5-methylisoxazole-4-carboxylic acid (4-trifluoromethyl)anilide
leflunomide
CAS: 75706-12-6
Molecular Formula: C12H9F3N2O2
5-methylisoxazole-4-carboxylic acid (4-trifluoromethyl)anilide - Names and Identifiers
5-methylisoxazole-4-carboxylic acid (4-trifluoromethyl)anilide - Physico-chemical Properties
| Molecular Formula | C12H9F3N2O2 |
| Molar Mass | 270.21 |
| Density | 1.392±0.06 g/cm3(Predicted) |
| Melting Point | 166.5 °C |
| Boling Point | 289.3±40.0 °C(Predicted) |
| Solubility | Soluble in DMSO (54 mg/ml at 25 °C), ethanol (54 mg/ml at 25 °C), and water (<1 mg/ |
| Appearance | neat |
| Color | White |
| Merck | 14,5432 |
| pKa | 10.8(at 25℃) |
| Storage Condition | 2-8°C |
| Stability | Stable for 2 years from date of purchase as supplied. Solutions in DMSO or ethanol may be stored at -20° for up to 1 month. |
| Sensitive | Sensitive to heat |
| MDL | MFCD00867593 |
| Physical and Chemical Properties | White crystalline powder, melting point 166.5 °c. |
| Use | For anti-rheumatoid arthritis drugs |
5-methylisoxazole-4-carboxylic acid (4-trifluoromethyl)anilide - Risk and Safety
| Risk Codes | R22 - Harmful if swallowed R36/37/38 - Irritating to eyes, respiratory system and skin. |
| Safety Description | S26 - In case of contact with eyes, rinse immediately with plenty of water and seek medical advice. S36 - Wear suitable protective clothing. |
| UN IDs | UN 2811 6.1/PG 3 |
| WGK Germany | 3 |
| RTECS | NY2354200 |
| HS Code | 2934990002 |
| Hazard Class | 6.1 |
| Packing Group | III |
5-methylisoxazole-4-carboxylic acid (4-trifluoromethyl)anilide - Reference
| Reference Show more | 1. [IF=5.037] Zhijie Wan et al."Hepatoprotective effect of gentiopicroside in combination with leflunomide and/or methotrexate in arthritic rats."Life Sci. 2021 Jan;265:118689 |
5-methylisoxazole-4-carboxylic acid (4-trifluoromethyl)anilide - Nature
Open Data Verified Data
white or off-white crystalline powder. Melting point 16 6.5 deg C; pK. 10.8. 2 5 degrees Celsius in water 25~27mg/L. Soluble in methanol, ethanol, acetone.
Last Update：2024-01-02 23:10:35
5-methylisoxazole-4-carboxylic acid (4-trifluoromethyl)anilide - Preparation Method
Open Data Verified Data
ethyl acetoacetate, triethyl orthoformate and acetic anhydride were refluxed together until the starting material was completely reacted. The compound fractions were collected by distillation. This compound was dissolved in absolute ethanol, and a mixture of hydroxylamine hydrochloride, sodium acetate and water was added dropwise to the mixture for reaction. After completion of the reaction, concentrated hydrochloric acid and glacial acetic acid were added, refluxed, concentrated under reduced pressure, cooled, filtered, and recrystallized from ethanol-water. The compound obtained by recrystallization was dissolved in toluene, added dropwise with sulfoxide chloride, refluxed, concentrated, fractionated, and fractions were collected. The obtained compound was added dropwise to dichloromethane solution of p-trifluoromethylaniline and triethylamine, water was added after reaction, the organic layer was separated, washed, dried, concentrated under reduced pressure, petroleum ether was added, cooled, filtered, recrystallization of acetic acid from ethanol to obtain product lef
Milt.
Last Update：2022-01-01 09:09:31
5-methylisoxazole-4-carboxylic acid (4-trifluoromethyl)anilide - Standard
Authoritative Data Verified Data
This product is N-(4-trifluoromethylphenyl)-5-methylisoparazole-4-carboxamide, calculated as dry product, containing c12h3n202 should be 98.0% ~ 102.0%.
