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[ CAS No. 652-67-5 ] {[proInfo.proName]}

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Chemical Structure| 652-67-5
Chemical Structure| 652-67-5
Structure of 652-67-5 * Storage: {[proInfo.prStorage]}
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Product Details of [ 652-67-5 ]

CAS No. :652-67-5 MDL No. :MFCD00064827
Formula : C6H10O4 Boiling Point : -
Linear Structure Formula :- InChI Key :KLDXJTOLSGUMSJ-JGWLITMVSA-N
M.W :146.14 Pubchem ID :12597
Synonyms :
Isosorbide

Calculated chemistry of [ 652-67-5 ]

Physicochemical Properties

Num. heavy atoms : 10
Num. arom. heavy atoms : 0
Fraction Csp3 : 1.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 4.0
Num. H-bond donors : 2.0
Molar Refractivity : 31.22
TPSA : 58.92 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) : -8.15 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.27
Log Po/w (XLOGP3) : -1.35
Log Po/w (WLOGP) : -1.49
Log Po/w (MLOGP) : -1.52
Log Po/w (SILICOS-IT) : -0.4
Consensus Log Po/w : -0.7

Druglikeness

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

Water Solubility

Log S (ESOL) : 0.1
Solubility : 186.0 mg/ml ; 1.27 mol/l
Class : Highly soluble
Log S (Ali) : 0.61
Solubility : 599.0 mg/ml ; 4.1 mol/l
Class : Highly soluble
Log S (SILICOS-IT) : 1.07
Solubility : 1730.0 mg/ml ; 11.8 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 3.38

Safety of [ 652-67-5 ]

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

Application In Synthesis of [ 652-67-5 ]

* 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 [ 652-67-5 ]

