5147-80-8|2-(Bis(methylthio)methylene)malononitrile| Ambeed

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Quality Control of [ 5147-80-8 ] Purity: 97% SDS Specification

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Product Details of [ 5147-80-8 ]

CAS No. :	5147-80-8
Formula :	C₆H₆N₂S₂
M.W :	170.26
SMILES Code :	N#CC(C#N)=C(SC)SC
MDL No. :	MFCD00052730
InChI Key :	FICQFRCPSFCFBY-UHFFFAOYSA-N
Pubchem ID :	99229

Safety of [ 5147-80-8 ]

GHS Pictogram:
Signal Word:	Danger
Hazard Statements:	H301+H311+H331-H315-H319
Precautionary Statements:	P501-P261-P270-P271-P264-P280-P337+P313-P305+P351+P338-P361+P364-P332+P313-P301+P310+P330-P302+P352+P312-P304+P340+P311-P403+P233-P405
Class:	6.1
UN#:	3439
Packing Group:	Ⅲ

Computational Chemistry of [ 5147-80-8 ] Show Less

Physicochemical Properties

Num. heavy atoms	10
Num. arom. heavy atoms	0
Fraction Csp3	0.33
Num. rotatable bonds	2
Num. H-bond acceptors	2.0
Num. H-bond donors	0.0
Molar Refractivity	45.16
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	98.18 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.7
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	1.38
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.97
Log P_o/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.	0.26
Log P_o/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	0.96
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.25

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.63
Solubility	3.96 mg/ml ; 0.0233 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.	-3.05
Solubility	0.153 mg/ml ; 0.000902 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	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	-1.13
Solubility	12.6 mg/ml ; 0.0738 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	No
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.	-6.36 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.	1.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	1.0 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)	2.92

Application In Synthesis of [ 5147-80-8 ]

* 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.

Downstream synthetic route of [ 5147-80-8 ]

[ 5147-80-8 ] Synthesis Path-Downstream 1~35

1
[ 5147-80-8 ]
[ 62-53-3 ]
[ 17823-65-3 ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; for 1.5h;	2-(Bis-methylsulfanyl-methylene)-malononitrile (3.40 g, 20 mmol) and aniline (1.82 ml, 20 mmol) were refluxed in ethanol (50 ml) for 1.5 h until reaction completion (LCMS). The mixture was allowed to cool down, the precipitate formed was filtered, washed with ethanol (3 x 7 ml), and dried on air to afford 2-(methylsulfanyl-phenylamino-methylene)-malononitrile (2.97 g, 13.8 mmol) as an off-white solid.
	In ethanol; for 8h;Reflux;	General procedure: Method A (three components)Equimolar amounts (3 mmol) of bis(methylthio)methylenemalononitrile (1) and primary amine 2 namely: aniline,4-chloro-, 2-methy-, 3-methy-, 4-methy-aniline, 2-aminopropaneor b-phenylethylamine in 40 cm3 ethanol werestirred with reflux for about 8 h,
4.85 g	In methanol; at 65℃;	Add aniline (3.00 g, 32.24 mmol), 2-(bis(methylthio)methylene)malononitrile (5.48 g, 32.24 mmol) and 50 ml methanol to a 100 ml reaction flask, and react at 65C. After the reaction was monitored by TLC, most of the methanol was evaporated under reduced pressure, cooled and filtered to obtain 4.85 g of white solid.