Last Update：2024-01-02 23:10:35
5-methylisoxazole-4-carboxylic acid (4-trifluoromethyl)anilide - Trait
Authoritative Data Verified Data
- This product is white crystal or powder, odorless.
- This product is soluble in methanol or glacial acetic acid, soluble in ethanol, slightly soluble in chloroform, almost insoluble in water.
melting point
The melting point of this product (General 0612) is 165~168°C.
Last Update：2022-01-01 11:56:31
5-methylisoxazole-4-carboxylic acid (4-trifluoromethyl)anilide - Differential diagnosis
Authoritative Data Verified Data
- in the chromatogram recorded under the content determination item, the retention time of the main peak of the test solution should be consistent with the retention time of the main peak of the reference solution.
- The infrared absorption spectrum of this product should be consistent with that of the reference product (General rule 0402).
Last Update：2022-01-01 11:56:31
5-methylisoxazole-4-carboxylic acid (4-trifluoromethyl)anilide - Exam
Authoritative Data Verified Data
Related substances
take the test solution under the content determination item as the test solution (1); Take about 125mg of this product, weigh it accurately, put it in a 50ml measuring flask, add 10ml of acetonitrile to dissolve, dilute to scale with mobile phase, shake well, and use as test solution (2); Take test solution (1) precisely, quantitative dilution with mobile phase to prepare a solution containing about 0.5ug per 1 ml as a control solution; Take an appropriate amount of 4-trifluoromethylaniline (impurity I) control, the mobile phase was added to dissolve and quantitatively dilute to prepare a solution containing about 0.25ug per 1 ml as a control solution. According to the chromatographic condition test under the content determination item, 20 u1 of each of the above four solutions are accurately measured and injected into the human liquid chromatograph respectively, and the chromatogram is recorded to 2 times of the retention time of the main peak. In the chromatogram of the reference solution, the signal-to-noise ratio of the peak height of the principal component should be greater than 10. If there are impurity peaks in the chromatogram of the test solution (1), the peak area of impurity II shall not be more than 3 times (0.3%) of the main peak area of the control solution, other single impurity peak area shall not be greater than the main peak area of the control solution (0.1% ) , and the sum of other impurity peak areas shall not be greater than 2 times the main peak area of the control solution (0.2% ) ; Test solution (2) if there is a chromatographic peak consistent with the retention time of impurity I in the chromatogram, the peak area shall be calculated by external standard method, and shall not exceed 0.01%.
residual solvent
take about 0.5g of this product, precision weighing, precision plus internal standard solution (take an appropriate amount of N-propanol, add N,N-dimethylformamide to dissolve and dilute to make a solution containing about 0.25mg per lml) 5ml to dissolve, shake, as a test solution; Precision weighing anhydrous ethanol, dichloromethane and toluene, plus internal standard solution dissolved and diluted to make about 0.5mg of ethanol per 1 ml, A mixed solution of 0.06mg of dichloromethane and 0.089mg of toluene was used as a control solution. According to the test for determination of residual solvents (General rule 0861, third method), the capillary column with 5% phenyl-95% methyl polysiloxane (or similar polarity) as stationary liquid is used as the column, and the initial temperature is 40 ° C., and the retention time is 10 minutes, the temperature was increased to 140°C at a rate of 10°C per minute, and then to 250°C at a rate of 20°C per minute for 5 minutes, and the inlet temperature was 240°C; And the detector temperature was 270°C. The reference solution 1M1 is injected into the gas chromatograph, and the separation degree between the peaks of each component shall meet the requirements. 1ul of each of the reference solution and the test solution were respectively injected into the human gas chromatograph, and the chromatogram was recorded. According to the internal standard method, the residual amount of ethanol, dichloromethane and toluene shall be in accordance with the provisions.
loss on drying
take this product, dry to constant weight at 105°C, weight loss shall not exceed 0.5% (General rule 0831).
ignition residue
take l.Og of this product and check it according to law (General rule 0841). The residue left shall not exceed 0.1%.
Heavy metals
The residue left under the item of taking the ignition residue shall not contain more than 20 parts per million of heavy metal when examined by law (General rule 0821, Law II).
