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Chemical Structure| 1003-31-2 Chemical Structure| 1003-31-2

Structure of 1003-31-2

Chemical Structure| 1003-31-2

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Product Details of [ 1003-31-2 ]

CAS No. :1003-31-2
Formula : C5H3NS
M.W : 109.15
SMILES Code : C1=C(SC=C1)C#N
MDL No. :MFCD00005416
InChI Key :CUPOOAWTRIURFT-UHFFFAOYSA-N
Pubchem ID :66087

Safety of [ 1003-31-2 ]

GHS Pictogram:
Signal Word:Danger
Hazard Statements:H225-H302-H312-H314
Precautionary Statements:P280-P303+P361+P353-P305+P351+P338-P310
Class:3(8)
UN#:2924
Packing Group:

Computational Chemistry of [ 1003-31-2 ] Show Less

Physicochemical Properties

Num. heavy atoms 7
Num. arom. heavy atoms 5
Fraction Csp3 0.0
Num. rotatable bonds 0
Num. H-bond acceptors 1.0
Num. H-bond donors 0.0
Molar Refractivity 29.03
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

52.03 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

1.56
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

1.27
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

1.62
Log Po/w (MLOGP)?

MLOGP: Topological method implemented from
Moriguchi I. et al. 1992 Chem. Pharm. Bull.
Moriguchi I. et al. 1994 Chem. Pharm. Bull.
Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.

0.37
Log Po/w (SILICOS-IT)?

SILICOS-IT: Hybrid fragmental/topological method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

2.55
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.47

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-1.85
Solubility 1.56 mg/ml ; 0.0143 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Very soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-1.96
Solubility 1.19 mg/ml ; 0.0109 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Very soluble
Log S (SILICOS-IT)?

SILICOS-IT: Fragmental method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

-1.69
Solubility 2.24 mg/ml ; 0.0205 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble

Pharmacokinetics

GI absorption?

Gatrointestinal absorption: according to the white of the BOILED-Egg

High
BBB permeant?

BBB permeation: according to the yolk of the BOILED-Egg

Yes
P-gp substrate?

P-glycoprotein substrate: SVM model built on 1033 molecules (training set)
and tested on 415 molecules (test set)
10-fold CV: ACC=0.72 / AUC=0.77
External: ACC=0.88 / AUC=0.94

No
CYP1A2 inhibitor?

Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.83 / AUC=0.90
External: ACC=0.84 / AUC=0.91

No
CYP2C19 inhibitor?

Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.80 / AUC=0.86
External: ACC=0.80 / AUC=0.87

No
CYP2C9 inhibitor?

Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set)
and tested on 2075 molecules (test set)
10-fold CV: ACC=0.78 / AUC=0.85
External: ACC=0.71 / AUC=0.81

No
CYP2D6 inhibitor?

Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set)
and tested on 1068 molecules (test set)
10-fold CV: ACC=0.79 / AUC=0.85
External: ACC=0.81 / AUC=0.87

No
CYP3A4 inhibitor?

Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set)
and tested on 2579 molecules (test set)
10-fold CV: ACC=0.77 / AUC=0.85
External: ACC=0.78 / AUC=0.86

No
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-6.06 cm/s

Druglikeness

Lipinski?

Lipinski (Pfizer) filter: implemented from
Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev.
MW ≤ 500
MLOGP ≤ 4.15
N or O ≤ 10
NH or OH ≤ 5

0.0
Ghose?

Ghose filter: implemented from
Ghose AK. et al. 1999 J. Comb. Chem.
160 ≤ MW ≤ 480
-0.4 ≤ WLOGP ≤ 5.6
40 ≤ MR ≤ 130
20 ≤ atoms ≤ 70

None
Veber?

