144494-65-5

Basic information

• Product Name: Tirofiban
• Synonyms: TIROFIBAN;(2s)-2-(butylsulfonylamino)-3-[4-[4-(4-piperidyl)butoxy]phenyl]propanoic acid;Aggrastat;MK-383;N-(Butylsulfonyl)-O-[4-(4-piperidinyl)butyl]-L-tyrosine;C07965;Tirofiban/Tirofiban HCl;irofiban
• CAS NO: 144494-65-5
• Molecular Formula: C₂₂H₃₆N₂O₅S*ClH
• Molecular Weight: 440.6
• EINECS: 1806241-263-5
• Product Categories: Inhibitors
• Mol File: 144494-65-5.mol
• Article Data: 9

Chemical Properties

• Melting Point: 223-225°
• Boiling Point: 611.7 °C at 760 mmHg
• Flash Point: 323.7 °C
• Appearance: /
• Density: 1.154 g/cm³
• Vapor Pressure: 8.09E-16mmHg at 25°C
• Refractive Index: 1.531
• Storage Temp.: Keep in dark place,Sealed in dry,Store in freezer, under -20°C
• PKA: 3.37±0.10(Predicted)
• BRN: 6182267
• CAS DataBase Reference: Tirofiban(CAS DataBase Reference)
• NIST Chemistry Reference: Tirofiban(144494-65-5)
• EPA Substance Registry System: Tirofiban(144494-65-5)

Safety Data

• Hazard Codes: Xi
• Statements: 36/37/38
• Safety Statements: 26
• WGK Germany: 3
• RTECS: YP2364100
• Hazardous Substances Data: 144494-65-5(Hazardous Substances Data)

Usage

Chemical Properties

Tirofiban is an Off-White to Pale Yellow Solid. It is soluble in organic solvents such as ethanol, DMSO, and dimethyl formamide, which should be purged with an inert gas. The solubility of tirofiban in these solvents is approximately 30 mg/ml.

Originator

Aggrastat,Merck and Co., Inc.

Uses

Tirofiban (Aggrastatt, MK-0383; L-700,462) is a parenteral, highly specific, and potent GPIIb/IIIa antagonist that was approved for patient use in 1998 for the treatment of unstable angina and non-Q-wave myocardial infarction.Tirofiban is a nonpeptide GP IIb/IIIa antagonist that binds reversibly to IIb/IIIa receptors. Tirofiban is a non-peptide reversible antagonist of the platelet integrin glycoprotein (GP) IIbIIIa receptor used as an antiplatelet drug.Tirofiban is a small molecule inhibitor of the protein-protein interaction between fibrinogen and the platelet integrin receptor GP IIb/IIIa and is the first drug candidate whose origins can be traced to a pharmacophore-based virtual screening lead.

Definition

ChEBI: Tirofiban is a member of the class of piperidines that is L-tyrosine in which a hydrogen attached to the amino group is replaced by a butylsulfonyl group and in which the hydrogen attached to the phenolic hydroxy group is replaced by a 4-(piperidin-4-yl)butyl group. It has a role as a fibrin modulating drug, a platelet glycoprotein-IIb/IIIa receptor antagonist and an anticoagulant. It is a member of piperidines, a sulfonamide and a L-tyrosine derivative.

General Description

Tirofiban is a nonpeptide that appears unrelatedchemically to eptifibatide, but actually has many similarities.The chemical architecture incorporates a systemthat is mimicking the RGD moiety that is present in eptifibatide.This can be seen in the distance between the nitrogenof the piperidine ring, which mimics the basic nitrogen ofarginine in the RGD sequence, and the carboxylic acid,which mimics the acid of aspartate in the RGD sequence.The basic nitrogen and the carboxylic acid of tirofiban areseparated by approximately 15 to 17? (16–18 atoms). Thisis the optimum distance seen in the RGD sequence of theplatelet receptor. Tirofiban is useful in treating non–Q wavemyocardial infarction and unstable angina.

Clinical Use

Tirofiban is a member of a new class of antithrombotic agents known as the “ fibans”. These compounds have a structural similarity to disintegrin, which was originally isolated from snake venoms. The location of the –COO- and NH3+ in the fibans is identical to the distance between the same functional groups of the RGD loop of disintegrin, and as a result, the fibans are able to effectively block the binding of fibrinogen to the GPIIb/IIIa receptor in an reversible manor.

