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Chemical Structure| 22876-19-3
Chemical Structure| 22876-19-3
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Product Details of [ 22876-19-3 ]

CAS No. :22876-19-3 MDL No. :MFCD00175241
Formula : C7H4ClNOS Boiling Point : -
Linear Structure Formula :- InChI Key :BOBIZYYFYLLRAH-UHFFFAOYSA-N
M.W : 185.63 Pubchem ID :708870
Synonyms :

Calculated chemistry of [ 22876-19-3 ]

Physicochemical Properties

Num. heavy atoms : 11
Num. arom. heavy atoms : 9
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 1.0
Num. H-bond donors : 1.0
Molar Refractivity : 46.41
TPSA : 61.02 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.75 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.9
Log Po/w (XLOGP3) : 2.37
Log Po/w (WLOGP) : 3.14
Log Po/w (MLOGP) : 1.5
Log Po/w (SILICOS-IT) : 4.14
Consensus Log Po/w : 2.61

Druglikeness

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

Water Solubility

Log S (ESOL) : -3.09
Solubility : 0.151 mg/ml ; 0.000814 mol/l
Class : Soluble
Log S (Ali) : -3.29
Solubility : 0.0948 mg/ml ; 0.000511 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.64
Solubility : 0.0423 mg/ml ; 0.000228 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.37

Safety of [ 22876-19-3 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H332-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 22876-19-3 ]

* 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 [ 22876-19-3 ]
  • Downstream synthetic route of [ 22876-19-3 ]