Veber (GSK) filter: implemented from
Veber DF. et al. 2002 J. Med. Chem.
Rotatable bonds ≤ 10
TPSA ≤ 140

0.0
Egan?

Egan (Pharmacia) filter: implemented from
Egan WJ. et al. 2000 J. Med. Chem.
WLOGP ≤ 5.88
TPSA ≤ 131.6

0.0
Muegge?

Muegge (Bayer) filter: implemented from
Muegge I. et al. 2001 J. Med. Chem.
200 ≤ MW ≤ 600
-2 ≤ XLOGP ≤ 5
TPSA ≤ 150
Num. rings ≤ 7
Num. carbon > 4
Num. heteroatoms > 1
Num. rotatable bonds ≤ 15
H-bond acc. ≤ 10
H-bond don. ≤ 5

1.0
Bioavailability Score?

Abbott Bioavailability Score: Probability of F > 10% in rat
implemented from
Martin YC. 2005 J. Med. Chem.

0.55

Medicinal Chemistry

PAINS?

Pan Assay Interference Structures: implemented from
Baell JB. & Holloway GA. 2010 J. Med. Chem.

0.0 alert
Brenk?

Structural Alert: implemented from
Brenk R. et al. 2008 ChemMedChem

0.0 alert: heavy_metal
Leadlikeness?

Leadlikeness: implemented from
Teague SJ. 1999 Angew. Chem. Int. Ed.
250 ≤ MW ≤ 350
XLOGP ≤ 3.5
Num. rotatable bonds ≤ 7

No; 1 violation:MW<1.0
Synthetic accessibility?

Synthetic accessibility score: from 1 (very easy) to 10 (very difficult)
based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties,
trained on 12'782'590 molecules and tested on 40 external molecules (r2 = 0.94)

2.07

Application In Synthesis of [ 1003-31-2 ]

* 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.

  • Downstream synthetic route of [ 1003-31-2 ]

