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[ CAS No. 504-15-4 ] {[proInfo.proName]}

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Chemical Structure| 504-15-4
Chemical Structure| 504-15-4
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Product Details of [ 504-15-4 ]

CAS No. :504-15-4 MDL No. :MFCD00002291
Formula : C7H8O2 Boiling Point : -
Linear Structure Formula :- InChI Key :OIPPWFOQEKKFEE-UHFFFAOYSA-N
M.W : 124.14 Pubchem ID :10436
Synonyms :
3,5-Dihydroxytoluene;5-Methylresorcinol;NSC 12441

Calculated chemistry of [ 504-15-4 ]

Physicochemical Properties

Num. heavy atoms : 9
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.14
Num. rotatable bonds : 0
Num. H-bond acceptors : 2.0
Num. H-bond donors : 2.0
Molar Refractivity : 35.45
TPSA : 40.46 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 : Yes
Log Kp (skin permeation) : -5.94 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.19
Log Po/w (XLOGP3) : 1.58
Log Po/w (WLOGP) : 1.41
Log Po/w (MLOGP) : 1.15
Log Po/w (SILICOS-IT) : 1.35
Consensus Log Po/w : 1.33

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.1
Solubility : 0.99 mg/ml ; 0.00797 mol/l
Class : Soluble
Log S (Ali) : -2.04
Solubility : 1.13 mg/ml ; 0.00911 mol/l
Class : Soluble
Log S (SILICOS-IT) : -1.59
Solubility : 3.19 mg/ml ; 0.0257 mol/l
Class : Soluble

Medicinal Chemistry

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

Safety of [ 504-15-4 ]

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 [ 504-15-4 ]

* 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 [ 504-15-4 ]
  • Downstream synthetic route of [ 504-15-4 ]

