53885-35-1

Usage

Uses

Used in Pharmaceutical Industry:
Ticlopidine hydrochloride is used as an antithrombotic agent for its ability to inhibit ADP-induced platelet aggregation, thereby reducing the risk of blood clot formation and associated complications.
Used in Cardiovascular Applications:
Ticlopidine hydrochloride is used as a platelet aggregation inhibitor for preventing and treating conditions related to abnormal blood clotting, such as myocardial infarction, stroke, and peripheral artery disease.
Used in General Medicine:
Ticlopidine hydrochloride is used as a mucolytic agent to help break down and clear mucus from the respiratory system, providing relief for patients with respiratory disorders.
Used in Infection Control:
Ticlopidine hydrochloride is used as an antibacterial agent, exhibiting properties that help in the prevention and treatment of bacterial infections.
Used in Surface Active Applications:
Ticlopidine hydrochloride is used as a surface active agent, which can be applied in various industries for its ability to reduce surface tension and improve the interaction between different substances.

Originator

Ticlid,Millot,France,1978

Manufacturing Process

A solution of thieno[3,2-c]pyridine (13.5 g; 0.1 mol) and 2-chlorobenzyl chloride (17.7 g) in acetonitrile (150 ml) is boiled during 4 hours. After evaporation of the solvent, the solid residue consists of 5-(2- chlorobenzyl)-thieno[3,2-c]pyridinium chloride which melts at 166°C (derivative n° 30). Ticlopidine hydrochloride is taken up into a solution comprising ethanol (300 ml) and water (100 ml). Sodium borohydride (NaBH4)(20 g) is added portionwise to the solution maintained at room temperature. The reaction medium is maintained under constant stirring during 12 hours and is then evaporated. The residue is taken up into water and made acidic with concentrated hydrochloric acid to destroy the excess reducing agent. The mixture is then made alkaline with ammonia and extracted with ether. The ether solution is washed with water, dried and evaporated. The oily residue is dissolved in isopropanol (50 ml) and hydrochloric acid in ethanol solution is then added thereto. After filtration and recrystallization from ethanol, there are obtained 5-(2- chlorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride crystals (yield: 60%) having a melting point (Koefler block) of 190°C.

Therapeutic Function

Platelet aggregation inhibitor

Biological Activity

Selective P2Y 12 receptor antagonist. Inhibits ADP-induced platelet aggregation and displays antithrombotic activity following oral administration in vivo .

InChI:InChI=1/C14H14ClNS.ClH/c15-13-4-2-1-3-11(13)9-16-7-5-14-12(10-16)6-8-17-14;/h1-4,6,8H,5,7,9-10H2;1H

Synthetic route

N-(2-chloro-benzyl)-2-(thien-2-yl)-ethylamine hydrochloride (60612-23-9) → ticlopidine hydrochloride (53885-35-1)

Conditions	Yield
In 1,3-DIOXOLANE; ethyl acetate	95%
With hydrogenchloride In 1,3-dioxane; water at 90℃; for 6h; Temperature;	82%

1,3-DIOXOLANE (646-06-0) + N-(2-chloro-benzyl)-2-(thien-2-yl)-ethylamine hydrochloride (60612-23-9) → ticlopidine hydrochloride (53885-35-1)

Conditions	Yield
With hydrogenchloride	89%
With hydrogenchloride In water at 90℃; for 6h; Temperature;	82%
With hydrogenchloride In water at 90℃; for 6h; Temperature;	91 g

4,5,6,7-tetrahydrothieno[3,2-c]pyridine (54903-50-3) + 1-chloro-2-(chloromethyl)benzene (611-19-8) → ticlopidine hydrochloride (53885-35-1)

Conditions	Yield
Stage #1: 4,5,6,7-tetrahydrothieno[3,2-c]pyridine; 1-chloro-2-(chloromethyl)benzene In dichloromethane at 60℃; for 1h; Stage #2: With hydrogenchloride In dichloromethane Reagent/catalyst; Solvent; Temperature;	87%

[2-(2-thyenyl)ethyl]amine (30433-91-1) + aqueous potassium carbonate + methyleneamine (2053-29-4) + 1-chloro-2-(chloromethyl)benzene (611-19-8) → ticlopidine hydrochloride (53885-35-1)

Conditions	Yield
With hydrogenchloride; formaldehyd; potassium carbonate In tetrahydrofuran; methanol; water; toluene	84%

