135046-48-9

Basic information

• Product Name: Clopidogrel hydrogen sulfate
• Synonyms: PLAVIX;SR-25990C;CLOPIDOGREL BISULPHATE;CLOPIDOGREL HYDROGEN SULPHATE;CLOPIDOGREL SULPHATE;SR-25990C, Plavix, Methyl (+)-(S)-a-(2-Chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)acetate, Hydrogen sulfate salt;Methyl (S)-alpha-(2-Chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate hydrogen sulfate;SR-25990, Methyl (2-chlorophenyl)(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetate hydrogen sulfate
• CAS NO: 135046-48-9
• Molecular Formula: C₁₆H₁₆ClNO₂S*H₂O₄S
• Molecular Weight: 419.9
• EINECS: 1806241-263-5
• Product Categories: Active Pharmaceutical Ingredients;chiral;Intermediates & Fine Chemicals;Pharmaceuticals;Purinergics P2 receptor
• Mol File: 135046-48-9.mol

Chemical Properties

• Melting Point: 184°C
• Boiling Point: 423.7 °C at 760 mmHg
• Flash Point: 210 °C
• Appearance: white/
• Vapor Pressure: 8.71E-09mmHg at 25°C
• Storage Temp.: 2-8°C
• Solubility: DMSO: ~26mg/mL
• CAS DataBase Reference: Clopidogrel hydrogen sulfate(CAS DataBase Reference)
• NIST Chemistry Reference: Clopidogrel hydrogen sulfate(135046-48-9)
• EPA Substance Registry System: Clopidogrel hydrogen sulfate(135046-48-9)

Safety Data

• Safety Statements: 22-24/25
• WGK Germany: 3
• HazardClass: IRRITANT
• Hazardous Substances Data: 135046-48-9(Hazardous Substances Data)

Usage

Uses

1. Used in Pharmaceutical Industry:
Clopidogrel hydrogen sulfate is used as an antithrombotic agent for preventing blood clot formation. It is particularly effective in reducing the risk of heart attacks, strokes, and other cardiovascular events by inhibiting platelet aggregation.
2. Used in Cardiology:
Clopidogrel hydrogen sulfate is used as a platelet aggregation inhibitor for patients with coronary artery disease, peripheral vascular disease, and those who have undergone coronary stenting or angioplasty. It helps in maintaining the patency of the blood vessels and preventing the recurrence of heart attacks.
3. Used in the Synthesis of Clopidogrel Derivatives:
Clopidogrel hydrogen sulfate is used in the synthesis of Clopidogrel derivatives, which are also platelet aggregation inhibitors. These derivatives can be used for the development of new drugs with improved efficacy and reduced side effects.
4. Used in Research and Development:
Clopidogrel hydrogen sulfate is used as a research compound for studying its antithrombotic properties and potential applications in the development of new drugs for the treatment of cardiovascular diseases.

Anti-platelet aggregation drug

Thrombosis caused by arterial atheromatous plaque leads to acute thrombosis cardiovascular and cerebrovascular events. In this pathogenesis, platelets play a central role, which has been fully studied. Clopidogrel hydrogen sulfate is similar to ticlopidine, which is a new anti-platelet aggregation drug, successfully developed by French Sanofi-Synthelabo Fort for the prevention and treatment of heart, brain and other arterial circulation disorders caused by the high blood platelet aggregation, such as recent onset of stroke, myocardial infarction and patients diagnosed with peripheral arterial disease. Many countries have already used it, including United States, Europe and China. This product inhibited platelet activation by inhibiting adenosine diphosphate (ADP) pathway to inhibit platelet aggregation. Since clopidogrel hydrogen sulfate takes several days to achieve effective blood concentration, it does not apply to emergency treatment. Stop using 7 to 10 days, platelet function returned to normal state. The above information is edited by the lookchem of Kui Ming.

Biochem/physiol Actions

Inhibits ADP-induced platelet aggregation; anti-thrombotic drug.

