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Clobetasol CAS Registry Number: 25122-41-2 CAS Name: (11b,16b)-21-Chloro-9-fluoro-11,17-dihydroxy-16-methylpregna-1,4-diene-3,20-dione Molecular Formula: C22H28ClFO4, Molecular Weight: 410.91 Percent Composition: C 64.30%, H 6.87%, Cl 8.63%, F 4.62%, O 15.57% Literature References: Topical corticosteroid. Prepn: Elks et al.,DE1902340; eidem,US3721687 (1969, 1973 both to Glaxo). Review of pharmacology and clinical efficacy in skin disorders: E. A. Olsen, R. C. Cornell, J. Am. Acad. Dermatol.15, 246-255 (1986). Derivative Type: 17-Propionate CAS Registry Number: 25122-46-7 Manufacturers’ Codes: GR-2/925 Trademarks: Clobesol (GSK); Dermovate (GSK); Olux (Connetics); Psorex (GSK); Temovate (GSK) Molecular Formula: C25H32ClFO5 Molecular Weight: 466.97 Percent Composition: C 64.30%, H 6.91%, Cl 7.59%, F 4.07%, O 17.13% Properties: White or almost white colorless, crystalline powder, mp 195.5-197°. [a]D +103.8° (c = 1.04 in dioxane). uv max (ethanol): 237 nm (e 15000). Insol in water. Melting point: mp 195.5-197° Optical Rotation: [a]D +103.8° (c = 1.04 in dioxane) Absorption maximum: uv max (ethanol): 237 nm (e 15000) Therap-Cat: Glucocorticoid; anti-inflammatory. Keywords: Glucocorticoid. Clobetasol propionate is a corticosteroid used to treat corticosteroid-responsive dermatoses and plaque psoriasis.
Clobetasol propionate was patented in 1968 and came into medical use in 1978. It is available as a generic medication. In 2019, it was the 180th most commonly prescribed medication in the United States, with more than 3 million prescriptions.
SYNTHESIS OF KEY INTERMEDIATE
Clobetasol propionate (C25H32ClFO5); CAS Registry No.[25112-46-7]; IUPAC name: 17-(2′- Chloroacetyl)-9-fluoro-l l-hydroxy-10,13,16-trimethyl-3-oxo-6,7,8,l 1,12,14,15,16-octahydrocyclopenta[a]phenanthren-17-yl] propionate is a potent halogen adrenal corticosteroid of the gluco-corticoid class used to treat various skin disorders including eczema and psoriasis. It is also highly effective for contact dermatitis caused by exposure to poison ivy/oak.In the US 3721687Apatentshow use of methanesulfonyl chloride and Pyridine as base to protect alcohol and at the time of LiCI reaction results with 10-15%ene impurity and less yield.In the methanesulfonyl chloride step used with pyridine as base which is a hazardous.Mesyl compound converted to Clobetasol propionate by using LiCl in Dimethylformamide reaction at IOO-IlO0C forms 10-15% with ene impurity. The synthesis of Clobetasol propionate results in small quantities of the eneimpurity. Clobetasol propionate desired compound to be with impurities which must be minimized. Ene impurity can be reduced to very low levels by reaction itself. However, if used recrystallization reduce ene impurity it is time consuming and very expensive. Further, because recrystallizations have high losses, unacceptably low yields.
Example I: Betamethasone to betamethasone 17- propionate To a 100 ml 4-neck round bottom flask (RBF) equipped with halfmoon stirrer, thermowelland addition funnel, mounted in a tub bath, was charged betamethasone (5.0g, 0.0127mole), Dimethylformamide (20ml). Cooled the reaction mass to 10-15°C. Slowly added trimethyl ortho propionate (3.42g, 0.0255mole) and p-toluenesulfonic acid (PTSA)(0.30g, 0.00174 mole) to the reaction mass at 10-15°C. Stirred the contents 10-15°C for 4 hr. The reaction was monitored for completion by TLC. Further continued stirring at the same temperature for Ihr till reaction complies by TLC. After reaction completion, added H2SO4UP to pH=1.0-2.0 in to reaction mass.Reaction mass was quenched in Purified water (25ml) at 25-30°C. Cooled reaction mass temperature to 0-5°C. Stirred for I hr and filtered and washed with Purified water (10mlX2). Suck dried under vacuum completely to get cream coloured solid. Dried in tray drier at 50-55°C.Dry weight-5.40g(94.50%); HPLC: 98.5%;mp215-218°C. IR (KBr, on’):3454.90, 3370.99 (-OH); 1719.86, 1659.10 (C=O)iC25H33FO6;
Example 2: Betamethasone 17- propionateto betamethasone 21-tosylate 100ml 4-neck RBF equipped with halfmoon stirrer, thermowell, reflux condenser mountained in water bath, was charged Stage-1 (5.0g, O.Olllmole), Dimethylformamide (20ml). Added 4-Dimethylaminopyridine as base (4.10g, 0.0335mole) and p-toluenesulfonyl chloride (4.24.Og, 0.0222mole)slowly, Stirredfor2-3 hr at 25-30°C. Stirred reaction mass at 25-30°C till reaction complies by TLC.As such reaction mass used insitue for next step. Reaction mass aliquot taken (2ml) and quenched in DM water (20ml), precipited material fdtered and washed with DM water (20ml). Suck dried well. Dried in tray drier at 50-55°C to get dry white solid. Dry weight-0.598g, (89.0%); HPLC: 98.5%; mp-170-175°C (dec). IR (KBr,cm”1):3291.91, 2980.39 (-OH); 1739.15, 1661.99 (C=O); C32H39FO8S; MS 602.71mA 603.2317 [M+H]; 1HNMR (300MHz, CDCl3Sppm): Spectrum is recorded on Varian, and Tetra Methyl Silane (TMS) as internal standard. 1H-NMR Spectrum shows Aromatic-Ηκ7.17-7.22(d,lH); Hj-6.37-6.38 (d,lH);Hr6.14 (s,lH); HG-4.334-4.393 (m,lH);HF-3.846- 4.007(d,2H);HE-2.273-2.349 (q,2H);HD-l.671-1.688 (s,lH); Hc-I-306-1.331 (d,3H); Hb1.055-1.105 (t,3H);HA-0.941 -2.634 (m,18H).13CMR (300MHz, CDCl3Sppm): 9.055 (CH2- CH3); 17.244; 20.002; 21.353; 23.168; 27.901; 30.622; 33.508; 34.881; 36.783; 43.642; 46.637; 47.330; 48.113; 48.417; 66.613; 70.902; 93.801; 102.732; 124.415; 129.324; 130.443; 132.472; 145.632; 153.583; 168.042; 174.853 (O-C=O); 186.208 (Cyclic C=O); 205.491 (CH-CO-CH2-OAr).
