, the ice bath to cool to 5 , to the reaction mixture was slowly added dropwise liquid bromine (8.0ml, 0.155mol, 1.1eq), added dropwise in the temperature of the process control 0 ~ 5 , addition was complete, 32h is reacted at room temperature, the reaction process to receive exhaust HBr.After completion of the reaction, the reaction mixture was added Na2S2O3The aqueous solution (35.2g, 264ml), stirred for 1h, then methanol (200ml), extracted several layers washed with water twice, washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo to give a white solid which was toluene (4:1) recrystallized to give a white solid 20.4 g, yield 78.2percent.
66% With bromine; acetic acid In tetrachloromethane at 20℃; for 8 h; To a stirred solution of methyl 4-hydroxybenzoate (10.0 g, 84.935 mmol) in CCU (30 mL) was added AcOH (20 mL, 2 VoI). Br2 (1.80 mL, 71.428 mmol) was then added slowly at 0 0C. After the addition was completed, the reaction mixture was brought to RT and stirred for 8 h. Reaction mixture was quenched with water (50 mL), neutralized with saturated NaHCC^ solution and extracted with EtOAc (2 x 150 mL). The combined organic layers were washed with water (2 x 50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to obtain crude product. The crude material was purified via silica gel column chromatography eluting with 5percent EtOAc- 95percent hexanes to afford methyl 3-bromo-4-hydroxybenzoate (10.0 g, 66 percent) as a brown solid.
65% With bromine In dichloromethane at -5 - 20℃; for 4.5 h; Inert atmosphere To a solution of 36 (3.15 g, 20.7 mmol) in DCM (230 mL) was added slowly at −5 °C a solution of bromine (1.1 mL, 21 mmol) in DCM (50 mL). The mixture was stirred for 4.5 h at room temperature. The reaction mixture was diluted with EtOAc and the organic layer was washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/EtOAc) to give 37 (3.10 g, 65percent) as colorless solid. The compound was used, without structure determination, directly for the next step.

Reference: [1] Tetrahedron, 2010, vol. 66, # 34, p. 6906 - 6911
[2] Helvetica Chimica Acta, 1989, vol. 72, p. 594 - 607
[3] Tetrahedron, 2003, vol. 59, # 46, p. 9173 - 9177
[4] Synlett, 2011, # 11, p. 1537 - 1542
[5] Tetrahedron, 2011, vol. 67, # 34, p. 6300 - 6307
[6] Patent: WO2011/51704, 2011, A1, . Location in patent: Page/Page column 99
[7] Patent: WO2012/140419, 2012, A1, . Location in patent: Page/Page column 84
[8] Journal of Medicinal Chemistry, 2015, vol. 58, # 2, p. 943 - 962
[9] Journal of the American Chemical Society, 2001, vol. 123, # 49, p. 12202 - 12206
[10] Journal of the American Chemical Society, 2000, vol. 122, # 51, p. 12907 - 12908
[11] Patent: EP2963027, 2016, A1, . Location in patent: Paragraph 0108; 0109; 0110
[12] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 10, p. 2621 - 2625
[13] Patent: CN103467296, 2016, B, . Location in patent: Paragraph 0027; 0028
[14] Tetrahedron Letters, 1996, vol. 37, # 14, p. 2395 - 2398
[15] Patent: WO2009/158393, 2009, A1, . Location in patent: Page/Page column 108
[16] European Journal of Medicinal Chemistry, 2013, vol. 61, p. 26 - 40
[17] Journal of the Society of Chemical Industry, London, 1945, vol. 64, p. 212,214
[18] Yakugaku Zasshi, 1930, vol. 50, p. 224,227; dtsch. Ref. S. 27[19] Chem.Abstr., 1930, p. 3513
[20] Patent: US2011/98271, 2011, A1, . Location in patent: Page/Page column 37
[21] Patent: US2012/184587, 2012, A1, . Location in patent: Page/Page column 19
