75706-12-6 Usage
Uses
1. Used in Pharmaceutical Industry:
Leflunomide is used as a hydrogenated acid dehydrogenase inhibitor for its immunosuppressive and anti-inflammatory effects. It is particularly effective in the treatment of adults with active rheumatoid arthritis.
2. Used in Organ Transplantation:
Leflunomide is used as an immunosuppressive agent to inhibit T and B cell proliferation. Its activity is mainly attributed to its metabolite, a malononitrile derivative, which is believed to inhibit dihydroorotate dehydrogenase as well as several protein tyrosine kinases.
3. Used in Autoimmune Diseases:
Due to its immunosuppressant effects, leflunomide has found use in the treatment of rheumatoid arthritis and other autoimmune diseases. It has shown efficacy both prophylactically and therapeutically in diverse models of autoimmune or allergic diseases.
4. Used as a Nonsteroidal Anti-Inflammatory Drug (NSAID):
Leflunomide is also used as a nonsteroidal anti-inflammatory drug for its anti-inflammatory properties.
Note: Leflunomide is contraindicated in pregnancy or in women considering pregnancy, and careful monitoring of the patient's neurological status during treatment is mandatory due to the potential for toxic neuropathy.
Immunosuppressants
Leflunomide is a kind of isoxazole immunosuppressive drugs with anti-proliferative activity , modern pharmacology classifies? this product? as antipyretic, analgesic and anti-inflammatory drugs . This product can be rapidly converted to the active metabolites? and play a role by the liver and intestinal cytoplasm and microsomes , its; main mechanism is? during DNA synthesis, inhibiting a key enzyme-DHODH (DHODH) activity, so that the nucleotides within the B lymphocyte? are depleted , it terminates the biosynthesis of DNA and RNA, the cells can not enter s phase, and ultimately can not proliferate, resulting in anti-rheumatic effects, it is suitable for the treatment of adults with active rheumatoid arthritis, ankylosing spondylitis, it can slow bone destruction, alleviate the symptoms and signs. In addition, leflunomide can also inhibit the tyrosine kinase activity, thereby inhibiting proliferation of T cell, B cell? and non-immune cells, but it can also, by biosynthesis inhibition of cyclooxygenase-2 (COX2) , inhibit prostaglandin synthesis and exert anti-inflammatory effects and inhibit mast cells and basophils histamine release. When? this product is used in organ transplant patients,the? dose adjustment is difficult, it is mainly used to treat rheumatoid arthritis and other autoimmune diseases.
After oral administration of the product, it is rapidly transformed to the active metabolite? in the intestinal wall and liver? , F is 80%,it? does not affect the? absorption of the meal. Tmax is 6~12 h, if the first dose is administered as a loading dose of 100mg, it can reach steady-state plasma concentrations in 3 days, otherwise it needs numbers of months to reach steady-state plasma concentrations. Active metabolite PPB is 99.3%, which is mainly? distributed in the liver, kidney and skin, less in brain tissue. After further metabolization of the active metabolite,? 43% of the marker is excreted in the urine of, 48% is excreted by the fecal , T1/2 is about 2 weeks, enterohepatic circulation leads to a longer half-life of the active metabolite? which is the main factor. High-fat diet does not have a big effect on the plasma concentrations of drugs. Activated charcoal or cholestyramine inhibits absorption of the drug.
The main side effects of leflunomide include? anorexia, vomiting, abdominal pain, diarrhea, gastritis and gastroenteritis, skin rashes, hair loss and reversible transaminase elevation.
The drug may cause liver toxicity and is contraindicated in patients with preexisting liver disease. The ALT should be monitored monthly initially and periodically thereafter. Leflunomide may cause bone marrow toxicity; a complete blood cell count with platelets is recommended monthly for 6 months and then every 6 to 8 weeks thereafter. It is teratogenic and should be avoided during pregnancy.
Production method
Ethyl acetoacetate, triethyl orthoformate and acetic anhydride are refluxed together to the complete reaction of raw materials, about 5h. Distillate and collect? 140 150 ℃/1.87kPa fraction, the compound ( I) is obtained, in 85% yield.
Compound (I) is dissolved in ethanol,the mixture of hydroxylamine hydrochloride, sodium acetate and water is added dropwise at 10-15 ℃ and 1h, After dropping,react for about 8h.Concentrated hydrochloric acid and glacial acetic acid are added ,then reflux? for 5h. Concentrate under reduced pressure to 1/2 volume, cool to 10 ℃, filtration, recrystallize ethanol-water? ,compound (Ⅱ) is obtained, it is white crystalline powder, melting point 145-146.5 ℃, in 80% yield.