Example 3:Betamethasone 21-tosylateto Clobetasol propionate As such reaction mass used insitue for next step. Added. lithium chloride (LiCl)1.04 gm (0.0245mole). Stirred the reaction mass at 60-65°C for 5-6 hr.Reaction completion checked by TLC.After reaction completion, Added DM water (200ml). Stirred the reaction mass at 10-15°C for Ihr and Filtered washed with DM water (30mlx2).Dried in oven at 50-55°C to get white crystalline powder. Dry weight-4.42gm, (85.0%); HPLC:99.70%;mp-158-161°C. IR (KBr, cm_1):3299.62, 2976.53 (-OH); 1734.32, (C=0);1662.95 (C=C);C25H32C1F05; MSΑβ6.9Ίτη/ζ 467 [M+H];’HNMR (300MHz, CDCl35ppm): Spectrum is recorded on Varian, and Tetra Methyl Silane (TMS) as internal standard. 1H-NMR Spectrum shows AromaticHk-7.094-7. 128(d,IH); Hj-6.267-6.307 (d,lH); Hr6.066-6.076 (s,IH); H0-4.334-4.393 (m,lH); Hf-3.846-4.007 (d,2H); HE-2.273-2.349 (q,2H); Hd-I .671-1.688 (s,lH); Hc-1.306- 1.331 (d,3H); Hb-I .055-1.105 (t,3H); HA-0.941-2.634 (m,17H).13CMR (300MHz, CDCl35ppm): 8.692 (CH2-CH3); 16.693; 19.664; 21.353; 23.042; 27.568; 30.387; 36.456; 41.104; 46.547; 47.422; 71.760; 93.547; 124.307; 125.728; 127.903; 129.222; 130.443; 132.472; 145.632; 153.044; 168.312; 173.101 (O-C=O); 185.802 (Cyclic C=O); 204.602(CH-CO-CH2-C1)
Synthesis of clobetasol propionate (27.1.13) starts from the known betamethasone 17-propionate (27.1.26), a potent glucocorticoid steroid with antiinflammatory and immunosuppressive properties, which was mesylated with methanesulfonyl chloride in pyridine to produce 9α-fluoro-11β-hydroxy-21-methylsulfonyloxy-16β-methyl 17-propionyloxypregna-1,4-diene-3,20-dione (27.1.27). The obtained product was refluxed in acetone, DMF, and dry LiCl mixture to produce the desired clobetasol propionate (27.1.13)  (Scheme 27.2.).
Clobetasol propionate, its structural formula (formula (I)), is a potent halogen-containing adrenocorticoid drug, has strong anti-inflammatory, anti-pruritic and vasoconstrictive effects, and its anti-inflammatory effect is approximately hydrogenated It is 112 times that of cortisone, and it is also used to treat neurodermatitis, contact dermatitis, eczema, discoid lupus erythematosus and other symptoms. It is currently widely used in clinical practice. It has been very popular in the international market and ranks among the top hormones. At present, there are only a few domestic companies in normal production, and the total yield is about 88%.
 Formula (I). The process route for the production of synthetic clobetasol propionate is complex, technically difficult, and product quality requirements are strict. This is due to the complex structure of corticosteroids. The chemical structure of this type of drug is composed of three six-membered rings and one five-membered ring fused together to form a special molecular structure composed of 21 carbon atoms, with special molecular configuration steric effects and steric barriers. Group role. The functional groups on the drug structure interfere with each other, which makes the chemical reaction very complicated. It is manifested in many synthetic process steps, low raw material utilization rate, large amount of auxiliary materials, long production cycle, and many side reactions. The reaction process has various problems such as a large amount of solvents, a large amount of waste water and waste gas, and difficulty in recycling. Low technical indicators, low cost and other aspects. US patent, patent number 3721687, discloses two synthetic processes. Process method (1) adopts 9a-fluoro-113-hydroxy-16a-methyl-17 oxopropyl-1,4-diene-3,20-dione to synthesize clobetasol propionate, 9a -Fluoro-11-hydroxy-16 a -methyl-17oxopropyl-1,4-diene-3,20-dione and lithium chloride mixture, mixed with dimethylformamide (DMF) in acetone The solution is refluxed for four days, the solution is moved to a vacuum, ethanol, methanol, and acetone are added, and the mixture is refluxed for another 4 days. Most of the solution is moved to a vacuum, water is added to the residue, the crude product is put into the ether solution, and the mixture is passed through with chloroform. The aluminum is purified by filtration and recrystallized with ethanol to produce clobetasol propionate as a raw material. Method I uses too much acetone, and there is a certain risk of operation. Process method 2 adopts 21-chloro-9a-fluoro-1I@ -hydroxy-16a-methyl-17_oxopropyl-4ene-3,20-dione to synthesize clobetasol propionate Cable. Dissolve 21-chloro-9 a -fluoro-11 P -hydroxy-16 a -methyl-17oxopropyl_4ene-3,20-dione in acetone, cool in an ice bath, and add slowly while stirring Chromic acid (prepared by chromic acid: add 53.3ml of concentrated sulfuric acid to 250ml of water and add 66.7g of chromium trioxide); 4 hours later, the mixture reaches room temperature, ether is added, and it is left for another 20 minutes. The mixture is washed with water, and then the solution is moved to a vacuum ; The residue is recrystallized with acetone-petroleum ether, which pollutes the environment. In the past, organic solvents were not safe for production operations.  Chinese patent, application number 200610053511.5, provides a method of mixing betamethasone 17-propionate sulfonate and anhydrous lithium chloride in a ratio of 1:1 to 2 and dissolving in dimethylformamide ( DMF), the chlorination reaction is carried out; second, after the chlorination reaction is complete, it is separated by ice water, and then centrifuged to dry, after drying, the crude clobetasol propionate is obtained; third, the clobetasol propionate is crude The crude tasol is dissolved in methanol or ethanol, activated carbon is added, decolorized, filtered, and the activated carbon is recovered; fourth, the filtrate is concentrated under reduced pressure, crystallized, dehydrated, and dried to obtain the raw material of clobetasol propionate. It has the characteristics of easy availability of starting materials, simple reaction steps, less dangerous and harmful solvents, mature technology, and convenient industrial production. The process route is as follows:
 Clobetasol propionate uses betamethasone as the starting material, goes through the steps of cyclic ester-hydrolysis-sulfonation-chlorination, and then undergoes rough refinement to obtain clobetasol propionate-a refined substance, and then undergoes dissolution , Filtration, concentration, cooling, centrifugation, and drying to obtain clobetasol propionate. But its process route is longer, there are many influencing factors, and there are many side reactions. Moreover, the solvents used are very polluting and difficult to recycle.
