120202-66-6

Basic information

• Product Name: Clopidogrel sulfate
• Synonyms: PLAVIX;SR-25990C;CLOPIDOGREL SULFATE;CLOPIDOGREL SULPHATE;CLOPIDOGREL HYDROGEN SULPHATE;CLOPIDOGREL BISULPHATE;CLOPIDOGREL BISULFATE;Myogrel
• CAS NO: 120202-66-6
• Molecular Formula: C₁₆H₁₆ClNO₂S*H₂O₄S
• Molecular Weight: 419.9
• EINECS: 1806241-263-5
• Product Categories: INTERMEDIATES OF CLOPIDOGREL;Iscover;Cardiovascular APIs;Pharmaceutical intermediates;Cardiovascular Series;Clopidogrel;APIs;Chiral Reagents;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals;Sulfur & Selenium Compounds
• Mol File: 120202-66-6.mol

Chemical Properties

• Melting Point: 174-176°C
• Boiling Point: 423.7 °C at 760 mmHg
• Flash Point: 210 °C
• Appearance: white/solid
• Vapor Pressure: 8.71E-09mmHg at 25°C
• Storage Temp.: 2-8°C
• Solubility: DMSO: ~26 mg/mL
• BRN: 9967887
• CAS DataBase Reference: Clopidogrel sulfate(CAS DataBase Reference)
• NIST Chemistry Reference: Clopidogrel sulfate(120202-66-6)
• EPA Substance Registry System: Clopidogrel sulfate(120202-66-6)

Safety Data

• Safety Statements: 22-24/25
• RIDADR: 1759
• WGK Germany: 3
• HazardClass: 8
• PackingGroup: II
• Hazardous Substances Data: 120202-66-6(Hazardous Substances Data)

Usage

Uses

Used in Cardiovascular Applications:
Clopidogrel sulfate is used as an antithrombotic agent for inhibiting blood clots in patients with coronary artery disease, peripheral vascular disease, and cerebrovascular disease. It helps prevent vascular ischemic events in patients with acute coronary syndromes when used in combination with aspirin.
Used in Pharmaceutical Industry:
Clopidogrel sulfate is used as an active pharmaceutical ingredient in the formulation of antiplatelet drugs. Its role in inhibiting platelet aggregation makes it a crucial component in the development of medications aimed at reducing the risk of blood clot formation and associated complications in cardiovascular diseases.

Originator

Iscover,Bristol-Myers

Manufacturing Process

Levo-rotatory ammonium camphor-10-sulfonate is dissolved in a minimum of water and applied to the column of Amberlite IRN-77 resin. Elution is carried out with water. The eluted fractions containing the levo-rotatory camphor-10- sulfonic acid are lyophilized, melting point 198°C. 32 g (0.0994 mole) of racemic methyl-α-5-(4,5,6,7-tetrahydro-thieno(3,2- c)pyridyl)(2-chlorophenyl)-acetate are dissolved in 150 ml of acetone. 9.95 g (0.0397 mole) of levo-rotatory camphor-10-sulfonic acid monohydrate are added. The clear solution is left to stand at room temperature. After 48 hours the reaction mixture is concentrated to 50 ml and left to stand at room temperature for 24 hours. The obtained camphor-10-sulfonic acid salt of methyl-α-5-(4,5,6,7-tetrahydro-thieno(3,2-c)pyridyl)(2-chlorophenyl)-acetate (SR 25990) are filtered off, washed with acetone and dried (yield: 55% on the basis of the starting racemate), melting point 165°C, [α]D20=+24.67 (c=1.58 g/100 ml; methanol). The crystals obtained above are redissolved in the minimum of boiling acetone (50 ml). The crystals obtained after cooling are filtered off, washed with acetone and dried (yield: 88%), m.p. 165°C, [α]D20=+24.75 (c=1.68 g/100 ml; methanol). 12 g (0.022 mole) of the pure camphor-10-sulfonic acid salt of methyl-α-5- (4,5,6,7-tetrahydro-thieno(3,2-c)pyridyl)(2-chlorophenyl)-acetate are dissolved in a minimum of water. After cooling to 5°C, the aqueous solution obtained is made alkaline with a saturated aqueous solution of sodium hydrogen carbonate. The alkaline aqueous phase is extracted with dichloromethane. The organic extracts are dried over anhydrous sodium sulfate. On evaporation of the solvent a colorless oil of dextro-rotatory methyl-α-5-(4,5,6,7-tetrahydro-thieno(3,2-c)pyridyl)(2-chlorophenyl)-acetate is obtained (quantitative yield). Oil, [α]D20=+51.52 (c=1.61 g/100 ml; methanol). 800 ml of a saturated aqueous solution of sodium bicarbonate are added to a suspension of 200 g of SR 25990 in 800 ml of dichloromethane. After vigorous shaking, the organic phase is separated, dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is dissolved in 500 ml of ice-cold acetone and 20.7 ml of concentrated sulfuric acid (93.64%) areadded drop-wise. The precipitate formed is isolated by filtration and washed with 1 L of acetone, then dried in a vacuum oven at 50°C. 139 g of pure white crystals of hydrogen sulfate of dextro-rotatory methyl-α-5-(4,5,6,7- tetrahydro-thieno(3,2-c)pyridyl)(2-chlorophenyl)-acetate (SR 25990 C) are thus obtained, m.p. 184°C, [α]D20=+55.10 (c=1.891 g/100 ml; methanol).

