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[ CAS No. 1452-15-9 ] {[proInfo.proName]}

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Chemical Structure| 1452-15-9
Chemical Structure| 1452-15-9
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Product Details of [ 1452-15-9 ]

CAS No. :1452-15-9 MDL No. :MFCD00137817
Formula : C4H2N2S Boiling Point : -
Linear Structure Formula :- InChI Key :PNAFRZGWUVQUKH-UHFFFAOYSA-N
M.W : 110.14 Pubchem ID :15069
Synonyms :

Calculated chemistry of [ 1452-15-9 ]

Physicochemical Properties

Num. heavy atoms : 7
Num. arom. heavy atoms : 5
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 2.0
Num. H-bond donors : 0.0
Molar Refractivity : 26.83
TPSA : 64.92 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) : -6.26 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.27
Log Po/w (XLOGP3) : 1.0
Log Po/w (WLOGP) : 1.01
Log Po/w (MLOGP) : -0.97
Log Po/w (SILICOS-IT) : 2.14
Consensus Log Po/w : 0.89

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 2.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -1.68
Solubility : 2.29 mg/ml ; 0.0208 mol/l
Class : Very soluble
Log S (Ali) : -1.95
Solubility : 1.23 mg/ml ; 0.0112 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -1.32
Solubility : 5.31 mg/ml ; 0.0482 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.19

Safety of [ 1452-15-9 ]

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 [ 1452-15-9 ]

* 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 [ 1452-15-9 ]
  • Downstream synthetic route of [ 1452-15-9 ]

