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[ CAS No. 126-81-8 ] {[proInfo.proName]}

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Chemical Structure| 126-81-8
Chemical Structure| 126-81-8
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Product Details of [ 126-81-8 ]

CAS No. :126-81-8 MDL No. :MFCD00001588
Formula : C8H12O2 Boiling Point : -
Linear Structure Formula :- InChI Key :BADXJIPKFRBFOT-UHFFFAOYSA-N
M.W :140.18 Pubchem ID :31358
Synonyms :

Calculated chemistry of [ 126-81-8 ]

Physicochemical Properties

Num. heavy atoms : 10
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.75
Num. rotatable bonds : 0
Num. H-bond acceptors : 2.0
Num. H-bond donors : 0.0
Molar Refractivity : 38.6
TPSA : 34.14 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) : -6.58 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.42
Log Po/w (XLOGP3) : 0.81
Log Po/w (WLOGP) : 1.33
Log Po/w (MLOGP) : 0.65
Log Po/w (SILICOS-IT) : 2.21
Consensus Log Po/w : 1.28

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.22
Solubility : 8.46 mg/ml ; 0.0603 mol/l
Class : Very soluble
Log S (Ali) : -1.11
Solubility : 10.9 mg/ml ; 0.0779 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -2.06
Solubility : 1.22 mg/ml ; 0.00869 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.58

Safety of [ 126-81-8 ]

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

Application In Synthesis of [ 126-81-8 ]

* 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 [ 126-81-8 ]
  • Downstream synthetic route of [ 126-81-8 ]

[ 126-81-8 ] Synthesis Path-Upstream   1~16

  • 1
  • [ 17280-41-0 ]
  • [ 126-81-8 ]
  • [ 56008-20-9 ]
YieldReaction ConditionsOperation in experiment
52% With acetic acid; zinc In waterReflux Step 1. Synthesis of 3,6,6-trimethyl-6,7-dihydro-lH-indole-4(5H)-on [formula 6-2]Anti-pyruvic aldehyde- 1-oxime [formula 6-1] (0.50 g, 5.74 mmol) and 5,5-dimethyl- 1,3-cyclohexandion [formula 6-7] (0.80 g, 5.74 mmol) were dissolved in acetic acid (35 mL) and H20 (15 mL) . Thereto, zinc powder (0.75 g, 11.5 mmol) was added slowly maintaining room temperature. The reaction mixture was refluxed with stirring, concentrated under reduced pressure and extracted with CH2C12 and brine, of which pH was adjusted to 6 using saturated NaHC03. The reaction mixture was extracted with CH2C12; organic layer was dried over anhydrous MgS04 and filtered. Residue was concentrated under reduced pressure and purified by column chromatography (Si02; hexane/ethylacetate, 1/3) to yield the title compound as yellow solid (4.9 g, 52 percent).
45% With zinc In water; acetic acid at 20℃; Heating / reflux To a solution of anti-pyruvic aldehyde-1-oxime (10 g, 1 eq) and 5, 5-dimethyl-l, 3-cyclohexanedione (16.1 g, 1 eq) in HOAc- H2O (7:3, 200 mL) was added zinc powder (14.95 g, 2 eq) slowly with cooling by a water bath at room temperature. The mixture then was refluxed overnight, concentrated to dryness, partitioned between brine (300 mL) and dichloromethane (300 mL) . The pH was adjusted to ca. 6 with saturated aqueous NaHCO3, then the mixture was extracted with dichloromethane (3x200 mL) . The organic layers were combined, dried overNa2SO4, filtered, concentrated. The crude product was purified by flash chromatography eluting with 5percent ethyl acetate in dichloromethane. The combined organic fractions were concentrated, triturated in ether-hexane (2:1) for 1 hour, then filtered, washed with hexane to give the pure title compound (9 g, 45percent yield) as a solid. LCMS m/z: (M+H) = 178.1.
45%
Stage #1: With acetic acid; zinc In water at 20℃; Heating / reflux
Stage #2: With sodium hydrogencarbonate In dichloromethane; water
To a solution of anti-pyruvic aldehyde-1-oxime (10 g, 1 eq) and 5,5-dimethyl-1,3-cyclohexanedione (16.1 g, 1 eq) in HOAc-H2O (7:3, 200 mL), was added zinc powder (14.95 g, 2 eq) slowly cooling with a water bath at room temperature. The mixture was refluxed overnight, concentrated to dryness, partitioned between brine (300 mL) and dichloromethane (300 mL). The pH was adjusted to ca. 6 with saturated aqueous NaHCO3, then extracted with dichloromethane (3.x.200 mL). The organic layers were combined, dried over Na2SO4, filtered, concentrated to give crude product. This was purified by flash chromatography, eluting with 5percent ethyl acetate in dichloromethane to give expected product, which was triturated in ether-hexane (2:1) for 1 hour, then filtered, washed with hexane to give pure title compound (9 g, 45percent yield) as a solid.
45% With acetic acid; zinc In water at 20℃; Heating / reflux Example 1; 3,6,6-Trimethyl-1,5,6,7-tetrahydro-indol-4-one; To a solution of anti-pyruvic aldehyde-1-oxime (10 g, 1 eq) and 5,5-dimethyl-1,3-cyclohexanedione (16.1 g, 1 eq) in HOAc-H2O (7:3, 200 mL), was added zinc powder (14.95 g, 2 eq) slowly cooling with a water bath at room temperature. The mixture was refluxed overnight, concentrated to dryness, partitioned between brine (300 mL) and dichloromethane (300 mL). The pH was adjusted to ca. 6 with saturated aqueous NaHCO3, then extracted with dichloromethane (3.x.200 mL). The organic layers were combined, dried over Na2SO4, filtered, concentrated to give crude product. This was purified by flash chromatography, eluting with 5percent ethyl acetate in dichloromethane to give expected product, which was triturated in ether-hexane (2:1) for 1 hour, then filtered, washed with hexane to give pure title compound (9 g, 45percent yield) as a solid.