Therapeutic Function

Platelet aggregation inhibitor

Biochem/physiol Actions

(S)-(+)-Clopidogrel hydrogen sulfate is an antithrombotic antiplatelet agent. It specifically and irreversibly inhibits the Purinoceptor P2Y12 subtype which inhibits ADP-induced platelet aggregation. (S)-(+)-Clopidogrel hydrogen sulfate is the active isomer.

Veterinary Drugs and Treatments

Clopidogrel, a platelet aggregation inhibitor, may be useful for preventing thrombi in susceptible cats. It may also improve pelvic limb circulation in cats after a cardiogenic embolic event via a vasomodulating effect secondary to inhibition of serotonin release from platelets. Research is ongoing.

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

(S)-(+)-α-(2-thienylethylamino)-α-(2-chlorophenyl)acetic acid methyl ester hydrochloride + formaldehyd (50-00-0) → (S)-(+)-clopidogrel bisulfate (120202-66-6)

Conditions	Yield
Stage #1: (S)-(+)-α-(2-thienylethylamino)-α-(2-chlorophenyl)acetic acid methyl ester hydrochloride; formaldehyd In methanol at 43℃; for 5h; Stage #2: With sulfuric acid at 38℃; for 4h; Temperature;	100%
Stage #1: (S)-(+)-α-(2-thienylethylamino)-α-(2-chlorophenyl)acetic acid methyl ester hydrochloride; formaldehyd; hydrogenchloride In water at 80 - 85℃; for 1h; Stage #2: With sulfuric acid In methanol; acetone at 0 - 30℃; for 15h;	n/a
Stage #1: (S)-(+)-α-(2-thienylethylamino)-α-(2-chlorophenyl)acetic acid methyl ester hydrochloride; formaldehyd at 25 - 55℃; Stage #2: With sulfuric acid In acetic acid butyl ester at -10 - 0℃;
Stage #1: (S)-(+)-α-(2-thienylethylamino)-α-(2-chlorophenyl)acetic acid methyl ester hydrochloride; formaldehyd In cyclohexane; water at 40℃; for 6h; Large scale; Stage #2: With sulfuric acid In methanol; acetone at -5℃; for 8h; Solvent; Temperature; Concentration; Large scale;	72 kg
In water at 36 - 44℃;

(S)-(+)-clopidogrel (113665-84-2) → (S)-(+)-clopidogrel bisulfate (120202-66-6)

Conditions	Yield
With sulfuric acid In ethyl acetate at -5 - 30℃; for 3h; Temperature; Solvent;	99%
With sulfuric acid In ethyl acetate at -5 - 30℃; for 3h; Temperature; Solvent; Concentration; Inert atmosphere;	99%
With polyethylene glycol-200; sulfuric acid; sodium hydrogencarbonate In acetone at -5 - 20℃; for 0.0833333 - 0.116667h; pH=8; Conversion of starting material;	96%

methyl (S)-2-(2-chlorophenyl)-2-[2-(thien-2-yl)ethylamino]acetate (141109-20-8) + formaldehyd (50-00-0) → (S)-(+)-clopidogrel bisulfate (120202-66-6)

Conditions	Yield
Stage #1: methyl (S)-2-(2-chlorophenyl)-2-[2-(thien-2-yl)ethylamino]acetate; formaldehyd With sulfuric acid In chloroform at 20℃; Stage #2: With sulfuric acid In acetone at 10℃; for 2h; Solvent; Temperature;	96.2%

methyl (R)-2-(2-chlorophenyl)-2-benzenesulfonyloxyacetate (223123-46-4) + 6,7-dihydro-4H-thieno[3,2-c]pyridine hydrochloride (28783-41-7) → (S)-(+)-clopidogrel bisulfate (120202-66-6)

