27143-07-3

Basic information

• Product Name: Acetic acid, 2-chloro-2-[2-(4-methoxyphenyl)hydrazinylidene], ethyl ester
• Synonyms: Acetic acid, 2-chloro-2-[2-(4-methoxyphenyl)hydrazinylidene], ethyl ester;Chloro[(4-methoxyphenyl)hydrazono]acetic acid ethyl ester;Ethyl chloro[(4-methoxyphenyl)hydrazono]acetate;(Z)- Ethyl chloro[(4-Methoxyphenyl)hydrazono]acetate;Ethyl 2-chloro-2-(2-(4-Methoxyphenyl)hydrazono)acetate;(Z)-ethyl 2-chloro-2-(2-(4-Methoxyphenyl)hydrazono)acetate;2-chloro-2-[2-(4-Methoxyphenyl)hydrazinylidene], ethyl ester;ethyl chloro[2-(4-Methoxyphenyl)hydrazinylidene]acetate
• CAS NO: 27143-07-3
• Molecular Formula: C₁₁H₁₃ClN₂O₃
• Molecular Weight: 256.68552
• EINECS: 1592732-453-0
• Mol File: 27143-07-3.mol

Chemical Properties

• Melting Point: 94℃
• Boiling Point: 348.955 ºC at 760 mmHg
• Flash Point: 164.842 ºC
• Appearance: /
• Density: 1.23
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.533
• Storage Temp.: 2-8°C
• Solubility: Chloroform (Sparingly), Methanol (Slightly)
• PKA: 11.63±0.10(Predicted)
• CAS DataBase Reference: Acetic acid, 2-chloro-2-[2-(4-methoxyphenyl)hydrazinylidene], ethyl ester(CAS DataBase Reference)
• NIST Chemistry Reference: Acetic acid, 2-chloro-2-[2-(4-methoxyphenyl)hydrazinylidene], ethyl ester(27143-07-3)
• EPA Substance Registry System: Acetic acid, 2-chloro-2-[2-(4-methoxyphenyl)hydrazinylidene], ethyl ester(27143-07-3)

Safety Data

• Hazardous Substances Data: 27143-07-3(Hazardous Substances Data)

Usage

Uses

Acetic acid, 2-chloro-2-[2-(4-methoxyphenyl)hydrazinylidene], ethyl ester is an ester derivative and can be used as an intermediate in the synthesis of apixaban.

InChI:InChI=1/C11H13ClN2O3/c1-3-17-11(15)10(12)14-13-8-4-6-9(16-2)7-5-8/h4-7,13H,3H2,1-2H3

Synthetic route

4-methoxy-aniline (104-94-9) + ethyl 2-chloro-3-oxo-butyrate (609-15-4) → ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate (27143-07-3)

Conditions	Yield
Stage #1: 4-methoxy-aniline With hydrogenchloride; sodium nitrite In water at -10 - -5℃; for 0.5h; Stage #2: ethyl 2-chloro-3-oxo-butyrate With sodium acetate In water at -10 - -5℃; for 2h;	89%
Stage #1: 4-methoxy-aniline With hydrogenchloride; sodium nitrite In ethanol; water at 0 - 5℃; for 0.5h; Stage #2: ethyl 2-chloro-3-oxo-butyrate With sodium acetate In ethanol; water at 0 - 25℃;	85%
Stage #1: 4-methoxy-aniline With hydrogenchloride; sodium nitrite In water at 0℃; for 0.5h; Stage #2: ethyl 2-chloro-3-oxo-butyrate With sodium acetate In ethanol; water at -5 - 20℃; for 4h;	73.6%

4-methoxy-aniline (104-94-9) + chloroacetic acid ethyl ester (105-39-5) → ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate (27143-07-3)

Conditions	Yield
With hydrogenchloride; sodium acetate; sodium nitrite 1.) water; 2.) water, ethanol, 0 - 5 deg C, 3 h -> overnight; Multistep reaction;

ethyl (2-chloroaceto)acetate (638-07-3) + 4-methoxy-aniline (104-94-9) → ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate (27143-07-3)

Conditions	Yield
Stage #1: 4-methoxy-aniline With hydrogenchloride In water at 40℃; for 0.416667h; Stage #2: With sodium nitrite In water at -2℃; for 0.583333h; Stage #3: ethyl (2-chloroaceto)acetate With aminosulfonic acid; sodium acetate more than 3 stages;

