2756-87-8

Basic information

• Product Name: Monomethyl fumarate
• Synonyms: (E)-2-Butenedioic acid hydrogen 1-methyl ester;Fumaric acid hydrogen 1-methyl ester;Monomethyl trans-ethylene-1,2-dicarboxylate;Monomethyl fumarate;Methyl hydrogen fumarate;Fumaric acid monomethyl ester;mono-Methyl fumarate,Fumaric acid monomethyl ester, Methyl hydrogen fumarate;(2E)-4-Methoxy-4-oxobut-2-enoic acid
• CAS NO: 2756-87-8
• Molecular Formula: C₅H₆O₄
• Molecular Weight: 130.1
• EINECS: 220-412-6
• Mol File: 2756-87-8.mol

Chemical Properties

• Melting Point: 144-145 °C(lit.)
• Boiling Point: 249.959 °C at 760 mmHg
• Flash Point: 108.944 °C
• Appearance: /
• Density: 1.266 g/cm³
• Vapor Pressure: 0.00706mmHg at 25°C
• Refractive Index: 1.468
• Storage Temp.: 2-8°C
• Solubility: Chloroform (Slightly), DMSO (Slightly), Methanol (Slightly)
• PKA: 3.40±0.10(Predicted)
• CAS DataBase Reference: Monomethyl fumarate(CAS DataBase Reference)
• NIST Chemistry Reference: Monomethyl fumarate(2756-87-8)
• EPA Substance Registry System: Monomethyl fumarate(2756-87-8)

Safety Data

• Hazard Codes: Xi
• Statements: 41
• Safety Statements: 26-39
• WGK Germany: 3
• Hazardous Substances Data: 2756-87-8(Hazardous Substances Data)

Usage

Uses

1. Used in Pharmaceutical Industry:
Monomethyl fumarate is used as a treatment for the relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease. Although it does not cure MS, it may slow some of the disabling effects and decrease the number of relapses.
2. Used in Dermatology:
Monomethyl fumarate is used as an anti-psoriatic agent, being one of the most bioactive fumaric acid ester metabolites. It acts as a potent nicotinic acid receptor agonist and has been shown to selectively stimulate the T helper 2 cytokine response, making it a valuable compound in the treatment of psoriasis.
3. Used in Synthesis of Biochemical Compounds:
Monomethyl fumarate can be used as a reactant to synthesize various compounds, such as Jumonji C domain-containing histone demethylases (JCHDMs) inhibitors, (?)-Xylariamide A, a fungal metabolite, and (±)-Methoxyfumimycin ethyl ester, a potential bacterial peptide deformylase inhibitor.
4. Used in Antimicrobial Applications:
Monomethyl fumarate exhibits wide-spectrum antibacterial properties and possesses powerful antioxidant activity, making it a promising candidate for the development of new antimicrobial agents and antioxidants in various industries, including pharmaceuticals and cosmetics.

Preparation

Monomethyl fumarate was synthesized by maleic anhydride and methanol. monomethyl fumarate could inhibit the growth of mold, and the storage time of feed could be prolonged.

Synthesis Reference(s)

The Journal of Organic Chemistry, 23, p. 1559, 1958 DOI: 10.1021/jo01104a608

Biological Activity

Monomethyl fumarate is an active metabolite of the immune modulator dimethyl fumarate (Item No. 14714) that is rapidly formed from dimethyl fumarate by hydrolysis. It is an agonist of the hydroxycarboxylic acid 2 (HCA2) receptor/GPR109A with an EC50 value of 9.4 μM for inducing calcium accumulation in CHO cells expressing the receptor. Monomethyl fumarate reduces neutrophil adhesion to endothelial cells stimulated with TNF, decreases CXCL2-directed neutrophil migration, and increases the expression of the Nrf2 target gene NQO1 in wild-type but not HCA2-/- macrophages. It inhibits proliferation and induces differentiation in keratinocytes, as well as decreases the levels of TNF-α induced by phorbol 12-myristate 13-acetate (TPA; Item No. 10008014) in keratinocytes when used at a concentration of 1 mM. Monomethyl fumarate (1 mg/day) reduces symptoms of experimental autoimmune encephalomyelitis (EAE) in mice and isolated natural killer cells from these mice induced cytotoxicity in previously isolated immature and mature dendritic cells. Formulations containing monomethyl fumarate have been used in the treatment of multiple sclerosis.

Clinical claims and research

Mono Methyl Fumarate (MMF) is an active component of Fumaria sp. methanolic extract. In Iranian traditional medicine, Fumitory is used widely as a remedy for several diseases including liver dysfunction. The effect of monomethyl fumarate and Fumaria extract was investigated by Moghaddam et al. (2012) against APAP-induced acute liver damage and compared to a known hepatoprotective plant, Silybum marianum and its active ingredient, SM. APAP produced acute toxicity at the dose of 640 mg/kg in mice while pretreatment and posttreatment of animals (i.p., twice daily for 48 h) with monomethyl fumarate, SM (25, 50, and 100 mg/kg) or the plant extracts (300 and 500 mg/kg) significantly lowered the rise of ALT, AST, LDH, ALKP, and bilirubin (total and direct) in serum. In addition, both the compounds and the plant extracts significantly increased GSH content and reduced MDA level of the liver.