[ 652-67-5 ] Synthesis Path-Upstream   1~18

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YieldReaction ConditionsOperation in experiment
60 %Spectr. With 5% active carbon-supported ruthenium; hydrogen In water at 220℃; for 3 h; EXAMPLE 1; In a typical experiment the isosorbide solution in water was prepared by adjusting the pH using sodium hydroxide, and degassed with nitrogen by bubbling gas into the solution for 1 hour. The heterogeneous catalyst was weighed in air, placed in a glass liner with the stirring bar, and the liner was introduced into the reactor and the atmosphere was purged twice with nitrogen. The substrate solution was then added via syringe and the reactor was closed and purged 3 times with nitrogen. After purging of the gas lines, hydrogen was used to purge the reactor (3 times). The desired hydrogen pressure was then applied, stirring was started and heating began (typically heating was achieved in 25 minutes). The reaction time started when the desired temperature was reached. [0042] After reaction, the reactor was allowed to cool down to room temperature and the excess gas pressure was released. The crude solution was filtered twice using two microfilters (Millipore, 0.45 μm then 0.20 μm), pH was measured, and the crude reaction mixture was dried in an oven overnight (T=60° C.). The crude syrup was then dried further in a dessicator under high vacuum for ca. 5 hours before analysis. [0043] Experiments 1-12 are outlined in Table 1 below. The first set of reactions (code 1 to 6) was performed using 1.1 g of isosorbide in 30 mL of water with 10 to 20 wt percent of a 5percent Ru/C catalyst at 50° C. for 4 to 24 hours. The crude mixtures were analyzed by 1H NMR is D2O after drying of an aliquot of the solution. No epimerization was observed and only isosorbide was recovered. [0045] Reactions 7 to 10 were used to study the influence of temperature on the reaction and due to the closed system of the reactors, the initial pressure of hydrogen increased from 1 bar at room temperature to 24.5 bar at 220° C. for reaction 10. NMR analysis showed no conversion. [0046] For reaction 11 and 12, the initial hydrogen pressure at room temperature was set at 30.0 bar and 54.5 bar, respectively. The internal pressure increased to 47.0 bar for reaction 11 and to 81.1 bar for reaction 12 at 220° C. Aliquots of the crude reactions mixtures were analyzed with NMR, which showed that for both reactions the epimerization of isosorbide had occurred, and the ratios observed between the three isomers indicates that the thermodynamic equilibrium had been reached within the reaction time of 3 h. EXAMPLE 2; As compared to Example 1, a number of reaction conditions were varied. First the substrate concentration was increased to 33 wt/wt percent, and the catalyst loading was decreased from 20 wt percent to 4 wt percent (Table 2). The reactions were performed at 220° C. for 2 hours using different hydrogen pressures. EXAMPLE 3; A further set of experiments was performed to evaluate a) the effect of increasing the substrate concentration to 50 wt/wt percent isosorbide in water to obtain a good comparison with U.S. Pat. No. 3,023,223, and b) the influence of the support material. All reactions were performed at catalyst loading of 4 wt percent, at 220° C. with a reaction time of 4 hours. The hydrogen pressure was set at 40 bar at room temperature and reached approx. 58 bar at the reaction temperature. EXAMPLE 4; A next set of experiments was performed by tuning the initial pH (Table 4, 5, and 6). For all reactions the substrate concentration was fixed at 50 wt/wt percent isosorbide (10 g) in water, the catalyst used was the 5percent Ru/C (Escat 4401), the temperature was set at 220° C. and hydrogen pressure was tuned at approx. 40 bar at room temperature leading to a total pressure of approx. 60 bar at 220° C. [0050] It is important to notice that the reaction time relates to the time that the reaction mixture is maintained at the experiment temperature, therefore this time is not taking into account the heating time (approx. 30 min in all cases), and the cooling time back to room temperature (approx. 2 hours) The reactions were magnetically stirred and the stirring (1000 rpm) started after the pressurization of the reactors and before the heating started to avoid overshooting of the temperature. EXAMPLE 5; The effect of the catalyst loading on the reaction rate was studied next (Table 7). By decreasing the catalyst loading from 4 wt percent to 2 wt percent the thermodynamic equilibrium was not reached after 1 hour reaction (reaction 49) but was achieved after 2 hours, however with a mass loss of 6.7percent (reaction 56). Using 1 wt percent of catalyst the results appeared similar with the thermodynamic equilibrium reached after 2 hours and a mass loss reduced to 1.3percent (reaction 50, 55). Lower catalyst loading showed no activity (reaction 41). EXAMPLE 6; Different metal catalysts on different supports were tested using the standard reaction conditions and the results were compared to Ru/C (Table 8). EXAMPLE 7; A series of reactions was performed at different temperatures (Table 10). EXAMPLE 8; A large scale reaction was performed in a 600 mL Parr reactor with 200 g of isosorbide (1.37 mol) in 200 mL of water at pH 8 (mechanical stirrer at 500 rpm). Ruthenium (5percent) on carbon (reduced, 50percent water paste, Escat 4401) was used at a loading of 1 wt percent. The reaction vessel was pressurized with 40 bar of hydrogen and heated at 220° C. for 2 hours. Aliquots of the reaction mixture were taken during the heating time and along the reaction. Those aliquots were obtained by manually opening the deep tube tab, then by flushing the tube (2-3 mL), and finally by collecting the sample (2 mL), which was analyzed following the standard procedure (Table 11).