[22] Patent: US2012/264731, 2012, A1, . Location in patent: Page/Page column 33
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  • [ 41727-47-3 ]
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Reference: [1] Journal of Organic Chemistry, 1997, vol. 62, p. 4504 - 4506
[2] Journal of Organic Chemistry, 1997, vol. 62, p. 4504 - 4506
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  • [ 4837-20-1 ]
Reference: [1] Journal of Medicinal Chemistry, 2018, vol. 61, # 8, p. 3541 - 3550
  • 20
  • [ 99-76-3 ]
  • [ 3964-57-6 ]
Reference: [1] Synlett, 2011, # 11, p. 1537 - 1542
[2] Gazzetta Chimica Italiana, 1899, vol. 29 I, p. 387,388
[3] Liebigs Annalen der Chemie, 1992, # 8, p. 789 - 798
[4] Organic Letters, 2013, vol. 15, # 9, p. 2128 - 2131
  • 21
  • [ 99-76-3 ]
  • [ 67-63-0 ]
  • [ 4191-73-5 ]
Reference: [1] Synthesis, 2003, # 16, p. 2479 - 2482
  • 22
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  • [ 99-76-3 ]
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Reference: [1] Archiv der Pharmazie (Weinheim, Germany), 1953, vol. 286, p. 324,327
  • 23
  • [ 99-76-3 ]
  • [ 3337-66-4 ]
YieldReaction ConditionsOperation in experiment
99% With sodium percarbonate; acetic acid; potassium iodide In water for 2.5 h; General procedure: Potassium iodide (2.1 equiv) was added with stirring to 50percent (v/v) aq. AcOH (1.0 M) containing a phenol derivative S5, and sodium percarbonate (SPC) (3.8 equiv) was slowly added over 30 min. The stirring was continued for 2.0 h at 50 ºC under a reflux condenser. After cooling, the reaction mixture was slowly poured into a vigorously stirred biphasic mixtures made of CH2Cl2 and saturated aqueous Na2SO3. Separated aqueous layer was extracted twice with CH2Cl2. The combined organic layer was washed with saturated aqueous NaCl. The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to provide 23.
99% With acetic acid; periodic acid; potassium iodide In water at 60℃; 30.4 g of methyl p-hydroxybenzoate was added to a 2 L single-necked flask, 1 L of acetic acid, 500 ml of water, 42.8 g of periodic acid and 66.4 g of potassium iodide were added and reacted at 60 ° C overnight.The TLC plate showed complete reaction, where the TLC developing agent was PE: EA = 5: 1.The reaction solution was cooled to room temperature, added to 2 L of water, filtered, and the solid was dried with an infrared lamp to obtain 80 g of a yellow solid, that is, a compound having a structure represented by the formula M2-1 in a yield of 99percent.
86.7%
Stage #1: With iodine; sodium acetate In methanol for 1.5 h; Reflux
Stage #2: With sodium hydroxide In methanol; water for 2.5 h; Reflux
To methanol (150 mL)Was added methyl p-hydroxybenzoate (10 g, 65.7 mmol)Sodium acetate hydrate (18.78 g, 138 mmol) andIodine (35 g, 137.9 mmol)The resulting mixture was stirred under reflux for 1.5 hours.A solution of sodium hydroxide (5.52 g, 138 mmol)Of water (200 mL)Then reflux for 2.5 hours.Cool to room temperature and add dilute sulfurSodium hydrogen acid solution to the color faded. The filter cake was washed with a small amount of water and then dissolved with ethyl acetate (200 mL), anhydrous sulfuric acidSodium dry. The solvent was evaporated under reduced pressure and the resulting product was recrystallized from petroleum ether / ethyl acetate,4-hydroxy-3,5-diiodobenzoate (11) (23 g). The yield was 86.7percent.
