Gemfibrozil

Base Information

• Chemical Name: Gemfibrozil
• CAS No.: 25812-30-0
• Molecular Formula: C15H22O3
• Molecular Weight: 250.338
• Hs Code.: 2918992090
• European Community (EC) Number: 247-280-2,657-339-8
• NSC Number: 757024
• UNII: Q8X02027X3
• DSSTox Substance ID: DTXSID0020652
• Nikkaji Number: J40.721F
• Wikipedia: Gemfibrozil
• Wikidata: Q384295
• NCI Thesaurus Code: C29071
• RXCUI: 4719
• Pharos Ligand ID: AHSM1113H7C1
• Metabolomics Workbench ID: 43449
• ChEMBL ID: CHEMBL457
• Mol file: 25812-30-0.mol

Synonyms:Apo Gemfibrozil;Apo-Gemfibrozil;ApoGemfibrozil;Ausgem;Bayvit, Gemfibrozilo;Bolutol;Chem mart Gemfibrozil;CI 719;CI-719;CI719;DBL Gemfibrozil;Decrelip;Gemfi 1A Pharma;Gemfibrosil;Gemfibrozil;Gemfibrozil, GenRX;Gemfibrozil, Healthsense;Gemfibrozil, SBPA;Gemfibrozilo Bayvit;Gemfibrozilo Bexal;Gemfibrozilo Ur;Gemhexal;Gen Gemfibrozil;Gen-Gemfibrozil;GenGemfibrozil;GenRX Gemfibrozil;Healthsense Gemfibrozil;Jezil;Lipazil;Lipox Gemfi;Lipur;Litarek;Lopid;Lopid R;Novo Gemfibrozil;Novo-Gemfibrozil;Nu Gemfibrozil;Nu-Gemfibrozil;NuGemfibrozil;Pilder;PMS Gemfibrozil;PMS-Gemfibrozil;SBPA Gemfibrozil;Terry White Chemists Gemfibrozil;Trialmin

Chemical Property of Gemfibrozil

Chemical Property:

• Appearance/Colour: White crystalline powder
• Vapor Pressure: 6.13E-07mmHg at 25°C
• Melting Point: 61-63 °C
• Refractive Index: 1.511
• Boiling Point: 394.7 °C at 760 mmHg
• PKA: 4.75±0.45(Predicted)
• Flash Point: 141.6 °C
• PSA: 46.53000
• Density: 1.044 g/cm³
• LogP: 3.57320
• Storage Temp.: -20°C Freezer
• Solubility.: Practically insoluble in water, very soluble in methylene chloride, freely soluble in anhydrous ethanol and in methanol.
• Water Solubility.: >0.5g/L(temperature not stated)
• XLogP3: 3.8
• Hydrogen Bond Donor Count: 1
• Hydrogen Bond Acceptor Count: 3
• Rotatable Bond Count: 6
• Exact Mass: 250.15689456
• Heavy Atom Count: 18
• Complexity: 273

Purity/Quality:

99% ,99.9%, ^*data from raw suppliers

Gemfibrozil ^*data from reagent suppliers

Safty Information:

• Pictogram(s): Xn, Xi
• Hazard Codes: Xn,Xi
• Statements: 22-63-62-46-36/38-21
• Safety Statements: 36-53-36/37-26-25

MSDS Files:

Useful:

