624-49-7

Basic information

• Product Name: Dimethyl fumarate
• Synonyms: 2-Butenedioic acid (E)-, dimethyl ester; dimethyl (2E)-but-2-enedioate; Dimethylfumarate
• CAS NO: 624-49-7
• Molecular Formula: C₆H₈O₄
• Molecular Weight: 144.1253
• EINECS: 210-849-0
• Product Categories: Miscellaneous Reagents;mildew preventive;Acids & Esters;C6 to C7;Carbonyl Compounds;Esters
• Mol File: 624-49-7.mol
• Article Data: 145

Chemical Properties

• Melting Point: 102-105℃
• Boiling Point: 193°C at 760 mmHg
• Flash Point: 91.1°C
• Density: 1.124g/cm³
• Vapor Pressure: 0.475mmHg at 25°C
• Refractive Index: 1.435
• Storage Temp.: Store at RT.
• Solubility: 1.6g/l
• Water Solubility: Soluble in water (1.6 mg/ml at 20°C), methanol (30-36 mg/ml), ethanol (10 mg/ml at 25°C), DMSO (29 mg/ml at 25°C), and DMF (~12 mg/ml).
• Stability: Stable. Incompatible with acids, bases, oxidizing agents, reducing agents.
• Merck: 14,4287
• BRN: 774590
• CAS DataBase Reference: Dimethyl fumarate(CAS DataBase Reference)
• NIST Chemistry Reference: Dimethyl fumarate(624-49-7)
• EPA Substance Registry System: Dimethyl fumarate(624-49-7)

Safety Data

• Hazard Codes: Xn:Harmful
• Statements: R21:; R36/37/38:
• Safety Statements: S36/37/39:
• RIDADR: UN 3077 9 / PGIII
• WGK Germany: 1
• RTECS: EM6125000
• TSCA: Yes
• Hazardous Substances Data: 624-49-7(Hazardous Substances Data)

Usage

Overview

Dimethyl fumarate[DMF] is the methyl ester of fumaric acid[1, 2]. DMF, marketed in Germany under the trade name of Fumaderm, is used for oral therapy of psoriasis in combination with other drugs[2]. Later it has been used to treat adults with relapsing multiple sclerosis[a chronic inflammatory, demyelinating and neurodegenerative disease of the CNS resulting in neurological disability] since 2013(trade name Tecfidera)[3]. DMF is thought to have immunomodulatory properties without significant immunosuppression. In preclinical studies, dimethyl fumarate exhibited anti-inflammatory and cytoprotective properties that are generally thought to be mediated via activation of the nuclear factor [erythroid-derived 2]-like 2 transcriptional pathway, which is involved in the cellular response to oxidative stress. In a non-medical use, DMF has been used as a biocide in furniture or shoes to prevent growths of mold during storage or transport in a humid climate. However, due to incidences of allergic reactions after skin contact the European Union has banned DMF in consumer products since 1998, and since January 2009 the import of products containing DMF has also been banned[4].

Indication

Dimethyl fumarate[DMF] is mainly indicated for the treatment of the relapsing-remitting Multiple sclerosis(MS), which is a chronic inflammatory, demyelinating and neurodegenerative disease of the CNS, resulting in neurological disability[5, 6]. The disease typically begins in young adults(average age of onset &29 years) and affects twice as many women as men[7, 8]. Initially, most(80–85 %) individuals with MS have a relapsing-remitting[RRMS] disease course with defined clinical exacerbations of neurological symptoms, followed by complete or incomplete remission[7, 8]. Around 50 % of patients develop a secondary progressive MS within 10–15 years of RRMS onset and &89 % of patients develop secondary progressive MS after 25 years[9]. Globally, the estimated median incidence of MS is 2.5 per 100,000 persons and it has a median estimated prevalence of 30 per 100,000 persons[8]. The pathogenic process of the relapsing-remitting multiple sclerosis involves the migration of auto-reactive T cells across the blood–brain-barrier into the central nervous system where they damage myelin, oligodendrocyte and nerve fibers and lead to further immune cell recruitment[10]. This inflammatory process causes lesions[predominantly in the cerebellum, brain stem, spinal cord, optic nerves and white matter of brain ventricles] that result in the symptoms typical of MS, including weak/stiff muscles, limb numbness/tingling, balance problems, visual disturbances and cognitive dysfunction[11]. The lesional inflammatory environment also contributes to MS pathogenesis through the generation of proinflammatory cytokines and oxygen and nitrogen free radicals, establishing a cycle of inflammation and oxidative stress[12].

Mode of action

In MS, neuronal tissue damage is thought to be caused by aberrant activation and subsequent infiltration of immune cells into the CNS12. Infiltrating cells propagate inflammatory processes within the CNS13, ultimately leading to oligodendrocyte damage that results in demyelination and subsequent axonal transection and neurodegeneration[13, 14]. In addition to pathogenic adaptive autoimmunity processes, the release of free radicals[oxygen and nitrogen] by infiltrating monocytes leads to mounting oxidative stress[15-17]. As cells of the CNS are highly sensitive to excessive oxidative stress, this further promotes neurodegenerative processes. Dimethyl fumarate has demonstrated beneficial effects in preclinical models of neuro-inflammation, neuro-degeneration, and toxic oxidative stress but its precise mechanism of action remains unclear[18, 19]. As a second-generation fumarate ester, dimethyl fumarate appears to exert its effects predominantly through activation of the nuclear factor[erythroid-derived 2]-like 2[Nrf2] antioxidant response pathway[19], which modulates the expression of biomolecules involved in the phase 2 detoxification pathway, and is an important cellular defense mechanism involved in the response to oxidative and xenobiotic stress, and immune homeostasis. The activation of the Nrf2 pathway has a clear role in maintaining immune homeostasis and also appears to have a role in promoting modulation of functional immune responses[20].