Last Update：2022-01-01 11:56:32
5-methylisoxazole-4-carboxylic acid (4-trifluoromethyl)anilide - Content determination
Authoritative Data Verified Data
measured by high performance liquid chromatography (General 0512).
chromatographic conditions and system suitability test
silica gel bonded with eighteen alkyl silane as filler, with 0.025mOl / L potassium dihydrogen phosphate solution (adjusted to pH 3.0 with phosphoric acid)-acetonitrile (60:40) as mobile phase, the detection wavelength was 210nm. Leflunomide, (2Z)-2-cyano-3-hydroxy-n-(4-trifluoromethylphenyl)-2-butenamide (impurity II) with N-(4-trifluoromethylphenyl)-3-methylisoxazole-4-carboxamide (impurity III) each appropriate amount, add appropriate amount of acetonitrile to dissolve, dilute with mobile phase to prepare a mixed solution containing about 0.5mg of leflunomide, impurity II 1.5ug and impurity III 0.5ug per 1 ml. Inject 20ul into human liquid chromatograph and record the chromatogram. The resolution between the leflunomide peak and the impurity III peak shall be satisfactory.
assay
take 25mg of this product, accurately weigh it, put it in a 50ml measuring flask, add 10ml of acetonitrile to dissolve it, dilute it to the scale with mobile phase, shake it well, and use it as a test solution, the chromatogram was recorded by injection of 20u1 into human liquid chromatograph, and the other leflunomide reference substance was taken for determination by the same method. According to the external standard method to calculate the peak area, that is.
Last Update：2022-01-01 11:56:32
5-methylisoxazole-4-carboxylic acid (4-trifluoromethyl)anilide - Category
Authoritative Data Verified Data
antipyretic and analgesic, non-steroidal anti-inflammatory drugs, immunomodulatory drugs.
Last Update：2022-01-01 11:56:33
5-methylisoxazole-4-carboxylic acid (4-trifluoromethyl)anilide - Storage
Authoritative Data Verified Data
shade, seal, and store in a cool place.
Last Update：2022-01-01 11:56:33
5-methylisoxazole-4-carboxylic acid (4-trifluoromethyl)anilide - Leflunomide Tablets
Authoritative Data Verified Data
This product contains leflunomide (c12h1f3n202) should be 90.0% to 110.0% of the label.
trait
This product is a film-coated tablet, White after removing the coating.
identification
- the solution under the content uniformity was taken and measured by ultraviolet-visible spectrophotometry (General rule 0401), and there was a maximum absorption at a wavelength of Nm.
- in the chromatogram recorded under the content determination item, the retention time of the main peak of the test solution should be consistent with the retention time of the main peak of the reference solution.
examination
- for related substances, take the continued filtrate under the content determination item as the test solution; Take 1ml of the sample, put it in a 100ml measuring flask, dilute it to the mark with the mobile phase, and shake it well, as a control solution; An appropriate amount of the control of impurity I was taken, dissolved and quantitatively diluted with the mobile phase to prepare a solution containing about 0.5ug of leflunomide per 1ml as a control solution. According to the chromatographic condition test under the content determination item, take 10ul of the reference solution, inject the human liquid chromatograph, record the chromatogram, and the signal to noise ratio of the main component peak height should be greater than 10. Take 20 u1 of each of the above three solutions with precision, inject human liquid chromatography respectively, and record the chromatogram to 2 times of the retention time of the main component peak. If there are impurity peaks in the chromatogram of the test solution (except for the solvent peaks and excipient peaks before the retention time of 0.5 times of the relative main peak), the Peak area of impurity II shall not be greater than 1.5 times (1.5%) of the main peak area of the control solution, and the peak area of other individual impurities shall not be greater than 0.2 times (0.2%) of the main peak area of the control solution, if there is a chromatographic peak consistent with retention time of impurity I, calculated by the peak area according to the external standard method, 0.1% of the labeled amount of fluorine shall not be passed, and the total amount of impurities shall not exceed 2.0%.