InChI:InChI=1/C15H14ClNO2S.H2O4S/c16-12-4-2-1-3-11(12)14(15(18)19)17-7-5-13-10(9-17)6-8-20-13;1-5(2,3)4/h1-4,6,8,14H,5,7,9H2,(H,18,19);(H2,1,2,3,4)/t14-;/m0./s1

Synthetic route

clopidogrel (90055-48-4) → clopidogrel bisulfate (135046-48-9)

Conditions	Yield
With sulfuric acid In water; acetone at 20℃; for 2h;	91%
With sulfuric acid In acetone at 20 - 25℃; for 1 - 1.5h; Product distribution / selectivity;
With sulfuric acid In acetone at 0 - 5℃; Product distribution / selectivity;

6,7-dihydro-4H-thieno[3,2-c]pyridine hydrochloride (28783-41-7) + methyl 2-bromo-2-(2-chlorophenyl)acetate (85259-19-4) → clopidogrel bisulfate (135046-48-9)

Conditions	Yield
Stage #1: 6,7-dihydro-4H-thieno[3,2-c]pyridine hydrochloride With sodium carbonate In water at 25℃; for 0.5h; Stage #2: methyl 2-bromo-2-(2-chlorophenyl)acetate In water; toluene at 20℃; for 12h; Stage #3: With sulfuric acid In ethyl acetate for 1h; Reagent/catalyst; Solvent;	90%
Stage #1: 6,7-dihydro-4H-thieno[3,2-c]pyridine hydrochloride; methyl 2-bromo-2-(2-chlorophenyl)acetate With potassium carbonate In acetone Stage #2: With sulfuric acid

formaldehyd (50-00-0) + methyl 2-bromo-2-(2-chlorophenyl)acetate (85259-19-4) → clopidogrel bisulfate (135046-48-9)

Conditions	Yield
Stage #1: [2-(2-thyenyl)ethyl]amine; formaldehyd In 1,2-dichloro-ethane for 4h; Heating / reflux; Stage #2: With hydrogenchloride In 1,2-dichloro-ethane; N,N-dimethyl-formamide at 30 - 70℃; for 4h; Stage #3: methyl 2-bromo-2-(2-chlorophenyl)acetate With sulfuric acid; sodium carbonate Product distribution / selectivity; more than 3 stages;	85%

(-/+) methyl (2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetate camphor sulfonate → clopidogrel bisulfate (135046-48-9)

Conditions	Yield
Stage #1: (-/+) methyl (2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetate camphor sulfonate With sodium carbonate In dichloromethane; water at 30 - 35℃; pH=7.5 - 8.0; Stage #2: With sulfuric acid In acetone at 20 - 25℃; for 1h;	80%

(+)-clopidogrel camphorsulfonic acid → clopidogrel bisulfate (135046-48-9)

Conditions	Yield
Stage #1: (+)-clopidogrel camphorsulfonic acid With sodium hydrogencarbonate In water Stage #2: With potassium tert-butylate at 0℃; for 0.333333h; Stage #3: With sulfuric acid

Upstream product

• 28783-41-7 6,7-dihydro-4H-thieno[3,2-c]pyridine hydrochloride 
• 85259-19-4 methyl 2-bromo-2-(2-chlorophenyl)acetate 
• 50-00-0 formaldehyd 
• 30433-91-1 [2-(2-thyenyl)ethyl]amine 
• 90055-48-4 clopidogrel 

