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

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

• 142355-83-7 4-(1-tert-butoxycarbonylpiperidin-4-yl)-butan-1-ol 
• 142374-19-4 tert-butyl 4-(formylmethyl)piperidine-1-carboxylate 
• 142373-59-9 4-(4-{4-[(S)-2-(Butane-1-sulfonylamino)-2-carboxy-ethyl]-phenoxy}-butyl)-piperidine-1-carboxylic acid tert-butyl ester 
• 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 
• 149463-65-0 4-(4-pyridinyl)butyl chloride hydrochloride 
• 108-89-4 picoline 
• 149490-61-9 N-(n-butanesulfonyl)-O-(4-(4-pyridinyl)-butyl)-(S)-tyrosine 
• 180307-56-6 tert-butyl 4-ethenylpiperidine-1-carboxylate 
• 5264-15-3 4-(4-pyridinyl)butan-1-ol 
• 100-43-6 4-vinylpyridine 
• 102878-73-9 γ-(pyridin-4-yl)butyric acid 

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.

A method for one-step synthesis of carboxylic acids with two extended carbon chains from olefins

The invention relates to a method for one-step synthesis of carboxylic acid with two extended carbon chains from olefin, which comprises the following steps: under the protection of inert gas, sequentially adding an olefin substrate, a photocatalyst, a hydrogen atom transfer reagent, alpha-haloacetic acid, a reducing agent, a solvent and protonic acid into a reactor, and reacting at normal temperature under the irradiation of 25W blue light to obtain a reaction product; diluting, alkalizing, washing, acidifying and extracting the reaction product to obtain an organic phase; and finally, carrying out reduced pressure distillation and column chromatography on the organic phase to obtain a carboxylic acid product with two extended carbon chains; or carrying out reduced pressure distillation and column chromatography on the reaction product to obtain a carboxylic acid product with two extended carbon chains. The invention is simple to operate, direct synthesis conditions are mild, mutual conversion among various functional groups in the traditional carboxylic acid compound synthesis process is avoided, and the atom and step economy of the reaction is improved. Meanwhile, the method disclosed by the invention can also be applied to the simplified synthesis of the medicines cinacarbazide and tirofiban.

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.

Synthesis method of tirofiban hydrochloride intermediate III (by machine translation)

The invention belongs to the field, of medicine synthesis, and particularly relates to a synthesis method III of tirofiban hydrochloride intermediate. by, reduction of an intermediate I under the action of a sodium borohydride reducing system to obtain intermediate II, intermediate II under Lewis acid chloride in the presence. SOCl2 Reaction conditions of, process are mild III, and N - process operation is simple, the reaction conditions of the reaction yield, product are improved, the product purity is high, and the reaction yield is increased by, times without being subjected to column purification, to improve the clinical medication safety, of the injection using, the standard crude drug product of the pharmacopoeia standard, and is suitable, for industrial production. (by machine translation)

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.

Metallaphotoredox-catalysed sp3-sp3 cross-coupling of carboxylic acids with alkyl halides

In the past 50 years, cross-coupling reactions mediated by transition metals have changed the way in which complex organic molecules are synthesized. The predictable and chemoselective nature of these transformations has led to their widespread adoption across many areas of chemical research. However, the construction of a bond between two sp3-hybridized carbon atoms, a fundamental unit of organic chemistry, remains an important yet elusive objective for engineering cross-coupling reactions. In comparison to related procedures with sp2-hybridized species, the development of methods for sp3-sp3 bond formation via transition metal catalysis has been hampered historically by deleterious side-reactions, such as β-hydride elimination with palladium catalysis or the reluctance of alkyl halides to undergo oxidative addition. To address this issue, nickel-catalysed cross-coupling processes can be used to form sp3-sp3 bonds that utilize organometallic nucleophiles and alkyl electrophiles. In particular, the coupling of alkyl halides with pre-generated organozinc, Grignard and organoborane species has been used to furnish diverse molecular structures. However, the manipulations required to produce these activated structures is inefficient, leading to poor step-and atom-economies. Moreover, the operational difficulties associated with making and using these reactive coupling partners, and preserving them through a synthetic sequence, has hindered their widespread adoption. A generically useful sp3-sp3 coupling technology that uses bench-stable, native organic functional groups, without the need for pre-functionalization or substrate derivatization, would therefore be valuable. Here we demonstrate that the synergistic merger of photoredox and nickel catalysis enables the direct formation of sp3-sp3 bonds using only simple carboxylic acids and alkyl halides as the nucleophilic and electrophilic coupling partners, respectively. This metallaphotoredox protocol is suitable for many primary and secondary carboxylic acids. The merit of this coupling strategy is illustrated by the synthesis of the pharmaceutical tirofiban in four steps from commercially available starting materials.

Tirofiban hydrochloride process for preparing

The invention belongs to the field of medicine and chemical industry. According to the present invention, the tirofiban hydrochloride prepared through substitution, condensation, reduction, salification and other reactions has characteristics of high yield, good quality and good stability, and the preparation process of the present invention provides a synthesis process suitable for the practical industrial mass production.

Non-Peptide Fibrinogen Receptor Antagonists. 2. Optimization of a Tyrosine Template as a Mimic for Arg-Gly-Asp

Inhibitors of platelet-fibrinogen binding offer an opportunity to interrupt the final, common pathway for platelet aggregation.Small molecule inhibitors of the platelet fibrinogen receptor GPIIb/IIIa were prepared and evaluated for their ability to prevent platelet aggregation.Compound 23m (L-700, 462/MK-383) inhibited in vitro platelet aggregation with an IC50 of 9 nM and demonstrated a selectivity of >24000-fold between platelet and human umbilical vein endothelial cell fibrinogen receptors.Dose-dependent inhibition of ex vivo platelet aggregation induced by ADP was achieved with iv infusions 0.1-10 μg/kg/min of 23m in anesthetized dogs, with 10 μg/kg/min completely inhibiting platelet aggregation during the entire 6 h infusion protocol.Platelet aggregatability returned rapidly after the termination of the 23m infusions.These features suggest that 23m may be useful in the treatment of arterial occlusive disorders.

Novel sulfonamide fibrinogen receptor antagonists

A series of non-peptide derivatives of the formula STR1 that are antagonists of the fibrinogen IIb/IIIa receptor and thus are platelet anti-aggregation compounds useful in the prevention and treatment of diseases caused by thrombus formation.