[ 504-15-4 ] Synthesis Path-Upstream   1~9

  • 1
  • [ 504-15-4 ]
  • [ 68-12-2 ]
  • [ 487-69-4 ]
YieldReaction ConditionsOperation in experiment
98%
Stage #2: With sodium hydroxide In water
The alternative approach is outlined in Figure 2. FORMYLATION of orcinol 8 with POC13 and DMF gave aldehyde 9 (98percent), which was oxidized to the corresponding carboxylic acid 10 (NAC102, 90percent). See, Xie, L. , et al. , J. Med. CHEM., 2001,44, 664 and Nicolaou, K. C. et al. , Chem. Eur. J., 2000,6, 3095. But microwave irradiation of the mixture of compounds 10 and 3a failed to provide any desired product LA. Therefore, the-trimethylsilyl ethyl ester 11 was synthesized, that can be easily deprotected to yield the carboxylic acid. Reaction of 10 with 2- (trimethylsilyl) ethanol under Mitsunobu conditions afforded ester 11 in 90percent yield (Rousch, W. R. , J. Amer. Chem. SOC., 1997, 119, 11331. A mixture of compound 11, aldehyde 3a (2 eq.), CACL2, NEt3, and ETOH was sealed in a Teflon pressure vessel and was irradiated in the microwave oven for 20 times at 1 minute. The desired product 12 was isolated in 60percent yield. Treatment of compound 12 with TBAF gave daurichromenic acid (LA) in 95percent yield. Compound la was irradiated with a low-pressure mercury lamp for about 5 days to afford a mixture OF RHODODAURICHROMANIC acids A (40percent) (5A) and B (20percent) (6a) (based on recovered starting material). The physical data of synthetic daurichromenic acid, and rhododaurichromanic acids A and B are IDENTICAL TO THOSE REPORTED BY KASHIWADA, Y. , Tetrahedron, 2001,53, 1559. The absolute structures of these three compounds were determined based on extensive SPECTROSCOPIC examination and X-ray crystallographic analysis.
82% at 0 - 20℃; for 1 h; 5-methylbenzene-l,3-diol (25.0 g, 0.2 mol) in DMF (100 mL) was added dropwise to a mixture of POCl3 (44.0 g, 0.3 mol) in DMF (200 mL) at 0°C, the mixture was stirred at room temperature for lhr, then the reaction mixture was poured into ice water, solid precipitated and the mixture was filtered and washed with water three times, dried to give 2,4-dihydroxy-6-methylbenzaldehyde (21.0 g, 82.0percent), which was used for next step directly.
75% at 0 - 20℃; Example 39 N-(2-cyano- 1-0 -hydroxy-4-methyl- 1 ,3 -dihydrobenzo [c| [ 1 ,2"|oxaborol-6-yloxy)propan-2- yl)-4-(trifluoromethoxy)benzamide To DMF (233 mL) is added slowly POCl3 (115 mL, 1.23 mol) at 0-10°C. To the resulting mixture is added 5-methyl resorcinol (50.0 g, 0.40 mol) in DMF (116 mL) over 1 h. The resulting mixture is slowly warmed to rt and stirred overnight. It is cooled to -10°C and ice/water (166 mL) is slowly added at -10 to 0°C. The pH is adjusted to 10 with 30 percent NaOH solution (116 g, 0.87 mol). The mixture is heated to 100°C and stirred for 45 min. Then the mixture is cooled to 0°C and acidified by cone. HC1 to pH=l-2. The mixture is stirred at rt for lh, filtered, washed with water and dried to afford the desired product (46.1 g, 75percent yield) as a brown solid.
75%
Stage #1: for 0.5 h; Inert atmosphere; Heating
Stage #2: Inert atmosphere
Synthesis of 2,4-dihydroxy-6-methylbenzaldehyde (6)To a stirred solution of dry DMF (30 mL) was slowly added POCl3 (12.01 mL, 128.9mmol) dropwise at 0 °C under argon. The reaction mixture was stirred for 0.5 h, thenthe 1,3-dihydroxy-5-methylbenzene (5, 8.00 g, 64.4 mmol, dissolved in 30 mL of dryDMF) was slowly added into the mixture. The reaction mixture was stirred overnightand quenched with ice water. Then, an aqueous NaOH solution (10percent) was added tothe mixture until the pH of the solution was 10. The solution was heated to reflux for10 min. After cooling, the mixture was stirred at 0 °C and concentratedhydrochloric acid was added until the pH of solution was 3, then precipitated to afford white powder solid 6 (7.40 g, 75percent).
64% at 0 - 23℃; EXAMPLE 23: General procedure for the synthesis of compounds 2a-l via Mitsunobu cyclization.As depicted in Scheme 25, the preparation of compound 2a-l begins with commercially available orcinol, 8. The description below is not intended to be limiting and alternate analogs may be prepared with the same general process.Formylation of orcinol, synthesis of aldehyde 9. POCl3 (54.9 mL, 600 mmol, 2.0 equiv) was added slowly to a flask containing DMF (100 mL) at 0 0C. To this mixture was then added a solution of orcinol (42.65 g, 300 mmol, 1.0 equiv) as a solution in DMF (100 mL) and the reaction was allowed to warm up to 23 0C and stirred overnight. Then, the reaction was cooled to 0 0C and 200 mL of ice-water were added. The pH of the mixture was adjusted between 6 and 7 by addition of 10percent of NaOH. The mixture was allowed to stand for 30 minutes and then the precipitates were filtered to afford the desired aldehyde 9 (29.2 g, 64percent) as a white solid which was used in the subsequent step without further purification: Rf= 0.31 (Hexane/EtOAc 3/1); 1H NMR ((CD3)2CO, 400 MHz, 25 0C) δ 12.48 (s, IH), 10.10 (s, IH), 9.53 (s, IH), 6.30 (d, J = 2.4 Hz, IH), 6.17 (d, J = 2.0 Hz, IH), 2.54 (s, 3H); 13C NMR ((CD3)2CO, 100 MHz, 25 0C) δ 194.3, 167.3, 166.2, 146.1, 113.8, 111.5, 101.4, 18.2; HRMS (MALDI-TOF) m/z 175.0373 ([M+Na+], C8H8O3Na requires 175.0371).
63%
Stage #1: at 10 - 20℃;
Stage #2: at 90℃;
Stage #3: With hydrogenchloride In water at 10℃;
1.4 DMF (5 eq) is cooled to <10° C., and phosphoryl chloride (1.3 eq) is carefully added dropwise. 3,5-Dihydroxytoluene (1 eq) in DMF (3.4 eq) is subsequently carefully added dropwise at <10° C. and warmed to room temperature overnight. The suspension is cooled, and ice is added. The mixture is subsequently adjusted to pH 9-14 using concentrated NaOH and heated to 90° C. During this operation, the pH is constantly re-adjusted to pH 9-14 using conc. NaOH until the pH has stabilised. The mixture is subsequently cooled to 10° C. and adjusted to pH 1-3 using concentrated hydrochloric acid. The suspension is cooled overnight, filtered with suction and washed with ice-water. The crystals are dried in vacuo, giving the product "7" as orange-yellow powder in a yield of 63percent; m.p. 181-183°; LC-MS: 0.974 min, m/e: 153.1 (M+H+).