Downstream Products

• 90055-48-4 clopidogrel 
• 929200-21-5 (+/-)-(2-chlorophenyl)-(4,5,6,7-4H-thieno[3,2,-c]pyrid-5-yl) potassium acetate 
• 1373492-22-8 5-(2-chloro-1-(2-chlorophenyl)ethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine 
• 1373492-23-9 2-((2-chlorophenyl)-2-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)ethyl)malonic acid diethyl ester 
• 1373491-72-5 4-(2-chlorophenyl)-4-(6,7-dihydro-4H-thieno[3,2-c]pyridine-5-yl)butyric acid ethyl ester 
• 1373491-51-0 4-(2-chlorophenyl)-4-(6,7-dihydro-4H-thieno[3,2-c]pyridine-5-yl)butan-1-ol 
• 1376615-29-0 2-(2-chlorophenyl)-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetaldehyde 
• 1376615-30-3 2-(2-chlorophenyl)-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)ethyl acetate 
• 1376615-31-4 (E)-2-(2-chlorophenyl)-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetaldehyde O-methyl oxime 

Related news

In Situ Monitoring of Polymorph Transformation of Clopidogrel hydrogen sulfate (cas 135046-48-9) Using Measurement of Ultrasonic Velocity08/11/2019

ABSTRACTTransformation of polymorph I of clopidogrel hydrogen sulfate (CHS) to polymorph II of CHS during the crystallization was monitored by using in situ measurement of ultrasonic velocity. Drowning-out crystallization using methanol as a solvent and isopropyl alcohol as nonsolvent was carrie...detailed

Solubility measurement and prediction of Clopidogrel hydrogen sulfate (cas 135046-48-9) polymorphs in isopropanol and ethyl acetate08/09/2019

The solubility of an active pharmaceutical ingredient (API) in various solvents is extremely important for its manufacturing and development as a drug. In this work, the solubility of two polymorphs of clopidogrel hydrogen sulfate (CHS) in the solvents of isopropanol (IPA) and ethyl acetate (EA)...detailed

Relevant articles and documents

Efficient Synthesis of (S)-(+)-Clopidogrel Bisulfate-Capped Silver Nanoparticles

In this work primarily one-pot synthetic development in the preparation of clopidogrel bisulfate with a polymorphic crystalline form II in 90% yield was developed. This premade antiplatelet drug has been used to protect starch-stabilized silver nanoparticles (AgNPs).

RACEMIZATION PROCESS FOR THE PREPARATION OF AN INTERMEDIATE OF CLOPIDOGREL HYDROGEN SULPHATE

The invention relates to a process for the preparation of the pharmaceutically applicable methyl (S)-(+)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)- acetate hydrogen sulphate (also known as S-(+)-clopidogrel hydrogen sulphate) of formula (I) comprising racemizing methyl (R)-(-)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine- 5(4H)-acetate or methyl (S)-(+)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)- acetate, or a mixture thereof in any proportion with a weak base in the presence of an organic solvent, converting the methyl (R,S)-(±)-α-(2-chlorophenyl)-6,7-dihydrothieno [3,2-c]pyridine-5(4H)-acetate of fomula (II) obtained to its sulphuric acid addition salt methyl (R,S)-(±)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate hydrogen sulphate and converting it to methyl (S)-(+)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c] pyridine-5(4H)-acetate hydrogen sulphate of formula (I) by known manner.

PROCESS FOR THE PREPARATION OF POLYMORPHIC FORMS OF CLOPIDOGREL HYDROGEN SULFATE

The present invention relates to a novel process for the preparation of polymorphic forms of clopidogrel hydrogen sulfate, namely methyl(+)-(S)-α-(o-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate hydrogen sulfate of formula (I). Particularly the present invention relates to the process for the preparation of form (I) and amorphous clopidogrel hydrogen sulfate.

Preparation of Clopidogrel and Its Analogues Methyl Tetrahydrothienopyridine Acetate Compuunds

The present invention disclosed a preparation method of Clopidogrel (X=2-Cl) and its analogues of methyl tetrahydrothienopyridine acetate (I) by using halogen phenyl acetonitrile (VIII) as starting material and tetrahydrothienopyridine acetonitrile (IV), tetrahydrothienopyridine acetate (V) as key intermediates, and further using kinetic resolution to prepare the optical active Clopidogrel and compounds of methyl tetrahydrothenopridine acetate of formula (XII). The Clopidogrel of present invention is a novel high effective and safety drug for inhibition of platelet aggregation. This invention applied systematic technique of racemization of unwanted optical active enantiomer, recover recycle and reuse of resolution agent etc., with greater economic advantages and suitable for commercial scale industrial production. Wherein: X represents atoms of hydrogen, fluorine, chlorine, bromine or iodine, M represents an alkali metal ion.