Compound (II) is dissolved in toluene and thionyl chloride is added dropwise at 50-55℃, reflux for 3h. After concentration, distillation, collect? 78-79 ℃/1.87kPa fraction, the compound (III) is obtained, in 75% yield.
Trifluoromethyl aniline and triethylamine are dissolved? in dichloromethane, at 0-5 ℃ solution ,the compound (Ⅲ) is added. Then at 25--30 ℃ reaction lasts 3h. Water is added, the organic layer is separated, wash with water, wash with brine, and dry. Concentrate under reduced pressure to 1/3 volume, petroleum ether is added, cool, filter, and recrystallize from ethyl acetate to give white crystals powder of leflunomide , m.p. 166~167 ℃, in yield 81%.
Precautions
1, people who are leflunomide and its metabolites allergy, pregnant women or women who may become pregnant and lactating women are disabled.
2, patients with severe liver damage and hepatitis B or hepatitis C serology markers positive should use with caution. ALT and white cells should be checked regularly during medication.
3, patients with immune deficiency, uncontrolled infection, active gastrointestinal disease, renal insufficiency, bone marrow dysplasia should use with caution.
4. For males who prepare fertility, treatment interruption should be considered, at the same time?? cholestyramine should be taken .
5, during treatment of this product, the effect and safety of the immunization live vaccine have? no clinical data, the immunization vaccine should not be used during medication.
6, for children using the product,the safety and efficacy have not been studied, so patients younger than 18 years of age are not recommended to the FDA.
7, if the overdose or toxicity occurs, cholestyramine or activated charcoal? can be administered orally to promote excretion of leflunomide.
8, the active metabolite of the product can cause diclofenac, ibuprofen, tolbutamide plasma concentration increasing from 13% to 50%, while the combination of rifampicin can increase blood concentrations of the active metabolite increasing by about 40% . In addition, the product may increase the liver toxicity of methotrexate.
Precautions
Leflunomide is teratogenic in animal models; it is absolutelycontraindicated in pregnancy, in women whomay become pregnant, and in breast-feeding women.Because of its long half-life, the M1 metabolite ofleflunomide may remain in the body for up to 2 years;therefore, a drug elimination procedure using cholestyramineshould be used before any attempt at pregnancy.This drug is not recommended for use in children.Caution should be used when administering thisdrug to individuals with renal or hepatic disease, heavyalcohol use, or immunosuppression.The long half-life of leflunomide must be taken intoaccount to prevent drug interactions. Hepatotoxicity ispossible if leflunomide is given in conjunction with a hepatotoxicagent such as methotrexate or certain NSAIDs.Leflunomide inhibits CYP2C9, the enzyme responsiblefor the metabolism of numerous drugs. Rifampin inducesthe P450 enzyme responsible for converting leflunomide to its M1 metabolite.Cholestyramine enhances the clearanceof leflunomide and its M1 metabolite.
Originator
Hoechst
MarionRoussel (Germany)
Indications
Leflunomide (Arava) is an isoxazole derivative approved
for the treatment of rheumatoid arthritis in
1998. Limited data suggest that it is comparable in efficacy
to sulfasalazine and produces fewer adverse effects.
It has a faster onset of action (4 weeks) than other
DMARDs.
Manufacturing Process
In US Patent No. 4,284,786 is described two methods of preparation of 5-
methylisoxazole-4-carboxylic-(4-trifluoromethyl)-anilide.The method 1A mixture of 0.55 mole of diketene (46.3 g) and 30 ml of acetonitrile is added
dropwise, at 75°C, to a solution of 0.5 mole of 4-trifluoromethylaniline (30.6
g) in 150 ml of acetonitrile. The mixture is heated to boiling under reflux for
2.5 hours. When it has cooled to room temperature, the crystals which are
precipitated are filtered off, washed with cold ethanol and dried. This gives
79.1 g (64.5% of theory) of crystalline acetoacetic acid-4-
trifluoromethylanilide, melting point (after recrystallization from ethanol)
155°C.The acetonitrile phase is evaporated to dryness under reduced pressure. The
crystalline residue (42.1 g) is recrystallized from 80 ml of ethanol. This gives
a further 24.1 g (19.7% of theory) of crystals. Melting point (after
recrystallization from ethanol) 155°C. Total yield: 84.2% of theory.0.75 mole of acetoacetic acid 4-trifluoromethylanilide (183.9 g) is boiled
under reflux for 1.5 hours with 0.83 mole of orthoformic acid triethyl ester
(123 g) and 2.25 mole of acetic anhydride (229.7 g). After the mixture has
cooled to room temperature, the crystals which have precipitated are filtered
off and washed first with a small amount of acetic anhydride and then with
petroleum ether. This gives 116.1 g (51.4% of theory) of crystalline 2-
ethoxymethyleneacetoacetic acid 4-trifluoromethylanilide, melting point (after
recrystallization from toluene) 124-125°C.The combined filtrates are concentrated under reduced pressure. The crystals
of the crystal paste which thereupon remains are filtered off, washed first with
a small amount of acetic anhydride and then with petroleum ether and dried.