Reference: [1] Patent: EP2615093, 2013, A1, . Location in patent: Paragraph 0109
[2] Patent: WO2013/107735, 2013, A1, . Location in patent: Paragraph 00111
[3] Patent: US2014/371472, 2014, A1, . Location in patent: Paragraph 0041 - 0055
[4] ChemSusChem, 2013, vol. 6, # 4, p. 693 - 700
[5] Patent: WO2016/137833, 2016, A1, . Location in patent: Paragraph 00110-00113
[6] Advanced Synthesis and Catalysis, 2018, vol. 360, # 12, p. 2358 - 2363
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Reference: [1] ChemSusChem, 2010, vol. 3, # 5, p. 566 - 570
[2] Patent: US2009/253920, 2009, A1, . Location in patent: Page/Page column 3
[3] Patent: WO2012/15616, 2012, A1, . Location in patent: Page/Page column 23
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YieldReaction ConditionsOperation in experiment
21% at 150℃; for 5 h; The isosorbide, 1,2-dimethoxyethane, and heteropolyacid were charged into a stainless steel reaction kettle, the autoclave was sealed,The reaction was magnetically stirred at 150 ° C for 5 hours. Wherein the molar ratio of 1,2-dimethoxyethane to isosorbide is 20: 1, heteropoly acidAnd the mass ratio of isosorbide was 0.2: 1. After the reactor was cooled to room temperature, the reaction solution was analyzed by gas chromatography. IsosorbideThe conversion and the yield of its methylated product were calculated in terms of mole percent (molpercent) according to gas chromatography internal standard method.
Reference: [1] Patent: CN105646514, 2016, A, . Location in patent: Paragraph 0041; 0042; 0043; 0044; 0045; 0046
[2] RSC Advances, 2015, vol. 5, # 31, p. 24139 - 24143
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YieldReaction ConditionsOperation in experiment
17% at 130℃; for 15 h; Isosorbide,Methyl etherate and acid catalystAmberlyst-35 was put into a stainless steel reaction kettle,Closed reactor,130 ° C magnetic stirring for 15 hours. among them,The molar ratio of methylating reagent and isosorbide was 50: 1,The mass ratio of catalyst Amberlyst-35 to isosorbide was 0.5: 1. After the reactor was cooled to room temperature,The reaction solution was analyzed by gas chromatography. The conversion of isosorbide and its methylated product yield were calculated by gas chromatography internal standard method,In mole percent.
Reference: [1] Patent: CN105646514, 2016, A, . Location in patent: Paragraph 0029; 0030; 0031; 0032; 0033; 0034
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YieldReaction ConditionsOperation in experiment
15% at 130℃; for 15 h; Isosorbide,Methyl etherate and acid catalystAmberlyst-35 was put into a stainless steel reaction kettle,Closed reactor,130 ° C magnetic stirring for 15 hours. among them,The molar ratio of methylating reagent and isosorbide was 50: 1,The mass ratio of catalyst Amberlyst-35 to isosorbide was 0.5: 1. After the reactor was cooled to room temperature,The reaction solution was analyzed by gas chromatography. The conversion of isosorbide and its methylated product yield were calculated by gas chromatography internal standard method,In mole percent.
Reference: [1] Patent: CN105646514, 2016, A, . Location in patent: Paragraph 0029; 0030; 0031; 0032; 0033; 0034
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  • [ 5306-85-4 ]
YieldReaction ConditionsOperation in experiment
18% at 130℃; for 15 h; Isosorbide,Methyl etherate and acid catalystAmberlyst-35 was put into a stainless steel reaction kettle,Closed reactor,130 ° C magnetic stirring for 15 hours. among them,The molar ratio of methylating reagent and isosorbide was 50: 1,The mass ratio of catalyst Amberlyst-35 to isosorbide was 0.5: 1. After the reactor was cooled to room temperature,The reaction solution was analyzed by gas chromatography. The conversion of isosorbide and its methylated product yield were calculated by gas chromatography internal standard method,In mole percent.
Reference: [1] Patent: CN105646514, 2016, A, . Location in patent: Paragraph 0029; 0030; 0031; 0032; 0033; 0034
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Reference: [1] Patent: US2015/203507, 2015, A1, . Location in patent: Paragraph 0125-0138
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YieldReaction ConditionsOperation in experiment
18% at 100℃; for 3 h; The isosorbide, dimethoxymethane, diethylene glycol dimethyl ether and phosphorus tungsten heteropoly acid into the reaction of stainless steel Kettle, closed reactor, magnetic stirring, at 100 ° C reaction. Among them, the molar ratio of dimethoxymethane and isosorbideIs 30: 1, the molar ratio of diethylene glycol dimethyl ether and isosorbide is 0.5: 1, the mass ratio of phosphotungstic acid to isosorbide is0.5: 1. After the reactor was cooled to room temperature, the reaction solution was analyzed by gas chromatography. Conversion of isosorbide and its methylated product. The yield was calculated according to the gas chromatography internal standard method and expressed in mole percent (ppm).