Adverse reactions

Some severe adverse reactions associated with iodomethane may include anaphylaxis and angioedema, progressive multifocal leukoencephalopathy, lymphopenia, liver injury and flushing[21]. Common side effects may include flushing/warmth, itching, redness, and burning feeling of the skin. Taking this drug with food may reduce flushing. Some other side effects may also include stomach/abdominal pain, heartburn, indigestion, diarrhea, nausea, and vomiting may also occur. These effects usually improve or go away as your body adjusts to the medication. If any of these effects persist or worsen, tell your doctor or pharmacist promptly[22, 23].

Warning and Risk

Patients who are allergic to dimethyl fumarate should be disabled. To make sure dimethyl fumarate is safe for administration, the patients should tell your doctor if he/she have: an active infection; or low white blood cell[WBC] counts. It is not known whether dimethyl fumarate will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using dimethyl fumarate. If you are pregnant, your name may be listed on a pregnancy registry. This is to track the outcome of the pregnancy and to evaluate any effects of dimethyl fumarate on the baby. It is not known whether dimethyl fumarate passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby[23].

References

https://www.drugbank.ca/drugs/DB08908 Mrowietz, Ulrich; Altmeyer, Peter; Bieber, Thomas; et al.[2007]. "Treatment of psoriasis with fumaric acid esters[Fumaderm?]". JDDG. 5[8]: 716–7. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/204063s020lbl.pdf https://chemicalwatch.com/1719/eu-agrees-to-ban-dimethyl-fumarate-dmf-in-consumer-products Compston A, Coles A. Multiple sclerosis. Lancet. 2008;372[9648]:1502–17.? Nylander A, Hafler DA. Multiple sclerosis. J Clin Invest. 2012;122(4]:1180–8.? Menge T, Weber MS, Hemmer B, et al. Disease-modifying agents for multiple sclerosis: recent advances and future pros- pects. Drugs. 2008;68(17]:2445–68.? World Health Organization. Atlas: multiple sclerosis resources in the world; 2008. http://www.who.int/mental_health/neurology/ Atlas_MS_WEB.pdf. Accessed 14 Feb 2014.? Weinshenker BG, Bass B, Rice GP, et al. The natural history of multiple sclerosis: a geographically based study. I. Clinical course and disability. Brain. 1989;112(Pt 1]:133–46.? National Multiple Sclerosis Society. What is MS? 2015. http:// www.nationalmssociety.org. Accessed 3 Dec 2015. National Institute of Neurological Disorders and Stroke. Multiple sclerosis: hope through research. 2015. http://www.ninds.nih.gov/ disorders/multiple_sclerosis/detail_multiple_sclerosis.htm. Accessed 3 Dec 2015. Ortiz GG, Pacheco-Moises FP, Bitzer-Quintero OK, et al. Immunology and oxidative stress in multiple sclerosis: clinical and basic approach. Clin Dev Immunol. 2013;2013:708659. De Stefano N, Narayanan S, Matthews PM, et al. In vivo evidence for axonal dysfunction remote from focal cerebral demyelination of the type seen in multiple sclerosis. Brain 1999;122:1933-9 Ferguson B, Matyszak MK, Esiri MM, et al. Axonal damage in acute multiple sclerosis lesions. Brain 1997;120:393-9 Silber E, Sharief MK. Axonal degeneration in the pathogenesis of multiple sclerosis. J Neurol Sci 1999;170:11-18 Trapp BD, Peterson J, Ransohoff RM, et al. Axonal transection in the lesions of multiple sclerosis. N Engl J Med 1998; 338:278-85 Witherick J, Wilkins A, Scolding N, et al. Mechanisms of oxidative damage in multiple sclerosis and a cell therapy approach to treatment. Autoimmune Dis 2011;164608 Linker RA, Lee DH, Ryan S, et al. Fumaric acid esters exert Neuroprotective effects in neuro-inflammation via activation of the Nrf2 antioxidant pathway. Brain 2011;134:678-92 Scannevin RH, Chollate S, Jung MY, et al. Fumarates promote cytoprotection of central nervous system cells against oxidative stress via the Nrf2 pathway. J Pharmacol Exp Ther 2012;341:274-84 Nguyen T, Sherratt PJ, Pickett CB. Regulatory mechanisms controlling gene expression mediated by the antioxidant response element. Annu Rev Pharmacol Toxicol 2003;43:233-60 https://www.rxlist.com/tecfidera-drug.htm#side_effects_interactions https://www.webmd.com/drugs/2/drug-163864/dimethyl-fumarate-oral/details https://www.drugs.com/sfx/dimethyl-fumarate-side-effects.html

Description

In March 2013, the US FDA approved dimethyl fumarate for the treatment of relapsing forms of multiple sclerosis (MS). Dimethyl fumarate is the newest oral therapeutic for MS. While its mechanism is not completely understood, dimethyl fumarate increases anti-inflammatory cytokines (IL-10, IL-4, and IL-6), decreases proinflammatory cytokines (IL-1β, IL-6, and TNF-α), and activates the Nrf2 pathway to protect neuronal cells. Nrf2 is activated by covalent bond-forming electrophiles such as dimethyl fumarate, a Michael acceptor. Dimethyl fumarate has been used for the treatment of psoriasis in Europe since 1994 and has a favorable long-term safety profile. An exploratory study in patients with relapsing remitting MS showed significant reductions in MS lesions after 18 weeks of treatment with 720 mg/day of dimethyl fumarate. Evaluation of dimethyl fumarate in a mouse experimental autoimmune encephalomyelitis model of MS resulted in reduced spinal cord macrophage inflammation. Dimethyl fumarate is obtained in high purity by esterification of fumaric acid with methanol and catalytic sulfuric acid.