[ 22876-19-3 ] Synthesis Path-Upstream   1~11

  • 1
  • [ 22876-19-3 ]
  • [ 3621-81-6 ]
YieldReaction ConditionsOperation in experiment
91% With thionyl chloride; N,N-dimethyl-formamide In dichloromethane at 5 - 20℃; for 4 h; Thionyl chloride (885 g, 7.5 mol)And N, N-dimethylformamide (270 ml) were added to a solution of 5-chloro-2-mercaptobenzoxazole (540 g, 2.903 mol) in dichloromethane (5 L) at 5-10 ° C.Stirred until a clear solution was formed and the reaction solution was stirred at room temperature for 4 hours.After completion of the reaction, the reaction solution was poured into 4 L of ice water, neutralized to neutral with sodium bicarbonate in 1 hour, and extracted with dichloromethane (2.5 L * 2).The organic layer was washed with brine, dried over sodium sulfate and dried to give the crude product. The crude product was washed with n-hexane (2 L * 2) at -20 ° C, filtered and dried to give yellow liquid 2,5-dichlorobenzo (496.8 g, 91.0percent).
88.9% With thionyl chloride In dichloromethane; N,N-dimethyl-formamide at 5 - 20℃; for 4 h; Thionyl Chloride (540 mL) and Dimethyl formamide (270 mL) were added to a stirred mixture of 5-Chloro-1,3-benzoxazole-2-thiol (540 g, 2.903 moles) and dichloromethane (5 liter) at 5-10° C. and stirred till clear solution was observed.
The reaction mixture was then stirred at 10° C. to room temperature for 4 hour.
After completion of the reaction, the mixture was poured into cold water (4 liter), neutralized with solid sodium bicarbonate (1440 g) portion wise over a period of 1 hour and extracted with dichloromethane (2*2.5 liter).
The combined organic extracts were washed with brine solution, dried over anhydrous sodium sulphate (300 g) and concentrated under reduced pressure to give a crude compound.
The crude material was triturated with Hexane (2*2 liter) at -20° C., filtered and and dried under reduced pressure to obtain 2,5-dichloro-1,3-benzoxazole (475 g, 88.9percent) as a yellow liquid.
Reference: [1] Patent: CN106478537, 2017, A, . Location in patent: Paragraph 0027; 0028; 0039; 0040; 0050; 0051; 0065; 0066
[2] Patent: US2016/168138, 2016, A1, . Location in patent: Paragraph 0144-0145
[3] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 3, p. 907 - 911
[4] Advanced Synthesis and Catalysis, 2017, vol. 359, # 11, p. 1837 - 1843
[5] Journal of Medicinal Chemistry, 1988, vol. 31, # 9, p. 1719 - 1728
[6] Journal of Medicinal Chemistry, 1994, vol. 37, # 7, p. 913 - 923
[7] Chemical and Pharmaceutical Bulletin, 1998, vol. 46, # 3, p. 445 - 451
[8] Journal of Medicinal Chemistry, 1998, vol. 41, # 16, p. 3015 - 3021
[9] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 7, p. 1975 - 1980
[10] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 10, p. 3515 - 3523
[11] Patent: US2008/132490, 2008, A1, . Location in patent: Page/Page column 14
[12] Journal of Organic Chemistry, 2009, vol. 74, # 8, p. 3229 - 3231
[13] Patent: WO2011/77313, 2011, A1, . Location in patent: Page/Page column 35
[14] Patent: US2011/224269, 2011, A1, . Location in patent: Page/Page column 21
[15] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 9, p. 3044 - 3049
[16] Patent: WO2016/20404, 2016, A1, . Location in patent: Page/Page column 79
[17] Patent: WO2016/20405, 2016, A1, . Location in patent: Page/Page column 133
[18] Patent: WO2017/88759, 2017, A1, . Location in patent: Paragraph 00187
  • 2
  • [ 22876-19-3 ]
  • [ 3621-81-6 ]
Reference: [1] Journal of Organic Chemistry, 1996, vol. 61, # 10, p. 3289 - 3297
[2] Journal of Organic Chemistry, 1958, vol. 23, p. 1500,1502
  • 3
  • [ 22876-19-3 ]
  • [ 79-37-8 ]
  • [ 3621-81-6 ]
Reference: [1] Organic Process Research and Development, 2011, vol. 15, # 2, p. 367 - 375
  • 4
  • [ 75-15-0 ]
  • [ 95-85-2 ]
  • [ 22876-19-3 ]
YieldReaction ConditionsOperation in experiment
91%
Stage #1: With potassium hydroxide In ethanol for 4 h; Reflux
Stage #2: With hydrogenchloride In ethanol; water
To a stirred solution of 2-amino-4-chlorophenol (20.0 g, 139.3 mmol) in EtOH (500 mL) was added KOH (18.36 g, 327.3 mmol) followed by CS2 (126.7 mL, 1318 mmol) and refluxed for 4 h. Volatiles were removed and the residue was diluted with water (100 mL) and acidified with 2 M HCl (50 mL) and extracted with CH2Cl2 (2 x 250 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 23.5 g (91percent) of 18' as brown solid. 1H NMR (400 MHz, MeOD) δ 7.35-7.33 (m, IH), 7.25-7.22 (m, 2H), 3.31-3.30 (m, IH); MS: ESI m/z 186 [M + H]+.