Reference: [1] Patent: CN105646514, 2016, A, . Location in patent: Paragraph 0053; 0054; 0055; 0056; 0057; 0058
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YieldReaction ConditionsOperation in experiment
14% at 200℃; for 2 h; The isosorbide, diglyme, and acidic catalyst silicotungstic acid were charged into a stainless steel reaction kettle,Sealed reactor, a certain temperature magnetic stirring reaction for 2 hours. Wherein the molar ratio of diethylene glycol dimethyl ether to isosorbide20: 1, and the mass ratio of silicotungsten heteropoly acid to isosorbide was 0.01: 1. The reactor was cooled to room temperature and gas was usedThe reaction solution was analyzed by phase chromatography. The conversion of isosorbide and its methylated product yield were calculated by gas chromatography internal standard method.
Reference: [1] Patent: CN105646514, 2016, A, . Location in patent: Paragraph 0047; 0048; 0049; 0050; 0051; 0052
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Reference: [1] ChemSusChem, 2018, vol. 11, # 3, p. 547 - 551
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Reference: [1] Patent: CN105646514, 2016, A, . Location in patent: Paragraph 0029; 0030; 0031; 0032; 0033; 0034
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Reference: [1] ChemSusChem, 2010, vol. 3, # 5, p. 566 - 570
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Reference: [1] ChemSusChem, 2010, vol. 3, # 5, p. 566 - 570
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Reference: [1] Patent: US9321783, 2016, B2, . Location in patent: Page/Page column 10-11
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Reference: [1] ChemSusChem, 2010, vol. 3, # 5, p. 566 - 570
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Reference: [1] Journal of the Chemical Society, 1946, p. 390,392
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  • [ 652-67-5 ]
  • [ 16106-20-0 ]
  • [ 16051-77-7 ]
  • [ 87-33-2 ]
YieldReaction ConditionsOperation in experiment
214.2 g With nitric acid; acetic anhydride In 2-methyltetrahydrofuran; acetic acid at -10℃; for 0.0105556 h; Flow reactor (1) Preparation of nitrifying reagent: In a 500 mL dry three-necked flask, acetic anhydride (260 g, 2.5mol) was added, and the temperature was controlled at 0 to 10 ° C, and the fuming nitric acid (108g, 1.7mol) was slowly added dropwise. After the addition is completed, the insulation is reserved.(2)Preparation ofisosorbidealcohol solution: In a 2 L dry three-necked flask, isosorbide (250 g, 1.7 mol) was added, and a mixed solvent of750 mL of acetic acid/2-methyltetrahydrofuran (v/v = 2:1) was added. Stir, dissolve and set aside.(3) The nitrating reagent and the isosorbide liquid arefed into the microchannel reactorthrough respectivemetering pumps for mixing reaction, the flow rate of the nitrating reagent is set to 20 mL/min, andthe flow rate of theisosorbide liquidis 60 mL/min, and the reaction is controlled. The temperature was -10 ° C, 5 templates were connected in series, the liquid holding capacity was 50 mL,and the reaction time of thereaction liquid in the microchannelreactor was 38 s.(4) The reaction effluent was sampled by GC and the remaining amount of isosorbide andthe yieldof each productwerecalculated.The specific results are shown in Table 6.
161.5 g With nitric acid; acetic anhydride In 2-methyltetrahydrofuran; acetic acid at -10℃; for 0.0105556 h; Flow reactor (1) Preparation of nitrifying reagent: In a 500 mL dry three-necked flask, acetic anhydride (260 g,2.5 mol) was added, and the temperature was controlled at 0 to 10 ° C, and fuming nitric acid (108 g, 1.7 mol) was slowly added dropwise. After the addition is completed, keep warm for later use.(2)Preparation of isosorbide solution: In a 2 L dry three-necked flask, isosorbide (250 g, 1.7 mol) was added, and a mixed solvent of750 mL of acetic acid/2-methyltetrahydrofuran (v/v = 2:1) was added. Stir, dissolve and set aside.(3) and the nitrating agent isosorbide solution was passed througha respective metering pump is fed into the reaction were mixed in a microchannel reactor, set nitrating agent flow 40mL / min, isosorbidetraffic alcohol solution was 20mL / min, to control the reaction The temperature was -10 ° C, 5 templates were connected in series, the liquid holding capacity was 50 mL,and the reaction time of thereaction liquid in the microchannelreactor was 38 s.(4) The reaction effluent was sampled by GC and the remaining amount of isosorbide andthe yieldof eachproduct werecalculated.The specific results are shown in Table 10.
Reference: [1] Organic Process Research and Development, 2018, vol. 22, # 8, p. 991 - 995
[2] Patent: CN108610350, 2018, A, . Location in patent: Paragraph 0048-0078; 0095; 0097
[3] Patent: CN108610350, 2018, A, . Location in patent: Paragraph 0080-0094
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Reference: [1] Journal of the Chemical Society, Perkin Transactions 1, 2000, # 12, p. 1809 - 1810
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