Reference: [1] Angewandte Chemie - International Edition, 2010, vol. 49, # 32, p. 5563 - 5566
[2] Tetrahedron, 2013, vol. 69, # 21, p. 4338 - 4352
[3] Patent: CN106632180, 2017, A, . Location in patent: Paragraph 0054-0058
[4] Patent: CN106478619, 2017, A, . Location in patent: Paragraph 0097; 0098
[5] Chemistry Letters, 1987, p. 2109 - 2112
[6] Biochemical Journal, 1951, vol. 48, p. 188,189
[7] Journal of Organic Chemistry, 2013, vol. 78, # 7, p. 2965 - 2983
  • 24
  • [ 99-76-3 ]
  • [ 3337-66-4 ]
  • [ 15126-06-4 ]
Reference: [1] Synthesis, 2005, # 6, p. 1019 - 1027
  • 25
  • [ 107-30-2 ]
  • [ 99-76-3 ]
  • [ 854422-96-1 ]
  • [ 3337-66-4 ]
  • [ 139884-19-8 ]
Reference: [1] Synthesis, 2005, # 6, p. 1019 - 1027
  • 26
  • [ 99-76-3 ]
  • [ 70829-28-6 ]
Reference: [1] Journal of Medicinal Chemistry, 2002, vol. 45, # 26, p. 5755 - 5775
[2] Bioorganic and medicinal chemistry letters, 2002, vol. 12, # 4, p. 663 - 666
  • 27
  • [ 99-76-3 ]
  • [ 15126-06-4 ]
YieldReaction ConditionsOperation in experiment
90.3% With Iodine monochloride In acetic acid at 20 - 65℃; for 21.6667 h; Methyl 4-hydroxybenzoate (35.5g, 0.233 mol) was dissolved in 200 mL of acetic acid, and the stirred mixture was warmed to 65°C. A solution of ICI (37.8 g, 0.233 mol) in 50 mL of AcOH was added dropwise over 40 min. The mixture was stirred at 65°C for 5 h and then stirred an additional 16 h at room temperature. The precipitated product was isolated via filtration, washed with water and dried under vacuum to give 27.5 g (99percent pure by LCMS and HNMR) ) of desired product. The mother liquors were evaporated and resulting residue was washed with water and dried under vacuum to give another 31 g (95percent pure by LCMS and NMR) of desired product. The combined yield of methyl 4-hydroxy-3-iodobenzoate was 58.5 g (90.3percent yield). LCMS m/z [00438] Methyl 3-cyano-4-hydroxybenzoate 3: 28 g (0.1 mol) of methyl 4-hydroxy-3- iodobenzoate 2 dissolved in 100 mL of DMF was treated with 9.92 g (0.11 mol) of CuCN and 0.49 g (0.11 mol) of NaCN. The system was flushed with nitrogen after which the mixture warmed to 105°C and stirred to 18 h. The mixture was allowed to cool to room temperature, and any precipitates were removed via filtration and washed with EtOAc. The combined organics were diluted with 200 mL of water and then extracted with EtOAc (2x200 mL). The combined layers were dried over sodium sulfate, filtered and evaporated to dryness. After drying under vacuum, the resulting 18 g (100percent yield) of 3 was characterized by LCMS and HNMR. [00439] Methyl 3-cyano-4-isopropoxybenzoate 4: Methyl 3-cyano-4-hydroxybenzoate 3 (18 g, 0.1 I mol) was dissolved in 100 mL of DMF and treated with 14.2 mL (0.15 mol) of 2- bromopropane and 41,9 g (0.3 mol) of anhydrous potassium carbonate. The system was flushed with nitrogen, and the mixture was heated to 90°C and stirred ovemight. After cooling to room temperature, the mixture was diluted with 200 mL of water and extracted with CH2CI2 (2x200 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated to dryness to give 20.5 g (99percent yield) of 4 as an oil that was characterized by LCMS and HNMR. [00440] Perfluorophenyl 3-cyano-4-isopropoxybenzoate 6: 20.5 g (0.093 mol) of methyl 3-cyano-4-isopropoxybenzoate 4 was dissolved in 200 mL of a 6: 4 mixture of methanol and water. To this was added 5.61 g (0.14 mol) of NaOH, and the mixture was stirred for 2 hours at room temperature. The solution was then filtered through a silica gel plug and the solvents removed under vacuum. The resulting solid was re-dissolved in 200 mL of CH2Cl2 and treated with 19.3 mL (0.11 mol) of perfluorophenyl 2,?,2-trifluoroacetate 5 and 19.5 mL (0.14 mol) of triethylamine. After stining overnight, the solution was filtered and any solids rinsed with CH2Cl2. The combined organic mixtures were run through a short silica gel column and then evaporated to dryness to give 29 g (83.5percent yield) of 6 which was characterized by LCMS and HNMR
70% With sodium hydroxide; sodium hypochlorite; sodium iodide In methanol; water at 0 - 3℃; for 1 h; Preparation of 2-dimethylaminomethyl-benzofuran-5-carboxylic acid N'- [2- (2-phenoxy- ethylsulfanyl)-acetyl]-hydrazide a) 4-Hydroxy-3-iodo-benzoic acid methyl ester Methyl 4-hydroxybenzoate (15.22 g, 100 mmol, 1 eq. ), sodium iodide (14.99 g, 100 mmol, 1 eq. ), and sodium hydroxide (4.0 g, 100 mmol, 1 eq. ) were dissolved in 250 mL of cold methanol and treated with sodium hypochlorite (5.25percent aqueous solution, 142 mL, 100 mmol, 1 eq. ) keeping the temperature below 3°C. When addition of the sodium hypochlorite was complete, the reaction was allowed to stir at 0°C. After 1 hour, 100 mL of 10percent sodium thiosulfate was added followed by pH adjustment of the reaction with 5 M aqueous HC1 until the pH was about 2. The resulting white solid was collected by filtration and washed with water leaving 4-hydroxy-3-iodo-benzoic acid methyl ester (19.52 g, 70percent yield).
