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[ CAS No. 22717-55-1 ] {[proInfo.proName]}

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Chemical Structure| 22717-55-1
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Product Details of [ 22717-55-1 ]

CAS No. :22717-55-1 MDL No. :MFCD03407436
Formula : C8H7ClO3 Boiling Point : -
Linear Structure Formula :- InChI Key :QXDWMJQRXWLSDP-UHFFFAOYSA-N
M.W : 186.59 Pubchem ID :327085
Synonyms :

Calculated chemistry of [ 22717-55-1 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 12
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 : 44.75
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) : -4.86 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.97
Log Po/w (XLOGP3) : 3.63
Log Po/w (WLOGP) : 1.83
Log Po/w (MLOGP) : 1.91
Log Po/w (SILICOS-IT) : 1.85
Consensus Log Po/w : 2.24

Druglikeness

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

Water Solubility

Log S (ESOL) : -3.52
Solubility : 0.0561 mg/ml ; 0.000301 mol/l
Class : Soluble
Log S (Ali) : -4.3
Solubility : 0.00946 mg/ml ; 0.0000507 mol/l
Class : Moderately soluble
Log S (SILICOS-IT) : -2.52
Solubility : 0.569 mg/ml ; 0.00305 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 2.0
Synthetic accessibility : 1.42

Safety of [ 22717-55-1 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 22717-55-1 ]

* 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 [ 22717-55-1 ]
  • Downstream synthetic route of [ 22717-55-1 ]

[ 22717-55-1 ] Synthesis Path-Upstream   1~7

  • 1
  • [ 22717-55-1 ]
  • [ 3260-78-4 ]
Reference: [1] Patent: WO2018/122232, 2018, A1,
  • 2
  • [ 22717-55-1 ]
  • [ 16263-54-0 ]
Reference: [1] Journal of Medicinal Chemistry, 1986, vol. 29, # 3, p. 359 - 369
[2] Patent: EP2322520, 2011, A1,
[3] Patent: JP5714152, 2015, B2,
  • 3
  • [ 5106-98-9 ]
  • [ 74-88-4 ]
  • [ 22717-55-1 ]
YieldReaction ConditionsOperation in experiment
92% With caesium carbonate In N,N-dimethyl-formamide at 20℃; Step-I: Methyl 4-chloro-2-hydroxy-benzoate (VII-l-I): To a solution of 4-chlorosalicylic acid (75 g, 435.6 mmol) in anhydrous DMF (871 mL) was added Cs2C03 (70.7 g, 217.8 mmol) and Mel (27.5 mL, 439.9 mmol) sequentially. The reaction mixture was stirred at room temperature overnight. Ice cold water (3 L) was added to the reaction mixture and the precipitated solid was filtered and dried to provide VII- 1 -I (75 g, 92percent yield).
92% With caesium carbonate In N,N-dimethyl-formamide at 20℃; Step-I:
Methyl 4-chloro-2-hydroxy-benzoate (VII-1-I)
To a solution of 4-chlorosalicylic acid (75 g, 435.6 mmol) in anhydrous DMF (871 mL) was added Cs2CO3 (70.7 g, 217.8 mmol) and MeI (27.5 mL, 439.9 mmol) sequentially.
The reaction mixture was stirred at room temperature overnight.
Ice cold water (3 L) was added to the reaction mixture and the precipitated solid was filtered and dried to provide VII-1-I (75 g, 92percent yield).
92% With caesium carbonate In N,N-dimethyl-formamide at 20℃; Step-I: Methyl 4-chloro-2-hydroxy-benzoate (VII-1-I): To a solution of 4-chlorosalicylic acid (75 g, 435.6 mmol) in anhydrous DMF (871 mL) was added Cs2CO3 (70.7 g, 217.8 mmol) and MeI (27.5 mL, 439.9 mmol) sequentially. The reaction mixture was stirred at room temperature overnight. Ice cold water (3 L) was added to the reaction mixture and the precipitated solid was filtered and dried to provide VII-1-I (75 g, 92percent yield).
64.93% With caesium carbonate In N,N-dimethyl-formamide at 20℃; To a stirred solution of 4-chloro-2-hydroxybenzoic acid (5.0 g, 28.968 mmol, 1.0 eq)in DMF (60 mL) was added Cs2C03 (4.719 g, 14.484 mmol, 0.5 eq) and methyl iodide (4.52g, 31.864 mmol, 1.1 eq). The reaction mixture was stirred at room temperature for overnight.After completion of the reaction (monitored by TLC), the reaction mixture was diluted withwater (600 mL) and extracted with ethyl acetate (2xl00 mL). The combined organic extracts25 were washed with water (2x200 mL), dried over Na2S04, filtered and evaporated underreduced pressure to obtain the title compound (3.5 g, yield: 64.93percent) as a liquid. 1H NMR(300 MHz, CDCh): 8 ppm 10.86 (s, IH), 7.77 (d, J = 8.7 Hz, IH), 7.01 (d, J = 2.1 Hz, IH),6.87 (dd, J = 8.7, 2.1 Hz, IH), 3.96 (s, 3H).