Reference: [1] Patent: WO2010/39186, 2010, A2, . Location in patent: Page/Page column 48
[2] Journal of Medicinal Chemistry, 1994, vol. 37, # 7, p. 913 - 923
[3] Chemical and Pharmaceutical Bulletin, 1998, vol. 46, # 3, p. 445 - 451
[4] Journal of Medicinal Chemistry, 1998, vol. 41, # 16, p. 3015 - 3021
[5] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 10, p. 3515 - 3523
[6] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 9, p. 3044 - 3049
[7] Patent: WO2016/183266, 2016, A1, . Location in patent: Page/Page column 47
  • 5
  • [ 140-89-6 ]
  • [ 95-85-2 ]
  • [ 22876-19-3 ]
YieldReaction ConditionsOperation in experiment
99.1%
Stage #1: Reflux
Stage #2: With acetic acid In water
Compound 19:
A mixture of potassium ethyl xanthate (13.4 g, 84.0 mmol) and 4-chloro-2-aminophenol (10 g, 69.6 mmol) was dissolved in absolute ethanol (200 mL).
The mixture was stirred under reflux overnight.
After cooling, the solvent was evaporated under reduced pressure, the residue was dissolved in water (200 mL) and treated with HOAc to adjust pH to 5.
A solid formed, which was filtered and dried to afford 5-chloro-2-mercaptobenzoxazole (12.8 g, yield 99.1percent).
99.1% at 20 - 80℃; Potassium ethyl xanthate (535.8 g, 3.343 mol)Was slowly added to a solution of 2-amino-4-chlorophenol (400 g, 2.786 mol)In ethanol (3 L)And stirred at room temperature for 10 minutes, then slowly raised to 80 ° C until the reaction was complete.Point plate found that the raw material points disappeared, the reaction mixture into the ice water (7L) with acetic acid neutralization to neutral.Filter, filter residue with 5L ice water,2L n-hexane, and dried under reduced pressure to give a white solid (512.5 g, 99.1percent) of 5-chloro-2-mercaptobenzoxazole.
98.4% at 20 - 80℃; Potassium ethylxanthate (893.2 g, 5.572 moles) was added to a stirred mixture of 2-Amino-4-Chloro phenol (400 g, 2.786 moles) and Ethanol (3 liter) at room temperature and stirred for 10 minutes.
The obtained mixture was stirred at 80° C. until reaction was complete.
The progress of the reaction was monitored by TLC.
After completion of the reaction, reaction mixture was poured into cold water (7 liter) and neutralized with acetic acid (752 ml).
The solid was filtered and washed with cold water (5 liter), Hexane (2 liter) and dried under vacuum to furnish 5-Chloro-1,3-benzoxazole-2-thiol (510 g, 98.4percent) as an off white solid.
94.9% for 8 h; Reflux A mixture of 2-amino-4-chlorophenol (100 g, 0.69 mol) Potassium ethyl xanthate (13.3 g, 0.83 mol) and 1500 ml of absolute ethanol were added to a 3 L four-necked reaction flask, Heated to reflux for 8 hours. The ethanol was distilled off under reduced pressure, The residue was dissolved in 1300 ml of water, Acidified with 100 ml of concentrated hydrochloric acid and filtered to give 122.6 g of a white solid, Yield 94.9percent
90.2% for 7 h; Reflux Step 5) Synthesis of 5-chlorobenzo [d] oxazole-2-thiolTo ethanol (100 mL) were added sequentially 2-amino-4-chlorophenol (6.02 g, 41.94 mmol) and ehtyl potassium xanthate (7.07 g, 44.09 mmol) , the reaction was heated gradually to reflux and stirred for 7 hours, and then concentrated in vacuo. The thick oil was dissolved in water (150 mL) , and extracted with ethyl acetate (100 mL) . The aqueous layer was adjusted to pH 4 to 5 with aqueous hydrochloric acid solution (1 M) , and white solid precipitated out. Filtered under vacuum, the solid was dried to give the title compound as a white solid (7.02 g, 90.2 percent) .MS (ESI, pos. ion) m/z: 186.1 [M+H] +; and1H NMR (DMSO-d6, 600 MHz) d (ppm) : 13.99 (s, 1H) , 7.52 (d, J = 8.2 Hz, 1H) , 7.31-7.28 (m, 2H)
57% for 16 h; Heating / reflux Step 12-amino-4-chlorophenol 1.0 g (7 mmol) and 1.34 g (8.4 mmol) of potassiumO-ethylxanthate were dissolved in 20 ml of ethanol in a dried round flask provided with nitrogen gas, followed refluxing the mixture with stirring for 16 hrs. The resulting solution was concentrated under a reduced pressure, mixed with ethylacetate, and washed with water. The formed organic layer was washed with a sodium hydrogen carbonate solution and a saturated NaCl solution, dried over anhydrous magnesium sulfate, and distilled under a reduced pressure. The resulting residue was subjected to silica gel column chromatography (dichloromethane:methanol=49:l) to obtain 5-chloro-2-thiobenzooxazole(yield: 57percent).

