1558-82-3

Usage

Preparation

To a flask equipped as in Preparation 2-6 is added 162.0 gm (1.0 mole) of ethyl orthoacetate, 42.0 gm (1.0 mole) of cyanamide, and 134.0 gm (2.0 moles) of acetic anhydride. The reaction mixture is heated to 130-140°C and the ethyl acetate and acetic acid are distilled over. The heat is removed until the initial vigorous reaction subsides and then the heat-ing is continued at 135-140°C until most of the remaining ethyl acetate and acetid acid have distilled over (approx. 1 hr). The residue is then distilled under reduced pressure to afford 100.8 gm (90%), b.p. 90-95°C (20 mm Hg).

InChI:InChI=1/C5H8N2O/c1-3-8-5(2)7-4-6/h3H2,1-2H3/b7-5-

Synthetic route

CYANAMID (420-04-2) + ethyl acetimidate hydrochloride (2208-07-3) → ethyl N‐cyanoethanimidate (1558-82-3)

Conditions	Yield
With disodium hydrogenphosphate In water at 40℃; for 4h;	95.3%
With disodium hydrogenphosphate

CYANAMID (420-04-2) + Triethyl orthoacetate (78-39-7) → ethyl N‐cyanoethanimidate (1558-82-3)

Conditions	Yield
With acetic acid for 6h; Reflux;	78%
With acetic anhydride	58%
With acetic anhydride at 100 - 140℃;	30%
With acetic anhydride at 135 - 150℃;
In acetonitrile at 20℃; for 39h; Reflux;

CYANAMID (420-04-2) + ethyl acetate (141-78-6) → ethyl N‐cyanoethanimidate (1558-82-3)

Conditions	Yield
With acetic acid for 6h; Reflux;	78%

ethyl N‐cyanoethanimidate (1558-82-3) + 1-(6-chloropyridin-3-yl)-N-methylmethanamine (120739-62-0) → acetamiprid

Conditions	Yield
at 75℃; for 9h; Industrial scale;	96%

ethyl 2-cyanoacetate (105-56-6) + ethyl N‐cyanoethanimidate (1558-82-3) → ethyl 2-cyano-3-(cyanoamino)crotonate sodium salt

Conditions	Yield
With sodium In ethanol Ambient temperature;	87%

ethyl N‐cyanoethanimidate (1558-82-3) + 3-hydrazinylpropanenitrile (353-07-1) → C6H9N5 (1072106-44-5)

Conditions	Yield
In methanol for 20h; Reflux;	86%

phosphorohydrazidic acid diethyl ester (56183-69-8) + ethyl N‐cyanoethanimidate (1558-82-3) → 5-amino-3-methyl[1,2,4]triazol-1-ylphosphonic acid diethyl ester

Conditions	Yield
With toluene-4-sulfonic acid Reflux;	81%

1,2-diamino-benzene (95-54-5) + ethyl N‐cyanoethanimidate (1558-82-3) → 2-Methyl-1H-benzimidazole (615-15-6)

Conditions	Yield
In methanol for 10h; Reflux;	79%

1H-benzimidazol-2-amine (934-32-7) + ethyl N‐cyanoethanimidate (1558-82-3) → 4-Amino-2-methylbenzimidazole<1,2-a><1,3,5>triazine (76278-99-4)

Conditions	Yield
In 1,2-dimethoxyethane Heating;	73%

4,5-dimethyl-1,2-phenylenediamine (3171-45-7) + ethyl N‐cyanoethanimidate (1558-82-3) → 2,5,6-trimethylbenzimidazole (3363-56-2)

Conditions	Yield
In methanol for 10h; Reflux;	69%

monohydrazido thiophosphoric acid diphenylester (53144-23-3) + ethyl N‐cyanoethanimidate (1558-82-3) → 5-amino-3-methyl[1,2,4]triazol-1-ylthiophosphonic acid diphenyl ester

Conditions	Yield
With toluene-4-sulfonic acid Reflux;	68%

S,S-tetramethylenesulfoximide (50578-18-2) + ethyl N‐cyanoethanimidate (1558-82-3) → C7H11N3OS (114113-46-1)

Conditions	Yield
at 80℃; for 18h;	65%

ethyl N‐cyanoethanimidate (1558-82-3) + 3-hydrazinylpropanenitrile (353-07-1) → C6H9N5 (1072106-47-8)