65% With N-iodo-succinimide; titanium tetrachloride In dichloromethane at 0 - 20℃; for 1 h; To a suspension of methyl 4- hydroxybenzoate (1 .52 g; 10 mmol) and N-iodosuccinimide (2.25 g; 10 mmol) in anhydrous CH2CI2 (15 ml) TiCL4 (0.1 ml; 0.098 mmol) was added at 0°C with stirring. The resulting dark solution was stirred for 1 h at room temperature, then evaporated to dryness under reduced pressure. The residue was diluted to 80 ml with EtOAc, washed with H20, (3 x 10 ml), 5 percent Na2S203 (10 ml), brine, dried over anhydrous MgS04, filtered and filtrate evaporated to dryness. The residue was purified by FCC (Si02, CH2CI2) to give the title compound (1 .82 g, 65percent), as colorless solid. 1 H-NMR (CDCI3) 8.36 (d, 1 H, J = 2 Hz) ; 7.92 (dd, 1 H, J = 2, 8.5 Hz) ; 7.0 (d, 1 H, J = 8.5 Hz); 5.7 (s, 1 H); 3.27 (s, 3H).
55% at 20 - 65℃; for 24.67 h; Step 1:
Methyl 4-hydroxy-3-iodobenzoate (83).
To a stirred solution of methyl-4-hydroxybenzoate 82 (20 g, 132 mmol) in AcOH (100 mL) heated at 65° C. was added ICl (21.3 g, 7.0 mL, 132 mmol) in AcOH (25 mL) dropwise over 40 min.
The reaction mixture was further stirred at 65° C. for 8 h and then stirred an additional 16 h at room temperature.
The precipitated product was isolated via filtration, washed with water and dried under vacuum to give 83 (20 g, 55percent) as a white solid.
55% at 20 - 65℃; for 24.6 h; Step 1: Methyl 4-hydroxy-3-iodobenzoate (38). A stirred solution of methyl-4- hydroxybenzoate 37 (20 g, 132 mmol) in AcOH (100 mL) was heated to 65 °C. A solution of IC1 (21.3g, 7.0 mL, 132 mmol) in AcOH (25 mL) was added dropwise over 40 min. Stirring at 65 °C was continued for 8 h followed by stirring at RT for 16 h. The precipitated product was isolated via filtration, washed with water and dried under vacuum to give 38 (20 g, 55percent) as a white solid.

Reference: [1] Patent: WO2005/107762, 2005, A2, . Location in patent: Page/Page column 253-254
[2] Asian Journal of Chemistry, 2011, vol. 23, # 1, p. 41 - 43
[3] Patent: WO2005/40157, 2005, A2, . Location in patent: Page/Page column 59-60
[4] Patent: WO2014/63199, 2014, A1, . Location in patent: Page/Page column 74
[5] European Journal of Organic Chemistry, 2017, vol. 2017, # 22, p. 3234 - 3239
[6] Patent: US2010/249071, 2010, A1, . Location in patent: Page/Page column 60
[7] Patent: WO2017/4608, 2017, A1, . Location in patent: Paragraph 0156
[8] Journal of Medicinal Chemistry, 2002, vol. 45, # 26, p. 5755 - 5775
[9] Tetrahedron, 1995, vol. 51, # 31, p. 8555 - 8564
[10] Bioorganic and medicinal chemistry letters, 2002, vol. 12, # 4, p. 663 - 666
[11] Organic Letters, 2010, vol. 12, # 1, p. 192 - 195
[12] Journal of Organic Chemistry, 2010, vol. 75, # 12, p. 4131 - 4134
[13] Patent: WO2011/72488, 2011, A1, . Location in patent: Page/Page column 16; 23-24
[14] Patent: US2012/283297, 2012, A1, . Location in patent: Page/Page column 16-17
  • 28
  • [ 99-76-3 ]
  • [ 15126-06-4 ]
YieldReaction ConditionsOperation in experiment
82% With Iodine monochloride In chloroform; acetic acid Example 181
Methyl 4-hydroxy-3-iodobenzoate
To a 500 mL 3-necked flask equipped with a magnetic stirrer, a thermometer, and a condenser were added 10.0 g of methyl 4-hydroxybenzoate (Aldrich) and 30 mL of glacial acetic acid.