Example 1 20g of Betamethasone 17-ester obtained by cyclic ester hydrolysis reaction was dissolved in 150ml of acetone, and after fully stirring and dissolving, 6g of ZnCl2 was added, and the temperature was raised to 35°C, and then 30g of BTC was introduced, After the BTC is passed, the reaction is kept warm for 3 hours. After the reaction is completed, the temperature is 40°C, and the concentration is reduced under reduced pressure until the solution contains 30ml of acetone. Then 300ml of drinking water is added for water separation and filtration. After drying for 16 hours at °C, 19.64 g of crude clobetasol propionate was obtained. The yield was 98.2%, and the crude clobetasol propionate content was 96.9% after analysis.Example 2 20g of betamethasone 17-ester compound obtained by cyclic ester hydrolysis reaction was dissolved in 150ml of acetone, and after fully stirring and dissolving, 7.2g of FeCl3 was added, heated to 30°C, and then 24g of BTC was introduced After the BTC is passed, the reaction is kept warm for 2 hours. After the reaction is completed, the solution is concentrated under reduced pressure at a temperature of 35°C until the solution contains 20ml of acetone, and then 300ml of drinking water is added for water precipitation, filtered, and finally at the temperature After drying for 10 hours at 85°C, 19.5 g of crude clobetasol propionate was obtained. The yield was 97.5%, and the crude clobetasol propionate content was 95.6% after analysis.Example 3 20g of Betamethasone 17-ester obtained by the cyclic ester hydrolysis reaction was dissolved in 150ml of acetone, and after fully stirring and dissolving, 4g of AlCl3 was added and the temperature was raised to 35°C, and then 28g of BTC was introduced, After the BTC is passed through, the reaction is kept warm for 4 hours. After the reaction is completed, the temperature is 30°C, and concentrated under reduced pressure until the solution contains 20ml of acetone. Then 300ml of drinking water is added for water precipitation, filtered, and finally at a temperature of 75 After drying for 18 hours at °C, 19.62g crude clobetasol propionate was obtained. The yield was 98.1%, and the crude clobetasol propionate content was 95.8% after analysis.Example 4 The betamethasone 17-ester 20g obtained by the cyclic ester hydrolysis reaction was dissolved in 100ml of acetone, and after being fully stirred to dissolve, 4g of ZnCl3 was added, heated to 40°C, and then passed into 25g of BTC, After the BTC is passed, the reaction is kept for 5 hours. After the reaction is completed, the temperature is 40°C, and the concentration is reduced under reduced pressure until the solution contains 20ml of acetone. Then 200ml of drinking water is added for water precipitation, filtered, and finally at a temperature of 80°C. After drying for 18 hours at °C, 19.54 g of crude clobetasol propionate was obtained. The yield was 97.7%, and the crude clobetasol propionate content was 96.2% after analysis. Example 5  20g of Betamethasone 17-ester obtained by cyclic ester hydrolysis reaction was dissolved in 200ml of acetone, and after fully stirring and dissolving, 8g of ZnCl3 was added and the temperature was raised to 50°C. Then pass in 40g BTC. After passing the BTC, keep it warm and react for 3 hours. After the reaction is completed, perform vacuum concentration at a temperature of 40°C until the solution contains 40ml of acetone, and then add 400ml of drinking water for hydrolysis. Filter, and finally dry at 85°C for 18 hours to obtain 19.58 g of crude clobetasol propionate. The yield was 97.9%, and the crude clobetasol propionate content was 96.9% after analysis.Example 6 20g of betamethasone 17-ester compound obtained by cyclic ester hydrolysis reaction was dissolved in 80ml of acetone, and after fully stirring and dissolving, 6g of ZnCl3 was added, and after the temperature was raised to 40°C, 25g of BTC was introduced, After the BTC is passed, the reaction is kept for 3 hours. After the reaction is completed, it is concentrated under reduced pressure at a temperature of 40°C, and concentrated until the solution contains 10ml of acetone. Then 150ml of drinking water is added for water precipitation, filtered, and finally at a temperature of 85°C. After drying for 18 hours at °C, 19.3g crude clobetasol propionate was obtained. The yield was 96.5%, and the crude clobetasol propionate content was 96.5% after analysis. Publication numberPriority datePublication dateAssigneeTitleUS3721687A *1968-01-191973-03-20Glaxo Lab Ltd3-keto-delta 4-9alpha-halo-11-oxygenated-16-methyl or methylene-17alpha-acyloxy-20-keto-21-halo pregnenesCN1923842A *2006-09-112007-03-07Zhejiang Dingtai Pharmaceutical Co., Ltd.Manufacturing method of clobetasol propionate Publication numberPriority datePublication dateAssigneeTitleFamily To Family CitationsCN105646630A *2015-08-102016-06-08Shandong Taihua Biological Technology Co., Ltd.One-pot Preparation of Clobetasol Propionate IntermediateCN112110972A *2019-06-212020-12-22Henan Lihua Pharmaceutical Co., Ltd.A kind of preparation method of clobetasol propionateCN112028957A *2020-07-292020-12-04Henan Lihua Pharmaceutical Co., Ltd.A kind of clobetasol propionate intermediate and preparation method
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Clobetasol propionate is used cosmetically by dark-skinned women for skin whitening, although this use is controversial. The U.S. Food and Drug Administration has not approved it for that purpose, and sales without a prescription are illegal in the U.S. Nonetheless, skin-whitening creams containing this ingredient can sometimes be found in ethnic beauty supply stores in New York City and on the internet. It is also sold internationally, and does not require a prescription in some countries. Whitening creams with clobetasol propionate, such as Hyprogel, can make skin thin and easily bruised, with visible capillaries, and acne. It can also lead to hypertension, elevated blood sugar, suppression of the body’s natural steroids, and stretch marks, which may be permanent.
