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Chemical Structure| 25984-63-8
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Product Details of [ 25984-63-8 ]

CAS No. :25984-63-8 MDL No. :MFCD04973332
Formula : C7H7NOS Boiling Point : -
Linear Structure Formula :- InChI Key :VDTNKXSVUGXUOJ-UHFFFAOYSA-N
M.W : 153.20 Pubchem ID :2759344
Synonyms :

Calculated chemistry of [ 25984-63-8 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 10
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 1
Num. H-bond acceptors : 1.0
Num. H-bond donors : 2.0
Molar Refractivity : 43.93
TPSA : 78.34 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.57 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.15
Log Po/w (XLOGP3) : 0.93
Log Po/w (WLOGP) : 1.03
Log Po/w (MLOGP) : 1.06
Log Po/w (SILICOS-IT) : 1.95
Consensus Log Po/w : 1.22

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.75
Solubility : 2.7 mg/ml ; 0.0176 mol/l
Class : Very soluble
Log S (Ali) : -2.16
Solubility : 1.06 mg/ml ; 0.0069 mol/l
Class : Soluble
Log S (SILICOS-IT) : -1.6
Solubility : 3.86 mg/ml ; 0.0252 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.04

Safety of [ 25984-63-8 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302+H312+H332-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 25984-63-8 ]

* 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 [ 25984-63-8 ]
  • Downstream synthetic route of [ 25984-63-8 ]