• Drug Classes: Antilipemic Agents
• Canonical SMILES: CC1=CC(=C(C=C1)C)OCCCC(C)(C)C(=O)O
• Recent ClinicalTrials: A Study to Assess the Effect of Itraconazole, Phenytoin and Gemfibrozil on the Drug Levels of BMS-986166 in Healthy Participants
• Recent EU Clinical Trials: A Four-Part, Open-Label Study to Evaluate the Effects of Repeat Dose GSK2118436 on the Single Dose Pharmacokinetics of Warfarin, the Effects of Repeat Dose Oral Ketoconazole and Oral Gemfibrozil on the Repeat Dose Pharmacokinetics of GSK2118436, and the Repeat Dose Pharmacokinetics of GSK2118436 in Subjects with BRAF Mutant Solid Tumors.
• Uses: 1. Used for the treatment of hyperlipidemia. The agent is suitable for treatment of severe type IV or type V hyperlipoproteinemia patients with high-risk coronary heart disease who had no response to treatments such as dietary control or weight loss. It is also applicable to type II-b hyperlipoproteinemia patients with high-risk coronary heart disease who had failed to respond to treatments such as dietary control, weight loss, or other lipid-regulating medications. 2. Used as a lipid-regulating agent. It can significantly reduce the levels of triglyceride and cholesterol in blood, and can significantly reduce very low-density lipoprotein (VLDL) levels and increase high-density lipoprotein (HDL) levels, but it has little effect on low-density lipoprotein (LDL) levels. Clinically, it can be used in patients with all types of lipid metabolism disorders, such as primary and secondary hyperlipoproteinemias, hypercholesterolemias, hypertriglyceridemias, mixed hyperlipidemias, and lipid metabolism disorders caused by diabetes. It can also be used to prevent the occurrence of myocardial infarction. 3. The product belongs to phenoxy aromatic acid antihyperlipidemics, which is a group of drugs developed on the basis of clofibrate including fenofibrate, Etofylline Clofibrate, Bijiangzhi, gemfibrozil and so on. These drugs were similar in chemical structure. Clofibrate has rather serious adverse reactions (which include elevating the occurrence of gallstone). Improved drugs are more effective than clofibrate, with mild and fewer adverse reactions. 4. A lipid-regulating drug that can reduce cholesterol and triglyceride levels in blood. A serum lipid regulating agent used as an antihyperlipoproteinemic This drug is used for hyperlipoproteinemia that cannot be corrected by a special diet or by physical exertion. Gemfibrozil has been used to to study its effects on cell cycle progression in yeast. It has been used to study the effects of fibrates on cell proliferation and gene expression in human cell lines.
• Production method: (1) 1. 1-(2,5-dimethylphenoxy)-3-chloro-propane was obtained by the reaction of 2, 5-dimethylphenol with bromochloropropane. The reaction is carried out in toluene mixed with bromo-geramine in a reflux system for five hours. 2. Lithium isobutyrate was obtained by the reaction of sodium isobutyrate with lithium diisopropyl amine 3. Phenoxy acid was synthesized from 1-(2, 5-dimethylphenoxy)-3-chloro-propane and lithium isobutyrate by mixing the two intermediates slowly at 10-15℃, stirring the mixture for 15 minutes and then warming it till the temperature reaches 30℃ and keeping the reaction for five hours. (2) Method 1: the reaction of 2, 5-dimethylphenol with 1, 3-dibromopropan was used first to obtain an intermediate 3-(2, 5-dimethylphenoxy) propyl bromide. Then 26.4 g isobutyric acid, 6.0 g magnesium oxide and 250 ml toluene were stirred into a mixture and heated under reflux, and the water formed during the heating process was continuously removed. When there was no more water forming, the solution that contains magnesium isobutyrate was concentrated to half of its original volume, and was then cooled down with an ice bath. To this solution, 31.0 g diisopropyl amine dissolved with 200 ml dry tetrahydrofuran was added first, followed by 179 ml of 1.68 mol/l n-butyllithium in pentane being added. During this period, the reaction solution was maintained at a temperature below 10℃. After 15 minutes, the solution was heated at 30℃ for 0.5 hour, then was cooled down to 0-10℃, and 75.0 g of 3-(2, 5-dimethylphenoxy) propyl bromide was added. After being stirred at room temperature for 18 hours, the solution was diluted with 125 ml of 6 mol/l hydrochloric acid and 250 ml water. Finally, the organic layer was removed and the remaining solution was concentrated and underwent vacuum distillation to give gemfibrozil with a boiling point of 158-159℃ under a vacuum of 2.67 Pa. The product can also be obtained by the following steps: 51.0 g diisopropyl amine, 23.2 g of 57% sodium hydride in mineral oil suspension and 350 ml tetrahydrofuran were mixed and 44.1 g isobutyric acid was added into the mixture with stirring. When there was no more gas producing, the solution was heated under reflux for 15 min. Then the solution was cooled down to 0℃ and 345 ml of 1.45 mol/l n-butyllithium in pentane was added. After reacting for five hours, the solution was incubated at 30℃ for 0.5 hours, and was cooled down to 0℃ and 122.0 g 3-(2, 5-dimethylphenoxy) propyl bromide was added. After reacting for 1 hour, 500 ml water was added to the solution with stirring. Then the solution was allowed to stand to remove the aqueous layer. The remaining solution was acidified with 6mol/l hydrochloric acid and the acidic solution was extracted with ether. The extract was washed with saturated salt water, dried with anhydrous magnesium sulfate, and concentrated almost to dryness and then undergo vacuum distillation. The fraction was collect at 158-159℃ under a vacuum of 2.67 Pa, and was crystallized from hexane to give gemfibrozil of melting point 61-63℃. In the above-described method 4.4 g lithium hydride can be used to replace the sodium hydride. Method 2: isobutyl isobutyrate was used to react with 1-chloro-3-bromopropane in the presence of lithium diisopropyl amide to produce an intermediate 5-chloro-2, 2-dimethyl-pentanoic acid isobutyl ester. The intermediate was then used to reacts with 2, 5-dimethyl phenol and in the meanwhile generated gemfibrozil by hydrolysis reaction.
• Drug Interactions: 1. The product can obviously enhance the effect of oral anticoagulant drugs. When an oral anticoagulant is given in conjunction with gemfibrozil, the dosage of the oral anticoagulant should be reduced and the prothrombin time should be monitored frequently in order to adjust the dose of the anticoagulant. Its mechanism of action is unclear, which might be related to the product’s ability to replace warfarin from its binding site on the protein and enhances the role correspondingly. 2. The product, when used concomitantly with other protein-bound drugs such as furosemide, phenytoin, tolbutamide, and other sulfonylurea drugs, can also replace those drugs from the protein binding sites and thus enhance their roles. Doses of the above-mentioned drugs should be adjusted when they are taken during the lipid-lowering therapy. 3. Clofibric acid derivatives when used in combination with HMG-CoA reductase inhibitors such as lovastatin for the treatment of hyperlipidemia may increase the risks of severe muscle toxicity by both drugs, causing myopathy syndromes such as myalgia, rhabdomyolysis, and elevated blood creatine-phosphokinase, and thus should be avoided in combination. 4. Gemfibrozil, when used in combination with a bile acid-binding resin such as colestipol, should be taken at least two hours before, or after, taking the bile acid-binding resin, as the bile acid-binding resin can combine with other drugs if they are taken simultaneously and thereby affecting the absorption. 5. This product is mainly excreted by the kidneys. When it is used in combination with immunosuppressive agents such as cyclosporine, it can increase the plasma concentration of the latter as well as renal toxicity, leading to the risk of deterioration of renal function. Therefore, the immunosuppressive agent should be reduced in dose or discontinued during the therapy. Cautions should also be taken when using gemfibrozil concomitantly with other nephrotoxic drugs.
• Description: Gemfibrozil is a peroxisome proliferator-activated receptor α (PPARα) and PPARγ agonist (EC50s = 193.3 and 147.8 μM, respectively, in transactivation assays). In vivo, gemfibrozil (50 mg/kg, p.o.) reduces serum total cholesterol, triglyceride, and LDL levels in a rat model of high-cholesterol diet-induced hyperlipidemia. Gemfibrozil (100 mg/kg per day) reduces atherosclerotic plaque area, superoxide production, and expression of the genes encoding the NF-κB subunit p65 and chemokine (C-C) motif ligand 2 (CCL2) in ApoE-/- mice. Formulations containing gemfibrozil have been used in the treatment of high cholesterol.
• Therapeutic Function: Antihyperlipidemic
• Clinical Use: Hyperlipidaemias of types IIa, IIb, III, IV and V
• Drug interactions: Potentially hazardous interactions with other drugs Antibacterials: increased risk of myopathy with daptomycin - try to avoid concomitant use. Anticoagulants: enhances effect of coumarins and phenindione; dose of anticoagulant should be reduced by up to 50% and adjusted by monitoring INR. Antidiabetics: may improve glucose tolerance and have an additive effect with insulin or sulphonylureas; possibly enhanced effect with nateglinide; increased risk of severe hypoglycaemia with repaglinide - avoid. Antivirals concentration of paritaprevir increased - avoid. Ciclosporin: Parke-Davis have one report on file of an interaction with ciclosporin where serum ciclosporin levels were decreased. No effects on muscle were noted. Colchicine: possible increased risk of myopathy. Cytotoxics: bexarotene concentration increased - avoid; concentration of enzalutamide increased - avoid or halve enzalutamide dose. Lipid-regulating drugs: increased risk of myopathy in combination with statins and ezetimibe - avoid (maximum 20 mg of rosuvastatin).