References: [1]Chemical and Pharmaceutical Bulletin,2007,vol. 55,p. 881 - 889.
[2]Journal of the Chemical Society. Perkin transactions I,1986,p. 1187 - 1196.
[3]Journal of Heterocyclic Chemistry,1990,vol. 27,p. 775 - 783.
[4]Arzneimittel-Forschung/Drug Research,2002,vol. 52,p. 482 - 488.
[5]Chemische Berichte,1962,vol. 95,p. 2871 - 2880.
[6]Tetrahedron Letters,1981,vol. 22,p. 2285 - 2288.
[7]Chemistry Letters,1982,p. 1933 - 1936.
[8]Journal of Medicinal Chemistry,1997,vol. 40,p. 3601 - 3616.
[9]Patent: WO2009/62118,2009,A2 .Location in patent: Page/Page column 205.
[10]Heterocycles,2009,vol. 78,p. 899 - 903.
[11]Tetrahedron Letters,2015,vol. 56,p. 521 - 524.
[12]Monatshefte fur Chemie,2017,vol. 148,p. 2129 - 2134.
[13]Patent: CN111480649,2020,A .Location in patent: Paragraph 0296.
[14]Bioorganic Chemistry,2021,vol. 116.

2
[ 75-15-0 ]
[ 77-78-1 ]
[ 109-77-3 ]
[ 5147-80-8 ]

Yield	Reaction Conditions	Operation in experiment
85%		The reaction mixture of potassium hydroxide (0.2 mol, 27.0 g) in water (8 ml), DMF 25 ml was cooled at 0C. To this mixture, malononitrile (0.1 mol, 6.60 g) was added and the resultant solution stirred at the room temperature for 2 h. Carbon disulfide (0.22 mol, 15.20 ml) was then added dropwise through dropping funnel for 0.5 h. The reaction mixture was raised and kept for 1 h at room temperature. DMS (0.2 mol, 24.4 ml) was added dropwise at 0-5C and the reaction mixture stirred for 4 h at room temperature (TLC check, n-hexane:ethyl acetate, 8:2). The reaction mass was quenched by adding crushed ice with stirring, the solid was filtered and washed with water, dried and recrystallized from ethanol to give a faint yellow solid. Yield 85%; 14 g, m.p. 80C; m.p. Lit [2,21,22] 80-81C. The structure of compound 1 was determined on the basis of spectral and analytical data and compared to literature values.[2,21,22]

References: [1]Synthetic Communications,2003,vol. 33,p. 3989 - 3995.
[2]Journal of Sulfur Chemistry,2016,vol. 37,p. 426 - 437.
[3]Chemische Berichte,1962,vol. 95,p. 2861 - 2870.
[4]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 5453 - 5458.

3
[ 75-15-0 ]
[ 109-77-3 ]
[ 74-88-4 ]
[ 5147-80-8 ]

Yield	Reaction Conditions	Operation in experiment
93.9%		At room temperature, 7.5 g (113.7 mmol) of malononitrile and 17.3 g (125.0 mmol) of potassium carbonate were added to 75 mL of DMSO, cooled to 0 C and 7.5 mL (125 mmol) of carbon disulfide was gradually added dropwise. After dripping, stir at 20 C for 2h. Cool the reaction to 0 C. 14.1 mL (227.3 mmol) of methyl iodide was gradually added dropwise, and the reaction was completed at 20 C for 12 h. After the reaction is completed, the reaction solution is poured into 75 mL of ice water, and a yellow solid is precipitated. It was washed with water and dried to obtain 18.2 g of a yellow solid with a yield of 93.9%.
		General procedure: To a solution of malononitrile (100 g, 1.51 mol) in DMF (1 L) wasadded solid potassium carbonate (209 g, 1.51 mol). The mixture wasallowed to stir at 25 C for 15 min, then carbon disulfide (115 g,1.51 mol) was added dropwise. After being allowed to stir for 15 min,tetrabutylammonium iodide (55.9 g, 151 mmol) was added to thereaction mixture. The reaction mixture was allowed to cool in an icewaterbath and ethyl iodide (354 g, 2.27 mol) was added dropwise overone hour. Upon completion of addition, the reaction mixture waswarmed to 50 C for 16 h. Following the heating interval, the reactionmixture was cooled to rt, poured into a separatory funnel, diluted withwater (1 L) and extracted with ethyl acetate (3 × 500 mL). The combinedextracts were twice washed with brine, dried over sodium sulfate,filtered and concentrated under reduced pressure. The resulting crudeproduct was purified by silica gel chromatography (hexanes to 30/70ethyl acetate/hexanes) to afford 46 (120 g, 40%)