Reference: [1] Patent: WO2013/157022, 2013, A1, . Location in patent: Page/Page column 42-43
[2] Patent: US2015/64196, 2015, A1, . Location in patent: Paragraph 0128
[3] Patent: EP3042903, 2016, A1, . Location in patent: Paragraph 0115; 0116
[4] Patent: WO2018/29604, 2018, A1, . Location in patent: Page/Page column 53
[5] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 2, p. 334 - 343
[6] Patent: KR2015/31892, 2015, A, . Location in patent: Paragraph 0268-0271
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  • [ 5106-98-9 ]
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YieldReaction ConditionsOperation in experiment
88.6% With sulfuric acid In methanol a.
Preparation of methyl 4-chloro-2-hydroxybenzoate (2f)
A mixture of 4-chloro-2-hydroxybenzoic acid (200 g, 1.16 mol) and 40 ml conc. sulfuric acid in 400 ml of methanol was heated under reflux for 20 1/2 hours.
The solvent was evaporated under reduced pressure, the residue poured into aqueous saturated Na2 CO3, and then extracted with ethyl ether (3*500 ml).
The combined organic layers were dried over anhydrous Na2 SO4, and evaporated to give 2f (191.6 g, 88.6percent yield) as an oil.
This was used for the next reaction without purification. IR (neat) 3150 (OH), 1728 (C=0), and 1678 (C=0) cm-1. NMR (CDCl3) δ 10.27 (br s, 1H, OH), 7.47 (d, 1H, JBC =8 Hz, HC), 6.80 (d, 1H, JAB =2 Hz, HA), 6.63 (d of d, 1H, HB), and 3.85 (s, 3H, CH3).
88.6% With sulfuric acid In methanol a.
Preparation of methyl 4-chloro-2-hydroxybenzoate (2f)
A mixture of 4-chloro-2-hydroxybenzoic acid (200 g, 1.16 mol) and 40 ml conc. sulfuric acid in 400 ml of methanol was heated under reflux for 20 1/2 hours.
The solvent was evaporated under reduced pressure, the residue poured into aqueous saturated Na2CO3, and then extracted with ethyl ether (3 x 500 ml).
The combined organic layers were dried over anhydrous Na2SO4, and evaporated to give 2f (191.6 g, 88.6percent yield) as an oil.
This was used for the next reaction without purification. IR (neat) 3150 (OH), 1728 (C=0), and 1678 (C=0) cmmin1. NMR (CDCl3) δ 10.27 (br s, 1H, OH), 7.47 (d, 1H, JBC=8 Hz, HC), 6.80 (d, 1H, JAB=2 Hz, HA), 6.63 (d of d, 1H, HB), and 3.85 (s, 3H, CH3).
Reference: [1] Patent: US4888353, 1989, A,
[2] Patent: EP234872, 1991, B1,
[3] Patent: US6313310, 2001, B1,
[4] Patent: US5484763, 1996, A,
[5] Patent: US4420476, 1983, A,
[6] Patent: EP3404033, 2018, A1,
  • 5
  • [ 67-56-1 ]
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YieldReaction ConditionsOperation in experiment
98% for 18 h; Inert atmosphere; Reflux General procedure: Method A: The corresponding carboxylic acid (28.96 mmol) wasdissolved in MeOH (60 mL) and H2SO4 (98percent, 2 mL) was addeddropwise to the solution. The reaction mixture was heated under reflux for 18hours, subsequently it was cooled to 25 C and the solvent was removed undervacuum. The residue was diluted with water (50 mL), thereafter K2CO3was added until pH = 5-6, and the aqueous solution wasextracted with DCM (3 x 30 mL). Finally, the combined organic phases were driedover Na2SO4 and concentrated under vacuum to afford thedesired compound with enough purity to be usedin the next reaction without further purification.
95% for 3 h; Reflux Step 1. Methyl 4-chloro-2-hydroxybenzoateTo a solution of 4-chloro-2-hydroxybenzoic acid (20 g, 115.90 mmol) in methanol (500 was added thionyl chloride (26 mL). After refluxing for 3 h, the reaction mixture was concentrated under vacuum, dissolved in petroleum ether (300 mL) and filtered to give methyl 4-chloro-2-hydroxybenzoate as a white solid (21 g, 95percent).'H-NMR (300 MHz, CDC13) δ 10.88 (s, 1H), 7.77 (d, / = 8.4 Hz, 1H), 7.02 (d, J = 2.1 Hz, 1H), 6.86 - 6.90 (m, 1H), 3.97 (s, 3H)
88% for 17 h; Heating / reflux Step A: 4-Chlorosalicylic acid (34.51 g, 0.2 mol) (Aldrich) was suspended in a solution of methanol (100 mL) and concentrated sulfuric acid (8 mL). The mixture was heated at reflux for 17 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The resulting residue was dissolved in ether (400 mL) and washed successively with water (400 mL), saturated aqueous sodium bicarbonate (400 mL), and saturated aqueous sodium chloride (400 mL). The ether solution was then dried (MgSO4), filtered, and concentrated. The resulting yellow oil was distilled to give methyl 4-chlorosalicylate. (Yield 32.89 g, 88percent; b.p. 86 - 90 °C, 0.15 mm Hg).
83% With sulfuric acid In methanol; ethanol for 24 h; Reflux 1)
Preparation of methyl 4-chloro-salicylate
5 ml of concentrated sulfuric acid is drop-added slowly to 100 ml of methanol.
The solution is cooled and then added with a powder of 4-chloro-salicylic acid (17.20g, 0.1 mol), and a reaction is carried out at reflux for 24 hours.
After cooling the reaction, a large amount of deposit precipitates and is filtered out, washed with small amount of methanol, and recrystallized in anhydrous ethanol, to obtain 15.60g of methyl 4-chloro-salicylate, with a yield of 83percent.
83% for 24 h; Reflux 5 ml of concentrated sulfuric acid was slowly added dropwise to 100 ml of methanol,After cooling the solution, 4-chlorosalicylic acid powder (17.20 g, 0.1 mol) was added, refluxed for 24 hours, cooled and a large amount of precipitate was precipitated, filtered, washed with a small amount of methanol, To give 15.60 g of methyl 4-chlorosalicylate. with a Yield is 83percent.