A further 56.1 g (24.8% of theory) of crystals are thus obtained. Melting point
(after recrystallization from toluene) 124-125°C. Total yield: 76.2% of theory.A solution 0.1 mole of 2-ethoxymethyleneacetoacetic acid 4-
trifluoromethylanilide (30.1 g) in 60 ml of ethanol is added dropwise at 5-
10°C to the mixture of 0.11 mole of hydroxylamine hydrochloride (7.65 g) in
50 ml of water and 0.11 mole of sodium hydroxide (4.4 g) in 10 ml of water.
The mixture is heated under reflux for 15 min. The crystals which are
precipitated after cooling are filtered off, washed with water and dried. 19.6 g
(72.6% of theory) of crystalline 5-methylisoxazole-4-carboxylic acid 4-
trifluoromethyl-anilide are thus obtained, melting point (after recrystallization
from toluene) 166.5°C.A solution 0.1 mole of 2-ethoxymethyleneacetoacetic acid 4-
trifluoromethylanilide (30.1 g) in 60 ml of ethanol is added dropwise at 5-
10°C to the mixture of 0.11 mole of hydroxylamine hydrochloride (7.65 g) in
50 ml of water and 0.11 mole of sodium hydroxide (4.4 g) in 10 ml of water.
The mixture is heated under reflux for 15 min. The crystals which are
precipitated after cooling are filtered off, washed with water and dried. 19.6 g
(72.6% of theory) of crystalline 5-methylisoxazole-4-carboxylic acid 4-
trifluoromethyl-anilide are thus obtained, melting point (after recrystallization
from toluene) 166.5°C.The method 20.1 mole of 5-methylisoxazole-4-carboxylic acid chloride (14.6 g) and 20 ml of
a 5 N potassium hydroxide solution are added dropwise to 0.1 mole of
trifluoromethylaniline (16.1 g), suspended in 150 ml of water, in such a way
that the pH of the reaction mixture does not rise above 5. The mixture is
subsequently shaken with 150 ml of methylene chloride. The methylene
chloride phase is washed with water and, after drying with sodium sulfate is,
evaporated to dryness under reduced pressure. This gives 24.4 g (90.2% of
theory) of a crystalline 5-methylisoxazole-4-carboxylic acid 4-trifluoromethylanilide, melting point (after recrystallization from toluene) 166.5°C.
Therapeutic Function
Immunosuppressive, Antiarthritic
Biological Functions
Leflunomide is inactive, but teriflunomide inhibits pyrimidine de novo synthesis at low therapeutic doses by inhibiting
dihydroorotate dehydrogenase (the rate-determining enzyme for the synthesis of UMP), decreasing DNA and RNA
synthesis, and arresting the cell proliferation cycle and production of antibodies. The reduction of dihydroorotate to
orotate occurs concurrently with the reduction of its cofactor, ubiquinone (coenzyme Q). The inhibition of
dihydroorotate dehydrogenase by teriflunomide demonstrates noncompetitive and uncompetitive kinetics.
Administration of leflunomide in patients with rheumatoid arthritis results in progressive removal of B cells and
down-regulation of the immune process. Teriflunomide not only inhibits B-cell proliferation but also T-cell
proliferation, blocking the synthesis of immunosuppressive cytokines. At high therapeutic doses, leflunomide inhibits
protein tyrosine kinases.
Biological Activity
Immunosuppressant agent. In vitro the active metabolite A77 1726 (RS-61980) inhibits dihydroorotate dehydrogenase (K i = 2.7 μ M) and de novo pyrimidine synthesis in T-cells; blocks lymphocyte cell cycle progression and proliferation. A77 1726 also inhibits anti-CD3/CD28-induced cytokine production in PBMC cells (IC 50 = 21-27 μ g/ml). In vivo reduces inflammation in several animal models of autoimmune disease, arthritis, asthma and graft rejection.