Clobetasol propionate is, along with mercury and hydroquinone, “amongst the most toxic and most used agents in lightening products.” Many products sold illegally have higher concentrations of clobetasol propionate than is permitted for prescription drugs.
According to the California Environmental Protection Agency, clobetasol propionate should not be used by pregnant women, or women expecting to become pregnant soon, as studies with rats shows a risk of birth defects:
“Studies in the rat following oral administration at dosage levels up to 50 mcg/kg per day revealed that the females exhibited an increase in the number of resorbed embryos and a decrease in the number of living fetuses at the highest dose. Pregnancy: Teratogenic Effects (i.e., possibility of causing abnormalities in fetuses): Pregnancy Category C: Clobetasol propionate has not been tested for teratogenicity when applied topically; however, it is absorbed percutaneously, and when administered subcutaneously it was a significant teratogen in both the rabbit and mouse. Clobetasol propionate has greater teratogenic potential than steroids that are less potent. There are no adequate and well-controlled studies of the teratogenic effects of clobetasol propionate in pregnant women. Temovate Cream and Ointment should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.”
Clobetasol propionate is marketed and sold worldwide under numerous names, including Clobex, Clob-x (Colombia), Clovate, Clobet (Biolab Thailand) Clonovate (T.O. Chemicals, Thailand), Cormax (Watson, US), Haloderm (Switzerland, by ELKO Org), Pentasol (Colombia), Cosvate, Clop (Cadila Healthcare, India), Propysalic (India), Temovate (US), Dermovate (GlaxoSmithKline, Canada, Estonia, Pakistan, Switzerland, Portugal, Romania, Israel), Olux, ClobaDerm, Tenovate, Dermatovate, Butavate, Movate, Novate, Salac (Argentina), and Powercort, Lotasbat and Kloderma (Indonesia), Lemonvate (Italy), Delor (Ethiopia), Psovate (Turkey).
^ Hull C, McKeough M, Sebastian K, Kriesel J, Spruance S (March 2009). “Valacyclovir and topical clobetasol gel for the episodic treatment of herpes labialis: a patient-initiated, double-blind, placebo-controlled pilot trial”. Journal of the European Academy of Dermatology and Venereology. 23 (3): 263–7. doi:10.1111/j.1468-3083.2008.03047.x. PMID19143902. S2CID205588376.
CAS Index Name
SYN Synthesis of lornoxicam (DE2838851)
The sulfonation of 2,5-dichlorothiophene (I) with ClSO3H -SOCl2 gives 2,5-dichlorothiophene-3-sulfonic acid chloride (II), which by reaction with methylamine in CHCl3 yields the corresponding methylamide (III). The carboxylation of (III) with butyllithium and CO2 in ether affords 5-chloro-3-(N-methylsulfamoyl)thiophene-2-carboxylic acid (IV), which is esterified with PCl5 and methanol to the methyl ester (V). The condensation of (V) with methyl iodoacetate (VI) by means of NaH in DMF gives 5-chloro-3-[N-(methoxycarbonylmethyl)-N-methylsulfamoyl]thiophene-2-carboxylic acid methyl ester (VII), which is cyclized with sodium methoxide in methanol yielding 6-chloro-4-hydroxy-2-methyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxylic acid methyl ester 1,1-dioxide (VIII). Finally, this compound is treated with 2-aminopyridine (IX) in refluxing xylene.
Lornoxicam is an NSAID indicated in the treatment of mild to moderate pain, as well as rheumatoid arthritis and osteoarthritis.
It was patented in 1977 and approved for medical use in 1997. Brand names include Xefo and Xefocam among others.
Lornoxicam (chlortenoxicam) is a new nonsteroidal anti-inflammatory drug (NSAID) of the oxicam class with analgesic, anti-inflammatory and antipyretic properties. Lornoxicam differs from other oxicam compounds in its potent inhibition of prostaglandin biosynthesis, a property that explains the particularly pronounced efficacy of the drug. Lornoxicam is approved for use in Japan.
Lornoxicam is used for the treatment of various types of pain, especially resulting from inflammatory diseases of the joints, osteoarthritis, surgery, sciatica, and other inflammations.
The drug is contraindicated in patients who must not take other NSAIDs, possible reasons including salicylate sensitivity, gastrointestinal bleeding and bleeding disorders, and severe impairment of heart, liver or kidney function. Lornoxicam is not recommended during pregnancy and breastfeeding and is contraindicated during the last third of pregnancy.