[ 25984-63-8 ] Synthesis Path-Upstream   1~15

  • 1
  • [ 25984-63-8 ]
  • [ 7252-83-7 ]
  • [ 81015-49-8 ]
YieldReaction ConditionsOperation in experiment
60% With toluene-4-sulfonic acid In ethanol at 20 - 90℃; for 24 h; To a mixture of 4-hydroxybenzothioamide (30.64 g, 0.20 mol) and 2-bromo-l,l-dimethoxyethane (31.00 g, 0.20 mol) in EtOH (600 mL) was added 4-methylbenzenesulfonic acid (34.44 g, 0.20 mol) with stirring at rt. The reaction mixture was heated at 90 °C for 24 h, then cooled to rt and concentrated in vacuo. The mixture was diluted with H20 (200 mL), adjusted to pH 10 with saturated NaHC03aqueous solution and extracted with DCM (200 mL x 3). The combined organic phases were concentrated in vacuo to give the title compound as s yellow solid (21.3 g, 60percent).
60% With toluene-4-sulfonic acid In ethanol at 20 - 90℃; for 24 h; To a mixture of 4-hydroxybenzothioamide (30.64 g, 0.20 mol) and 2-bromo-1,1-dimethoxyethane (31.00 g, 0.20 mol) in EtOH (600 mL) was added 4-methylbenzenesulfonic acid (34.44 g, 0.20 mol) with stirring at rt.
The reaction mixture was heated at 90° C. for 24 h, then cooled to rt and concentrated in vacuo.
The mixture was diluted with H2O (200 mL), adjusted to pH 10 with saturated NaHCO3 aqueous solution and extracted with DCM (200 mL*3).
The combined organic phases were concentrated in vacuo to give the title compound as s yellow solid (21.3 g, 60percent).
60% With toluene-4-sulfonic acid In ethanol at 20 - 90℃; for 24 h; 4-hydroxythiobenzamide (30.64 g, 0.20 mol) and 2-bromo-1,1-dimethoxyethane (31.00 g, 0.20 mol) were stirred in ethanol (600 mL) at room temperature.P-toluenesulfonic acid (34.44 g, 0.20 mol) was added to the reaction solution.Heat to 90°C for 24 hours.After the reaction was completed, it was cooled to room temperature, the solvent was distilled off under reduced pressure, water (200 mL) was added, and the pH was adjusted to 8 with saturated sodium bicarbonate solution.Dichloromethane (200 mL x 3) was extracted and the organic phases were combined and concentrated by evaporation under reduced pressure to give a yellow solid (21.3 g, 60percent).
Reference: [1] Patent: WO2014/12360, 2014, A1, . Location in patent: Paragraph 00266
[2] Patent: US2015/87639, 2015, A1, . Location in patent: Paragraph 0511
[3] Patent: TWI607995, 2017, B, . Location in patent: Page/Page column 122
[4] Patent: CN108658937, 2018, A, . Location in patent: Paragraph 0175
  • 2
  • [ 767-00-0 ]
  • [ 25984-63-8 ]
YieldReaction ConditionsOperation in experiment
97.57%
Stage #1: With sodium hydrogensulfide In water at 20℃; for 0.5 h;
Stage #2: at 70℃; for 5.91667 - 6 h;
A mixture of 4-Cyanophenol (50.0 g, 0.42 mol), and NaSH (15.5 g, 0.21 mol) in distilled water (125 mL) was stirred at room temperature for 30 minutes.
The mixture was then put under a vacuum, flushed with H2S, and the pressure was brought to 40-50 psi for a period of a few minutes.
The mixture was then heated to 70° C. and stirred for 40-45 minutes.
The mixture was stirred vigorously at 70° C. under constant pressure of 56 psi for 5 hours and 15 minutes.
The H2S pressure was removed and the reaction was cooled to room temperature.
The reaction was neutralized to pH 5-7 with 2 M HCl (66 mL).
The product was filtered, and the filter cake washed with distilled water (2*50 mL), and dried under a vacuum at 80-85° C. for 22 hours to provide 62.74 g (97.57percent) desired product.
94% With sodium monohydrogen sulfide x-hydrate; ammonium chloride In water; N,N-dimethyl-formamide at 40℃; for 22 h; To a solution of a sodium hydrogen sulfide hydrate (2.35 g), N,N-dimethylformamide (3 ml) and water (0.5 ml) were added 4-hydroxybenzonitrile (1.0 g) and ammonium chloride (2.25 g) while stirring. After the mixture was stirred at 40° C. for 22 hours, 2N hydrochloric acid (9.5 ml) was added followed by the addition of water (2.0 ml) to the mixture. A solid formed under ice cooling and stirring was filtered and then dried to afford 4-hydroxybenzothioamide (1.21 g) (yield 94percent).