Biochem/physiol Actions
Immunosuppressive; inhibits T and B cell proliferation. Activity is attributed mainly to its metabolite, a malononitrile derivative, which is believed to inhibit dihydroorotate dehydrogenase (in the de novo pyrimidine synthesis pathway) as well as several protein tyrosine kinases.
Pharmacokinetics
Leflunomide is a pro-drug that is rapidly and almost completely metabolized (half-life, <60 minutes) following oral
administration to teriflunomide, the pharmacologically active α-cyanoenol metabolite. The C3-H of the
isoxazole ring is essential for the ring opening to its active metabolite. The reaction is similar to CYP1A2-catalyzed
dehydration of aldoximes. The exact mechanism of action of leflunomide in the management of rheumatoid arthritis
has not been fully elucidated but appears to principally involve inhibition of B-lymphocyte (B-cell) proliferation,
reducing antibody formation. Activated lymphocytes must proliferate and synthesize large quantities of cytokines,
requiring increased de novo synthesis of uridine monophosphate (UMP) and other pyrimidine nucleotides for its cell
life cycle. Therefore, any substance that reduces the intracellular concentration of pyrimidine nucleotides will affect
the growth of these activated cells.
Pharmacology
Leflunomide is a prodrug that is converted to an active
malonitrilamide metabolite, A77 1726 (M1). M1 inhibits
T-cell proliferation by blocking de novo pyrimidine synthesis
and inhibiting the tyrosine kinases that are associated
with certain cytokine and growth factor receptors.
Clinical Use
Leflunomide is a DMARD with anti-inflammatory and immunosuppressive activity used for the management of
rheumatoid arthritis. It retards structural damage associated with arthritis in adults who have moderate to severe
active rheumatoid arthritis. Leflunomide also is being investigated for use in patients with solid tumors and organ
transplant recipients.
Side effects
Diarrhea occurs in approximately one-third of patients
taking this drug; indigestion, nausea, and vomiting occur
in about 10%. Other common adverse effects include
weight changes, headache, skin rashes, pruritus, and reversible
alopecia and hepatic enzyme elevation.Although
leflunomide acts as an immunosuppressive, it does not appear
to cause significant bone marrow depression.
Veterinary Drugs and Treatments
Leflunomide is an immunomodulating drug that may be useful in
dogs for treating a variety of immune-related conditions such as
IMHA, systemic and cutaneous reactive histiocytosis, granulomatous
meningoencephalitis, etc; it can be used as part of transplant
rejection protocols in dogs.
Leflunomide has been used with methotrexate to treat rheumatoid
arthritis in cats.
Drug interactions
Potentially hazardous interactions with other drugs
Hepatotoxic or haemotoxic drugs: increased risk of
toxicity.
Cytotoxics: risk of toxicity with methotrexate.
Lipid-lowering agents: effect significantly reduced by
colestyramine - avoid.
Live vaccines: avoid concomitant use.
Metabolism
After oral doses leflunomide undergoes rapid first-pass
metabolism in the liver and gut wall to teriflunomide
(A-771726), which is responsible for the majority of the
in vivo activity.
Teriflunomide is mostly eliminated as unchanged drug in
the bile and as metabolites in the urine. It is thought to
undergo enterohepatic recycling and has an elimination
half-life of about 18-19 days after repeated oral doses.
References
1) Teschner et al. (2010), Leflunomide: a drug with a potential beyond rheumatology; Immunotherapy, 2 637
2) Davis et al. (1996), The immunosuppressive metabolite of leflunomide is a potent inhibitor of human dihydroorotate dehydrogenase; Biochemistry, 35 1270
3) Latchoumycandane et al. (2007), Mitochondrial protection by the JNK inhibitor leflunomide rescues mice from acetaminophen-induced liver injury; Hepatology, 45 412
Check Digit Verification of cas no
The CAS Registry Mumber 75706-12-6 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 7,5,7,0 and 6 respectively; the second part has 2 digits, 1 and 2 respectively.
Calculate Digit Verification of CAS Registry Number 75706-12:
(7*7)+(6*5)+(5*7)+(4*0)+(3*6)+(2*1)+(1*2)=136
136 % 10 = 6
So 75706-12-6 is a valid CAS Registry Number.