The present invention relates to the prepn. of high purity loroxicam. In particular, the prepn. method comprises a step of taking 6-chloro-4-hydroxy-2-methyl-2H-thieno[2,3-e]-1,2-Me thiazinecarboxylate-1,1-dioxide and 2-amino pyridine is used as the raw material and xylene is used as the solvent undergoes distn. reaction with solid acid catalyst, mixed gas obtained by the distn. reaction is condensed to obtain a condensate and solid acid catalyst is used to adsorb methanol in the condensate and the adsorbed condensate is recycled, filtering and refining to obtain loroxicam. The present inventive method distills out the methanol produced by the reaction to promote the pos. progress of the reaction and then catalyzes the absorption of methanol by H2SO4/MxOy solid super acid, so that the xylene returned to the reaction system does not contain methanol, which reduces the coking of the reaction, thereby improving product quality and yield. The prepd. lornoxicam has high purity, which can reach more than 99.9%, reduces the amt. of solvent and also suitable for industrial prodn.
The present invention relates to the prepn. of lornoxicam. In particular, the prepn. method comprises a step of taking 6-chloro-4-hydroxy-2-methyl-2-H-thieno[2,3-e]-1,2-thiazidecarboxylic acid Me ester-1,1-dioxide and 2-aminopyridine as raw materials, xylene is used as solvent, adding stabilizer, and carrying out aminolysis reaction, the solvent was removed by concn. under reduced pressure, adding org. solvent to make the slurry, filtering and refining to obtain lornoxicam. The inventive method uses p-toluene sulfonic acid as a stabilizer, while lowering the reaction temp., it promotes the reaction to proceed forward, and improve the product quality and yield; at the same time reduce the amt. of industrial solvents, the post-treatment process is optimized and the cost of the three wastes treatment is reduced.
Example: 1Preparation of 6-chloro-4-hydroxy-l,l-dioxo-l,2-dihydro-lX6-thieno [2,3-e][l,2] thiazine-3-carboxylic acid methyl ester To the mixture of methanol ( 1000 ml) and 5-chloro-3-(methoxy carbonyl methyl sulfamoyl)-thiophene-2-carboxylicacid methyl ester ( 100 g ,0.305 moles), added sodium methoxide solution (200 ml ) at 25-30Â°C over a period of 30-45 min. The resulting mixture was stirred for 60 min at same temperature; allowed to heat at 65-75Â°C and stirred for 10-12 hrs. After completion of reaction, methanol was distilled out under reduced pressure to obtained titled residual product which is directly used to next step
(Example-2). Example: – 2:Preparation of 6-chloro-4-hydroxy-2-methyl-l,l-dioxo-l,2-dihydro-U6- thieno[2,3-e][l,2] thiazine-3-carboxylic acid methyl ester 6-chloro-4-hydroxy-1,1 -dioxo-1,2-dihydro-1 X,6-thieno [2,3-e][ 1,2] thiazine-3-carboxylic acid methyl ester was suspended in DM water (500 ml) and cooled to 10-15Â° C, dimethyl sulphate ( 70 g) was slowly added to the mixture at 10-15Â°C in 30 min. The reaction mixture was raised to 25-30Â°C and maintained for 2-3 hours at same temperature. After completion of reaction, mixture was cooled to 10-15Â°C, methylene dichloride (1600 ml) was added, reaction mixture pH was adjust to 1.0 -2.0 with hydrochloric acid at 10-15Â° C, stir reaction mixture to separate the layers. The methylene dichloride layer was distilled out completely at below 30Â°C to get an residue, followed by addition of methanol (60 ml) and distilled out methanol completely under vacuum at below 50Â°C to get an residue; further it was crystallized by addition of methanol 190 ml and stirred for 30 min at 50-55Â°C; cooled the reaction mixture at 25-30Â°C and stirred for 60 min at same temperature. The resultant solid was filtered, washed with methanol (40 ml) and dried at 50-55Â°C for 4 – 6 hrs to obtain the titled product
Example: 3Preparation of 6-Chloro-4-hydroxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]-l,2-thiazine-3-carboxamide 1,1-dioxide (Lornoxicam) 6-chloro-4-hydroxy-2-methyl-l, 1 -dioxo-1,2-dihydro-l X.6-thieno[2,3-e][l ,2] thiazine-3-carboxylic acid methyl ester ( 50 g 0.161 moles) was suspended in O-xylene (500 ml) and allow to stirred at 70-75Â°C to obtained clear solution. To this clear solution slowly added the mixture of THF ( 50 ml) solution of 2-Amino pyridine ( 14 g ) and ethyl magnesium bromide 2 molar solution (100 ml) at 70-75Â°C and allow to stirred for 3-4 hrs at same temperature. After completion of reaction, the dilute hydrochloric acid was added to the mixture at 10-15Â°C and stirred for 60 min. The resultant solid was filtered, washed with water (100 ml) to obtain crude Lornoxicam.
Example: 4Preparation of 6-Chloro-4-hydroxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e)-l,2-thiazine-3-carboxamide 1,1-dioxide (Lornoxicam) 6-chloro-4-hydroxy-2-methyl-l,l-dioxo-l,2-dihydro-R6-thieno[2,3-e][l,2] thiazine-3-carboxylic acid methyl ester ( 50 g 0.161 moles) was suspended in O-xylene (500 ml) and allow to stirred at 70-75Â°C to obtained clear solution. To this clear solution slowly added the mixture of THF ( 50 ml) solution of 2-Amino pyridine ( 14 g ) and isopropyl magnesium bromide 2 molar solution (100 ml) at 70-75Â°C and allow to stirred for 3-4 hrs at same temperature. After completion of reaction, the dilute hydrochloric acid was added to the mixture at 10-15Â°C and stirred for 60 min. The resultant solid was filtered, washed with water (100 ml) to obtain crude Lornoxicam.