Reference: [1] Patent: WO2013/62344, 2013, A1, . Location in patent: Page/Page column 87
[2] Patent: WO2006/91963, 2006, A1, . Location in patent: Page/Page column 84; 89
[3] Patent: US2008/269193, 2008, A1, . Location in patent: Page/Page column 39
[4] Journal of Medicinal Chemistry, 2009, vol. 52, # 14, p. 4288 - 4305
[5] Patent: US2007/207984, 2007, A1, . Location in patent: Page/Page column 23
  • 2
  • [ 126-81-8 ]
  • [ 306-44-5 ]
  • [ 56008-20-9 ]
YieldReaction ConditionsOperation in experiment
52% With acetic acid; zinc In waterReflux Anti-pyruvic aldehyde-1-oxime [formula 6-1] (0.50 g, 5.74 mmol) and 5,5-dimethyl-1,3-cyclohexandion [formula 6-7] (0.80 g, 5.74 mmol) were dissolved in acetic acid (35 mL) and H2O (15 mL).
Thereto, zinc powder (0.75 g, 11.5 mmol) was added slowly maintaining room temperature.
The reaction mixture was refluxed with stirring, concentrated under reduced pressure and extracted with CH2Cl2 and brine, of which pH was adjusted to 6 using saturated NaHCO3.
The reaction mixture was extracted with CH2Cl2; organic layer was dried over anhydrous MgSO4 and filtered.
Residue was concentrated under reduced pressure and purified by column chromatography (SiO2; hexane/ethylacetate, 1/3) to yield the title compound as yellow solid (4.9 g, 52percent).
45% With acetic acid; zinc In waterReflux Example 1
3,6,6-Trimethyl-1,5,6,7-tetrahydro-indo1-4-one (Intermediate 1)
To a solution of anti-pyruvic aldehyde-1-oxime (10 g, 1 eq) and 5,5-dimethyl-1,3-cyclohexanedione (16.1 g, 1 eq) in HOAc-H2O (7:3, 200 mL) is added zinc powder (14.95 g, 2 eq) slowly with cooling by a water bath at room temperature.
The mixture is then refluxed overnight, concentrated to dryness, partitioned between brine (300 mL) and dichloromethane (300 mL).
The pH is adjusted to ca.
6 with saturated aqueous NaHCO3, then the mixture is extracted with dichloromethane (3*200 mL).
The organic layers are combined, dried over Na2SO4, filtered, concentrated.
The crude product is purified by flash chromatography eluting with 5percent ethyl acetate in dichloromethane.
The combined organic fractions are concentrated, triturated in ether-hexane (2:1) for 1 hour, then filtered, washed with hexane to give the pure title compound (9 g, 45percent yield) as a solid. LCMS m/z: (M+H)=178.1.
Reference: [1] Patent: US2014/315889, 2014, A1, . Location in patent: Paragraph 0417-0419; 0463-0465
[2] Patent: US2015/329493, 2015, A1, . Location in patent: Paragraph 0228; 0232; 0233
  • 3
  • [ 126-81-8 ]
  • [ 56008-20-9 ]
Reference: [1] Bulet. Soc. chim. Romania, vol. 10, p. 134[2] Chem. Zentralbl., 1929, vol. 100, # I, p. 2185
  • 4
  • [ 31915-82-9 ]
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  • [ 56008-20-9 ]
Reference: [1] Journal and Proceedings of the Royal Society of New South Wales, 1932, vol. 66, p. 477,481
  • 5
  • [ 555-16-8 ]
  • [ 126-81-8 ]
  • [ 105-45-3 ]
  • [ 3357-14-0 ]
  • [ 40588-46-3 ]
  • [ 21829-09-4 ]
YieldReaction ConditionsOperation in experiment
8% With C22H25F6N5S; ammonium acetate In dichloromethane at 20℃; for 1 h; To a mixture of 0.014 g (0.1 mol) of dimedone, 0.01 mL (0.1 mol) of methyl acetoacetate, 0.015 g (0.1 mol) of p-nitrobenzaldehyde, and 0.096 g (0.125 mmol) of ammonium acetate at room temperature was added 1 mL of methylene chloride and 5 mmol of catalyst 5–9, the mixture was stirred for 1 h, then the solution was evaporated on a rotary evaporator. From the residue the reaction products were isolated by column chromatography, eluent ethyl acetate–hexane,1 : 8. Compounds were eluted in the following order: 4, 2, 3, and 1. Yield of compound 1 64–72percent.