InChI:InChI=1/C12H9F3N2O2/c1-7-10(6-16-19-7)11(18)17-9-4-2-8(3-5-9)12(13,14)15/h2-6H,1H3,(H,17,18)
75706-12-6Relevant articles and documents
The trifluoromethylating sandmeyer reaction: A method for transforming C-N into C-CF3
Browne, Duncan L.
, p. 1482 - 1484 (2014)
A means to trifluoromethylate: The beneficial properties imparted by the trifluoromethylation of aromatic compounds continue to drive the discovery of novel reagents and reactions for the late-stage introduction of such moieties. Highlighted here is the recently discovered Sandmeyer trifluoromethylation approach, which now permits aromatic amines to be substrates in a direct trifluoromethylation strategy. Copyright
Simple preparation method of teriflunomide
-
Paragraph 0063-0068; 0072-0075; 0078-0081; 0084-0087; ..., (2021/07/08)
The invention provides a simple preparation method of teriflunomide, and belongs to the field of medicinal chemistry. The preparation method comprises the following steps of: (1) mixing 5-methylisoxazole-4-formic acid and a condensing agent in a solvent under an alkaline condition, and carrying out condensation reaction to obtain an active ester system; (2) mixing the active ester system and 4-trifluoromethylaniline in a solvent, and carrying out condensation reaction to obtain an intermediate leflunomide; and (3) carrying out alkali treatment and acid treatment on the obtained intermediate leflunomide to obtain teriflunomide. According to the method, the 5-methylisoxazole-4-formic acid reacts with the 4-trifluoromethylaniline in the form of active ester, so that the reaction activity of the 5-methylisoxazole-4-formic acid and the 4-trifluoromethylaniline is improved, the reaction condition is mild, the obtained intermediate leflunomide does not need to be purified, and the yield of teriflunomide is improved.
Preparation method of (by machine translation)
-
, (2020/06/24)
The invention relates to a novel process for preparing flutamipide by using a pharmaceutical active pharmaceutical ingredient, wherein ethyl acetoacetate is taken as a raw material and mixed with hydroxylamine hydrochloride to obtain fluticide. The process not only can better control the content of 3 - methyl isomers and 4 - trifluoromethylaniline in the baflunomide product, and is higher in yield and more concise. The industrial wastewater generated by the process is less in waste gas, environmentally friendly, capable of effectively reducing production cost and corrosion to equipment. (by machine translation)
A catalytic fluoride-rebound mechanism for C(sp3)-CF3 bond formation
Levin, Mark D.,Chen, Tiffany Q.,Neubig, Megan E.,Hong, Cynthia M.,Theulier, Cyril A.,Kobylianskii, Ilia J.,Janabi, Mustafa,O'Neil, James P.,Toste, F. Dean
, p. 1272 - 1275 (2017/06/30)
The biological properties of trifluoromethyl compounds have led to their ubiquity in pharmaceuticals, yet their chemical properties have made their preparation a substantial challenge, necessitating innovative chemical solutions. We report the serendipitous discovery of a borane-catalyzed formal C(sp3)-CF3 reductive elimination from Au(III) that accesses these compounds by a distinct mechanism proceeding via fluoride abstraction, migratory insertion, and C-F reductive elimination to achieve a net C-C bond construction. The parent bis(trifluoromethyl)Au(III) complexes tolerate a surprising breadth of synthetic protocols, enabling the synthesis of complex organic derivatives without cleavage of the Au-C bond. This feature, combined with the fluoride-rebound mechanism, was translated into a protocol for the synthesis of 18F-radiolabeled aliphatic CF3-containing compounds, enabling the preparation of potential tracers for use in positron emission tomography.
Exploiting intramolecular hydrogen bonding for the highly (: Z)-selective & metal free synthesis of amide substituted β-aminoenones
Subramaniam, Palaniraja,Ramasubbu, Chandrasekaran,Athiramu, Selvaraj
, p. 2541 - 2545 (2017/07/17)
Herein, we report the metal free and intramolecular hydrogen bonding (IMHB) directed (Z)-selective synthesis of amide substituted β-aminoenones. Systematically, we confirm the role of dual IMHB (CO?H-N) on the Z-direction using single-crystal X-ray analysis and 1D and 2D NMR studies. High stereoselectivity, atom efficiency, excellent yields and high purity are achieved by mere filtration. We avoid column purification and the formed by-product in the process is environmentally friendly.