Chemical Properties

fine white crystalline powder

Originator

Biogen Idec (United States)

Uses

Dimethyl fumarate acts as an immunomodulator. It is also used in cycloaddition reactions involving ylides, benzenes and amino acids. It is added to food grains,tobacco,leather and preservation. Clothing

Definition

ChEBI: Dimethyl fumarate is an enoate ester resulting from the formal condensation of both carboxy groups of fumaric acid with methanol. Used for treatment of adults with relapsing forms of multiple sclerosis. It has a role as an immunomodulator and an antipsoriatic. It is an enoate ester, a methyl ester and a diester. It is functionally related to a methanol and a fumaric acid.

Brand name

Tecfidera

Synthesis Reference(s)

Synthetic Communications, 21, p. 223, 1991 DOI: 10.1080/00397919108020815The Journal of Organic Chemistry, 55, p. 329, 1990 DOI: 10.1021/jo00288a056

General Description

Dimethyl fumarate is a novel oral therapeutic agent, which can be used for patients suffering from relapsing-remitting multiple sclerosis. It shows an effective inhibition of mould in bread and can also serve as a potential candidate for the treatment of psoriasis, a chronic autoimmune condition.

Contact allergens

Dimethylfumarate, a strong irritant, is used as an industrial wide spectrum biocide in Asia and mainly in China, for textiles, leather, seeds, food, and cosmetic ingredients. It provoked a worldwide epidemic of severe contact dermatitis, initially from Chinese sofas sold in Finland, Great Britain, and France. It also induced severe burning and contact allergy due to shoes, and to contaminated clothing as well. This chemical, presents as is (white powder) or as tablets contained in little bags disposed in/or around the materials to protect, progressively evaporates and contaminates the environment. It is forbidden in the European Union since 2008

Clinical Use

Treatment of relapsing-remitting multiple sclerosisTreatment of moderate to severe plaque psoriasis

Drug interactions

Potentially hazardous interactions with other drugsAminophylline and theophylline: enhanced effect of aminophylline and theophylline.Anaesthetics: enhanced hypotensive effect. Anti-arrhythmics: increased risk of bradycardia, AV block and myocardial depression with amiodarone; increased risk of bradycardia and myocardial depression with dronedarone.Antibacterials: metabolism increased by rifampicin; metabolism possibly inhibited by clarithromycin, erythromycin and telithromycin.Antidepressants: enhanced hypotensive effect with MAOIs; concentration of imipramine and possibly other trycyclics increasedAntiepileptics: effect probably reduced by barbiturates, fosphenytoin, phenytoin, and primidone; enhanced effect of carbamazepine; increased levels of fosphenytoin and phenytoin.Antifungals: negative inotropic effect possibly increased with itraconazole.Antihypertensives: enhanced hypotensive effect; increased risk of first dose hypotensive effect of postsynaptic alpha-blockersAntipsychotics: concentration of lurasidone increased.Antivirals: concentration increased by atazanavir and ritonavir - reduce dose of diltiazem with atazanavir; concentration reduced by efavirenz; use telaprevir with caution.Avanafil: possibly increases avanafil concentration.Beta-blockers: risk of bradycardia and AV block if co-prescribed with beta-blockers.Cardiac glycosides: increased digoxin concentration.Ciclosporin: increased ciclosporin concentrations.Cilostazol: increased cilostazol concentration - avoid.Colchicine: possibly increased risk of colchicine toxicity - suspend or reduce colchicine, avoid concomitant use in renal or hepatic failure.Cytotoxics: concentration of bosutinib, ibrutinib and olaparib possibly increased - avoid or reduce dose; possibly increased risk of bradycardia with crizotinib.Fingolimod: increased risk of bradycardia.Ivabradine: concentration of ivabradine increased - avoid.Lipid lowering drugs: concentration of lomitapide possibly increased - avoid.Sirolimus: sirolimus concentration increased.

Metabolism

Diltiazem is almost completely absorbed from the gastrointestinal tract after oral doses, but undergoes extensive first-pass hepatic metabolism resulting in a bioavailability of about 40%. It is extensively metabolised in the liver, mainly by the cytochrome P450 isoenzyme CYP3A4; one of the metabolites, desacetyldiltiazem, has been reported to have 25-50% of the activity of the parent compound.About 2-4% of a dose is excreted in urine as unchanged diltiazem with the remainder excreted as metabolites in bile and urine.

Synthetic route

dimethyl cis-but-2-ene-1,4-dioate (624-48-6) → dimethylfumarate (624-49-7)

Conditions	Yield
With 1-hexylimidazolium DL-lactate at 70℃; for 24h; Kinetics; Product distribution; Further Variations:; Reagents; Temperatures;	100%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane Heating;	100%
With bromine In dichloromethane at 50℃; for 5h; Irradiation;	98%

(P(CH2CH2P(C6H5)2)3)Co(H2)(1+)*PF6(1-) = (P(CH2CH2P(C6H5)2)3)CoH2PF6 (117753-93-2) + dimethyl cis-but-2-ene-1,4-dioate (624-48-6) → dimethylfumarate (624-49-7)

Conditions	Yield
In tetrahydrofuran	100%

methanol (67-56-1) + (2E)-but-2-enedioic acid (110-17-8) → dimethylfumarate (624-49-7)