Reference: [1] Russian Journal of Organic Chemistry, 2016, vol. 52, # 5, p. 701 - 705[2] Zh. Org. Khim., 2016, vol. 52, # 5, p. 713 - 717,5
  • 6
  • [ 126-81-8 ]
  • [ 77571-23-4 ]
  • [ 354-38-1 ]
  • [ 57857-72-4 ]
Reference: [1] Journal of Organic Chemistry USSR (English Translation), 1981, vol. 17, p. 777[2] Zhurnal Organicheskoi Khimii, 1981, vol. 17, # 4, p. 883 - 884
  • 7
  • [ 4244-59-1 ]
  • [ 126-81-8 ]
  • [ 62462-05-9 ]
YieldReaction ConditionsOperation in experiment
47% With pyridine In dichloromethane at 0 - 20℃; To a solution of 3-methoxy propionyl chloride (51.7 g, 359 mmol) and pyridine (87 mL, 1077 mmol) in DCM (400 mL), dimedon (44 g, 359 mmol) was added dropwise at 0 °C to 10 °C. The reaction mixture was stirred overnight at room temperature, 1 N HC1 (400 mL) was added, extracted with DCM (500 mL x 3). The organic layer was washed with water, dried over Na2SO4, filtered, and concentrated to dryness. The oily residue was dissolved in MeOH (400 mL) and refluxed for 2 hrs. The reaction mixture was concentrated to dryness. The residue was purified by silica gel column (PE : EA = 15 : 1) to give the title compound (27 g, 47.0 percent yield) as white oil. 1H NMR (400 MHz CDCl3): δ 3.72 (s, 3H), 3.65-3.62 (m, 2H), 3.49 (s, 2H), 3.31 (s, 3H), 2.78-2.75 (m, 2H).
Reference: [1] Patent: WO2014/64038, 2014, A1, . Location in patent: Page/Page column 45; 46
  • 8
  • [ 126-81-8 ]
  • [ 71942-14-8 ]
  • [ 203808-81-5 ]
Reference: [1] Journal of the Chemical Society, 1913, vol. 103, p. 2181
[2] Journal of the Chemical Society, 1913, vol. 103, p. 1301
[3] Proceedings of the Chemical Society, London, 1913, vol. 28, p. 333[4] Journal of the Chemical Society, 1913, vol. 103, p. 989
  • 9
  • [ 7789-69-7 ]
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  • [ 71942-14-8 ]
  • [ 203808-81-5 ]
  • [ 838841-06-8 ]
Reference: [1] Journal of the Chemical Society, 1913, vol. 103, p. 2181
[2] Journal of the Chemical Society, 1913, vol. 103, p. 1301
[3] Proceedings of the Chemical Society, London, 1913, vol. 28, p. 333[4] Journal of the Chemical Society, 1913, vol. 103, p. 989
  • 10
  • [ 126-81-8 ]
  • [ 150629-67-7 ]
Reference: [1] Patent: US2014/134110, 2014, A1,
[2] Journal of Medicinal Chemistry, 2017, vol. 60, # 22, p. 9290 - 9298
  • 11
  • [ 503-74-2 ]
  • [ 126-81-8 ]
  • [ 172611-72-2 ]
Reference: [1] Tetrahedron Letters, 1998, vol. 39, # 12, p. 1603 - 1606
  • 12
  • [ 126-81-8 ]
  • [ 100-83-4 ]
  • [ 17356-08-0 ]
  • [ 863774-58-7 ]
Reference: [1] RSC Advances, 2015, vol. 5, # 60, p. 48506 - 48515
[2] ACS Catalysis, 2013, vol. 3, # 7, p. 1420 - 1430
[3] Chemistry - A European Journal, 2013, vol. 19, # 13, p. 4156 - 4168
  • 13
  • [ 126-81-8 ]
  • [ 100-83-4 ]
  • [ 17356-08-0 ]
  • [ 863774-58-7 ]
  • [ 1242471-67-5 ]
Reference: [1] Letters in Organic Chemistry, 2010, vol. 7, # 4, p. 314 - 318
  • 14
  • [ 141-97-9 ]
  • [ 126-81-8 ]
  • [ 3218-36-8 ]
  • [ 1099644-42-4 ]
YieldReaction ConditionsOperation in experiment