C11H10N2O4 + ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate (27143-07-3) → C22H22N4O7

Conditions	Yield
With triethylamine In ethyl acetate at 70℃;	95%

(2E,2'E)-1,4-bis[(2-(3-(dimethylamino)-1-oxoprop-2-en-1-yl)benzofuran-5-yl)methyl]piperazine + ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate (27143-07-3) → 1,4-bis[((2-(3-(ethoxycarbonyl)-1-(4-methoxyphenyl)-1H-pyrazole-4-yl)carbonyl)benzofuran-5-yl)methyl]piperazine

Conditions	Yield
With triethylamine In 1,4-dioxane for 6h; Reflux; regioselective reaction;	95%

3-(morpholin-4-yl)-1-(4-nitrophenyl)-5,6-dihydropyridin-2(1H)-one (503615-03-0) + ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate (27143-07-3) → 4,5,6,7-tetrahydro-1-(4-methoxyphenyl)-6-(4-nitrophenyl)-7-oxo- 1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester

Conditions	Yield
Stage #1: 3-(morpholin-4-yl)-1-(4-nitrophenyl)-5,6-dihydropyridin-2(1H)-one; ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate With triethylamine; potassium iodide In ethyl acetate for 4.5h; Reflux; Stage #2: With hydrogenchloride In water; ethyl acetate at 5 - 20℃; for 4h;	94.6%

(3,4-dihydro-6,7-dimethoxyisoquinolin-1-yl)acetonitrile (43052-77-3) + ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate (27143-07-3) → 8,9-Dimethoxy-2-[(4-methoxy-phenyl)-hydrazono]-3-oxo-2,3,5,6-tetrahydro-pyrrolo[2,1-a]isoquinoline-1-carbonitrile

Conditions	Yield
With sodium ethanolate In ethanol for 1h; Ambient temperature;	90%

ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate (27143-07-3) + 1,5-diphenyl-3-mercaptoformazan (60-10-6) → 2-ethoxy-N′-(4-methoxyphenyl)-2-oxoacetohydrazonic-N′,2-diphenyldiazenecarbohydrazonic thioanhydride

Conditions	Yield
With sodium ethanolate In ethanol for 2h;	90%

5,6‑dihydro‑3‑(4‑morpholinyl)‑1‑[4‑(2‑oxo‑1‑piperidinyl)phenyl]‑2(1H)‑pyridone (545445-44-1) + ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate (27143-07-3) → 1-(4-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (503614-91-3)

Conditions	Yield
With triethylamine; potassium iodide In ethyl acetate for 24h; Reflux;	89.9%
With potassium carbonate; carbonic acid dimethyl ester at 82℃; for 0.5h; Temperature; Reagent/catalyst;	80.33%
With triethylamine In ethyl acetate; toluene at 85℃; for 7h;	76%
With triethylamine; potassium iodide In ethyl acetate at 25 - 80℃; for 24h;	54 mg
Stage #1: 5,6‑dihydro‑3‑(4‑morpholinyl)‑1‑[4‑(2‑oxo‑1‑piperidinyl)phenyl]‑2(1H)‑pyridone; ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate With triethylamine Stage #2: With hydrogenchloride In water

2-(1-(10H-phenothiazin-2-yl)ethylidene)hydrazine-1-carbothioamide + ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate (27143-07-3) → 2-(2-(1-(10H-phenothiazin-2-yl)ethylidene)hydrazinyl)-5-(2-(4-methoxyphenyl)hydrazono)thiazol-4(5H)-one

Conditions	Yield
With triethylamine In ethanol at 110℃; for 0.25h; Microwave irradiation;	88%

2‐hydroxy‐5‐((p‐tolylthio)methyl)benzaldehyde + thiosemicarbazide (79-19-6) + ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate (27143-07-3) → 2‐(2‐(2‐hydroxy‐5‐((p‐tolylthio)methyl)benzylidene)hydrazineyl)‐5‐(2‐(4‐methoxyphenyl)hydrazineylidene)thiazol‐4(5H)‐one