92% With sodium hydrogen sulfide; triethylamine hydrochloride; triethylamine In ethanol at 5 - 50℃; for 12 h; 11 g of sodium hydrosulfide,6 g of p-hydroxybenzonitrile,6.9 mL of triethylamine,40 mL of ethanol was added to a 100 mL three-necked flask, ice bath temperature control 5 ~ 10 °C, A solution of 27.5 g of triethylamine hydrochloride was added in portions, Add the elevated temperature to 50 °C ,Stirring under the insulation for 12 hours, TLC monitoring reaction is complete, liquid phase control shows the conversion rate of 95percent or more, the final yield of 92percent.After the end of the reaction, the ethanol recovered by distillation can be directly applied. Distilled by adding 40 mL of ethanol to beat at 50 ° C for 0.5 hour and filtering to obtain a higher purity sodium chloride solid salt.The ethanol filtrate was concentrated to dryness, and 25 mL of water was added to the beater, filtered and dried to give 7.32 g of a yellowish solid. Liquid content of more than 97percent, the yield of 92percent.The filtered aqueous phase can be repeatedly applied in multiple batches and finally concentrated to dryness, resulting in triethylamine hydrogen sulfide and triethylamine hydrochloride, which can be recycled to the reaction. The whole process is basically no waste generated.
87.5% With O,O-Diethyl hydrogen phosphorodithioate In water at 50℃; for 3 h; EXAMPLE- 1 (preparation of 4-hydroxythiobenzamide) 0.23 moles of diethyldithiophosphoric acid was added to 1.66 moles of water followed by addition of 0.21 moles of 4-cyanophenol. The reaction mixture was heated to 50°C and was maintained at this temperature with stirring for 3 hrs. The reaction mass was then cooled to 25-30°C. 100 ml of dichloromethane was added to the mixture and it was maintained at 25-30°C for 30 min. It was then filtered and the solid product was washed with saturated sodium carbonate solution followed by 70 ml water. It was dried at 75oC to obtain 4-hydroxythiobenzamide in 87,5percent yield.
70% With tetraphosphorus decasulfide In ethanol at 70℃; for 12 h; P2S5 (0.37 g, 16.8 mmol) was dissolved in ethanol (10 mL) and stirred at rt for 1 h. Then the solution became clear. To this reaction mixture, 4-hydroxy-benzonitrile (1) (1 g, 8.4 mmol) was added. The RM was then heated at 70 °C for 12 h. The RM was evaporated to dryness and the resultant crude mixture was purified by column chromatography on silica, product eluted with 50percent EA/Hex to afford 4-hydroxy benzamide (2) (800 mg, 70percent) as white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.08 (s, 1H), 9.52 (s, 1H), 9.20 (s, 1H), 7.86 (d, J = 8.56 Hz, 2H), 6.74 (d, J = 8.6 Hz, 2H). MS (ESI): m/z calc. for C7H7NOS+: 153.0; found: 154.1 [M+H]+.
97.57% With hydrogenchloride; NaSH In water EXAMPLE 1
4-hydroxybenzene carbothioamide
A mixture of 4-Cyanophenol (50.0 g, 0.42 mol), and NaSH (15.5 g, 0.21 mol) in distilled water (125 mL) was stirred at room temperature for 30 minutes.
The mixture was then put under a vacuum, flushed with H2S, and the pressure was brought to 40-50 psi for a period of a few minutes.
The mixture was then heated to 70° C. and stirred for 40-45 minutes.
The mixture was stirred vigorously at 70° C. under constant pressure of 56 psi for 5 hours and 15 minutes.
The H2S pressure was removed and the reaction was cooled to room temperature.
The reaction was neutralized to pH 5-7 with 2 M HCl (66 mL).
The product was filtered, and the filter cake washed with distilled water (2*50 mL), and dried under a vacuum at 80-85° C. for 22 hours to provide 62.74 g (97.57percent) desired product.