[ 1452-15-9 ] Synthesis Path-Upstream   1~14

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Reference: [1] Journal of Medicinal Chemistry, 1972, vol. 15, p. 982 - 985
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YieldReaction ConditionsOperation in experiment
85% at 325℃; for 1 h; General procedure: Into a 1L open reactor was added 500g of carboxylic acid raw material (chemically pure) and stirring was turned on (600 r/min) from the reactorThe bottom is continuously fed with ammonia gas (chemical purity, water content of 5.1percent by weight, flow rate of 100 g/min) to the carboxylic acid feed. After the reaction was allowed to proceed for TC hours at the reaction temperature TA, ammonia gas flow was stopped. The contents of the reactor were sampled and subjected to nuclear magnetic proton and elemental analysis to characterize the amide intermediate. Specific reaction conditions and characterization results are shown in Table A-1, Table A-2, Table A-3, Table A-4, Table A-5 and Table A-6. These characterization results show that the amide intermediates obtained have an extremely high purity (above 99percent).In this embodiment, the ammonia gas can be directly replaced with waste ammonia gas (from Yangzi Petrochemical Plant, containing approximately50wtpercent of ammonia gas, the rest were toluene, oxygen, nitrogen, steam, carbon monoxide, and carbon dioxide, and the flow rate of this waste ammonia was 130g/min).
7.6 g With triethylamine; trifluoroacetic anhydride In tetrahydrofuran at 0 - 20℃; for 18 h; To a solution of thiazole-4-carboxamide (10. Og, 67.1 mmol) in THF (150 mL) were slowly added triethylamine ( 42.1 mL, 302 mmol) and TFAA (19 mL, 134 mmol) at 0 °C successively. After being slowly warmed to rt and stirred for 18 hrs, the reaction mixture was diluted with H20 (100 mL) and extracted in DCM (50 mL) for three times. The combined organic phase was concentrated in vacuo and the residue was purified by column chromatography (eluting with PE/EA=5/1, v:v) to give thiazole-4-carbonitrile (7.6 g) as yellow oil.
Reference: [1] Patent: CN104557357, 2018, B, . Location in patent: Paragraph 0150; 0151; 0152; 0162
[2] ACS Medicinal Chemistry Letters, 2014, vol. 5, # 6, p. 628 - 633
[3] Helvetica Chimica Acta, 1957, vol. 40, p. 554,558
[4] Bulletin de la Societe Chimique de France, 1969, p. 4026 - 4031
[5] Journal of the Chemical Society, 1960, p. 916 - 925
[6] Patent: WO2018/83081, 2018, A1, . Location in patent: Page/Page column 42; 43
[7] Patent: WO2007/138343, 2007, A1, . Location in patent: Page/Page column 7; 8
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Reference: [1] Organic Letters, 2015, vol. 17, # 2, p. 202 - 205
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Reference: [1] Synlett, 2009, # 20, p. 3378 - 3382
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Reference: [1] Patent: US4010173, 1977, A,
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Reference: [1] Angewandte Chemie - International Edition, 2013, vol. 52, # 38, p. 10035 - 10039[2] Angew. Chem., 2013, vol. 125, # 38, p. 10219 - 10223
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Reference: [1] Journal of the American Chemical Society, 2015, vol. 137, # 2, p. 648 - 651
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Reference: [1] Synthesis, 1976, p. 681 - 682
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YieldReaction ConditionsOperation in experiment
87.1% With methanesulfonic acid In water EXAMPLE 18
Synthesis of thiabendazole using anhydrous methanesulfonic acid as the acid catalyst
To a 500 ml four-neck, round-bottom flask fitted with a mechanical stirrer, thermometer with N2 inlet and a condenser equipped with a water scrubber (200 ml of water) were charged 160 ml of 1-butanol and 0.1 g (5.7*10-4 mole) of ascorbic acid.
The entire assembly was flushed with N2 and a N2 sweep was maintained on the system for the duration of the reaction.
Following this, 54 g (0.5 mole) of o-phenylenediamine and 55 g (0.5 mole) of 4-cyanothiazole were charged to the reaction vessel.
Next, 26 ml (0.39 mole) of methanesulfonic acid were added dropwise to the reaction vessel and a 20° C. rise in the room temperature mixture was observed.
Subsequently, the mixture was heated to reflux, 127.5° C., and after 2 hours the reflux temperature decreased to 120° C.
After 6 hours at reflux, the reaction was determined to be complete via gas chromatography.
The same procedure as that described in Example 1 was used to transfer, isolate and dry thiabendazole.
The weight of dry thiabendazole crystals was 87.60 g, which corresponds to an 87.1percent yield.
The purity was determined to be 99.84percent (based on area percent) using HPLC analysis.
75.4% With acetic acid In water EXAMPLE 19
Synthesis of thiabendazole using anhydrous acetic acid as the acid catalyst
To a 500 ml four-neck, round-bottom flask fitted with a mechanical stirrer, thermometer with N2 inlet and a condenser equipped with a water scrubber (200 ml of water) were charged 75 ml of 1-butanol and 0.05 g (2.8*10-4 mole) of ascorbic acid.
The entire assembly was flushed with N2 and a N2 sweep was maintained on the system for the duration of the reaction.
Following this, 27 g (0.25 mole) of o-phenylenediamine, 27.5 g (0.25 mole) of 4-cyanothiazole, and 13 ml (0.23 mole) of acetic acid were charged to the reaction vessel.
The mixture was heated to reflux, 121° C., and after 8 hours at reflux the reaction was determined to be complete via gas chromatography.
The reaction mass was cooled to room temperature and 20 ml of 1-butanol were added to thin the reaction mixture.
The same procedure as that described in Example 1 was used to isolate and dry thiabendazole.
The weight of dry thiabendazole crystals was 37.92 g, which corresponds to a 75.4percent yield.
The purity was determined to be 99.73percent (based on area percent) using HPLC analysis.
Reference: [1] Patent: US5310923, 1994, A,
[2] Patent: US5310923, 1994, A,
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YieldReaction ConditionsOperation in experiment
91.7% With hydrogenchloride; ethylenediaminetetraacetic acid In methanol; water EXAMPLE 5
Preparation of Thiabendazole in Water with Dropwise Addition of 4-Cyanothiazole Dissolved in Methanol, Which is Distilled Off During Addition
To a 500 ml four-neck, round-bottom flask fitted with a mechanical stirrer, condenser, thermometer and pH probe were charged 100 ml of deionized water, 0.1 grams (3.4*10-4 mole) of EDTA and 0.1 grams (5.7*10-4 mole) ascorbic acid.
The reaction vessel was purged with nitrogen and then nitrogen blanketed for the duration of the reaction.
The aqueous solution containing EDTA and ascorbic acid was heated using an oil bath.
When the solution temperature reached 95° C., 54 grams (0.5 mole) of o-phenylenediamine were charged, followed by, dropwise addition of 16 ml concentrated hydrochloric acid (corresponding to 38percent hydrogen chloride) to adjust the pH to a value of 4.0.
Subsequently, 55 grams (0.5 mole) of 4-cyanothiazole were dissolved in 100 ml of methanol and added dropwise over 2 hours to the aqueous solution of o-phenylenediamine monohydrochloride.
Methanol was distilled out of the reaction vessel via a take off condenser during addition.
The reaction mixture was heated to reflux and after 50 min at reflux 50 ml of deionized water was added.
The reaction mixture was held at reflux (103°-104° C.) for a period of 3 hours.
During this time, the pH was maintained at approximately 4.0 (+/-0.2) by periodic addition of 38percent HCl solution.
An additional 25.5 ml of 38percent HCl solution was added to the reaction mixture during the course of the reaction.
The reaction mass was allowed to cool to 50° C. before being vacuum filtered using a medium fritted glass filter.
The same procedure as that described in Example 1 was carried out for washing and drying of thiabendazole.
A total of 92.20 grams of thiabendazole were obtained which corresponds to a 91.7percent yield. HPLC analysis showed that the purity was 98.80percent (based on percent area).
Reference: [1] Patent: US5310924, 1994, A,
[2] Patent: US5310924, 1994, A,
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YieldReaction ConditionsOperation in experiment
92.7% With hydrogenchloride; ethylenediaminetetraacetic acid In water EXAMPLE 9
Preparation of Thiabendazole in Water Using Inverse Addition
The same procedure as that described in Example 1 was carried out with the exception that 54 grams (0.5 mole) of o-phenylenediamine were dissolved in 100 ml of deionized water and adjusted to a pH of 4.0 at room temperature using 28 ml of concentrated hydrochloric acid (corresponding to 38percent hydrogen chloride).
The resulting solution was added dropwise over 2 hours to the reaction vessel containing a solution at 95° C. comprising 100 ml of deionized water, 0.1 gram (3.4*10-4 mole) of EDTA, 0.1 gram (5.7*10-4 mole) of ascorbic acid and 55 grams (0.5 mole) of 4-cyanothiazole.
Following this, the reaction mixture was refluxed (103°-104° C.) for 7 hours.
During this time the reaction mixture was maintained at a pH of approximately 4.0 (+/-0.2) by addition of 38percent HCl solution.
An additional 13.5 ml of 38percent HCl solution was added to the reaction mixture during the course of the reaction.
The same procedure as that described in Example 5 was carried out for filtration, washing and drying of thiabendazole.
A total of 93.22 grams of thiabendazole were obtained which corresponds to a 92.7percent yield. HPLC analysis showed that the purity was 98.64percent (based on percent area).
Reference: [1] Patent: US5310924, 1994, A,
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Reference: [1] Patent: US5310923, 1994, A,
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Reference: [1] Patent: US5310923, 1994, A,
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Reference: [1] Patent: US5310923, 1994, A,
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