[ 1003-31-2 ] Synthesis Path-Downstream   1~8

  • 1
  • [ 1003-31-2 ]
  • [ 21512-16-3 ]
YieldReaction ConditionsOperation in experiment
6.9 g (84%) With n-butyllithium; diisopropylamine; citric acid; In tetrahydrofuran; N-methyl-acetamide; water; ethyl acetate; EXAMPLE 65 STR100 A) Preparation of 2-cyano-5-formylthiophene To a flame-dried 3 neck 1 L round bottom flask was added diisopropylamine (9 mL, 66 mmol) and THF (150 mL) under a nitrogen atmosphere. The flask was cooled to an internal temperature of -78° C. (dry ice/acetone). To this stirring solution was added n-butyllithium (1.6 M in hexanes, 41.3 mL, 66.1 mmol) via syringe and the mixture was allowed to stir for 5 min. To this solution was added a solution of 2-thiophenecarbonitrile (6.55 g, 60 mmol) in THF (30 mL) over 10 min. The resulting bright red solution was allowed to stir at -78° C. for 45 min, at which time dimethylformamide (23.3 mL, 300 mmol) was added via syringe. This mixture was allowed to stir for 2 h at -78° C. and then solid citric acid (about 10 g) was added followed by water (60 mL). Volatile solvents were removed in vacuo and the residue was partitioned between diethyl ether and brine (200 mL each). Layers were separated and the aqueous phase was washed once with diethyl ether. The combined organic phase was washed once with brine, dried (MgSO4), filtered and concentrated in vacuo to give a yellow solid which was purified by silica gel chromatography using an ethyl acetate/hexanes gradient (hexanes to 50percent ethyl acetate/hexanes). Fractions containing pure product were pooled and concentrated in vacuo to give 6.9 g (84percent) of 2-cyano-5-formyl-thiophene.
6.9 g (84%) With n-butyllithium; diisopropylamine; citric acid; In tetrahydrofuran; N-methyl-acetamide; water; ethyl acetate; EXAMPLE 65 STR95 A) Preparation of 2-cyano-5-formylthiophene To a flame-dried 3 neck 1L round bottom flask was added diisopropylamine (9 mL, 66 mmol) and THF (150 mL) under a nitrogen atmosphere. The flask was cooled to an internal temperature of -78° C. (dry ice/acetone). To this stirring solution was added n-butyllithium (1.6M in hexanes, 41.3 mL, 66.1 mmol) via syringe and the mixture was allowed to stir for 5 min. To this solution was added a solution of 2-thiophenecarbonitrile (6.55 g, 60 mmol) in THF (30 mL) over 10 min. The resulting bright red solution was allowed to stir at -78° C. for 45 min, at which time dimethylformamide (23.3 mL, 300 mmol) was added via syringe. This mixture was allowed to stir for 2 h at -78° C. and then solid citric acid (about 10 g) was added followed by water (60 mL). Volatile solvents were removed in vacuo and the residue was partitioned between diethyl ether and brine (200 mL each). Layers were separated and the aqueous phase was washed once with diethyl ether. The combined organic phase was washed once with brine, dried (MgSO4), filtered and concentrated in vacuo to give a yellow solid which was purified by silica gel chromatography using an ethyl acetate/hexanes gradient (hexanes to 50percent ethyl acetate/hexanes). Fractions containing pure product were pooled and concentrated in vacuo to give 6.9 g (84percent) of 2-cyano-5-formyl-thiophene.