To this suspension was added a solution of 11.74 g of iodine monochloride in 30 mL of glacial acetic acid via addition funnel.
The solution was heated at 80°C for 1h, 45°C for 18h, and 90°C for an additional 4h.
Cooling to RT afforded a thick red-orange suspension which was transferred to a 1L separatory funnel and dissolved in 500 mL of CHCl3 by shaking vigorously.
The dark purple solution was washed with water (2x100 mL), saturated aqueous sodium thiosulfate (2x100 mL), and 5percent aqueous NaHCO3 (2x100 mL).
A light yellow solution resulted which was dried over MgSO4, and concentrated in vacuo to give a white solid.
This material was recystallized from water-MeOH to afford 14.92 g (82percent) of methyl 4-hydroxy-3-iodobenzoate as a white crystalline solid, m.p. 145-146°C.
Reference: [1] Patent: EP728018, 2003, B1,
  • 29
  • [ 99-76-3 ]
  • [ 3337-66-4 ]
  • [ 15126-06-4 ]
Reference: [1] Synthesis, 2005, # 6, p. 1019 - 1027
  • 30
  • [ 99-76-3 ]
  • [ 30762-06-2 ]
Reference: [1] Journal of Medicinal Chemistry, 1988, vol. 31, # 1, p. 84 - 91
[2] New Journal of Chemistry, 2017, vol. 41, # 11, p. 4672 - 4679
  • 31
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  • [ 99-76-3 ]
  • [ 30762-06-2 ]
Reference: [1] Patent: US2404691, 1944, ,
[2] Patent: US2415235, 1944, ,
  • 32
  • [ 99-76-3 ]
  • [ 403-01-0 ]
Reference: [1] Journal of the American Chemical Society, 1990, vol. 112, # 23, p. 8563 - 8575
[2] Journal of Fluorine Chemistry, 2003, vol. 120, # 2, p. 173 - 183
  • 33
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  • [ 403-01-0 ]
  • [ 170572-47-1 ]
Reference: [1] Journal of Fluorine Chemistry, 2000, vol. 102, # 1-2, p. 169 - 173
  • 34
  • [ 99-76-3 ]
  • [ 106047-17-0 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 1997, vol. 7, # 13, p. 1595 - 1600
  • 35
  • [ 2926-29-6 ]
  • [ 99-76-3 ]
  • [ 115933-50-1 ]
Reference: [1] Tetrahedron Letters, 1991, vol. 32, # 51, p. 7525 - 7528
  • 36
  • [ 93148-78-8 ]
  • [ 2008-75-5 ]
  • [ 99-76-3 ]
  • [ 84449-80-9 ]
YieldReaction ConditionsOperation in experiment
87.7% With potassium carbonate In Isopropyl acetate; water EXAMPLE 4
Preparation of 4-(2-piperidinoethoxy)benzoic acid hydrochloride
To a 250 mL 3 neck flask equipped with mechanical stirring, condenser, and heating apparatus consisting of a RTD probe hooked via a temperature controller to a heating mantle and under nitrogen atmosphere, the following were added: 7.61 g methyl 4-hydroxybenzoate, 11.05 g β-chloroethylpiperidine hydrochloride, 16.59 g powdered potassium carbonate, and 60 mL isopropyl acetate.
The mixture was heated slowly to 80° C.
After 5 hours, high performance liquid chromatography showed reaction to be 90percent complete.
After being left overnight at 80° C., reaction was complete.
The mixture was then cooled to ambient temperature, after which 60 mL deionized water was added.
The mixture was stirred until all solids dissolved.
The aqueous layer was separated and discarded.
The organic layer was extracted 3 times with 20 mL 4N hydrochloride.
The combined aliquots, containing 4-(2-piperidinoethoxy)benzoic acid, ethyl ester, were heated at reflux (92° C., 30 minutes required to reach reflux).