Conditions	Yield
Stage #1: methyl (R)-2-(2-chlorophenyl)-2-benzenesulfonyloxyacetate; 6,7-dihydro-4H-thieno[3,2-c]pyridine hydrochloride With sodium hydrogencarbonate In acetone for 6h; Reflux; Stage #2: With sulfuric acid In acetone	95.2%

methyl (R)-2-(2-chlorophenyl)-2-(4-methoxybenzenesulfonyloxy)acetate + 4,5,6,7-tetrahydrothieno[3,2-c]pyridine dihydrogen phosphate → (S)-(+)-clopidogrel bisulfate (120202-66-6)

Conditions	Yield
Stage #1: methyl (R)-2-(2-chlorophenyl)-2-(4-methoxybenzenesulfonyloxy)acetate; 4,5,6,7-tetrahydrothieno[3,2-c]pyridine dihydrogen phosphate With N-ethyl-N,N-diisopropylamine In acetone for 6h; Reflux; Stage #2: With sulfuric acid In acetone	94.9%

methyl (R)-2-(2-chlorophenyl)-2-(4-methylbenzenesulfonyloxy)acetate + 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrobromide → (S)-(+)-clopidogrel bisulfate (120202-66-6)

Conditions	Yield
Stage #1: methyl (R)-2-(2-chlorophenyl)-2-(4-methylbenzenesulfonyloxy)acetate; 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrobromide With triethylamine In acetone for 5h; Reflux; Stage #2: With sulfuric acid In acetone	94.4%

clopidogrel hydrogen sulfate → (S)-(+)-clopidogrel bisulfate (120202-66-6)

Conditions	Yield
In dichloromethane; water at 25 - 30℃; Conversion of starting material;
under 2 - 5 Torr; Conversion of starting material; Melting;

(S)-(+)-clopidogrel (113665-84-2) + methyl (R)-2-(2-chlorophenyl)-2-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-yl)acetate (120202-69-9) → (S)-(+)-clopidogrel bisulfate (120202-66-6)

Conditions	Yield
With sulfuric acid In acetone at 15℃; for 2.5h;

Upstream product

• 113665-84-2 (S)-(+)-clopidogrel 
• 90055-48-4 clopidogrel 
• 120202-71-3 clopidogrel hydrogen sulfate 
• 120202-69-9 methyl (R)-2-(2-chlorophenyl)-2-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-yl)acetate 
• 141109-18-4 (S)-(+)-α-(2-thienylethylamino)-α-(2-chlorophenyl)acetic acid methyl ester hydrochloride 
• 50-00-0 formaldehyd 
• 7664-93-9 sulfuric acid 
• 909279-85-2 clopidogrel camphorsulfonate 
• 40412-06-4 2-(2-thienyl)ethyl tosylate 
• 54903-50-3 4,5,6,7-tetrahydrothieno[3,2-c]pyridine 
• 1198409-05-0 (1R)-1-methyl-2-oxo-2-tetrahydro-1H-pyrrolylethyl 2-bromo-2-(2-chlorophenyl)acetate 
• 1198409-07-2 (1R)-1-methyl-2-oxo-2-tetrahydro-1H-pyrrolylethyl (2S)-α-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl)-2-chlorophenylacetate 
• 28783-41-7 6,7-dihydro-4H-thieno[3,2-c]pyridine hydrochloride 
• 85259-19-4 methyl 2-bromo-2-(2-chlorophenyl)acetate 

Downstream Products

• 684269-95-2 clopidogrel-sec-butyl sulfate 
• 120202-71-3 clopidogrel hydrogen sulfate 
• 113665-84-2 (S)-(+)-clopidogrel 
• 144457-28-3 SR 26334 
• 744256-69-7 clopidogrel besylate 
• 1326217-43-9 (S)-methyl 2-(2-bromo-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)acetate 

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).

Copper (II) bromide catalysed one pot bromination and amination for the green, cost-effective synthesis of clopidogrel

Copper (II) bromide catalyzed one pot α-bromination and followed by amination of a benzylic ester is reported. The α-bromination of ester by copper (II) bromide generates copper (I) bromide and HBr. The copper (I) bromide is oxidized to copper (II) bromide by N-Methylmorpholine-N-Oxide (NMO) in presence of HBr. The amines undergo nucleophilic substitution reaction with α-brominated ester compound. This methodology was applied for the synthesis of the familiar antiplatelet drug clopidogrel. This green process is an alternate to classical methods for the synthesis of clopidogrel, which requires, generates stochiometric amount of brominating agents and HBr, respectively.