Conditions	Yield
In neat (no solvent) at 120℃; for 0.5h; Wavelength; Microwave irradiation;	87%

5,6-dihydro-3-(4-morpholinyl)-1-[4-(2-oxo-6-methyl-1-piperidinyl)phenyl]-2(1H)-pyridone + ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate (27143-07-3) → 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-6-methylpiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazole [3,4-c]pyridine-3-carboxylic acid ethyl ester

Conditions	Yield
Stage #1: 5,6-dihydro-3-(4-morpholinyl)-1-[4-(2-oxo-6-methyl-1-piperidinyl)phenyl]-2(1H)-pyridone; ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate With triethylamine In chloroform at 0 - 62℃; for 64h; Inert atmosphere; Stage #2: With hydrogenchloride In chloroform; water at 0 - 25℃; for 4.5h; Inert atmosphere;	83.7%
With triethylamine at 90 - 95℃; for 3h;	74%

methylamine (74-89-5) + ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate (27143-07-3) → ethyl 2-(2-(4-methoxyphenyl)hydrazono)-2-(methylamino)acetate

Conditions	Yield
In tetrahydrofuran at 0℃; for 5h;	81.4%

3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one (545445-40-7) + ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate (27143-07-3) → 1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3, 4-c]pyridine-3-carboxylic acid ethyl ester (503614-56-0)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In ethyl acetate at 85 - 95℃; for 20h; Reagent/catalyst; Solvent; Temperature; Inert atmosphere; Green chemistry;	81.2%
Stage #1: 3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one; ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate With triethylamine In toluene at 100℃; for 12h; Reflux; Stage #2: With trifluoroacetic acid In dichloromethane; toluene at 20℃; for 2h;

3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one (545445-40-7) + ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate (27143-07-3) → 1-(4-methoxyphenyl)-7a-(morpholin-4-yl)-7-oxo-3a,4,5,6,7,7a-hexahydro-1H-pyrazolo[3,4-c]pyridine-3-formic acid ethyl ester

Conditions	Yield
With triethylamine In ethyl acetate at 80℃; for 5h;	80%

1,4-bis[(3-((2-carbamothioylhydrazineylidene)methyl)-4-hydroxyphenyl)methyl]piperazine + ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate (27143-07-3) → 1,4-bis[(4-hydroxy-3-((2-(5-(2-(4-methoxyphenyl)hydrazineylidene)-4-oxo-4,5-dihydrothiazol-2-yl)hydrazineylidene)methyl)phenyl)methyl]piperazine

Conditions	Yield
With triethylamine In N,N-dimethyl-formamide at 120℃; for 0.5h; Temperature; Microwave irradiation;	80%

C21H27N3O3 + ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate (27143-07-3) → C28H30N4O5

Conditions	Yield
With triethylamine In toluene at 120℃; Inert atmosphere;	78.4%

N-(4-(2,5-dihydro-2,3-dimethyl-5-oxo-1-phenyl-1H-pyrazol-4-yl)thiazol-2-yl)-3-phenylthiourea (1519975-07-5) + ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate (27143-07-3) → ethyl 3-(4-anisyl)-2-(4-(2,3-dimethyl-1-phenyl-5-oxo-pyrazol-4-yl)thiazol-2-ylimino)-1,3,4-thiadiazole-5-carboxylate (1519975-44-0)

Conditions	Yield
With triethylamine In ethanol Reflux;	78%

N-methylmaleimide (930-88-1) + ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate (27143-07-3) → ethyl 1-(4-methoxyphenyl)-5-methyl-4,6-dioxo-1,3a,4,5,6,6a-hexahydropyrrolo[3,4-c]pyrazole-3-carboxylate

Conditions	Yield
With TEA In m-xylene at 150℃; for 1.5h; Solvent; Temperature; Microwave irradiation; Sealed tube; regioselective reaction;	78%

C20H25N3O3 + ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate (27143-07-3) → C27H28N4O5

Conditions	Yield
With triethylamine In toluene at 120℃; Inert atmosphere;	77.9%
With triethylamine In toluene at 120℃;	77%

C20H25N3O3 + ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate (27143-07-3) → C27H28N4O5