97% With ammonium acetate In neat (no solvent) at 80℃; for 0.166667 h; Green chemistry General procedure: A mixture of aromatic aldehyde (1 mmol), dimedone (0.14 g, 1 mmol), ethyl acetoacetate (0.13 g, 1 mmol), ammonium acetate (0.115 g, 1.5 mmol), and Fe2O3(at)HAP(at)Melamine (0.15 g) was heated at for 80 °C. Completion of the reactions was monitored by TLC (n-hexan/ethyl acetate 10:3). After satisfactory completion of the reaction and cooling, the reaction mixture was washed with hot ethel acetate and the catalyst was removed by a magnetic field. The solid residue was isolated and purified by recrystallization in hot EtOH.
96% With ammonium acetate In neat (no solvent) at 20℃; for 0.166667 h; Green chemistry General procedure: The nickel(II) Schiff base complex immobilized on MWCNTs as a heterogeneous catalyst (0.005 g) was added to a mixture of aromatic aldehyde (1 mmol), 1,3-dione (1 mmol), ethyl acetoacetate (1 mmol), and ammonium acetate (1.5 mmol) in a round bottom flask and the resulting mixture was stirred magnetically under solvent-free conditions at room temperature. After reaction, as observed by TLC (n-hexane/ethyl acetate: 5/2), ethyl acetate (5 mL) was added to the reaction mixture, stirred and refluxed for 10 min, washed with ethanol (5 mL) and decanted to separate catalyst from other materials (the reaction mixture was soluble in hot ethyl acetate and nanocatalyst was insoluble). The solvent of organic layer was evaporated and the crude product was purified by recrystallization from ethanol. In this study, nanoheterogeneous catalyst was recycled and reused for seven times without significant loss of its catalytic activity.
96% With ammonium acetate; ascorbic acid In neat (no solvent) at 80℃; for 5 h; Green chemistry General procedure: A mixture of aldehyde (1 mmol), cyclic 1,3-diketone (1 mmol), ethyl acetoacetate (1 mmol), ammonium acetate (1 mmol), and ascorbic acid (5percent mol) was stirred at 80 °C under solvent-free conditions for appropriate time (Table 3). After complete conversion as indicated by TLC, the reaction mixture was cooled to room temperature, poured onto ice-cold water (10 mL), and stirred for about 10 min. The formed solid was filtered off, washed with cold water, and purified by simple crystallization in ethanol.
88% With bismuth(III) bromide; ammonium acetate In ethanol at 20℃; for 3 h; General procedure: A homogeneous mixture of p-tolualdehyde (0.5000 g,4.16 mmol), dimedone (0.6417 g, 4.58 mmol, 1.1 equiv), ethyl acetoacetate(0.5968 g, 0.58 mL, 4.58 mmol, 1.1 equiv), and ammonium acetate (0.3528 g,4.58 mmol, 1.1 equiv) was stirred in anhydrous ethanol (10.0 mL) at roomtemperature as BiBr3 (0.0373 g, 2.0 mol percent) was added. The reaction progresswas monitored by TLC (2,4-DNP stain). After 1.5 h, the reaction mixture waspoured onto 20 g of ice and the resulting yellow precipitate was collected viasuction filtration. The crude product was recrystallized using anhydrousethanol (approximately 30 mL) to yield 1.2694 g (86percent yield) of a slightly offwhite,powdery compound. Mpt: 258–259 C (Lit: 258–259 C).
38% With ammonium acetate; iodine In ethanol at 20℃; General procedure: 1 eq. of a cyclic 1,3-dicarbonyl compound 2, 1 eq. of the desired aldehyde 5, 1 eq. of a 1,3-dicarbonyl compound 3, 1 eq. of dried NH4OAc and 0.3 eq. of iodine were stirred in EtOH (2.5 mL/mmol) overnight at room temperature. The solvent was evaporated and the residue was dissolved in EtOAc. The organic layer was washed twice with a saturated solution of NaS2O3 and brine, dried over MgSO4 and concentrated under reduced pressure. The crude material was purified by recrystallization or flash chromatography.