Conditions	Yield
With sulfuric acid for 8h; Reflux;	99%
With acetyl chloride at 45 - 60℃; for 5.5h; Temperature; Reagent/catalyst;	99.85%
With sulfuric acid at 105℃; for 0.266667h; Temperature;	99%

methanol (67-56-1) + methyl hydrogen fumarate (2756-87-8) → dimethylfumarate (624-49-7)

Conditions	Yield
With sulfuric acid at 55℃; for 2h;	98.6%
With thionyl chloride at 10 - 65℃;	80 g

tert-butyl methyl ether (1634-04-4) + (2E)-but-2-enedioic acid (110-17-8) → dimethylfumarate (624-49-7)

Conditions	Yield
With sulfuric acid Reflux; regioselective reaction;	96%
With perchloric acid for 18h; Reflux;	9.3 g

(4R,5R)-2-methoxy-[1,3]dioxolane-4,5-dicarboxylic acid dimethyl ester (112193-23-4) → dimethylfumarate (624-49-7)

Conditions	Yield
In acetic anhydride for 4h; Heating;	95%

dimethyl 2-(p-toluenesulfonamido)-3-(triphenylphosphoranylidene)butanedioate → dimethyl cis-but-2-ene-1,4-dioate (624-48-6) + N-p-tolylsulfonylphosphine imide (1058-14-6) + dimethylfumarate (624-49-7)

Conditions	Yield
In toluene for 14h; Heating;	A n/a B 93% C n/a

N,N-dimethyl-formamide dimethyl acetal (4637-24-5) + (2E)-but-2-enedioic acid (110-17-8) → dimethylfumarate (624-49-7)

Conditions	Yield
In tetrahydrofuran at 20℃; Reflux;	93%

(4R,5R)-2,2-Dioxo-2λ6-[1,3,2]dioxathiolane-4,5-dicarboxylic acid dimethyl ester → dimethylfumarate (624-49-7)

Conditions	Yield
With lithium iodide In acetone for 0.166667h; Ambient temperature;	90%
With magnesium iodide In acetonitrile for 0.0833333h; Ambient temperature;	90%
With iodine; triphenylphosphine In dichloromethane for 2h; Ambient temperature; various conditions;	85%

methanol (67-56-1) + carbon monoxide (201230-82-2) + acetylene (74-86-2) → cis,cis-dimethyl muconate (692-91-1, 692-92-2, 1119-43-3, 1733-37-5) + dimethyl cis-but-2-ene-1,4-dioate (624-48-6) + dimethylfumarate (624-49-7)

Conditions	Yield
PdI2-KI at 60℃; under 19000 Torr; for 15h;	A 7% B 89% C 3%

methyl crotonate (623-43-8, 4358-59-2, 18707-60-3, 130981-57-6) + (3SR,5SR)-1-(benzyloxy)oct-7-ene-3,5-diol → methyl (5SR,7SR,E)-9-(benzyloxy)-5,7-dihydroxynon-2-enoate + dimethylfumarate (624-49-7)

Conditions	Yield
With tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidine][benzylidene]ruthenium(II) dichloride In dichloromethane for 3h; Inert atmosphere; Reflux;	A 89% B n/a

dimethyl meso-tartrate cyclic sulfate → dimethylfumarate (624-49-7)

Conditions	Yield
With iodine; triphenylphosphine In dichloromethane Ambient temperature;	86%
With triphenylphosphine In xylene at 110℃;	45%

methanol (67-56-1) + carbon monoxide (201230-82-2) + acetylene (74-86-2) → dimethyl cis-but-2-ene-1,4-dioate (624-48-6) + dimethylfumarate (624-49-7)

Conditions	Yield
With hydrogenchloride; oxygen; copper dichloride; palladium dichloride under 1 Torr; for 2h;	A 86% B 14%

methyl diazoacetate (6832-16-2) + 3-morpholino-but-2-enoic acid methyl ester (55261-56-8) → dimethyl cis-but-2-ene-1,4-dioate (624-48-6) + dimethylfumarate (624-49-7) + (1R,2R)-3-Methyl-3-morpholin-4-yl-cyclopropane-1,2-dicarboxylic acid dimethyl ester

Conditions	Yield
copper acetylacetonate In ethyl acetate Heating;	A n/a B n/a C 86%

dimethyl (S)-malate (617-55-0) → dimethyl (2R)-fluorosuccinate (76003-45-7) + dimethylfumarate (624-49-7)

Conditions	Yield
With diethylamino-sulfur trifluoride In chloroform at 0℃; for 0.5h;	A 85% B 6%

3-<1.2.4>trioxolan-3-ylmethyl-cyclohexanone (132559-56-9) + methyl (triphenylphosphoranylidene)acetate (21204-67-1) → 4-(3-oxocyclohexyl)-2(E)-butenoic acid methyl ester (132559-62-7) + dimethylfumarate (624-49-7)

Conditions	Yield
In dichloromethane at 20℃; for 12h; Wittig type reaction;	A 85% B 3%

4-(pyrrolidin-1-yl)pent-3-en-2-one (23652-59-7) + methyl diazoacetate (6832-16-2) → methyl 2-acetyl-4-oxovalerate (85392-47-8) + dimethyl cis-but-2-ene-1,4-dioate (624-48-6) + dimethylfumarate (624-49-7)

Conditions	Yield
copper(I) triflate In dichloromethane at 20℃; for 24h;	A 84% B n/a C n/a

methyl diazoacetate (6832-16-2) + E-methyl β-morpholino-cinnamate (137201-66-2) → dimethyl cis-but-2-ene-1,4-dioate (624-48-6) + dimethylfumarate (624-49-7) + (1R,2R)-3-Morpholin-4-yl-3-phenyl-cyclopropane-1,2-dicarboxylic acid dimethyl ester