After 7.5 hours at reflux, the mixture was then distilled to remove approximately 10 mL water and cooled in an ice bath for 15 minutes.
The resulting crystalline 4-(2-piperidinoethoxy)benzoic acid, hydrochloride was removed by filtration and rinsed with acetone and dried. Yield=12.53 g of product (87.7percent of theoretical).
Reference: [1] Patent: US5631369, 1997, A,
  • 37
  • [ 2008-75-5 ]
  • [ 99-76-3 ]
  • [ 89407-97-6 ]
  • [ 84449-80-9 ]
YieldReaction ConditionsOperation in experiment
95.3% With potassium carbonate In Isopropyl acetate; water a.
To a 250 mL 3 neck flask, with mechanical stirring, condenser, and RTD probe were added the following under nitrogen atmosphere: 0.05 mol methyl 4-hydroxybenzoate, 0.06 mol β-chloroethylpiperidine hydrochloride, 16.59 grams of potassium carbonate, and 60 mL of isopropyl acetate.
The mixture was heated at 75° C.-80° C. for 20 hours, at which time all the methyl 4-hydroxybenzoate was consumed.
60 mL of water was then added to dissolve the potassium carbonate.
The organic and aqueous phases were then Separated and the aqueous layer discarded.
The organic layer was washed with a second 60 mL aliquot of water; the layers were separated and the aqueous layer discarded.
The reaction product, 4-(2-piperidinoethoxy)benzoic acid, methyl ester, was then extracted into 25 mL 8N hydrochloric acid.
The aqueous phase was separated and the organic phase discarded.
The aqueous phase was refluxed in a 50 mL round bottomed flask with magnetic stirring and condenser for 48 hours.
The mixture was then cooled to 0° C.-5° C. and the crystals removed by filtration.
The crystals were rinsed with acetone and dried overnight in 50° C. vacuum oven.
13.63 g of 4-(2-piperidinoethoxy)benzoic acid hydrochloride were recovered, which is 95.3percent of the theoretical yield.
Reference: [1] Patent: US5631369, 1997, A,
  • 38
  • [ 408538-22-7 ]
  • [ 1648-99-3 ]
  • [ 99-76-3 ]
  • [ 84449-80-9 ]
Reference: [1] Patent: US5852193, 1998, A,
[2] Patent: EP875507, 1998, A1,
  • 39
  • [ 408538-22-7 ]
  • [ 628-63-7 ]
  • [ 99-76-3 ]
  • [ 84449-80-9 ]
Reference: [1] Patent: US5852193, 1998, A,
[2] Patent: EP875507, 1998, A1,
  • 40
  • [ 2008-75-5 ]
  • [ 99-76-3 ]
  • [ 84449-80-9 ]
Reference: [1] Patent: US5631369, 1997, A,
  • 41
  • [ 628-63-7 ]
  • [ 2008-75-5 ]
  • [ 99-76-3 ]
  • [ 84449-80-9 ]
YieldReaction ConditionsOperation in experiment
12.61 g (83.6% theoretical) With hydrogenchloride; potassium carbonate In water EXAMPLE 5
Preparation of 4-(2-piperidinoethoxy)benzoic acid hydrochloride
To a 125 mL 3 neck flask with mechanical stirring, condenser, and a heating apparatus consisting of an RTD probe hooked via a temperature controller to a heating mantle, the following were added: 7.61 g methyl 4-hydroxybenzoate, 11.05 g β-chloroethylpiperidine hydrochloride, 16.59 g powdered potassium carbonate, and 60 mL amyl acetate.
The mixture was heated in an oil bath under nitrogen to 115° C.-120° C. for 4 hour. HPLC indicated that the reaction was complete.
The mixture was then cooled to ambient temperature and 40 mL of deionized water were added to dissolve solids.
The aqueous layer was separated and discarded and the water wash was repeated.
5 mL of the organic phase was removed as an analytical standard.
25 mL 8N hydrochloric acid was added to remaining organic phase to extract the intermediate.
The layers were separated and the acidified aqueous layers returned to the reaction flasks.
The organic phase was discarded.
The aqueous phase was heated to 95° C. until HPLC indicated complete hydrolysis of the ester (about 4 hours).
The mixtures were cooled to 0° C.-5° C. for 1 hour and filtered.
The filter cakes were rinsed with acetone (approx. 25 mL) and dried.
Yield 12.61 g (83.6percent theoretical).