References: [1]Gazzetta Chimica Italiana,1995,vol. 125,p. 115 - 118.
[2]Organic process research and development,2011,vol. 15,p. 556 - 564.
[3]Patent: CN110759900,2020,A .Location in patent: Paragraph 0105; 0106.
[4]Tetrahedron,2009,vol. 65,p. 10453 - 10458.
[5]Journal of Medicinal Chemistry,2003,vol. 46,p. 1229 - 1241.
[6]Journal of Chemical Research - Part S,1999,p. 492 - 493.
[7]Tetrahedron,1976,vol. 32,p. 1779 - 1787.
[8]Chemische Berichte,1990,vol. 123,p. 541 - 547.
[9]Synthetic Communications,2002,vol. 32,p. 3509 - 3517.
[10]Synthetic Communications,2005,vol. 35,p. 693 - 699.
[11]Synthetic Communications,2006,vol. 36,p. 2963 - 2973.
[12]Synthesis,2009,p. 1271 - 1278.
[13]Egyptian Journal of Chemistry,2012,vol. 55,p. 529 - 547.
[14]Patent: WO2003/101455,2003,A2 .Location in patent: Page 35-36.
[15]Bioorganic and medicinal chemistry,2020,vol. 28.

4
[ 123-75-1 ]
[ 5147-80-8 ]
[ 85106-63-4 ]

Yield	Reaction Conditions	Operation in experiment
	In pentanonitrile; at 50℃; for 1h;	General procedure: to a solution of 5 (1.0 mmol) in n-BuCN (1.0 ml), R1R2NH (1.0 equiv) was added, and then the resulting solution was stirred at 50 C for 1 h. K2CO3 (2.0 equiv) and R3-BnNH2 (1.2 equiv) were added to the solution, and the mixture was stirred for 5 h at 130 C. After cooling to room temperature, K2CO3 (2.0 equiv), NMP (1.0 ml), ethyl bromoacetate (1.5 equiv), and H2O (10 μl) were added. The resulting mixture was stirred for 4 h at 110 C. The slurry was filtered through Celite, then filtrate was concentrated, and the residue was purified by SiO2 in a column chromatgraphy (hexane/EtOAc = 8:1-3:1).

References: [1]Chemistry Letters,1982,p. 1933 - 1936.
[2]European Journal of Medicinal Chemistry,2003,vol. 38,p. 245 - 252.
[3]Tetrahedron,2009,vol. 65,p. 10453 - 10458.
[4]Tetrahedron Letters,2011,vol. 52,p. 2767 - 2770.
[5]European Journal of Medicinal Chemistry,2013,vol. 64,p. 464 - 476.
[6]Journal of Chemical Research,2015,vol. 39,p. 220 - 222.
[7]Tetrahedron Letters,2015,vol. 56,p. 7016 - 7019.

5
[ 110-89-4 ]
[ 5147-80-8 ]
[ 3012-89-3 ]

Yield	Reaction Conditions	Operation in experiment
	In pentanonitrile; at 50℃; for 1h;	General procedure: to a solution of 5 (1.0 mmol) in n-BuCN (1.0 ml), R1R2NH (1.0 equiv) was added, and then the resulting solution was stirred at 50 C for 1 h. K2CO3 (2.0 equiv) and R3-BnNH2 (1.2 equiv) were added to the solution, and the mixture was stirred for 5 h at 130 C. After cooling to room temperature, K2CO3 (2.0 equiv), NMP (1.0 ml), ethyl bromoacetate (1.5 equiv), and H2O (10 μl) were added. The resulting mixture was stirred for 4 h at 110 C. The slurry was filtered through Celite, then filtrate was concentrated, and the residue was purified by SiO2 in a column chromatgraphy (hexane/EtOAc = 8:1-3:1).