Example: 5Purification of Lornoxicam.The crude Lornoxicam was suspended in methanol (500 ml) and cooled to 5-10Â°C, resulting suspension was basified to pH 11-13 by using sodium hydroxide solution to get clear solution; followed by filtration through hyflo bed; the obtain filtrate was acidified to pH 4.5 – 5.0 with dil. HC1 (1:1) at 5-10Â°C; stirred the slurry for 30 min. at 5-10Â°C. The resultant solid was filtered, washed with DM water (100 ml) and dried at 50-55Â°C to obtained pure Lornoxicam.
.EXAMPLES:Preparation of Lornoxicam crudeExample ITo 1200ml o-xylene, 20gm Methyl-6-chloro-4-hydroxy-2-methyl-2//-thieno [2, 3-e] [1, 2] thiazine-3- carboxyate 1,1-dioxide and 6.44gm 2-aminopyridine was added. The reaction mass was stirred under nitrogen atmosphere. Temperature was raised to 140-145Â°C and maintained for 6hrs. The reaction mass was cooled to 30-35Â°C and nitrogen was removed. Reaction mass was further stirred for 3hrs- Filtered and washed twice with 50ml of o-xylene. 19.8gm of crude Lornoxicam was obtained. Purification of Lornoxicam crude
Example 219.8gm of crude Lornoxicam was added to the solvent mixture of water (5 vol with respect to Lornoxicam) and methanol (10 vol with respect to Lornoxicam) under stirring. Subsequently 48% sodium hydroxide was added to form a clear solution and 5% activated charcoal was further added. The reaction mass was heated to 50-55Â°C and stirred for around Ihr followed by filtration through Hyflo. To the filtrate, mixture of hydrochloric acid and water in the ratio of 1:1 was added at 50-55Â° C, til! the reaction mass reached pH of 2-3, and then stirred for around I hi*. The reaction mass was cooled to room temperature, filtered, and then washed with 1:1 mixture of methanol and water. Purified wet Lornoxicam was dried at 60-65Â°C for 6-8hrs. 19.1 gm of pure Lornoxicam was obtained. (HPLC purity- 99.95%)
Example 3!7.9gm of crude Lornoxicam (prepared as per example 1) was added to the solvent mixture of water (5 vol with respect to Lornoxicam) and methanol (10 vol with respect to Lornoxicam) under stirring. Subsequently 48% sodium hydroxide was added to form a clear solution, and 5% activated charcoal was further added. The reaction mass was heated to 50-55Â°C and stirred for around Ihr followed by filtration through Hyflo. To the filtrate, mixture of hydrochloric acid and water in the ratio of 1:1 was added at 50-55Â° C till the reaction mass reached pH of 2-3, and then stirred for around Ihr. The reaction mass was cooled to room temperature, filtered and then washed with 1:1 mixture of methanol and water. Purified wet Lornoxicam was dried at 60-65Â°C for 6-8hrs. 17.2 gm of pure Lornoxicam was obtained. (HPLC purity- 99.9%) clear solution and 5% activated charcoal was further added. The reaction mass was heated to 50-55Â°C and stirred for around lhr followed by filtration through Hyflo. To the filtrate, mixture of hydrochloric acid and water in the ratio of 1:1 was added at 50-55Â° C, till the reaction mass reached pH of 2-3, and then stirred for around lhr. The reaction mass was cooled to 30-35Â°C, filtered and then washed with 1:1 mixture of isopropyl alcohol and water. Purified wet Lornoxicam was dried at 60-65Â°C for 6-8hrs. 4.85 gm of pure Lornoxicam was obtained. (HPLC purity- 99.8%)
Example 55 gm of crude Lornoxicam (prepared as per example 1) was added to the solvent mixture of water (5 vol with respect to Lornoxicam) and ethanol (10 vol with respect to Lornoxicam) under stirring. Subsequently 48% sodium hydroxide was added to form a clear solution, and 5% activated charcoal was further added. The reaction mass was heated to 50-55Â°C and stirred for around lhr followed by filtration through Hyflo. To the filtrate, mixture of hydrochloric acid and water in the ratio of 1:1 was added at 50-55Â° C, til! the reaction mass reached pH of 2-3 and then stirred for around lhr. The reaction mass was cooled to 30-35Â°C and filtered, washed with 1:1 mixture of ethanol and water. Purified wet Lornoxicam was dried at 60-65Â°C for 6-8hrs. 4.8 gm of pure Lornoxicam was obtained. (HPLC purity- 99.8%)
Example 619.4 gm of crude Lornoxicam (prepared as per example I) was added to the solvent mixture of water (5 vol with respect to Lornoxicam) and methanol (10 vol with respect to Lornoxicam) under stirring. Subsequently 48% sodium hydroxide was added to form a clear solution, and 20% activated charcoal was further added. The reaction mass was stirred for around lhr at room temperature followed by filtration through Hyflo. To the filtrate, mixture of hydrochloric acid and water in the ratio of 1:1 was added till the reaction mass reached pH of 2-3 and then stirred for around 1 hr. The reaction mass was * filtered and washed with 1:1 mixture of methanol and water. Purified wet Lornoxicam was dried at 60-65Â°C for 6-8hrs. 18.9 gm of pure Lornoxicam was obtained. (HPLC purity- 99.3%).
Hitzenberger G, Radhofer-Welte S, Takacs F, Rosenow D: Pharmacokinetics of lornoxicam in man. Postgrad Med J. 1990;66 Suppl 4:S22-7. [Article]
Pruss TP, Stroissnig H, Radhofer-Welte S, Wendtlandt W, Mehdi N, Takacs F, Fellier H: Overview of the pharmacological properties, pharmacokinetics and animal safety assessment of lornoxicam. Postgrad Med J. 1990;66 Suppl 4:S18-21. [Article]
Bonnabry P, Leemann T, Dayer P: Role of human liver microsomal CYP2C9 in the biotransformation of lornoxicam. Eur J Clin Pharmacol. 1996;49(4):305-8. [Article]
Tralokinumab is a human monoclonal antibody which targets the cytokine interleukin 13, and is designed for the treatment of asthma and other inflammatory diseases. Tralokinumab was discovered by Cambridge Antibody Technology scientists, using Ribosome Display, as CAT-354 and taken through pre-clinical and early clinical development. After 2007 it has been developed by MedImmune, a member of the AstraZeneca group, where it is currently in Ph3 testing for asthma and Ph2b testing for atopic dermatitis. This makes it one of the few fully internally discovered and developed drug candidates in AstraZeneca’s late stage development pipeline.