Reference: [1] Patent: US5631369, 1997, A,
[2] Patent: US5631369, 1997, A,
  • 42
  • [ 408538-22-7 ]
  • [ 628-63-7 ]
  • [ 99-76-3 ]
  • [ 98-59-9 ]
  • [ 84449-80-9 ]
Reference: [1] Patent: US5852193, 1998, A,
[2] Patent: EP875507, 1998, A1,
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Reference: [1] European Journal of Medicinal Chemistry, 2007, vol. 42, # 1, p. 71 - 80
[2] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 23, p. 7250 - 7256
  • 44
  • [ 99-76-3 ]
  • [ 103177-37-3 ]
Reference: [1] Journal of Medicinal Chemistry, 1988, vol. 31, # 1, p. 84 - 91
  • 45
  • [ 99-76-3 ]
  • [ 83883-26-5 ]
Reference: [1] Reactive and Functional Polymers, 2010, vol. 70, # 4, p. 217 - 222
  • 46
  • [ 1765-93-1 ]
  • [ 99-76-3 ]
  • [ 129623-61-6 ]
YieldReaction ConditionsOperation in experiment
90%
Stage #1: With molecular sieve; copper diacetate; triethylamine In dichloromethane at 20℃; for 16 h;
Stage #2: With hydrogenchloride; lithium hydroxide In 1,4-dioxane; water at 20℃; for 18 h;
To a flask with 4-fluorophenyl boronic acid (2.1 g, 15 mmol), copper(II) acetate (1.4 g, 7.5 mmol), activated powdered molecular sieves (approximately 2 g), and methyl 4-hydroxybenzoate (1.2 g, 7.5 mmol) is added TEA (5.2 mL, 38 mmol) followed by CH2Cl2 (75 mL). The reaction is stirred for 16 hours at room temperature with air bubbling through it. The reaction mixture is diluted with CH2Cl2 and filtered through silica gel. The silica gel is washed with EtOAc-heptane. The solution is concentrated in vacuo and dissolved in dioxane (15 mL). To this solution is added aqueous LiOH (1N, 15 mL) and stirred for 18 hours at room temperature. To this reaction mixture is added aqueous HCl (IN) until acidic, having a pH less than 6. The resulting precipitate is collected by filtration and rinsed with water, and dried in vacuo to give 4-(4-fluorophenoxy)benzoic acid (1.6 g, 90percent). MS for C13H9FO3 (ESI) (M-H)- m/z 231.
Reference: [1] Patent: US2003/236279, 2003, A1, . Location in patent: Page 34
  • 47
  • [ 1765-93-1 ]
  • [ 99-76-3 ]
  • [ 129623-61-6 ]
YieldReaction ConditionsOperation in experiment
90% With hydrogenchloride; triethanolamine In 1,4-dioxane; dichloromethane Step F.
Preparation of 4-(4-fluorophenoxy)benzoic acid.
To a flask with 4-fluorophenyl boronic acid (2.1 g, 15 mmol), copper(II) acetate (1.4 g, 7.5 mmol), activated powdered molecular sieves (approximately 2 g), and methyl 4-hydroxybenzoate (1.2 g, 7.5 mmol) is added TEA (5.2 mL, 38 mmol) followed by CH2Cl2 (75 mL).
The reaction is stirred for 16 hours at room temperature with air bubbling through it.
The reaction mixture is diluted with CH2Cl2 and filtered through silica gel.
The silica gel is washed with EtOAc-heptane.
The solution is concentrated in vacuo and dissolved in dioxane (15 mL).
To this solution is added aqueous LiOH (1N, 15 mL) and stirred for 18 hours at room temperature.
To this reaction mixture is added aqueous HCl (1N) until acidic, having a pH less than 6.
The resulting precipitate is collected by filtration and rinsed with water, and dried in vacuo to give the desired product (1.6 g, 90percent). MS for C13H9FO3 (ESI) (M-H)- m/z 231.