Conditions	Yield
copper acetylacetonate In ethyl acetate Heating;	A n/a B n/a C 84%

methyl diazoacetate (6832-16-2) + (E)-3-Morpholin-4-yl-3,N-diphenyl-acrylamide → dimethyl cis-but-2-ene-1,4-dioate (624-48-6) + dimethylfumarate (624-49-7) + (1R,3R)-2-Morpholin-4-yl-2-phenyl-3-phenylcarbamoyl-cyclopropanecarboxylic acid methyl ester

Conditions	Yield
copper acetylacetonate In ethyl acetate Heating;	A n/a B n/a C 83%

dimethyl L-tartrate (608-68-4, 608-69-5, 5057-96-5, 13171-64-7, 117356-23-7) → dimethylfumarate (624-49-7)

Conditions	Yield
With 1H-imidazole; iodine; chloro-diphenylphosphine In toluene; acetonitrile Ambient temperature;	81%

methyl (triphenylphosphoranylidene)acetate (21204-67-1) → Triphenylphosphine selenide (3878-44-2) + dimethylfumarate (624-49-7)

Conditions	Yield
With selenium In toluene for 3h; Heating;	A 77.6% B 73.6%

dimethyl acetylenedicarboxylate (762-42-5) → dimethyl phenylmaleate (89330-93-8) + dimethyl cis-but-2-ene-1,4-dioate (624-48-6) + dimethylfumarate (624-49-7)

Conditions	Yield
With cyclopentadienylchromiumtricarbonyl hydride In benzene Inert atmosphere;	A 76% B 17% C 5%

methyl (triphenylphosphoranylidene)acetate (21204-67-1) → dimethylfumarate (624-49-7)

Conditions	Yield
With selenium In toluene for 4h; Heating;	74%

dimethylsulfite (616-42-2) + (2E)-but-2-enedioic acid (110-17-8) → dimethylfumarate (624-49-7)

Conditions	Yield
sulfuric acid In methanol Heating;	73%

3-morpholin-4-yl-1-phenyl-but-2-en-1-one (70008-80-9) + methyl diazoacetate (6832-16-2) → dimethyl cis-but-2-ene-1,4-dioate (624-48-6) + 3-oxo-2-(2-oxo-2-phenyl-ethyl)-butyric acid methyl ester (75519-84-5) + dimethylfumarate (624-49-7) + 3-Methyl-5-phenyl-furan-2-carboxylic acid methyl ester

Conditions	Yield
copper(I) triflate In dichloromethane at 20℃;	A n/a B 73% C n/a D 4%

7-isopropyl-1,4-dimethyl-azulene (489-84-9) + dimethyl acetylenedicarboxylate (762-42-5) → dimethyl 1,6-dimethyl-9-(1-methylethyl)heptalene-4,5-dicarboxylate (98525-07-6, 72898-39-6, 98525-12-3, 98525-13-4) + dimethyl cis-but-2-ene-1,4-dioate (624-48-6) + dimethyl (E)-1-(5'-isopropyl-3',8'-dimethylazulen-1-yl)-ethene-1,2-dicarboxylate (145948-88-5) + dimethyl (Z)-1-(5-isopropyl-3,8-dimethylazulen-1-yl)ethene-1,2-dicarboxylate (145948-89-6) + dimethylfumarate (624-49-7)

Conditions	Yield
In acetonitrile at 100℃; for 4h; Mechanism; other solvents, other substrates;	A 71% B 1% C 15% D 11% E 1%

7-isopropyl-1,4-dimethyl-azulene (489-84-9) + dimethyl acetylenedicarboxylate (762-42-5) → dimethyl 1,6-dimethyl-9-(1-methylethyl)heptalene-4,5-dicarboxylate (98525-07-6, 72898-39-6, 98525-12-3, 98525-13-4) + dimethyl (E)-1-(5'-isopropyl-3',8'-dimethylazulen-1-yl)-ethene-1,2-dicarboxylate (145948-88-5) + dimethyl (Z)-1-(5-isopropyl-3,8-dimethylazulen-1-yl)ethene-1,2-dicarboxylate (145948-89-6) + dimethylfumarate (624-49-7)

Conditions	Yield
In acetonitrile at 100℃; for 4h; Further byproducts given;	A 71% B 15% C 11% D 1%

methanol (67-56-1) + (2E)-but-2-enedioic acid (110-17-8) → methyl hydrogen fumarate (2756-87-8) + dimethylfumarate (624-49-7)

Conditions	Yield
sulfuric acid at 60 - 70℃; for 3h; Product distribution / selectivity; Industry scale;	A n/a B 71%

diethyl (2-bromo-1-phenylvinyl)phosphonite (67866-50-6) + dimethyl cis-but-2-ene-1,4-dioate (624-48-6) → 1-ethoxy-2-phenyl-4,5-dimethoxycarbonyl-Δ2-λ5-phospholene 1-oxide + dimethylfumarate (624-49-7)

Conditions	Yield
for 4h; Ambient temperature;	A 27% B 70%

(E)-3-morpholin-4-yl-1,3-diphenylpropenone (70008-81-0) + methyl diazoacetate (6832-16-2) → dimethyl cis-but-2-ene-1,4-dioate (624-48-6) + methyl α,β-dibenzoyl-propionate (90904-37-3) + dimethylfumarate (624-49-7)

Conditions	Yield
copper(I) triflate In dichloromethane at 20℃;	A n/a B 70% C n/a

formaldehyd (50-00-0) + N-benzylglycine (17136-36-6) + dimethylfumarate (624-49-7) → dimethyl (3R,4R)-1-benzylpyrrolidine-3,4-dicarboxylate (87813-05-6, 87813-06-7, 111186-67-5)