4,5,6,7-tetrahydrothieno[3,2-c]pyridine (54903-50-3) + di-isopropyl ether (108-20-3) + 1-chloro-2-(chloromethyl)benzene (611-19-8) → ticlopidine hydrochloride (53885-35-1)

Conditions	Yield
With hydrogenchloride; sodium hydrogencarbonate In ethanol	83%

C13H14ClNS*(x)ClH → ticlopidine hydrochloride (53885-35-1)

Conditions	Yield
With hydrogenchloride In 1,3-dioxane; water at 90℃; for 6h; Temperature;	82%

pyrographite (7440-44-0) + N-(2-chloro-benzyl)-2-(thien-2-yl)-ethylamine hydrochloride (60612-23-9) → ticlopidine hydrochloride (53885-35-1)

Conditions	Yield
Stage #1: N-(2-chloro-benzyl)-2-(thien-2-yl)-ethylamine hydrochloride With hydrogenchloride In 1,3-dioxane; water at 7 - 90℃; for 9h; Stage #2: pyrographite In ethanol at 4℃; for 4h; Temperature;	82%

Chloromethyl pivalate (18997-19-8) + N-(2-chloro-benzyl)-2-(thien-2-yl)-ethylamine (69061-17-2) → ticlopidine hydrochloride (53885-35-1)

Conditions	Yield
In dimethyl sulfoxide	51%

1,3 dithiane (505-23-7) + N-(2-chloro-benzyl)-2-(thien-2-yl)-ethylamine hydrochloride (60612-23-9) → ticlopidine hydrochloride (53885-35-1)

Conditions	Yield
In 1,2-dimethoxyethane	9.4 g (62.7%)

N-(2-chloro-benzyl)-2-(thien-2-yl)-ethylamine (69061-17-2) → ticlopidine hydrochloride (53885-35-1)

Conditions	Yield
With sodium hydroxide; methanesulfonic acid; paraformaldehyde In N-methyl-acetamide; dichloromethane

[2-(2-thyenyl)ethyl]amine (30433-91-1) → ticlopidine hydrochloride (53885-35-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: potassium carbonate / methanol / 2 h / Reflux 2: sodium tetrahydroborate / methanol / 0 - 20 °C 3: N,N-dimethyl-formamide / 0 - 60 °C View Scheme

N-(2-chloro-benzyl)-2-(thien-2-yl)-ethylamine (69061-17-2) + chloromethyl methyl ether (107-30-2) → ticlopidine hydrochloride (53885-35-1)

Conditions	Yield
Stage #1: N-(2-chloro-benzyl)-2-(thien-2-yl)-ethylamine; chloromethyl methyl ether In N,N-dimethyl-formamide at 0 - 60℃; Stage #2: With hydrogenchloride In ethanol

2-chloro-benzaldehyde (89-98-5) → ticlopidine hydrochloride (53885-35-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: potassium carbonate / methanol / 2 h / Reflux 2: sodium tetrahydroborate / methanol / 0 - 20 °C 3: N,N-dimethyl-formamide / 0 - 60 °C View Scheme

C13H12ClNS (122853-32-1) → ticlopidine hydrochloride (53885-35-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium tetrahydroborate / methanol / 0 - 20 °C 2: N,N-dimethyl-formamide / 0 - 60 °C View Scheme

2-thiophenethanol (5402-55-1) → ticlopidine hydrochloride (53885-35-1)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: potassium carbonate / toluene / 3.5 h / 0 - 20 °C 2.1: toluene / 3 h / 85 °C 2.2: 4 h / 2 °C / pH 5 - 8.5 3.1: hydrogenchloride / water; 1,3-dioxane / 6 h / 90 °C View Scheme
Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine / toluene / 3.5 h / 0 - 20 °C 2.1: toluene / 3 h / 85 °C 2.2: 1 h / 20 °C / pH 8.5 3.1: hydrogenchloride / water; 1,3-dioxane / 6 h / 90 °C View Scheme
Multi-step reaction with 3 steps 1.1: triethylamine / toluene / 3 h / 0 - 20 °C 2.1: toluene / 4 h / 20 - 85 °C 2.2: pH 8.5 3.1: hydrogenchloride / water; 1,3-dioxane / 9 h / 7 - 90 °C 3.2: 4 h / 4 °C View Scheme
Multi-step reaction with 3 steps 1.1: potassium carbonate / toluene / 3.5 h / 0 - 20 °C 2.1: toluene / 3 h / 85 °C 2.2: 4 h / 2 °C / pH 5 - 8.5 3.1: hydrogenchloride / water / 6 h / 90 °C View Scheme
Multi-step reaction with 3 steps 1.1: triethylamine / toluene / 3.5 h / 0 - 25 °C 2.1: toluene / 4 h / 25 - 90 °C 2.2: 4 h / 2 °C / pH 5 3.1: hydrogenchloride / water / 6 h / 90 °C View Scheme