6.9 g (84%) With n-butyllithium; diisopropylamine; citric acid; In tetrahydrofuran; N-methyl-acetamide; water; ethyl acetate; A) Preparation of 2-cyano-5-formylthiophene To a flame-dried 3 neck 1L round bottom flask was added diisopropylamine (9 mL, 66 mmol) and THF (150 mL) under a nitrogen atmosphere. The flask was cooled to an internal temperature of -78° C. (dry ice/acetone). To this stirring solution was added n-butyllithium (1.6M in hexanes, 41.3 mL, 66.1 mmol) via syringe and the mixture was allowed to stir for 5 min. To this solution was added a solution of 2-thiophenecarbonitrile (6.55 g, 60 mmol) in THF (30 mL) over 10 min. The resulting bright red solution was allowed to stir at -78° C. for 45 min, at which time dimethylformamide (23.3 mL, 300 mmol) was added via syringe. This mixture was allowed to stir for 2 h at -78° C. and then solid citric acid (about 10 g) was added followed by water (60 mL). Volatile solvents were removed in vacuo and the residue was partitioned between diethyl ether and brine (200 mL each). Layers were separated and the aqueous phase was washed once with diethyl ether. The combined organic phase was washed once with brine, dried (MgSO4), filtered and concentrated in vacuo to give a yellow solid which was purified by silica gel chromatography using an ethyl acetate/hexanes gradient (hexanes to 50percent ethyl acetate/hexanes). Fractions containing pure product were pooled and concentrated in vacuo to give 6.9 g (84percent) of 2-cyano-5-formyl-thiophene.
6.9 g (84%) With n-butyllithium; diisopropylamine; citric acid; In tetrahydrofuran; N-methyl-acetamide; water; ethyl acetate; EXAMPLE 65 STR106 A) Preparation of 2-cyano-5-formylthiophene To a flame-dried 3 neck 1 L round bottom flask was added diisopropylamine (9 mL, 66 mmol) and THF (150 mL) under a nitrogen atmosphere. The flask was cooled to an internal temperature of -78° C. (dry ice/acetone). To this stirring solution was added n-butyllithium (1.6M in hexanes, 41.3 mL, 66.1 mmol) via syringe and the mixture was allowed to stir for 5 min. To this solution was added a solution of 2-thiophenecarbonitrile (6.55 g, 60 mmol) in THF (30 mL) over 10 min. The resulting bright red solution was allowed to stir at -78° C. for 45 min, at which time dimethylformamide (23.3 mL, 300 mmol) was added via syringe. This mixture was allowed to stir for 2 h at -78° C. and then solid citric acid (about 10 g) was added followed by water (60 mL). Volatile solvents were removed in vacuo and the residue was partitioned between diethyl ether and brine (200 mL each). Layers were separated and the aqueous phase was washed once with diethyl ether. The combined organic phase was washed once with brine, dried (MgSO4), filtered and concentrated in vacuo to give a yellow solid which was purified by silica gel chromatography using an ethyl acetate/hexanes gradient (hexanes to 50percent ethyl acetate/hexanes). Fractions containing pure product were pooled and concentrated in vacuo to give 6.9 g (84percent) of 2-cyano-5-formyl-thiophene.
50%Chromat. A solution of diisopropylamine (35.3 ml, 0.251 moles) in tetrahydrofuran (500 ml) was cooled to -78 C. under a nitrogen blanket. To this was added 1.6M n-butyllithium in hexanes (157 ml, 0.251 moles) and allowed to stir for 5 min. Then slowly added thiopene-2-carbonitrile (21.33 ml, 0.229 moles) in tetrahydrofuran (115 ml) and allowed to stir. After 45 min. was added NN-dimethylformamide (88.66 ml, 1.145 moles) at -78 C. Citric acid (40 g) was added after 2 h. followed by water (240 ml) and stirred for 18 h. The reaction was concentrated in vacuo, transferred to a separatory funnel, diluted with brine, and extracted twice with ether. The combined ether layers were washed with brine, dried over magnesium sulfate, filtered, and the solvent removed in vacuo. Chromatography yielded 15.8 g (50percent) of 2-cyano-5-formylthiophene (EX-55A) as a brown solid: 1H NMR (300 MHZ, CDCl3) d 10.02 (s, 1H), 7.79 (m, 1H), 7.30 (m, 1H).