Conditions	Yield
In toluene for 0.25h; Heating;	100%
In benzene for 3h; Heating;	63%
In toluene

n-Butyl chloride (109-69-3) + (E)-N-(phenylmethylene)-1-(trimethylsilyl)methylamine (90606-10-3) + dimethylfumarate (624-49-7) → (3R,4R)-2-Phenyl-pyrrolidine-3,4-dicarboxylic acid dimethyl ester (82959-82-8, 82959-83-9, 82959-84-0, 82959-85-1)

Conditions	Yield
In N,N,N,N,N,N-hexamethylphosphoric triamide at 40 - 45℃;	100%

N-<(trimethylsilyl)methyl>benzaldimine (57402-97-8) + dimethylfumarate (624-49-7) → (3R,4S)-2-Phenyl-pyrrolidine-3,4-dicarboxylic acid dimethyl ester (82959-82-8, 82959-83-9, 82959-84-0, 82959-85-1)

Conditions	Yield
With water; acetic acid In N,N,N,N,N,N-hexamethylphosphoric triamide for 24h; Ambient temperature;	100%

3-methylene-2-phenyl-4-penten-2-ol (61201-25-0) + dimethylfumarate (624-49-7) → (1S,2S)-4-(1-Hydroxy-1-phenyl-ethyl)-cyclohex-4-ene-1,2-dicarboxylic acid dimethyl ester

Conditions	Yield
In benzene for 16h; Heating;	100%

isoquinolinium phenylacylide (40448-79-1) + dimethylfumarate (624-49-7) → (1R,2R,3R,10bR)-3-Benzoyl-1,2,3,10b-tetrahydro-pyrrolo[2,1-a]isoquinoline-1,2-dicarboxylic acid dimethyl ester (97204-11-0, 97275-44-0, 105017-20-7)

Conditions	Yield
In chloroform for 0.166667h; Ambient temperature;	100%

5H-cyclopropisobenzofuran (33059-38-0) + dimethylfumarate (624-49-7) → C15H14O5 (113605-10-0)

Conditions	Yield
In cyclohexane at 25℃; Rate constant;	100%
In tetrahydrofuran at -30℃; for 0.0833333h;	100%

Benzoic acid 4-methoxythiocarbonylsulfanyl-but-2-ynyl ester + dimethylfumarate (624-49-7) → (5S,6S)-2-Oxo-4,5,6,7-tetrahydro-benzo[1,3]dithiole-5,6-dicarboxylic acid dimethyl ester

Conditions	Yield
In chlorobenzene Heating;	100%

2-(4-methoxyphenyl)-3-methylenepent-4-en-2-ol (100281-17-2) + dimethylfumarate (624-49-7) → (1S,2S)-4-[1-Hydroxy-1-(4-methoxy-phenyl)-ethyl]-cyclohex-4-ene-1,2-dicarboxylic acid dimethyl ester

Conditions	Yield
In benzene for 10h; Heating;	100%

1-(2-oxo-2-phenylethyl)pyridazin-1-ium bromide + dimethylfumarate (624-49-7) → (4aS,5R,6R,7R)-7-Benzoyl-4a,5,6,7-tetrahydro-pyrrolo[1,2-b]pyridazine-5,6-dicarboxylic acid dimethyl ester

Conditions	Yield
With triethylamine In chloroform for 0.166667h; Ambient temperature;	100%

1H-2-naphtho<2,1-b>thiete (23134-50-1) + dimethylfumarate (624-49-7) → trans-2,3-Dihydro-1H-naphtho<2,1-b>thiopyran-2,3-dicarbonsaeure-dimethylester

Conditions	Yield
In toluene at 80 - 110℃;	100%
at 80 - 110℃; Yield given;

(diisopropoxyphosphinoyl)formonitriole oxide (162889-67-0) + dimethylfumarate (624-49-7) → 3-(diisopropoxyphosphinoyl)-4,5-trans-bis(methoxycarbonyl)isoxazoline

Conditions	Yield
In dichloromethane at -78℃;	100%

2H-naphtho<1,2-b>thiete (174006-54-3) + dimethylfumarate (624-49-7) → trans-3,4-Dihydro-2H-naphtho<1,2-b>thiopyran-2,3-dicarbonsaeure-dimethylester

Conditions	Yield
In toluene at 80 - 110℃;	100%
In toluene Heating;	100%

2-oxo-4H-3,1-naptho<1,2-d>oxathiin (177028-67-0) + dimethylfumarate (624-49-7) → trans-3,4-Dihydro-2H-naphtho<1,2-b>thiopyran-2,3-dicarbonsaeure-dimethylester

Conditions	Yield
In toluene for 16h; Heating;	100%

3-aminothieno<3,4:3',4'>benzopyran-4-one (41078-15-3) + dimethylfumarate (624-49-7) → dimethyl 4-aminobenzocoumarin-2,3-dicarboxylate

Conditions	Yield
Heating;	100%
at 170℃; for 4h;	76%

2-iodo-propane (75-30-9) + 1-phenyl-1-(tributylstannyloxy)ethene (17851-98-8) + dimethylfumarate (624-49-7) → dimethyl 2-isopropyl-3-phenacylbutanedioate

Conditions	Yield
With 2,2'-azobis(isobutyronitrile) In benzene at 80℃; for 4h;	100%

5-(4-methoxyphenyl)-2-phenyl-2H-tetrazole (20433-10-7) + dimethylfumarate (624-49-7) → (4RS,5SR)-dimethyl 3-(4-methoxyphenyl)-1-phenyl-4,5-dihydro-1H-pyrazole-4,5-dicarboxylate