4-(3-(pyridin-2-ylthio)propyl)morpholine + ticlopidine hydrochloride (53885-35-1) → 4-(3-((2-((6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)phenyl)thio)propyl)morpholine

Conditions	Yield
Stage #1: ticlopidine hydrochloride With sodium hydrogencarbonate In water Inert atmosphere; Stage #2: 4-(3-(pyridin-2-ylthio)propyl)morpholine With bis(1,5-cyclooctadiene)nickel (0); 3,4-thiene-2,3-diylbis(dicyclohexylphosphine); zinc In toluene at 150℃; for 24h; Inert atmosphere; Glovebox; Sealed tube;	76%

Upstream product

• 505-23-7 1,3 dithiane 
• 60612-23-9 N-(2-chloro-benzyl)-2-(thien-2-yl)-ethylamine hydrochloride 
• 18997-19-8 Chloromethyl pivalate 
• 69061-17-2 N-(2-chloro-benzyl)-2-(thien-2-yl)-ethylamine 
• 30433-91-1 [2-(2-thyenyl)ethyl]amine 
• 2053-29-4 methyleneamine 
• 611-19-8 1-chloro-2-(chloromethyl)benzene 
• 7440-44-0 pyrographite 
• 54903-50-3 4,5,6,7-tetrahydrothieno[3,2-c]pyridine 
• 5402-55-1 2-thiophenethanol 
• 122853-32-1 C₁₃H₁₂ClNS 
• 89-98-5 2-chloro-benzaldehyde 
• 107-30-2 chloromethyl methyl ether 
• 108-20-3 di-isopropyl ether 

Relevant academic research and scientific papers

A method for preparing pyridine [...] of hydrochloric acid

The invention discloses a preparation method of ticlopidine hydrochloride. The preparation method comprises the following steps: A, adding a certain amount of reactive raw materials into a reaction container, and carrying out reaction at the temperature of 30-80 DEG C for 1-10 hours, wherein the raw materials include 2-thiophene ethylamine, methanal, a haloalkane solvent and a solid super acidic catalyst; B, cooling the solution of reaction to room temperature; C, adding a certain amount of a solid alkaline catalyst and 2-chlorobenzyl chloride into the solution of reaction, carrying out reaction at the temperature of 30-80 DEG C for 1-10 hours, stopping heating, and standing to precipitate; D, filtering to obtain a filtrate; and E, introducing hydrogen chloride into the filtrate to obtain ticlopidine hydrochloride. The solid super acidic catalyst and the solid alkaline catalyst are adopted by the preparation method, and the heterogeneous tandem reaction is carried out. The technology has the advantage of convenience in post-treatment, is easy to operate, can not cause corrosion to equipment and is economical, practical and environment-friendly, less three wastes are produced, and the solid acid and alkali can be reused.

Method for synthesizing ticlopidine hydrochloride

The invention provides a method for synthesizing ticlopidine hydrochloride. The method comprises the following steps of taking thiopheneethanol as a raw material, and protecting and activating hydroxyl by means of reacting the thiopheneethanol with paratoluensulfonyl chloride under the action of an acid-binding agent; then performing a condensation reaction with o-chlorobenzylamine; performing a ring closing reaction with 1,3-dioxolane under an acidic condition so as to obtain the ticlopidine hydrochloride. The method provided by the invention has the advantages of mild reaction condition, low production cost, high product yield, good quality and convenience for industrialized production.

Method for synthesizing ticlopidine hydrochloride

The invention provides a method for synthesizing ticlopidine hydrochloride. The method comprises the following steps: by using thiopheneethanol as a raw material, under the action of an acid binding agent, firstly, performing a reaction on the thiopheneethanol and paratoluensulfonyl chloride to carry out protection and activation on hydroxy; performing a condensation reaction with chlorobenzylamine; then under an acid condition, performing a ring closing reaction with 1,3-dioxolane to obtain the ticlopidine hydrochloride. The method is mild in reaction condition, low in production cost, high in product yield and high in quality, and is convenient for industrial production.