Reference: [1] Patent: US2005/75503, 2005, A1, . Location in patent: Page/Page column 3
[2] Patent: US2012/78013, 2012, A1, . Location in patent: Page/Page column 4
[3] Patent: CN106928108, 2017, A, . Location in patent: Paragraph 0043; 0044; 0046; 0048; 0063; 0065; 0067; 0071
[4] Patent: WO2016/46836, 2016, A2, . Location in patent: Page/Page column 3
[5] Synthetic Communications, 2000, vol. 30, # 6, p. 1083 - 1094
[6] Tetrahedron, 1989, vol. 45, # 14, p. 4599 - 4604
[7] ACS Medicinal Chemistry Letters, 2013, vol. 4, # 10, p. 904 - 908
[8] Journal of Photochemistry and Photobiology A: Chemistry, 2017, vol. 334, p. 1 - 12
[9] Chemical and Pharmaceutical Bulletin, 2005, vol. 53, # 4, p. 410 - 418
[10] Collection of Czechoslovak Chemical Communications, 1991, vol. 56, # 12, p. 2964 - 2968
[11] Journal of the American Chemical Society, 1972, vol. 94, p. 3153 - 3159
[12] Synlett, 2004, # 14, p. 2615 - 2617
[13] Patent: US2005/27128, 2005, A1,
[14] New Journal of Chemistry, 2018, vol. 42, # 1, p. 76 - 84
  • 3
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YieldReaction ConditionsOperation in experiment
87% With Lawessons reagent In tetrahydrofuran at 20℃; for 6 h; 4-Hydroxybenzamide (3.6 g, 26.5 mmol) was dissolved in dryTHF (100 mL), and then Lawesson's reagent (11.77 g, 29.1 mmol)was added. The reaction mixture was stirred at room temperaturefor 6 h. The solvent was then evaporated under reduced pressureand the residue was partitioned between aq. NaHCO3 (0.2 M,50 mL) and ethyl acetate (50 mL x 2). The organic solvent wasseparated and dried over anhydrous MgSO4. The crude product wasfurther purified by silica gel flash chromatography, using EtOAc:Petroleum ether (85:15) to yield the corresponding thioamide as ayellow solid (3.5 g, 87percent); m.p 172-176°C.
Reference: [1] European Journal of Medicinal Chemistry, 2017, vol. 126, p. 604 - 613
  • 4
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Reference: [1] Patent: US2002/52392, 2002, A1,
  • 5
  • [ 767-00-0 ]
  • [ 62-55-5 ]
  • [ 25984-63-8 ]
Reference: [1] Patent: CN104529935, 2017, B, . Location in patent: Paragraph 0049
  • 6
  • [ 767-00-0 ]
  • [ 298-06-6 ]
  • [ 25984-63-8 ]
Reference: [1] Phosphorus and Sulfur and the Related Elements, 1985, vol. 25, p. 297 - 306
  • 7
  • [ 16890-86-1 ]
  • [ 108-95-2 ]
  • [ 25984-63-8 ]
Reference: [1] Helvetica Chimica Acta, 1933, vol. 16, p. 1003[2] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1933, vol. 196, p. 1031
  • 8
  • [ 25984-63-8 ]
  • [ 57677-80-2 ]
Reference: [1] Journal of Molecular Structure, 2018, vol. 1173, p. 81 - 91
[2] Journal of Chemical Research, 2018, vol. 42, # 7, p. 366 - 370
  • 9
  • [ 25984-63-8 ]
  • [ 70-23-5 ]
  • [ 57677-79-9 ]
Reference: [1] Journal of Molecular Structure, 2018, vol. 1173, p. 81 - 91
[2] Journal of Chemical Research, 2018, vol. 42, # 7, p. 366 - 370
  • 10
  • [ 25984-63-8 ]
  • [ 609-15-4 ]
  • [ 161797-99-5 ]
YieldReaction ConditionsOperation in experiment
98% at 65 - 70℃; for 3 h; EXAMPLE-2 (preparation of ethyl 2-(4-hydroxyphenyl)-4-methyl-5- thiazolecarboxylate) 0.26 moles of 4-hydroxythiobenzamide suspended in 180 ml of ethanol was taken in the reactor. 0.29 Moles of ethyl-2- chloroacetoacetate was added. The reaction mixture was then heated to 65-70°C and maintained at this temperature for 3 hrs. Ethanol was distilled off and 300 ml water was added to the reaction mass. It was then cooled to 25-30°C and maintained at this temperature for 30 min. The solid obtained was filtered and washed with 70 ml water. The product was dried at 80oC to obtain ethyl 2- (4- hydroxyphenyl)- 4- methyl- 5-thiazolecarboxylate with 98percent yield.
90.7% at 60 - 65℃; for 2.5 h; Example 1 : Synthesis of Ethyl 2-(4-HvdroxyphenvO-4-Methyl-5-Thiazol CarboxylateA mixture of 4-hydroxy thiobenzamide (100 g, 0.653 mol) and ethyl 2- chloroacetoacetate (118.3 g, 0.719 mol) in denatured spirit (DNS) (500 mL) was heated at about 60°C to 65°C for about 2.5 hours. The reaction mixture was cooled to about 0°C to 5°C and stirred for about 1 hour at the same temperature. The solid obtained was filtered, washed with denatured spirit and dried to obtain the title compound. (Yield: 156 g, 90.7percent)
58% at 55 - 85℃; for 3 h; 4-hydroxy thiobenzamide (2) (0.79 g, 5.16 mmol) was dissolved in isopropanol (4 mL) and the reaction mixture was then heated to 55 °C and under this heating condition, 2-chloroacetoacetic acid ethyl ester (1.27 g, 7.74 mmol) was added drop wise to it. After addition, the reaction mixture was heated at 85 °C for 3 h. During this reaction a white solid was found. The reaction mixture was cooled at rt and the resultant solid was filtered and washed with cold isopropanol, dried under rotavapour to afford 2-(4-Hydroxy-phenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester (3) (1 g, 58percent) as white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.83 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.64 Hz, 2H), 4.28 (q, J = 7.04 Hz, 2H), 2.65 (s, 3H), 1.29 (t, J = 7.08 Hz, 3H). 13C NMR (100 MHz, CDCl3):169.01, 168.70, 162.19, 161.01, 152.65, 130.60, 128.01, 122.26, 121.94, 21.12, 17.48, 14.30. MS (ESI): m/z calc. for C13H13NO3S+: 263.0; found: 264.0 [M+H]+.
38 g With phosphoric acid In ethanol; water at 30 - 80℃; After the sulfonylation reaction is complete,Do not need to separate, continue to the next thiazolyl reaction,In the reaction system was added organic solvent 60g ethanol,Get anhydrous phosphoric acid + alcohol system,Then 30 g of ethyl 2-chloroacetoacetate was slowly added dropwise,Temperature control 30-80 ,Insulation reaction, the reaction time is 3-6 hours,The reaction was complete by HPLC, 60 g of water was added,Slowly cool to 0 filter,Washed with a small amount of ice ethanol (10g)The wet product was dried to give 38 g of ethyl 2- (4-hydroxyphenyl) -4-methyl-5-thiazolecarboxylate (formula III) as a pale yellow solid with a chromatographic purity of ≥99percentTwo-step yield of about 86percent, content of 99.5percent;