Preparation method of clopidogrel hydrogen sulfate

The invention relates to a preparation method of clopidogrel hydrogen sulfate. The preparation method comprises the following steps: reacting (S)-o-chlorophenylglycine methyl ester with 1, 1, 1, 3, 3,3-hexamethyldisilazane to obtain trimethylsilyl protected (S)-o-chlorophenylglycine methyl ester; in the presence of acetonitrile, superfine powder potassium carbonate and the trimethylsilyl protected (S)-o-chlorophenylglycine methyl ester, adding 2- (2-bromoethyl) thiophene, evaporating acetonitrile in batches, adding water and methyl acetate, extracting to obtain a methyl acetate solution of (S)-2-thiophene ethylamino-2-chlorophenylmethyl acetate, dropwise adding concentrated hydrochloric acid, carrying out pulping and cooling to obtain (S)-2-thiophene ethylamino methyl-2-chlorophenyl acetate hydrochloride, mixing the (S)-2-thiophene ethylamino methyl-2-chlorophenyl acetate hydrochloride with a formaldehyde aqueous solution for reaction, and carrying out reaction with concentrated sulfuric acid to obtain the clopidogrel hydrogen sulfate. According to the method, the high-purity (S)- 2-thiophene ethylamino-2-chlorophenyl methyl acetate hydrochloride and clopidogrel hydrogen sulfate can be obtained with high efficiency and high yield, and the method is suitable for industrial production.

Preparation method of clopidogrel hydrogen sulfate and intermediate N-(2-thiopheneethyl) methyleneimine of clopidogrel hydrogen sulfate

The invention discloses a preparation method of clopidogrel hydrogen sulfate and an intermediate N-(2-thiophene ethyl) methyleneamine of the clopidogrel hydrogen sulfate. The synthesis method of the intermediate comprises the step of carrying out an Eschweiler-Clarke methylation reaction by taking 2-thiophene ethylamine and paraformaldehyde as raw materials to obtain the N-(2-thiophene ethyl) methyleneamine. The invention also provides a method for preparing clopidogrel hydrogen sulfate. According to the synthesis method provided by the invention, the required solid product (N-(2-thiopheneethyl) methyleneimine) is synthesized in one step, the synthesis method is simple, the qualified solid compound is directly obtained, the time and the raw material cost are saved, the storage and the transportation are convenient, the purity is good, the yield is high, and the synthesis method is suitable for industrial production.

Preparation method of clopidogrel hydrogen sulfate intermediate

The present invention relates to a preparation method of a clopidogrel hydrogen sulfate intermediate. (+)-2-chlorophenylglycine methyl ester and alpha-thiopheneethanol p-toluenesulfonate are adopted as raw materials, a reaction solvent and an acid-binding agent are added for a condensation reaction, the condensation reaction process is divided into a first stage and a second stage, and when 60-95% of the condensation reaction is completed, first-stage reaction is completed; after the first-stage reaction is completed, firstly part of the reaction solvent is removed, and then second-stage reaction is carried out; and after the second-stage reaction is completed, a target product is obtained, namely the clopidogrel hydrogen sulfate intermediate. After the first-stage reaction is completed, part of the reaction solvent is removed firstly, and then the second-stage reaction is continued, so that the concentration of the reaction material can be increased in the later stage of the condensation reaction, the use amount of the reaction solvent is reduced, and racemization and side reaction in the reaction process are effectively inhibited, thereby improving the chiral purity of the product, increasing the yield, reducing the use of auxiliary materials greatly, and reducing the production cost.

A preparation method of clopidogrel hydrogen sulfate type II

The invention discloses a preparation method of clopidogrel hydrogen sulfate type II. The method comprises the following steps: (4) taking clopidogrel free alkali as a raw material, and reacting the clopidogrel free alkali with (1R)-(-)-10-camphorsulfonic acid in a reaction solvent to obtain clopidogrel camphorsulfonate, and hydrolyzing under an alkaline condition to obtain clopidogrel free alkali; and then preparing the clopidogrel hydrogen sulfate type II by taking the clopidogrel free alkali obtained in the step (4) as a raw material. The synthetic route is simple, the used solvent is cheap, the cost is saved, the generation of waste liquid is reduced, the recycling of the solvent is improved, and the prepared clopidogrel hydrogen sulfate type II has the characteristics of high purity,good quality, high yield, good stability, suitability for industrial mass production and the like.