Discovery and development
Tralokinumab (CAT-354) was discovered by Cambridge Antibody Technology scientists using protein optimization based on Ribosome Display. They used the extensive data sets from ribosome display to patent protect CAT-354 in a world-first of sequence-activity-relationship claims. In 2004, clinical development of CAT-354 was initiated with this first study completing in 2005. On 21 July 2011, MedImmune LLC initiated a Ph2b, randomized, double-blind study to evaluate the efficacy of tralokinumab in adults with asthma.
In 2016, MedImmune and AstraZeneca were developing tralokinumab for asthma (Ph3) and atopic dermatitis (Ph2b) while clinical development for moderate-to-severe ulcerative colitis and idiopathic pulmonary fibrosis (IPF) have been discontinued. In July of that year AstraZeneca licensed Tralokinumab to LEO Pharma for skin diseases.
A phase IIb study of Tralokinumab found that treatment was associated with early and sustained improvements in atopic dermatitis symptoms and tralokinumab had an acceptable safety and tolerability profile, thereby providing evidence for targeting IL-13 in patients with atopic dermatitis.
On 15 June 2017, Leo Pharma announced that they were starting phase III clinical trials with tralokinumab in atopic dermatitis.
Society and culture
On 22 April 2021, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Adtralza, intended for the treatment of moderate‑to‑severe atopic dermatitis.
The applicant for this medicinal product is LEO Pharma A/S.
Psoriasis is a chronic skin disorder caused by inflammatory cell infiltration into the dermis and epidermis, and is accompanied by keratinocyte hyperproliferation.Once triggered, a strong T-cell response is mounted, and a cascade of cytokine and chemokine production is induced.
Down-regulation of certain cytokines and chemokines is considered to be a good approach to treatment, and indeed, the biologics targeting TNF-α demonstrate the effectiveness of this approach.However, biologics have intrinsic challenges, such as limited administration route, side effects, quality control and production cost.
Small molecule approaches to treat psoriasis include systemic or topical steroids, cyclosporine, psoralen plus UVA (PUVA), retinoids, methotrexete, and vitamin D3 analogs.Atopic dermatitis is an allergic skin disorder, which is typically treated with topical steroids, antihistamines, and calcineurin inhibitors.
However, there is still a need for new treatment with improved safety profile. Recently phosphodiesterase 4 (PDE4) inhibitors have been in development for such skin diseases. CC-10004 is in development as an oral treatment for psoriasis and atopic dermatitis. AWD-12-281 was, until recently, in development for the topical treatment of atopic dermatitis. In addition, roflumilast is under Phase 1 development for both diseases.
PDE4 inhibitors aiming at skin inflammatory diseases.
Anacor’s lead product candidate is crisaborole, an investigational non-steroidal topical PDE-4 inhibitor in development for the potential treatment of mild-to-moderate atopic dermatitis and psoriasis
crisaborole is an investigational topical antiinflammatory drug in phase III clinical development by Anacor Pharmaceuticals for the treatment of mild to moderate atopic dermatitis and in phase II clinical trials in mild to moderate psoriasis
A novel boron-containing small molecule, Crisaborole inhibits the release of pro-inflammatory cytokines including TNF-alpha, IL-12, and IL-23, known mediators of the inflammation associated with psoriasis.
Discovery and structure-activity study of a novel benzoxaborole anti-inflammatory agent (AN2728) for the potential topical treatment of psoriasis and atopic dermatitis
Bioorg Med Chem Lett 2009, 19(8): 2129
Anacor Pharmaceuticals, Inc., 1020 E. Meadow Circle, Palo Alto, CA 94303, USA
A series of phenoxy benzoxaboroles were synthesized and screened for their inhibitory activity against PDE4 and cytokine release. 5-(4-Cyanophenoxy)-2,3-dihydro-1-hydroxy-2,1-benzoxaborole (AN2728) showed potent activity both in vitro and in vivo. This compound is now in clinical development for the topical treatment of psoriasis and being pursued for the topical treatment of atopic dermatitis
Reagents and conditions: (a) ethylene glycol, p-TsOH, toluene, reflux, 6 h (quant.); (b) K2CO3, DMF, 100 °C, overnight (82–96%); (c) 3 M HCl, THF, reflux, 2 h (80–100%); (d) NaBH4, MeOH, rt, 1 h (quant.); (e) 3,4-dihydro-2H-pyran, camphorsulfonic acid, CH2Cl2, rt, 2 h (quant.); (f) (i-PrO)3B, n-BuLi, THF, −78 °C to rt, 3 h; (g) 6 M HCl, THF, rt, 3 h (37–44%); (h) 6 M NaOH, MeOH, 1,4-dioxane, reflux, 6 days (79%); (i) diethylamine (for 5f) or morpholine (for 5g), EDCI, HOBt, DMAP, DMF, rt, overnight (41–70%).
(a) (4-cyanophenyl) (4-bromophenyl) ether. Under nitrogen, the mixture of 4-fluorobenzonitrile (7.35 g, 60.68 mmol), 4-bromophenol (10 g, 57.8 mmol) and potassium carbonate (12 g, 1.5 eq) in DMF (100 mL) was stirred at 1000C for 16 h and then filtered. After rotary evaporation, the residue was dissolved in ethyl acetate and washed with IN NaOH solution to remove unreacted phenol. The organic solution was dried and passed through a short silica gel column to remove the color and minor phenol impurity. Evaporation of the solution gave (4-cyanophenyl)(4- bromophenyl)ether (13.82 g, yield 87.2%) as a white solid. 1H NMR (300 MHz, DMSO-de): δ 7.83 (d, 2H), 7.63 (d, 2H), 7.13 (d, 2H) and 7.10 (d, 2H) ppm.