Drug interactions

Potentially hazardous interactions with other drugs Iloprost: increased risk of bleeding. Heparin: increased risk of bleeding

Metabolism

Tirofiban is eliminated largely unchanged in the urine, with some biliary excretion in the faeces.

Mode of action

Tirofiban is a reversible antagonist that inhibits platelet aggregation by reversibly binding to the receptor glycoprotein (GP) IIb/IIIa of human platelets, thus preventing the binding of fibrinogen. Inhibition of platelet aggregation occurs in a dose- and concentrationdependent manner.?

InChI:InChI=1/C22H36N2O5S/c1-2-3-16-30(27,28)24-21(22(25)26)17-19-7-9-20(10-8-19)29-15-5-4-6-18-11-13-23-14-12-18/h7-10,18,21,23-24H,2-6,11-17H2,1H3,(H,25,26)/t21-/m0/s1

Upstream product

• 142374-19-4 tert-butyl 4-(formylmethyl)piperidine-1-carboxylate 
• 192643-83-7 4-(pyridin-4-yl)butyl-3-yn-1-ol 
• 1352839-95-2 N-n-butylsulfonyl-L-tyrosine ethyl ester 
• 949-67-7 L-tyrosine ethyl ester 
• 5264-17-5 4-(pyridin-4-yl)-1-chlorobutane 
• 149490-61-9 N-(n-butanesulfonyl)-O-(4-(4-pyridinyl)-butyl)-(S)-tyrosine 
• 51052-78-9 4-piperidinylacetic acid 
• 142355-84-8 4-{4-[4-((S)-2-Benzyloxycarbonylamino-2-carboxy-ethyl)-phenoxy]-butyl}-piperidine-1-carboxylic acid tert-butyl ester 
• 142356-28-3 4-{4-[4-((S)-2-Amino-2-carboxy-ethyl)-phenoxy]-butyl}-piperidine-1-carboxylic acid tert-butyl ester 
• 142355-82-6 methyl 4-piperidin-4-yl>butanoate 
• 142355-80-4 methyl 4-piperidin-4-yl>but-2-enoate 
• 142247-38-9 4-[1-(tert-butoxycarbonyl)piperidin-4-yl]butanoic acid 
• 157688-46-5 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid 
• 142355-81-5 tert-butyl 4-(4-bromobutyl)piperidine-1-carboxylate 

Relevant articles and documents

A practical synthesis of fibrinogen receptor antagonist MK-383. Selective functionalization of (S)-tyrosine

A practical 4-step synthesis of fibrinogen receptor antagonist MK-383, N-(n-butanesulfonyl)-O-4-(4-piperidinyl)-butyl)-(S)-tyrosine, is accomplished in 48% overall yield from (S)-tyrosine. Highlights include: (1) the dual use of 4-picoline as a masked form of piperidine, and as a nucleophile precursor for a 3-carbon homologation with 3-bromo-1-chloropropane; (2) the use of trimethylsilyl groups for temporary protection of phenolic and carboxylate oxygens of (S)-tyrosine that enable selective N-sulfonylation to be carried out in high yield; (3) the selective phenolic O-alkylation of the tyrosine derivative in high yield with no racemization using aqueous KOH/DMSO; and (4) the selective hydrogenation of the pyridine ring in the presence of the tyrosine ring using Pd/C in acetic acid.

Synthesis of tirofiban hydrochloride

The invention relates to a method for preparing tirofiban hydrochloride. The method comprises the following steps: carrying out a condensation reaction between 4-pyridine butanol or 4-(pyridine-4-yl)-butyl-3- alkynyl-1-ol and (S)-3-(4-halogenated phenyl)-2-(n-butylsulfonylamino)-propionate in the presence of a copper reagent/alkali/additive/solvent to generate (S)-2-(n-butylsulfonylamino)-3-(4-(4-(pyridine-4-yl)butoxy)phenyl)-propionate or (S)-2-(n-butylsulfonylamino)-3-(4-((4-(pyridine-4-yl)-butyl-3-alkynyl-1-yl)oxo) phenyl) propionate.

Tirofiban hydrochloride intermediate and preparation method of tirofiban hydrochloride

The invention provides a tirofiban hydrochloride intermediate and a preparation method of tirofiban hydrochloride. The content of isomers of the tirofiban hydrochloride intermediate and tirofiban hydrochloride prepared by the method is not higher than 0.5%, preferably not higher than 0.3%, and more preferably not higher than 0.1%; all indexes of the prepared pharmaceutical composition meet the medicinal requirements, the quality is stable in the placing process, and the clinical curative effect and the medication safety can be guaranteed.