- Content uniformity take 1 tablet of this product, put it in a 50ml measuring flask, add an appropriate amount of 60% ethanol solution, sonicate for 10 minutes, let it cool, dilute it to the scale with 60% ethanol solution, shake it well, filter it, precisely take appropriate amount of continued filtrate, dilute with 60% ethanol solution to make a solution containing about 8ug per 1 ml, according to UV-Vis spectrophotometry (General 0401), the absorbance was measured at a wavelength of 261nm; An appropriate amount of the leflunomide reference substance was accurately weighed, dissolved and diluted with 60% ethanol solution to prepare a solution containing about 1 ml per 1 ml, which was determined by the same method. Calculation of the content, should be in accordance with the provisions (General 0941).
- dissolution the dissolution medium is 0931 of 30% sodium dodecyl sulfate solution prepared by 0.5% ethanol solution according to the dissolution and release determination method (General rule second method); the rotational speed is 100 rpm, operated according to law. After 45 minutes, take the appropriate amount of solution, filter, take the appropriate amount of filtrate, dilute with dissolution medium to make a solution containing about 5ug per 1 ml, measure absorbance at the wavelength of 261mn by UV-Vis spectrophotometry (General rule 0401); Take leflunomide as reference, the dissolution medium was added to dissolve and quantitatively dilute to prepare a solution containing about 5ug per 1 ml, and the dissolution amount of each tablet was calculated by the same method. The limit is 75% of the labeled amount and shall be in accordance with the provisions.
- others shall be in accordance with the relevant provisions under the item of tablets (General rule 0101).
Content determination
- chromatographic conditions and system suitability test using eighteen alkyl silane bonded silica gel as filler, 0.025mol/L potassium dihydrogen phosphate solution (adjusted to pH 3.0 with phosphoric acid)-acetonitrile (60:40) as mobile phase, the detection wavelength was 210nm. Leflunomide, (2Z)-2-cyano-3-hydroxy-n-(4-trifluoromethylphenyl)-2-butenamide (impurity II) with N-(4-trifluoromethylphenyl)-3-methylisoxazole-4-carboxamide (impurity m) each appropriate amount, add appropriate amount of acetonitrile to dissolve, dilute with mobile phase to make a mixed solution containing about 0.5mg of leflunomide, 1.5ug of impurity II and 10.5ug of impurity in 1 ml. Inject 20m1 into human liquid chromatograph and record the chromatogram. The resolution between the leflunomide peak and the impurity III peak shall be satisfactory.
- determination of this product 20 tablets, precision weighing, fine, precision weighing take appropriate amount (about equivalent to leflunomide 25mg), put 50ml flask, add acetonitrile 10ml and mobile phase 20ml, shake for 20 minutes, dissolve leflunomide, dilute to the scale with mobile phase, shake well, filter, take the continued filtrate as the test solution, inject it into the liquid chromatograph, record the chromatogram; in addition, the appropriate amount of leflunomide reference substance was accurately weighed, and acetonitrile (10ml) and mobile phase (20ml) were added, fully shaken to dissolve, and diluted with mobile phase to prepare a solution containing 0.5mg of reference substance per 1 ml, which was determined by the same method. According to the external standard method to calculate the peak area, that is.
category
with leflunomide.
specification
(l)5mg (2)10mg (3)20mg
storage
shading, sealing, storage in dry place.