Reference: [1] Organic Letters, 2003, vol. 5, # 23, p. 4481 - 4484
[2] Patent: WO2004/58738, 2004, A1, . Location in patent: Page 2/2; 10
[3] Journal of Medicinal Chemistry, 2001, vol. 44, # 5, p. 664 - 671
[4] Patent: WO2017/151489, 2017, A1, . Location in patent: Paragraph 0284
[5] Molecules, 2018, vol. 23, # 10,
[6] Journal of Organic Chemistry, 2005, vol. 70, # 22, p. 8884 - 8889
[7] Tetrahedron Letters, 2010, vol. 51, # 23, p. 3092 - 3094
[8] Patent: WO2014/149793, 2014, A1, . Location in patent: Page/Page column 113-114
[9] Beilstein Journal of Organic Chemistry, 2017, vol. 13, p. 855 - 862
[10] Chemistry - A European Journal, 2005, vol. 11, # 17, p. 4935 - 4952
[11] Patent: WO2008/21213, 2008, A1, . Location in patent: Page/Page column 114; 144
[12] Patent: US2010/16372, 2010, A1, . Location in patent: Page/Page column 12
[13] MedChemComm, 2015, vol. 6, # 4, p. 647 - 652
[14] Organic Letters, 2004, vol. 6, # 20, p. 3617 - 3619
[15] Organic and Biomolecular Chemistry, 2005, vol. 3, # 19, p. 3488 - 3495
[16] Bioorganic and Medicinal Chemistry Letters, 1998, vol. 8, # 16, p. 2151 - 2156
[17] Journal of Medicinal Chemistry, 1998, vol. 41, # 24, p. 4819 - 4832
[18] Journal of Medicinal Chemistry, 1999, vol. 42, # 14, p. 2662 - 2672
[19] Drug Design, Development and Therapy, 2017, vol. 11, p. 1891 - 1904
  • 2
  • [ 504-15-4 ]
  • [ 557-21-1 ]
  • [ 487-69-4 ]
YieldReaction ConditionsOperation in experiment
76%
Stage #1: With hydrogenchloride In diethyl ether for 2 h; Inert atmosphere
Stage #2: at 100℃;
Step 1: Compound (i) to compound (2) Orcinol (5g, 40mmol) and Zn(CN)2 (7-ig, 6ommol) were placed into a 3 necked flask with mechanical stirrer under N2. 50ml of Ether was added, and the reaction was saturated with HC1 gas. After 2 hours, the Ether was decanted off and 50mls of water added to the reaction mixture. This was heated to ioo°C where the product crashed out of solution. The crude product was collected via buchner filtration, and recrystallised from water to yield the aldehyde (4.6g) in 76percent yield.
76%
Stage #1: With hydrogenchloride In diethyl ether for 2 h; Inert atmosphere
Stage #2: With water In diethyl ether at 100℃; Inert atmosphere
Orcinol (5 g, 4 mmol) and Zn(CN)2 (7.1 g, 60 mmol) were placed into a 3 necked flask with mechanical stirrer under N2. 50 ml of Ether was added, and the reaction was saturated with HCl gas. After 2 hours, the Ether was decanted off and 50 mls of water added to the reaction mixture. This was heated to 100° C. where the product crashed out of solution. The crude product was collected via buchner filtration, and recrystallised from water to yield the aldehyde (4.6 g) in 76percent yield.
Reference: [1] Patent: WO2013/160670, 2013, A1, . Location in patent: Page/Page column 24
[2] Patent: US2015/203445, 2015, A1, . Location in patent: Paragraph 0112
  • 3
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  • [ 557-21-1 ]
  • [ 487-69-4 ]
Reference: [1] Angewandte Chemie - International Edition, 1999, vol. 38, # 22, p. 3334 - 3339
[2] Tetrahedron Letters, 1982, vol. 23, # 44, p. 4567 - 4568
[3] Journal of Organic Chemistry, 1985, vol. 50, # 21, p. 3997 - 4005
[4] Angewandte Chemie - International Edition, 1998, vol. 37, # 13-14, p. 1874 - 1876
  • 4
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  • [ 487-69-4 ]
Reference: [1] Tetrahedron Asymmetry, 1990, vol. 1, # 3, p. 187 - 198
[2] Tetrahedron, 1986, vol. 42, # 10, p. 2635 - 2642
  • 5
  • [ 504-15-4 ]
  • [ 74-90-8 ]
  • [ 487-69-4 ]
Reference: [1] Justus Liebigs Annalen der Chemie, 1907, vol. 357, p. 373
[2] Chemische Berichte, 1898, vol. 31, p. 1767
[3] Chemische Berichte, 1899, vol. 32, p. 279
[4] Chemische Berichte, 1899, vol. 32, p. 279
[5] Journal of the American Chemical Society, 1923, vol. 45, p. 2377
  • 6
  • [ 504-15-4 ]
  • [ 50-00-0 ]
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Reference: [1] Angewandte Chemie - International Edition, 2018, vol. 57, # 30, p. 9425 - 9429[2] Angew. Chem., 2018, vol. 130, # 30, p. 9569 - 9573,5
[3] Patent: DE105798, , ,
  • 7
  • [ 504-15-4 ]
  • [ 92114-96-0 ]
  • [ 487-69-4 ]
Reference: [1] Chemische Berichte, 1901, vol. 34, p. 1443
[2] Patent: DE114195, , ,
  • 8
  • [ 504-15-4 ]
  • [ 2032-76-0 ]
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Reference: [1] Chemische Berichte, 1964, vol. 97, p. 2606 - 2613
  • 9
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  • [ 76619-89-1 ]
Reference: [1] Tetrahedron Letters, 1993, vol. 34, # 29, p. 4713 - 4716
[2] Monatshefte fuer Chemie, 1952, vol. 83, p. 24,27, 28
[3] Patent: WO2007/36743, 2007, A2, . Location in patent: Page/Page column 23
[4] Patent: WO2010/40989, 2010, A1, . Location in patent: Page/Page column 24-25
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