Conditions	Yield
In toluene for 48h; Reflux;	64%

1-Methyl-5-(4-methylphenyl)-1λ4,4-thiazin-3-amin-1-oxid (102423-32-5) + ethyl N‐cyanoethanimidate (1558-82-3) → N-Cyan-N'-(1-methyl-5-p-tolyl-1λ4,4-thiazin-3-yl)acetamidin-S-oxid (107325-92-8)

Conditions	Yield
at 150℃; for 0.25h;	61%

5-aminotetrazole (4418-61-5) + ethyl N‐cyanoethanimidate (1558-82-3) → 4-Azido-6-methyl-[1,3,5]triazin-2-ylamine

Conditions	Yield
With triethylamine In pyridine for 264h; Ambient temperature;	60%

S-benzyl-S-ethyl-sulfodiimide (30223-23-5) + ethyl N‐cyanoethanimidate (1558-82-3) → N1-(Benzylethylimino-λ6-sulfanyliden)-N2-cyanacetamidin (111268-17-8)

Conditions	Yield
at 60℃;	57%

1-Methyl-5-phenyl-1λ4,4-thiazin-3-amin-1-oxid (102423-30-3) + ethyl N‐cyanoethanimidate (1558-82-3) → N-Cyan-N'-(1-methyl-5-phenyl-1λ4,4-thiazin-3-yl)acetamidin-S-oxid (107325-91-7)

Conditions	Yield
at 150℃; for 0.25h;	57%

Methyl thioglycolate (2365-48-2) + ethyl N‐cyanoethanimidate (1558-82-3) → 4-amino-2-methyl-thiazole-5-carboxylic acid methyl ester

Conditions	Yield
With sodium hydride In tetrahydrofuran at 20℃; for 12h; Condensation;	57%

4-amino-1H-imidazole (4919-03-3) + ethyl N‐cyanoethanimidate (1558-82-3) → N-cyano-N'-(imidazol-4-yl)acetamidine (145837-48-5)

Conditions	Yield
In 1,4-dioxane	54%

tetrahydrothiophene-S,S-diimine (53245-06-0) + ethyl N‐cyanoethanimidate (1558-82-3) → N2-Cyan-N1-(tetrahydro-1-imino-λ6-thiophen-1-yliden)acetamidin (111268-15-6)

Conditions	Yield
at 60℃;	54%

ethyl 2-sulfanylacetate (623-51-8) + ethyl N‐cyanoethanimidate (1558-82-3) → 4-amino-2-methyl-thiazole-5-carboxylic acid ethyl ester

Conditions	Yield
With sodium hydride In tetrahydrofuran at 20℃; for 12h; Condensation;	53%

dimethylsulfoximine (1520-31-6) + ethyl N‐cyanoethanimidate (1558-82-3) → C5H9N3OS (114113-54-1)

Conditions	Yield
at 80℃; for 18h;	50%

dimethylsulfoxonium methylide (70775-39-2, 5367-24-8) + ethyl N‐cyanoethanimidate (1558-82-3) → <2-(Dimethyloxo-λ6-sulfanyliden)-1-methylethyliden>cyanamid (102423-28-9)

Conditions	Yield
In dimethyl sulfoxide for 24h; Ambient temperature;	46%

S-benzyl-S-methyl-sulfodiimine (30223-22-4) + ethyl N‐cyanoethanimidate (1558-82-3) → N1-(Benzyliminomethyl-λ6-sulfanyliden)-N2-cyanacetamidin (111268-16-7)

Conditions	Yield
at 60℃;	43%

(7S,8S)-8-Amino-7-hydroxy-6,6-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-2-carbonitrile + ethyl N‐cyanoethanimidate (1558-82-3) → trans-4-<(N-cyanoacetimidoyl)amino>-2,2-dimethyl-3-hydroxy-1-oxo-1,2,3,4-tetrahydronaphthalene-6-carbonitrile

Conditions	Yield
at 100℃;	40%

(2-methoxyethyl)hydrazine (3044-15-3) + ethyl N‐cyanoethanimidate (1558-82-3) → C6H12N4O

Conditions	Yield
With triethylamine In ethanol at 0 - 20℃; for 18h;	39%

5-amino-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide hydrochloride + ethyl N‐cyanoethanimidate (1558-82-3) → 5-[[N-cyano-C-methyl-carbonimidoyl]amino]-2-(cyclopropanecarbonylamino)-N-(cyclopropylmethyl)-4,5,6,7-tetrahydrobenzothiophene-3-carboxamide

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In ethanol at 100℃; for 4h; Microwave irradiation;	37%