Conditions	Yield
With triethylamine In toluene at 120℃; Inert atmosphere;	77.7%

ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate (27143-07-3) + 1-(ethoxycarbonylmethylene)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline → ethyl 2,3,5,6-tetrahydro-8,9-dimethoxy-2-(2-(4-methoxyphenyl)hydrazono)-3-oxopyrrolo[2,1-a]isoquinoline-1-carboxylate (1161946-83-3)

Conditions	Yield
With triethylamine In chloroform at 20℃; Reflux;	77%

diexo 5,8-methano-2-thioxo-1,4,4a,5,8,8a-hexahydroquinazolin-4-one + ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate (27143-07-3) → ethyl (4aS*,5S*,8R*,8aR*)-1-(4-methoxyphenyl)-9-oxo-1,4a,5,8,8a,9-hexahydro-5,8-methano[1,2,4]triazolo[4,3-a]quinazoline-3-carboxylate

Conditions	Yield
With triethylamine In 1,4-dioxane Reflux; regioselective reaction;	77%

1-(4-iodo-phenyl)-3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one (473927-69-4) + ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate (27143-07-3) → 1-(4-methoxy-phenyl)-6-(4-iodo-phenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (473927-64-9)

Conditions	Yield
With triethylamine In ethyl acetate at 0℃; for 2h; Inert atmosphere; Cooling with ice; Reflux;	75%
Stage #1: 1-(4-iodo-phenyl)-3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one; ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate With triethylamine In toluene for 2h; Reflux; Stage #2: With hydrogenchloride In dichloromethane; water at 25 - 30℃; for 2h;	30.4%

C21H27N3O4 + ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate (27143-07-3) → C28H30N4O6

Conditions	Yield
With triethylamine In ethyl acetate at 80℃; Inert atmosphere;	74.8%

2-amino-benzenethiol (137-07-5) + ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate (27143-07-3) → 2-[(4-methoxy-phenyl)-hydrazono]-4H-benzo[1,4]thiazin-3-one

Conditions	Yield
With triethylamine In ethanol for 6h; Heating;	74%

1-(3-cyano-4,6-diphenylpyridin-2-yl)-3-phenylthiourea + ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate (27143-07-3) → ethyl 5-((3-cyano-4,6-diphenylpyridin-2-yl)imino)-4-(4-methoxyphenyl)-4,5-dihydro-1,3,4-thiadiazole-2-carboxylate

Conditions	Yield
With triethylamine In ethanol Reflux;	74%

ethyl 3-((E)-1-(2-((E)-2-cyano-3-(phenylamino)-3-thioxopropanoyl)hydrazono)ethyl)-1,5-diphenyl-1H-pyrazole-4-carboxylate + ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate (27143-07-3) → (E)-ethyl 5-(1-cyano-2-((E)-2-(1-(4-(ethoxycarbonyl)-1,5-diphenyl-1H-pyrazol-3-yl)ethylidene)-hydrazinyl)-2-oxoethylidene)-4-(4-methoxyphenyl)-4,5-dihydro-1,3,4-thiadiazole-2-carboxylate

Conditions	Yield
With triethylamine In ethanol for 4h; Reflux;	74%

5-ethyl-4-(2-hydroxyphenylmethyleneamino)-3-mercapto-1,2,4-triazole (119153-17-2) + ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate (27143-07-3) → ethyl 3'-ethyl-5-(2-hydroxyphenyl)-5'-mercapto-1-(4-methoxyphenyl)-1,5-dihydro-[4,4'-bi(1,2,4-triazole)]-3-carboxylate

Conditions	Yield
With triethylamine In 1,4-dioxane Reflux;	74%

Upstream product

• 104-94-9 4-methoxy-aniline 
• 105-39-5 chloroacetic acid ethyl ester 
• 638-07-3 ethyl (2-chloroaceto)acetate 
• 609-15-4 ethyl 2-chloro-3-oxo-butyrate 