A preparation method of clopidogrel hydrogen sulfate type II

The invention discloses a preparation method of clopidogrel hydrogen sulfate type II. According to the method, clopidogrel hydrogen sulfate type II is prepared by taking clopidogrel free alkali as a raw material, and a preparation method of clopidogrel free alkali comprises the following steps: (1) preparing a reaction mixed solution of R-chloromandelic acid methyl ester by the reaction of R-chloromandelic acid and methanol in an organic solvent and in the presence of a catalyst; (2) mixing the reaction mixed solution of R-chloromandelic acid methyl ester with an organic base and a catalyst, reacting in the presence of benzenesulfonyl chloride to obtain a reaction mixed solution of methyl 2-benzenesulfonyl-2-chlorophenylacetate; (3) mixing the reaction mixed solution of methyl 2-benzenesulfonyl-2-chlorophenylacetate obtained in the step (2) with 4,5,6,7-Tetrahydrothieno[3,2,c] pyridine hydrochloride and potassium carbonate for reaction to obtain the clopidogrel free alkali. According to the method, the solvent does not need to be supplemented in the last two steps, the solvent is directly used, and the reaction liquid concentration time is saved.

Synthetic hydrosulfuric acid clopidogrel and intermediate of the new method (by machine translation)

The invention relates to a synthesis of the clopidogrel hydrogen sulfate of the new method, through 2 - thiophene ethylamine and N - benzyl - 2 - (2 - chlorophenyl) - 2 - carbonyl acetamide generate condensation reaction, generating imine; imine asymmetric hydrogenation reaction is reduced to the corresponding secondary amine. Under acidic conditions, secondary amine with formaldehyde generating ring, get the clopidogrel free base, then acidified by sulfuric acid, to obtain the clopidogrel hydrogen sulfate. The present invention provides a synthetic route of the short, relates to the reaction are classical organic chemical reaction, mild reaction conditions, the operation is simple, with high enantio-selectivity, high yield, high turn over number of characteristics, the vast majority of the substrate in the thousandths of a dosage of the catalyst obtained in the circumstances of 99% or more of the conversion and 97% -99% ee value of, to achieve the highest transformed number 100000, has extremely high industrial application value. (by machine translation)

Method for preparing high-purity type-II crystal form hydrogen sulfate clopidogrel

The invention discloses a method for preparing high-purity type-II crystal form hydrogen sulfate clopidogrel. The method comprises the following steps: dissolving a first clopidogrel free alkali crudeproduct into dichloromethane, performing decontamination by using a 4wt% sodium hydroxide solution, performing alkali wash on an organic phase, and performing drying, suction filtration and concentration so as to obtain a seconda clopidogrel free alkali crude product; and adding ethyl acetate or a mixed liquid of ethyl acetate and acetonitrile, increasing the temperature to 37-39 DEG C, adding dropwise concentrated sulfuric acid to be subjected to crystallization, performing room-temperature crystallization, performing filtering, and drying filter cakes so as to obtain a final product, namelytype-II crystal form hydrogen sulfate clopidogrel. The method is mild in reaction condition and free of toxic or harmful substance, in addition, the amount of a precursor solvent is reduced, the reaction time is shortened to 4-6 hours from 14-16 hours, the energy consumption is reduced, related substances of the type-II crystal form hydrogen sulfate clopidogrel are ensured to meet various domestic and abroad standards, and generation of impurities is avoided when strong acids are added dropwise; and the obtained type-II crystal form hydrogen sulfate clopidogrel is high in purity and high in yield.

Synthesis method of clopidogrel hydrogen sulfate

The invention discloses a synthesis method of clopidogrel hydrogen sulfate. The synthesis method takes o-phenylphthalic chloroacetic acid and 4,5,6,7tetrahydrothiophene[3,2-c] as raw materials and comprises the following steps: (1) carrying out acylation reaction; (2) carrying out bromination reaction; (3) carrying out esterification reaction; (4) preparing a clopidogrel base crude product; (5) extracting clopidogrel base; (5) carrying out racemic racemate reductionresolution; (7) preparing the clopidogrel hydrogen sulfate. According to the synthesis method of the clopidogrel hydrogen sulfate, disclosed by the invention, reasonable raw material selection and process route design are carried out, so that on one hand, a process flow is simplified and synthesis operation is easy to realize; on the other hand, reaction conditions are reduced, the reaction conditions are moderate and the method is easily smoothly carried out; the obtained finished product clopidogrel hydrogen sulfate has high yield and good quality; industrial production is easy to realize and a market prospect is wide.