  • 2
  • [ 1003-31-2 ]
  • [ 68-12-2 ]
  • [ 21512-16-3 ]
YieldReaction ConditionsOperation in experiment
76% Method C5- Formylthiophene-2-carbonitrile (Intermediate compound)Under inert atmosphere BuLi (1 1 .7 ml, 29.3 mmol, 2.5 M) was added to a mixture of diisopropylamine (4.1 ml, 29.3 mmol) and THF (150 ml) at below - 70°C. When addition was finished, the mixture was allowed to reach room- temperature. The mixture was cooled back to -70°C again, where 2- thiophenecarbonitrile (3.0 g, 26.7 mmol), solved in THF (15 ml) was added drop- wise and stirred an additional hour. At -78°C. DMF (8.2 ml, 106.6 mmol) was added below -70°C. The mixture was stirred for 1 .5 h at -78°C. Citric acid (10 g) was added to the reaction-mixture. The reaction-mixture was poured out on water. The aqueous phase was extracted with diethylether. The product was dried and evaporated. The reaction mixture was purified by silica gel column chromatography using 10-50percent heptane/EtOAc as solvent. The product was isolated as a solid. Yield 2.8 g (76percent).
5-formylthiophene-2-carbonitrile A tetrahydrofuran solution (250 mL) of lithium diisopropyl amide (1.09N hexane solution, 92.8 mL, manufactured by Kanto Chemical Co., Inc) was cooled down at -78° C., and a tetrahydrofuran solution (50 mL) of 2-cyanothiophene (8.55 mL, manufactured by Aldrich) was dropped thereto. After that, the resultant mixture was stirred for 45 minutes at the same temperature, N,N-dimethyl formamide (30 mL, manufactured by Kanto Chemical Co., Inc) was added to the mixture, and the resultant blend was stirred for 1 hour. After the stirring was ended, citric acid (20 g, manufactured by Wako Pure Chemical Industries, Ltd.) was added to the reaction solution and the resultant was poured into water. After tetrahydrofuran was distilled away, extraction was performed by using diethyl ether. An organic layer was washed with a saturated saline solution, and dried by using magnesium sulfate. After concentrating at a reduced pressure, chromatography (as an elution solution, 4:1 (v/v) of hexane/ethyl acetate was used) using Biotage 40M cartridge was performed, so that the titled compound (7.45 g) was obtained. 1H-NMR (CDCl3): 10.0 (1H, s), 7.77 (1H, d, J=3.3), 7.74 (1H, d, J-3.3)
  • 3
  • [ 1003-31-2 ]
  • [ 1455-20-5 ]
  • [ 1322575-28-9 ]
  • 5
  • [ 1003-31-2 ]
  • [ 1000623-95-9 ]
  • [ 1269004-58-1 ]
  • 6
  • [ 188290-36-0 ]
  • [ 1003-31-2 ]
  • [ 704-38-1 ]
  • 7
  • [ 1003-31-2 ]
  • [ 4805-22-5 ]
  • [2,2’:5′,2’’:5'',2''-quaterthiophene]-5,5''''-dicarbonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
72% With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; Trimethylacetic acid; In N,N-dimethyl acetamide; toluene; at 110℃; for 48h;Inert atmosphere; General procedure: A mixture of aryl bromide (1 eq.), 2-thiophenecarbonitrile (3 eq.per site), K2CO3 (1.5 eq. per site), pivalic acid (0.15 eq. per site) andPd(PPh3)4 (4 mol % per site) in a solvent mixture of dry N,Ndimethylacetamide/toluene 50:50 (v/v %), C:0.23 M, was stirredunder argon atmosphere at 110 C during 48h. The reaction mixturewas then diluted with water, filtered on Celite and washed withdiethyl ether. The solidwas resolubilized in THF/diethyl ether 50:50(v/v %) and centrifuged (15 min, 4000 rpm, rt). The white solid waseliminated and the solution evaporated to give a product whichwas purified by successive recrystallizations in appropriate solvents:3, 4 and 6 in 1-butanol and 5 in toluene at room temperature.Yields: (3) 35%, yellow solid; (4) 45%, orange solid; (5) 72%, redsolid; (6) 93%, green solid. All amounts were calculated based oneach reactive site (-Br) of the starting precursor.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; Trimethylacetic acid; In N,N-dimethyl acetamide; toluene; at 110℃; for 48h;Inert atmosphere;Catalytic behavior; A mixture of 1a (745 mg, 2.30 mmol), 2-thiophenecarbonitrile (1.28 mL, 13.7 mmol, 6 equiv), K2CO3 (950 mg, 6.87 mmol, 3 equiv), pivalic acid (77.7 μL, 0.69 mmol, 0. 3 equiv) and Pd(PPh3)4 (212 mg, 0.18 mmol, 0.08 equiv) in a solvent mixture of anhydrous toluene/DMA (1:1 (v/v), 10 mL) was stirred under argon atmosphere at 110 C for 48 h. The reaction mixture was diluted with toluene (50 mL), filtered over celite and the solvent was evaporated in vacuo. The crude was purified by precipitation from toluene (3 times) giving 1f (629 mg, 72%) which was used without any further purification to the next step. 1H NMR at 40 C (DMSO-d6, 600 MHz) δ (ppm): 7.95-7.94 (d, J = 3.8 Hz, 2H), 7.57-7.56 (d, J = 3.8 Hz, 2H), 7.52-7.51 (d, J = 3.8 Hz, 2H), 7.47-7.46 (d, J = 3.8 Hz, 2H). 13C NMR at 40 C (DMSO-d6, 150 MHz) δ (ppm): 143.09, 140.11, 136.62, 133.42, 128.05, 126.25, 124.76, 113.93, 106.32. MS(ESI+): m/z = 379.8. UV-Visible (DMSO) λmax = 424 nm. IR(ATR): 3094 cm-1 (Ar-H)str, 2215 cm-1 (Ar-CN)str, 1446 cm-1 (C=C)bending, 852 cm-1 (R1CH=CR2R3)str. Elemental analysis: calculated: C 56.82; H 2.12; N 7.36; S 33.70; found: C 56.95; H 1.97; N 6.83; S 31.71.
  • 8
  • [ 1003-31-2 ]
  • [ 1046864-83-8 ]
 

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