(b) 4-(4-cyanophenoxy)phenylboronic acid. The procedure described in Example 2d was used for the synthesis of 4-(4-cyanophenoxy)phenylboronic acid using (4-cyanophenyl)(4-bromophenyl)ether as starting material. The title compound was obtained as a white solid. M.p.l94-198°C. MS: m/z = 239 (M+), 240 (M+ 1) (ESI+) and m/z = 238 (M-I) (ESI-). HPLC: 95.3% purity at 254 nm and 92.1% at 220 nm. 1H NMR (300 MHz, DMSO-d6 + D2O): δ 7.83-7.76 (m, 4H), 7.07 (d, 2H) and 7.04 (d, 2H) ppm.
Example 154-(4-Cyanophenoxy)phenylboronic acid (C97)
(a) (4-cyanophenyl)(4-bromophenyl)ether. Under nitrogen, the mixture of 4-fluorobenzonitrile (7.35 g, 60.68 mmol), 4-bromophenol (10 g, 57.8 mmol) and potassium carbonate (12 g, 1.5 eq) in DMF (100 mL) was stirred at 100° C. for 16 h and then filtered. After rotary evaporation, the residue was dissolved in ethyl acetate and washed with 1N NaOH solution to remove unreacted phenol. The organic solution was dried and passed through a short silica gel column to remove the color and minor phenol impurity. Evaporation of the solution gave (4-cyanophenyl)(4-bromophenyl)ether (13.82 g, yield 87.2%) as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 7.83 (d, 2H), 7.63 (d, 2H), 7.13 (d, 2H) and 7.10 (d, 2H) ppm.
(b) 4-(4-cyanophenoxy)phenylboronic acid. The procedure described in Example 2d was used for the synthesis of 4-(4-cyanophenoxy)phenylboronic acid using (4-cyanophenyl)(4-bromophenyl)ether as starting material. The title compound was obtained as a white solid. M.p. 194-198° C. MS: m/z=239 (M+), 240 (M+1) (ESI+) and m/z=238 (M−1) (ESI−). HPLC: 95.3% purity at 254 nm and 92.1% at 220 nm. 1H NMR (300 MHz, DMSO-d6+D2O): δ 7.83-7.76 (m, 4H), 7.07 (d, 2H) and 7.04 (d, 2H) ppm.
As a part of our continued efforts to discover new COX inhibitors, a series of 3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-ones were synthesized and evaluated for in vitro COX inhibitory potential. Within this series, seven compounds (3a–d, 3h, 3k and 3q) were identified as potential and selective COX-2 inhibitors (COX-2 IC50’s in 1.79–4.35 μM range; COX-2 selectivity index (SI) = 6.8–16.7 range). Compound 3b emerged as most potent (COX-2 IC50 = 1.79 μM; COX-1 IC50 >30 μM) and selective COX-2 inhibitor (SI >16.7). Further, compound 3b displayed superior anti-inflammatory activity (59.86% inhibition of edema at 5 h) in comparison to celecoxib (51.44% inhibition of edema at 5 h) in carrageenan-induced rat paw edema assay. Structure–activity relationship studies suggested that N-phenyl ring substituted with p-CF3 substituent (3b, 3k and 3q) leads to more selective inhibition of COX-2. To corroborate obtained experimental biological data, molecular docking study was carried out which revealed that compound 3b showed stronger binding interaction with COX-2 as compared to COX-1.
Cyclooxygenase (COX) or prostaglandin endoperoxide synthase (PGHS), catalyzes the conversion of arachidonic acid to inflammatory mediators such as prostaglandins (PGs), prostacyclins and thromboxanes. COX exists in mainly two isoforms: COX-1 and COX-2. Nonsteroidal anti-inflammatory drugs (NSAIDs), widely used for relief of fever, pain and inflammation, act by inhibiting COX catalyzed biosynthesis of inflammatory mediators.
However, the therapeutic use of classical NSAIDs is associated with well-known side effects at the gastrointestinal level (mucosal damage, bleeding) and, less frequently, at the renal level.
Two decades after the discovery of COX isoforms, it was recognized that selective inhibition of COX-2 might be endowed with improved anti-inflammatory properties and reduced gastrointestinal toxicity profiles than classical NSAIDs.
Overall, these selective COX-2 inhibitors (coxibs) have fulfilled the hope of possessing reduced risk in gastrointestinal events, but unfortunately cardiovascular concerns regarding the use of these agents have emerged that led to the withdrawal of rofecoxib (Vioxx) and valdecoxib (Bextra) from the market in 2004 and 2005, respectively.
Ongoing safety concerns pertaining to the use of non-selective NSAIDs have spurred development of coxibs with improved safety profile.
Unprecedented cyclization was observed during N-sulfonylation of 3-[1-(phenylhydrazono)-ethyl]-chromen-2-one in pyridine, affording 3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-ones. To avoid use of noxious pyridine, reaction was tried in different basic conditions and the best results were obtained with potassium carbonate in acetone. A wide range of substrates bearing either electron-donating or electron-withdrawing substituents on phenylhydrazine ring were compatible with the developed methodology. Rapid access of starting material, 3-acetylcoumarin, excellent yields of products, and use of environmentally benign base and solvent for the cyclization make this strategy an efficient and convenient method for synthesis of 3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-ones.
1. Jones, G.; Willett, P.; Glen, R. C.; Leach, A. R.; Taylor, R. J. Mol. Biol. 1997, 267, 727.
2. Bernstein, F. C.; Koetzle, T. F.; Williams, G. J. B.; Meyer, E. F.; Brice, M. D.; Rodgers, J. R.; Kennard, O.; Shimanouchi, T.; Tasumi, M. J. Mol. Biol. 1977, 112, 535.