Industrial process for preparation a polmorph of clopidogrel hydrogen sulphate

An improved process for the manufacture of Clopidogrel starting from 2-(2-thienyl) ethylamine, which eliminates the isolation of an unstable intermediate like 2-(2-thienyl) ethyl formimine by subjecting it to a one pot cyclization to get 4,5,6,7-tetrahydrothieno (3,2-c) pyridine of Formula II and further reacting with halo-compound of Formula III (where X is Cl or Br) at 20 to 90 °C temperature characterized in a solvent like water and/or dichloroethane in presence of organic or inorganic bases is disclosed herein. This invention further discloses a process for resolution of racemic clopidogrel into its optical antipodes and converting the dextroclopidogrel base into its known polymorphs namely 'Form I' or 'Form II' in solvents selected from methyl propyl ketone, methyl isopropyl ketone, diethyl ketone or their mixture thereof, mixture of ethyl acetate and methyl propyl ketone, mixture of ethyl acetate and methyl isopropyl ketone, or mixture of ethyl acetate and diethyl ketone or ethyl acetate.

Process for the recovery of S -(+)-methyl- (2-chlorophenyl)- (6,7-dihydro- 4H-thieno [3,2-c] pyrid-5-yl) acetate hydrogen sulfate (clopidogrel bisulfate) from its (R) and mixture of (R) and (S)- isomers

A process for the recovery of compound of formula (I) where X represents hydrogen, fluoro, chloro, bromo or iodo atom, preferably 2-chloro which comprising the steps of f. preparing compound (?) or (±)-(2-chloro phenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetate methyl ester hydrogen sulfate from its corresponding camphorsulfonic acid salt compound. g. transforming the obtained compound of step (a), into the compound of (2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetic acid. h. converting the compound of step (b) into racemic compound (±)-(2-chloro phenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetate methyl ester hydrogen sulfate. i. resolving the obtained racemic compound of step (c), into the optically active (+)-(2-chloro phenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetate methyl ester camphor sulfonic acid salt. j. further transforming the optically active (+) form compound of step (d) into their pharmaceutically acceptable salts.

RACEMIZATION AND ENANTIOMER SEPARATION OF CLOPIDOGREL

Processes for separation of enantiomers of clopidogrel, and converting one enantiomer of clopidogrel to another enantiomer of clopidogrel are provided. The enantiomers are separated by crystallizing the (S) enantiomer as camphor sulfonate salt from a hydrocarbon, or a mixture of a hydrocarbon and a co-solvent, preferably DMF:toluene. The (R) enantiomer is then racemized and recycled by reaction with a catalytic amount of a base, preferably with t-butoxide.

SALT OF BENZOSULFONIC ACID CONTAINING CLOPIDOGREL AND USE THEREOF FOR THE PRODUCTION OF PHARMACEUTICAL FORMULATIONS

The invention relates to the salt of benzosulfonic acid containing clopidogrel and pharmaceutical formulations comprising said salt.

Process for the preparation of a pharmacologically active substance

The present invention relates to a process for the preparation of the racemic or optically active compounds of general formula (VI): wherein the meaning of X is a halogen atom, or their salts, characterized in that, a racemic or optically active new compound of general formula (VII): wherein the meaning of X is a halogen atom, is transformed into the racemic or optically active compound of general formula (VIII):

Intermediates and process for the preparation thereof

A process for the preparation of 2-[(2-thienyl)-ethylamino]-(2-halogenophenyl)-acetamides of general formula (VII) starting from the nitriles of general formula (I). Compounds of general formula (VII) are valuable intermediates.