Conditions	Yield
In ethyl acetate for 2h; UV-irradiation;	100%

isopropylamine (75-31-0) + dimethylfumarate (624-49-7) → dimethyl 2-(iso-propylamino)succinate (17459-45-9)

Conditions	Yield
In acetonitrile at 0 - 20℃; for 16h;	100%

Cr(CO)3(C9(CH3)7)Rh(CO)2 (159665-98-2) + dimethylfumarate (624-49-7) → trans-[Cr(CO)3(heptamethylindenyl)Rh(CO)(fumaric acid dimethyl ester)]

Conditions	Yield
In dichloromethane Ar-atmosphere; 35°C (1 h); evapn. (Ar-stream), washing (pentane); elem. anal.;	100%

(platinum)(hydride)(bromide)(1,3-bis(2,4,6-trimethylphenyl)imidazolin-2-ylidene)(1,2-dimethyl-3-propylimidazole) + (platinum)(hydride)(bromide)(1,3-bis(2,4,6-trimethylphenyl)imidazolin-2-ylidene)(1,2-dimethyl-3-propylimidazole) + dimethylfumarate (624-49-7) → (1,3-dimesitylimidazol-2-ylidene)platinum(0) bis(η2-dimethylfumarate)

Conditions	Yield
In acetone byproducts: C3H2N2(CH3)2(C3H7)Br; reductive elimination for 3 h;	100%

(3S,4S)-3-((E)-Buta-1,3-dienyl)-4-(4-chloro-phenyl)-1-cyclohexyl-azetidin-2-one + dimethylfumarate (624-49-7) → 3-[2-(4-chlorophenyl)-1-cyclohexyl-4-oxoazetidin-3-yl]cyclohex-3-ene-1,2-dicarboxylic acid dimethyl ester

Conditions	Yield
With titanium tetrachloride In dichloromethane at -78℃; Diels-Alder reaction;	100%

C19H16ClNO + dimethylfumarate (624-49-7) → 3-[2-(4-chlorophenyl)-4-oxo-1-phenylazetidin-3-yl]cyclohex-3-ene-1,2-dicarboxylic acid dimethyl ester

Conditions	Yield
With titanium tetrachloride In dichloromethane at -78℃; Diels-Alder reaction;	100%

(3R,4S)-3-((E)-Buta-1,3-dienyl)-1,4-diphenyl-azetidin-2-one + dimethylfumarate (624-49-7) → 3-(2-oxo-1,4-diphenylazetidin-3-yl)cyclohex-3-ene-1,2-dicarboxylic acid dimethyl ester

Conditions	Yield
With titanium tetrachloride In dichloromethane at -78℃; Diels-Alder reaction;	100%

trans-3-(1,3-butadienyl)-1-phenyl-(4-methoxyphenyl)azetidin-2-one + dimethylfumarate (624-49-7) → 3-[2-(4-methoxyphenyl)-4-oxo-1-phenylazetidin-3-yl]cyclohex-3-ene-1,2-dicarboxylic acid dimethyl ester

Conditions	Yield
With titanium tetrachloride In dichloromethane at -78℃; Diels-Alder reaction;	100%

dimethylfumarate (624-49-7) + cis-3-(1',3'-butadienyl)-1-cyclohexyl-4-phenylazetidin-2-one → 3-(1-cyclohexyl-2-oxo-4-phenylazetidin-3-yl)cyclohex-3-ene-1,2-dicarboxylic acid dimethyl ester

Conditions	Yield
With titanium tetrachloride In dichloromethane at -78℃; Diels-Alder reaction;	100%

dimethylfumarate (624-49-7) + cis-3-(1',3'-butadienyl)-1-cyclohexyl-4-(p-methoxyphenyl)azetidin-2-one → 3-[1-cyclohexyl-2-(4-methoxyphenyl)-4-oxoazetidin-3-yl]cyclohex-3-ene-1,2-dicarboxylic acid dimethyl ester

Conditions	Yield
With titanium tetrachloride In dichloromethane at -78℃; Diels-Alder reaction;	100%

cyclopenta-1,3-diene (542-92-7) + dimethylfumarate (624-49-7) → dimethyl norborn-5-ene-2,3-endo-dicarboxylate

Conditions	Yield
at 20℃; for 8h; Diels-Alder cycloaddition;	100%

dicarbonylcyclopentadienylcobalt (12078-25-0) + dimethylfumarate (624-49-7) → [(η5-C5H5)Co(CO)(dimethyl fumarate)]

Conditions	Yield
In toluene Irradiation (UV/VIS); reflux, 3 h; flash chromy. on silica gel;	100%
In toluene for 3h; Reflux; Irradiation;

1,2-bis(diphenylphosphino)ethane hydridoplatinum molybdenum cyclopentadiene (CO)3 (189559-57-7) + dimethylfumarate (624-49-7) → hydrido(tricarbonyl)(cyclopentadienyl)molybdenum (12176-06-6) + C32H32O4P2Pt

Conditions	Yield
In benzene-d6 at 30℃; for 0.25h; Inert atmosphere; Schlenk technique;	A 100% B 74%

Upstream product

• 6832-16-2 methyl diazoacetate 
• 55514-36-8 dimethyl 2-diazosuccinate 
• 60-29-7 diethyl ether 
• 624-48-6 dimethyl cis-but-2-ene-1,4-dioate 
• 111-92-2 dibutylamine 
• 100-66-3 methoxybenzene 
• 109-89-7 diethylamine 
• 67-56-1 methanol 
• 110-16-7 maleic acid 
• 110-17-8 (2E)-but-2-enedioic acid 
• 77-78-1 dimethyl sulfate 
• 141-05-9 Diethyl maleate 
• 1191-99-7 2,3-dihydro-2H-furan 
• 100-42-5 styrene 