InChI:InChI=1/C5H6O4/c1-9-5(8)3-2-4(6)7/h2-3H,1H3,(H,6,7)/b3-2+

Upstream product

• 67-56-1 methanol 
• 1874-23-3 methyl 5-nitrofuran-2-carboxylate 
• 124-41-4 sodium methylate 
• 3052-50-4 monomethyl maleate 
• 17081-97-9 methyl (E)-4-chloro-4-oxo-2-butenoate 
• 2459-05-4 malonic acid monoethyl ester 
• 17356-08-0 thiourea 
• 151-50-8 potassium cyanide 
• 624-49-7 dimethylfumarate 
• 624-48-6 dimethyl cis-but-2-ene-1,4-dioate 
• 108-31-6 maleic anhydride 
• 5837-72-9 methyl (E)-4-oxo-2-butenoate 
• 110-17-8 (2E)-but-2-enedioic acid 
• 3878-55-5 methyl hydrogen succinate 

Downstream Products

• 71704-29-5 (E)-But-2-enedioic acid cyclohex-2-enyl ester methyl ester 
• 111911-75-2 6-benzyl-8-endo-methoxycarbonyl-7-oxo-6-azabicyclo<3.2.1>oct-2-ene-2-carboxylic acid 
• 74502-21-9 (1S,2R)-3-Acetoxy-cyclohex-4-ene-1,2-dicarboxylic acid 1-methyl ester 
• 115819-76-6 (E)-But-2-enedioic acid methyl ester (E)-3-(2,6,6-trimethyl-cyclohex-1-enyl)-allyl ester 
• 130406-65-4 tricyclo<3.3.1.1^3,7>dec-2-yl *,R^*)>-3-(1H-indol-3-ylmethyl)-3-methyl-4,9,12-trioxo-7-phenyl-13-oxa-2,5,8-triazatetradec-10-enoate 
• 130406-53-0 tricyclo<3.3.1.1^3,7>dec-2-yl *,S^*(E)>>-3-(1H-indol-3-ylmethyl)-3-methyl-4,9,12-trioxo-6-(phenylmethyl)-13-oxa-2,5,8-triazatetradec-10-enoate 
• 33176-41-9 2-imino-2,3,4,5-tetrahydro-4-oxo-1,3-thiazol-5-acetic acid 
• 6270-74-2 3-oxo-1,4-benzothiazin-2-ylacetic acid 
• 7556-63-0 3,4-dihydro-2-methoxycarbonylmethyl-3-oxo-2H-1,4-benzothiazine 
• 1053248-37-5 3-(4-{4-[2-(2,4-diamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-ethyl]-benzoylamino}-4-methoxycarbonyl-butylcarbamoyl)-acrylic acid methyl ester 
• 907999-88-6 3E,5-hexadien-1-yl methyl 2E-butenedioate 
• 862458-59-1 (-)-dechloroxylariamide A 
• 72782-06-0 β-fuoxymorphamine 
• 1117905-50-6 methyl 2-((E)-5-methyl-3-oxohexa-1,4-dienyl)phenyl fumarate 

Relevant articles and documents

Dimethyl Fumarate: Heterogeneous Catalysis for the Development of an Innovative Flow Synthesis

The present work describes the development of an improved synthesis of the active pharmaceutical ingredient (API) dimethyl fumarate. The use of continuous flow technology and the newly developed methylation conditions solve some of the issues of previous commercial production strategies, e.g., reaching complete conversion and avoiding the formation of toxic impurities. The optimization was carried out using the design of experiment approach and afforded a very efficient, sustainable process, suitable for the industrial application.

Isolation and structure elucidation of the new fungal metabolite (-)-xylariamide A

Chemical investigations of the terrestrial microfungus Xylaria sp. have afforded the new natural product (-)-xylariamide A (1). The gross structure of 1 was determined by interpretation of 1D and 2D NMM, UV, IR, and MS data. Confirmation of the structure and the absolute stereochemistry of 1 were determined by the total synthesis of (4-)-xylariamide A (2). Synthetic 2 was produced by N,O-bis(trimethylsilyl)-acetamide-induced coupling of 3-chloro-L-tyrosine (3) with (E)-but-2-enedioic acid 2,5-dioxo-pyrrolidin-1-yl ester methyl ester (4). Optical rotation comparison of 1 with 2 indicated that the natural product (1) contained 3-chloro-D-tyrosine. Both enantiomers of xylariamide A were tested in a brine shrimp lethality assay, and only the natural product (1) showed toxicity.