Reference: [1] Tetrahedron Letters, 2014, vol. 55, # 32, p. 4484 - 4488
[2] Dalton Transactions, 2015, vol. 45, # 2, p. 479 - 483
[3] Patent: WO2012/119046, 2012, A2, . Location in patent: Page/Page column 90-91
[4] Patent: EP1149092, 2003, B1, . Location in patent: Page/Page column 36
[5] Patent: EP2322520, 2011, A1, . Location in patent: Page/Page column 12
[6] Patent: JP5714152, 2015, B2, . Location in patent: Paragraph 0068
[7] Journal of the American Chemical Society, 2010, vol. 132, # 11, p. 3664 - 3665
[8] Journal of Medicinal Chemistry, 1992, vol. 35, # 2, p. 310 - 319
[9] Heterocycles, 1998, vol. 48, # 10, p. 2173 - 2183
[10] Journal of Medicinal Chemistry, 1999, vol. 42, # 6, p. 1076 - 1087
[11] Patent: US2004/106653, 2004, A1, . Location in patent: Page/Page column 40
[12] Patent: WO2004/45610, 2004, A1, . Location in patent: Page/Page column 130
[13] Patent: WO2010/56767, 2010, A1, . Location in patent: Page/Page column 88
[14] Tetrahedron Letters, 2016, vol. 57, # 48, p. 5301 - 5303
[15] Organic and Biomolecular Chemistry, 2018, vol. 16, # 11, p. 1837 - 1842
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  • [ 119-36-8 ]
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Reference: [1] J. Appl. Chem. USSR (Engl. Transl.), 1981, vol. 54, # 4, p. 771 - 772[2] Zhurnal Prikladnoi Khimii (Sankt-Peterburg, Russian Federation), 1981, vol. 54, # 4, p. 930 - 932
  • 7
  • [ 1126-46-1 ]
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  • [ 22717-55-1 ]
  • [ 873-76-7 ]
Reference: [1] Organic and Biomolecular Chemistry, 2008, vol. 6, # 7, p. 1251 - 1259
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