S,S-dibenzylsulphurdi-imide (30223-27-9) + ethyl N‐cyanoethanimidate (1558-82-3) → N2-Cyan-N1-(dibenzylimino-λ6-sulfanyliden)acetamidin (111268-18-9)

Conditions	Yield
at 60℃;	19%

2-Isopropyl-1-methyl-1H-imidazol-4-ylamine + ethyl N‐cyanoethanimidate (1558-82-3) → N-cyano-N'-(2-isopropyl-1-methylimidazol-4-yl)acetamidine (145837-47-4)

Conditions	Yield
In 1,4-dioxane for 1h;	16%

Upstream product

• 420-04-2 CYANAMID 
• 78-39-7 Triethyl orthoacetate 
• 141-78-6 ethyl acetate 
• 1000-84-6 O-ethyl acetimidate 
• 64-17-5 ethanol 
• 75-05-8 acetonitrile 
• 2208-07-3 ethyl acetimidate hydrochloride 

Downstream Products

• 3363-56-2 2,5,6-trimethylbenzimidazole 
• 534-26-9 lysidine 
• 615-15-6 2-Methyl-1H-benzimidazole 
• 1072106-44-5 C₆H₉N₅ 
• 129147-66-6 (4-Amino-2-methyl-benzo[4,5]imidazo[1,2-a][1,3,5]triazin-7-yl)-phenyl-methanone 
• 135410-20-7 acetamiprid 
• 51108-32-8 1,3-Dimethyl-5-amino-1,2,4-triazol 
• 339363-03-0 N'-cyano-N-(cyanomethyl)-N-methylacetimidamide 
• 107325-92-8 N-Cyan-N'-(1-methyl-5-p-tolyl-1λ⁴,4-thiazin-3-yl)acetamidin-S-oxid 
• 107325-91-7 N-Cyan-N'-(1-methyl-5-phenyl-1λ⁴,4-thiazin-3-yl)acetamidin-S-oxid 
• 111268-18-9 N²-Cyan-N¹-(dibenzylimino-λ⁶-sulfanyliden)acetamidin 
• 111268-17-8 N¹-(Benzylethylimino-λ⁶-sulfanyliden)-N²-cyanacetamidin 
• 111268-16-7 N¹-(Benzyliminomethyl-λ⁶-sulfanyliden)-N²-cyanacetamidin 

Relevant academic research and scientific papers

Ethyl N-cyanoethylimidoate preparation method

The invention belongs to the field of organic matter synthesis, and particularly relates to an ethyl N-cyanoethylimidoate preparation method, wherein the ethyl N-cyanoethylimidoate is prepared by using acetonitrile as a solvent, using a 50% cyanamide aqueous solution to replace cyanamide, and using ethyl acetimidate hydrochloride as an intermediate. According to the present invention, the new synthesis method is used so as to achieve advantages of cost reducing, environment protection, simple operation, convenient post-treatment, high yield and simple synthesis, and is suitable for industrialproduction.

Preparation method of acetamiprid

The invention relates to a preparation method of acetamiprid. The preparation method comprises the following steps of enabling 2-chloro-5-chloromethylpyridine and a methylamine water solution to be reacted so as to synthesize N- (6-chloro-3-pyridylmethyl) methylamine; enabling acetonitrile, ethanol and cyanamide to be reacted so as to synthesize ethyl N-cyanoethanimideate; and further synthesizing the acetamiprid from the N-(6-chloro-3-pyridylmethyl) methylamine and the ethyl N-cyanoethanimideate. The preparation method of the acetamiprid, disclosed by the invention, has the following advantages that through control of reaction conditions, the conversion rate of used raw materials is increased, and the preparation method is suitable for industrial production. In addition, the acetamiprid product prepared by the preparation method is high in purity, low in impurity content, and high in mole yield, and a favorable economic benefit is obtained.

A simple and efficient approach to the synthesis of 1-phosphonated 5-amino-1-H-[1,2,4]-triazole from N-functionalized imidates

In this study, we describe a new and easy synthetic approach to variously substituted triazoles based on the reaction of imidates with phosphorylated hydrazine in good yields. A general mechanism of the reactions was also proposed. Characterization of the products was carried out by several analytical and spectroscopic tools including infrared and nuclear magnetic resonance spectroscopies (1H,13C NMR,31P NMR).