A NOVEL PROCESS FOR THE PREPARATION OF TERIFLUNOMIDE
-
, (2017/01/02)
The present invention provides a process for the preparation of Teriflunomide (Formula-I). The present invention describes the synthesis of Teriflunomide without isolating the intermediate Leflunomide. Teriflunomide is prepared from 5-Methyl isoxazole-4-carboxylic acid by converting to its acid chloride and coupling with 4-trifluoromethyl aniline to obtain Leflunomide (which is not isolated) followed by ring opening reaction using aq. Sodium Hydroxide to form Teriflunomide. In other words, the process is telescoped from 5- methylisoxazole-4-carbonyl chloride.
Comprehensive Study of the Organic-Solvent-Free CDI-Mediated Acylation of Various Nucleophiles by Mechanochemistry
Mtro, Thomas-Xavier,Bonnamour, Julien,Reidon, Thomas,Duprez, Anthony,Sarpoulet, Jordi,Martinez, Jean,Lamaty, Frdric
supporting information, p. 12787 - 12796 (2015/09/01)
Acylation reactions are ubiquitous in the synthesis of natural products and biologically active compounds. Unfortunately, these reactions often require the use of large quantities of volatile and/or toxic solvents, either for the reaction, purification or isolation of the products. Herein we describe and discuss the possibility of completely eliminating the use of organic solvents for the synthesis, purification and isolation of products resulting from the acylation of amines and other nucleophiles. Thus, utilisation of N,N′-carbonyldiimidazole (CDI) allows efficient coupling between carboxylic acids and various nucleophiles under solvent-free mechanical agitation, and water-assisted grinding enables both the purification and isolation of pure products. Critical parameters such as the physical state and water solubility of the products, milling material, type of agitation (vibratory or planetary) as well as contamination from wear are analysed and discussed. In addition, original organic-solvent-free conditions are proposed to overcome the limitations of this approach. The calculations of various green metrics are included, highlighting the particularly low environmental impact of this strategy.
CuCF3: A [18F]trifluoromethylating agent for arylboronic acids and aryl iodides
Ivashkin, Pavel,Lemonnier, Gerald,Cousin, Jonathan,Gregoire, Vincent,Labar, Daniel,Jubault, Philippe,Pannecoucke, Xavier
, p. 9514 - 9518 (2014/08/18)
Positron emission tomography has emerged as the leading method for medical imaging with fluorine-18 as the most widely used radioactive isotope. Here we report a semi-automated method for the preparation of valuable [ 18F]trifluoromethylcopper, as well as its use for the radiosynthesis of [18F]trifluoromethylarenes and heteroarenes. Mild conditions of [18F]trifluoromethylation make this method particularly useful for the radiosynthesis of pharmacologically relevant [18F] trifluoromethylarenes and heteroarenes. 18F Radiochemistry: A semi-automated method for the fast preparation of radiolabelled (trifluoromethyl)copper is reported (see scheme), thus making [ 18F]CuCF3 almost as accessible as [18F]fluoride itself for the preparation of radiolabelled trifluoromethylated probes. It can be used for the preparation of radiolabelled trifluoromethylarenes from arylboronic acids and aryliodides. This methodology is clean, efficient and consistent with the specific requirements of radiochemistry.
Copper-promoted sandmeyer trifluoromethylation reaction
Dai, Jian-Jun,Fang, Chi,Xiao, Bin,Yi, Jun,Xu, Jun,Liu, Zhao-Jing,Lu, Xi,Liu, Lei,Fu, Yao
, p. 8436 - 8439 (2013/07/19)
A copper-promoted trifluoromethylation reaction of aromatic amines is described. This transformation proceeds smoothly under mild conditions and exhibits good tolerance of many synthetically relevant functional groups. It provides an alternative approach for the synthesis of trifluoromethylated arenes and heteroarenes. It also constitutes a new example of the Sandmeyer reaction.
Mechanosynthesis of amides in the total absence of organic solvent from reaction to product recovery
Metro, Thomas-Xavier,Bonnamour, Julien,Reidon, Thomas,Sarpoulet, Jordi,Martinez, Jean,Lamaty, Frederic
supporting information, p. 11781 - 11783 (2013/01/15)
The synthesis of various amides has been realised avoiding the use of any organic solvent from activation of carboxylic acids with CDI to isolation of the amides. Mechanochemistry was the key point of the process allowing rapid formation of the amide bond and efficient water-based purification of the final products.