Novel preparation method for ticlopidine hydrochloride

The invention provides a novel preparation method for ticlopidine hydrochloride. The method comprises the following steps: with thiopheneethanol as a raw material, reacting thiopheneethanol with p-toluene sulfonyl chloride under the action of an acid binding agent so as to protect and activate a hydroxyl group; then subjecting a reaction product obtained in the previous step and o-chlorobenzylamine to a condensation reaction; and carrying out a ring closure reaction on a condensation reaction product and 1,3-dioxolane so as to obtain ticlopidine hydrochloride. The novel preparation method has the advantages of mild reaction conditions, low production cost, high product yield, good product quality and easy realization of industrial production.

Method for preparing ticlopidine hydrochloride

The invention provides a method for preparing ticlopidine hydrochloride, which comprises the following steps: reacting thienyl ethanol used as a raw material with paratoluensulfonyl chloride under the action of an acid-binding agent to protect and activate the hydroxy group; carrying out condensation reaction with ortho-chlorobenzylamine; and carrying out cyclization reaction with 1,3-dioxolane under acidic conditions to obtain the ticlopidine hydrochloride. The method has the advantages of mild reaction conditions, low production cost, high product yield and good product quality, and is convenient for industrial production.

Preparation method of ticlopidine hydrochloride

The invention provides a preparation method of ticlopidine hydrochloride. The preparation method comprises the following steps: reacting thiophene ethanol as a raw material with paratoluensulfonyl chloride at first under the action of an acid-binding agent so as to protect and activate hydroxyl radicals; then performing condensation reaction with o-chlorobenzylamine; and then under an acidic condition, performing ring-closing reaction with 1,3-dioxolane to obtain ticlopidine hydrochloride. The preparation method is mild in reaction condition, low in production cost, high in product yield and good in product quality, and can conveniently realize industrial production.

One pot synthesis of 5-(substituted aryl) methyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridine using chloromethyl methyl ether

Ticlopidine and its analogues were prepared by one pot synthesis without isolating the intermediates. This sequential one pot synthesis avoided a lengthy separation process, workup and purification of the intermediate compounds and thus could save the time and resources and increased the yield.

Method of making thieno-pyridine derivatives

The present invention provides a method of preparing thieno[3,2-c]pyridine derivatives of formula I: wherein R1 is selected from the group consisting of lower alkyl; lower alkylene phenyl; substituted lower alkylene phenyl wherein the phenyl is substituted from 1 to 3 times with lower alkyl, lower alkoxy, lower acyloxy, hydroxy, nitro and halo; lower alkylene naphthyl, lower alkylene thienyl; lower alkylene diphenyl; lower alkylene-hydroxy-phenyl; substituted lower alkylene-hydroxy-phenyl wherein the phenyl is substituted from 1 to 3 times with lower alkyl, lower alkoxy, lower acyloxy, hydroxy, nitro, and halo; lower alkylene-hydroxy-naphthyl; lower alkylene-hydroxy-thienyl; lower alkylene-hydroxy-diphenyl, and R2 is H or lower alkylene. The method comprises reacting a compound of a formula II: with a cyclic dioxy or cyclic dithio in the presence of catalyst.

A modified Mannich reaction using 1,3-dioxolane

Mannich reaction of ketones using 1,3-dioxolane instead of formaldehyde, paraformaldehyde, or 1,3,5-trioxane afforded the corresponding Mannich bases in high yields. Under the same conditions the aminomethylation of aromatics did not proceed but the intramolecular aminomethylation, like a Pictet-Spengler type reaction, proceeded smoothly.

Preparation of 2-(2-thienyl) ethylamine and synthesis of thieno [3,2-C] pyridine derivatives therefrom

Compounds of the formulae:and wherein:, R1, R2, R3 and R4 are independently hydrogen, lower alkyl of one to six carbon atoms, aryl or substituted aryl;, are advantageously converted to isocyanurate compounds, 2-(2-thienyl)ethylamine compounds and thieno[3,2-c]pyridine derivatives and the pharmaceutically acceptable salts thereof, particularly ticlopidine hydrochloride.