6
[ 5147-80-8 ]
[ 72760-85-1 ]

Yield	Reaction Conditions	Operation in experiment
85%	With hydrazine hydrate; In ethanol;Cooling with ice; Reflux;	[Bis(methylsulfanyl)methylene]malononitrile (10 g) was added to a solution of hydrazine monohydrate (4.5 g) in ethanol (10 ml) under ice-cooling. After stirred at room temperature for 30 minutes and refluxed at 80C for one hour, water was added dropwise to the reaction solution under ice-cooling. The precipitated solid was separated by filtration and dried to obtain 5-amino-3-(methylsulfanyl)-1H-pyrazole-4-carbonitrile (colorless solid) (7.6 g, 85%). MS(ESI):155(M+H)+,153(M-H)- 1H NMR(600MHz,DMSO-D6)δppm 2.44(s,3H),6.47(bs,2H), 12.00(bs,1H)
	With hydrazine hydrate; In methanol; at 50℃; for 5h;	General procedure: 2-(Bis(ethylthio)methylene)malononitrile (46, 120 g, 0.605 mol)was dissolved in methanol (1 L). The solution was allowed to stir at rt.To the stirred solution was added hydrazine hydrate (35.3 mL,726 mmol) dropwise over 1 h. Upon completion of addition, the reactionmixture was allowed to stir at 50 C for 4 h before cooling to rt, atwhich time the reaction was complete. Solvent was removed underreduced pressure to afford the product 47 (100 g, quant.)

References: [1]Journal of Heterocyclic Chemistry,1990,vol. 27,p. 775 - 783.
[2]Patent: EP2123654,2009,A1 .Location in patent: Page/Page column 17-18.
[3]Journal of the Iranian Chemical Society,2018,vol. 15,p. 2803 - 2809.
[4]Monatshefte fur Chemie,1999,vol. 130,p. 1167 - 1173.
[5]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,2006,vol. 45,p. 483 - 488.
[6]Bioorganic and medicinal chemistry,2020,vol. 28.

7
[ 134-32-7 ]
[ 5147-80-8 ]
[ 85106-73-6 ]

Yield	Reaction Conditions	Operation in experiment
3 g	With sodium hydride; In tetrahydrofuran; at 65℃;	Weigh out 1-naphthylamine (2.00 g, 13.97 mmol), 2-(bis(methylthio)methylene)malononitrile (0.84 g, 14.71 mmol), and sodium hydride (0.84 g, 21.00 mmol) Put 30 ml of tetrahydrofuran and 30 ml of tetrahydrofuran in a 50 ml single-necked flask and react under reflux at 65C. After the reaction is monitored by TLC, most of the tetrahydrofuran is evaporated under reduced pressure, cooled and filtered to obtain 3.00 g of white solid.

References: [1]Chemistry Letters,1982,p. 1933 - 1936.
[2]Patent: CN111480649,2020,A .Location in patent: Paragraph 0298.

8
[ 5147-80-8 ]
[ 3656-03-9 ]
[ 155375-45-4 ]

Yield	Reaction Conditions	Operation in experiment
90%	In N,N-dimethyl-formamide; at 154℃; for 0.166667h;Microwave irradiation;	General procedure: A solution of compounds 1 (10 mmol) and 2-(bis(methylthio)methylene) malononitrile8 (10 mmol) dissolved in DMF (20 mL) and boiled at 154C undermicrowave 600Wfor 10 minutes. The reaction was monitored by TLC (petroleumether-EtOAc 3;1) until the reactants disappeared. The solvent was then evaporatedand the remaining residue was trituratedwithMeOHto afford compounds 10 whichwas separated by column chromatography and recrystallized from the appropriatesolvent. Yield (86%).