Reference: [1] Patent: US2011/224269, 2011, A1, . Location in patent: Page/Page column 21
[2] Patent: CN106478537, 2017, A, . Location in patent: Paragraph 0025; 0026; 0037; 0038; 0048; 0049; 0062-0064
[3] Patent: US2016/168138, 2016, A1, . Location in patent: Paragraph 0142-0143
[4] Patent: CN106632121, 2017, A, . Location in patent: Paragraph 0031; 0032
[5] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 3, p. 907 - 911
[6] Patent: WO2017/88759, 2017, A1, . Location in patent: Paragraph 00186
[7] Patent: WO2008/153325, 2008, A1, . Location in patent: Page/Page column 29
[8] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 4, p. 1617 - 1625
[9] Journal of Medicinal Chemistry, 1988, vol. 31, # 9, p. 1719 - 1728
[10] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 7, p. 1975 - 1980
[11] Patent: WO2011/77313, 2011, A1, . Location in patent: Page/Page column 34-35
  • 6
  • [ 137-26-8 ]
  • [ 95-85-2 ]
  • [ 22876-19-3 ]
YieldReaction ConditionsOperation in experiment
67%
Stage #1: With potassium carbonate In N,N-dimethyl-formamide for 0.0833333 h;
Stage #2: at 120℃; for 12 h;
General procedure: 2-Aminophenol (1.0 mmol), K2CO3 (3.0 mmol) was dissolved in DMF (3 mL) in a dried tube, equipped with a magnetic stirring bar and a septum. The mixture was stirred for 5 minutes, and then TMTD (0.6 mmol) was added. The reaction mixture was then heated at 120 °C and checked by TLC until the starting material was finished (around 12 hours). The reaction was cooled down to room temperature, and then quenched with sat. NH4Cl solution and extracted with ethyl acetate, dried over anhydrous Na2SO4 and evaporated under vacuum. The residue was purified by flash column chromatography to afford the desired product.
Reference: [1] Green Chemistry, 2017, vol. 19, # 23, p. 5591 - 5598
[2] Tetrahedron Letters, 2017, vol. 58, # 46, p. 4352 - 4356
[3] Journal of Organic Chemistry, 2018,
  • 7
  • [ 17200-29-2 ]
  • [ 22876-19-3 ]
YieldReaction ConditionsOperation in experiment
73.7% With 1.3-propanedithiol; potassium hydroxide In dimethyl sulfoxide at 130℃; for 12 h; Inert atmosphere; Sealed tube 153.57 mg (1 mmol) of 5-chlorobenzoxazole, 216 μL (2.0 mmol) of 1,3-propanedithiol, 280.55 mg (5.0 mmol) of potassium hydroxide and 3 mL of DMSO were placed in a reaction equipped with a magnetic stir bar. The tube was sealed with argon, heated and stirred, and reacted in an oil bath at 130 ° C for 24 hours. After the reaction is completed, the reaction solution is transferred to a separating funnel with water washing, an appropriate amount of dilute hydrochloric acid is added, the aqueous phase is adjusted to pH 1-3, and the organic phase is extracted with ethyl acetate, and the upper organic phase is transferred with anhydrous magnesium sulfate. The mixture was dried under reduced pressure and purified by column chromatography to yield 113.2mg of product as a red-brown solid, yield 73.7percent.
Reference: [1] Patent: CN108530374, 2018, A, . Location in patent: Paragraph 0030; 0031
[2] Organic and Biomolecular Chemistry, 2017, vol. 15, # 39, p. 8276 - 8279
  • 8
  • [ 463-71-8 ]
  • [ 95-85-2 ]
  • [ 22876-19-3 ]
YieldReaction ConditionsOperation in experiment
5.81 kg at 0 - 20℃; for 2 h; Large scale 2-Amino-4-chlorophenol (2.50 kg, 17.4 mol) was charged to a vessel and suspended in water (52 L) and methanol (10.4L). High dilution was required to prevent slow and difficult filtration of the product. The mixture was stirred, cooled to 0° C., then thiophosgene (2.00 kg, 17.4 mol) was added to the suspension ensuring that the internal temperature remained at 5° C. throughout the addition. Water (8 L) andmethanol (2 L) were added to aid stirring and the slurry was warmed to 13° C. for 1 h, followed by aging at 20° C. for a thrther 1 h. The slurry was then filtered and the solid washed with water (5 L). The batch was repeated and combined to dry in a vacuum oven (T=40° C.) for 15 h togive 9-a (5.81 kg, 31.3 mol). The data corresponds to the commercially available material. ‘H NMR (400 MHz, d5-DMSO): ö 7.51 (d, 1H, J=9.2 Hz), 7.30726 (m, 2H). ‘3C NMR (100.6 MHz, d5-DMSO): ö 181.2, 147.4, 133.1, 129.7, 123.9, 111.6, 110.8. HRMS (ESI): m/z [M+H] calcd for C7H4C1NOS: 185.9780; found: 185.9785.
Reference: [1] Organic Process Research and Development, 2011, vol. 15, # 2, p. 367 - 375
[2] Patent: WO2012/148553, 2012, A1, . Location in patent: Page/Page column 38
[3] Patent: US9441254, 2016, B2, . Location in patent: Page/Page column 9
  • 9
  • [ 95-85-2 ]
  • [ 22876-19-3 ]
Reference: [1] Patent: US6037342, 2000, A,
  • 10
  • [ 89-64-5 ]
  • [ 22876-19-3 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 10, p. 3515 - 3523
[2] Patent: WO2011/77313, 2011, A1,
  • 11
  • [ 108-43-0 ]
  • [ 22876-19-3 ]
Reference: [1] Patent: WO2011/77313, 2011, A1,
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