Reference: [1] Patent: US2002/40035, 2002, A1,
  • 48
  • [ 99-76-3 ]
  • [ 129623-61-6 ]
YieldReaction ConditionsOperation in experiment
1.57g (90% from ester) With hydrogenchloride; LiOH; triethanolamine In 1,4-dioxane; 3-fluorobenzene boronic acid; dichloromethane Preparation of 4-(4-fluorophenoxy)benzoic acid
In a dry flask is placed 4-fluorobenzene boronic acid (2.11 g, 15.07 mmol, 2.00 equiv), methyl 4-hydroxybenzoate (1.15 g, 7.54 mmol, 1.00 equiv), copper(II) acetate (1.37 g, 7.54 mmol, 1.00 equiv), powdered molecular sieves (~2g), TEA (5.24 ml, 37.68 mmol, 5.00 equiv) and then CH2Cl2 (75 ml).
Dry air is bubbled through the reaction mixture for 18 h.
The mixture is diluted with CH2Cl2, loaded onto silica gel and the product-and biphenyl by-product eluted with EtOAc-heptane (1:9, 1L) through a pad of silica gel.
The desired fractions are collected, and the solvent is removed in vacuo to provide 1.9 g of the methyl ester that contained 92percent desired methyl ester by NMR (1.69 g, 91percent).
This methyl ester (1.84 g, 7.5 mmol, 1.0 equiv) is stirred with dioxane (15 ml) until dissolved. LiOH (1.0N(aq), 15.0 ml, 2.0 equiv) is then added, and the reaction mixture is stirred for 18 h. HCl (1.0N, aqueous) is slowly added until pH<4.
The resulting precipitate is collected by filtration, rinsed with water and dried at 60° C. in a vacuum oven for three days to provide 1.57g (90percent from ester) of a white solid. MS for C13H9FO3 (EI) m/z: 232 (M)+.
Reference: [1] Patent: US2003/69296, 2003, A1,
  • 49
  • [ 99-76-3 ]
  • [ 403-01-0 ]
  • [ 170572-47-1 ]
Reference: [1] Journal of Fluorine Chemistry, 2000, vol. 102, # 1-2, p. 169 - 173
  • 50
  • [ 99-76-3 ]
  • [ 156001-68-2 ]
Reference: [1] Journal of Medicinal Chemistry, 2002, vol. 45, # 26, p. 5755 - 5775
[2] Bioorganic and medicinal chemistry letters, 2002, vol. 12, # 4, p. 663 - 666
[3] Patent: WO2011/72488, 2011, A1,
[4] Patent: WO2017/4608, 2017, A1,
[5] Patent: CN106674053, 2017, A,
[6] Patent: CN106674044, 2017, A,
[7] Patent: US2012/184587, 2012, A1,
[8] Patent: WO2009/158393, 2009, A1,
  • 51
  • [ 99-76-3 ]
  • [ 258273-31-3 ]
Reference: [1] Patent: WO2011/72488, 2011, A1,
[2] Patent: US2012/283297, 2012, A1,
[3] Patent: WO2017/4608, 2017, A1,
[4] Patent: CN106674044, 2017, A,
  • 52
  • [ 99-76-3 ]
  • [ 499770-67-1 ]
Reference: [1] Journal of Organic Chemistry, 2013, vol. 78, # 7, p. 2965 - 2983
  • 53
  • [ 32779-36-5 ]
  • [ 99-76-3 ]
  • [ 926304-76-9 ]
YieldReaction ConditionsOperation in experiment
89%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.5 h;
Stage #2: at 130℃; for 0.5 h;
To a solution of methyl 4-hydroxybenzoate (260 mg, 1.71 mmol) in DMF (25 mL) at rt was added NaH (60percent, 75 mg, 1.9 mmol) and the mixture was stirred for 30 minutes. 5- Bromo-2-chloropyrimidine (300 mg, 1.55 mmol) was added and the mixture heated to 130 0C for 0.5 hours. Standard work-up and purification afforded 4-(5-bromo~pyrimidin-2-yloxy)- benzoic acid methyl ester (428 mg, 89percent).
Reference: [1] Patent: WO2007/22371, 2007, A2, . Location in patent: Page/Page column 65
  • 54
  • [ 99-76-3 ]
  • [ 934240-30-9 ]
Reference: [1] Patent: WO2011/29762, 2011, A1,
  • 55
  • [ 99-76-3 ]
  • [ 934240-31-0 ]
Reference: [1] Patent: WO2011/29762, 2011, A1,
  • 56
  • [ 99-76-3 ]
  • [ 946150-57-8 ]
Reference: [1] Organic Process Research and Development, 2016, vol. 20, # 10, p. 1812 - 1820
[2] Organic Process Research and Development, 2016, vol. 20, # 10, p. 1812 - 1820
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