Technology Process of Gemfibrozil

There total 28 articles about Gemfibrozil which guide to synthetic route it. The literature collected by LookChem mainly comes from the sharing of users and the free literature resources found by Internet computing technology. We keep the original model of the professional version of literature to make it easier and faster for users to retrieve and use. At the same time, we analyze and calculate the most feasible synthesis route with the highest yield for your reference as below:

synthetic route:

Reference yield: 90.0%

2,2-dimethyl-5-(2,5-dimethylphenoxy)-3-hydroxypentanoic acid β-lactone (169295-45-8) → gemfibrozil (25812-30-0)

Guidance literature:

With sodium tetrahydroborate; In N,N-dimethyl-formamide; for 12h; Ambient temperature;

Reference yield: 82.0%

1,3-Bis[2.2-dimethyl-5-(2,5-dimethylphenoxy)-pentanoyloxy]-propane (139483-63-9) → gemfibrozil (25812-30-0)

Guidance literature:

With sodium hydroxide; In diethyl ether; ethanol; water;

Reference yield: 77.6%

methyl 5-(2,5-dimethylphenoxy)-2,2-dimethyl-pentanoate → gemfibrozil (25812-30-0)

Guidance literature:

With tetrabutylammomium bromide; water; sodium hydroxide; at 73 - 75 ℃; for 3h; Inert atmosphere;

DOI:10.14233/ajchem.2015.17491

upstream raw materials:

2,2-dimethyl-5-(2,5-dimethylphenoxy)-3-hydroxypentanoic acid β-lactone

carbon monoxide

2-methyl-5-(2,5-dimethylphenoxy)-2-pentene

2,5-Dimethylphenol

Downstream raw materials:

2-hydroxyethyl 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoate

N-{4-[4-(biphenyl-4-yl)-4-oxobutanamido]butyl}-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide

gemfibrozil 1-benzotriazolide

sodium 2,5-dimethylphenolate

Refernces

• 1、 -. "Synthesis method for SIPI7623 metabolite of FXR antagonist". Paragraph 0016; 0020-0021. . Retrieved 2020/07/15.
• 2、 -. "Gemfibrozil hapten, artificial antigen and antibody and preparation method thereof and purpose thereof". Paragraph 0024-0029. . Retrieved 2019/02/04.