NOVEL ANTIVIRAL COMPOUNDS

The present invention relates to compounds of formula (A) as defined herein having antiviral activity, more specifically HIV (Human Immunodeficiency Virus) replication inhibiting properties. The invention also relates to pharmaceutical compositions comprising an effective amount of such compounds as active ingredients. This invention further relates to the use of such compounds as medicines or in the manufacture of a medicament useful for the treatment of animals suffering from viral infections, in particular HIV infection. This invention further relates to methods for the treatment of viral infections in animals by the administration of a therapeutical amount of such compounds, optionally combined with one or more other drugs having antiviral activity.

PROTEIN KINASE INHIBITORS AND METHODS FOR USING THEREOF

The invention provides compounds and pharmaceutical compositions thereof, which are useful as protein kinase inhibitors, and methods for using such compounds to treat, ameliorate or prevent a condition associated with abnormal or deregulated kinase activity. In some embodiments, the invention provides methods for using such compounds to treat, ameliorate or prevent diseases or disorders that involve abnormal activation of Alk, Abl, Aurora-A, B-Raf, C-Raf, Bcr-Abl, BRK, Blk, Bmx, BTK, C-Kit, CSK, C-Src, EphB1, EphB2, EphB4, FLT1, Fms, Flt3, Fyn, FRK3, JAK2, KDR, Lck, Lyn, PDGFRα, PDGFRβ, PKCα, SAPK2α, Src, SIK, Syk, Tie2 and TrkB kinases.

Easy access to triazoles, triazolopyrimidines, benzimidazoles and imidazoles from imidates

We have described a new and easy synthesis of triazoles, triazolopyrimidines, benzimidazoles and imidazoles variously substituted based on the reaction of imidates with diamine derivatives. The products were obtained in moderate to good yields. A general mechanism for the reactions is proposed.

MITOTIC KINESIN INHIBITORS AND METHODS OF USE THEREOF

This invention relates to inhibitors of mitotic kinesins, particularly KSP, and methods for producing these inhibitors. The invention also provides pharmaceutical compositions comprising the inhibitors of the invention and methods of utilizing the inhibitors and pharmaceutical compositions in the treatment of various disorders.

Triazole derivative and pharmaceutical use thereof

An agent for the prophylaxis and treatment of immune-related diseases, in particular, immunosuppressant, an agent for the prophylaxis and treatment of allergic diseases, an agent for the prophylaxis and treatment of eosinophil-related diseases and an eosinophilia inhibitor, comprising, as an active ingredient, a series of triazole derivatives of the following formula (I) STR1 or the following formula (III) STR2 wherein each symbol is as defined in the specification, or a pharmaceutically acceptable salt thereof. A novel monocyclic or bicyclic triazole derivative. The agent for the prophylaxis and treatment of immune-related diseases, in particular, immunosuppressant, the agent for the prophylaxis and treatment of allergic diseases, the agent for the prophylaxis and treatment of eosinophil-related diseases, the eosinophilia inhibitor and the novel triazole derivative of the present invention all, have superior eosinophilia-inhibitory action and lymphocyte activation-inhibitory action. They are low toxic and persistent in action. They are particularly effective in the treatment of accumulation and activation of eosinophil and lymphocytes, inflammatory respiratory tract diseases, eosinophil-related diseases such as eosinophilia, and immune-related diseases.

Synthesis and pharmacological activity of triazole derivatives inhibiting eosinophilia

In order to develop novel antiasthmatic agents based on a new mechanism of action, a series of 3-substituted 5-amino-1- [(methylamino)(thiocarbonyl)]-1H-1,2,4-triazole derivatives were synthesized and evaluated in a model in which eosinophilia was induced in the airway through intravenous (iv) injection of Sephadex particles on days 0, 2, and 5. After screening of several hundred derivatives, we finally identified the highly potent eosinophilia inhibitor 5-amino-3-(4-chlorophenyl)-1- [(methylamino)(thiocarbonyl)]-1H-triazole (23c, GCC-AP0341), which had ID50 values of 0.3 and 0.07 mg/kg when administered orally (os) and intraperitoneally (ip), respectively. This compound showed complete inhibition of the hypersensitivity induced by ascaris inhalation at an ip dose of 1 mg/kg as well as low toxicity, with an LD50 value of >2.0 g/kg in mice. Extensive study of its mechanism of action revealed that 23c inhibited eosinophil survival induced by interleukin-5 (IL-5), but had little or no effect on leukotriene D4 (LTD4) or platelet-activating factor (PAF)- induced responses. Taken together, these results suggest 23c as a novel candidate for the treatment of chronic asthma. Further studies are now underway.