Reference: [1] Patent: WO2016/46836, 2016, A2, . Location in patent: Page/Page column 4
[2] Patent: WO2012/14117, 2012, A1, . Location in patent: Page/Page column 12
[3] Journal of Photochemistry and Photobiology A: Chemistry, 2017, vol. 334, p. 1 - 12
[4] Journal of Medicinal Chemistry, 2007, vol. 50, # 4, p. 685 - 695
[5] Patent: WO2012/168948, 2012, A2, . Location in patent: Page/Page column 10
[6] Letters in Organic Chemistry, 2015, vol. 12, # 3, p. 217 - 221
[7] Patent: CN104529935, 2017, B, . Location in patent: Paragraph 0050
  • 11
  • [ 25984-63-8 ]
  • [ 84911-18-2 ]
  • [ 161797-99-5 ]
YieldReaction ConditionsOperation in experiment
91% for 3 h; Reflux 4-Hydroxybenzothioamide 1 (20 mmol), 2-bromo-3-oxobutyric acid ethyl ester 2 (24 mmol) andabsolute ethanol (30 mL) were added to a round-bottomed flask. The mixture was refluxed for 3 h.After cooling to room temperature, the green solid was filtered off, and washed with ethanol. Thecrude product recrystallized from ethanol to give compound 3 in 91percent yield
Reference: [1] Molecules, 2016, vol. 21, # 8,
  • 12
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  • [ 161797-99-5 ]
Reference: [1] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2015, vol. 54B, # 8, p. 1005 - 1010
  • 13
  • [ 25984-63-8 ]
  • [ 638-07-3 ]
  • [ 161797-99-5 ]
Reference: [1] New Journal of Chemistry, 2018, vol. 42, # 1, p. 76 - 84
  • 14
  • [ 25984-63-8 ]
  • [ 161798-01-2 ]
Reference: [1] Patent: WO2012/14117, 2012, A1,
[2] Patent: WO2012/168948, 2012, A2,
[3] Letters in Organic Chemistry, 2015, vol. 12, # 3, p. 217 - 221
[4] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2015, vol. 54B, # 8, p. 1005 - 1010
[5] Journal of Photochemistry and Photobiology A: Chemistry, 2017, vol. 334, p. 1 - 12
[6] Patent: CN104529935, 2017, B,
  • 15
  • [ 25984-63-8 ]
  • [ 161798-03-4 ]
Reference: [1] Patent: WO2012/168948, 2012, A2,
[2] Patent: CN104529935, 2017, B,
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