Last Update：2022-01-01 11:56:34
5-methylisoxazole-4-carboxylic acid (4-trifluoromethyl)anilide - Reference Information
| immunosuppressant | , is a kind of anti-proliferative activity of isoxazole immunosuppressant, modern medicine will be classified as antipyretic, analgesic anti-inflammatory drugs. Due to the difficulty of dose adjustment for organ transplant patients, it is mainly used for the treatment of autoimmune diseases such as rheumatoid arthritis. After oral administration of this product in the intestinal wall and liver rapidly converted to active metabolites, F 80%, meal does not affect the absorption. Tmax for 6~12 h, such as the first dose of a loading dose of 100mg,3d that is to reach the steady-state blood concentration, otherwise months to reach the steady-state blood concentration. The active metabolite PPB was 99.3%, mainly distributed in liver, kidney and skin, with less brain tissue. After further metabolism of the active metabolite, 43% of the marker is excreted by urine and 48% by feces. T1/2 is about 2 weeks. High-fat diet does not have a large effect on plasma concentrations of the drug. Activated carbon or cholangiography can inhibit drug absorption. |
| mechanism of action | Leflunomide is rapidly converted into active metabolites by the cytoplasm and microsomes of the liver and intestinal wall, its mechanism of action is mainly to inhibit the activity of dihydroorotate dehydrogenase (DHODH), a key enzyme in the process of DNA synthesis, so that the consumption of nucleotides in B lymphocytes is neglected, termination of DNA and RNA biosynthesis, so that cells can not enter the S phase, and ultimately can not proliferate, resulting in anti rheumatic effects, suitable for the treatment of active rheumatoid arthritis in adults, ankylosing spondylitis, can slow bone destruction, relief of symptoms and signs. In addition, leflunomide can also inhibit the activity of tyrosine kinase, thereby inhibiting the proliferation of T cells, B cells and non-immune cells, but also through the inhibition of cyclooxygenase-2 (COX2) biosynthesis and inhibition of prostaglandin synthesis to play an anti-inflammatory effect, and can inhibit the release of histamine in mast cells and basophils. |
| adverse reactions | The main adverse reactions of leflunomide were anorexia, Vomit, Abdominal Pain, Diarrhea, gastritis and gastroenteritis, rash, reversible alopecia, and elevated transaminases. |
| note | 1, allergic to leflunomide and its metabolites, pregnant or potentially pregnant women and lactating women are contraindicated. 2, severe liver damage and hepatitis B or hepatitis C serological markers positive patients with caution. ALT and white blood cells were checked regularly during the medication. 3, immune deficiency, uncontrolled infection, active gastrointestinal disease, renal insufficiency, bone marrow dysplasia patients with caution. 4. Men who are ready to give birth should consider discontinuing treatment with cholangiography. 5, there is no clinical data on the efficacy and safety of live vaccination during the treatment period of this product. Therefore, live immunization vaccine should not be used during medication. 6, the efficacy and safety of this product has not been studied in children, so patients younger than 18 years of age are not recommended to use this product. 7, if the dose is too large or toxic, can be oral bile amine or activated carbon to promote the elimination of leflunomide. 8, the active metabolites of this product can cause the blood concentration of diclofenac, ibuprofen, tolbutamide increased by 13% ~ 50%, the combination of Rifampicin can increase the blood concentration of the active metabolite by about 40%. In addition, this product may increase the liver toxicity of methotrexate. |
| Use | a hydrogenated orotate dehydrogenase inhibitor with immunosuppressive and anti-inflammatory effects for the treatment of active rheumatoid arthritis in adults. Anti-inflammatory and analgesic drugs Non-steroidal anti-inflammatory drugs. Anti-rheumatoid arthritis drugs |
| production method | ethyl acetoacetate, triethyl orthoformate and acetic anhydride were refluxed together until the starting materials were completely reacted for about 5 hours. A fraction of 140 ° C./150 kPa was collected by distillation to obtain compound (I) in a yield of 85%. Compound (I) was dissolved in absolute ethanol, and a mixture of hydroxylamine hydrochloride, sodium acetate and water was added dropwise at 10-15 °c and 1H. The reaction was continued for about 8h after instillation. Concentrated hydrochloric acid and glacial acetic acid were added and refluxed for 5H. It is concentrated to 1/2 volume under reduced pressure, cooled to below 10 ° C., filtered, and recrystallized from ethanol-water to obtain compound (II) as white crystalline powder, melting point 145-146.5 ° C., yield 80%. Compound (II) was dissolved in toluene, thionyl chloride was added dropwise at 50-55 °c and refluxed for 3 hours. The mixture was concentrated and fractionated, and a fraction of 78-79 ° C./1.87KPA was collected to obtain compound (III) in a yield of 75%. P-trifluoromethylaniline and triethylamine were dissolved in dichloromethane and compound (III) was added dropwise at 0-5 °c. The reaction was continued for 3H at 25-30 °c. Water was added and the organic layer was separated, washed with water, washed with saturated brine and dried. It is concentrated to 1/3 volume under reduced pressure, petroleum ether is added, cooling, filtering, ethyl acetate recrystallization, obtains white crystalline powder leflunomide, melting point 166~167 deg C, yield 81%. |
| toxic substance data | information provided by: pubchem.ncbi.nlm.nih.gov (external link) |
Last Update：2024-04-10 22:29:15
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