PROCESS FOR PREPARATION OF DIROXIMEL FUMARATE

The present invention relates to a process for the preparation of diroximel fumarate, a compound of formula I. The present invention relates to amorphous solid dispersion comprising diroximel fumarate, a compound of formula I or salt thereof together with at least one pharmaceutically acceptable carrier and process for its preparation.

Continuous-flow synthesis of dimethyl fumarate: A powerful small molecule for the treatment of psoriasis and multiple sclerosis

Dimethyl fumarate (DMF) is a methyl ester of fumaric acid and has recently gained attention due to its use as a pro-drug in different pharmaceutical preparations, besides the low price of the final molecule and no active patents being available for the synthesis of DMF, the prices of multiple sclerosis treatment are still high. In our continuous effort for the development of process intensification strategies towards the synthesis of active pharmaceutical ingredients, here we present our work on a cascade methodology for dimethyl fumarate synthesis in short reaction times and quantitative yields.

AN IMPROVED PROCESS FOR THE SYNTHESIS OF DIMETHYL FUMARATE

The present invention describes an improved process for the industrial scale production of dimethyl fumarate. The process involves a one-pot ring opening reaction of maleic anhydride to monomethyl maleate and isomerization into the corresponding monomethyl fumarate in presence of a Lewis acid. Finally the mono methyl fumarate was converted into the dimethyl fumarate by an acid catalyzed esterification reaction.

METHOD FOR PRODUCING MONOMETHYL FUMARATE COMPOUNDS

The present invention relates to a novel method for preparing monomethyl fumarate, which can preferably be used in the treatment and/or prevention of systemic diseases, autoimmune diseases, inflammatory diseases such as multiple sclerosis and psoriasis. Further, the present invention relates to the use of specific compounds as intermediates in the process for preparing a monomethyl fumarate prodrug.

Hexahydro - 1H - pyrrolo [3, 4 - d] pyrimidine compound and its preparation method

The invention discloses a hexahydro-1H-pyrrolo[3,4-d]pyrimidine compound and a preparation method thereof. The invention relates to the technical field of organic synthesis. The key point of the technical scheme of the invention is that the hexahydro-1H-pyrrolo[3,4-d]pyrimidine compound has a following structure shown in the specification, wherein R1 is H, methyl, ethyl, isopropyl, cyclopropylmethyl, methyletherethyl, isobutyl or benzyl; R2 is H or cyclopropylmethyl. The invention also discloses the preparation method of the hexahydro-1H-pyrrolo[3,4-d]pyrimidine compound. The preparation method provided by the invention is simple and feasible. The raw materials are cheap and easily available. The method also has the advantages of high reaction efficiency and good repeatability.

Synthesis, DFT and antimicrobial activity assays in vitro for novel cis/trans-but-2-enedioic acid esters

Six novel cis/trans-but-2-enedioic acid esters had been synthesized to discover the new bioactive molecules that could kill food-related bacteria and fungi. Their structures were analyzed by melting point, LC-MS, 1H NMR and 13C NMR. 4-(Methoxycarbonyl) phenyl ethyl fumarate (6b) was also characterized by single-crystal X-ray diffraction. Their antimicrobial activities were evaluated in vitro by measuring the minimal inhibitory concentration (MIC). Compared with the single monomethyl fumarate and methyl 4-hydroxybenzoate, these compounds had stronger antimicrobial activity against all the eight microorganisms. Among the antibacterial and antifungal compounds, 4-(methoxycarbonyl) phenyl methyl fumarate (6a) showed the best antimicrobial activity. The electronic properties of these compounds were calculated by the density functional theory (DFT) method with 6-31G (d, p) basis set. DFT studies indicated that molecular electrostatic potential (MEP) map, ELUMO, energy gap, electronegativity and electrophilicity index could be helpful to understand the various antimicrobial activities among these compounds. The antimicrobial activity of compound 6a was evaluated in vitro against Salmonella choleraesuis subsp. choleraesuis, Lactococcus lactis subsp. lactis and Saccharomyces cerevisiae by time-kill, and it was found that compound 6a exhibited significant microbiocidal activity against the three microorganisms.

METHOD OF MAKING MONOMETHYL FUMARATE

Methods of making monomethyl fumarate, which can then also be used in methods of making prodrugs of monomethyl fumarate, are disclosed. Monomethyl fumarate and prodrugs of monomethyl fumarate are useful for treating neurodegenerative, inflammatory, and autoimmune diseases including multiple sclerosis, psoriasis, irritable bowel disorder, ulcerative colitis, arthritis, chronic obstructive pulmonary disease, asthma, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis.

PROCESS FOR PREPARING HIGH PURITY AND CRYSTALLINE DIMETHYL FUMARATE

The present invention describes a process for the preparation of dimethyl fumarate. The process involves the esterification of fumaric acid and methanol in the presence of sulfuric acid as an acid catalyst. The high purity dimethyl fumarate contains no more than trace amounts of dimethyl sulfate. The present invention also provides a process for the preparation of highly pure dimethyl fumarate with a particle size from 20 to 250 μπι.