Downstream Products

• 19329-22-7 (+/-)-5c-phenyl-4,5-dihydro-1H-pyrazole-3,4r-dicarboxylic acid dimethyl ester 
• 19329-22-7 (+/-)-5t-phenyl-4,5-dihydro-1H-pyrazole-3,4r-dicarboxylic acid dimethyl ester 
• 17669-30-6 dimethyl 3-phenyl-4,5-dihydroisoxazole-4,5-dicarboxylate 
• 3014-58-2 dimethyl (exo,endo)-bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylate 
• 118044-68-1 (4-chloro-phenyl)-fumaric acid dimethyl ester 
• 36689-52-8 2-chloro-3-(4-chloro-phenyl)-succinic acid dimethyl ester 
• 4545-84-0 dimethyl bicyclo<2,2,2>oct-5-ene-endo-2,exo-3-dicarboxylate 
• 17673-68-6 dimethyl trans-cyclohex-4-ene-1,2-dicarboxylate 
• 20089-06-9 (+/-)-7-oxo-1,4,5,6-tetraphenyl-norbornene-⁽⁵⁾-dicarboxylic acid-(2endo,3exo)-dimethyl ester 
• 5240-54-0 N₁,N₄-dibenzylfumaramide 
• 2756-87-8 methyl hydrogen fumarate 
• 4148-97-4 dimethyl 2-methoxybutanedioate 
• 41401-14-3 (+/-)-3-(3-nitro-phenyl)-4,5-dihydro-isoxazole-4r,5t-dicarboxylic acid dimethyl ester 
• 54795-49-2 (+/-)-3ξ-methyl-cyclohex-4-ene-1r,2t-dicarboxylic acid dimethyl ester 

Relevant articles and documents

Dimethyl fumarate is an allosteric covalent inhibitor of the p90 ribosomal S6 kinases

Dimethyl fumarate (DMF)?has been applied for decades in the treatment of psoriasis and now also multiple sclerosis. However, the mechanism of action has remained obscure and involves high dose over long time of this small, reactive compound implicating many potential targets. Based on a 1.9 ? resolution crystal structure of the C-terminal kinase domain of the mouse p90 Ribosomal S6 Kinase 2 (RSK2) inhibited by DMF?we describe a central binding site in RSKs and the closely related Mitogen and Stress-activated Kinases (MSKs). DMF reacts covalently as a Michael acceptor to a conserved cysteine residue in the αF-helix of RSK/MSKs. Binding of DMF prevents the activation loop of the kinase from engaging substrate, and stabilizes an auto-inhibitory αL-helix, thus pointing to an effective, allosteric mechanism of kinase inhibition. The biochemical and cell biological characteristics of DMF inhibition of RSK/MSKs are consistent with the clinical protocols of DMF treatment.

Protic, imidazolium ionic liquids as media for (Z)- to (E)-alkene isomerization

The quantitative isomerization of (Z)- to (E-alkene in protic, imidazolium ionic liquids is demonstrated. The isomerization parameters were determined. The mechanism on the addition of the protic imidazolium species to carbon-carbon double bond is presented. Copyright

Unusual formation of tetrahydropyridazine-3,4,5,6-tetracarboxylic and pyrroletetracarboxylic esters upon decomposition of methyl diazoacetate in the presence of pyridine

Thermal, photolytic, and thermocatalytic decomposition of methyl diazoacetate (MDA) in the presence of Rh2(OAc)4 or Cu(acac)2 in refluxing pyridine afforded isomeric trans, cis- and cis, trans-3,4,5,6-tetra(methoxycarbonyl)-1,4,5,6-tetrahydropyridazines (～1 : 1) in a total yield of 30-70%. Decomposition of MDA in refluxing o-xylene in the presence of Rh2(OAc)4 and pyridine (20 mol.%) gave rise to 2,3,4,5-tetra(methoxycarbonyl)pyrrole in a yield of up to 40%. In these transformations of MDA, neither dimethyl fumarate (or dimethyl maleate) nor the corresponding 2-pyrazolines were generated as intermediates.

Zwitterion-Catalyzed Isomerization of Maleic to Fumaric Acid Diesters

Fumaric acid diesters are important building blocks for organic synthesis. A class of zwitterionic organocatalysts based on an amide anion/iminium cation charge pair were found to be effective in catalyzing the isomerization of maleic acid diesters to give fumaric acid diesters. Comparison of the performance of different zwitterionic organocatalysts toward the reaction revealed that nonclassical hydrogen bonding was involved in the stabilization of the Michael adduct intermediate.

A donor-acceptor complex enables the synthesis of: E -olefins from alcohols, amines and carboxylic acids

Olefins are prevalent substrates and functionalities. The synthesis of olefins from readily available starting materials such as alcohols, amines and carboxylic acids is of great significance to address the sustainability concerns in organic synthesis. Metallaphotoredox-catalyzed defunctionalizations were reported to achieve such transformations under mild conditions. However, all these valuable strategies require a transition metal catalyst, a ligand or an expensive photocatalyst, with the challenges of controlling the region- and stereoselectivities remaining. Herein, we present a fundamentally distinct strategy enabled by electron donor-acceptor (EDA) complexes, for the selective synthesis of olefins from these simple and easily available starting materials. The conversions took place via photoactivation of the EDA complexes of the activated substrates with alkali salts, followed by hydrogen atom elimination from in situ generated alkyl radicals. This method is operationally simple and straightforward and free of photocatalysts and transition-metals, and shows high regio- and stereoselectivities.

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.