Downstream Products

• 56885-95-1 4-(4-methoxy-phenyl)-5-(2-oxo-2-p-tolyl-ethylidene)-4,5-dihydro-[1,3,4]thiadiazole-2-carboxylic acid ethyl ester 
• 63514-81-8 ethyl 4-acetyl-1-(4-methoxyphenyl)-5-methyl-1H-pyrazole-3-carboxylate 
• 204512-13-0 3-[(4-Methoxy-phenyl)-hydrazono]-3,4-dihydro-1H-quinoxalin-2-one 
• 733746-35-5 3-[(4-methoxy-phenyl)-hydrazono]-8-nitro-3,4-dihydro-1H-quinoxalin-2-one 
• 89844-62-2 5-amino-3-cyano-2-phenylamino-4-(N-phenylaminothiocarbonyl)thiophene 
• 204511-94-4 2-(4-hydroxyphenyl)-[1,2,4]triazolo[4,3-a]quinoxaline-1,4(2H,5H)-dione 
• 204511-87-5 2-(4-Methoxy-phenyl)-2H,5H-[1,2,4]triazolo[4,3-a]quinoxaline-1,4-dione 
• 269716-99-6 4-Chloro-2-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-a]quinoxalin-1(2H)-one 
• 269716-68-9 4-amino-2-(4-methoxyphenyl)-1,2,4-triazolo[4,3-a]quinoxalin-1-one 
• 733746-39-9 4-Chloro-2-(4-methoxyphenyl)-6-nitro-[1,2,4]triazolo[4,3-a]quinoxalin-1(2H)-one 
• 733746-31-1 4,6-diamino-2-(4-methoxy-phenyl)-2H-[1,2,4]triazolo[4,3-a]quinoxalin-1-one 
• 733746-20-8 2-(4-hydroxyphenyl)-6-nitro-[1,2,4]triazolo[4,3-a]quinoxaline-1,4(2H,5H)-dione 
• 733746-29-7 4-amino-2-(4-methoxyphenyl)-6-nitro-1,2,4-triazolo[4,3-a]quinoxalin-1-one 
• 733746-19-5 2-(4-methoxyphenyl)-6-nitro-[1,2,4]triazolo[4,3-a]quinoxaline-1,4(2H,5H)-dione 

Relevant articles and documents

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Apixaban derivatives as well as preparation method and application thereof

The invention belongs to the technical field of medicines and discloses apixaban derivatives and analogues as well as a preparation method and application thereof. The structure of the compounds is shown as the following formula. Cheap and readily available paranitroaniline serves as an initial raw material. The preparation method comprises the following steps: performing amidation-cyclization, chlorination, condensation-elimination, cyclization-elimination, reduction, amidation-cyclization so as to obtain a key intermediate; and dehydrating, performing ammonolysis or chlorination, and condensing to synthesize the target compound. The method is simple in operation, convenient in after-treatment and high in yield. The in-vitro anti-coagulant activity of the target compound is investigated by determining the activated partial thromboplastin time (APTT) and thromboplastin time (PT). The EC2X(APTT) of result compounds APX-02, APX-15 and APX-16 is respectively 2.15mug/L, 3.65mug/L and 2.35mug/L, the EC2X(PT) of the result compounds is respectively 0.12mug/L, 3.57mug/L and 1.57mug/L, which are higher than the EC2X(APTT) value of 3.78mug/L and the EC2X(PT) value of 1.59mug/L of a positive control agent Apixaban. The compounds have high anti-coagulant activities. The EC2X(APTT) value of the rest compounds is between 5mug/L and 65mug/L, and the EC2X(PT) value is between 3mug/L and 18mug/L. The structural formula is as shown in the specification.

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Pyrazolo[3,4-c]pyridine derivative

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NOVEL PROCESS FOR THE PREPARATION OF A LACTAM-CONTAINING COMPOUND

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DIHYDROPYRAZOLE GPR40 MODULATORS

The present invention provides compounds of Formula (I): or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein all of the variables are as defined herein. These compounds are GPR40 G protein-coupled receptor modulators which may be used as medicaments.

APIXABAN PREPARATION PROCESS

Process for the preparation of apixaban and intermediates useful for the preparation thereof.

A new method for the synthesis of 1-aryl-1,2,4-triazole derivatives

A new and convenient one-step recyclization method for the synthesis of ethyl 1-aryl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxylates is reported. Various ethyl chloro(2-arylhydrazinylidene)ethanoates react with thiazolidine-2,4-dione in the presence of potassium hydroxide to produce the 1-aryl-1,2,4-triazole derivatives in moderate to good yields. The procedure is economical, environmentally friendly and simple to perform. Georg Thieme Verlag Stuttgart - New York.