Reference: [1] RSC Advances, 2014, vol. 4, # 101, p. 57662 - 57670
[2] Research on Chemical Intermediates, 2015, vol. 41, # 10, p. 7227 - 7244
[3] Applied Organometallic Chemistry, 2016, vol. 30, # 5, p. 311 - 317
[4] Journal of Coordination Chemistry, 2017, vol. 70, # 2, p. 340 - 360
[5] Synthetic Communications, 2017, vol. 47, # 12, p. 1185 - 1191
[6] RSC Advances, 2016, vol. 6, # 110, p. 108896 - 108907
[7] RSC Advances, 2015, vol. 5, # 68, p. 55303 - 55312
[8] Tetrahedron Letters, 2015, vol. 56, # 27, p. 4060 - 4062
[9] Chemical Communications, 2011, vol. 47, # 1, p. 529 - 531
[10] RSC Advances, 2017, vol. 7, # 89, p. 56764 - 56770
[11] European Journal of Medicinal Chemistry, 2015, vol. 95, p. 249 - 266
  • 15
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  • [ 105-45-3 ]
  • [ 3218-36-8 ]
  • [ 1099644-42-4 ]
Reference: [1] Journal of Medicinal Chemistry, 2012, vol. 55, # 22, p. 9946 - 9957
  • 16
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  • [ 126-81-8 ]
  • [ 91-59-8 ]
  • [ 311795-38-7 ]
Reference: [1] Patent: WO2016/90350, 2016, A1, . Location in patent: Paragraph 0125
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